A Multicenter Equivalence Study of Oral Amoxicillin versus Injectable Penicillin in Children Aged 3 to 59 Months with Severe Pneumonia Amoxicillin Penicillin

A Multicenter Equivalence Study of A Multicenter Equivalence Study of Oral Amoxicillin versus Injectable Oral Amoxicillin versus Injectable Penicillin in Children Aged 3 to 59 Penicillin in Children Aged 3 to 59 Months with Severe PneumoniaMonths with Severe Pneumonia

Amoxicillin Penicillin PneumoniaAmoxicillin Penicillin PneumoniaInternational Study (APPIS) GroupInternational Study (APPIS) Group

Colombia, Ghana, India, Mexico,Colombia, Ghana, India, Mexico,Pakistan, South Africa, Vietnam, ZambiaPakistan, South Africa, Vietnam, Zambia

Center for International Health, SPH, Boston UniversityCenter for International Health, SPH, Boston UniversityDepartment of Child and Adolescent Health & Development, WHODepartment of Child and Adolescent Health & Development, WHO

2

BackgroundBackground

• Estimated 2.1 million ARI deaths in Estimated 2.1 million ARI deaths in children every yearchildren every year

• WHO-defined severe pneumonia: WHO-defined severe pneumonia: admission & treatment with injectable admission & treatment with injectable penicillin / ampicillinpenicillin / ampicillin

• Drawbacks of hospitalization and Drawbacks of hospitalization and injectable therapy:injectable therapy:– Side effects: local and needle-borne Side effects: local and needle-borne

infections infections – Costs: dispensing drugs, hospitalizationCosts: dispensing drugs, hospitalization

Amoxicillin Penicillin Pneumonia International Study (APPIS)Amoxicillin Penicillin Pneumonia International Study (APPIS)

3

Research QuestionsResearch Questions

• Primary:Primary: Is treatment failure at 48 h Is treatment failure at 48 h among children aged 3-59 months with among children aged 3-59 months with WHO-defined severe pneumonia WHO-defined severe pneumonia treated with oral amoxicillin equivalent treated with oral amoxicillin equivalent to that with injectable penicillinto that with injectable penicillin?

• Secondary: Do the two treatments Secondary: Do the two treatments remain clinically equivalent through remain clinically equivalent through follow-up on days 5 and 14?follow-up on days 5 and 14?


4

Study design and settingStudy design and setting

• Non-blinded, equivalency randomized clinical Non-blinded, equivalency randomized clinical trialtrial

• Nine tertiary care centers in eight low & Nine tertiary care centers in eight low & middle income countries in three continents:middle income countries in three continents:

- ColombiaColombia- GhanaGhana- IndiaIndia- MexicoMexico- Pakistan (2 sites)Pakistan (2 sites)- South AfricaSouth Africa- VietnamVietnam- ZambiaZambia


5

Inclusion CriteriaInclusion Criteria

Children aged 3 to 59 months with Children aged 3 to 59 months with WHO-defined severe pneumonia WHO-defined severe pneumonia

(lower chest indrawing in children (lower chest indrawing in children with cough and/or difficult breathing)with cough and/or difficult breathing)

Informed consent by a legal guardianInformed consent by a legal guardian


6

Exclusion CriteriaExclusion Criteria

• Very severe disease (severe malnutrition)Very severe disease (severe malnutrition)• Chronic or congenital conditionsChronic or congenital conditions• Antibiotics for more than 48 hrsAntibiotics for more than 48 hrs• Hospitalization in prior two weeksHospitalization in prior two weeks• Bronchial asthma or wheeze whose LCI Bronchial asthma or wheeze whose LCI

improved with inhaled salbutamol improved with inhaled salbutamol • Measles in the last one monthMeasles in the last one month• Oxygen saturation < 80%/75% in room airOxygen saturation < 80%/75% in room air• Clinical evidence of HIV infection (clinical Clinical evidence of HIV infection (clinical

category B or C, CDC-defined)category B or C, CDC-defined)• Known penicillin allergyKnown penicillin allergy• Previous inclusion in studyPrevious inclusion in study• Living outside study areaLiving outside study area


7

Trial Entry and InterventionsTrial Entry and Interventions

• Clinical baseline and naso - pharyngeal Clinical baseline and naso - pharyngeal sampling for RSV and routine sampling for RSV and routine microbiologymicrobiology

• Randomization:Randomization:– Computer generated at coordinating center Computer generated at coordinating center

(WHO)(WHO)– Opaque, sealed and numbered envelopesOpaque, sealed and numbered envelopes

• Interventions:Interventions:– Injectable penicillin G 200,000 IU/kg/day in Injectable penicillin G 200,000 IU/kg/day in

four dosesfour doses– Oral amoxicillin 45 mg/kg/day in three doses Oral amoxicillin 45 mg/kg/day in three doses


8

Follow upFollow up

• In hospital: every 6 h for at least 48 In hospital: every 6 h for at least 48 hh

• Outpatient clinic: 5 and 14 daysOutpatient clinic: 5 and 14 days• Data collected by trained observers: Data collected by trained observers:

– Vital signsVital signs– Presence of danger signsPresence of danger signs– Lower chest indrawingLower chest indrawing– Oxygen saturation by pulse oximetryOxygen saturation by pulse oximetry– Adverse eventsAdverse events


9

OutcomesOutcomes

• Primary: failure at 48 hours:Primary: failure at 48 hours:– Persistence of severe pneumonia (LCI)Persistence of severe pneumonia (LCI)– Danger signs (very severe disease)Danger signs (very severe disease)– DeathDeath– Severe hypoxemia (< 80%/75%)Severe hypoxemia (< 80%/75%)– Life-threatening or serious adverse drug Life-threatening or serious adverse drug

reactionreaction– Received another antibioticReceived another antibiotic– Newly diagnosed conditionNewly diagnosed condition– Voluntary withdrawalVoluntary withdrawal

• Secondary: failure at 5 and 14 days:Secondary: failure at 5 and 14 days:– As for failure at 48 hAs for failure at 48 h– Recurrence of LCI or hypoxemia (<90%/88%)Recurrence of LCI or hypoxemia (<90%/88%)– Non-severe pneumonia on day 14Non-severe pneumonia on day 14


10

Sample size and analysisSample size and analysis

• Sample size: Equivalence trial:Sample size: Equivalence trial:– Expected failure rate with penicillin: 10%Expected failure rate with penicillin: 10%– Equivalence: rate amoxicillin = penicillin Equivalence: rate amoxicillin = penicillin

5%5%– Alpha 0.05 (one side), power 90%Alpha 0.05 (one side), power 90%– Loss to follow-up at 48 h: 1%Loss to follow-up at 48 h: 1%– Three interim and one final analysesThree interim and one final analyses– 861 children per group (1,722)861 children per group (1,722)

• Analysis: Analysis: – Failure rates difference and 95%CIFailure rates difference and 95%CI– Intention to treat and per protocol analysis Intention to treat and per protocol analysis


11

Ethical issuesEthical issues

• Review and approval by the Institutional Review Review and approval by the Institutional Review Board in all participating and coordinating centersBoard in all participating and coordinating centers

• Monitoring by an independent Data Safety Monitoring by an independent Data Safety Monitoring Board three times along the studyMonitoring Board three times along the study

• Second interim analysis: trend to increased early Second interim analysis: trend to increased early deaths at sites with high prevalence of HIV = deaths at sites with high prevalence of HIV = exclusion of children under one year with oral exclusion of children under one year with oral thrush, hepatosplenomegaly or parent known to be thrush, hepatosplenomegaly or parent known to be HIV-infected HIV-infected


12

Baseline comparisonBaseline comparison Variable Penicillin

(n = 845) Amoxicillin (n = 857)

Male 520/845 (62 %) 537/857 (63 %) Infants (3 to 12 months) 513/825 (62 %) 532/844 (63 %) Breast feeding (under 2 y) 532/717 (74 %) 561/725 (78 %) Immunizations up to date 719/811 (89 %) 739/824 (90 %) Antibiotics in last 48 h 82/828 (10 %) 75/846 (9 %) Weight / age Z score -0.7 (-2 to 0.25) -0.7 (-1 to 0.31) Weight / age < –2Z score 133/841 (16 %) 124/845 (15 %) Temperature (ºC) 37.4 (37 to 38) 37.5 (37 to 38) Respiratory rate per minute 60 (54 to 67) 60 (53 to 67) Oxygen saturation 94 (91 to 96) 94 (92 to 97) RSV positive 183/759 (24 %) 192/769 (25 %) S. pneumoniae isolated 217/743 (29 %) 201/743 (29 %) H. influenzae isolated 145/739 (20 %) 146/743 (20 %) Values are median (IQR) unless otherwise indicated


13

Study profile

Randomized 1702

Penicillin

857 Amoxicillin

845

Failure at 48 hours Improved at 48 hours

161

696

166

679

Failure from 48 hours to 5 days Cured at day 5

26

670

19

660

Failure from day 5 to day 14 Cured at 14 days

26

644 (75%)

39

621 (74%)

14

Treatment failuresTreatment failures Outcome Penicillin

(n = 845) Amoxicillin (n = 857)

Difference (95% CI)

At 48 h

161 (19%)

166 (19%)

-0.4%

(-4.2 to 3.3)

At 5 days

187 (22%) 185 (22%) 0.5% (-3.4 to 4.5)

At 14 days

213 (25%)

224 (26%)

-0.9% (-5.1 to 3.2)


15

Reasons for failure at 48 hoursReasons for failure at 48 hours

Reason Penicillin (n = 845)

Amoxicillin (n = 857)

Difference (95% CI)

Total LCI persisting Very severe disease Hypoxaemia Serious adverse reaction Received another antibiotic Newly diagnosed condition Voluntary withdrawal Deaths

161 (19% ) 131 (16%) 11 (1%) 19 (2%) 5 (1%) 13 (2%) 16 (2%) 3 (0%) 7 (1%)

166 (19% ) 139 (16%)

7 (1%) 12 (1%) 0 (0%) 10 (1%) 6 (1%) 8 (1%) 0 (0%)

-0.4% (-4.2 to 3.3) -0.7% (-4.2 to 2.8) 0.5% (-0.5 to 1.5) 0.8% (-0.4 to 2.1) 0.6% (0.1 to 1.1) 0.4% (-0.7 to 1.5) 1.2% (0.1 to 2.3)

-0.6% (-1.3 to 0.2) 0.8% (0.2 to 1.4)


16

Baseline risk factors for failure at Baseline risk factors for failure at 48 h48 h

Variable OR

95% CI

Age 3 to 11 months Very fast breathing Hypoxaemia Amoxicillin

2.72 1.94 1.95 1.03

1.95 to 3.79 1.42 to 2.65 1.34 to 2.82 0.79 to 1.85


17

Cost-minimization StudyCost-minimization Study

• Conducted at Indira Gandhi Conducted at Indira Gandhi Medical College, Nagpur, India Medical College, Nagpur, India (Dr. A. Patel)(Dr. A. Patel)

• Amoxicillin therapy is associated Amoxicillin therapy is associated with significant reductions in:with significant reductions in:– Medication costsMedication costs– Direct medical costsDirect medical costs– Total costsTotal costs


18

DiscussionDiscussion

• Main finding: oral amoxicillin and injectable Main finding: oral amoxicillin and injectable penicillin are equally effective in terms of penicillin are equally effective in terms of treatment failures and clinical relapse ratestreatment failures and clinical relapse rates

• Treatment failure rates higher than expected:Treatment failure rates higher than expected:– Strict but non validated criteriaStrict but non validated criteria– High incidence of wheeze associated with lower High incidence of wheeze associated with lower

chest indrawing at 48 hchest indrawing at 48 h– HIV – infected children with newly diagnosed HIV – infected children with newly diagnosed

conditionsconditions– Hypoxemia associated with high altitudeHypoxemia associated with high altitude

• Clinical efficacy of amoxicillin and penicillin is Clinical efficacy of amoxicillin and penicillin is equivalent to other more expensive antibiotics equivalent to other more expensive antibiotics


19

ConclusionsConclusions

• Oral amoxicillin and injectable Oral amoxicillin and injectable penicillin are equally effective in penicillin are equally effective in hospitalized children with severe hospitalized children with severe pneumoniapneumonia

• Use of oral amoxicillin reduces the Use of oral amoxicillin reduces the costs associated with treatmentcosts associated with treatment

• Caution is needed for using these Caution is needed for using these findings in high HIV prevalence areasfindings in high HIV prevalence areas


20

AcknowledgementsAcknowledgements

• Participating children and their parentsParticipating children and their parents• Sponsors:Sponsors:

– Department of Child and Adolescent Health & Department of Child and Adolescent Health & Development, WHODevelopment, WHO

– ARCH ProjectARCH Project

• Data Safety Monitoring Board membersData Safety Monitoring Board members• Staff at research centersStaff at research centers


A Multicenter Equivalence Study of A Multicenter Equivalence Study of Oral Amoxicillin versus Injectable Oral Amoxicillin versus Injectable Penicillin in Children Aged 3 to 59 Penicillin in Children Aged 3 to 59 Months with Severe PneumoniaMonths with Severe Pneumonia

Amoxicillin Penicillin PneumoniaAmoxicillin Penicillin PneumoniaInternational Study (APPIS) GroupInternational Study (APPIS) Group

Colombia, Ghana, India, Mexico,Colombia, Ghana, India, Mexico,Pakistan, South Africa, Vietnam, ZambiaPakistan, South Africa, Vietnam, Zambia

Center for International Health, SPH, Boston UniversityCenter for International Health, SPH, Boston UniversityDepartment of Child and Adolescent Health & Department of Child and Adolescent Health &

Development, WHODevelopment, WHO

WHO/ FCH/ CAH/ 03.9

Consultative Meeting to Review Evidence and

Research Priorities in the Management of Acute Respiratory Infections (ARI)

Geneva 29th September - 1st October 2003

DRAFT MEETING REPORT

23

Some Potential Policy Some Potential Policy ImplicationsImplications

• Practical benefits of switching-over to Practical benefits of switching-over to oral amoxicillin:oral amoxicillin:– Simpler treatmentSimpler treatment– Reduction in direct costsReduction in direct costs– Health workers can start therapy at Health workers can start therapy at

primary facilitiesprimary facilities– Treatment option for severe pneumonia Treatment option for severe pneumonia

when referral is not feasible / desirablewhen referral is not feasible / desirable


24

Some Limitations of Data for Some Limitations of Data for PolicyPolicy

• RCT conducted in controlled environment (close RCT conducted in controlled environment (close monitoring)monitoring)

• Safety of treating severe pneumonia in communities is Safety of treating severe pneumonia in communities is unknownunknown

• Children with severe pneumonia are admitted to hospital Children with severe pneumonia are admitted to hospital due to several reasons:due to several reasons:– Administration of injectable antibioticsAdministration of injectable antibiotics– Identification and treatment of associated hypoxemiaIdentification and treatment of associated hypoxemia– Ensuring compliance with treatmentEnsuring compliance with treatment– Need for additional observationNeed for additional observation

APPIS data do not address home treatment of severe APPIS data do not address home treatment of severe pneumoniapneumonia


25

How to move on?How to move on?

• Further analysis of APPIS data:Further analysis of APPIS data:– Features that predict severe hypoxemiaFeatures that predict severe hypoxemia– Relationship between hypoxemia and therapy failureRelationship between hypoxemia and therapy failure– Further look of children screened but excludedFurther look of children screened but excluded

• Need to collect information from hospitals in LMIC Need to collect information from hospitals in LMIC about:about:– Availability of oxygen for treating severe pneumoniaAvailability of oxygen for treating severe pneumonia– Current prevalent practices for oxygen administrationCurrent prevalent practices for oxygen administration

• Home vs. hospital treatment of severe pneumonia:Home vs. hospital treatment of severe pneumonia:– RCT of outpatient management of severe pneumoniaRCT of outpatient management of severe pneumonia– Carefully conducted descriptive studiesCarefully conducted descriptive studies


Documents

A Multicenter Equivalence Study of Oral Amoxicillin versus Injectable Penicillin in Children Aged 3 to 59 Months with Severe Pneumonia Amoxicillin Penicillin