Embed Size (px)
Citation preview
1
APPLICATION TO INCLUDE NIFURTIMOX-EFLORNITHIN COMBINATION AS
TREATEMENT FOR STAGE 2 TRYPANOSOMA BRUCEI GAMBIENSE HUMAN
AFRICAN TRYPANOSOMIASIS (SLEEPING SICKNESS) ON THE
4TH WHO MODEL LIST OF ESSENTIAL MEDICINES FOR CHILDREN
Submitted by
Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland
Persons to contact:
Olaf Valverde Mordt
Séverine Blesson
Drugs for Neglected Diseases initiative (DNDi)
15 Chemin Louis-Dunant
1202 Geneva
Switzerland
Tel: +41 (0)22 906 9230
Fax: +41 (0)22 906 9231
The NECT Field study mentioned in this application has just recently ended the
24 month follow up. Only the in-hospital safety has been published, the final
efficacy data mentioned is still being analysed and should be submitted for
publication in the first quarter of 2013. As soon as it is available it will also be
presented to the Expert Committee.
2
1. Summary statement of the proposal for inclusion, change or deletion
The medicine reported here does not represent a new inclusion per se, rather an
extension of indication. The combination of nifurtimox and eflornithine (known as Nifurtimox-Eflornithine Combination Therapy or NECT) was included in the 16th WHO Model List of Essential Medicines for adults, and in most affected countries
has already become the first-line treatment for second-stage human African trypanosomiasis (HAT - neurologic infection) due to Trypanosome brucei
gambiense, also known as Sleeping Sickness.
Nifurtimox is included since the 1st WHO Model List for the treatment of Chagas
in children, and eflornithin is for the treatment of Sleeping Sickness in children.
New evidence of NECT safety and effectiveness in adults, children, pregnant and
breastfeeding women has been collected to complete existing treatment information and brings confidence to apply for the extension for use in children.
Between 2010 and 2011, over 6,000 second-stage T.b. gambiense HAT patients have been treated in six of the most affected countries (source: HAT Platform).
Of 2,510 patients especially followed, 484 children below 15 years of age have been reported in three publications1-3 and showed a better safety profile than
adults.
We propose to extend the indication for nifurtimox, in co-administration with
eflornithine, for the treatment of pediatric HAT in the 4th WHO Model List of Essential Medicines for Children.
2. Name of the focal point in WHO submitting or supporting the application (where relevant)
Dr Pere P. Simarro;
Dr José Ramón Franco Minguell
Human African Trypanosomiasis
WHO/HTM/NTD/IDM
World Health Organization
1211 Geneva 27, Switzerland
Tel: +41 (0) 22 791 1345
Fax: +41 (0) 22 791 4777
3. Name of the organization(s) consulted and/or supporting the application
Médecins Sans Frontières/Doctors Without Borders, International
Swiss Tropical and Public Health Institute, Basel, Switzerland Programme National de Lutte contre la Trypanosomiase Humaine Africaine
(PNLTHA), Kinshasa, DRC HAT Platform, Kinshasa, DRC (HAT platform is a consortium of HAT endemic
countries representatives, gathering Central African Republic, Chad,
Democratic Republic of the Congo, Republic of Congo, South Sudan, Sudan, and Uganda – secretariat is based in Kinshasa).
3
4. International Nonproprietary Name (INN, generic name) of the medicine
Nifurtimox (4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine 1,1-dioxide)
5. Formulation proposed for inclusion; including adult and paediatric (if appropriate)
Tablets: 30mg and 120 mg. Currently, 120 mg breakable scored tablets are
being used for children, divided into 4 parts (30 mg each), as 30 mg tablets are not produced at present.
6. International availability - sources, if possible manufacturers and trade names
Nifurtimox is currently manufactured by Bayer as Lampit. It is packaged in glass bottles containing 100 tablets of 120 mg. It is supplied internationally free of charge through an agreement between Bayer and WHO
(http://www.who.int/neglected_diseases/Donation_table_2012.pdf).
Transport costs as well as the companion drug, eflornithine (Ornidyl), are included in another agreement between WHO and Sanofi renewed in 2011 for 5 years
(http://www.who.int/neglected_diseases/WHO_sanofi_partnership_2011/en/). Sanofi stated publicly in January 2012 to extend it to 2020, during the meeting
leading to what has been called the “London Declaration”.
Drug quantities are forecasted by WHO and supplied directly to the national
Control programmes or to requests arising from International NGOs involved directly in treatment of Sleeping Sickness.
7. Whether listing is requested as an individual medicine or as an example of a therapeutic group
The listing of nifurtimox is requested as an individual medicine, to be administered in combination with eflornithine, which is already listed as an
individual medicine.
8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population)
Disease burden
Human African trypanosomiasis is transmitted by tse-tse flies of the Glossina
genus, which are present in 36 sub-Saharan African countries. Of those, 13 have reported cases of sleeping sickness caused by Trypanosoma brucei gambiense
since the year 2000.
The following graph shows the evolution of new cases detected in all reporting
countries (T.b. gambiense on top) between 1998 and 2009.4
4
In 2010 and in 2011, 9,688 and 6,743 cases respectively were declared, confirming the declining trend.5 Overall, patients in 2nd stage of T.b. gambiense disease are half of the total.
The detection of new cases has steadily decreased, mainly due to increased
effectiveness of control strategies and to the availability of free treatment at the point of delivery, thanks to the agreement between WHO and the pharmaceutical companies producing the drugs (Sanofi and Bayer). The recently available
treatment protocols for second stage of the disease, replacing the feared melarsoprol by the safer and effective eflornithine and lately by the use of NECT
(both over 96% cure rate6 have also contributed to facilitate the intake of treatment and case reduction.
There is still a risk of stagnation or increase of cases as the active screening has been reduced since 2011 due to the reduction of external investment in control
activities by several major donors. At present some areas remain still uncovered.7
Disease burden in Children
As far as we were able to determine, no data has been published in peer-
reviewed journals specifically relating to age distribution of the disease, most HAT publication referring to children were concentrated in the clinical description
of case series, but data from one thesis from the University of Basel8 combining 7 different databases shows the proportion of children among the detected cases.
Range refers to minimum and maximum data in a particular site.
5
Proportion of children with HAT (in age categories)
Age N % Cum % Range %
1 (0-23m) 164 1.1% 1% 0.2-2.9
2 (2-5y) 441 3.0% 4% 1.6-5.5
3 (6-11y) 1'111 7.6% 12% 3.4-12.9
4 (12-16y) 1'619 11.1% 23% 3.8-17.4
5 (>16y) 11'273 77.2% 100% 63.3-88.7
Total 14'608 100.0%
In addition, the biggest database to date with age data shows the following information (Gerardo Priotto, personal communication).
MSF patient distribution by age groups.
Age N % Cum %
<5 1343 4.22 4.22
[5-10[ 2110 6.63 10.85
[10-15[ 4081 12.82 23.67
[15-40[ 17946 56.35 80.02
[40-50[ 3292 10.34 90.36
[50-60[ 1921 6.03 96.39
[60-70[ 852 2.68 99.07
[70-80[ 265 0.83 99.9
[80-90[ 31 0.10 100
≥90 4 0.001 100
Total 31845 100.00
Based on these data, a proportion approximating 23% of children below 15 years
of age among all cases can be assumed.
Estimation of Risk
The following table shows the estimates of populations at risk for T.b.
gambiense, based on the information on the precise geographical origin of the reported cases included in the HAT Atlas prepared by WHO and modeled
according to population figures.5
6
Table 1. Population at risk of T. b. gambiense infection in western and central
Africa (no. persons x103).
Risk in children
From the data presented above, it can be estimated that if 5,162,000 people are at high or very high risk of infection (defined as more than 1/1,000 people annual risk), and over 23% of these are children below 15 years of age, that
approximately 1,2 million children are at high risk of infection by HAT gambiense.
Current use and Target population
Few months after its listing in the 16th Model List for Essential Medicines in 2009,
NECT has become the main treatment for second-stage T.b. gambiense sleeping sickness. By the end of 2010, 59% of adult patients were being treated with
NECT9 and in 2011, this proportion raised to 86.2% in the seven of the HAT Platform member countries (Central African Republic, Chad, Democratic Republic of the Congo, Republic of Congo, South Sudan, Sudan, Uganda), according to
data gathered by the Platform secretariat (unpublished data).
The big disadvantage of eflornithine monotherapy (previously recommended
treatment for children, included since the 1st Model List for Essential Medicines in Children 2007) is its schedule: 14 days of treatment with slow infusions every six
hours. This means a tremendous burden for the patient, especially for children. “Nearly every expert experienced in treating HAT in children has mentioned
mechanical problems with the use of eflornithine in children”.8
Feasibility of the NECT use was assessed in a thesis written by Petra Bäumelt10
based on key informant interviews performed during the NECT Field Study, using
7
qualitative assessment methodology. The following paragraph is extracted from
the thesis summary:
“Staff members seem to be aware of the importance of following the NECT
treatment guideline accurately and they stick to hygiene regulations. Nonetheless, the intravenous route of application and the complex treatment schedule cause complications. Catheter insertion was clearly defined to be a
difficult task and there is some insecurity concerning the preparation and the end of the eflornithine infusion. There is a need to continuously train health staff
involved in HAT treatment in injection technique”. The decrease in number of daily infusions (compared to eflornithine monotherapy) has decreased the burden for staff even though surveillance is needed at all time for those patients.
Considering the advantages in using the NECT (see below treatment details) compared to eflornithine monotherapy, children below 15 years of age are routinely treated with NECT in most of the above-mentioned countries despite
the absence of formal guidance from WHO. This use has been carefully documented and is now being published.1-3
The inclusion of NECT in the Model List for Essential Medicines for children would help the adoption of this treatment in the remaining areas/treatment centres not
using it already. WHO will thus be able to adapt in their user leaflet the recommendation for use to children below 35 kg, improving by this way the
security of use of the NECT combination.
9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostics, treatment or monitoring facilities and skills)
According to the current WHO treatment guidelines, published after the randomized control trial comparing NECT with eflornithine alone,6 nifurtimox in co-administration with eflornithine, the treatment lasts for 10 days overall.
Dosing of nifurtimox is 5 mg/kg orally every 8 hours for 10 days.
Dosing of eflornithine is 200 mg/kg in slow IV infusion, every 12 hours for the first 7 days of treatment.
Eflornithine can be added to 250 ml (adults) or 100 ml (children) of sterile water for injections, to be administered for 2 hours.
WHO has put together a kit, which includes all necessary drugs and material for four adult treatment courses.
NECT is exclusively recommended for T.b. gambiense second-stage (neurological) human African trypanosomiasis.
Diagnostic tools and techniques to diagnose second stage sleeping sickness
remain unchanged since 200511 and are comparable between adults and children: it is recommended to demonstrate the presence of trypanosomes in any body fluid by using existing tools and to determine either the presence of
trypanosomes in cerebro-spinal fluid (CSF) or the presence of over five White Blood Cells in the CSF count. At present the screening test continues to be the
8
CATT (total blood and dilution), but a new, simplified rapid diagnostic test (FIND
RDT) has recently passed field trials and may be made available for field use in the near future in some specific contexts.12
Treatment is administered to hospitalized patients in health care structures with nursing staff specifically trained in intravenous administration techniques for
children, as it is already recommended for eflornithine monotherapy.
Both NECT and eflornithine monotherapy share the same type of constrains (intravenous infusion, personnel involvement, etc.). Nevertheless, the use of NECT has clearly simplified the usability of Eflornithine, but remains still of
limited application, requiring hospital settings.
10. Summary of comparative effectiveness in a variety of clinical settings:
• Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data)
Clinical evidence for the use of nifurtimox in combination with eflornithine for
second stage human African trypanosomiasis caused by the Trypanosoma brucei gambiense was submitted by DNDi to the 17th Expert Committee on Selection and Use Essential Medicines that led to its inclusion in the 16th Model List for
adults.
NECT has not been tested in comparative trial in children. Only cohort studies or
single arm study have been conducted.
A clinical trial (phase IIIb) to assess the use of NECT in field conditions was conducted in 6 sites in the Democratic Republic of Congo (DRC) and was recently completed. The objective of NECT field study (NCT00906880) was to document
the use of NECT in real and field settings, and in enlarged target population (Pregnant and breastfeeding women as well as children of all ages were
included). All patients with second stage T.b. gambiense sleeping sickness, except those unable to receive oral treatment, were eligible to participate in the NECT Field trial at the appreciation of the investigators. Results from this trial will
be reported below. From a total of 630 patients included in the trial, 100 were children below 12 years of age, 13 were pregnant women and 34 breastfeeding
mothers. In-hospital safety data were reported in Schmid 2012,3 while effectiveness data have just been completed (Last patient last visit in September 2012) and are reported here as provisional data. With a 24-month follow-up
close to 89%, the trial showed overall similar cure rate to adults (provisional data).
Results from the cohort study of patients from MSF treatment centers were reported by Alirol, their cohort including 120 children.
WHO study was a pharmacovigilance study and thus was more focused on safety
than efficacy. Some available data are summarized below.
9
• Summary of available data* (appraisal of quality, outcome measures, summary
of results)
We copy here a summary of trial data that was presented to the application for
the 16th Model List Table.
Table 2. Summary of trial data.
Study site Trial type Study Total
n° of
patient
s
N° of
patients
receivin
g N+E
Results
Omugo, Uganda
(BTT)13
Randomise
d open
label trial
(terminate
d early)
Compared efficacy/safety of three
drug combinations:
melarsoprol plus nifurtimox,
M+N
melarsoprol plus eflornithine,
M+E
nifurtimox plus eflornithine,
N+E
Follow up: 24 months post-
treatment
54
17 Cure rate:
ITTa
M+N – 44.4%
M+E – 78.9%
N+E – 94.1%
PPb
M+N – 50.0%
M+E – 83.3%
N+E – 100.%
Yumbe, Uganda
(NECS)14
Prospectiv
e case
series
All patients received N+E
combination
Follow up: 24 months post-
treatment
31 31 Cure rate:
ITTa
N+E – 90.3%-
93.5%
PPb
N+E – 100.%
Multi-Centre
(NECT trial):
Nkayi, Republic of
Congo (RoC);
Isangi, Dipumba
and Katanda, DRC6
Randomise
d open
label
active
control
phase III
non-
inferiority
trial
Compared efficacy/safety of the
NECT combination over that of
standard eflornithine
monotherapy
Follow up: 18 months post-
treatment
286 143 Cure rate:
ITTa
E – 91.6 %
NECT –96.5%
PPb
E – 91.7 %
NECT –97.7%
All trials were carried out on patients diagnosed with stage 2 T.b. gambiense HAT.
BTT = Bi-therapy trial; NECS = Nifurtimox-eflornithine case series; NECT = Nifurtimox-eflornithine combination
therapy. aITT = Intention to treat population includes all patients randomised; deaths during treatment or follow-up are
regarded as treatment failures. bPP= Per protocol population includes only relapses and HAT-related deaths
considered failures.
M = Melarsoprol; N = Nifurtimox; E = Eflornithine.
The randomised clinical trial was limited to patients over 14 years of age, further
evidence needed to be gathered about the wider safety and effectiveness in all population groups.
Table 3 below summarises the primary efficacy endpoint of the NECT study,6 which was cure rate at 18-month follow-up after treatment.
10
Table 3. Efficacy outcome of NECT study.
Arm
Total Cured
Cure rate (%)
Δ cure rate (%)
(E - NECT)
One-sided 95%
CI* (%)
ITT
E 143 131 91.6 -4.9
-0.3 NECT 143 138 96.5
MITT
E 142 131 92.3 -5.6
-1.4 NECT 141 138 97.9
PP
E 133 122 91.7 -6
-1.5 NECT 132 129 97.7
ITT = Intention to treat; MITT = Modified ITT (excluding patients completely lost to follow-up); PP = Per
protocol.
* According to method of Blackwelder: Upper limit of a two-sided 90% CI around the difference (Δ) of cure
rates.
The test of non-inferiority showed that the one-sided 95% confidence interval (or upper limit of the 90% CI) was less than the target difference (Δ) of 10% in all populations analysed, clearly establishing the non-inferiority of the N+E
combination (Table 6 and Figure 2).
Figure 1. Overall cure rates. Non-inferiority analysis6.
The x-axis shows Δ (delta) = difference between cure rates (Eflornithine – NECT); the
shaded area to the left of Δ=10% shows the non-inferiority zone; the area to the left of
Δ=0% is the superiority zone.
11
Table 4. Effectiveness results of NECT Field (30-11-2012 Provisional data)
all <15 years >15
Status nb % nb % nb %
A Cured 525 83.5 102 83.6 423 83.4 B Favourable evolution 52 8.3 10 8.2 42 8.3 C Relapse 9 1.4 4 3.3 5 1.0 D Death 28 4.5 3 2.5 25 4.9
E Missing 15 2.4 3 2.5 12 2.4
Total 629 100.0 122 100.0 507 100.0
all <15 years >15
Outcome nb % nb % nb %
Positive (A+B) 577 94.0 112 94.1 465 93.9
Negative (C+D) 37 6.0 7 5.9 30 6.1
A Visit at 24 months without parasites and less than 20 WBC in CSF or good clinical status
B At least one visit at 18, 12 or 6 months without parasites and less than 20 WBC in CSF or good clinical status
C Parasites in CSF or received rescue treatment because of poor clinical status or over 20 WBC in CSF
D Deaths during hospitalisation or follow up
E Complete lost to follow up
• Summary of available estimates of comparative effectiveness
Table 5. Comparative results from 3 studies
NECT Field Trial Provisionnal data
Alirol 20122 MSF cohorts
Simarro 20129 WHO
Pharmacovigilance
Adults children <15y
Adults children <15y
Adults children <14y
Number of patients
507 122 564 120 1473 262
Relapses 5 4 14 13 6
Deaths 25 3 5 9 0
Complete lost to
follow up 12 3 332 Not available
11. Summary of comparative evidence on safety*:
• Estimate of total patient exposure to date.
General treatment experience with NECT has cumulated to over 6,000 treated
patients according to data gathered from six HAT platform countries (DRC, CAR, Chad, Uganda, South Sudan and Congo) between 2010 and the first half of 2012 (data compiled from country presentations to HAT platform board meetings).
Three recent publications report on treatment experience with NECT and the
occurrence of adverse events. Those publications followed 1,735 patients from
12
the WHO Pharmacovigilance database in nine countries;1 684 treated patients in
a cohort study from the MSF site in Dingila, DRC (538 of them included in the Franco et al. study published in 2012);2 629 in a DNDi phase IIIb clinical trial
(NECT Field) in 6 sites in DRC.3 Altogether, safety data was gathered from 2,510 patients in these studies.
Of those patients, 262 reported in the 2012 Franco et al. study, and 120 in the 2012 Alirol et al. study were children below 15 years of age (89 of them also
reported in the 2012 Franco et al. study). Finally, 100 children below 12 years of age were included in NECT Field trial.3 Overall, 393 children were examined in these three studies. Safety data is reported below.
Further to the original evidence three publications have been available;
concentrating in the safety follow up of NECT treated cases. In the following table we present the results, mentioning findings in children.
Table 6. Comparative data of latest safety publications
Origin of cases Study
type
Study N° of patients
receiving NECT
Results
9 endemic
countries and 22
treatment centre
Pharmaco
-vigilance
Monitoring the use
of NECT
1735
262 children
below 15 years
1043 patients with AE
9 Deaths, all adults;
155 children with AE
2 = 0.075 p>0.5
19 relapses,
6 relapses in children
Doruma and
Dingila Hospitals
DRC
Cohort
study
All patients treated
with NECT between
January 2010 and
June 2011
684
120 children
below 15 years
Cure rate: 95.1%
AE (all) 85%
AE (children) 67.5%
In-hospital mortality
0.15%
NECT FIELD Multi-
Centre: Dipumba,
Katanda,
N’gandajika,
Bandundu,
Kwamouth,
Yasa Bonga DRC
Phase
IIIb
multicentr
e open
label
single
arm trial
Effectiveness/safety
of the NECT
All patients with 2nd
stage HAT initially
eligible
Follow up: 24
months post-
treatment
629
122 children
below 15 years
100 children
below 12 years
Cure rate (all):94.0%
Cure rate (children
below 15) :94.1%
AE (all) 92%
AE (children <12) 92%
In-hospital mortality
(all) 1.6%
In-hospital mortality
(children) 0.0%
All studies were carried out on patients diagnosed with stage 2 T.b. gambiense HAT.
• Description of adverse effects/reactions.
Adverse effects were characterized in the three above-mentioned studies.
The 2012 Franco et al. study gathers data from voluntary reports using a specific format prepared by WHO and proposed to National Control programmes and
international NGOs.
“Data were collected for 1,735 patients treated with NECT in nine disease
endemic countries during 2010–2011. At least one adverse event (AE) was described in 1043 patients (60.1%) and a total of 3,060 AE were reported.
Serious adverse events (SAE) were reported for 19 patients (1.1% of treated),
13
leading to nine deaths (case fatality rate of 0.5%). The most frequent AEs were
gastrointestinal disorders (vomiting/nausea and abdominal pain), followed by headache, musculoskeletal pains, and vertigo. The most frequent SAE (serious
AE) and cause of death were convulsions, fever, and coma that were considered as reactive encephalopathy. Two hundred and sixty-two children below 15 years old were treated. The characteristics of AEs were similar to adults, but the major
AEs were less frequent in children, with only one SAE and no deaths registered in this group. Gastrointestinal problems (vomiting and abdominal pain) were more
frequent than in adults, but musculoskeletal pains, vertigo, asthenia, neuropsychiatric troubles (headaches, seizures, tremors, hallucinations, insomnia) were less frequent in children”.
The results of 18 months experience of NECT use in treatment centres run by
Médecins Sans Frontières (MSF) in Democratic Republic of the Congo (DRC) were
reported in:2 This cohort study included 120 second‐stage HAT children (and 464
adults) treated with NECT between January 2010 and June 2011. Safety and efficacy data were retrieved from the WHO pharmacovigilance forms and from Epitryps, a program monitoring database. 86% of the patients experienced at
least one AE during treatment. On average, children experienced less AEs than adults. Most AEs were mild (37.9%) or moderate (54.7%). Severe AEs included
vomiting (n=32), dizziness (n=16), headache (n=11) and convulsions (n=11).
The in‐hospital case fatality rate was low (0.15%) and relapses were rare
(n=14)”. “In comparison with previous treatments, NECT was effective, safe and
well tolerated in non‐trial settings in DRC, further supporting the roll out of NECT
as first line treatment in second‐stage T.b. gambiense HAT.”
Regarding tolerance in children, Alirol states: “Strikingly, NECT was better
tolerated in children than in adults. Adults had 4 times more chances to develop 1 or more AEs, and on average, experienced more events than children. This
may be related to the better safety profile of nifurtimox in children, or to a better general condition of children on admission, as reflected by the better mean Karnofsky score.”
The applicants have just published the in-hospital safety report of NECT Field Trial,3 which comes to similar conclusions through a stricter follow-up in a clinical
trial setting, but respecting field conditions (see below for details). “Children had less psychiatric events and reported less headaches but had more fever and
injection site reaction”.3
14
Table 7. Most common adverse events in NECT-Field trial per special study
group
Most Common Adverse All Children Pregnant Breast feeding
% of patients experiencing adverse events
% % % %
n=629 n=100 n=14 n=33
Gastro-intestinal 61 43 93 64
Vomiting 43 31 79 58
Nausea 20 13 21 6
General disorders 46 57 86 61
Fever 30 44 29 42
Asthenia 18 13 57 27
Nervous system 34 21 57 24
Headache 14 8 36 12
Vertigo 10 0 14 6
Convulsions 9 10 0 9
Metabolic 26 22 29 12
Anorexia 25 21 29 9
Psychiatric 16 9 0 12
Agitation 6 5 0 12
Insomnia 6 3 0 0
Musculoskeletal (pain) 14 4 21 15
Respiratory 10 7 14 9
Skin disorders 9 9 7 6
Pruritus 7 6 7 6
• Identification of variation in safety due to health systems and patient factors
The NECT Field trial was set to assess precisely the possible variation in safety due to switch from highly monitored clinical trial setting to local health care system. “The nature, frequency and intensity of adverse events were situated in
the expected range as shown in previous studies”.3
15
Table 8. Comparison of the severities of the adverse events of NECT treatment in
different studies (NECT-FIELD, NECT phase III) – (extract from Schmid et al.3)
• Summary of comparative safety against comparators
NECT has not been tested in comparative trial in children. Only cohort study and single arm study have been conducted, as previously above.
12. Summary of available data on comparative cost** and cost-effectiveness within the pharmacological class or therapeutic group:
• Range of costs of the proposed medicine
NECT is being distributed free at the point of delivery through a WHO programme that sends kits containing all necessary drugs and materials for 4 adults full treatments. These kits advantageously replaced previously designed kits for
eflornithine monotherapy, which contained only treatment for 2 patients each.
Adverse events*
Number of patients n (%) All events Severe events All events Severe events
Total subjects with at least 1 adverse event (clinical) 578 (91.9) 79 (12.6) 134 (93.7) 18 (12.6)
Fatalities
Cardiac disorders
Arrythmia 10 (1.6) 1 (0.2) 27 (18.9) 0
Palpitations 23 (3.7) 0 NA NA
Gastrointestinal disorders
Diarrhea 45 (7.2) 1 (0.2) 9 (6.3) 0
Nausea 124 (19.7) 1 (0.2)
Vomiting 271 (43.1) 2 (0.3)
General disorders and administration site conditions
Asthenia 111 (17.6) 12 (1.9) 34 (23.8) 0
Fever 187 (29.7) 2 (0.3) 37 (25.9) 7 (4.9)
Injection site reaction 17 (2.7) 0 14 (9.8) 0
Infections and infestations 33 (5.2) 17 (2.7) 14 (9.8) 1 (0.7)
Bronchopneumonia 1 (0.2) 1 (0.2)
Injection site infection 0 0 4 (2.8) 0
Pneumonie 4 (0.6) 2 (0.3) 0 0
Sepsis 2 (0.3) 2 (0.3) NA NA
Tissue infection 0 0 6 (4.2) 0
Metabolism and nutrition disorders (Anorexia) 159 (25.3) 0 36 (25.2) 1 (0.7)
Musculoskeletal and connective tissue disorders 86 (13.7) 2 (0.3) 43 (30.1) 0
Nervous system disorders
Coma 6 (1.0) 6 (1.0) 1 (0.7) 0
Convulsions 57 (9.1) 4 (0.6) 18 (12.6) 6 (4.2)
Dizziness 67 (10.7) 2 (0.3) 26 (18.2) 0
Headache 91 (14.5) 16 (2.5) 55 (38.5) 1 (0.7)
Psychiatric disorders
Agitation 36 (5.7) 5 (0.8) 4 (2.8) 0
Insomnia 40 (6.4) 0 14 (9.8) 0
Skin and sub-cutaneous tissue disorders (Pruritus) 41 (6.5) 11 (1.7) 13 (9.1) 0
NA: Not applicable (not mentioned)
1All adverse (probable, possible, no relation) event are reported in this table (NECT-FIELD results)
2Only treatment related adverse event are described in this trial (Priotto 2009)
3Adverse event recorded in NECT phase III trial (Priotto et al) have not been coded with MedDRA dictionary
69 (48.3) 1 (0.7)
NECT-FIELD1
(N=629)
NECT (Priotto 2009)2,3
(N=143)
10 (1.6) 1 (0.7)
16
The weight and volume of the NECT kit for 4 patients is lower than the volume of
eflornithine kit for 2 patients. The main reason for this is the reduction of the number of eflornithine infusions from 56 (eflornithine alone, given 4 times a day
during 14 days) to 14 (NECT, twice a day for 7 days).9
A pre-packaged medical kit containing all the necessary drugs, infusion materials
and accessories to administer 2 eflornithine treatments was designed. The kit’s weight was 40 kg, its volume 190 dm3 and its cost €1107, including transport to
health facilities in HAT foci, making the cost of a single eflornithine treatment an estimated €554 (2010 prices).
The new medical kit for NECT, with the same volume as the eflornithine kit, now includes sufficient material for 4 treatment regimens, weights 38 kg and costs
€1152. The cost of 1 NECT treatment is therefore estimated at €288 (2010 prices), including transport to health facilities in HAT foci.
Below is the content of the existing NECT kit, as designed by WHO and prepared and shipped by MSF Logistique to the National Control Programmes of the
affected countries on their demand:
Eflornithine (Ornidyl®) 100 ml (200mg/ml), 3 boxes with 12 glass
bottles each for a total of 36 bottles Nifurtimox (Lampit®) tablets of 120mg, 3 boxes with 100 tablets each
for a total of 300 tablets. Water for injections (sterile), 60 plastic pouches of 250 ml. Infusion set 'Y' Luer lock, air inlet, sterile, 1 box with 120 sets. (20
drops per ml) Catheter IV single use 20G (1,0x32 mm) pink, 1 box with 50
catheters Stopper for Catheter, Luer male, sterile, 1 box with 100 stoppers. Needle single use, Luer IV, 19G (1,1x40 mm) cream, 2 boxes with
100 needles each for a total of 200 needles. Syringe single use, Luer 20 ml, 1 box with 100 syringes
Syringe single use, Luer 2 ml, 1 box with 100 syringes Gauze compresses10 cm sterile, 28 boxes with 5 compresses each for
a total of 140 compresses.
Gauze bandage 8cm x 4m, 1 box with 20 bandages. Tape zinc oxyde perforated 10cm x 5 m, 1 roll.
Cotton wool hydrophilic 500 gr, 1 roll Polyvidone iodine 10% 200ml, 1 bottle Examination gloves, single use "big", 1 box with 100 gloves
Examination gloves, single use "middle", 1 box with 100 gloves Tourniquet, elastic 100 x 1,8 cm, 2 units
Comparative cost-effectiveness presented as range of cost per routine outcome (e.g. cost per case, cost per cure, cost per month of treatment, cost per case
prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality adjusted life year gained)
Regarding cost-effectiveness, it is estimated that each treatment equals almost one life saved, as the disease is almost invariably fatal in its second stage if left
untreated, and the treatment has consistently shown an efficacy over 90%, non-inferior to that of eflornithine alone.
17
The introduction of the combination of nifurtimox and eflornithine (NECT) has
accelerated the shift from melarsoprol to the best treatment available, due to reduced dosage and treatment time compared to eflornithine. This has
significantly decreased the cost and lowered the burden of logistics encountered during treatment and distribution. The decrease in the use of cheaper melarsoprol (due to dangerousness) has meant a rise in the per patient cost of
treating HAT:
The ethical imperative of replacing melarsoprol by the most safe and effective treatment available brought a high price increase, related to the introduction of eflornithine first (from 2001 to 2006). Initially used almost exclusively by
international NGOs due to its complexity, in 2006 WHO designed and introduced the kit which led to a subsequent extension to National Control Programmes
accompanied by a big increase in total costs (2006 to 2009) that was not compensated by the reduction of cases. From 2009 onwards, even if NECT cost is about half the cost of eflornithine alone, the generalization of the treatment with
the safest treatment and the reduction of the melarsoprol use to the minimum as second line treatment for relapses, led to a further increase in global costs to
WHO as can be seen in the graph below.9
The ethical decision of shifting to the best available treatment imposes a financial
burden on HAT control programmes that might render long-term application unsustainable if the WHO support is discontinued. These factors call for
continuing research to provide new safer and more effective drugs that are simple to administer and cheaper when compared to current drugs.9
18
13. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well)
Nifurtimox is registered for treatment of Chagas disease in Argentina, Chile, Colombia, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, and Uruguay.
The latest update of the Lampit prospectus (Bayer) dated 24th April 2012 does not include the indication for HAT. The drug is produced in a GMP-certified Bayer factory in Ilopango, El Salvador, Central America.
Sanofi, the company producing eflornithine, has submitted the indication of the
co-administration with nifurtimox to the French regulatory authorities in 2011.
14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia)
Nifurtimox is included in Reynolds JEF, editor. Martindale, the extra
pharmacopeia. 28th ed. London: The Pharmaceutical Press, 1982: 508, 522, as a treatment for American Trypanosomiasis.
15. Proposed (new/adapted) text for the WHO Model Formulary
Medicines for the treatment of second-stage human African trypanosomiasis
nifurtimox* Tablet: 30 mg; 120 mg.
* To be used in combination with eflornithine only, for the treatment of Trypanosoma brucei gambiense infections.
19
References
1. Franco JR SP, Diarra A, Ruiz-Postigo JA, Samo M, Jannin JG. Monitoring the use of nifurtimox-eflornithine combination therapy (NECT) in the treatment of second stage gambiense human African trypanosomiasis Research and Reports in Tropical Medicine. 2012; 3(1): 93-101. 2. Alirol E, Shrumpf D, Heradi JA, Riedel A, de Patoul C, Quere M, et al. Nifurtimox-Eflornithine Combination Therapy (NECT) for second-stage gambiense human African trypanosomiasis: MSF experience in the Democratic Republic of the Congo. Clinical Infectious Diseases. 2012. 3. Schmid C, Kuemmerle A, Blum J, Ghabri S, Kande V, Mutombo W, et al. In-Hospital Safety in Field Conditions of Nifurtimox Eflornithine Combination Therapy (NECT) for <italic>T. b. gambiense</italic> Sleeping Sickness. PLoS Negl Trop Dis. 2012; 6(11): e1920. 4. Simarro P, Diarra A, Postigo J, Franco J, Jannin J. The Human African Trypanosomiasis Control and Surveillance Programme of the World Health Organization 2000–2009: The Way Forward Pere. PLoS Negl Trop Dis. 2011; 5(2). 5. Simarro PP, Cecchi G, Franco JR, Paone M, Diarra A, Ruiz-Postigo JA, et al. Estimating and Mapping the Population at Risk of Sleeping Sickness. PLoS Negl Trop Dis. 2012; 6(10): e1859. 6. Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian S, Arnold U, et al. Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet. 2009; 374(9683): 56-64. 7. Tong J, Valverde O, Mahoudeau C, Yun O, Chappuis F. Challenges of controlling sleeping sickness in areas of violent conflict: experience in the Democratic Republic of Congo. Conflict and Health. 2011; 5(7). 8. Ludwig N. Epidemiology and treatment of human African trypanosomiasis in children. Basel: University of Basel; 2009. 9. SIMARRO PP, FRANCO J, DIARRA A, POSTIGO JAR, JANNIN J. Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis. Parasitology. 2012; 139(07): 842-6. 10. Bäumelt P. Feasibility of NECT Treatment for HAT Under Field Conditions in Rural Health Structures of the Democratic Republic of Congo (DRC): University of Basel; 2010. 11. Chappuis F, Loutan L, Simarro P, Lejon V, Buscher P. Options for field diagnosis of human african trypanosomiasis. Clin Microbiol Rev. 2005; 18(1): 133-46. 12. Enock Matovu AJK, Claire Mack Mugasa, Joseph Mathu Ndungu, and Zablon Kithingi Njiru. Towards Point-of-Care Diagnostic and Staging Tools for Human African Trypanosomiaisis. Journal of Tropical Medicine. 2012; 2012. 13. Priotto G, Fogg C, Balasegaram M, Erphas O, Louga A, Checchi F, et al. Three drug combinations for late-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Uganda. PLoS Clin Trials. 2006; 1(8): e39. 14. Checchi F, Piola P, Ayikoru H, Thomas F, Legros D, Priotto G. Nifurtimox plus Eflornithine for Late-Stage Sleeping Sickness in Uganda: A Case Series. PLoS Negl Trop Dis. 2007; 1(2): e64.
20
Annexes.
1. Franco JR, Simarro PP, Diarra A, Ruiz Postigo JA, Samo M et Jannin J.
Monitoring the use of Nifurtimox eflornithine combination therapy (NECT) in the treatment of second stage gambiense human African
trypanosomiasis. Res Rep Trop Med 2012:3 1-9
2. Alirol E, Schrumpf D, Amici Heradi J, Riedel A, de Patoul C, Quere M, et al.
Nifurtimox-Eflornithine Combination Therapy for Second-Stage Gambiense Human African Trypanosomiasis: Medecins Sans Frontieres Experience in
the Democratic Republic of the Congo. Clin Infect Dis. 2012 Nov 9. PubMed PMID: 23074318.
3. Schmid C, Kuemmerle A, Blum J, Ghabri S, Kande V, Mutombo M, et al. In-hospital safety in field conditions of nifurtimox eflornithine combination
therapy (NECT) for T. b. gambiense sleeping sickness. PLoS Negl Trop Dis. 2012;6(11):e1920.
4. Proposal for the inclusion of Nifurtimox-Eflornithine Combination as a treatment for stage 2 Trypanosoma brucei gambiense human African
trypanosomiasis (Sleeping Sickness) in the WHO model List of Essential Medicines. Drugs for neglected Diseases initiative, October 2008
5. MSF Support letter NECT Pediatric EML
6. STPH Support letter NECT Pediatric EML
7. HAT Platform Support letter NECT Pediatric EML
AUTHOR
PROOF
COPY
Not for
publication
© 2012 Franco et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
Research and Reports in Tropical Medicine 2012:3 1–9
Research and Reports in Tropical Medicine
Monitoring the use of nifurtimox-eflornithine combination therapy (NECT) in the treatment of second stage gambiense human African trypanosomiasis
Jose R Franco1
Pere P Simarro1
Abdoulaye Diarra2
Jose A Ruiz-Postigo3
Mireille Samo1
Jean G Jannin1
1World Health Organization, Control of Neglected Tropical Diseases, Innovative and Intensified Disease Management, Geneva, Switzerland; 2World Health Organization, Regional Office for Africa, Brazzaville, Congo; 3World Health Organization, Communicable Disease Control, Control of Tropical Diseases and Zoonoses Regional Office for the Eastern Mediterranean, Cairo, Egypt
Correspondence: Jose Ramon Franco World Health Organization, Control of Neglected Tropical Diseases, 1211 Geneva, Switzerland Tel +41 22 791 33 13 Fax +41 22 791 47 77 Email [email protected]
Abstract: After inclusion of the nifurtimox-eflornithine combination therapy (NECT) in the
Model List of Essential Medicines for the treatment of second-stage gambiense human African
trypanosomiasis (HAT), the World Health Organization, in collaboration with National Sleeping
Sickness Control Programs and nongovernmental organizations set up a pharmacovigilance
system to assess the safety and efficacy of NECT during its routine use. Data were collected
for 1735 patients treated with NECT in nine disease endemic countries during 2010–2011.
At least one adverse event (AE) was described in 1043 patients (60.1%) and a total of 3060
AE were reported. Serious adverse events (SAE) were reported for 19 patients (1.1% of treated),
leading to nine deaths (case fatality rate of 0.5%). The most frequent AE were gastroin testinal
disorders (vomiting/nausea and abdominal pain), followed by headache, musculoskeletal pains,
and vertigo. The most frequent SAE and cause of death were convulsions, fever, and coma that
were considered as reactive encephalopathy. Two hundred and sixty-two children below 15 years
old were treated. The characteristics of AE were similar to adults, but the major AE were less
frequent in children with only one SAE and no deaths registered in this group. Gastrointestinal
problems (vomiting and abdominal pain) were more frequent than in adults, but musculosk eletal
pains, vertigo, asthenia, neuropsychiatric troubles (headaches, seizures, tremors, hallucinations,
insomnia) were less frequent in children. Patient follow-up after treatment is continuing, but
initial data could suggest that NECT is effective as only a low number of relapses have so far
been reported (19 cases). However, additional monitoring is required to assess the efficacy of
the treatment, particularly in children. NECT has given satisfactory results of safety in the usual
conditions where HAT patients are managed and it is currently the best option for treatment of
second stage of gambiense HAT.
Keywords: human African trypanosomiasis, sleeping sickness, T. b. gambiense, nifurtimox,
eflornithine, pharmacovigilance
IntroductionHuman African trypanosomiasis (HAT) (sleeping sickness) is a neglected tropical
disease considered as lethal without treatment. It is found in sub-Saharan countries
with a patchy distribution in foci.1 Many of these foci are in remote rural areas with
difficult access to health services, such that treatment of HAT patients often relies on
limited human and material resources.2
Most of the medicines used for the treatment of HAT are cumbersome to use and
have a non-negligible toxicity.3 Choice of medicine depends on the form (HAT due to
infection with Trypanosoma brucei gambiense or with T. b. rhodesiense) and stage of
Dovepress
submit your manuscript | www.dovepress.com
Dovepress 1
O R I G I N A L R E S E A R C H
open access to scientific and medical research
Open Access Full Text Article
34399
Research and Reports in Tropical Medicine 2012:3
disease: early or first stage, with presence of trypanosomes
in lymph, blood, and peripheral organs, or late or second
stage, characterized by trypanosomes invading the central
nervous system (CNS).4
For second-stage gambiense HAT, available medicines
are melarsoprol (a toxic arsenical derivative) and eflorni-
thine (less toxic but complicated to use).5 In March 2009,
however, the World Health Organization (WHO) Expert
Committee on the Selection and Use of Essential Medicines
recommended inclusion of nifurtimox in combination with
eflornithine in the Model List of Essential Medicines (EML),
to be used for treatment of second stage of T. b. gambiense
infection.6 This decision was mainly supported by results
from a multicenter clinical trial comparing eflornithine
monotherapy with the nifurtimox-eflornithine combination
treatment (NECT);7,8 this trial concluded that the NECT
combination had comparable safety and efficacy with
eflornithine monotherapy but improved treatment feasibil-
ity,8 reducing the costs and the logistic difficulties. The
eflornithine in monotherapy is administered at the daily dose
of 400 mg/kg in slow infusion every 6 hours for 14 days
for a total of 56 infusions, meanwhile eflornithine in NECT
is used at the same dose but with slow infusions every
12 hours for 7 days, for a total of 14 infusions, combined
with nifurtimox orally at the daily dose of 15 mg/kg, three
times a day for 10 days.
NECT has since been adopted as first-line treatment for
second-stage gambiense HAT in the majority of endemic
countries.9 The nifurtimox and eflornithine are donated to
WHO through a Public-Private-Partnership by the phar-
maceutical companies, Sanofi and Bayer, and are then sup-
plied free-of-charge by WHO as a medical kit that includes
basic material needed for administration of the combination
treatment. WHO has also organized training of key staff in
the use of NECT.
By 2010, 59% of reported new cases of second-stage gam-
biense HAT were treated with NECT10 and the proportion of
cases treated with NECT has since been increasing. Consider-
ing the short experience in the use of this combination, how-
ever, and in accordance with the Committee on the Selection
and Use of Essential Medicines, WHO took the responsibility
to set up a pharmacovigilance system in collaboration with
Sleeping Sickness National Control Programs (SSNCP) and
non-governmental organizations (NGOs).
MethodsIn 2010, an active pharmacovigilance system for assessing
the safety and efficacy of NECT in routine use was set up
through WHO. The system was based on the collection
and analysis of NECT safety and efficacy in regular use
in different settings. Safety is assessed from characteriza-
tion of adverse events (AE) during treatment, and efficacy
assessed from the register of relapses in patients during the
2 years following treatment. For the pharmacovigilance of
safety, simplified forms (see Appendix) were developed by
expert consensus and validated with a group of the users.
The qualifications of health staff in charge of HAT case
management, the limited resources, the isolation, and dif-
ficulties in communication of the centers treating the cases
were considered as well as the attempt to avoid overload
of work.
The forms were filled for each patient presenting any
adverse event during the treatment with NECT by the
professional in charge of the patient (medical officer, clinical
officer, or nurse) and sent quarterly straight to WHO or
through the SSNCP.
Adverse events were considered as any undesirable sign,
symptom, or medical condition occurring at the same time
as treatment with NECT, which may or may not have been
causally related. A major AE was defined when the intensity
of the event was described as severe, very severe, or lethal, by
the reporter, and a serious adverse event (SAE) was consid-
ered as any event that was fatal, life-threatening, permanently
or significantly disabling, or that required or prolonged
hospitalization, or caused a congenital anomaly.11
Training in pharmacovigilance and the use of the report
forms was included during the guidance sessions for staff of
disease endemic countries in the use of the NECT kit. The
report forms were provided to the centers implementing
NECT and all forms received by WHO from January 2010
to January 2012 were included in the present analysis.
The AE referred were listed and classified according to
the common toxicity criteria for adverse events (CTCAE;
version 4), of the National Cancer Institute (NCI).12
Information from the report forms was compiled into
a database built in Access Microsoft® software (IBM,
Armonk, NY). For the safety data, the following variables
were considered:
• Putative relationship between the AE and treatment –
graded by the health staff in charge of the treatment
as: lack of relationship, unlikely relationship, possible
relationship, probable relationship, or cer tain
relationship.
• Intensity of the AE – graded over five levels: mild, moder-
ate, severe, very severe, and lethal, following the criteria
referred in the CTCAE/v 4/NCI.12
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
2
Franco et al
Research and Reports in Tropical Medicine 2012:3
• Action taken to mitigate the AE – noted as: NECT continued,
temporarily suspended, or stopped definitively.
• Outcome of the AE – as completely disappeared, still
present at the end of NECT, or if there were any sequelae
or lethal outcome.
Treatment efficacy was assessed from the frequency of
relapses, according to the criteria of the SSNCPs and WHO
recommendations. A patient is considered cured when during a
follow-up period of 24 months after treatment, no trypanosomes
were detected and when the CSF returned to normal.13
As required by current regulation in pharmacovigilance,
these data have been communicated to the manufacturers.
Ethical approval was not required because this study is limited
to analyzing data that were collected within the standard
medical data recording and did not involve any experimental
intervention. Treatment and patient management were all part
of the routine activities of the SSNCP. The anonymity of the
patients has been always maintained and the identification of
the patients has never been available for authors.
ResultsThis analysis includes all the data reported to WHO
from January 1, 2010 to January 31, 2012. Twenty-two
sites in nine countries reported information (Table 1).
Pharmacovigilance forms were filled in by medical officers
(76%), medical assistants (1%), and nurses (22%), although
in 1% of the cases it was not described who filled in the form.
Of the 1735 cases treated, 1043 patients (60.1%) reported
AE during NECT.
Safety: analysis of AEThere were 3060 AE reported, with an average of 2.9 events
for each patient reporting any AE. The AE were classified
and grouped as 83 different AE according to CTCAE/v 4/NCI
(Table 2).12
The most frequent adverse events were related to
gastrointestinal disorders, followed by neuropsychiatric
disorders. The most common were vomiting, headache,
gastrointestinal pain, nausea, abdominal pain, vertigo, and
anorexia. Other infections were uncommon.
Safety: relationship with treatmentOf the total AE reported, 2794 (91%) were considered
as having a possible, probable, or clear relationship with
the treatment (Table 2), while the remainder (9%) were
considered to be unrelated to the treatment.
Table 1 Centers reporting NECT pharmacovigilance data
Country Treatment center Cases treated with NECT Patients with AE
Central African Republic (CAR)
Hôpital Sous-préfectoral Batangafo 234 (13.5%) 152 (14.5%)Hôpital Maitikoulou 30 (1.7%) 21 (2.0%)
Chad Hôpital Moissala 23 (1.3%) 3 (0.3%)Centre de Santé Bodo Est 131 (7.5%) 76 (7.3%)
Democratic Republic of Congo (DRC)
Hôpital, Roi Baudouin, Kinshasa 60 (3.6%) 31 (3.0%)HGR (Hôpital General de Reference) de Doruma 378 (21.8%) 236 (22.6%)HGR de Dingila 538 (31.0%) 450 (43.1%)CDTC (Centre de Dépistage, Traitement et Contrôle) de Katanda
20 (1.1%) 2 (0.2%)
CRT (Centre de Référence et de Traitement) de Dipumba
40 (2.3%) 2 (0.2%)
Equatorial Guinea Hospital Regional de Bata 12 (0.7%) 8 (0.8%)South Sudan Juba Teaching Hospital 7 (0.4%) 1 (0.1%)
Yei Civil Hospital 72 (4.1%) 23 (2.2%)Lui Hospital 38 (2.2%) 10 (1.0%)Nimule Hospital 14 (0.8%) 6 (0.6%)Yambio Hospital 27 (1.6%) 2 (0.2%)
Uganda Adjumani District Hospital 13 (0.7%) 3 (0.3%)Omugo Health Center 47 (2.7%) 11 (1.0%)Yumbe District Hospital 12 (0.7%) 1 (0.1%)Moyo District Hospital 23 (1.3%) 0 (0.0%)
Cote d’Ivoire PRCT Daloa 3 (0.2%) 1 (0.1%)Congo Hôpital Ngabe 3 (0.2%) 2 (0.2%)Guinea Hypnoserie Dubreka 10 (0.6%) 2 (0.2%)Total 1735 1043
Abbreviations: AE, adverse events; NECT, nifurtimox-eflornithine combination therapy.
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
3
Pharmacovigilance of NECT in second stage of gambiense HAT
Research and Reports in Tropical Medicine 2012:3
Table 2 Total adverse events reported (according to CTCAE classification)
AE Total Adults ($15 years)
Children (,15 years)
Total Related to NECT
Total Related to NECT
Total Related to NECT
Gastrointestinal disorders 1214 1138 1017 955 196 183 Vomiting 429 413 339 327 90 86 Gastrointestinal pain 242 239 228 226 14 13 Nausea 214 212 179 178 35 34 Abdominal pain 201 171 158 134 42 37 Diarrhea (including dysentery) 100 82 88 71 12 11 Others 28 21 25 19 3 2Nervous system disorders 522 474 478 439 40 32 Headache 308 271 281 249 25 21 Seizure 106 102 100 97 6 5 Tremor 68 63 65 61 3 2 Others 40 38 32 32 6 4General disorders 257 212 220 189 34 21 Fatigue, asthenia, malaise 121 121 115 115 5 5 Fever 94 53 69 41 25 12 Others 42 38 36 33 4 4Musculoskeletal and connective tissue disorders 245 205 232 199 12 6 Back pain 100 81 91 78 9 3 Neck pain 77 68 75 66 2 2 Others 68 56 66 55 1 1Psychiatric disorders 242 233 228 222 10 9 Insomnia 102 101 101 100 1 1 Agitation, anxiety 48 42 39 35 7 6 Others 92 90 88 87 2 2Ear and labyrinth disorders 201 199 195 195 6 4 Vertigo/dizziness 190 190 186 186 4 4 Others 11 9 9 9 2 0Metabolism and nutrition disorders 166 165 140 139 26 26 Anorexia 164 163 138 137 26 26 Others 2 2 2 2 0 0Skin and subcutaneous tissue disorders 59 50 53 45 6 5 Pruritus 50 44 46 41 4 3 Others 9 6 7 4 2 2Vascular disorders 55 42 47 37 8 5Respiratory, thoracic and mediastinal disorders 31 23 21 15 9 7Infections and infestations 19 10 15 8 4 2Eye disorders 19 17 18 16 1 1Renal and urinary disorders 14 12 13 12 0 0Cardiac disorders 12 12 12 12 0 0Blood and lymphatic system disorders 4 2 3 2 1 0Total 3060 2794 2692 2485 353 301
Abbreviations: CTCAE, common toxicity criteria for adverse events; NECT, nifurtimox-eflornithine combination therapy.
Safety: outcome of the AE and actions taken to mitigate the AEThe majority of the patients with AE (82.4%) recovered
completely before the end of the treatment. One hundred and
seventy-one patients (16.4%) had AE still present at the end
of treatment, three patients (0.3%) remained with sequelae,
and nine (0.9%) died during treatment.
Vertigo (55 patients), fatigue, asthenia, or malaise
(52 patients), anorexia (33 patients), headaches (19 patients),
gastrointestinal pain (15 patients), tremor (12 patients),
vomiting (10 patients), nausea (9 patients), abdominal pain
(9 patients), pruritus (8 patients), and seizure (8 patients) were
the AE that more often were still present after treatment. Fifty
point five percent of patients having vertigo during treatment
and 43.0% having asthenia remained with these symptoms
at the end of treatment.
Out of the 1043 patients presenting any AE, treatment
had to be suspended temporarily due to an AE in 30 patients
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
4
Franco et al
Research and Reports in Tropical Medicine 2012:3
(2.9%) and in 12 cases (1.1%) had to be definitely stopped
for the same reason.
Safety: intensity of AE, serious AE, lethalityOf the 1735 patients treated with NECT, 202 individuals pre-
sented a major AE: 189 individuals (10.9%) had a severe AE,
and 23 (1.3%) had very severe or fatal events. The majority of
AE were mild or moderate (90.5%) but there were 290 major
AE recorded, of which 262 (90%) were considered as having
a possible, probable, or clear relationship with treatment. The
most frequent major AE were vomiting, seizures, nausea,
vertigo, headache, and agitation/anxiety.
A total of 36 SAE were reported in 19 patients (1.1%
of treated patients), leading to death in nine patients.
Convulsions (eight patients), fever (seven patients), and coma
(six patients) were the most frequent SAE (Table 3). In 11 of
these 19 patients, the SAE were consistent with the concept of
reactive encephalopathy, or encephalopathic syndrome (rate
of reactive encephalopathy of 0.63%), which is defined as a
life-threatening event taking place during treatment for HAT,
and characterized by a sudden deterioration of neurological
status with either convulsions, progressive coma or psychotic
reactions, or abnormal behavior.14 Of the nine deaths occur-
ring during treatment (0.52% case fatality rate), five were
compatible with the clinical signs of reactive encephalopathy
(high fever, coma, and convulsions) and can be assumed to
be related to the treatment. The other four deaths were due to
causes considered as not related to treatment: two probably
related to sleeping sickness, one to severe anemia, and one
to an acute abdomen (Table 3).
Safety: data in childrenThere are no data on the safety and efficacy in the use of
NECT in children as the clinical trial was limited to indi-
viduals above 14 years old.7,8 Nevertheless, eflornithine for
HAT and nifurtimox for Chagas disease have been largely
used in children, and even nifurtimox has showed a safer
profile in children.15
Amongst the 262 children below 15 years included in
this dataset, AE were as frequent as in adults (χ2 = 0.075,
P . 0.5) (Table 4). Three hundred and fifty-three AE were
reported in 155 of these children (59.2% of those treated, with
an average of 2.3 AE per case). Three hundred and one AE
(85.3%) were considered as possibly, probably, or certainly
related to the NECT.
The most frequent AE in children were gastrointes-
tinal (vomiting, nausea, and abdominal pain), nervous
system disorders (headache), general troubles (fever), and
anorexia. The gastrointestinal problems (vomiting and
abdominal pain) were more frequent in children than in
adults (χ2 = 7.23, P , 0.001), but the musculoskeletal pains
Table 3 Patients with serious adverse events reported
No Event Considered related to NECT
Death Compatible with reactive encephalopathy?
1 Depressed level of consciousness with fever and death
No Yes No
2 Coma with seizures and death Yes Yes Yes3 Coma with seizures and fever Yes No Yes4 Coma with hypotension, seizures,
fever, and deathYes Yes Yes
5 Ataxia and urinary retention Yes No No6 Psychotic reaction Yes No No7 High fever and death No Yes No8 High fever and death Yes Yes Yes9 Agitation, abnormal behavior,
fever, and encephalopathyYes No Yes
10 Severe anemia and death No Yes No11 Fever and seizures Yes No Yes12 Fever, seizures, coma, and death Yes Yes Yes13 Repeated seizures Yes No Yes14 Severe dyspnea Yes No No15 Seizure and encephalopathy Yes No Yes16 Paralysis Yes No No17 Seizure, confusion, paralysis Yes No Yes18 Acute abdomen and death No Yes No19 Confusion, coma, and death Yes Yes Yes
Abbreviation: NECT, nifurtimox-eflornithine combination therapy.
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
5
Pharmacovigilance of NECT in second stage of gambiense HAT
Research and Reports in Tropical Medicine 2012:3
Table 4 Distribution of cases treated and presenting AE according to age group
Age Cases treated Patients with AE
0–4 years 40 (2.3%) 26 (2.5%)5–14 years 222 (12.8%) 129 (12.4%).14 years 1452 (83.7%) 876 (84.0%)NA 21 (1.2%) 12 (1.1%)Total 1735 1043
Abbreviations: AE, adverse events; NA, not available.
(χ2 = 25.6, P , 0.001), vertigo (χ2 = 28.9, P , 0.001),
asthenia (χ2 = 13.1, P , 0.001), nervous system (headaches,
seizures, tremors) (χ2 = 41.3, P . 0.001), and psychiatric
disorders (hallucinations, insomnia) (χ2 = 28.5, P , 0.001)
were relatively more frequent in adults (Table 2).
There were 26 major AE registered in 19 children
(7.2% of all children treated), with the most frequent being
vomiting and nausea, and agitation/anxiety. Only one SAE
was reported in a child (a case of paralysis with sequelae),
but no reactive encephalopathy or death was registered in
children.
There was no difference in the analysis of data for chil-
dren below 5 years. Twenty-six children (65.0%) of this
group presented AE, in a proportion not significantly higher
than the rest of patients (χ2 = 0.401, P . 0.5). Sixty-four
AE were reported in this group and the most frequent were
vomiting, fever, nausea, anorexia, and abdominal pain. Fever
was significantly more frequent in small children than in the
rest (χ2 = 16.98, P , 0.001). Seven of the AE in five children
were considered as major and none as a SAE.
Efficacy: analysis of relapsesSo far, 19 relapses have been reported after NECT, from six
different treatment centers. These were detected between
5 to 13 months after treatment (average 8.6 months).
Although patient follow-up after HAT treatment can be
limited,16–19 it is often seen that relapsing patients do tend to
come for assessment because of their clinical symptoms.20
Cautiously therefore, the data can be taken to indicate the
apparent rate of relapse: 551 cases have completed at least
1 year after finishing the treatment, and during this time,
ten relapses have been reported – a relapse rate of 1.8% at
1 year after treatment.
There were six relapses (32%) reported in children below
15 years with an estimated relapse rate at 1 year of 3.6%.
These data could suggest a minor efficacy in children but it
is not statistically significant and more completed data are
needed.
Discussion: comparison with previous dataPrevious data about the use of NECT derived primarily
from a clinical trial comparing NECT and eflornithine in
the treatment of second-stage gambiense HAT.8 Other series
of cases treated with NECT were short and used different
schemas.21,22 During the referred clinical trial, a limited
number of patients (143) received NECT subject to speci-
fied criteria for inclusion in the study. Treated patients were
in hospital under daily supervision during treatment and for
at least 1 week afterwards. By contrast, the current dataset
derives from treatment taking place in the normal routine of
treatment centers, including all the cases in second stage, as
for instance patients with serious health conditions or patients
with 5–20 leukocytes per µL in the cerebrospinal fluid, that
were not included in the clinical trial.
In the clinical trial, reports of adverse events took into
account all the biological and clinical events occurring dur-
ing treatment, whereas from the routine treatment system
described here, the AE were reported just on the basis of
clinical manifestations. As expected therefore, the frequency
of AE registered in the clinical trial was higher (94% of
patients treated), but data about major clinical AE, SAE, and
deaths during treatment, are similar (Table 5).
The most frequent AE in both datasets included vomiting,
nausea, headache, musculoskeletal pain, abdominal pain, and
anorexia. Patients affected by vomiting and nausea, tremors,
and hallucination, also had the same frequency in both
studies. The number of patients reported with fever, seizures,
other infections, and cardiovascular events was higher in the
clinical trial, but lower for those with abdominal pain.
Previous first-line treatment for second-stage HAT
gambiense was eflornithine in monotherapy. Compared
to this treatment,9,18,23 the NECT has shown fewer serious
adverse events and fewer deaths (Table 5), which may reflect
reduced drug-related toxicity due to the shorter eflornithine
regimen.24
Since April 2009, the Drug Neglected Diseases Initiative
(DNDi) has sponsored a further clinical trial (NECT Field) of
the feasibility, safety, and efficacy of NECT in second stage
cases of gambiense sleeping sickness in DRC (hospitals of
Bandundu, Dipumba, Katanda, Kwamouth, Ngandajika, Yasa
Bonga). Six hundred and twenty-nine patients have been
included in the study and treated with NECT. Thirty-nine
SAE have so far been reported in 32 patients, with ten deaths
during treatment (O Valverde, personal communication).25
This study has a close active follow-up of the patients, and
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
6
Franco et al
Research and Reports in Tropical Medicine 2012:3
Table 5 Comparison of eflornithine monotherapy treatment (in the NECT clinical trial,7,8 and during routine use in the Ibba MSF treatment Centre, South Sudan),20 and NECT (in the NECT clinical trial7,8 and in routine use as monitored by WHO)
Eflornithine NECT
NECT clinical trial Control program Ibba (S. Sudan)
NECT clinical trial Routine use PV system
n % n % n % n %
Cases treated (n) 143 1055 143 1735Cases with at least one AE 134 93.7 962 91.2 134 93.7 1043 60.1Cases with major clinical AE 33 23.1 138 13.1 18 12.6 189 10.9Cases with SAE 6 4.2 1 0.7 19 1.1Cases requiring treatment interruption 9 6.3 109 10.3 45 2.6Deaths during treatment 3 2.1 16 1.5 1 0.7 9 0.5
Abbreviations: AE, adverse event; MSF, Médecins Sans Frontières ; NECT, nifurtimox-eflornithine combination therapy; SAE, serious adverse event; WHO, World Health Organization.
should provide important further information mainly about
the efficacy of the clinical use of NECT.
Nifurtimox has been used in monotherapy, mainly in the
treatment of Chagas disease, showing a significant risk of
AEs, mainly gastrointestinal (anorexia, nausea, abdominal
pain, vomiting), neuropsychiatric (headache, insomnia,
mood alteration), and fatigue. SAEs are also described
and mainly related to allergic reactions (eosinophilia, rash,
pruritus, edema, dyspnea).26 Nevertheless, the duration of
treatment with nifurtimox is much longer in Chagas disease
(60–120 days).
A limitation of pharmacovigilance data is the subjective
component in the report of AEs and SAEs. In the present
analysis, the heterogeneity between the different sites
and the judgment of the different reporters is an added
limitation. However, at the same time, this heterogeneity
gives added value to the results as it includes different set-
tings with different circumstances, making the situation
closer to real life. Comparison with previous studies has
to be cautiously considered as the conditions of the studies
were not the same.
ConclusionA simplified pharmacovigilance system has provided key
information in the routine use of the NECT protocol for
gambiense trypanosomiasis. In spite of the isolation and
limited resources in most of the treatment centers, awareness
of the importance and usefulness of the system has given a
satisfactory reporting rate.
The reports from the routine use of NECT are consistent
with the results of the original clinical trial. NECT generates a
number of adverse events, mainly linked to gastrointestinal
and neuropsychiatric problems. However, the severity of
these events is relatively low compared to previous treat-
ments, and the majority of patients treated make a good
recovery.
Safety in children does not show important differences
compared with adults but more complete data are needed.
For the moment, the data suggest the treatment to be
effective against gambiense trypanosomiasis, since only
a low number of relapses have been reported during the
analysis period, and no critical problems in efficacy have
been detected. However, further patient follow-up is required
to provide a full measure of efficacy, stressing the collection
of data in children.
With the data obtained so far and despite the frequent
adverse events, it can be considered that use of NECT in
second-stage gambiense sleeping sickness has given sat-
isfactory safety results in the usual conditions where HAT
patients are managed, and it is currently the best option for
treating this disease.
AcknowledgmentsWe thank the health professionals from the national sleep-
ing sickness control programs (Central African Republic,
Chad, Cote d’Ivoire, Democratic Republic of Congo,
Republic of Congo, Equatorial Guinea, Guinea, Republic
of South Sudan, and Uganda) and NGOs (Médecins Sans
Frontières, Merlin) for compiling the pharmacovigilance
reports. Special thanks to Andrea Riedel, Apai Onesta,
Beatrice Kola-Bongo, David Schrumpf, François Chappuis,
Jose Amici, Emile Alirol, Fioboy Marcel, Cecilia Maracci,
Eustaquio Nguema, Justin Rubena, Jane Pita, Nines Lima,
Ble Sepe, Nsengi Ntamabyaliro, Elizeous Surur, Joseph
Zahiri, Gabriel Giris, Repent Buba, Ariga Musa, Joseph
A Idoru, Victor Kande, Peka Mallaye, Stephane Ngampo,
and Olema Erphas for their work in collecting, filtering, and
transferring the reports.
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
7
Pharmacovigilance of NECT in second stage of gambiense HAT
Research and Reports in Tropical Medicine 2012:3
We acknowledge the support of Sanofi in the analysis
of data.
DisclosureThe authors report no conflicts of interest in this work. As
stated in the paper, drugs used in the treatment of HAT are
provided free of charge by Sanofi and Bayer.
References 1. Simarro PP, Cecchi G, Paone M, et al. The Atlas of human African
trypanosomiasis: a contribution to global mapping of neglected tropical diseases. Int J Health Geogr. 2010;9:57.
2. Simarro PP, Jannin J, Cattand P. Eliminating human African try-panosomiasis: where do we stand and what comes next? PLoS Med. 2008;5:e55.
3. Barrett MP, Boykin DW, Brun R, Tidwell RR. Human African trypano-somiasis: pharmacological re-engagement with a neglected disease. Br J Pharmacol. 2007;152:1155–1171.
4. Burri C, Brun R. Human African trypanosomiasis. In: Cook GC, Zumla A, editors. Manson’s Tropical Diseases. 21st ed. London, UK: Elsevier Science limited; 2003:1303–1323.
5. Burri C. Chemotherapy against human African trypanosomiasis: Is there a road of success ? Parasitology. 2010;137:1987–1994.
6. World Health Organization. WHO model list of essential medicines, 16th list March 2009. Geneva, Switzerland: WHO; 2009. Available from: http://www.who.int/medicines/publications/essentialmedicines/en/index.html. Accessed January 30, 2012.
7. Priotto G, Kasparian S, Ngouama D, et al. Nifurtimox-Eflornithine combination therapy for second-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Congo. Clin Infect Dis. 2007;45:1435–1442.
8. Priotto G, Kasparian S, Mutombo W, et al. Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet. 2009;374:56–64.
9. Who.int [homepage on the Internet]. World Health Organization: Human African trypanosomiasis. Symptoms, diagnosis and treatment. Available from: http://www.who.int/trypanosomiasis_african/diagnosis/en/index.html. Accessed April 30, 2012.
10. Simarro PP, Franco JR, Diarra A, Postigo JA, Jannin J. Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis. Parasitology. 2012;139(7):842–846.
11. World Health Organization. Safety of Medicines – A Guide to Detecting and Reporting Adverse Drug Reactions – Why Health Professionals Need to Take Action. WHO/EDM/QSM/2002. Geneva, Switzerland: WHO; 2002.
12. Evs.nci.nih.gov [homepage on the Internet]. US Department of Health and human services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.01. Available from http://evs.nci.nih.gov/ftp1/CTCAE/About.html. Accessed January 30, 2012.
13. World Health Organization. Epidemiology and control of African trypanosomiasis. Report of a WHO Expert Committee. Technical Report Series 739. Geneva, Switzerland: WHO; 1986.
14. Blum J, Nkunku S, Burri C. Clinical description of encephalopathic syndromes and risk factors for their occurrence and outcome during melarsoprol treatment of human African trypanosomiasis. Trop Med Int Health. 2001;6(5):390–400.
15. Altcheh J, Biancardi M, Lapena A, Ballering G, Freilij H. Congenital Chagas disease: experience in the Hospital de Niños, Ricardo Gutiérrez, Buenos Aires, Argentina. Rev Soc Bras Med Trop. 2005;38 Suppl 2: 41–45. Spanish.
16. Ngampo S. Suivi post-thérapeutique des malades trypanosomés à T. b. gambiense: problèmes et perspectives. [post-therapeutical follow-up of T.b. gambiense: problems and perspectives]. Antwerp, Belgium: Instituut voor Tropische Geneeskunde; 1992. French.
17. Robays J, Lefort A, Lutumba P, et al. Drug toxicity and cost as barriers to community participation in HAT control in the Democratic Republic of Congo. Trop Med Int Health. 2007;12:290–298.
18. Miézan TW, Djé NN, Doua F, Boa F. Human African trypanosomiasis in Ivory Coast: biological characteristics after treatment. 812 cases treated in the Daloa focus (Ivory Coast). Bull Soc Pathol Exot Fil. 2002;95:362–365. French.
19. World Health Organization. Recommendations of the informal consultation on issues for clinical product development for human African trypanosomiasis. Geneva, Switzerland: WHO/CDS/NTD/IDM; 2007.
20. Priotto G, Pinoges L, Badi Fursa I, et al. Safety and effectiveness of first line eflornithine for Trypanosoma brucei gambiense sleeping sickness in Sudan: cohort study. BMJ. 2008;29:336:(7646):705–708.
21. Checchi F, Piola P, Ayikoru H, Thomas F, Legros D, Priotto G. Nifurtimox plus Eflornithine for late-stage sleeping sickness in Uganda: a case series. PloS Negl Trop Dis. 2007;1:e64.
22. Priotto G, Fogg C, Balasegaram M, et al. Three drug combinations for late-stage Trypanosoma brucei gambiense sleeping sickness: a random-ized clinical trial in Uganda. PLoS Clin Trials. 2006;1:e39.
23. Priotto G. Eflornithine for first line-treatment of trypanosomiasis: assessment of safety and effectiveness. Ibba, South Sudan. Paris, France: Epicentre; 2003.
24. Pepin J, Khonde N, Maiso F, et al. Short course eflornithine in Gambian trypanosomiasis: a multicentre randomized controlled trial. Bull World Health Organ. 2000;78:1284–1295.
25. Valverde Mordt O, Schmid C, Kande V, et al. In-hospital safety of NECT use to treat 2nd stage T. b. gambiense in African children, pregnant and breast-feeding women. European Congress of Tropical Medicine and International Health; Barcelona, Spain; October 5, 2011.
26. Jackson Y, Alirol E, Getaz L, Wolff H, Combescure C, Chappuis F. Tolerance and safety of nifurtimox in patients with chronic chagas disease. Clin Infect Dis. 2010;51:e69–e75.
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
8
Franco et al
Research and Reports in Tropical Medicine
Publish your work in this journal
Submit your manuscript here: http://www.dovepress.com/research-and-reports-in-tropical-medicine-journal
Research and Reports in Tropical Medicine is an international, peer-reviewed, open access journal publishing original research, case reports, editorials, reviews and commentaries on all areas of tropical medicine, including: Diseases and medicine in tropical regions; Entomology; Epidemiology; Health economics issues; Infectious disease; Laboratory
science and new technology in tropical medicine; Parasitology; Public health medicine/health care policy in tropical regions; and Microbiology. The manuscript management system is completely online and includes a very quick and fair peer-review system. Visit http://www.dovepress.com/testimonials.php to read real quotes from published authors.
Research and Reports in Tropical Medicine 2012:3
Description of the adverse
event
Starting date of the adverse
event
Duration in days
Intensity1. Mild 2. Moderate 3. Severe 4. Life-threatening 5. Death
Relationship with the treatment
1. Unrelated 2. Unlikely 3. Possible 4. Probable 5. Certain
Action0. Treatment continued
1. Treatment suspended (temporary)
2. Treatment stopped (definite)
Outcome1. Complete recovery2. Still present 3. Sequelae 4. Death
___/___/______/___/______/___/______/___/______/___/___
Appendix
Sleeping Sickness National Control Program Pharmacovigilance for nifurtimox-eflornithine combina-tion treatment
ADVERSE EVENTS DURING NIFURTIMOX-EFLORNITHINE COMBINATION TREATMENT REPORT FORM
Country: Year: Treatment center:
PATIENT INITIALS: CODE: AGE: SEX:
Starting date Nifurtimox-Eflornithine combination treatment ______ / ______ / ______
Other drugs used Date started Duration in days Indicate the underlying pathology for which the drug was administered
___/___/___
___/___/___
___/___/______/___/___
Date: Reporter: Qualification:
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
Dovepress
9
Pharmacovigilance of NECT in second stage of gambiense HAT
M A J O R A R T I C L E
Nifurtimox-Eflornithine Combination Therapyfor Second-Stage Gambiense Human AfricanTrypanosomiasis: Médecins Sans FrontièresExperience in the Democratic Republic of theCongo
Emilie Alirol,1,2,a David Schrumpf,1,2,a Josué Amici Heradi,2 Andrea Riedel,2 Catherine de Patoul,2 Michel Quere,2 andFrançois Chappuis1,2
1Division of International and Humanitarian Medicine, University Hospitals of Geneva, and 2Médecins Sans Frontières, Operational Centre Geneva,Switzerland
Background. Existing diagnostic and treatment tools for human African trypanosomiasis (HAT) are limited.The recent development of nifurtimox-eflornithine combination therapy (NECT) has brought new hopes for pa-tients in the second stage. While NECT has been rolled out in most endemic countries, safety data are scarce andderive only from clinical trials. The World Health Organization (WHO) coordinates a pharmacovigilanceprogram to collect additional data on NECT safety and efficacy. We report here the results of 18 months ofexperience of NECT use in treatment centers run by Médecins Sans Frontières in the Democratic Republic of theCongo (DRC).
Methods. This cohort study included 684 second-stage HAT patients (including 120 children) treated withNECT in Doruma and Dingila hospitals, northeastern DRC, between January 2010 and June 2011. All treatment-emergent adverse events (AEs) were recorded and graded according to the Common Terminology Criteria forAdverse Events version 3.0. Safety and efficacy data were retrieved from the WHO pharmacovigilance forms andfrom Epitryps, a program monitoring database.
Results. Eighty-six percent of the patients experienced at least 1 AE during treatment. On average, childrenexperienced fewer AEs than adults. Most AEs were mild (37.9%) or moderate (54.7%). Severe AEs included vom-iting (n = 32), dizziness (n = 16), headache (n = 11), and convulsions (n = 11). The in-hospital case fatality ratewas low (0.15%) and relapses were rare (n = 14).
Conclusions. In comparison with previous treatments, NECT was effective, safe, and well tolerated in nontrialsettings in DRC, further supporting the roll-out of NECT as first-line treatment in second-stage Trypanosomabrucei gambiense HAT. Tolerance was particularly good in children.
Human African trypanosomiasis (HAT), also knownas sleeping sickness, is a vector-borne disease transmit-ted to humans by tsetse flies in sub-Saharan Africa [1].
It thrives among impoverished populations, mostly inremote rural areas and conflict zones. HAT is causedby 1 of 2 subspecies of a protozoan parasite. Trypano-soma brucei (T.b.) gambiense occurs in Western andCentral Africa and is responsible for the majority ofHAT cases, while T.b. rhodesiense is found in Easternand Southern Africa [2].
The incidence of reported HAT cases has drasticallydecreased in recent years, from >26 000 in 2000 to<7200 in 2010. However, the true number of casesmay be underestimated by a factor of 4 to 5 [3, 4].“Hot spots” still occur in areas of conflict or instability,
Received 24 May 2012; accepted 2 October 2012.aE. A. and D. S. contributed equally to this work.Correspondence: Emilie Alirol, PhD, Division of International and Humanitarian
Medicine, University Hospitals of Geneva, rue Gabrielle Perret-Gentil 6, 1211Geneva 14, Switzerland ([email protected])
Clinical Infectious Diseases© The Author 2012. Published by Oxford University Press on behalf of the InfectiousDiseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected]: 10.1093/cid/cis886
NECT for Second-Stage HAT in DRC • CID • 1
Clinical Infectious Diseases Advance Access published November 9, 2012
and large areas in endemic countries have not been surveyedfor decades. In July 2007, Médecins Sans Frontières (MSF)began population screening for HAT in the districts of Haut-Uélé and Bas-Uélé in northeastern Democratic Republic of theCongo (DRC), close to the borders with South Sudan and theCentral African Republic [5].This region is subjected to sus-tained instability and conflict due to the presence of the Lord’sResistance Army, a revolutionary group from Uganda.Through early 2009, screening activities revealed an overallHAT prevalence rate of 3.4%, reaching 10% in some villages.
HAT due to T.b. gambiense occurs in 2 stages [6]. The he-molymphatic infection (first stage) is characterized by fever,headache, and joint pain. Transition to the meningoencepha-litic stage (second stage) occurs after the parasite crosses theblood-brain barrier. Patients present with neuropsychiatricsymptoms, including sensory motor deficit, walking difficul-ties, and psychotic behavior, leading to coma and death in theabsence of treatment [7]. Treatment options for HAT are fewand stage-specific. Of the 5 existing drugs, 3 are active insecond-stage T.b. gambiense HAT [8]: melarsoprol, eflorni-thine, and nifurtimox; all present drawbacks.
Since 1949, melarsoprol intravenous injections have beenthe mainstay therapy for second-stage HAT [9]. The drug, anarsenic derivative, is very toxic. It is associated with severe re-active encephalopathies in 5%–10% of the cases and kills 3%–5% of patients [10, 11]. Studies have also shown an increase intreatment failure rates over recent years [12–14].
Eflornithine (D, L, α-difluoromethyleflornithine, DFMO)was shown to be active against T.b. gambiense in the 1980s[15]. Although better tolerated than melarsoprol, eflornithinealso produces several side effects, including gastrointestinalproblems, fever, hypertension, and convulsions [16]. The treat-ment involves 56 intravenous infusions over 14 days, thereforerequiring complex logistics and trained health staff. The po-tential for resistance when used in monotherapy is an addi-tional concern. Several studies have compared the safety andefficacy of melarsoprol and eflornithine. Mortality was foundto be significantly lower in patients treated with eflornithinecompared to those treated with melarsoprol [17–19].
Nifurtimox, which is registered for the treatment of Chagasdisease, has shown some, albeit limited, efficacy againstsecond-stage HAT [20–22]. In recent years, combination regi-mens of the above-mentioned drugs have been evaluated insecond-stage T.b. gambiense HAT. Nifurtimox-eflornithinecombination therapy (NECT: oral nifurtimox 15 mg/kg/dayfor 10 days plus eflornithine infusions 400 mg/kg/day for 7days) proved to be the best combination in terms of bothsafety and efficacy [23–25]. The low mortality (0.7%) and highcure rates (97.7% at 18 months) reported with NECT prompt-ed the World Health Organization (WHO) to add the combi-nation to its Essential List of Medicines in 2009 [26].
However, the population exposed to NECT during clinicaltrials was limited (n = 191), and the WHO set up a pharmaco-vigilance system to monitor the safety of NECT after its roll-out in endemic countries. In parallel, the Drug for NeglectedDiseases initiative launched a pragmatic trial (NECT-FIELD)to document the use of NECT as first-line therapy for second-stage HAT under field conditions [27].
Since December 2009, MSF has implemented NECT asfirst-line treatment in all of its programs, including the chal-lenging region of Haut-Uélé and Bas-Uélé in DRC. Here wepresent a retrospective analysis of 684 patients treated withNECT in the Uélé districts and discuss the safety and feasibili-ty of this treatment in remote, conflict-torn areas.
METHODS
Study SettingThis retrospective cohort study was conducted in the ZonesDe Santé of Doruma and Dingila, in the Province Orientale,northeastern DRC. All second-stage HAT patients diagnosedon site or by mobile teams were hospitalized in wards set upby MSF in the reference hospitals (equivalent to district hospi-tals) of Doruma (Haut-Uélé) or Dingila (Bas-Uélé), both runby the DRC Ministry of Health.
Participants and ProceduresAll second-stage HAT patients treated with NECT between 1January 2010 and 30 June 2011 were included in the analysis.Patients were mainly Congolese, with a high proportion of dis-placed people from neighboring areas owing to rampantinsecurity.
Second-stage HAT was defined by the presence of trypano-somes in the cerebrospinal fluid (CSF) or a CSF leukocytecount >5 cells/μL in patients with trypanosomes found inlymph or blood, or in patients with positive high (1:16) cardagglutination Trypanosoma test (CATT) titer. The CATT is anagglutination method based on the detection of circulating an-tibodies against T.b. gambiense [28]. Parasites detection in thelymph or blood relied on microscopic examination ofsamples. Cervical lymph nodes, when present, were puncturedand the fluid was directly observed under microscope for thepresence of motile trypanosomes. Prior to microscopy, bloodsamples were subjected to capillary tube centrifugation [29] ormini-anion exchange centrifugation [30] techniques. CSF wasexamined immediately after lumbar puncture, leukocytes werecounted, and trypanosomes were searched for after single cen-trifugation. Positive laboratory results and CSF leukocyte countswere confirmed by 2 independent laboratory technicians.
Relapse cases were defined as patients with (1) history ofHAT treatment and (2) presence of trypanosomes in lymph,blood, or CSF, or CSF leukocyte count >20 cells/μL, increased
2 • CID • Alirol et al
compared with previous count or associated with clinical fea-tures consistent with HAT. All patients who did not meet thisdefinition at 6 or 12 months were considered cured.
Second-stage HAT patients were pretreated with albenda-zole, and those testing positive for malaria also received oralartesunate and amodiaquine. All patients received 3 meals perday (2100 kcal/day for adult patients). NECT (nifurtimox peroral 5 mg/kg every 8 hours for 10 days and eflornithine intra-venous 200 mg/kg every 12 hours for 7 days) was administrat-ed to all second-stage HAT patients except pregnant women(treated with pentamidine intramuscular 4 mg/kg/day for 7days with NECT administered after delivery) and patientswith signs of hepatic insufficiency (treated with eflornithineintravenous 400 mg/kg/day for 14 days). Eflornithine wasdiluted in distilled water and infused over 2 hours. Nifurtimoxintake was directly observed, administered outside meals, andreadministered if vomiting occurred within 30 minutes. Pa-tients remained hospitalized during the entire treatmentperiod. All patients were asked to return for follow-up visits 6,12, 18, and 24 months after discharge. For patients diagnosedand treated between 1 January 2010 and 31 December 2010,treatment outcomes at 6 and 12 months could be assessed.For patients diagnosed and treated between 1 January 2011and 30 June 2011, only the treatment outcome at 6 monthswas collected. NECT relapses were treated with a combinationof melarsoprol (intravenous 1.2 mg/kg/day) and nifurtimox(per oral 15 mg/kg/day) for 10 days.
Data CollectionBaseline demographic and clinical characteristics, diagnosticand treatment data, adverse events, and laboratory follow-updata were entered in the Epitryps (Epicentre, France) database.In addition, all treatment-emergent adverse events (AEs) wererecorded in pharmacovigilance forms designed by WHO. AEswere graded based on the Common Terminology Criteria forAdverse Events version 3.0. The causality between AE andNECT was assessed by the treating physician as either notrelated, unlikely to be related, possibly related, probablyrelated, definitely related, or unknown. The start date andtotal duration of each AE were recorded together with theaction taken and the outcome of the AE. Relapses were docu-mented in WHO relapse forms.
Statistical AnalysisResults are presented with medians and interquartile ranges(IQRs) for numerical variables, which were compared with theStudent t test. Mann-Whitney U test or Kruskal-Wallis testwas used for nonnormally distributed values. Categorical vari-ables were compared with χ2 test or Fisher exact test as appro-priate. Logistic regression was used for univariate andmultivariate analysis of risk factors. Only variables that
showed a significant association (P < .05) in the univariateanalysis were included in the multivariate model.
EthicsThe data were collected as part of a routine pharmacovigilanceprogram. As for most a posteriori studies, individual informedconsent was not deemed necessary in accordance with MSFEthics Committee rules [31].
RESULTS
Between 1 January 2010 and 30 June 2011, 1481 HAT patientswere diagnosed and treated by MSF in Doruma and Dingila(Figure 1). Among 690 second-stage patients, 684 receivedNECT, 5 pregnant women were treated with pentamidine, and1 patient with clinical signs of hepatic insufficiency receivedeflornithine monotherapy. The NECT group composed thestudy cohort. Patients treated with NECT had a median age of36 years (IQR, 20–50 years) and 324 (47.4%) were females.The cohort included 120 children: 21 (3.1%) <5 years of ageand 99 (14.5%) aged 5–15 years. Patients diagnosed by activescreening represented 37.1% (n = 254) of the cohort. Amongall patients treated with NECT, 23 were relapse cases. Table 1shows the demographic and clinical characteristics of thecohort.
Adverse EventsAmong 684 patients treated with NECT, most (n = 590 [86%])experienced at least 1 AE during treatment. AEs occurred in82 of 120 children (67.5%).
A total of 1878 events occurred during hospital stay, with amean of 3.2 AEs per patient (range, 1–7). On average, adultsexperienced more AEs than children (mean difference = 1.19AEs per patient; 95% confidence interval [CI], .904–1.475;P < .001). Most AEs were considered mild (grade 1) (n = 711[37.9%]) or moderate (grade 2) (n = 1027 [54.7%]) by thephysicians. Severe (grade 3) and very severe (grade 4) AEswere less frequent (n = 130 [6.9%] and n = 8 [0.4%], respec-tively). These included vomiting (n = 32), dizziness (n = 16),headache (n = 11), and convulsions (n = 11). AEs were consid-ered related (certainly, probably, or possibly) to NECT in94.3% (n = 1771) of cases by the physicians. All severe andvery severe AEs were considered related to NECT. The in-hos-pital case fatality rate was low: 0.15% (n = 1). The patient whodied during hospitalization presented with features of reactiveencephalopathy, and the physician in charge considered it tobe related to NECT.
Gastrointestinal AEs were the most frequently reported AEs(Table 2). Most AEs occurred early during treatment course.Among children treated with NECT, vomiting (49.2%), ab-dominal/stomach pain (28.3%), and anorexia (18.3%) were the
NECT for Second-Stage HAT in DRC • CID • 3
most frequent AEs. Among young (0–4 years) children(n = 21), vomiting was frequently reported (62%), but nonepresented with insomnia or anorexia, and no AE was gradedas very severe.
When compared with the 94 patients who did not experi-ence AEs, age >15 years increased the probability of having 1or more AEs by 3.7-fold (Table 3). Presenting with fever onadmission doubled the chances of AE occurrence, while beingdiagnosed by active screening decreased the chances by 1.7-fold. None of the other baseline characteristics included in themultivariate analysis affected the risk of developing AEsduring treatment.
Adherence to Treatment and Follow-upSix hundred seventy-seven of 684 patients completed theirtreatment. Reasons for discontinuation included death duringtreatment (n = 1), treatment toxicity (n = 4), or patient default
(n = 2). Six months of follow-up data were available for 336 of684 patients (49.1%), and 12 months of follow-up data wereavailable for 106 of 305 patients (34.8%). At 6 months, 9 pa-tients (2.7%) were considered to have relapsed (5 had trypano-somes in the CSF), 4 had died, and 323 (96.1%) wereconsidered cured. At 12 months, 5 patients (4.8%) were con-sidered to have relapsed (2 had trypanosomes in the CSF),and 101 (95.2%) were considered cured. The overall cure ratewas 94.6% (333/352 patients for whom a final outcome wasavailable).
DISCUSSION
NECT showed a relatively good safety profile and good effica-cy among 684 patients with second-stage T.b. gambienseHAT treated in 2 hospitals supported by MSF in northeastern
Figure 1. Flowchart of human African trypanosomiasis patients included in the study. Abbreviations: HAT, human African trypanosomiasis; NECT,nifurtimox-eflornithine combination therapy; ttt, treatment.
4 • CID • Alirol et al
DRC, a region characterized by poor health infrastructures, re-moteness, and insecurity. The in-hospital mortality rate wasvery low (0.15%), confirming previous findings [23–25]. Thisfigure corresponds to the lowest case fatality rate ever observedin HAT programs conducted by MSF, a nongovernmental or-ganization that has treated approximately 50 000 T.b. gam-biense HAT patients since 1986. Although the majority ofpatients (86%) developed at least 1 AE during treatment, mostevents were mild or moderate. Major events (grade 3 andgrade 4) were relatively uncommon (7.4%). These figures arelower than those reported by Priotto et al [25] and Checchiet al [23], who observed major events in 14% and 25%, respec-tively, of NECT-treated patients. In addition, in contrast withprevious publications, the frequency of seizures among pa-tients with major AEs remained low (15% [11 of 70 events])in our study. Vomiting, on the other hand, was the most
common major AE (45.7% [32 of 70 events]). These differenc-es could be explained by the interobserver variability ingrading AEs.
Strikingly, NECT was better tolerated in children than inadults. Adults had 4 times more chances to develop 1 or moreAEs, and on average, experienced more events than children.This may be related to the better safety profile of nifurtimoxin children [33–35], or to a better general condition of chil-dren on admission, as reflected by the better mean Karnofskyscore. Most AEs occurred early during treatment, which sug-gests that NECT-related AEs do not depend on cumulativedoses. Digestive symptoms were the most common events inboth adults and children. Abdominal pain (40.6%), vomiting(38.7%), and headache (29.9%) were most frequently observed,similar to what was reported by others [23–25]. Conversely,fever was less frequent in our cohort (1.5%; 10 of 684 patients)as were infections (2.2%; 15 of 684 patients) and diarrhea(7.2%; 49 of 684 patients). This is likely to be due to the highproportion (73%) of patients with early second-stage disease(6–20 cells/μL in the CSF) in our cohort, as this category ofpatients was not included in the largest previous report [25].The pattern of treatment-emergent AEs noted in the presentstudy is overall consistent with that of nifurtimox and eflorni-thine monotherapies, although the incidence and severity ofspecific AEs appears lower, most likely due to the shortertreatment duration [16, 36].
The overall cure rate was high (95.1%), and comparable tothe figures reported earlier [23–25]. Only 14 relapses were re-ported, of which 9 were diagnosed at the 6-month follow-upvisit, and 5 at the 12-month follow-up visit. We observed ahigher relapse rate when NECT was given for HAT relapse(7.1%) than in first-time treated patients (1.8%). The previoustreatments administered in the 23 relapse patients were pent-amidine (n = 18), eflornithine (n = 5), and unknown (n = 1).The low number of relapses treated with NECT in our cohortprevents any definite conclusion, but this issue should bestudied in larger cohorts.
With only 14 infusions over a week, NECT is much easierto administer than eflornithine monotherapy, entails a de-creased workload for medical staff, shortens the duration ofhospitalization, and significantly reduces costs. Yun et al esti-mated that the cost of treatment, excluding drug costs, isreduced from €107 to €39 per patient [37]. Theoretically,NECT may also prevent the emergence of resistance. The rela-tive ease of administration allowed a rapid roll-out of NECTin endemic countries. In 2008, half of stage 2 HAT patientswere still receiving melarsoprol as first-line treatment; in 2010this figure was reduced to 10% [38]. This shift in treatmentuse is most welcome, and should be further encouraged by thefinding that NECT is well tolerated in the field setting.
Table 1. Demographic and Clinical Characteristics of 684Patients Treated With Nifurtimox-Eflornithine Combination Therapyin Doruma and Dingila, Democratic Republic of the Congo
Patient Characteristics All Patients (N = 684)
Age, y, median (IQR) 36 (20–50)
Age >15 y 564 (82.5)
Female 324 (47.4)Diagnosed by active screening 254 (37.1)
BMI, kg/m2, median (range)a 19.6 (17.5–21.7)
Body temperature on admission, °C,median (range)
36.2 (35–38.5)
Malaria coinfection 185 (27)
Karnofsky scoreb, median (range) 90 (10–100)Symptoms on admission
Headache 462 (67.5)
Arthralgia 351 (51.3)Pruritus 318 (46.5)
Somnolence 206 (30.1)
Fever 199 (29.1)Amenorrhea/impotence 166 (24.3)
Behavioral changes 113 (16.5)
Insomnia 35 (5.1)Convulsion 5 (0.7)
Presence of trypanosomes in CSF 137 (20)
Leukocytes in CSF6–20 cells/µL 502 (73.4)
21–99 cells/µL 164 (24)
≥100 cells/µL 18 (2.6)
Data are presented as No. (%) unless otherwise specified.
Abbreviations: BMI, body mass index; CSF, cerebrospinal fluid; IQR,interquartile range.a BMI was calculated only for patients >5 years of age.b The Karnofsky performance status score is a quantification of a patient’sgeneral well-being and activities of daily living [32].
NECT for Second-Stage HAT in DRC • CID • 5
Table 2. Description of Adverse Events During Nifurtimox-Eflornithine Combination Therapy in 684 Patients With Second-Stage Human African Trypanosomiasis in Doruma andDingila Hospitals, Democratic Republic of the Congo
Adverse Event No. of Events No. (%) of PatientsNo. (%) of
Children (<15 y)
Severity Gradea, No. (% of all events)Time of Onset,Median d (IQR)
Duration of AE,Median d (IQR)1 2 3 4
Stomach/abdominal pain 309 278 (40.6%) 34 (28.3%) 110 (35.6%) 196 (63.4%) 3 (1%) 2 (1–5) 2 (1–3)
Vomiting 265 265 (38.7%) 59 (49.2%) 100 (37.7%) 133 (50.2%) 30 (11.3%) 2 (0.8%) 2 (1–4) 2 (1–3)
Headache 205 205 (29.9%) 14 (11.6%) 97 (47.3%) 97 (47.3%) 11 (5.4%) 2 (1–4) 2 (1–4)Musculoskeletal pain 204 168 (24.6%) 11 (9.1%) 71 (34.8%) 126 (61.8%) 7 (3.4%) 1.5 (0–4) 1 (1–3)
Anorexiab 144 144 (21.1%) 22 (18.3%) 72 (50%) 67 (46.5%) 4 (2.8%) 5 (3–6) 2 (1–5)
Dizziness 136 136 (19.9%) 3 (2.5%) 50 (36.7%) 70 (51.4%) 16 (11.7%) 5 (2.25–7) 2 (1–4)Insomnia 82 82 (11.9%) 1 (0.1%) 39 (47.6%) 40 (48.8%) 3 (3.7%) 5 (3–7) 2 (1–3)
Fatigue 76 76 (11.1%) 4 (3.3%) 17 (22.4%) 51 (67.1%) 8 (10.5%) 5 (3–8) 2 (1–3)
Mood/behavior change 61 56 (8.2%) 2 (1.7%) 18 (29.5%) 33 (54.1%) 9 (14.8%) 1 (1.6%) 6 (4–7) 2 (1–1.75)Nausea 52 52 (7.6%) 1 (0.1%) 29 (55.8%) 21 (40.4%) 2 (3.9%) 2 (1–4) 2 (1–3)
Diarrhea 50 49 (7.2%) 6 (5%) 13 (26%) 30 (60%) 7 (14%) 5 (2–7) 2 (1–3)
Tremor 46 46 (6.7%) 0 (0%) 19 (41.3%) 25 (54.3%) 2 (4.3%) 6 (4–8) 2 (1–3)Pruritus 30 30 (4.4%) 2 (1.7%) 11 (36.7%) 16 (53.3%) 3 (1%) 4.5 (2.75–6.25) 2 (2–4)
Convulsion 28 28 (4.1%) 2 (1.7%) 6 (21.4%) 11 (39.3%) 10 (35.7%) 1 (3.6%) 5 (2.25–6) 1 (1–2)
Psychosis 20 20 (2.9%) 0 (0%) 3 (15%) 11 (55%) 4 (20%) 2 (10%) 6 (4–7) 2.5 (1–6.25)
Abbreviations: AE, adverse event; IQR, interquartile range..a Severity was graded from 1 (mild) to 5 (fatal) according to the Common Terminology Criteria for Adverse Events version 3.0.b Missing value = 1.
6•
CID
•Alirolet
al
However, NECT cannot yet be considered as an ideal treat-ment. The requirement for 7 days of intravenous administrationstill represents a definite obstacle for use in the primary
healthcare setting. Despite the overall good tolerance, someAEs are troublesome. Vomiting is frequent and may cause in-sufficient bioavailability of nifurtimox, requiring frequent use
Table 3. Risk Factors for Developing 1 or More Adverse Events Among 684 Second-Stage Human African Trypanosomiasis PatientsTreated With Nifurtimox-Eflornithine Combination Therapy in Doruma and Dingila Hospitals, Democratic Republic of the Congo
Patient Characteristic on Admission Univariate OR (95% CI) P Value Multivariate OR (95% CI) P Value
Age >15 y
No 1Yes 3.965 (2.467–6.372) <.001 3.681 (2.146–6.315) <.001
Sex
Male 1Female 1.459 (.936–2.275) .095 …
Detected by active screening
No 1Yes 0.420 (.271–.653) <.001 0.579 (.358–.937) .026
Malaria coinfection
No 1Yes 1.352 (.842–2.169) .212 …
Symptoms on admission
Amenorrhea/impotenceNo 1
Yes 1.102 (.652–1.862) .716 …
ArthralgiaNo 1
Yes 1.741 (1.115–2.719) .015 0.895 (.533–1.505) .677
FeverNo 1
Yes 2.610 (1.44–4.729) .002 2.191 (1.164–4.123) .015
HeadacheNo 1
Yes 1.562 (.997–2.448) .052 …
InsomniaNo 1
Yes 2.645 (.624–11.218) .187 …
PruritusNo 1
Yes 1.884 (1.158–3.067) .011 1.462 (.858–2.492) .163
Psychiatric symptomsNo 1
Yes 1.767 (.886–3.523) .106 …
SomnolenceNo 1
Yes 1.392 (.842–2.301) .197 …
Trypanosomes in CSFNo 1
Yes 2.506 (1.224–5.130) .012 1.939 (.922–4.078) .081
Leukocytes in CSF≤20 × 109 cells/L 1
21–99 × 109 cells/L 2.335 (.808–6.749) .117 …
≥100 × 109 cells/L 3.120 (.996–9.771) .051 …
Abbreviations: CI, confidence interval; CSF, cerebrospinal fluid; OR, odds ratio.
NECT for Second-Stage HAT in DRC • CID • 7
of antiemetics and occasional readministration of nifurtimox.Psychotic behavior and convulsions are less frequent but are asource of distress for patients and relatives, and can be asource of rumors within local populations. In addition,NECT is unlikely to be effective against second-stage T.b.rhodesiense HAT, with melarsoprol left as the only drugoption. To overcome NECT shortcomings, the developmentof an oral drug such as fexinidazole holds great promise[39]. In the meantime, NECT provides a safe and effectivetreatment option.
This study bears some limitations. First, heterogeneity inthe reporting of AEs occurred. The number and nature ofthe AEs captured in the pharmacovigilance forms variedbetween the 3 reporting clinicians during the study period.In addition, as laboratory investigations were limited, diag-nosis relied mainly on clinical assessment, impeding conclu-sive diagnosis of AEs and cause of death. In particular,hematological abnormalities such as neutropenia, which is acommon side effect of eflornithine, could not be assessed.Also, causality assessment of AEs is highly observer-dependent, and the absence of a comparative control groupin our study makes it difficult to ascertain the relationshipbetween the AEs observed and NECT. Hospitalized patientswith second-stage HAT usually have numerous AEs, regard-less of the regimen used. In most cases, it cannot be conclu-sively established if the AEs are due to the treatment, to thedisease itself, or to concurrent illnesses. The high proportionof patients with early second-stage disease may also limit theexternal validity of our findings. Finally, the efficacy ofNECT is likely to be overestimated as 6 and 12 months offollow-up data were available only for a fraction of patients,and none were followed up until 24 months. A substantialproportion of relapses can indeed occur after 12 months fol-lowing treatment [25].
Nevertheless, this study provides crucial information andcomplements the existing safety data generated by the onlyrandomized controlled trial conducted so far [25]. Of note,our cohort included 120 children <15 years of age, in whomNECT was particularly well tolerated, as well as 23 relapsecases. The population assessed during clinical trials is subject-ed to specific inclusion and exclusion criteria, and patientswith comorbidities, pregnant women, children, and the elderlyare systematically excluded. It is therefore particularly impor-tant to continue assessing the safety of new treatments aftertheir large-scale introduction in the general population. Phar-macovigilance programs such as that deployed by WHO areparticularly important. As MSF is one of the main treatmentproviders for several neglected tropical diseases, its participa-tion in pharmacovigilance activities provides crucial comple-mentary safety data on newly developed therapies such asNECT. Such involvement makes particular sense, as MSF
initiated and participated in the development of NECT andother new therapies.
Note
Potential conflicts of interest. All authors: No reported conflicts.All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to thecontent of the manuscript have been disclosed.
References
1. Brun R, Blum J, Chappuis F, Burri C. Human African trypanosomia-sis. Lancet 2010; 375:148–59.
2. Fevre EM, Wissmann BV, Welburn SC, Lutumba P. The burden ofhuman African trypanosomiasis. PLoS Negl Trop Dis 2008; 2:e333.
3. Human African trypanosomiasis (sleeping sickness): epidemiologicalupdate. Wkly Epidemiol Rec 2006; 81:71–80.
4. Chappuis F, Lima MA, Flevaud L, Ritmeijer K. Human African try-panosomiasis in areas without surveillance. Emerg Infect Dis 2010;16:354–6.
5. Tong J, Valverde O, Mahoudeau C, Yun O, Chappuis F. Challenges ofcontrolling sleeping sickness in areas of violent conflict: experience inthe Democratic Republic of Congo. Confl Health 2011; 5:7.
6. Barrett MP, Burchmore RJ, Stich A, et al. The trypanosomiases.Lancet 2003; 362:1469–80.
7. Blum J, Schmid C, Burri C. Clinical aspects of 2541 patients with secondstage human African trypanosomiasis. Acta Trop 2006; 97:55–64.
8. Barrett MP, Boykin DW, Brun R, Tidwell RR. Human African try-panosomiasis: pharmacological re-engagement with a neglecteddisease. Br J Pharmacol 2007; 152:1155–71.
9. Friedheim EA. Mel B in the treatment of human trypanosomiasis. AmJ Trop Med Hyg 1949; 29:173–80.
10. Blum J, Nkunku S, Burri C. Clinical description of encephalopathicsyndromes and risk factors for their occurrence and outcome duringmelarsoprol treatment of human African trypanosomiasis. Trop MedInt Health 2001; 6:390–400.
11. Pepin J, Milord F, Khonde AN, et al. Risk factors for encephalopathyand mortality during melarsoprol treatment of Trypanosoma bruceigambiense sleeping sickness. Trans R Soc Trop Med Hyg 1995;89:92–7.
12. Burri C, Keiser J. Pharmacokinetic investigations in patients fromnorthern Angola refractory to melarsoprol treatment. Trop Med IntHealth 2001; 6:412–20.
13. Legros D, Evans S, Maiso F, Enyaru JC, Mbulamberi D. Risk factorsfor treatment failure after melarsoprol for Trypanosoma brucei gam-biense trypanosomiasis in Uganda. Trans R Soc Trop Med Hyg 1999;93:439–42.
14. Robays J, Nyamowala G, Sese C, et al. High failure rates of melarso-prol for sleeping sickness, Democratic Republic of Congo. EmergInfect Dis 2008; 14:966–7.
15. Schechter PJ, Sjoerdsma A. Difiuoromethylornithine in the treatmentof African trypanosomiasis. Parasitol Today 1986; 2:223–4.
16. Priotto G, Pinoges L, Fursa IB, et al. Safety and effectiveness of firstline eflornithine for Trypanosoma brucei gambiense sleeping sicknessin Sudan: cohort study. BMJ 2008; 336:705–8.
17. Chappuis F, Udayraj N, Stietenroth K, Meussen A, Bovier PA. Eflorni-thine is safer than melarsoprol for the treatment of second-stage Try-panosoma brucei gambiense human African trypanosomiasis. ClinInfect Dis 2005; 41:748–51.
18. Balasegaram M, Harris S, Checchi F, et al. Melarsoprol versus eflorni-thine for treating late-stage Gambian trypanosomiasis in the Republicof the Congo. Bull World Health Organ 2006; 84:783–91.
19. Balasegaram M, Young H, Chappuis F, et al. Effectiveness of melarso-prol and eflornithine as first-line regimens for gambiense sleeping
8 • CID • Alirol et al
sickness in nine Medecins Sans Frontieres programmes. Trans R SocTrop Med Hyg 2009; 103:280–90.
20. Janssens PG, De Muynck A. Clinical trials with “nifurtimox” inAfrican trypanosomiasis. Ann Soc Belg Med Trop 1977; 57:475–80.
21. Moens F, De Wilde M, Ngato K. Clinical trial of nifurtimox inhuman African trypanosomiasis. Ann Soc Belg Med Trop 1984; 64:37–43.
22. Pepin J, Milord F, Mpia B, et al. An open clinical trial of nifurtimoxfor arseno-resistant Trypanosoma brucei gambiense sleeping sicknessin central Zaire. Trans R Soc Trop Med Hyg 1989; 83:514–7.
23. Checchi F, Piola P, Ayikoru H, et al. Nifurtimox plus eflornithine forlate-stage sleeping sickness in Uganda: a case series. PLoS Negl TropDis 2007; 1:e64.
24. Priotto G, Fogg C, Balasegaram M, et al. Three drug combinations forlate-stage Trypanosoma brucei gambiense sleeping sickness: a random-ized clinical trial in Uganda. PLoS Clin Trials 2006; 1:e39.
25. Priotto G, Kasparian S, Mutombo W, et al. Nifurtimox-eflornithinecombination therapy for second-stage African Trypanosoma bruceigambiense trypanosomiasis: a multicentre, randomised, phase III,non-inferiority trial. Lancet 2009; 374:56–64.
26. World Health Organization. WHO includes combination of eflorni-thine and nifurtimox in its Essential List of Medicines for the treat-ment of human African trypanosomiasis, 2009. Available at: http://www.who.int/neglected_diseases/disease_management/drug_combination/en/.Accessed 31 August 2012.
27. Valverde Mordt O, Schmid C, Kande C, et al. A multicenter, openlabel, phase III study of therapeutic use of the co-administration ofnifurtimox and eflornithine (NECT) for human African trypanosomi-asis (NECT FIELD): safety profile in children during initial hospi-talization. 7th European Congress on Tropical Medicine andInternational Health, Barcelona, Spain, 3–6 October 2011.
28. Magnus E, Vervoort T, Van Meirvenne N. A card-agglutination testwith stained trypanosomes (C.A.T.T.) for the serological diagnosis ofT. B. gambiense trypanosomiasis. Ann Soc Belg Med Trop 1978;58:169–76.
29. Woo PT. The haematocrit centrifuge technique for the diagnosis ofAfrican trypanosomiasis. Acta Trop 1970; 27:384–6.
30. Lumsden WH, Kimber CD, Evans DA, Doig SJ. Trypanosoma brucei:miniature anion-exchange centrifugation technique for detection oflow parasitaemias: adaptation for field use. Trans R Soc Trop MedHyg 1979; 73:312–7.
31. Schopper D, Upshur R, Matthys F, et al. Research ethics review inhumanitarian contexts: the experience of the independent ethicsreview board of Medecins Sans Frontieres. PLoS Med 2009; 6:e1000115.
32. Karnofsky D, Burchenal J. The clinical evaluation of chemotherapeuticagents in cancer. In: MacLeod CM, ed. Evaluation of chemotherapeu-tic agents. New York: Columbia University Press, 1949:196.
33. Altcheh J, Biancardi M, Lapena A, Ballering G, Freilij H. CongenitalChagas disease: experience in the Hospital de Ninos, Ricardo Gutier-rez, Buenos Aires, Argentina. Rev Soc Bras Med Trop 2005; 38(suppl2):41–5.
34. Castro JA, de Mecca MM, Bartel LC. Toxic side effects of drugs usedto treat Chagas’ disease (American trypanosomiasis). Hum ExpToxicol 2006; 25:471–9.
35. Saulnier Sholler GL, Bergendahl GM, Brard L, et al. A phase 1 studyof nifurtimox in patients with relapsed/refractory neuroblastoma. JPediatr Hematol Oncol 2011; 33:25–30.
36. Jackson Y, Alirol E, Getaz L, et al. Tolerance and safety of nifurtimoxin patients with chronic Chagas disease. Clin Infect Dis 2010; 51:e69–75.
37. Yun O, Priotto G, Tong J, Flevaud L, Chappuis F. NECT is next: im-plementing the new drug combination therapy for Trypanosomabrucei gambiense sleeping sickness. PLoS Negl Trop Dis 2010; 4:e720.
38. Simarro PP, Franco J, Diarra A, Postigo JA, Jannin J. Update on fielduse of the available drugs for the chemotherapy of human Africantrypanosomiasis. Parasitology 2012; 139:842–6.
39. Kaiser M, Bray MA, Cal M, et al. Antitrypanosomal activity of fexini-dazole, a new oral nitroimidazole drug candidate for treatment ofsleeping sickness. Antimicrob Agents Chemother 2011; 55:5602–8.
NECT for Second-Stage HAT in DRC • CID • 9
In-Hospital Safety in Field Conditions of NifurtimoxEflornithine Combination Therapy (NECT) for T. b.gambiense Sleeping SicknessCaecilia Schmid1,2, Andrea Kuemmerle1,2¤, Johannes Blum1,2, Salah Ghabri3, Victor Kande4,
Wilfried Mutombo4, Medard Ilunga4, Ismael Lumpungu4, Sylvain Mutanda4, Pathou Nganzobo4,
Digas Tete4, Nono Mubwa4, Mays Kisala5, Severine Blesson6, Olaf Valverde Mordt6*
1 Department of Medicines Research, Swiss Tropical and Public Health Institute, Basel, Switzerland, 2 University of Basel, Basel, Switzerland, 3 Consultant, Paris, France,
4 Programme National de Lutte contre la Trypanosomiase Humaine Africaine (PNLTHA), Kinshasa, Democratic Republic of the Congo, 5 Bureau Diocesain d’Oeuvres
Medicales (BDOM), Kikwit, Democratic Republic of the Congo, 6 DNDi, Geneva, Switzerland
Abstract
Background: Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease.Until 2009, available treatments for 2nd stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic,and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT)demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World HealthOrganisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support itswider use.
Methodology: In a multicentre, open label, single arm, phase IIIb study of the use of NECT for 2nd stage T.b. gambiense HAT,all patients admitted to the trial centres who fulfilled inclusion criteria were treated with NECT. The primary outcome wasthe proportion of patients discharged alive from hospital. Safety was further assessed based on treatment emergent adverseevents (AEs) occurring during hospitalisation.
Principal Findings: 629 patients were treated in six HAT treatment facilities in the Democratic Republic of the Congo (DRC),including 100 children under 12, 14 pregnant and 33 breastfeeding women. The proportion of patients discharged aliveafter treatment completion was 98.4% (619/629; 95%CI [97.1%; 99.1%]). Of the 10 patients who died during hospitalisation,8 presented in a bad or very bad health condition at baseline; one death was assessed as unlikely related to treatment. Nomajor or unexpected safety concerns arose in any patient group. Most common AEs were gastro-intestinal (61%), general(46%), nervous system (mostly central; 34%) and metabolic disorders (26%). The overall safety profile was similar topreviously published findings.
Conclusions/Significance: In field conditions and in a wider population, including children, NECT displayed a similartolerability profile to that described in more stringent clinical trial conditions. The in-hospital safety was comparable topublished results, and long term efficacy will be confirmed after 24 months follow-up.
Registration: The trial is registered at ClinicalTrials.gov, number NCT00906880.
Citation: Schmid C, Kuemmerle A, Blum J, Ghabri S, Kande V, et al. (2012) In-Hospital Safety in Field Conditions of Nifurtimox Eflornithine Combination Therapy(NECT) for T. b. gambiense Sleeping Sickness. PLoS Negl Trop Dis 6(11): e1920. doi:10.1371/journal.pntd.0001920
Editor: Joseph Mathu Ndung’u, Foundation for Innovative New Diagnostics (FIND), Switzerland
Received May 3, 2012; Accepted October 11, 2012; Published November , 2012
Copyright: � 2012 Schmid et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was funded by the Drugs for Neglected Diseases initiative (DNDi, Geneva, Switzerland), which was involved in the conception of the study,the interpretation of results and in the preparation of this manuscript. DNDi would like to acknowledge the following donors for their support of DNDi’s NECT-related activities: the Department for International Development (DFID, UK); the Ministry of Foreign and European Affairs (MAEE, France); Republic and Canton ofGeneva, Department International Solidarity (Switzerland); Spanish Agency for International Development Cooperation (AECID, Spain); Swiss Agency forDevelopment and Cooperation (SDC, Switzerland); Medecins Sans Frontieres (Doctors Without Borders) International; the Medicor Foundation (Liechtenstein); andothers who would like to remain anonymous. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of themanuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: [email protected]
¤ Current address: CRP-SANTE, Centre for Health Studies, Public Research Centre for Health, Strassen, Luxembourg
Introduction
Human African trypanosomiasis (HAT) is one of the most
neglected tropical diseases (NTDs), suffering from a lack of optimal
control tools and insufficient research efforts. It affects people in
sub-Saharan Africa who often live in remote and/or insecureareas, with limited access to health care [1]. Owing to past andongoing surveillance and control efforts of the National Controlprogrammes from the affected countries supported mainly byWHO (World Health Organisation), BTC (Belgian Development
PLOS Neglected Tropical Diseases | www.plosntds.org 1 November 2012 | Volume 6 | Issue 11 | e1920
29
Agency) and MSF (Medecins Sans Frontieres), less than 10’000
HAT patients are currently reported each year [2]. However,
funding to keep up an adequate level of control activities is
nowadays increasingly difficult to obtain. Moreover, in almost all
cases, HAT is fatal if untreated. T.b. gambiense accounts for 95% of
currently reported HAT cases. The disease progresses from 1st
stage (infecting blood and lymph) to 2nd stage (affecting the central
nervous system), which ultimately leads to severe sleep distur-
bances, other neurological and psychiatric disorders, coma and
eventually death.
Until 2009, treatment for the 2nd stage of T.b. gambiense HAT
was limited to melarsoprol, an arsenic derivative, or eflornithine.
Treatment with melarsoprol is associated with high toxicity, is
sometimes fatal (mean 9.4% (range 2.7–34%) [3]), and displays
high rates of failure in several geographic areas [4,5,6,7,8,9].
Although safer and more effective [4], eflornithine monotherapy
comes with burdensome treatment administration requiring 56
slow infusions administered every 6 hours over 2 weeks that are
difficult to implement outside well-staffed hospital settings.
A new treatment alternative, nifurtimox-eflornithine combina-
tion therapy (NECT), was added to the World Health Organisa-
tion’s Essential Medicines List (WHO EML) in 2009 for the
treatment of 2nd stage T.b. gambiense HAT [10], based on its
efficacy and safety profile observed in a randomised controlled
trial conducted in a well-defined study population [11]. NECT is
easier to administer and requires fewer hospital resources than
eflornithine monotherapy, with only 14 slow infusions adminis-
tered every 12 hours for 1 week, with a concurrent 10 days oral
treatment with nifurtimox. The needed quantity of eflornithine for
NECT (and consequently the drug production and transportation
cost) is 2 times lower than for the eflornithine monotherapy
regimen. NECT now stands as the preferred first-line treatment
for 2nd stage T.b. gambiense HAT. However, it is not yet the ideal
HAT treatment and to enable its wider use in remote rural
settings, financial and logistical barriers must be overcome, health
care staff must be well trained, and, importantly, the safety profile
under such conditions needs to be better known.
This study aimed to further document the clinical tolerability,
feasibility and effectiveness of treatment with NECT in field
conditions, i.e. with less stringent inclusion/exclusion criteria and
in a larger population including children, pregnant and breast-
feeding women and patients with a HAT treatment history.
Methods
ObjectivesThe primary objective was to assess the clinical response of
NECT for the treatment of 2nd stage T.b. gambiense HAT in field
conditions. Secondary objectives included assessing the incidence
and type of adverse events (AE), the feasibility of NECT
implementation by the health facilities and the effectiveness of
NECT at 24 months after treatment. Patient follow-up is still
ongoing at the time of publication, therefore the current analysis
deals with in-hospitalisation safety only.
OutcomesThe primary outcome was the proportion of patients discharged
alive from the hospital (treatment facility). This was directly
assessed by the site Investigators after treatment at the time of
discharge. Secondary outcomes were frequency, nature, severity
and relatedness of adverse events and adherence to treatment
(interruptions, cessations, dose deviations, length of hospitalisa-
tion).
Study design, settings and participantsThis was a multicentre, open label, single arm, phase IIIb study
of the therapeutic use of NECT for treatment of 2nd stage T.b.
gambiense HAT in the Democratic Republic of the Congo (DRC).
The study took place in two of the most endemic provinces,
Bandundu and Kasai Oriental, at five HAT treatment facilities
operated by the national HAT control program (Programme
National de Lutte contre la Trypanosomiase Humaine Africaine,
PNLTHA): Bandundu, Dipumba, Katanda, Kwamouth and
Ngandajika and one treatment facility operated by the BDOM/
KIKWIT (Bureau Diocesain d’Oeuvres Medicales) and supervised
by the PNLTHA: General Hospital of Yasa Bonga.
All second stage HAT patients admitted to the treatment
facilities and routinely diagnosed according to the national
guidelines and who gave their Informed Consent for participation,
were included in the trial. At inclusion, special attention was given
to children and pregnant and breastfeeding women. It was under
the Investigator’s decision to include these sub-populations.
Exclusion criteria were inability to take oral medication and
impossibility to use a nasogastric tube, treatment failure after
previous NECT treatment or any other condition for which the
Investigator judged that another treatment was warranted. The
patients were hospitalised and treated with NECT and monitored
for adverse events. During the trial, an independent Data Safety
Monitoring Board (DSMB) reviewed the data for patient safety.
No interim analyses were done.
InterventionPrior to NECT initiation, the patients received standard pre-
treatment (according to the facilities’ guidelines, usually antima-
larial, anthelminthic and antipyretic/analgesic medication). All
patients received NECT [11], the co-administration of nifurtimox
(oral 15 mg/kg/day, three times a day) for 10 days and
eflornithine (slow intravenous infusions, 400 mg/kg/day, twice a
day) for 7 days.
All patients, including the children and offspring of pregnant or
breastfeeding women, were monitored during treatment and
Author Summary
Sleeping sickness is a neglected tropical disease affectingpeople in Sub-Saharan Africa, most of them in poor, ruralsettings. If not treated, the disease usually progresses intoa serious stage affecting the central nervous system,causing severe sleep disturbances, as well as otherneurological and psychiatric disorders, coma, and death.Until recently, the only ways to treat 2nd stage gambiensesleeping sickness involved drugs that were either toxic(such as the arsenic derivative melarsoprol) or difficult toadminister in resource-constrained settings (e.g. eflor-nithine). A new treatment, nifurtimox-eflornithine combi-nation therapy (NECT), was developed and tested inclinical trials, and is now recommended as the treatmentof choice for 2nd stage sleeping sickness. NECT is easier toadminister than eflornithine, but more information needsto be gathered for its use in the field: logistical barriersmust be overcome, health care staff must be well trained,and, importantly, the safety profile of the treatment in real-life conditions needs to be better evaluated. We reporthere the results of a study designed to gain betterunderstanding of the clinical tolerability, feasibility andeffectiveness of NECT in field conditions, and to gatherdata on its use in specific populations, such as children andpregnant women.
NECT for HAT Implemented in Field Conditions
PLOS Neglected Tropical Diseases | www.plosntds.org 2 November 2012 | Volume 6 | Issue 11 | e1920
followed-up for safety issues. Patients underwent daily evaluations,
including vital signs, physical examination, adverse event moni-
toring, and recording of concomitant medications throughout the
admission and treatment period, as well as at the end of treatment,
just before patients were discharged from hospital.
The severity of the treatment emergent adverse events was
graded by the Investigator, according to the Common Toxicity
Criteria for adverse events (CTCAE, v03 [12] from grades 1 to 5
as mild, moderate, severe, life-threatening and death) and related
to the treatment according to the Investigator’s analysis. Treat-
ment emergent adverse events were evaluated as being probably,
possibly or not related to the study drugs.
Follow-up assessment visits were scheduled 6, 12, 18 and 24
months after the end of the treatment. Twenty-four months after
end of treatment, patients will be assessed for the final effectiveness
of treatment; these results will be reported later.
Sample sizeAccording to available literature [4,11,13,14], the proportion of
patients discharged alive from hospital (P1) was expected to be
equal or superior to 98%. The proportion of patients discharged
alive from hospital (under the null hypothesis) was assumed to be
equal to P0 = 96%, which corresponds to the average of
proportions obtained in previous studies on eflornithine.
The sample size was calculated according to a confidence
interval approach with a precision of 2%. According to Fleiss’
method [15], a sample size of 620 achieved 80% power to detect a
difference (P1-P0) of 2% using a two-sided binomial test. The target
significance level was 5%. Sample size was performed using PASS
2008 [16].
Statistical analysisThe main analysis set was the safety population, which included
all subjects who received at least one dose of study drug. For this
trial design, safety and ITT (intention to treat) populations are the
same. As the percentage of patients who had protocol deviations
was very small (0.7%), the per-protocol population was not
analysed.
All statistical evaluations were descriptive, as the aim of the
study was to further document NECT implemented in field
conditions and the trial was open-label and uncontrolled. Means,
standard deviations and number of patients were provided for
continuous variables, as well as frequency distributions for binary
and categorical variables. An exact Wilson 95% confidence
interval was calculated for the primary outcome. Statistical
analyses were performed using the SAS software version 9.1
(SAS Institute, Cary, NC).
All data were captured at the participating treatment facility on
patient case report forms (CRFs). Data were double-entered and
discrepancies reviewed and corrected against the hard copy CRF.
Adverse events were coded with the MedDRA dictionary
(version 11.0 [17]) and concomitant treatments with the WHO-
Drug dictionary [18].
EthicsThis research was conducted in full accordance with the ethical
principles for medical research involving human subjects, as
expressed in the Declaration of Helsinki and following amend-
ments. Eligible patients were asked to meet the study Investigator
or his delegate, who explained the study protocol in detail
according to the patient information sheet, and requested written
consent from the patient or, in case of minors, severely ill or
mentally impaired patients unable to fully consent, from her/his
parent(s)/guardian(s). Whenever possible (depending on age and
level of understanding), the children received the information and
their assent was obtained. Two Ethics Committees approved the
study protocol: the Ethics Committee of both cantons of Basel
(EKBB, Basel, Switzerland; 26 February, 2009) and the local
Ethics Committee in the DRC (Comite d’Ethique sur la
Trypanosomiase Humaine Africaine, Kinshasa, Democratic Re-
public of the Congo, 7 May 2009). All interventions (including
follow-up visits) were free of charge to the patients.
Results
The total enrolment period lasted 13 months and took place
between May 2009 and May 2010 in six HAT treatment facilities
of the DRC. One facility (Yasa Bonga) recruited patients only
between November 2009 and May 2010. Here, we report the in-
hospitalisation safety of 629 2nd stage HAT patients treated with
NECT.
Study population - participant flowPatients who reported passively or were sent by the mobile
teams to the HAT treatment facilities were screened and
diagnosed for HAT. 726 patients were diagnosed as HAT cases,
of them, 680 were classified in stage 2 and potentially eligible for
participation, 49 were excluded by the Investigators or failed to
show up for treatment, 1 refused and 630 gave their informed
consent. One patient died prior to receiving any medication and
was not included in the analysis. In total, 629 patients were treated
with NECT at the HAT treatment facilities. Reasons for non-
inclusion and the patient flow are detailed in Figure 1.
BaselineThe demographic, diagnostic and clinical characteristics varied
between the treatment facilities (Table 1). About 16% of the
patients were children below 12 years of age. Katanda had the
highest (22%) rate of children admitted and Bandundu (9%) the
lowest. The overall ratio of males to females was 1.3 (range 0.9 to
2.0). Amongst the patients, there were 33 (5%) breastfeeding
women, 14 (2%) pregnant women and 135 (22%) patients with
HAT treatment history (range 3% to 39%). Of patients with a
HAT history, two thirds were considered true relapses (84/135)
who were treated for HAT within 2 years prior admission to the
current treatment (Table 1). There were 188 (30%) malnourished
patients (172 (33%) adults and 16 (16%) children aged below 12
years,; based on age specific underweight classification of
anthropometric data according to WHO [19,20]). However, the
extent of malnutrition amongst the study population varied
between the facilities, with Dipumba reporting the lowest (15%)
and Bandundu and Yasa Bonga the highest proportion (40%) of
undernourished patients admitted.
All patients were diagnosed as stage 2 HAT patients with .5
leucocytes per ml CSF (cerebro-spinal fluid), of those, 89% (558/
629) were parasitologically confirmed and 11% (71/629) based on
their raised WBC (white blood cell) levels in CSF and clinical signs.
The latter presented either positive serology (7%, 44/629) or had
already a HAT history (4%, 27/629, data not shown). The clinical
and diagnostic findings differed slightly between sites.
Common disease symptoms by frequency of occurrence were
sleeping disorders (nocturnal insomnia and/or diurnal somno-
lence), headache, asthenia, fever, pruritus and weight loss, each
affecting more than half of all patients (Table 1).
Treatment and adherence to treatmentAll patients were hospitalised for the entire treatment period.
Ninety-nine percent (621/629) and 94% (590/629) of the patients
NECT for HAT Implemented in Field Conditions
PLOS Neglected Tropical Diseases | www.plosntds.org 3 November 2012 | Volume 6 | Issue 11 | e1920
received the complete eflornithine and nifurtimox doses, respec-
tively (as per protocol 14 intravenous doses of eflornithine and 30
oral doses of nifurtimox). Minor divergences occurred in the
timing of drug administration or by administration of additional
doses of nifurtimox (at the end of treatment) and/or in case of
vomiting within the first 30 minutes after the intake. Major
treatment deviations were due to overdosing of more than 10% of
correct treatment (calculated based on body weight; 3 patients) or
to withdrawal by family (1 patient) or to treatment cessation after 1
dose due to intolerance (1 patient). The adherence to treatment
varied slightly between the facilities and also amongst the patient
groups - lowest adherence was in the pregnant women group
(nifurtimox 79% & eflornithine 93%) and in small children below
5 years of age (nifurtimox 89% & eflornithine 86%; Table 2).
Concomitant medication during NECT therapy was common:
93% (585/629) of patients received in median 4 additional
different drugs (range 1–14). All pregnant women (14/14) and
86% (30/35) of children below 5 years of age received
concomitant treatment.
The median length of hospitalisation was 16 days, and
measured from the day of admission to the day of discharge,
including days when pre-medication was given (Table 2). The
length of the hospitalisation stay was similar for all patient groups,
but varied between the facilities (12 days in Bandundu, 15 days in
Dipumba, 16 days in Katanda, Ngandajika & Kwamouth, and 20
days in Yasa Bonga) mainly due to differing routine practices at
the facilities (reduced pre-treatment days in Bandundu or
prolonged observation days in Yasa Bonga).
Figure 1. Flow diagram of the multicentre NECT trial for treatment of 2nd stage HAT. The diagram includes detailed information onexcluded patients.doi:10.1371/journal.pntd.0001920.g001
NECT for HAT Implemented in Field Conditions
PLOS Neglected Tropical Diseases | www.plosntds.org 4 November 2012 | Volume 6 | Issue 11 | e1920
In-hospitalisation safety98.4% (619/629) of patients were discharged alive
(95%CI = [97.1%; 99.1%], Table 2). All children younger than 12
years of age were discharged alive (100/100), as were breastfeeding
women (33/33). Due to a death of one pregnant woman, the survival
in that group was low, at 92.9% (13/14). The proportions of patients
discharged alive were similar for all other adults (97.3%–98.8%),
including for patients with history of previous HAT.
At the time of discharge from the treatment facility, clinical
characteristics had substantially improved (Karnofsky index, the
classification of patients performance as to their functional
impairment raised from mean 70% to 86%; neurological signs
decreased from 89% to 37%, bad general health state had reduced
from 80% to 14% and lymphadenopathy from 54% to 22%; the
patients who died during the treatment were excluded from this
analysis; data not shown).
Table 1. Baseline demographic, diagnostic and clinical characteristics of the patients, by centre.
Demographic characteristics All patients KASAI ORIENTAL province BANDUNDU province
Dipumba Katanda Ngandajika Bandundu Kwamouth Yasa Bonga
n (%) if not otherwise noted
Number of Patients treated 629 146 132 94 98 97 62
Children 0–4 years 35 (6%) 7 (5%) 7 (5%) 5 (5%) 5 (5%) 5 (5%) 6 (10%)
Children 5–11 years 65 (10%) 15 (10%) 22 (17%) 9 (10%) 4 (4%) 8 (8%) 7 (11%)
Adolescents/Adults .11 years 529 (84%) 124 (85%) 102 (77%) 80 (85%) 89 (91%) 84 (87%) 50 (81%)
Male/female ratio 1.3 1.8 1.2 2.0 0.9 0.9 1.1
Breastfeeding women 33 (5%) 9 (6%) 2 (2%) 2 (2%) 7 (7%) 9 (9%) 4 (6%)
Pregnant women 14 (2%) 1 (1%) 4 (3%) 1 (1%) 3 (3%) 2 (2%) 3 (5%)
Age, years, mean (SD)* 30 (16) 32 (16) 26 (15) 27 (14) 35 (18) 29 (16) 27 (18)
Weight, kg, mean (SD) 45 (16) 50 (17) 44 (17) 47 (18) 45 (14) 44 (14) 38 (16)
Malnutrition by age category
0–4 years: Weight for height .22SD 2 (0%) 0 (0%) 0 (0%) 1 (1%) 0 (0%) 0 (0%) 1 (1%)
5–14 years: Body-mass Index for age .22SD 14 (2%) 3 (2%) 4 (3%) 2 (2%) 1 (1%) 2 (2%) 2 (3%)
.14 years: Body-mass index ,18.5 kg/m2 172 (27%) 22 (15%) 19 (14%) 29 (31%) 39 (40%) 38 (39%) 25 (40%)
Previous HAT 135 (21%) 27 (18%) 51 (39%) 24 (26%) 12 (12%) 19 (20%) 2 (3%)
within 2 years of admission 84 (13%) 18 (12%) 27 (21%) 20 (21%) 8 (8%) 9 (9%) 2 (3%)
Parasitological findings
Presence of trypanosomes 558 (89%) 132 (90%) 128 (97%) 80 (85%) 85 (87%) 75 (77%) 58 (94%)
in lymph nodes 218 (35%) 53 (37%) 32 (24%) 44 (47%) 23 (23%) 40 (41%) 26 (42%)
in blood 162 (26%) 25 (17%) 32 (24%) 7 (8%) 44 (45%) 18 (19%) 36 (58%)
in CSF{ 341 (54%) 99 (68%) 86 (65%) 39 (42%) 49 (50%) 41 (42%) 27 (43%)
Leucocyte count in CSF, cells per ml, median 153 207 208 183 89 114 49
lower (25%) and upper (75%) quartiles 49; 345 96; 380 98; 442 85; 442 23; 250 25; 382 11; 172
.100 cells per ml 397 (63%) 108 (74%) 98 (74%) 66 (70%) 48 (49%) 53 (54%) 24 (39%)
Clinical characteristics
Karnofski index1, mean (SD) 70 (12) 65 (15) 67 (9) 68 (10) 74 (10) 70 (8) 80 (13)
Altered or bad general health state 502 (80%) 106 (73%) 108 (82%) 88 (94%) 69 (70%) 96 (99%) 35 (56%)
Lymphadenopathy 340 (54%) 73 (50%) 61 (46%) 62 (66%) 46 (47%) 69 (71%) 30 (48%)
Facial oedema 63 (10%) 11 (8%) 21 (16%) 22 (23%) 1 (1%) 4 (4%) 2 (3%)
Fever, axillary .37.5uC 38 (6%) 13 (9%) 4 (3%) 3 (3%) 10 (10%) 0 (0%) 8 (13%)
Sleeping disorders (insomnia, somnolence) 503 (80%) 126 (86%) 117 (89%) 83 (88%) 74 (76%) 60 (62%) 40 (64%)
Headache 472 (75%) 92 (63%) 115 (87%) 69 (73%) 72 (73%) 73 (75%) 49 (79%)
Asthenia 384 (61%) 107 (73%) 115 87%) 51 (54%) 69 (70%) 24 (25%) 20 (32%)
Fever history 371 (59%) 61 (42%) 111 (84%) 40 (43%) 63 (64%) 66 (68%) 30 (48%)
Pruritus 365 (58%) 102 (70%) 104 (79%) 45 (48%) 49 (50%) 41 (42%) 24 (39%)
Weight loss 346 (55%) 61 (42%) 103 (78%) 10 (11%) 73 (74%) 84 (87%) 13 (21%)
Tremor 277 (44%) 88 (60%) 82 (62%) 36 (38%) 44 (45%) 19 (20%) 5 (8%)
Walking disorder 258 (41%) 74 (51%) 86 (65%) 39 (41%) 49 (50%) 5 (5%) 4 (6%)
Behavioral disorder 208 (33%) 35 (24%) 74 (56%) 18 (19%) 36 (37%) 32 (33%) 16 (26%)
Convulsions 31 (5%) 10 (7%) 12 (9%) 2 (2%) 3 (3%) 4 (4%) 2 (3%)
doi:10.1371/journal.pntd.0001920.t001
NECT for HAT Implemented in Field Conditions
PLOS Neglected Tropical Diseases | www.plosntds.org 5 November 2012 | Volume 6 | Issue 11 | e1920
Treatment emergent adverse events were reported from the
first dose of study drug until discharge of the patient from the
treatment facility. Five hundred and seventy-eight patients (92%)
suffered from at least one adverse event and 79 patients (13%)
from at least one severe adverse event (CTCAE grades 3 to 5
including death cases). The overall safety profile and the nature
of the most frequently observed adverse events and severe
adverse events were similar for the study populations of interest,
with a few exceptions (Table 3). Pregnant women tended to be
affected more frequently by vomiting, asthenia and headache.
On the other hand, it was the only group not developing any
psychiatric disorder. Breastfeeding women showed double the
incidence of agitation than others (12%). Children had less
psychiatric events and reported less headaches, but had more
fever and injection site reactions. Anorexia was more frequently,
and fever less frequently reported in the population with previous
HAT.
6.5% of the patients received a repeated or added dose of
nifurtimox, often due to vomiting during the 30 minutes following
drug intake. This tended to occur more frequently in small
children (8.6%), pregnant (14.1%) and breastfeeding (9.1%)
women and patients with previous HAT (11.9%). One patient
ceased his NECT treatment due to recurrent convulsions
occurring just after 1 eflornithine administration, without having
had a known convulsion history. One patient had a temporary
nifurtimox interruption of 16 hours due to coma.
Thirty-two (5.1%) patients had a serious adverse event (SAE)
during hospitalisation. From those, 25 were considered as possibly
or probably related to study drug (Table 2). Thirteen patients had
an SAE affecting the nervous system including mood disorders,
psychosis, convulsions, ataxia and coma, while 8 patients had an
SAE that may have been induced by myelotoxicity, including
infections and anaemia (data not shown). All patients with an SAE
who did not die recovered without sequelae. No SAE was reported
for children of breastfeeding mothers during their hospitalisation
(Table 2).
During hospitalisation, 10 patients died of various causes
(infections, coma, anaemia, cardiogenic shock and non-specific
diagnosis). Three patients died during treatment, whilst 7 died
during the observation period. Eight of the 10 patients were
already in a bad health state prior to treatment, as reflected by
their Karnofsky Index at 60% or lower. Nine deaths were
considered to be possibly (7/9) or probably (2/9) related to NECT.
One death was considered unrelated.
Table 2. Treatment compliance, length of hospitalisation and in-hospitalisation safety of NECT by sub-population of interest.
Number of patients with All patients
Total Children Adolescents/adults Other female Previous HAT
0–4 years 5–11 years Male FemalePregnantwomen
Breastfeedingwomen within 2 years
n (%) (N = 629) (N = 35) (N = 65) (N = 299) (N = 183) (N = 14) (N = 33) (N = 84)
Treatment and adherence
Treatment adherence
30 nifurtimox dosesreceived
590 (94%) 31 (89%) 63 (97%) 278 (93%) 177 (97%) 11 (79%) 30 (91%) 79 (94%)
14 eflornithine dosesreceived
621 (99%) 30 (86%) 65 (100%) 298 (100%) 182 (100%) 13 (93%) 33 (100%) 82 (98%)
Patients withconcomitant treatment
585 (94%) 30 (86%) 57 (88%) 281 (94%) 171 (93.4%) 14 (100%) 32 (97%) 76 (91%)
median concomitantdrugs per patient
4 4 4 4 5 6 4 5
Length of hospitalisation*
Median stay, in days 16 16 16 16 16 15.5 15 16
Range, in days 5–46 12–40 12–27 10–46 6–36 5–26 12–31 5–36
In-hospitalisation safety
Any adverse event 578 (92%) 31 (89%) 61 (94%) 273 (91%) 171 (93%) 14 (100%) 28 (85%) 77 (92%)
mean adverse eventsper patient
4.2 2.7 3.4 4.3 4.5 5.7 4.2 4.5
Related adverse event{ 556 (88%) 30 (86%) 57 (88%) 264 (88%) 164 (90%) 14 (100%) 27 (82%) 71 (85%)
Severe adverse event{ 79 (13%) 4 (11%) 5 (8%) 38 (13%) 26 (14%) 3 (21%) 1 (3%) 12 (14%)
Serious adverse event 32 (5%) 1 (3%) 1 (2%) 16 (5%) 10 (6%) 1 (7%) 3 (9%) 5 (6%)
possibly or probablyrelated to treatment
25 (4%) 1 (3%) 0 12 (4%) 8 (4%) 1 (7%) 3 (9%) 4 (5%)
Death during hospitalisation 10 (1.6%) 0 0 4 (1.3%) 5 (2.7%) 1 (7%) 0 1 (1.2%)
Discharged alive 619 (98.4%) 35 100%) 65 (100%) 295 (98.7%) 178 (97.3%) 13 (92.9%) 33 (100%) 83 (98.8%)
HAT = Human African trypanosomiasis.*Calculated from day of admission to day of discharge.{Possibly or probably related to study drug.{CTC grades 3–5.doi:10.1371/journal.pntd.0001920.t002
NECT for HAT Implemented in Field Conditions
PLOS Neglected Tropical Diseases | www.plosntds.org 6 November 2012 | Volume 6 | Issue 11 | e1920
Ta
ble
3.
Inci
de
nce
of
tre
atm
en
te
me
rge
nt
adve
rse
eve
nts
and
tre
atm
en
tin
terr
up
tio
ns
by
sub
-po
pu
lati
on
of
inte
rest
.
Inci
de
nce
of
ad
ve
rse
ev
en
ts(A
Ein
%)
All
pa
tie
nts
Pre
vio
us
To
tal
Ch
ild
ren
Ad
ole
sce
nts
/ad
ult
sO
the
ra
du
lts
HA
T
Sy
ste
mO
rga
nC
lass
Lo
we
stL
ev
el
Te
rmL
LT
an
yA
Ese
ve
reA
E*
seri
ou
sA
E0
–4
ye
ars
5–
11
ye
ars
Ma
leF
em
ale
Bre
ast
fee
din
gw
om
en
Pre
gn
an
tw
om
en
wit
hin
2y
ea
rs
(N=
62
9)
(N=
35
)(N
=6
5)
(N=
29
9)
(N=
18
3)
(N=
33
)(N
=1
4)
(N=
84
)
Pa
tie
nts
wit
ha
tle
ast
1a
dv
ers
ee
ve
nt
92
13
.05
.18
99
49
19
38
51
00
92
Ga
stro
inte
stin
al
dis
ord
ers
61
1.1
0.5
37
46
60
71
67
93
64
Vo
mit
ing
43
0.3
0.0
14
40
39
51
58
79
49
Nau
sea
20
0.2
0.0
61
72
12
46
21
23
Co
litis
70
03
88
83
01
1
Dia
rrh
ea
70
.20
.31
45
69
37
7
Epig
astr
alg
ia6
0.2
00
24
12
32
16
Ab
do
min
alp
ain
60
.30
63
66
01
46
Ge
ne
ral
dis
ord
ers
an
da
dm
inis
tra
tio
nsi
teco
nd
itio
ns
46
2.9
0.6
63
54
39
46
61
86
35
Feve
r3
00
.30
49
42
24
28
42
29
17
Ast
he
nia
18
1.9
02
09
13
23
27
57
20
Inje
ctio
nsi
tere
acti
on
30
06
54
10
02
Oth
er
(he
alth
stat
e,
de
ath
)0
.60
.60
.60
00
.70
.50
71
Ne
rvo
us
syst
em
dis
ord
ers
34
6.0
2.1
14
25
37
37
24
57
35
He
adac
he
15
2.5
03
11
14
18
12
36
16
Diz
zin
ess
11
0.3
00
01
11
66
14
8
Co
nvu
lsio
ns
90
.61
.09
11
10
79
01
2
Co
ma
11
0.5
00
0.5
0.3
07
1
Ata
xia
0.3
0.2
0.2
00
00
.30
01
Me
tab
oli
sma
nd
nu
trit
ion
dis
ord
ers
26
0.2
01
72
52
92
61
22
93
8
An
ore
xia
25
00
17
23
28
25
92
93
8
Psy
chia
tric
dis
ord
ers
16
1.7
0.5
31
21
81
71
20
18
Inso
mn
ia6
00
05
87
00
7
Ag
itat
ion
60
.80
36
57
12
05
Oth
er
(De
liriu
m,
psy
cho
se,
mo
od
dis
ord
er)
1.7
0.5
0.5
02
21
60
1
Mu
scu
losk
ele
tal
an
dco
nn
ect
ive
tiss
ue
dis
ord
ers
14
0.3
00
61
71
31
52
11
0
Lum
bag
o6
00
03
84
62
16
Re
spir
ato
ry,
tho
raci
ca
nd
me
dia
stin
al
dis
ord
ers
11
0.6
09
61
38
91
41
0
Co
ug
h3
00
62
32
07
4
NECT for HAT Implemented in Field Conditions
PLOS Neglected Tropical Diseases | www.plosntds.org 7 November 2012 | Volume 6 | Issue 11 | e1920
Ta
ble
3.
Co
nt.
Inci
de
nce
of
ad
ve
rse
ev
en
ts(A
Ein
%)
All
pa
tie
nts
Pre
vio
us
To
tal
Ch
ild
ren
Ad
ole
sce
nts
/ad
ult
sO
the
ra
du
lts
HA
T
Sy
ste
mO
rga
nC
lass
Lo
we
stL
ev
el
Te
rmL
LT
an
yA
Ese
ve
reA
E*
seri
ou
sA
E0
–4
ye
ars
5–
11
ye
ars
Ma
leF
em
ale
Bre
ast
fee
din
gw
om
en
Pre
gn
an
tw
om
en
wit
hin
2y
ea
rs
(N=
62
9)
(N=
35
)(N
=6
5)
(N=
29
9)
(N=
18
3)
(N=
33
)(N
=1
4)
(N=
84
)
Sk
ina
nd
sub
-cu
tan
eo
us
tiss
ue
dis
ord
ers
91
.70
61
11
09
67
10
Pru
ritu
s7
1.7
06
67
66
76
Va
scu
lar
dis
ord
ers
81
.30
.33
37
10
61
45
Hyp
ote
nsi
on
50
.80
.33
33
86
14
4
Ca
rdia
cd
iso
rde
rs7
0.3
0.2
63
88
37
7
Pal
pit
atio
ns
40
00
04
60
02
Car
dio
ge
nic
sho
ck0
.20
.20
.20
00
10
00
Infe
ctio
ns
an
din
fest
ati
on
s5
2.7
1.0
11
65
43
14
2
Ce
llulit
is1
00
30
11
07
0
Pa
tie
nts
wit
h,
n(%
)
Pe
rman
en
ttr
eat
me
nt
inte
rru
pti
on{
2(0
.3)
00
1(0
.3)
1(0
.5)
00
0
Re
pe
ate
dd
ose
so
fn
ifu
rtim
ox
41
(6.5
)3
(8.6
)4
(6.2
)2
1(7
.0)
8(4
.4)
3(9
.1)
2(1
4.2
)1
0(1
1.9
)
HA
T=
Hu
man
Afr
ican
Try
pan
oso
mia
sis.
*CT
Cg
rad
es
3–
5.
{ Excl
ud
ing
tre
atm
en
tin
terr
up
tio
ns
du
eto
de
ath
(3p
atie
nts
;1
pre
gn
ant
wo
man
,1
fem
ale
and
1m
ale
pat
ien
t).
do
i:10
.13
71
/jo
urn
al.p
ntd
.00
01
92
0.t
00
3
NECT for HAT Implemented in Field Conditions
PLOS Neglected Tropical Diseases | www.plosntds.org 8 November 2012 | Volume 6 | Issue 11 | e1920
Discussion
Based on the results of randomised controlled trials [11,21] and
a case series [22], NECT is currently used as first-line treatment in
several African countries to treat 2nd stage T.b. gambiense HAT. To
better implement NECT in remote rural HAT treatment facilities,
the knowledge on the safety profile under such conditions must be
more extensively known. Here, we report the in-hospitalisation
safety of NECT obtained from 629 treated HAT patients in six
different treatment facilities in the DRC. Also, for the first time,
special populations, such as children below 15 years of age,
pregnant women and HAT relapses, were treated with NECT and
are described here. The effectiveness analysis will be available
once the 24 months follow-up of patients is completed in late 2012.
A matter of concern may be that similar dosages as for adults have
been administered to children below age 12, as in monotherapy
higher doses of nifurtimox and eflornithine are recommended for
children.
NECT in-hospitalisation safety in field conditionsAlmost all - 98.4% (619/629) patients were discharged alive
after treatment. The nature, frequency and intensity of adverse
events were situated in the expected range as shown in previous
studies [11,21,22] and considering the fatal outcome of the disease.
NECT was sufficiently tolerated among all population sub-groups
in the context of 2nd stage HAT treatment. Most patients saw their
health improve during hospitalisation (Karnofsky index raise from
70% before treatment to 86% after treatment and general health
state improvement of 85% of the patients as judged by the
Investigators, data not shown). Concomitant treatments used to
manage adverse events and co-existing diseases were mainly
antiparasitic, antiinfective, analgesic, antipyretic, antiemetic drugs
and benzodiazepines.
LimitationsThe evaluation of adverse events and causes of mortality was
complex, as symptoms were often related and confused with the
symptoms of the disease itself [23,24] or concomitant disease in a
background of severely ill and often malnourished patients. Apart
from nausea and vomiting, the symptoms observed during
NECT treatment are similar to HAT symptoms described
during anamnesis at enrolment and reported in the literature
[23]. A clear distinction of causality between the disease itself, the
co-morbidities and the study treatment is not possible in most
cases.
Similar in-hospital safety rates and profiles were observed
among the different population sub-groups including the small
children, pregnant (considering the low number in this group) or
breastfeeding women and patients having previously relapsed.
Implementing a clinical trial inevitably modifies field conditions,
as study procedures, patient’s safety recommendations, study
forms and external expertise are being brought to the centres.
Nevertheless, the study was carefully designed to minimise these
modifying effects, while maintaining adequate quality standards.
The facilities’ hospitalisation conditions were maintained: for
example food was not systematically provided, unless a patient was
suffering from advanced malnutrition; concomitant medication
was based on routine stock of drugs. However, for safety reasons,
emergency kits containing drugs for treatment of potentially severe
or life threatening events were provided to the centres before the
inclusion of the first patient. The study was implemented in six
treatment facilities in the DRC under conditions mimicking field
reality as much as possible.
Comparison to previous studies and generalisabilityThe demographic characteristics of patient populations varied
slightly between facilities, but nonetheless reflected the observed
distribution of the HAT populations described in the literature
[4,13] and therefore allows comparison with previous studies even
if here additional groups have been added with similar baseline
and in-hospitalisation safety profiles.
The proportion of patients discharged alive after NECT
treatment in field conditions was comparable to eflornithine
monotherapy and to previous NECT trials in field conditions,
varying from 94.1% to 99.3%, depending on the drug in use
[4,11,13,14,21,22]. The fatality rate during hospitalisation did not
exceed the projected values derived from literature and field
reports (0.8–2.1%; [4,11,13,14]).
The median length of hospitalisation for a patient was 16 days
including premedication and observation period compared to 25–
30 days for melarsoprol [3] or 20 days for eflornithine
monotherapy (personal communication PNLTHA DRC). The
NECT therapy could be accomplished in 10 days for most
patients. Its dosage schedule is simpler to apply than eflornithine
monotherapy (56 versus 14 intravenous infusions [4]), requiring
less nursing staff.
Compared to the formerly used standard HAT treatments,
NECT is safer than melarsoprol (2.7–34% melarsoprol case
fatality rate [3,4]) and similar to eflornithine monotherapy.
The overall safety profile of NECT in the present study is
similar to the safety data of NECT obtained during previous
studies comparing different drug combinations [21], Nifurtimox-
Eflornithine case series [22] and the NECT phase III RCT
comparing NECT to eflornithine monotherapy [11]. In this study,
arrhythmias, musculoskeletal and connective tissue disorders,
injection site reactions and headaches were reported less
frequently compared to the NECT phase III RCT [11]. All other
adverse events were similar in nature, intensity and frequency.
These differences in adverse event reporting can be explained by
the different design and context of both studies. Another limitation
of the comparability is that adverse events reported during
previous studies were coded according to different standard
dictionaries (i.e. the CTC).
Potentially harmful neurological adverse events, such as
convulsions (9%) and coma (1%) compatible with an encephalo-
pathic syndrome were observed in 13 SAE cases (2.1%). However,
as convulsions already occurred in 31 patients (5%) prior to
treatment (Table 1), it is difficult to assess if they were caused by
the disease, were related to the treatment regimen or resulted from
a combination of both. These cases of encephalopathic-like
reactions are not directly comparable to previous eflornithine
[4,13,14] or melarsoprol [3,25,26] trials, as the same definition of
the encephalopathic syndrome [25,27] was not consistently used in
all those trials.
Switching from a controlled environment, such as during the
NECT phase III RCT where patients were closely followed [11] to
field conditions raised some concerns about infection risk at the
injection site and infections in general. However, during the
present trial, no evidence of increased infection was observed.
As already expressed by Priotto [11], vomiting remains a
concern because of its frequency, especially during the first days of
NECT therapy. Nifurtimox doses were repeated once or twice in
6.5% of the patients. The final effectiveness analysis will enable
evaluation of the impact of vomiting on the cure rate. A close
observation of nausea and vomiting is recommended in order to
allow the timely administration of a second nifurtimox dose if
necessary, as well as the prescription of an anti-emetic drug.
NECT for HAT Implemented in Field Conditions
PLOS Neglected Tropical Diseases | www.plosntds.org 9 November 2012 | Volume 6 | Issue 11 | e1920
Conclusions and recommendationsThe in-hospital safety and feasibility of NECT in field
conditions have been shown to be satisfactory in this trial.
Consequently, its use in remote, rural sleeping sickness treatment
facilities in endemic countries seems justified. In field conditions
and in a wider population, including children, the use of NECT
displayed a similar tolerability profile to that previously described
in more stringent clinical trial conditions [11]. However, wide
implementation of NECT demands sufficient levels of human
resources for IV infusion treatment and that financial and
logistical barriers in the supply chain management are overcome.
In addition, a common international, standardised pharmacov-
igilance system should be supported to further improve the
collection of safety and efficacy data in specific populations
(pregnant/breastfeeding women and children) and to monitor the
emergence of rare severe adverse events.
The in-hospital evolution of patients was similar to previously
published NECT results. The effectiveness will be assessed at the
end of the 24 months follow-up period.
Acknowledgments
We thank the patients and their families for their participation, as well as
the medical and support staff of the PNLTHA and BDOM/KIKWIT for
their hard work in caring for patients. The authors thank the work of the
provincial heads and directorate of the PNLTHA and the BDOM who
permitted the conduct of the study (Drs Claude Sese, Crispin Lumbala,
Florent Mbo, van Kumpel and Cecile van Geerts). The World Health
Organisation (WHO) Geneva and Kinshasa provided the drugs for free
and supported the logistics (Drs. Pere Simarro, Jose Ramon Franco and
Carmelo Santercole). Logistic support was also received from Doctors
Without Borders (MSF) logistic centre in Bordeaux, France and the DNDi
local office in Kinshasa (Mr Richard Mvumbi). The HAT Platform in
Kinshasa (Dr Augustin Ebeja) provided liaison with the local ethics
committee. The Swiss Tropical and Public Health Institute, Basel and
Kinshasa supported the implementation and monitoring of the study (Drs.
Sonja Bernhard, Gabriele Pohlig, Christian Burri, Didier Kalemwa and
Mr Jean-Bosco Inyamweni). Training was given by Drs. Jorge Seixas
(Institute of Hygiene and Tropical Medicine IHMT Lisbon, Portugal),
Serge Kazadi (Doctors Without Borders, MSF Switzerland) and the
medical staff of the PNLTHA Kasai Oriental (Dr Medard Ilunga, Jeremy
Ilunga and Patrice Kabangu). Scientific advice was received from Drs. Els
Torreele, Francois Chappuis, Marc Gastellu, Abiy Tamrat, Nathalie Strub,
Gerardo Priotto and Christian Burri. We also thank the Data Safety and
Monitoring Board (DSMB, Drs. Dominique Legros, Bruno Scherrer and
Pascal Lutumba). Data management was provided by RCTs, Lyon, France
and pharmacovigilance reporting by EP consultants, Paris, France.
Author Contributions
Conceived and designed the experiments: CS AK SG VK WM. Performed
the experiments: WM MI IL SM PN DT NM MK. Analyzed the data: CS
AK JB SG SB OVM. Wrote the paper: CS AK SG OVM.
References
1. WHO (2011) Neglected Tropical Diseases. Available: http://www.who.int/
trypanosomiasis_african/en/. Accessed 2012 Feb 20.2. Simarro PP, Cecchi G, Paone M, Franco JR, Diarra A, et al. (2010) The Atlas of
human African trypanosomiasis: a contribution to global mapping of neglected
tropical diseases. Int J Health Geogr 9: 57.3. Schmid C, Richer M, Bilenge CM, Josenando T, Chappuis F, et al. (2005)
Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stagehuman African trypanosomiasis: Confirmation from a multinational study
(Impamel II). Journal of Infectious Diseases 191: 1922–1931.
4. Balasegaram M, Young H, Chappuis F, Priotto G, Raguenaud ME, et al. (2009)Effectiveness of melarsoprol and eflornithine as first-line regimens for gambiense
sleeping sickness in nine Medecins Sans Frontieres programmes. Trans R SocTrop Med Hyg 103: 280–290.
5. Dahl B (2011) From sentinel surveillance for sleeping sickness treatment failureto the development of a pharmacovigilance approach [PhD thesis]. Basel:
University of Basel. 149 p.
6. Robays J, Nyamowala G, Sese C, Betu Ku Mesu Kande V, Lutumba P, et al.(2008) High failure rates of melarsoprol for sleeping sickness, Democratic
Republic of Congo. Emerg Infect Dis 14: 966–967.7. Pepin J, Mpia B (2005) Trypanosomiasis relapse after melarsoprol therapy,
Democratic Republic of Congo, 1982–2001. Emerg Infect Dis 11: 921–927.
8. Matovu E, Enyaru JC, Legros D, Schmid C, Seebeck T, et al. (2001)Melarsoprol refractory T. b. gambiense from Omugo, north-western Uganda.
Trop Med Int Health 6: 407–411.9. Stanghellini A, Josenando T (2001) The situation of sleeping sickness in Angola:
a calamity. Tropical Medicine and International Health 6: 330–334.10. WHO (2010) WHO Model List of Essential Medicines Available: http://www.
who.int/medicines/publications/essentialmedicines/Updated_sixteenth_adult_
list_en.pdf. Accessed 2012 Feb 20.11. Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian S, et al. (2009)
Nifurtimox-eflornithine combination therapy for second-stage African Trypano-soma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III,
non-inferiority trial. Lancet 374: 56–64.
12. Program CTE (2006) Common Terminology Criteria for Adverse Events,Version 3.0 Available: http://ctep.cancer.gov/protocolDevelopment/
electronic_applications/docs/ctcaev3.pdf. Accessed 2012 Feb 20.13. Chappuis F, Udayraj N, Stietenroth K, Meussen A, Bovier PA (2005)
Eflornithine is safer than melarsoprol for the treatment of second-stage
Trypanosoma brucei gambiense human African trypanosomiasis. Clin Infect
Dis 41: 748–751.14. Priotto G, Pinoges L, Fursa IB, Burke B, Nicolay N, et al. (2008) Safety and
effectiveness of first line eflornithine for Trypanosoma brucei gambiense sleeping
sickness in Sudan: cohort study. BMJ 336: 705–708.15. Fleiss JL, Levin B, Paik MC (2003) Statistical Methods for Rates and
Proportions. New York: John Wiley & Sons.16. NCSS (2008) PASS 2008 (http://www.ncss.com/download_PASS11.html)
accessed (20.02.2012).
17. MEDRA (2010) Medical Dictionary for regulatory activities - Maintenance andService Support Organisation. Available: http://www.meddramsso.com/index.
asp. Accessed 2012 Feb 20.18. WHO (2006) ATC/DDD Index (http://www.whocc.no/atc_ddd_index/)
accessed (20.02.2012)19. WHO (1995) Physical status: The use and interpretation of anthropometry
(http://whqlibdoc.who.int/trs/WHO_TRS_854.pdf) Accessed 2012 Feb 20.
20. WHO (2007) Growth reference data for 5–19 years. Available: http://www.who.int/growthref/en/. Accessed 2012 Feb 20.
21. Priotto G, Fogg C, Balasegaram M, Erphas O, Louga A, et al. (2006) Three drugcombinations for late-stage Trypanosoma brucei gambiense sleeping sickness: a
randomized clinical trial in Uganda. PLoS Clin Trials 1: e39.
22. Checchi F, Piola P, Ayikoru H, Thomas F, Legros D, et al. (2007) Nifurtimoxplus Eflornithine for Late-Stage Sleeping Sickness in Uganda: A Case Series.
PLoS Negl Trop Dis 1: e64.23. Blum J, Schmid C, Burri C (2006) Clinical aspects of 2541 patients with second
stage human African trypanosomiasis. Acta Trop 97: 55–64.24. Blum JA, Schmid C, Burri C, Hatz C, Olson C, et al. (2009) Cardiac Alterations
in Human African Trypanosomiasis (T.b. gambiense) with Respect to the
Disease Stage and Antiparasitic Treatment. PLoS Negl Trop Dis 3: e383.25. Blum J, Nkunku S, Burri C (2001) Clinical description of encephalopathic
syndromes and risk factors for their occurrence and outcome during melarsoproltreatment of human African trypanosomiasis. Trop Med Int Health 6: 390–400.
26. Burri C, Nkunku S, Merolle A, Smith T, Blum J, et al. (2000) Efficacy of new,
concise schedule for melarsoprol in treatment of sleeping sickness caused byTrypanosoma brucei gambiense: a randomised trial. Lancet 355: 1419–1425.
27. Seixas J (2005) Investigations on the encephalopathic syndrome duringmelarsoprol treatment of human african trypanosomiasis [PhD]. Lisboa:
Universidade Nova de Lisboa. 250 p.
NECT for HAT Implemented in Field Conditions
PLOS Neglected Tropical Diseases | www.plosntds.org 10 November 2012 | Volume 6 | Issue 11 | e1920
PROPOSAL FOR THE INCLUSION OF
NIFURTIMOX-EFLORNITHINE COMBINATION AS A TREATMENT FOR STAGE 2 TRYPANOSOMA BRUCEI GAMBIENSE
HUMAN AFRICAN TRYPANOSOMIASIS (SLEEPING SICKNESS) IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES
Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland Persons to contact: Dr Els Torreele Drugs for Neglected Diseases initiative (DNDi) 15 Chemin Louis-Dunant 1202 Geneva Switzerland Tel: +41 (0)22 906 9230 Fax: +41 (0)22 906 9231 Email: [email protected] Dr Gerardo Priotto NECT Study - Principal Investigator Epicentre 8 Rue St Sabin 75011 Paris France Tel: +33 (0)1 4021 2848 Email: [email protected]
October 2008 *Please note that the following drafts in preparation will be made available, in draft form, to EML Committee members either upon finalisation or at the time of the meeting. These drafts include:
• Seixas & Lutje manuscript (Cochrane review) • Harhay et al systematic review on stage 2 chemotherapy • Priotto et al primary article on Phase III NECT study • Finalised clinical study report of the Phase III NECT study
1
Contents WHO Model List Application, October 2008 Abbreviations………………………………………………………………………………………………………….………………………2 Synopsis…………….…………………………………………………………………………………………………………………………..3 1. Summary statement of the proposal for inclusion……………………………………………………………………………5 2. Name of the focal point in WHO for this application…………………………………………………..……………………5 3. Name of the organisation(s) consulted and/or supporting the application………………………………………….5 4. International Nonproprietary Name (INN, generic name) of the medicine……………………………………….…5 5. Formulation proposed for inclusion…………………..……………………………………………………………………………6 6. International availability……………………………………………………………………………………………………………….6 7. Whether listing is requested as an individual medicine or as an example of a therapeutic
group…………………………………………………………………………………………………………………………………………8 8. Information supporting the public health relevance:
8.1 Disease burden – Epidemiological information…………………………………………………………………….…….8 8.2 Assessment of current use and target population…………………………………………………………..…….…10
9. Treatment details: 9.1 Dosage regimen, duration…………………………………………………………………………………….………………13 9.2 Reference to existing WHO and other clinical guidelines………………………………………….…………….…14 9.3 Need for special diagnostic or treatment facilities and skills………………………………………………………15
10. Summary of comparative effectiveness (and/or efficacy): 10.1 Identification of clinical evidence (search strategy, systematic reviews identified, reasons for
selection/exclusion of particular data) ……………………………………………………….……………………….…16 10.2 Summary of available data (appraisal of quality, outcome measures, summary of
results)………………………………………………………………………………………………………………………….……17 10.3 Summary of available estimates of comparative effectiveness………………………………..………………21
11. Summary of comparative evidence on safety: 11.1 Estimate of total patient exposure to date…………………………………………………………………………….22 11.2 Description of adverse effects/reactions……………………………………………………………………………….22 11.3 Identification of variation in safety due to health systems and patient factors………….………………25 11.4 Summary of comparative safety against comparators…………………………………………………………….25
12. Methodological concerns with studies ………………………………………………………………….……………………29 13. Summary of available data on comparative cost and cost effectiveness within the pharmacological class or therapeutic group:
13.1 Range of costs of the proposed medicine……………………………………………………………………………..30 13.2 Comparative cost effectiveness presented as range of cost per routine outcome (e.g. cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality-adjusted life year gained)……….………………….31
14. Summary of regulatory status of medicines……………………………………………………………………….……….31 15. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia)……………………………………………………………………….………………………….………………32 16. Proposed text for WHO Model Formulary…………………………………………………….……………………………..32 Appendix……………………………………………………………………………………………………………..…………………….…36 References…………………………………………………………………………………………………………………………..…….…40
2
Abbreviations AE : Adverse event BTT : Bi-therapy trial CATT : Card agglutination test for trypanosomiasis CNS : Central nervous system CSF : Cerebrospinal fluid DALYs : Disability-adjusted life years DFMO : α-difluoro-methyl-ornithine (eflornithine) DNDi : Drugs for Neglected Diseases initiative DRC : Democratic Republic of Congo EML : Essential Medicines List GCP : Good clinical practice HAT : Human African trypanosomiasis ISCTRC : International Scientific Council for Trypanosomiasis Research and Control INN : International nonproprietary name ITT : Intention to treat iv : Intravenous MSF : Médecins Sans Frontières NECS : Nifurtimox-eflornithine case series NECT : Nifurtimox-eflornithine combination therapy NGO : Non-governmental organisation PNLTHA : Programme Nationale de Lutte contre la Trypanosomiase Humaine
Africaine PP : Per protocol RCT : Randomised controlled trial RoC : Republic of Congo SAE : Serious adverse event STI : Swiss Tropical Institute T.b. gambiense : Trypanosoma brucei gambiense T.b. rhodesiense : Trypanosoma brucei rhodesiense TDR : Special Programme for Research and Training in Tropical Diseases (TDR) THA : Trypanosomose Humaine Africaine USD : US dollars WBC : White blood cells WHO : World Health Organization WHO HQ : World Health Organization headquarters WHO/HTM/NTD/IDM : World Health Organization/HTM Cluster/Control of
Neglected Tropical Diseases/Innovative and Intensified Disease Management
3
Synopsis Human African trypanosomiasis (HAT), also known as sleeping sickness, threatens millions of people in sub-Saharan Africa, mainly affecting those in poverty-stricken, remote, rural areas. The late, meningo-encephalitic stage of the disease (referred to hereafter as stage 2 HAT) is characterised by serious neurological and behavioural symptoms including severe sleep disturbances that progress to coma. Without treatment, stage 2 HAT is invariably fatal. Case management (i.e. diagnosis and treatment) of infected individuals is one of the main aspects of HAT control, along with vector control and mass-screening/surveillance of the population at risk. However, few medicines are currently available to treat stage 2 HAT, the stage at which the disease is most frequently diagnosed. The main pharmaceutical treatment used, intravenous melarsoprol, is painful for patients to receive and can produce severe drug-related toxic side effects and even death. Eflornithine, a trypanostatic drug currently given as a monotherapy, is effective and safer but its use is greatly limited by its impracticality of administration, particularly in resource-poor settings. It needs to be given by repeated slow intravenous (iv) infusion, every 6 hours for 14 consecutive days, and requires careful nursing care, medical supervision, and large amounts of extra materials (e.g. infusion fluids, infusions sets, sterile gauze). Because of these constraints, only 30% of stage 2 patients are estimated to receive this treatment. A third medicine, oral nifurtimox, is a trypanocidal drug licensed for treatment of Chagas disease which has been used off-label on a compassionate need basis for treatment for stage 2 HAT, but has insufficient efficacy for use as a monotherapy. It has been well established that eflornithine is far better tolerated than melarsoprol; it is now the recommended first-line treatment for stage 2 HAT wherever it can be implemented. However, as stated above, practical constraints have precluded its widespread use. Increasingly high rates of melarsoprol treatment failure have been reported in several regions, sometimes up to 50%. Long-term and possibly inappropriate use of eflornithine monotherapy may also lead to increasing failure rates; the development of resistance to this medicine would have serious consequences. No new drugs for stage 2 HAT are in clinical development, so there is an urgent need to develop new regimens based on currently available drugs. However, undertaking research, especially clinical trials in HAT, is very difficult due to the remote location of the patients, the lack of health infrastructure and research capacity, and the frequency of civil disruption and war in these areas. Despite these considerable challenges, a major randomised controlled study into treatment of stage 2 HAT has just been completed; the results form the core evidence for this application. In this multicentre non-inferiority study comparing the simplified co–administration of nifurtimox and eflornithine (NECT) with eflornithine monotherapy, both treatments were shown to be well tolerated and efficacious in stage 2 HAT patients. Compared to eflornithine monotherapy, the combination treatment has the following advantages:
• The number of infusions of eflornithine is reduced from 56 to 14: o Less burdensome for the health care staff o Less risk of infections o More convenient for the patient
4
• The treatment duration is reduced from 14 to 10 days: o Less expensive for the severely cost-constrained health system o More capacity for the treatment centre o More convenient for the patient
• The number of infusions per day is reduced from 4 (every 6 hours) to 2 (every 12 hours): o Less burdensome for the health care staff o More convenient for the patient
• Reduced logistical challenges: o A half of the volume/weight (cheaper transportation) o A same volume treatment kit can contain 4 instead of 2 full treatments
• Resistance is less likely to develop as the two drugs have different modes of action, thus mutual protection is to be expected.
This application proposes the co-administration of nifurtimox (oral) and eflornithine (iv) (Nifurtimox-Eflornithine Combination Therapy – NECT) as an alternative treatment for stage 2 Trypanosoma brucei gambiense (T.b. gambiense) HAT. Both nifurtimox and eflornithine are already listed separately on the World Health Organization (WHO) Model List of Essential Medicines (sections 6.5.5.2 on Chagas disease and 6.5.5.1 on African Trypanosomiasis respectively). It is proposed that nifurtimox, to be used in combination with eflornithine, is added to section 6.5.5.1: African Trypanosomiasis (under ‘Medicines for the treatment of 2nd stage African trypanosomiasis’ with a specific point that NECT should be used exclusively for T.b.gambiense infections).
5
1. Summary statement of the proposal for inclusion Co-administration of oral nifurtimox with iv eflornithine (Nifurtimox-Eflornithine Combination Therapy – NECT) is proposed for inclusion in the World Health Organization (WHO) Model List of Essential Medicines, section 6.5.5.1, as an alternative treatment for patients with stage 2 (late stage, meningo-encephalitic stage)Trypanosoma brucei gambiense human African trypanosomiasis (T.b. gambiense HAT; also known by other names including gambiense HAT, West African trypanosomiasis, or chronic sleeping sickness). 2. Name of the focal point in WHO for this application Dr Pere P. Simarro Human African Trypanosomiasis WHO/HTM/NTD/IDM World Health Organization 1211 Geneva 27, Switzerland Tel: +41 (0) 22 791 1345 Fax: +41 (0) 22 791 4777 [email protected] 3. Name of the organisation(s) consulted and/or supporting the application Epicentre, Paris, France Médecins Sans Frontières (MSF) Swiss Tropical Institute (STI), Basel, Switzerland Programme National de Lutte contre la Trypanosomiase Humaine Africaine (PNLTHA), Democratic Republic of Congo (DRC) 4. International Nonproprietary Name (INN, generic name) of the medicine Nifurtimox (4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine 1,1-dioxide) and eflornithine (eflornithine hydrochloride; α-difluoro-methyl-ornithine, DFMO)
6
5. Formulation proposed for inclusion Two individual medicines co-administered (one oral, one iv) as a combination therapy for stage 2 T.b. gambiense HAT. The suggested NECT regimen is:
• Nifurtimox (oral tablets): 15 mg/kg/day (5 mg/kg every 8 hours) for 10 days Plus • Eflornithine (slow iv infusion): 400 mg/kg/day (200 mg/kg every 12 hours) for 7 days
Nifurtimox is available as 120 mg oral tablets. Eflornithine is available in 100 ml glass bottles containing a 200 mg/ml solution. This needs to be diluted with sterile watera prior to slow iv infusion over 2 hours. aAlternatives to sterile water are normal saline or 5% dextrose. Although sterile water is the recommended diluent, normal saline in a larger volume (250 ml instead of 100 ml) has been used extensively (over 6,000 patients treated between 2001 and 2007) as an alternative as it has been more widely available in endemic regions than sterile water (personal communication: G Priotto).
6. International availability Table 1. Availability of eflornithine and nifurtimox. Drug name (generic)
Drug name (proprietary)
Manufacturer Supplied in
Eflornithine (DFMO)
Ornidyl® sanofi-aventis Glass bottles (200 mg/ml in 100 ml bottles). Eflornithine must be diluted before use. Once diluted, eflornithine can be stored in the fridge for up to 24 hours.
Nifurtimox Lampit®
Bayer Glass bottles, each containing 100 tablets of 120 mg.
Donated by sanofi-aventis to WHO, eflornithine is provided free-of-charge to national diagnosis and treatment programmes through MSF Logistique. The agreement between WHO and sanofi-aventis, first set up in 2001, was renewed in 2006 until 2011. Nifurtimox is provided free-of-charge to WHO by Bayer for the treatment of Chagas disease (American trypanosomiasis); it is expected that a similar arrangement would be made for HAT. Treatment kits A major barrier in the widespread use of eflornithine is the need for a range of infusion-associated materials for the proper administration of the treatment. In an effort to make the treatment more accessible for patients, a treatment kit has been developed in collaboration between WHO, sanofi-aventis, and MSF. The kit, which consists of the medicines and all of the materials needed for the proper administration of eflornithine, generally contains 2 full adult treatments (see Table 2 below). While
7
eflornithine is available as a donation, the cost of the additional materials is ~110 euros (€) per treatment (personal communication P. Simarro). The total weight of the kit containing 2 adult treatments is 37.6 kg. Table 2. Contents of the eflornithine kit (containing 2 full adult treatments). Item Quantity
Eflornithine chlorhydrate, éq. 200 mg/ml base, 100 ml, ampoules 36 Other equipment:
Water for injection, 100 ml, plastic pouch 120 'Y' joint, Luer lock, air intake, sterile 120 IV catheter, injection, 20 G (1.0 x 32 mm), pink 50 IV catheter, Bouchon, male Luer cap, sterile 100 Needle, Luer, 19G (1.1 x 40 mm) cream, IV 200 Syringe, u.u., Luer, 20 ml 100 Syringe, u.u., Luer, 2 ml 100 Strip of gauze, 8 cm x 4 m, with edges 20 Gauze pad, 10 cm, 12 ply, sterile 140 Zinc oxide tape, roll, perforated, 10 cm x 5 cm 1 Cotton, roll, 500 g 1 Examination gloves, latex, one-time usage, large 100 Examination gloves, latex, one-time usage, small 100 Povidone iodine, 10% solution, 200 ml vial for pouring 1 Elastic tourniquet 100 cm x 1.8 cm 2
If nifurtimox is included in the WHO Model List of Essential Medicines (EML) for stage 2 HAT, it is expected that a similar NECT kit will be developed by WHO and its partners. This kit would be made available free-of-charge to national control programmes and non-governmental organisations (NGOs) treating HAT. Given the reduction in eflornithine-related materials, it is expected that, within the same volume, the NECT kit will be able to contain 4 full treatments as opposed to the current 2 full treatments/kit. International availability of HAT drugs Today, all HAT drugs are available through donations from the manufacturers – sanofi-aventis for eflornithine, eflornithine kits, melarsoprol and pentamidine; Bayer HealthCare for suramin. (Suramin and pentamindine are used to treat stage 1 HAT.) Currently, requests for HAT drugs arrive at WHO headquarters (WHO HQ) for approval via three routes:
1. Requests are sent by the national control programmes to WHO HQ via the regional offices WHO-AFRO or WHO-EMRO.
2. Requests are sent from the national control programmes, NGOs or other implementing partners to WHO HQ direct.
3. Requests are sent from MSF missions to WHO HQ via MSF Logistique in Bordeaux, France. WHO HQ then confirms the order and requests MSF Logistique to prepare and dispatch the orders to the national control programmes via the WHO country office or NGO headquarters in the disease-endemic country. Further distribution to the HAT treatment centres is the responsibility of the recipient (national control programme or NGO), who then also bears the costs for this in-country distribution.
8
7. Whether listing is requested as an individual medicine or as an example of a therapeutic group It is requested that nifurtimox (already listed in section 6.5.5.2 as an essential medicine for American trypanosomiasis [Chagas disease]) be listed for the treatment of stage 2 T.b. gambiense HAT (in section 6.5.5.1) as a combination therapy with another WHO EML-listed medicine (eflornithine, already listed in section 6.5.5.1). 8. Information supporting the public health relevance
8.1 Disease burden – epidemiological info Introduction: Human African trypanosomiasis (HAT), also known as sleeping sickness, is a life-threatening illness from which 60 million people in 36 countries, primarily in sub-Saharan Africa, are at risk1 (Harhay et al. submitted for publication). Infection does not appear to confer immunity, so re-infection remains possible after treatment. HAT mainly affects working adults, which means it has an immense social and economic impact on local communities in HAT-endemic countries, many of which already have to contend with poverty and armed conflict as well as other major diseases such as malaria. Transmitted by tsetse flies, HAT exists in two forms, Trypanosoma brucei gambiense (T.b. gambiense) or Trypanosoma brucei rhodesiense (T.b. rhodesiense) disease. T.b. gambiense HAT accounts for ~97% of reported cases and is endemic in 24 countries; the disease is more chronic than its rhodesiense counterpart. In both disease forms an initial haemolymphatic stage disease (stage 1), which may be subclinical, progresses to an advanced meningo-encephalitic stage (stage 2) that affects the central nervous system (CNS)2-5. This stage 2 disease causes neuropsychiatric problems, convulsions, and serious sleep disturbance6; eventually these symptoms lead to coma. Without appropriate treatment, the disease is invariably fatal. HAT places a large burden on communities and individual households. In 2002, WHO estimated that approximately 1.5 million disability-adjusted life years (DALYs) were lost due to HAT. A more recent study in the DRC showed that the cost to each household following a HAT outbreak was equivalent to 5 months’ income for that household7. Epidemiology: HAT is a major public health concern in parts of sub-Saharan Africa. Although it is highly focalised, with the vast majority (>90%) of cases occurring in DRC, Angola, Central African Republic, and Sudan (Harhay et al. manuscript submitted for publication), cases have been reported in 36 countries in total. The total number of new cases reported has decreased over recent years. In 2007 the total number of reported cases of T.b. gambiense HAT was 10,446 (personal communication, Pere Simarro), descending from a peak incidence of 37,000 per year in the late 1990s. However, a key issue with HAT is that it affects hard-to-access communities in regions with a poor health infrastructure; as a result there is probably considerable underreporting of the condition. Poor access to medical facilities, a lack of resources and skills, and misdiagnosis are all likely to contribute to this issue. Taking into account such underreporting, current WHO estimates are 50,000 – 70,000 infected people8, 9.
9
Threat of epidemics: Three major HAT epidemics impacted Africa throughout the 20th century. The first, which killed an estimated 800,000 people, occurred from 1896, lasted until 1906, and mainly affected Uganda and Congo. A second epidemic, which occurred from 1926 and lasted until the early 1940s, spurred colonial powers on to invest in mobile teams, vector control, and to assess the use of arsenicals to treat this fatal disease. Despite being almost eliminated in the 1960s, poor control and surveillance activities, exacerbated by socio-political unrest, led to a third epidemic which began in the 1970s and mainly affected Angola, Congo, southern Sudan, and northwest Uganda; this epidemic lasted until the late 1990s10-16. While the current situation seems to be under control, the historical evidence indicates that endemic areas remain at risk of devastating epidemics if surveillance efforts are weakened. Control strategy: There are three main pillars to HAT control – mass-screening (active case finding) of the population, routine diagnosis and treatment at health facilities, and vector control. All of these efforts require trained/skilled healthcare staff and specific equipment. Diagnosis: A field-adapted serological screening test, the card-based agglutination test (CATT), is available to identify people with a risk of having been in contact with the parasite responsible for the T.b. gambiense form of HAT17, 18; this test is used for both passive and active case finding. The blood or lymph of these seropositive individuals is examined subsequently by microscopy for a visual confirmation of the parasite. Because the number of circulating parasites is generally low, a series of increasingly complicated techniques are needed to concentrate the parasite in the sample so as to see it under the microscope. Once HAT infection is confirmed, disease staging requires a lumbar puncture to determine the presence of parasites or of elevated levels of white blood cells in the cerebrospinal fluid (CSF), which characterises stage 2 disease. Staging is of critical importance because treatments for stage 2 HAT are different from those for stage 1 disease. Most importantly, current stage 2 treatments are more likely to give serious adverse effects and are more cumbersome to administer. HAT staging requires trained clinical staff to collect CSF samples by lumbar puncture, and trained laboratory staff to analyse samples and interpret results. Laboratory criteria for stage 2 diagnosis are:
• presence of parasites in the blood, lymph node fluid or CSF or CATT positivity in diluted serum (degree of dilution varies per country and per epidemiological criteria)
and • an elevated white blood cell (WBC) count in the CSF. (Generally, stage 2 is confirmed with a
count of more than 5 WBCs per microlitre in CSF, but this criterion varies from 5 to 20 according to country and protocol).
Speedy microscope examination is needed, as trypanosomes need to still be alive and moving if they are to be detected. Treatment: Stage 1 HAT is treated relatively easily and safely with pentamidine (used for T.b. gambiense) or suramin (used for T.b. rhodesiense). However, patients in the early disease stage often go unnoticed since symptoms (such as intermittent fever, headache and weight loss) may be mild or confused with other conditions. Thus, patients mostly present to a hospital after stage 2 symptoms have occurred. This is particularly true in the remote rural settings where the disease is found, and where there
10
is relatively poor access to healthcare facilities. Therefore, it is crucial that control programmes have access to safe, cost-effective and practical stage 2 treatments. Pentamidine and suramin are not effective when stage 2 has been reached as they do not cross the blood-brain barrier at therapeutic levels, so other treatments (melarsoprol and eflornithine; detailed discussion in Section 8.2) need to be given. The administration of both melarsoprol and eflornithine requires medical supervision; this can be a major burden on understaffed, isolated healthcare facilities. Melarsoprol, which is given by daily direct intravenous injections, is known as ‘fire in the blood’ because of the pain that can be induced by administration; more importantly, 1 in 10 patients will suffer from reactive encephalopathy during treatment, with fatal consequences for half of them19-22. Eflornithine needs to be administered by slow iv infusions; these infusions are given every 6 hours for 14 days (a total of 56 infusions). Although eflornithine has been shown to be safer than melarsoprol and is recommended as first-line treatment for stage 2 HAT, practical constraints mean it is only utilised in a fraction of HAT treatment centres (shown in Table 3). HAT and HIV/AIDS: Little is currently known about the incidence of HAT in HIV-positive individuals, primarily because HIV testing is not yet commonplace in HAT-endemic areas (which are typically the remote, rural areas with poor health infrastructure). The presence of HIV/AIDS in HAT-endemic regions is an important factor to bear in mind as there is some evidence that eflornithine, one of the drugs used to treat trypanosomiasis, might not be as effective in HIV-positive individuals23.
8.2 Assessment of current use and target population Current treatment options: HAT has often progressed to stage 2 disease by the time symptoms emerge and the disease is diagnosed. While relatively safe and easy-to-administer drugs are available to treat stage 1 HAT, this is not the case for stage 2 treatments. One reason is that these drugs need to be able to cross the blood-brain barrier at therapeutic levels. Current treatment options for stage 2 T.b .gambiense disease primarily rely on two drugs, melarsoprol and eflornithine (see Table 3). From period between 2003 and 2007, a total of 46,265 stage 2 HAT patients were treated (approximately 60% of total HAT cases treated). Table 3. Percentage of stage 2 patients treated with melarsoprol versus eflornithine, 2003 – 2007 (P Simarro, personal communication). Stage 2 Treatment
2003 2004 2005 2006 2007
Melarsoprol, n (%)
10,179 (83.1) 9092 (85.7) 8205 (83.5) 6287 (88.3) 4393 (68.0)
Eflornithine, n (%)
2058 (16.8) 1506 (14.2) 1611 (16.4) 826 (11.6) 2061 (31.9)
Other, n (%)
12 (0.1) 11 (0.1) 10 (0.1) 7 (0.1) 7 (0.1)
The trivalent arsenical derivative melarsoprol, a trypanothione reductase inhibitor (introduced in 1949) is the most commonly used treatment. The mechanism of action is not fully understood, but it appears that the drug inhibits parasitic glycolysis24, 25. The drug has severe toxic side effects including reactive
11
encephalopathy and is associated with ~3 – 6% fatality19, 20, 22, 26, 27; as such, the corticosteroid prednisolone is often given to reduce the risk of encephalopathy21, 28. Other potentially life-threatening adverse effects include liver toxicity, peripheral neuropathy, skin toxicity and severe enterocolitis1, 26. Injection of the drug can also be extremely painful and may be associated with phlebitis and necrosis at the injection site. Treatment of adverse effects caused by melarsoprol is an additional drain on resources, needing intensive nursing and medical care. As is often the case with treatments for neglected diseases, dose regimens for melarsoprol have been established on an empirical basis29. WHO guidelines (published in 1998) suggest administration via 3 – 4 series of daily injections for 3 – 4 days, with rest periods of 7 – 10 days1, 30. No specific dose is suggested there, but examples of treatment schedules give a total dose at the end of treatment of 27 – 32.4 mg/kg. A dose of 3.6 mg/kg in 3 – 4 series of four injections a week apart is commonly used. More recently, based on pharmacological and clinical evidence, a concise treatment schedule of 2.16 mg/kg/day for 10 days (a total dose at the end of treatment of 21.6 mg/kg) has been recommended by the International Scientific Council for Trypanosomiasis Research and Control (ISCTRC) in 200322, 26, 27, 29, 31. This reduces the period of hospital stay and the workload on staff; however, it does not improve the safety nor efficacy profile. Recently, increasingly high rates of melarsoprol treatment failure (some as high as 50%32) have been reported in countries such as Uganda, Sudan, Angola, Central African Republic, and the DRC33-43. While the reasons underlying these treatment failures are unclear, melarsoprol is becoming increasingly ineffective against HAT in many regions. The toxicity of melarsoprol, the increase in treatment failures, and its painful administration emphasise the need for alternative treatments. Initially developed as an anti-cancer drug, the drug eflornithine44, 45 (α-difluoro-methyl-ornithine, DFMO – an ornithine decarboxylase inhibitor with trypanostatic effects) was shown to be effective against HAT in the 1980s, and is an efficacious and less toxic alternative to melarsoprol for treatment of T.b. gambiense HAT46-48. Retrospective analyses of large cohorts in NGO-administered treatment programmes have found field efficacy to be around 90%49. However, drug administration is complex (slow iv infusion under hospital medical supervision; the most common treatment schedule is 400 mg/kg/day at 6 hourly intervals for 14 days – a total of 56 infusions, each lasting 2 hours)1, 49. Equipment is required for iv administration, and large volumes of sterile infusion fluids are required (56 infusion bags to dilute eflornithine prior to administration). This means that although eflornithine has recently become the treatment of choice where feasible (as confirmed by clinical research in the past decade and as recommended in 2005 by the ISCTRC50), its widespread use in disease-endemic settings has been hampered by practical constraints. Studies in which the regimen was changed from a 14-day to a 7-day regimen suggested that the 7-day regimen was inferior to the 14 day one for new cases, although it may be useful for patients with a relapse following treatment with melarsoprol51-53. Its use against T.b. rhodesiense remains unadvised because of the innately reduced susceptibility of the parasite54. When correctly administered and well managed, eflornithine monotherapy is relatively well tolerated with case fatality rates from 0.7% to 1.5%, as documented in large series of cases within NGO treatment programmes46, 49. However, field experience has shown that, in absence of close medical supervision and
12
adequate nursing care, mortality rates can be much higher, mainly as a result of infusion-related infections (F Chappuis, personal communication). Eflornithine treatment is associated with adverse effects including suppression of bone marrow activity, seizures, hyperthermia, infections and gastrointestinal disorders1. The most frequently observed major drug reactions have been fever spikes, generalised seizures, and diarrhoea. In most patients, these conditions have resolved favourably with supportive care and/or temporary treatment withdrawal1. Its safety for use during pregnancy has not been established. Field evidence indicates a failure rate of approximately 10% in response to eflornithine49. As the drug is trypanostatic, there is concern about the possibility of rapidly emerging resistance, particularly when used as monotherapy45.
Nifurtimox (a synthetic 5-nitrofuran that inhibits trypanothione reductase) is an orally administered, relatively inexpensive drug (costing ~15 € per NECT treatment if not available as donation), that is licensed for the treatment of American trypanosomiasis (Chagas disease; caused by Trypanosoma cruzi). A trypanocidal drug which acts through oxidative stress, nifurtimox has been used for compassionate treatment of stage 2 HAT24, 25, 55-57, although it is not registered for this purpose. There is no consensus treatment schedule for HAT; regimens range from ~6 – 30 mg/kg/day in 3 doses for 14 – 60 days. As a monotherapy it shows poor cure rates (60% to 75%)58, 59. Nifurtimox is associated with neuropsychiatric (e.g. headaches, sleep disturbance, mood changes, paraesthesia) and gastrointestinal (e.g. anorexia, nausea) adverse-effects when used to treat Chagas disease60-62, though this is not well documented for HAT. Both eflornithine and nifurtimox are already listed on the 15th edition of the WHO Model List of Essential Medicines – eflornithine as treatment for stage 2 HAT (section 6.5.5.1), and nifurtimox for American trypanosomiasis/Chagas disease (section 6.5.5.2). The only prospect of improved case management for stage 2 patients in the next few years is combination therapy, in particular NECT, as there are few available drugs, each with serious limitations, and with no other new treatments expected to become available, with not even one new drug in clinical development. Moreover, the increasing failure rates with melarsoprol, and the risk of parasite resistance developing when eflornithine is used as monotherapy, highlights the urgent need to make NECT available to stage 2 HAT T.b. gambiense patients. Target population: HAT is found in 36 African countries, and it is estimated that 60 million people are at risk from the disease8. In 2007, 56% of T.b. gambiense cases reported were in stage 2 of the disease (P Simarro, personal communication). The target patient population for the NECT combination therapy includes all individuals diagnosed with stage 2 HAT following either active case finding or self-reporting at medical facilities.
13
9. Treatment details:
9.1 Dosage regimen, duration Dosage regimen: Combination therapy: nifurtimox plus eflornithine.
• Nifurtimox (oral tablets): 15 mg/kg/day (5 mg/kg every 8 hours) for 10 days Plus • Eflornithine (slow iv infusion over at least 45 mins): 400 mg/kg/day (200 mg/kg every 12 hours)
for 7 days
Both drugs are started on the same day. Thus, on the last 3 days nifurtimox is given alone. The decision on when the two drugs should be administered in relation to each other is based on the most practical schedule to be compatible with the overall routine of the medical centre. In the recently conducted clinical trial that forms the basis of this application (see NECT study, manuscript in preparation) eflornithine infusions were started at 6 am and 6 pm, and nifurtimox was given at 6 am, 2 pm, and 10 pm. Duration of treatment: Nifurtimox: 10 days Eflornithine: 7 days Reinfection/relapse: The definition of relapse is not well defined and is not standardized across all programmes, but it normally involves the detection of parasites in any body fluid (blood, lymph, or CSF) at any time point during 24 months post-treatment. Because parasitemia is generally low in HAT, and therefore difficult to detect, the steady and/or significant increase of WBCs in CSF can be used as a surrogate marker, as well as the reemergence of clinical signs and symptoms. In HAT, the distinction between relapse and re-infection cannot be made because no specific field-adapted tools exist. It is generally thought that the likelihood of re-infection is low as incidence rates are low in most endemic areas and most relapses are generally found to be in stage 2. If re-infection was common, most patients would be diagnosed in stage 1 because of the slow evolution of the disease. Diagnosis: The NECT combination should only be administered to individuals diagnosed with stage 2 HAT T.b. gambiense according to the currently used diagnostic protocols (see section 8.1). Treatment facilities: The NECT combination can be administered to individuals in the same facilities that are currently used to treat stage 2 HAT patients (see section 9.3 below on information related facilities and skills needed).
14
9.2 Reference to existing WHO and other clinical guidelines WHO guidelines: The most recent guidelines from WHO for the treatment of stage 2 HAT are contained in Control and Surveillance of African Trypanosomiasis, 19981. Recommended treatments are melarsoprol, eflornithine or nifurtimox. Melarsoprol:
• 3 – 4 series of daily injections for 3 – 4 days, with rest periods of 7 – 10 days. • No specific dose is suggested, but examples of treatment schedules give a total dose at the end
of treatment of 27 – 32.4 mg/kg. Eflornithine:
• For T.b. gambiense HAT: 400 mg/kg/day in four divided doses for 14 days (adults). • The dosage for children should ideally be based on body surface area, to take into account the
more rapid elimination of the drug. The recommended dose for children is 4 g per m2. Nifurtimox:
• Dosages vary: 15 – 20 mg/kg/day in three divided doses. Treatment duration: 30 – 60 days. Additional treatment (stage 2 HAT treated with melarsoprol):
• Concurrent treatment with oral corticosteroids. Relapse:
• Relapse after melarsoprol treatment: eflornithine or nifurtimox. • Relapse after eflornithine: not mentioned within 1998 guidelines.
There has been no update to the 1998 WHO guidelines in the last 10 years. However, more recent expert consensus has emerged around the use of melarsoprol: at the 27th ISCTRC meeting in Pretoria, South Africa, in 200331, a concise treatment regimen of 10 consecutive days of melarsoprol treatment was recommended, based on new clinical evidence22, 27. In addition, MSF (which has been one of the NGOs at the frontline of treating HAT patients in the past twenty years) also developed guidelines for its field personnel. Summary of MSF guidelines (2005)63:
• Eflornithine is listed as a first line stage 2 (T.b. gambiense HAT) treatment at 100 mg/kg (150 mg/kg for children below age 12 years) iv four times daily for 14 days.
• As a second line treatment, where melarsoprol was given first line: eflornithine 100 mg/kg iv four times daily for 14 days.
• As a third line treatment: eflornithine 100 mg/kg (150 mg/kg for children below age 12 years) iv four times daily for 14 days + nifurtimox 15 mg/kg (20 mg/kg for children below age 15 years) oral, divided in 3 doses for 14 days.
• In HIV-positive individuals, in areas with known resistance to melarsoprol, MSF suggest a combination of melarsoprol and nifurtimox for 10 days or eflornithine and nifurtimox. If nifurtimox is not available, then they suggest considering a combination of melarsoprol and eflornithine (melarsoprol 2.2 mg/kg for 10 days and eflornithine 100 – 150 mg/kg four times daily for 7 days).
15
9.3 Need for special diagnostic or treatment facilities and skills
In most HAT-endemic countries, HAT diagnosis and treatment is organised through vertical programmes that ensure the necessary specific training and equipment required. Compared with currently used practice, no additional special diagnostic or treatment facilities are needed. NECT will be administered to patients in the same facilities and with the same healthcare staff as are currently treating stage 2 patients.
• In facilities using eflornithine as first-line treatment, human and physical resources will be saved because the treatment regimen proposed is shorter and simpler than current therapy
• In facilities using melarsoprol, additional training related to treatment infusions will be needed; however, the reduction of serious complications will save resources.
16
10. Summary of comparative effectiveness (and/or efficacy) This application proposes the use of a combination of nifurtimox-eflornithine (NECT) as an alternative treatment for stage 2 T.b. gambiense HAT. A recently completed randomised controlled non-inferiority study, which was carried out in HAT-endemic regions (ie. rural health sites) and which was conducted according to good clinical practice (GCP) research standards, compared NECT with eflornithine monotherapy. Results show that both treatments are well tolerated in the context of stage 2 HAT, and that the efficacy of NECT is non-inferior to eflornithine monotherapy. At 18 months after treatment, overall cure rates of over 96% were observed with NECT and over 90% with eflornithine monotherapy. Significantly, both treatments show markedly less mortality than melarsoprol (case fatality rates of 1-2% for NECT and eflornithine, as compared with 5-6% historical evidence for melarsoprol). Considering its improved ease of use, the overall effectiveness of the combination is expected to be superior to both eflornithine monotherapy and melarsoprol. The NECT combination has several advantages over eflornithine monotherapy (which is currently the best available first-line treatment):
• The number of slow intravenous infusions of eflornithine is reduced from 56 to 14. • The treatment duration is reduced from 14 to 10 days. • The risk of iv catheter-related local or systemic bacterial infection is reduced. • It is more practical for procurement, transport, storage and distribution. • Drug resistance is less likely to develop (as the two drugs are co-administered and have different
modes of action). • It is cheaper than eflornithine monotherapy.
To date, the high complexity of use and the cost of transport have remained the main barriers to the introduction of eflornithine as a safer alternative to melarsoprol. NECT will be a more practical and cheaper alternative to eflornithine monotherapy in replacing the highly toxic and sometimes ineffective melarsoprol. The clinical trial data submitted in this application indicate that NECT is safe and effective in patients with stage 2 HAT. In addition, the use of eflornithine in combination with nifurtimox may help avert the development of drug resistance.
10.1 Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data)
A systematic review, which forms the basis for this section, was undertaken of reported clinical evidence on the efficacy and/or safety of stage 2 HAT treatment, found through Medline searching since 1990 (Harhay et al. manuscript submitted for publication). A Cochrane review on stage 2 HAT chemotherapy is ongoing (Seixas and Lutje, manuscript in preparation) and information has been shared for the purpose of this application.
17
A number of papers have documented the use of melarsoprol22, 26, 27, 46, 47, 58, 64, 65, eflornithine monotherapy51, 53, 66 and nifurtimox56, 59 for the treatment of HAT. Three published papers have reported on the safety and efficacy of the nifurtimox-eflornithine combination67-69. The recently completed randomised controlled trial (RCT) (NECT study, manuscript in preparation) has provided the pivotal evidence on the combination’s safety and efficacy; this evidence forms the basis of this EML application and will be submitted for publication in the coming months.
10.2 Summary of available data (appraisal of quality, outcome measures, summary of results)
A summary of trial data is provided in Table 4 below. Table 4. Summary of trial data. Study site Trial type Study Total n°
of patients
N° of patients receiving N+E
Results
Omugo, Uganda (BTT)67
Randomised open label trial (terminated early)
Compared efficacy/safety of three drug combinations: • melarsoprol plus nifurtimox, M+N • melarsoprol plus eflornithine, M+E • nifurtimox plus eflornithine, N+E Follow up: 24 months post-treatment
54
17 Cure rate: ITTa • M+N – 44.4% • M+E – 78.9% • N+E – 94.1% PPb • M+N – 50.0% • M+E – 83.3% • N+E – 100.0%
Yumbe, Uganda (NECS)69
Prospective case series
All patients received N+E combination Follow up: 24 months post-treatment
31 31 Cure rate: ITTa • N+E – 90.3%-
93.5% PPb • N+E – 100.0%
Multi-Centre: Nkayi, Republic of Congo (RoC)68; Isangi, Dipumba and Katanda, DRC (NECT study, manuscript in preparation)
Randomised open label active control phase III non-inferiority trial
Compared efficacy/safety of the NECT combination over that of standard eflornithine monotherapy Follow up: 18 months post-treatment
286 143 Cure rate: ITTa • E – 91.6 % • NECT – 96.5% PPb • E – 91.7 % • NECT – 97.7%
All trials were carried out on patients diagnosed with stage 2 T.b. gambesiense HAT. BTT = Bi-therapy trial; NECS = Nifurtimox-eflornithine case series; NECT = Nifurtimox-eflornithine combination therapy. aITT = Intention to treat population includes all patients randomised; deaths during treatment or follow-up are regarded as treatment failures. bPP= Per protocol population includes only relapses and HAT-related deaths considered failures. M = Melarsoprol; N = Nifurtimox; E = Eflornithine.
The first study (bi-therapy trial, BTT) investigating a combination of eflornithine and nifurtimox (N+E) for stage 2 HAT T.b. gambiense was carried out in Omugo, Uganda by Epicentre and MSF during 2001 – 2004 and reported by Priotto and colleagues in 200667. The study compared the three different combinations of melarsoprol, nifurtimox, and eflornithine. For the arm given the N+E combination,
18
eflornithine was given at 100 mg/kg four times a day for 7 days, together with 10 days of oral nifurtimox given at 5 mg/kg three times a day. After enrolling a total of 54 patients in the three arms, the trial was terminated prematurely due to the high toxicity (including fatalities) observed in the melarsoprol-containing arms together with the fact that the Ugandan government had meanwhile adopted the use of eflornithine monotherapy as a first-line treatment. The favourable tolerability in the 17 patients who had received N+E combination in this trial, combined with a good clinical response, prompted Epicentre and MSF to further investigate this combination in a case series of 31 patients (NECS, nifurtimox-eflornithine case series). This reinforced the concept of the good tolerability of the N+E combination, in particular there were no treatment-related fatalities69. Furthermore, no relapses were observed during the 24 months follow-up of the 48 patients treated with the N+E combination in these 2 studies. Table 5 summarises the efficacy of the two Uganda (BTT and NECS) studies (copied with permission from Checchi et al.69) Table 5. Efficacy endpoints and estimates (for N+E combination). BTT (n= 17)
NECS (n=31) BTT+NECS (n=48)
Endpoints n % n % n % Died within 30 days of treatment start
0 0.0 0 0.0 0 0.0
Died during follow upa 1 5.9 2 6.5 3 6.3 Lost to follow-up 0 0.0 1 3.2 1 2.1 Relapsed 0 0.0 0 0.0 0 0.0 Cured at 24 months 16 94.1 28 90.3 44 91.7 Efficacy estimates n % (95% CI) n % (95% CI) n % (95% CI) ITT analysis Cured 16 94.1 29 93.5 45 93.8 Patients in analysis 17 (71.3 – 99.9) 31 (78.6 – 99.2) 48 (82.8 – 98.7) PP analysis Cured 17 100.0 31 100.0 48 100.0 Patients in analysis 17 (80.5 – 100.0)b 31 (88.7 – 100.0) b 48 (92.6 – 100.0) b BTT = Bi-therapy trial; NECS = Nifurtimox-eflornithine case series ITT = Intention to treat. PP = Per protocol. CI = confidence interval. aNone of the deaths were judged HAT- or treatment-related. bOne-sided confidence interval.
Following these first two studies indicating the potential of this combination, a confirmatory multicentre randomised control trial (RCT) was set up by Epicentre and MSF in 2003, comparing the N+E combination to standard eflornithine monotherapy. While the drug dose for the combination was the same as that used in the studies mentioned above (i.e. 400 mg/kg/day for 7 days), the administration schedule was further simplified: eflornithine in the combination was administered at 12 hourly (rather than 6 hourly) intervals, reducing the total number of infusions to 14. Nifurtimox in the combination was administered at 5 mg/kg, three times a day for 10 days. This simplified N+E treatment schedule is hereafter referred to as the nifurtimox-eflornithine combination therapy (NECT). The study was designed to test non-inferiority for the efficacy of the combination with 95% confidence and with a 10% margin on non-inferiority; accounting for a maximum 20% drop-out rate, a sample size of
19
280 was calculated to achieve statistical significance. Initially set up in Nkayi, Republic of Congo (RoC)68, the study was subsequently extended, in collaboration with Drugs for Neglected Diseases initiative (DNDi), to 3 sites (Isangi, Dipumba and Katanda) in the DRC, in 2 different disease foci (see figure 1). Patients who were 15 years and older, non-pregnant women, with parasitologically confirmed stage 2 HAT, and who had not received prior stage 2 HAT treatment were enrolled in the study. The primary outcome measure was efficacy at 18 months post-treatment. Figure 1. Map showing location of study sites in RoC (Nkayi) and in DRC (Dipumba, Isangi, and Katanda).
Baseline characteristics of the study population are given in the appendix – no significant differences were seen among the study arms. This trial was conducted in accordance with international GCP research standards (confirmed by independent audit in October 2007) and is one of the few RCTs to be conducted and completed in the field of HAT, given the lack of health infrastructure, research capacity, political stability, and remote location of patients. The independent auditors were able to confirm that the rights and safety of trial subjects had been safeguarded, and to confirm the integrity of the NECT trial data. No critical findings were found during the audit and they concluded: “There is nothing to deter from the completion of the follow-up and the generation of the envisaged reports. The trial data is reliable and any decisions made based on the conclusions of data analysis(es) should be accepted as valid.”
20
The 18-month follow-up rate of the study was balanced between the two arms and was 93%, which is which is exceptionally high for these types of studies and further contributes to the robustness of these data (NECT study, manuscript in preparation). Only 3/286 patients (1.0%) were completely lost to follow-up. Table 6 below summarises the primary efficacy endpoint of the NECT study, which was cure rate at 18-month follow-up after treatment. Table 6. Efficacy outcome of NECT study.
Arm
Total Cured
Cure rate (%)
Δ cure rate (%)
(E - NECT) One-sided 95%
CI* (%) E 143 131 91.6 -0.3 ITT
NECT 143 138 96.5 -4.9
E 142 131 92.3 -1.4 MITT
NECT 141 138 97.9 -5.6
E 133 122 91.7 -1.5 PP
NECT 132 129 97.7 -6
ITT = Intention to treat; MITT = Modified ITT (excluding patients completely lost to follow-up); PP = Per protocol. * According to method of Blackwelder: Upper limit of a two-sided 90% CI around the difference (Δ) of cure rates.
The test of non-inferiority showed that the one-sided 95% confidence interval (or upper limit of the 90% CI) was less than the target difference (Δ) of 10% in all populations analysed, clearly establishing the non-inferiority of the N+E combination (Table 6 and Figure 2). Figure 2. Overall cure rates. Non-inferiority analysis.
The x-axis shows Δ (delta) = difference between cure rates (Eflornithine – NECT); the shaded area to the left of Δ=10% shows the non-inferiority zone; the area to the left of Δ=0% is the superiority zone.
21
The probability of event-free survival, defined as survival without relapse, was also examined. In Figure 3, the Kaplan-Meier curve represents the duration of event-free survival up to the last follow-up assessment in the ITT population. The log-rank test for equality of survival functions shows a significant statistical difference for NECT (confirmed for all populations analysed: ITT, MITT, PP). Figure 3. Survival analysis showing probability of event-free survival for ITT population (log rank test, p = 0.0497).
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Pro
babi
lity
of e
vent
free
sur
viva
l
0 6 12 18 24Months since start of treatment
E N+E
10.3 Summary of available estimates of comparative effectiveness Overall, the available evidence on use of the NECT combination therapy shows that the safety and efficacy of the combination is non-inferior to that of eflornithine monotherapy, with markedly less mortality than melarsoprol (see Table 7). Table 7. Case fatality and cure rates following different treatments. Treatment Case Fatality Rate
(died during treatment) Cure Rates at 18 or 24 months
Melarsoprol22 5.9%, 10-day concise tx; 5.3%, standard tx (IMPAMEL); 9.4%, standard tx in literature
70 – 92% (24 month)
Eflornithine (Cohort study)49 1.7% 89-90% (24 month) Eflornithine (NECT study, manuscript in preparation)
2.1% 91-92% (18 month)
NECT68 (NECT study, manuscript in preparation)
<1% 96-98% (18 month)
22
11. Summary of comparative evidence on safety The safety data discussed in this section will focus on major clinical and laboratory adverse events (AEs), and deaths, comparing the NECT combination therapy with eflornithine monotherapy based on the recently conducted randomised controlled NECT trial. Comparisons with melarsoprol will rely on retrospective data as no trial has compared melarsoprol to eflornithine or the NECT combination. It is difficult to determine safety based on clinical trials alone. As such, pharmacovigilance systems are essential to monitor the long term safety of programmatic use of the NECT combination therapy; however, expectations should be limited given the state of the overall health system in most affected countries.
11.1 Estimate of total patient exposure to date
A total of 143 patients were exposed to the NECT combination therapy in the multicentre NECT trial. Another 48 patients were exposed to NECT combination in the two earlier studies (BTT and NECS)67, 69 which used a slightly different administration schedule, but the same daily and total drug doses67, 69, making a total of 191 patients exposed to NECT combination therapy on whom data have been reported. The NECT combination has also been used on a compassionate need basis in a number of HAT patients. For instance, it is known that MSF programmes (Ibba, Tambura, and Yambio in Sudan, Omugo in Uganda, and Mossaka and Nkayi in RoC) have treated at least 50 additional HAT patients with NECT* on a compassionate basis since 2000 (M Balasegaram/G Priotto, personal communications). The NECT combination therapy has also been used as rescue treatment in some treatment centres in DRC after eflornithine failure. Finally, another 55 patients have been treated in Uganda in an another study comparing the same, simplified NECT combination regimen with eflornithine monotherapy (ongoing TDR study not to be concluded until end-2009).
11.2 Description of adverse effects/reactions
Safety assessment in the NECT study was done according to GCP guidelines, with careful reporting of all adverse events (AEs). In-hospital safety was assessed by AE reporting which included severity grading per CTC criteria and relatedness to treatment. Treatment-related mortality was evaluated over an extended evaluation period of 30 days after the start of the treatment; a total of 4 deaths occurred among the 286 treated patients, 3 in the eflornithine monotherapy group and one in the NECT group. This is considerably less than would be expected with melarsoprol and similar to previous experience with eflornithine montherapy. There is no evidence for increased mortality or other serious adverse events (SAEs) with the NECT combination.
*In compassionate use cases, both drugs were generally given for 14 days and children received 600 mg/kg/day of eflornithine and 20 mg/kg/day of nifurtimox.
23
The major safety endpoints assessed in the NECT study were:
• The number of patients with adverse events during hospitalisation by severity and relationship to study treatment and onset time.
• The proportion of patients without grade 3 and 4 AEs (Common Toxicity Criteria guidelines, NIH/NCI) during the hospitalisation period.
• The number of treatment-emergent deaths (defined as deaths within 30 days from initiation of treatment) by likely cause of death (HAT, adverse events of the treatment, causes unrelated to HAT or treatment for HAT, unknown causes).
• The number of patients with treatment-emergent SAEs by relationship to treatment and onset time (during hospitalisation, plus deaths ≤ 30 days from initiation of treatment).
• The number of patients with permanently interrupted treatment.
• The number of patients with temporary treatment suspensions (at least 1, more than 1).
An AE was defined as any untoward medical occurrence (any unfavourable and unintended sign, symptom or disease, including an abnormal laboratory finding) in temporal association with the use of the investigational treatment that may or may not be causally related to it. An AE was defined as serious (i.e. an SAE) if it was fatal or life-threatening, required or prolonged a hospitalisation, or resulted in persistent or significant disability, a congenital anomaly/birth defect, resulted in an important medical event that may not be immediately life threatening or directly result in death or hospitalisation, but which may jeopardise the patient or may require intervention to prevent the other outcomes listed above. Major AEs were defined as AEs of intensity graded at level 3 (severe) and 4 (very severe), per the Common Toxicity Criteria v2.0 guidelines (NIH/NCI, 1999: available at http://ctep.cancer.gov/reporting/ctc_archive.html). Deaths occurring within 30 days after the start of treatment or resulting from an event that started within that period were regarded as temporally associated with treatment and therefore recorded as AE, even if they occurred after the hospitalisation period. They are, by definition, SAEs. In the following tables, only the AEs regarded as ‘related’ (1,262 in total - having been reported as ‘unlikely’, ‘possibly’, ‘probably’, ‘certainly’ related or ‘unknown’) are included; the 101 ‘not related’ events are not reported here. Clinical AEs were very frequent. However, it must be kept in mind that, for most events, it is difficult to discern the causality between the disease itself, other co-morbidities, concomitant treatments and the study treatment. In our description we take a conservative approach: all events are regarded as related to the treatment unless the investigators were certain to the contrary.
24
Table 8 summarises the number and proportion of patients having at least one AE (including all related clinical and serious AEs). Of 286 patients, 268 (93.7%) had at least one related clinical AE. Seven patients experienced treatment-related SAEs, of which 6 received eflornithine monotherapy and 1 received NECT. A total of 61 patients experienced related major AEs – the proportion of patients suffering major adverse events (clinical and laboratory) was significantly lower (p=0.002) in the NECT arm. Table 8. Number of patients presenting at least one related AE.
E (n=143) NECT (n=143)
n % n % p-value
N° of patients having at least one related AE 138 96.5 136 95.1 0.555
N° of patients having at least one related clinical AE 134 93.7 134 93.7 1
N° of patients having at least one related serious AE 6 4.2 1 0.7 0.120
N° of patients whose treatment was interrupted 9 6.3 1 0.7 0.019
N° of deaths treatment-related deaths 3 2.1 1 0.7 0.622
N° of patients having at least one related major AE 41 28.7 20 14.0 0.002
The most frequently seen related clinical and laboratory AEs are shown in Table 9. Some AEs were more frequent in the eflornithine arm: diarrhoea, fever, infection, anorexia, and hypertension. Nausea and/or vomiting were more frequently seen with NECT. Table 9. Most frequently seen adverse events during hospitalisation, by study arm. Occurrence of clinical AEs E (n=143) N+E (n=143) p-value
n % n %
Neurological
Seizures 13 9.1 18 12.6 0.342
Anxiety/agitation 11 7.7 4 2.8 0.109*
Dizziness 24 16.8 26 18.2 0.756
Inner ear disturbance 7 4.9 10 7.0 0.365
Insomnia 14 9.8 14 9.8 1.000
Gastrointestinal
Anorexia 20 14.0 36 25.2 0.017
Abdominal pain 42 29.4 35 24.5 0.351
Diarrhoea 41 28.7 9 6.3 0.000
Nausea and/or Vomiting 29 20.3 69 48.3 0.000
Cardiovascular
Arrhythmia 31 21.7 27 18.9 0.556
Hypertension 19 13.3 6 4.2 0.006
Other
Fever 61 42.7 37 25.9 0.003
Infection 32 22.4 18 12.6 0.029 * Fisher’s exact test
25
Table 10 shows the most frequently seen grade 3 &4 AEs (by event). Some AEs, namely fever and neutropenia, were more frequent in the eflornithine arm. Table 10. Number of most frequent clinical and laboratory AEs (grade 3 & 4), by study arm. Major AEs E (n=143) N+E (n=143)
n % n % p-value
Seizures 6 4.2 6 4.2 1.000
Coma 3 2.1 1 0.7 0.622
Confusion 1 0.7 2 1.4 1.000
Hallucinations 1 0.7 1 0.7 1.000
Other neurological 2 1.4 3 2.1 -
Gastrointestinal 2 1.4 2 1.4 -
Fever 18 12.6 7 4.9 0.021
Infection 7 4.9 1 0.7 0.066
Hypertension 3 2.1 0 0.0 0.247
Headache 2 1.4 1 0.7 1.000
Acute Respiratory Distress 1 0.7 1 0.7 1.000
Other clinical AE 2 1.4 2 1.4 -
Total of major clinical AEs 48 33.6 27 18.9 -
Total of patients concerned 33 23.1 18 12.6 0.020
Anemia 1 0.7 2 1.4 1.000
Leukopenia 0 0.0 0 0.0 1.000
Neutropenia 10 7.2 2 1.4 0.035
Total of major laboratory AEs 11 7.7 4 2.8 -
Total of patients concerned 11 7.7 4 2.8 0.109
11.3 Identification of variation in safety due to health systems and patient factors No information available.
11.4 Summary of comparative safety against comparators Nifurtimox+eflornithine combination versus eflornithine The safety data from the multicentre NECT trial confirm that the combination is well tolerated in the context of stage 2 HAT, with no major safety concerns for either the NECT combination or eflornithine monotherapy. The data show a statistically significant difference in related major adverse events in favour of the NECT combination as compared with eflorntihine monotherapy (p=0.002).
26
Melarsoprol It is well established that melarsoprol can result in severe adverse reactions which, in some cases, are deadly – the most worrying of these adverse reactions being reactive encephalopathy. Table 11 summarises the severe AEs documented with melarsoprol treatment in 2 recent studies that examined the concise (10 days) regimen (IMPAMEL I and II) and compared these to historical data with the earlier standard course (table copied with permission from Schmid et al, 200522). Table 11. Summary of severe adverse events documented with melarsoprol.
Impamel II Centre History Impamel I Literature
10-day
treatment (N = 2020)
Standard treatment (N = 2215)
10-day treatment (N = 250)
Standard treatment (N = 250)
Standard treatment
mean % (range)a
n° (%) n° (%) n° (%) n° (%) % (range)
Fatalities28, 70-72 119 (5.9) 117 (5.3) 6 (2.4) 6 (2.4) 9.4 (2.7 – 34) Encephalopathic syndromes (ES)b,28,
72, 73 152 (7.5) 184 (8.3) 14 (5.6) 14 (5.6) 4.7 (1.5 – 23.5)
Fatal ES (Grade 3 ES) 80 (4.0) 87 (3.9) 6 (2.4) 6 (2.4) 4.1 (3.3 – 34)
ES case fatality rate (% fatal ES) 52.6 47.3 42.9 42.9 43.8 (33 – 100)
Skin reactions28, 74 166 (8.2) 35 (1.6) 23 (9.2) 13 (5.2) < 3
Bullous eruptions 17 (0.8) 4 (0.2) 3 (1.2) 1 (0.4) < 1
Maculopapular eruptions 138 (6.8) 20 (0.9) 12 (4.8) 6 (2.4) ND
Pruritus 66 (3.3) 11 (0.5) 8 (3.2) 6 (2.4) 5
Polyneuropathiesc, 28, 75 54 (2.7) 24 (1.1) 2 (0.8) 1 (0.4) < 10
Febrile reaction74 233 (11.5) 72 (3.2) 15 (6.0) 12 (4.8) 12
Headache 146 (7.2) 43 (1.9) ND ND ND
Diarrhoea76, 77 45 (2.2) 19 (0.9) 6 (2.4) 4 (1.6) < 25
Hypotension1 16 (0.8) 19 (0.9) ND ND < 1
Jaundice1 5 (0.2) 3 (0.1) ND ND < 3 Data are number (%) unless otherwise indicated. aN highly variable, often only percentages were published bGrades 2 (convulsion, coma) and Grades 3 (fatal) cmotor or sensitivity polyneuropathies
ND = Not determined or no data available. Melarsoprol versus eflornithine While no comparative trials have been conducted with eflornithine and melarsoprol, historical data including retrospective comparative analyses have clearly shown the superior safety profile of eflornithine over melarsoprol.
27
In a retrospective analysis in an MSF-treatment centre in Kiri, southern Sudan, patients with second-stage human African trypanosomiasis treated in 2003 with eflornithine (n=251) had an adjusted relative risk of death of 0.2 and experienced significantly fewer cutaneous and neurological adverse effects than did patients who were treated with melarsoprol in 2001 and 2002 (n=708) (Table 12). Table 12. Comparison of outcomes for patients with stage 2 HAT treated with eflornithine and melarsoprol in Kiri, Kajo-Keji County, southern Sudan. Data from southern Sudan (2000 – 2003). Copied with permission from Chappuis et al.46 Characteristic Eflornithine
(n = 251) Melarsoprol (n = 708)
p
Mortality during treatment 2 (0.8) 25 (3.5) .024
Adverse effects of treatment
Fever 27 (10.8) 218 (32.3) <.001
Hypotension 0 (0.0) 6 (0.9) .13
Hypertension
All 8 (3.2) 48 (7.3) .02
Severea 0 (0.0) 17 (2.4) .013
Macular rash
All 1 (0.4) 49 (7.5) <.001
Severeb 1 (0.4) 18 (2.5) .036
Bullous rash 0 (0.0) 4 (0.6) .22
Jaundice 0 (0.0) 8 (1.2) .08
Diarrhoea
All 52 (20.9) 68 (10.3) <.001
Severec 4 (1.6) 18 (2.5) .39
Headaches
All 105 (42.2) 270 (39.7) .5
Severeb 0 (0.0) 111 (15.7) <.001
Peripheral neuropathy
All 5 (2) 78 (11.8) <.001
Severed 0 (0.0) 12 (1.7) .038
Tremor
All 6 (2.4) 149 (22.7) <.001
Severee 0 (0.0) 18 (2.5) .011
Acute reactive encephalopathyf
All 1 (0.4) 80 (11.3) <.001
Grade 1 0 (0.0) 21 (3) .006
Grade 2 1 (0.4) 59 (8.3) <.001
Date shown are number (%) of patients, unless otherwise indicated. aSeverity is defined as systolic blood pressure of >180 mm Hg and/or diastolic blood pressure of >100 mm Hg. bSeverity is defined as an event leading to interruption of treatment. cSeverity is defined as bloody diarrhoea and/or signs of dehydration. dSeverity is defined as an event leading to motor weakness, walking disability and/or interruption of treatment. eSeverity is defined as an event impairing simple activities. fGrade 1 acute reactive encephalopathy is defined as new onset of psychosis during treatment. Grade 2 acute reactive encephalopathy is defined as prolonged or repeated convulsions (status epilepticus) or rapid deterioration of the state of consciousness (with a Glasgow Coma Score of ≤8).
28
In another retrospective analysis in an MSF treatment centre in the RoC (Table 13), eflornithine treatment was recommended as a better first-line therapy for stage 2 HAT patients, based on superior safety profile (case fatality rate of 1.7% with eflornithine as compared with 4.8% with melarsoprol ) and improved treatment outcome (8.1% relapse rate compared to 14 – 15.5% with melarsoprol after 12 months follow-up). Table 13. Case fatality rate and risk factors for death within 30 days after admission among patients with stage 2 T.b. gambiense HAT (n = 661) treated with melarsoprol or eflornithine, RoC, April 2001 – April 2004. Adapted from Balasegaram et al, 200647 (p783), data from Republic of Congo (2001-2005). Baseline risk factor Case fatality rate Crude odds ratioa Adjusted odds ratiob
Drug Regimen
Eflornithine 1.7% (5/288) 1.00 1.00
Melarsoprol (standard) 4.8% (15/311) 2.87 (1.03 – 8.00) 2.87 (1.03 – 8.00)
Melarsoprol (short course) 6.5% (4/62) 3.90 (1.02 – 14.98) 3.90 (1.02 – 14.98) aValues in parentheses are 95% confidence intervals. bAdjusted odds ratios based on logistic regression model with P = 0.05 (for goodness of fit).
29
12. Methodological considerations related to HAT studies HAT presents a number of challenges in the design and conduct of clinical studies. According to the WHO Recommendations of the 2004 Informal Consultation on Issues for Clinical Product Development for HAT78, ‘the conduct of clinical studies in patients with HAT faces several difficulties which are rarely encountered simultaneously in clinical trials for other tropical diseases, and rarely in non-tropical diseases of the developed countries’. These include the facts that:
• Disease-endemic regions are difficult to access, have a poor healthcare infrastructure, and suffer extreme poverty.
• There is a lack of suitable sites and trained staff. • Endemicity, even in disease foci, is low. • Non-specific signs and symptoms mean that a large number of individuals need to be screened to
identify patients. • There are no ubiquitous diagnostic and treatment standards. • Successful treatment causing the patient base to be eliminated. • A long follow-up period to determine efficacy. • Poor follow up due to patient ‘loss’ – e.g. due to a lack of patient transport, or high patient
mobility. • Civil unrest and political instability. • Patients fear of lumbar puncture (particularly if they experience no signs and symptoms of the
disease). • Lack or inappropriately trained/functioning of review boards in the affected countries (ethics
committee, research committee, regulatory etc.). Given this context, it’s important to recognize the accomplishment of the NECT study, one of the few randomised controlled trials to be successfully completed in the field of HAT. The study has been compliant with international Good Clinical Practice (GCP) standards as verified through an independent audit, and has achieved 93% patient follow-up at 18 months. Additional considerations related to NECT study design This application proposes that NECT combination becomes the alternative treatment for stage 2 T.b. gambiense HAT over melarsoprol which remains the drug most commonly used, in particular when eflornithine monotherapy cannot be introduced due to logistic and human resource constraints. In 2007, 68% of stage 2 patients were still being treated with melarsoprol (see Table 3). Direct comparative studies versus melarsoprol are not considered to be ethical as the drug is known to be toxic and is associated with a proportion of treatment-related deaths. Therefore, the NECT combination has been assessed in comparison with eflornithine monotherapy, the current first-line stage 2 HAT treatment, in a randomised, controlled, non-inferiority trial. This design was chosen based on the rationale that, if both the safety and efficacy of the combination therapy were comparable with eflornithine monotherapy, the far greater ease of use of the combination therapy would be an advantage of practical significance, as this today is the major barrier for the wider utilisation of eflornithine. In addition, the combination is expected to provide protection against the possible rapid development of resistance that can be expected when giving a trypanostatic drug, with a narrow therapeutic window, as monotherapy.
30
13. Summary of available data on comparative cost and cost effectiveness within the pharmacological class or therapeutic group:
13.1 Range of costs of the proposed medicine It is difficult to assess what the exact costs might be for NECT as there are a number of variable factors, but it can be concluded that the combination treatment will offer a substantial reduction in cost as compared with 1 treatment course of eflornithine monotherapy (given a reduction in cost of transport and storage as well as a reduction in the number of iv infusions and treatment days; see Table 14). Transportation and storage costs remain critical issues for national control programmes, especially for distribution within countries. In some countries infusion fluids can be obtained locally, thereby substantially reducing the costs of transport. The drugs are provided free-of-charge through a donation programme organised by the WHO. Eflornithine and all materials needed for the iv infusions (provided as a kit), are currently supplied to HAT control programmes free-of-charge by the WHO, thanks to an agreement made with sanofi-aventis in 2001 and renewed until 2011. Bayer, the manufacturer of nifurtimox, currently provides the drug free-of-charge to WHO for the treatment of Chagas disease. It is anticipated that a similar donation will be made by Bayer for the use of nifurtimox in HAT. Bayer has also made donations for compassionate use of nifurtimox for HAT treatment and for clinical trials. Table 14. Comparison of treatment kits, including drugs and consumables needed for infusion (cost in Euros, €). Calculations based on data provided by WHO (Pere Simarro, personal communication). 1 eflornithine
treatment 1 NECT treatment
Cost of kit content (excl. HAT drugs)a€ 86.5 € 27.5 € Eflornithine 360 € 180 € Nifurtimox - 15 € Volume (dm3) 85 dm3 25 dm3 Weight per treatment (kg) 19 kg 9 kg Number of treatments per container for shipment 520 1,760 Cost for transportb € 22 € 6 € Cost per treatment € Excl. cost HAT drugs
109 €
34 €
Cost per treatment € Incl. cost HAT drugs
469 € 228.5€
Treatment duration 14 days 10 days aDrugs are made available free-of-charge via the WHO drug donation programme. The composition of the eflornithine kit is given in Section 6, Table 2; the expected cost of the NECT-kit was calculated derived from this. bExample for kits transported to Kinshasa.
Today’s eflornithine kits include 2 adult treatments and all related materials needed for the proper administration of the treatment (see Section 6, Table 2). It is expected that, considering a comparable weight and volume per kit, the NECT combination kits will contain 4 full treatments.
31
13.2 Comparative cost effectiveness presented as range of cost per routine outcome (e.g. cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality-adjusted life year gained)
No detailed analysis has been conducted on the cost and cost effectiveness of the NECT combination treatment compared with current treatments for stage 2 T.b. gambiense HAT (melarsoprol and eflornithine monotherapy). However, considering that the safety and efficacy is comparable to eflornithine, it can be concluded that the NECT combination will be more cost-effective as it uses less eflornithine, less iv infusion equipment and infusion fluids, less staff time in administering and monitoring the treatment, and treatment duration is shorter. The unacceptably high toxicity of melarsoprol should preclude its consideration. Despite high cost implications for eflornithine (i.e. drug infusion materials, and medical supervision), eflornithine monotherapy (14 day regimen at 400 mg/kg/day, given at 6 hourly intervals) was shown to be a cost-effective alternative (according to WHO choice criteria) to melarsoprol monotherapy in an MSF treatment setting in Angola because eflornithine saves more lives than melarsoprol48. The paper showed that:
• The cost/patient was 504.6 US dollars (USD) for melarsoprol and 552.3 USD for eflornithine • The cost/life saved was 527.5 USD for melarsoprol and 559.8 USD for eflornithine without cost of
drugs* (this increases to 600.4 USD and 844.6 USD per patient saved and 627.6 USD and 856.1 USD per life saved when cost of drugs are included)
*anti-trypanosomal drugs are currently available free-of-charge due to a WHO donation programme arranged with manufacturers.
The proposed NECT has considerable additional cost advantages over standard eflornithine monotherapy. Not only is the cost of the drug reduced (as less is needed per patient), but the costs of drug delivery are also substantially reduced as the number of infusions are reduced from 56 per patient to 14 (see section 13.1) 14. Summary of regulatory status of medicines Eflornithine was registered for the treatment of African trypanosomiasis in 1991. It is currently registered in the USA and France. Nifurtimox is registered for treatment of Chagas disease in Argentina, Chile, Colombia, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, and Uruguay.
32
15. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) International Pharmacopoeia (4th edition, 2006): Eflornithine: No Nifurtimox: Yes, listed as Nifurtimoxum-Nifurtimox in antitrypanosomal drug category British Pharmacopoeia (2008): Eflornithine: No Nifurtimox: No United States Pharmacopeia: Eflornithine (see http://www.usp.org/standards/international/guidelines.html) Nifurtimox (see http://www.usp.org/standards/international/guidelines.html) 16. Proposed text for WHO Model Formulary The NECT co-administered combination therapy of oral nifurtimox and intravenous eflornithine in this application is proposed for the anti-infective medicines/antitrypanosomal medicines/African trypanosomiasis section/medicines for the treatment of 2nd stage African trypanosomiasis subsection (to be used exclusively for the treatment of the 2nd stage of Trypanosoma brucei gambiense infection) of the WHO Model Formulary under the heading ‘Nifurtimox + eflornithine’. Dosage form and strength: Tablet (nifurtimox): 120 mg + Injection (eflornithine): 200 mg (hydrochloride)/ml in 100ml bottle. The co-administered combination therapy, referred to here as the NECT combination, is: Nifurtimox: 10 days at 15 mg/kg/day (5 mg/kg every 8 hours) administered orally plus Eflornithine: 7 days at 400 mg/kg/day (200 mg/kg every 12 hours) administered as an iv infusion over 2 hours. ATC code: To be provided by WHO Listing: To be provided by WHO Disease indication: Therapy for stage 2 (late stage, meningo-encephalitic stage) African trypanosomiasis (sleeping sickness) due to Trypanosoma brucei gambiense. Rationale for inclusion: The combination of nifurtimox and eflornithine (NECT) is less toxic than melarsoprol, the current most commonly used treatment. NECT is as efficacious and well tolerated as eflornithine monotherapy, which is considered the current first choice where it is feasible to implement. Moreover, NECT is a more practical and less costly alternative as fewer infusions are needed during the course of therapy, for a shorter period
33
of time, and only need to be administered at 12-hour intervals (twice per day). NECT may prevent the emergence of resistant parasites. General information: Description:
The two medicines to be used in combination are: • Oral nifurtimox (a 5-nitrofuran): a trypanothione reductase inhibitor with trypanocidal effects. The
chemical name is 3-methyl-4-5(5’nitrofurfuryliden-amino)-tetrahydro-4H-1,4-tianzine-1,1 dioxide. • Injectable eflornithine (eflornithine hydrochloride, α-difluoro-methyl-ornithine, DFMO): an
ornithine decarboxylase inhibitor with trypanostatic effects. The chemical name is 2-(difluormethyl)-DL-ornithine monohydrochloride monohydrate.
Uses: Treatment of patients diagnosed (see details below) with stage 2 human African trypanosomiasis due to Trypanosoma brucei gambiense. Contraindications: Hypersensitivity/allergy to eflornithine or nifurtimox. Precautions:
• Pregnancy: The safety of the NECT combination therapy during pregnancy has not been tested or established and therefore it should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the foetus (i.e. when there is no alternative). Animal studies have shown that eflornithine may cause birth defects or may cause death of the foetus and the manufacturer suggests that eflornithine should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. The effect of nifurtimox in pregnancy has not been evaluated.
• Breastfeeding: It is not known if eflornithine and/or nifurtimox pass into breast milk. Therefore physicians may wish to suggest alternative methods of feeding infants, if appropriate.
• Renal impairment: No data are available on NECT. The manufacturer of eflornithine suggests caution should be exercised in patients with renal impairment receiving eflornithine as approximately 80% of the intravenous dose of eflornithine is eliminated unchanged in the urine. Nifurtimox is not eliminated by the renal route.
• Paediatric and geriatric use: No studies on the use of the NECT combination therapy have been carried out.
• HIV/AIDS: The safety and efficacy of NECT for use in HIV/AIDS patients has not been tested or established. Data on the individual medicines is not available. The physician should make a judgment as to whether the benefits of treatment with NECT outweigh possible adverse effects, based on current knowledge.
• Chronic abuse of medications or alcohol: No data available. Due to the nature of drug administration and some of the adverse effects, the NECT combination therapy should only be administered in a medical facility. Also:
• The patient should be kept under medical supervision while eflornithine is administered and should be observed for the full period of treatment. Any decision to modify dosage or
34
interrupt/cease treatment should be based on the severity of any adverse event(s) and access to support facilities. Such modifications should be documented in the patient’s hospital notes for future reference.
• Close observation is recommended when giving nifurtimox to patients with a history of cerebral damage, predisposition to epilepsy, psychosis and serious behavioural alterations.
• Patients are advised to avoid alcohol to prevent possible side effects. • Physicians are advised to monitor haematological profiles before, during and after treatment due
to the risk of myelosuppression whenever facilities are available for this. In case of abnormality, profiles should be obtained once a week after therapy until the abnormal parameter returns to baseline levels.
• Physicians are advised to follow up patients for at least 24 months after treatment wherever possible (in case of relapse and the need for further treatment) and to document outcomes in the patient’s hospital notes for future reference.
• It is advised to ensure that patients are properly fed during the treatment. • The patient should be observed specifically for signs of infection emerging during or shortly after
treatment, in which case prompt antibiotic therapy should be started. Dose: Nifurtimox: 5 mg/kg every 8 hours for 10 days orally plus Eflornithine: 200 mg/kg every 12 hours for 7 days by intravenous infusion over 2 hours Paediatrics: No specific data is available for the use of the NECT combination therapy in children. Nifurtimox is administered orally while eflornithine is administered by slow intravenous infusion. The eflornithine concentrate must be diluted in sterile water, sterile saline solution or 5% dextrose in distilled water immediately before use. In studies carried out to date, the first daily dose of nifurtimox has been administered at the same time point as the point at which the first eflornithine infusion was started each day, so that the daily treatment regimen can be completed without disturbing the patient during the night. Adverse effects: Major (i.e. severe and very severe – grades 3&4 per CTC) adverse effects that have been reported following NECT combination therapy include fever (4.9%), seizures (4.2%), confusion (1.4%), infection (0.7%), nausea and vomiting (0.7%), coma (0.7%), hallucinations (0.7%), hemiplegia (0.7%), ataxia (0.7%), tinnitus (0.7%), anorexia (0.7%), sepsis (0.7%), headache (0.7%), rash (0.7%), acute respiratory distress (0.7%) and dehydration (0.7%). Only one death has occurred so far among 143 patients treated with NECT. Other adverse effects include:
• Nausea and/or vomiting (48.3%), fever (25.9%), anorexia (25.2%), abdominal pain (24.5%), , arrhythmia (18.9%), dizziness (18.2%), infection (12.6%), seizures (12.6%), insomnia (9.8%), inner ear disturbance (7.0%), diarrhoea (6.3%), hypertension (4.2%), and anxiety/agitation (2.8%), peripheral neuropathy (motor or sensory), tremor, hiccups, hypotension/shock, injection site reaction, pruritus, cough, chest pain, leucopenia and abnormal levels of bilirubin.
35
In addition, according to the manufacturer’s inserts, the individual drugs may cause adverse effects as listed below: Nifurtimox:
• Main adverse effects include nausea, vomiting, and abdominal pain. • Central nervous system effects include memory loss, sleep disturbances excitatory states, seizures
and psychotic behaviour. • Long-term treatment may affect the peripheral nervous system, causing tremors, muscle
weakness, mild paraesthesia and polyneuritis. Eflornithine:
• Eflornithine has been reported to cause thrombocytopenia, anaemia and leucopenia, in particular neutropenia; these adverse effects are usually reversible on stopping treatment.
• Eflornithine has been temporally associated with seizures (an adverse effect that can also be caused by the underlying disease).
• Other adverse effects include: vomiting, alopecia, abdominal pain, anorexia, headache, transient hearing impairment, asthenia, facial oedema, eosinophilia and dizziness.
Overdosage: No data are currently available on the effects of overdosage in humans. Drug interactions: No data are available. Storage:
• Nifurtimox: Store below 25°C and away from direct light. • Eflornithine: Store vial at room temperature, ideally below 30°C. Protect from freezing and from
light. The manufacturer’s package inserts of the individual drugs are given in the appendices.
36
Appendix (on the following pages) • Pack insert – Ornidyl (eflornithine) • Pack insert – Lampit (nifurtimox) • Baseline characteristics of the study population
Attached to the application as separate files:
• Slide presentation of NECT ICTM17, Jeju Island, October 2008 • Priotto et al., 2006 • Checchi et al., 2007 • Priotto et al., 2007
37
38
39
Baseline characteristics of the 286 subjects included in the safety analysis of the Phase III NECT study (Priotto et al. manuscript in preparation)
N E (n=143) N+E (n=143) Total p-value
Sex (M/F ratio) 286 1.6 1.4 1.5 0.545 Age in years (mean, SD) 285 34.6 (13.5) 32.8 (12.5) 33.7 (13.0) 0.277 Weight in kg (mean, SD) 286 53.9 (8.7) 53.0 (8.3) 53.4 (8.5) 0.390 Height in cm (mean, SD) 286 165.8 (9.1) 165.8 (7.9) 165.9 (8.5) 0.894 BMI Normal >=18.5 Thinness < 18.5
286 96 (67.1) 47 (32.9)
89 (62.2) 54 (37.8)
185 (64.7) 101 (35.3)
0.386
Mode of screening Active Passive
286 51 (35.7) 92 (64.3)
59 (41.3) 84 (58.7)
110 (38.5) 176 (61.5)
0.331
Lymph node aspirate Positive Negative or no nodes
286 88 (61.5) 55 (38.5)
88 (61.5) 55 (38.5)
176 (61.5) 110 (38.5)
1.000
Tryps in blood Positive Negative
286 74 (51.8) 69 (48.3)
67 (46.9) 76 (53.2)
141 (49.3) 145 (50.7)
0.408
Tryps in CSF Positive Negative
285 105 (74.4) 37 (25.9)
103 (72.0) 40 (28.0)
208 (72.7) 77 (26.9)
0.716
White cells count in CSF 6-20 cells/uL 21-99 cells/uL >=100 cells/uL
286 2 (1.4) 26 (18.2) 115 (80.4)
2 (1.4) 34 (23.8) 107 (74.8)
4 (1.4) 60 (21.0) 222 (77.6)
0.473
CSF IgM titer up to 1/128 1/256 to 1/1024
279 107 (75.9) 34 (24.1)
111 (80.4) 27 (19.6)
218 (78.1) 61 (21.9)
0.330
Hemoglobin g/dL (mean, SD) 286 11.8 (1.86) 11.9 (1.92) 11.8 (1.89) 0.917 Malaria co-infection 285 29 (20.4) 22 (15.4) 51 (17.9) 0.267 Clinical characteristics Lymphadenopathy 286 88 (61.5) 88 (61.5) 176 (61.5) 1.000 Hepatomegaly 286 6 (4.2) 9 (6.3) 15 (5.2) 0.426 Splenomegaly 285 29 (20.3) 21 (14.8) 50 (17.5) 0.223 Coma score < 15 284 6 (4.2) 13 (9.2) 19 (6.7) 0.097 Karnofsky index, median (mean, SD) 286 80 (77.1[12.8]) 80 (75.3[15.7]) 80 (76.2[14.4]) 0.486 Fever (>=37.5°C axillary) 286 29 (20.3) 22 (15.4) 51 (17.8) 0.799 Headache 285 119 (83.8) 115 (80.4) 234 (82.1) 0.456 Pruritus 284 102 (71.8) 104 (73.2) 206 (72.5) 0.790 Amenorrhea 88 19 (47.5) 23 (47.9) 42 (47.7) 0.969 Impotence 167 42 (48.8) 46 (56.8) 88 (52.7) 0.304 Unusual behaviour 281 66 (47.1) 56 (39.7) 122 (43.4) 0.209 Anorexia 284 42 (29.6) 53 (37.3) 95 (33.5) 0.167 Seizures 285 16 (11.3) 10 (7.0) 26 (9.1) 0.210 Tremors 284 51 (36.2) 51 (35.7) 102 (35.9) 0.929 Diurnal somnolence 285 109 (76.2) 96 (67.6) 205 (71.9) 0.105 Nocturnal insomnia 284 65 (45.8) 59 (41.5) 124 (43.7) 0.473 Speech disorder 285 24 (16.8) 29 (20.4) 53 (18.6) 0.430 Neurological signs 284 49 (34.3) 52 (36.9) 101 (35.6) 0.645 Duration of symptoms, months (mean, SD)
284 8.5 (9.19) 8.6 (9.39) 8.6 (9.27) 0.850
Figures in parenthesis are percentages, unless specified. Amenorrhoea evaluated on women of age 51 or younger. Chi2 test, Student t test, or Wilcoxon-Mann-Whitney test, as appropriate. Baseline data show a balanced distribution of subjects per arm, suggesting that the randomisation procedure was effective and that the two groups are comparable.
40
References 1. Control and surveillance of African trypanosomiasis. Report of a WHO Expert Committee. World
Health Organ Tech Rep Ser. 1998;881:I-VI, 1-114. 2. Kennedy PG. Human African trypanosomiasis of the CNS: current issues and challenges. J Clin
Invest. Feb 2004;113(4):496-504. 3. Kennedy PG. Diagnostic and neuropathogenesis issues in human African trypanosomiasis. Int J
Parasitol. May 1 2006;36(5):505-512. 4. Kennedy PG. Diagnosing central nervous system trypanosomiasis: two stage or not to stage?
Trans R Soc Trop Med Hyg. Apr 2008;102(4):306-307. 5. Enanga B, Burchmore RJ, Stewart ML, Barrett MP. Sleeping sickness and the brain. Cell Mol Life
Sci. May 2002;59(5):845-858. 6. Blum J, Schmid C, Burri C. Clinical aspects of 2541 patients with second stage human African
trypanosomiasis. Acta Trop. Jan 2006;97(1):55-64. 7. Lutumba P, Makieya E, Shaw A, Meheus F, Boelaert M. Human African trypanosomiasis in a rural
community, Democratic Republic of Congo. Emerg Infect Dis. Feb 2007;13(2):248-254. 8. Simarro PP, Jannin J, Cattand P. Eliminating human African trypanosomiasis: where do we stand
and what comes next? PLoS Med. Feb 2008;5(2):e55. 9. African trypanosomiasis (sleeping sickness). World Health Organ fact sheet No.259;
http://www.who.int/mediacentre/factsheets/fs259/en/. 2006. 10. Smith DH, Pepin J, Stich AH. Human African trypanosomiasis: an emerging public health crisis. Br
Med Bull. 1998;54(2):341-355. 11. Trypanosomiasis re-emerges under cover of war. Afr Health. Sep 1997;19(6):3. 12. Barrett MP. The fall and rise of sleeping sickness. Lancet. Apr 3 1999;353(9159):1113-1114. 13. Barrett MP. The rise and fall of sleeping sickness. Lancet. Apr 29 2006;367(9520):1377-1378. 14. Kaba D, Dje NN, Courtin F, et al. [The impact of war on the evolution of sleeping sickness in west-
central Cote d'Ivoire]. Trop Med Int Health. Feb 2006;11(2):136-143. 15. Berrang Ford L. Civil conflict and sleeping sickness in Africa in general and Uganda in particular.
Confl Health. 2007;1:6. 16. Steverding D. The history of African trypanosomiasis. Parasit Vectors. 2008;1(1):3. 17. Magnus E, Vervoort T, Van Meirvenne N. A card-agglutination test with stained trypanosomes
(C.A.T.T.) for the serological diagnosis of T. B. gambiense trypanosomiasis. Ann Soc Belg Med Trop. 1978;58(3):169-176.
18. Magnus E, Lejon V, Bayon D, et al. Evaluation of an EDTA version of CATT/Trypanosoma brucei gambiense for serological screening of human blood samples. Acta Trop. Jan 2002;81(1):7-12.
19. Pepin J, Milord F. The treatment of human African trypanosomiasis. Adv Parasitol. 1994;33:1-47. 20. Blum J, Nkunku S, Burri C. Clinical description of encephalopathic syndromes and risk factors for
their occurrence and outcome during melarsoprol treatment of human African trypanosomiasis. Trop Med Int Health. May 2001;6(5):390-400.
21. Pepin J, Milord F, Khonde AN, et al. Risk factors for encephalopathy and mortality during melarsoprol treatment of Trypanosoma brucei gambiense sleeping sickness. Trans R Soc Trop Med Hyg. Jan-Feb 1995;89(1):92-97.
22. Schmid C, Richer M, Bilenge CM, et al. Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stage human African trypanosomiasis: confirmation from a multinational study (IMPAMEL II). J Infect Dis. Jun 1 2005;191(11):1922-1931.
23. Pepin J, Ethier L, Kazadi C, Milord F, Ryder R. The impact of human immunodeficiency virus infection on the epidemiology and treatment of Trypanosoma brucei gambiense sleeping sickness in Nioki, Zaire. Am J Trop Med Hyg. Aug 1992;47(2):133-140.
24. Barrett MP, Boykin DW, Brun R, Tidwell RR. Human African trypanosomiasis: pharmacological re-engagement with a neglected disease. Br J Pharmacol. Dec 2007;152(8):1155-1171.
25. Fairlamb AH. Chemotherapy of human African trypanosomiasis: current and future prospects. Trends Parasitol. Nov 2003;19(11):488-494.
41
26. Schmid C, Nkunku S, Merolle A, Vounatsou P, Burri C. Efficacy of 10-day melarsoprol schedule 2 years after treatment for late-stage gambiense sleeping sickness. Lancet. Aug 28-Sep 3 2004;364(9436):789-790.
27. Burri C, Nkunku S, Merolle A, Smith T, Blum J, Brun R. Efficacy of new, concise schedule for melarsoprol in treatment of sleeping sickness caused by Trypanosoma brucei gambiense: a randomised trial. Lancet. Apr 22 2000;355(9213):1419-1425.
28. Pepin J, Milord F, Guern C, Mpia B, Ethier L, Mansinsa D. Trial of prednisolone for prevention of melarsoprol-induced encephalopathy in gambiense sleeping sickness. Lancet. Jun 3 1989;1(8649):1246-1250.
29. Blum J, Burri C. Treatment of late stage sleeping sickness caused by T.b. gambiense: a new approach to the use of an old drug. Swiss Med Wkly. Feb 9 2002;132(5-6):51-56.
30. Legros D, Ollivier G, Gastellu-Etchegorry M, et al. Treatment of human African trypanosomiasis--present situation and needs for research and development. Lancet Infect Dis. Jul 2002;2(7):437-440.
31. 27th Meeting of the ISCTRC. Pretoria, South Africa; http://www.au-ibar.org/isctrc/27Meeting/Index.html. 2003.
32. Moore AC. Prospects for improving African trypanosomiasis chemotherapy. J Infect Dis. Jun 1 2005;191(11):1793-1795.
33. Nerima B, Matovu E, Lubega GW, Enyaru JC. Detection of mutant P2 adenosine transporter (TbAT1) gene in Trypanosoma brucei gambiense isolates from northwest Uganda using allele-specific polymerase chain reaction. Trop Med Int Health. Nov 2007;12(11):1361-1368.
34. Ollivier G, Legros D. [Human african trypanosomiasis: A history of its therapies and their failures.]. Trop Med Int Health. Nov 2001;6(11):855-863.
35. Brun R, Schumacher R, Schmid C, Kunz C, Burri C. The phenomenon of treatment failures in Human African Trypanosomiasis. Trop Med Int Health. Nov 2001;6(11):906-914.
36. Legros D, Fournier C, Gastellu Etchegorry M, Maiso F, Szumilin E. [Therapeutic failure of melarsoprol among patients treated for late stage T.b. gambiense human African trypanosomiasis in Uganda]. Bull Soc Pathol Exot. Jul 1999;92(3):171-172.
37. Pepin J, Mpia B. Trypanosomiasis relapse after melarsoprol therapy, Democratic Republic of Congo, 1982-2001. Emerg Infect Dis. Jun 2005;11(6):921-927.
38. Burri C, Keiser J. Pharmacokinetic investigations in patients from northern Angola refractory to melarsoprol treatment. Trop Med Int Health. May 2001;6(5):412-420.
39. Stanghellini A, Josenando T. The situation of sleeping sickness in Angola: a calamity. Trop Med Int Health. May 2001;6(5):330-334.
40. Balasegaram M, Harris S, Checchi F, Hamel C, Karunakara U. Treatment outcomes and risk factors for relapse in patients with early-stage human African trypanosomiasis (HAT) in the Republic of the Congo. Bull World Health Organ. Oct 2006;84(10):777-782.
41. Robays J, Nyamowala G, Sese C, et al. High failure rates of melarsoprol for sleeping sickness, Democratic Republic of Congo. Emerg Infect Dis. Jun 2008;14(6):966-967.
42. Maina N, Maina KJ, Maser P, Brun R. Genotypic and phenotypic characterization of Trypanosoma brucei gambiense isolates from Ibba, South Sudan, an area of high melarsoprol treatment failure rate. Acta Trop. Nov-Dec 2007;104(2-3):84-90.
43. Matovu E, Enyaru JC, Legros D, Schmid C, Seebeck T, Kaminsky R. Melarsoprol refractory T. b. gambiense from Omugo, north-western Uganda. Trop Med Int Health. May 2001;6(5):407-411.
44. Bacchi CJ, Nathan HC, Hutner SH, McCann PP, Sjoerdsma A. Polyamine metabolism: a potential therapeutic target in trypanosomes. Science. Oct 17 1980;210(4467):332-334.
45. Burri C, Brun R. Eflornithine for the treatment of human African trypanosomiasis. Parasitol Res. Jun 2003;90 Supp 1:S49-52.
46. Chappuis F, Udayraj N, Stietenroth K, Meussen A, Bovier PA. Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis. Clin Infect Dis. Sep 1 2005;41(5):748-751.
42
47. Balasegaram M, Harris S, Checchi F, Ghorashian S, Hamel C, Karunakara U. Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of the Congo. Bull World Health Organ. Oct 2006;84(10):783-791.
48. Robays J, Raguenaud ME, Josenando T, Boelaert M. Eflornithine is a cost-effective alternative to melarsoprol for the treatment of second-stage human West African trypanosomiasis in Caxito, Angola. Trop Med Int Health. Feb 2008;13(2):265-271.
49. Priotto G, Pinoges L, Fursa IB, et al. Safety and effectiveness of first line eflornithine for Trypanosoma brucei gambiense sleeping sickness in Sudan: cohort study. BMJ. Mar 29 2008;336(7646):705-708.
50. 28th Meeting of the ISCTRC. Addis Ababa, Ethiopia; http://www.au-ibar.org/isctrc/28Meeting/en/home/home.html 2005.
51. Pepin J, Khonde N, Maiso F, et al. Short-course eflornithine in Gambian trypanosomiasis: a multicentre randomized controlled trial. Bull World Health Organ. 2000;78(11):1284-1295.
52. Eflornithine trial results. TDR News. Oct 1998(57):1-2. 53. Khonde N, Pepin J, Mpia B. A seven days course of eflornithine for relapsing Trypanosoma brucei
gambiense sleeping sickness. Trans R Soc Trop Med Hyg. Mar-Apr 1997;91(2):212-213. 54. Iten M, Mett H, Evans A, Enyaru JC, Brun R, Kaminsky R. Alterations in ornithine decarboxylase
characteristics account for tolerance of Trypanosoma brucei rhodesiense to D,L-alpha-difluoromethylornithine. Antimicrob Agents Chemother. Sep 1997;41(9):1922-1925.
55. Janssens PG, De Muynck A. Clinical trials with "nifurtimox" in African trypanosomiasis. Ann Soc Belg Med Trop. 1977;57(4-5):475-480.
56. Pepin J, Milord F, Mpia B, et al. An open clinical trial of nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness in central Zaire. Trans R Soc Trop Med Hyg. Jul-Aug 1989;83(4):514-517.
57. Moens F, De Wilde M, Ngato K. [Clinical trial of nifurtimox in human African trypanosomiasis]. Ann Soc Belg Med Trop. Mar 1984;64(1):37-43.
58. Bisser S, N'Siesi FX, Lejon V, et al. Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness. J Infect Dis. Feb 1 2007;195(3):322-329.
59. Pepin J, Milord F, Meurice F, Ethier L, Loko L, Mpia B. High-dose nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness: an open trial in central Zaire. Trans R Soc Trop Med Hyg. May-Jun 1992;86(3):254-256.
60. Wegner DH, Rohwedder RW. The effect of nifurtimox in acute Chagas' infection. Arzneimittelforschung. Sep 1972;22(9):1624-1635.
61. Castro JA, de Mecca MM, Bartel LC. Toxic side effects of drugs used to treat Chagas' disease (American trypanosomiasis). Hum Exp Toxicol. Aug 2006;25(8):471-479.
62. Wegner DH, Rohwedder RW. Experience with nifurtimox in chronic Chagas' infection. Preliminary report. Arzneimittelforschung. Sep 1972;22(9):1635-1641.
63. Practical manual for the treatment and control of human african trypanosomiasis. Médecins Sans Frontières. 2005.
64. Eperon G, Schmid C, Loutan L, Chappuis F. Clinical presentation and treatment outcome of sleeping sickness in Sudanese pre-school children. Acta Trop. Jan 2007;101(1):31-39.
65. Pepin J, Mpia B. Randomized controlled trial of three regimens of melarsoprol in the treatment of Trypanosoma brucei gambiense trypanosomiasis. Trans R Soc Trop Med Hyg. May 2006;100(5):437-441.
66. Eozenou P, Jannin J, Ngampo S, Carme B, Tell GP, Schechter PJ. [A trial treatment with eflornithine of trypanosomiasis caused by Trypanosoma brucei gambiense in the Peoples Republic of the Congo]. Med Trop (Mars). Apr-Jun 1989;49(2):149-154.
67. Priotto G, Fogg C, Balasegaram M, et al. Three drug combinations for late-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Uganda. PLoS Clin Trials. 2006;1(8):e39.
43
68. Priotto G, Kasparian S, Ngouama D, et al. Nifurtimox-eflornithine combination therapy for second-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Congo. Clin Infect Dis. Dec 1 2007;45(11):1435-1442.
69. Checchi F, Piola P, Ayikoru H, Thomas F, Legros D, Priotto G. Nifurtimox plus Eflornithine for Late-Stage Sleeping Sickness in Uganda: A Case Series. PLoS Negl Trop Dis. 2007;1(2):e64.
70. Veeken HJ, Ebeling MC, Dolmans WM. Trypanosomiasis in a rural hospital in Tanzania. A retrospective study of its management and the results of treatment. Trop Geogr Med. Apr 1989;41(2):113-117.
71. Odiit M, Kansiime F, Enyaru JC. Duration of symptoms and case fatality of sleeping sickness caused by Trypanosoma brucei rhodesiense in Tororo, Uganda. East Afr Med J. Dec 1997;74(12):792-795.
72. Pepin J, Mpia B, Iloasebe M. Trypanosoma brucei gambiense African trypanosomiasis: differences between men and women in severity of disease and response to treatment. Trans R Soc Trop Med Hyg. Jul-Aug 2002;96(4):421-426.
73. Haller L, Adams H, Merouze F, Dago A. Clinical and pathological aspects of human African trypanosomiasis (T. b. gambiense) with particular reference to reactive arsenical encephalopathy. Am J Trop Med Hyg. Jan 1986;35(1):94-99.
74. Doua F, Yapo FB. Human trypanosomiasis in the Ivory Coast: therapy and problems. Acta Trop. Sep 1993;54(3-4):163-168.
75. Nkanga NG, Kazadi K, Kazyumba GL, Dechef G. [Clinical neurological signs of human African trypanosomiasis at the meningoencephalitis stage (apropos of 23 cases)]. Bull Soc Pathol Exot Filiales. 1988;81(3 Pt 2):449-458.
76. Ginoux PY, Bissadidi N, Frezil JL. [Complications observed in the treatment of trypanosomiasis in the Congo]. Med Trop (Mars). Oct-Dec 1984;44(4):351-355.
77. Doua F, Boa, Y. F., Merouze, F., Sanon, R., Diai, D., Miezan, T. B., Cattand, P. and De, Raadt P. Traitement actuel de la Trypanosomiase humaine Africaine: Résultats obtenus chez 324 patients atteints de T.H.A. à T. b. gambiense dans le foyer de Daloa (Côte d'Ivoire). 18ème Réunion du Conseil Scientifique International de Recherches sur les Trypanosomiases et leur Contrôle (CSIRTC) de la CSTR/OUA.; 1985.
78. Recommendations of the Informal Consultation on Issues for Clinical Product Development for Human African Trypanosomiasis. World Health Organization, WHO/CDS/NTD/IDM/2007.1. 2007.
Department of Medicines Research
Swiss TPH, Socinstrasse 57, P. O. Box, CH-4002 Basel, T +41 61 284 81 11, F +41 61 284 89 99, www.swisstph.ch
The Secretary of the WHO Expert Committee on The Selection and Use of Essential Medicines Policy, Access and Rational use Department of Medicines Policy and Standards World Health Organisation (WHO) 20, avenue Appia 1211 Genève 27 Letter to support the inclusion of the nifurtimox - eflornithine combination therapy (NECT) for treatment for second stage human African for children in the WHO Model List of Essential Medicines for Children In 2009 the Swiss Tropical and Public Health Institute had the pleasure to support DNDi’s application for
the inclusion of NECT, the co-administration of oral nifurtimox with i.v. eflornithine, into the WHO Model
List of Essential Medicines for the treatment of second stage T.b. gambiense sleeping sickness (Human
African Trypanosomiasis, HAT). In the meantime, NECT has almost completely superseded melarsoprol
(2010: 88% cases treated with NECT, 12% melarsoprol versus 2006: 12% eflornithine, 88% melarsoprol) (1). Although the introduction of eflornithine monotherapy already was a major step forward, the
introduction of the drug combination was clearly the key factor for the almost complete abandonment of
melarsoprol. The main reason for this success must be seen in NECT’s significantly reduced toxicity
versus melarsoprol and its significantly reduced complexity and logistic awkwardness versus eflornithine
monotherapy. Given the case fatality rates of melarsoprol in the order of 5% and of NECT of less than 1%
the switch away from melarsoprol has saved about 1’000 additional lives of seriously ill patients, the
majority of them since the introduction of NECT.
During its extensive field use the very good safety and efficacy described in the clinical trials performed
(2-5) could be corroborated: The results of a cohort of 684 second-stage HAT patients treated with NECT
in Doruma and Dingila hospitals, North-eastern DRC between January 2010 and June 2011 were recently
published. The authors reported that 86% of the patients experienced at least one adverse event during
treatment. Most adverse events were mild (37.9%) or moderate (54.7%). Severe adverse events included
vomiting (n = 32), dizziness (n = 16), headache (n = 11), and convulsions (n = 11). The in-hospital case
fatality rate was 0.15%. The rate of relapses reported was 2%; the relapse rate was higher when NECT
was given for HAT relapse (7.1%) than in first-time treated patients (1.8%) (6).
The above mentioned cohort study included including 120 children, 21 (3.1%) <5 years of age and 99
(14.5%) aged 5–15 years. On average, children experienced fewer adverse events than adults with the
only exception of vomiting. In another very recently published study, Schmid et al. also reported a better
Page 2
tolerability of NECT in children and 100/100 children admitted for treatment were discharged alive in this
study cohort. Less psychiatric events and fewer headaches were reported, however, fever and injection
site reactions were more frequent (7).
The relapse rate of eflornithine monotherapy was higher in children than in adults. Therefore an increased
dose of eflornithine was proposed for the treatment of children (150 mg kg–1 body weight instead of 100
mg kg–1 body weight at intervals of 6 h for 14 days) (8). This distinction was omitted in the NECT
treatment protocol and a close follow up of the efficacy is hence necessary. So far there is not yet much
detailed information about the efficacy of NECT in children: The study recently published by Alirol et al.
does not discriminate the efficacy in children and adults (6) and the one by Schmid et al. is concentrating
on safety. Unpublished information on the use of NECT in children in those two populations, but also by
the National Sleeping Sickness Program of the Democratic Republic of the Congo (PNLTHA) indicates
that the relapse rates in children may be a touch higher than in adults, but the difference appears to be
non-significant and the relapse rate is certainly significantly below the one after treatment with eflornithine
monotherapy or melarsoprol. Therefore, the present lack of those data should not prevent from adding
this very useful tool to the list of essential medicines in children, but pharmacovigilance programs should
be encouraged where possible (the major interveners, e.g. the PNLTHA, as well as Médecins sans
Frontières have respective partner organizations).
The Swiss Tropical Institute has a longstanding experience in clinical research on sleeping sickness. In
our experience, NECT is a significant improvement in the treatment of second stage T.b. gambiense
HAT. The risk – benefit assessment of NECT for children versus eflornithine mono therapy and
particularly versus melarsoprol is favourable, acknowledging the still limited data available. In conclusion,
we recommend the WHO’s Expert Committee on the Selection and Use of Essential Medicines to adopt
this new combination treatment into the WHO Model List of Essential Medicines for children.
Prof. Dr. Christian Burri Head, Department for Pharmaceutical Medicine Professor for Pharmacy & Clinical Pharmacology
Page 3
References used
1. Simarro PP, Franco J, Diarra A, Postigo JA, Jannin J. Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis. Parasitology. 2012 Feb 6;139(7):842-6. PubMed PMID: 22309684.
2. Priotto G, Fogg C, Balasegaram M, Erphas O, Louga A, Checchi F, et al. Three drug combinations for late-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Uganda. PLoS Clin Trials. 2006;1(8):e39. PubMed PMID: 17160135.
3. Chappuis F. Melarsoprol-free drug combinations for second-stage Gambian sleeping sickness: the way to go. Clin Infect Dis. 2007 Dec 1;45(11):1443-5. PubMed PMID: 17990226.
4. Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian S, Arnold U, et al. Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet. 2009 Jul 4;374(9683):56-64. PubMed PMID: 19559476.
5. Yun O, Priotto G, Tong J, Flevaud L, Chappuis F. NECT is next: implementing the new drug combination therapy for Trypanosoma brucei gambiense sleeping sickness. PLoS Negl Trop Dis. 2010;4(5):e720. PubMed PMID: 20520803.
6. Alirol E, Schrumpf D, Amici Heradi J, Riedel A, de Patoul C, Quere M, et al. Nifurtimox-Eflornithine Combination Therapy for Second-Stage Gambiense Human African Trypanosomiasis: Medecins Sans Frontieres Experience in the Democratic Republic of the Congo. Clin Infect Dis. 2012 Nov 9. PubMed PMID: 23074318.
7. Schmid C, Kuemmerle A, Blum J, Ghabri S, Kande V, Mutombo M, et al. In-hospital safety in field conditions of nifurtimox eflornithine combination therapy (NECT) for T. b. gambiense sleeping sickness. PLoS Negl Trop Dis. 2012;6(11):e1920.
8. Burri C, Brun R. Eflornithine for treatment of human African trypanosomiasis. Parasitol Res. 2003;90, Supp 1(S49-52).
![Review Article Treatment of Chagas Cardiomyopathy · complete atrioventricular block, and right bundle block [ , , , ]. Morphologically, hypertrophy, dilatation, and ... To reduce](https://img.pdfslide.net/doc/110x75/60f750f1c199d5733c62132f/review-article-treatment-of-chagas-cardiomyopathy-complete-atrioventricular-block.jpg)
