Upload
georgi-daskalov
View
77
Download
0
Embed Size (px)
Citation preview
Is cytisine at least as effective as
nicotine replacement therapy for
smoking cessation? Findings from a non-inferiority trial
Walker N*, Howe C, Glover M, McRobbie H, Barnes J,
Nosa V, Parag V, Bassett B, Bullen C.
Australian NZ Clinical Trials Registry (ACTRN12610000590066).
Presented at pre-conference cytisine workshop,
SRNT Seattle, USA Feb 2014
Conflicts of interest
• No direct conflicts of interest • Heart Foundation Douglas Senior Fellowship in Heart
Health (Prevention)
• Trial funding – Health Research Council of New Zealand
– Sopharma/Extab supplied cytisine
• Unrelated – Manufacturers of cessation medications
• Consultancy, honoraria, benefits in kind, travel support and
research grants
– Liaison with two tobacco companies
• Very low nicotine content cigarettes
Design
Single blind, non-inferiority trial – Is cytisine + behavioural support at least as effective
as usual care (NRT + behavioural support)?
Randomisation – Stratified by gender, ethnicity and level of nicotine
dependence (≤5, >5 on the Fagerström).
Primary outcome – Continuous abstinence at one month (≤ 5 cigarettes
since quit date, including during the 7 days prior to
follow-up, not biochemically verified)
Eligibility criteria
• Inclusion criteria – Smokers calling the national Quitline in New Zealand
– ≥ 18 years of age
– Able to provide verbal consent
– Have access to a telephone
• Exclusion criteria – Pregnant / breastfeeding
– Non-daily smokers
– Heart attack, stroke or severe angina in last 2 weeks, uncontrolled
high blood pressure, phaeochromcytoma, schizophrenia
– Current users of NRT products or non-nicotine based cessation
therapies
– Currently enrolled in another smoking cessation study
Treatment allocation
• Intervention group 25-day course of cytisine (1.5mg per tablet)
• Days 1-3: 1 tablet every 2 hours through the day
• Days 4-12: 1 tablet every 2.5 hours; designated QD is day 5
• Days 13-16: 1 tablet every 3 hours
• Days 17-20: 1 tablet every 4-5 hours
• Days 21-25: 1 tablet every 6 hours
• Usual care group Eight weeks NRT: Patch (7, 14, or 21mg) and/or gum (2mg or 4mg) or
lozenge (1mg or 2mg)
All received voluntary, low-intensity, telephone behavioural
support: An average of three 10-15 minute phone calls from
trained Quitline advisors over eight weeks
Treatment regime
Cytisine Days 1-3: 1.5mg every 2 hrs
Days 4-12: 1.5mg every 2.5 hrs
Designated Quit Date is day 5
Days 13-16: 1.5mg every 3 hrs
Days 17-20: 1.5mg every 4-5 hrs
Days 21-25: 1.5mg every 6 hrs
Varenicline Days 1-3: 0.5 mg once daily
Days 4 to 7 0.5 mg twice daily
Designated Quit Date is day 7-14
Day 8 to wk 12 1 mg twice daily.
Sample size
• 1310 required (25% Māori, 15% Pacific)
– 655 in each arm, 20% LTFU
– Non-inferiority margin of 5% (i.e Quit rates for
cytisine are no worse than 5% less than the
rate for NRT)
– 90% power, p=0.025
– Assumed 50% quit rate in NRT at one month
Outcome assessments
Randomisation 1 week 1 month 2 months 6 months
Demographics X X
Smoking history X
Cigarettes smoked X X X X X
Alcohol use X X X
Mood and symptoms X X X
NRT use X X X X X
Quitting X X X X
Smoking satisfaction X X X
Compliance X X X
Adverse events X X X X
Acceptability X X
Consort flowchart
Registered: N = 11,071
Eligible and randomised: N = 1,310
Intervention
N=655
One month
N=565
(LTFU = 90, 13.7%)
Six months
N=456
(LTFU = 199, 30.4%)
Usual care
N=655
One month
N=560
(LTFU = 95, 14.5%)
Six months
N=467
(LTFU = 188, 28.7%)
Excluded: n = 9,761
Declined = 702
Ineligible = 989
Not contacted = 8,070
Baseline
Intervention
N=655 (%)
Usual care
N=655 (%)
Gender
Female
372 (57)
372 (57)
Age (yrs)
Mean
SD
37.8
11.8
38.4
11.9
Ethnicity
Maori
Pacific
Non-Maori non-Pacific
215 (33)
75 (11)
365 (56)
213 (33)
63 (10)
379 (58)
Education*
< 12 years or none
≥ 12 years
344 (53)
309 (47)
329 (50)
325 (50)
Self-efficacy
Mean
SD
4.2
0.9
4.2
0.9
Baseline smoking history
Intervention
N=655 (%)
Usual care
N=655 (%)
Type of tobacco
Factory made only
Both factory & RYO
RYO only
280 (43)
90 (14)
285 (43)
294 (45)
87 (13)
274 (42)
Years smoked continuously
Mean
SD
20.8
11.7
21.0
11.8
Age started smoking (yrs)
Mean
SD
15.2
4.2
15.5
4.4
Number of cigarettes per day
Mean
SD
19.3
11.9
19.0
10.0
Number of cigarettes per day
≤ 10
11-20
21-30
>30
125 (19)
332 (51)
158 (24)
40 (6)
136 (21)
322 (49)
150 (23)
47 (7)
FTND
Mean
SD
5.4
2.1
5.3
2.3
Intervention
N=655 (%)
Usual care
N=655 (%)
P-value RR
(95% CI)
RD
(95% CI)
One week 394 (60%) 303 (46%) <0.001 1.30
(1.17 - 1.44)
13.9
(8.5 - 19.2)
One month 264 (40%) 203 (31%) 0.0004 1.30
(1.12 - 1.51)
9.3
(4.2 - 14.5)
Two months 202 (31%) 143 (22%) 0.0002 1.41
(1.17 - 1.70)
9.0
(4.3 - 13.8)
Six months 143 (22%) 100 (15%) 0.002 1.43
(1.13 - 1.80)
6.6
(2.4 - 10.8)
Continuous abstinence
• Similar findings with complete case analysis and per protocol analysis
• NNT = 11
Intervention
N=655 (%)
Usual care
N=655 (%)
X2
P-value
RR
(95% CI)
P-value
Gender
- Female
- Male
158 (42)
106 (37)
102 (27)
101 (36)
<0.0001
0.66
1.55 (1.26-1.90)
1.05 (0.84 – 1.30)
0.011
Subgroup analysis
No statistical difference for other subgroups
Age group (< 40, ≥ 40 years)
Education (< 12 years or none vs ≥ 12 years)
Ethnicity (Maori vs non-Maori)
Cigarette type (RYO, factory-made, both)
AUDIT-C score (high vs low)
Adjusted Logistic regression model for one month CA,
adjusted for gender, ethnicity, and nicotine
dependency, gives an Odds Ratio of 1.53, 95% CI
1.22-1.93.
Intervention
N=655 (%)
Usual care
N=655 (%)
P-value RR
(95% CI)
RD
(95% CI)
One week 266 (41%) 199 (30%) 0.0001 1.34
(1.15 - 1.55)
10.2
(5.1 – 15.4)
One month
273 (42%) 215 (33%) 0.0009 1.27
(1.10 - 1.46)
8.9
(3.6 - 14.1)
Two months 246 (38%) 206 (32%) 0.0201 1.19
(1.03 - 1.39)
6.1
(1.0 - 11.2)
Six months 206 (32%) 196 (30%) 0.5491 1.05
(0.89 - 1.24)
1.5
(-3.5 - 6.5)
7-day point prevalence
Time to relapse
Medium time to relapse (Log rank test p-value = 0.0003):
- Intervention = 53 days (95% CI 36 - 100 days)
- Usual care = 11 days (95% CI 6 - 22 days)
Symptoms of withdrawal (Abstainers)
0123456789
10111213
B 1w 1m 2m B 1w 1m 2m
Mean
sco
re
Intervention
Usual care
Urge score MPSS score
MPSS: Whether they felt depressed, irritable, restless, hungry or had poor concentration
in the last week (total score out of 25, higher the score = the more they feel it)
p=0.016
p=0.005
Satisfaction and craving reduction (mCEQ)
Satisfaction
0
1
2
3
4
5
6
7
B 1w 1m 2m B 1w 1m 2m B 1w 1m 2m B 1w 1m 2m B 1w 1m 2m
Mean
sco
re
Intervention
Usual care
Reward Aversion Sensation Craving
In those still smoking
Each scale is 1-7, where: 1 is not at all, 2 is very little, 3 is a little,
4 is moderately, 5 is a lot, 6 is quite a lot, and 7 is extremely
Reduced consumption by at least 25%
81
60
77
59
0
10
20
30
40
50
60
70
80
90
100
One month Six months
% t
hat
red
uced
co
nsu
mp
tio
n
by a
t le
ast
25%
Intervention
Usual care
Alcohol use and abuse
76
53 54
74
54 53
0
20
40
60
80
100
Baseline One month Two months
Perc
en
tag
e a
t h
igh
ris
k
Intervention
Usual care
High risk: AUDIT-C score ≥ 4 for men and ≥ 3 for women, indicating an
increased risk of hazardous drinking or dependence and thus an opportunity to
deliver a brief intervention
Compliance with cytisine
49
72
63
100
0
20
40
60
80
100
120
One week One month
Mean
n
um
ber
of
tota
l ta
ble
ts t
aken
Actual
Expected
Reasons for stopping cytisine
0
20
40
60
80
Confidence AE Quit Not used Forgot Stress
Nu
mb
er
of
part
icip
an
ts
One week
One month
What they liked about cytisine
51
4
11
2
46
2
9
2 0
20
40
60
80
100
Reduced cravings Less AEs Easy to take No nicotine
Perc
en
tag
e o
f p
art
icip
an
ts
One week
One month
What they didn’t like about cytisine
20
6
13 18
5
12
0
20
40
60
80
100
AEs Forgot to take Dosing regime
Pe
rce
nta
ge
of
pa
rtic
ipa
nts
One week
One month
Compliance with treatment
0
20
40
60
80
100
One week One month
Perc
en
tag
e u
sin
g
allo
cate
d t
reatm
en
t
Intervention
Usual care
Proportion of participants in the intervention group that used NRT as well
as cytisine: 1 week: 2%; 1 month 1%; 2 months 2%
Reasons for not using NRT
0
20
40
60
80
100
Didn't need Didn't like it Haven't gotaround to it
Startedsmoking
Other
Perc
en
tag
e
One week
One month
Adverse events over six months
Intervention Usual care
n % n %
Total participants 204 134
Total events 288 174
Event type
Any non-serious event 232 80.6 129 74.1
Serious event
- Death 1 0.3 1 0.6
- Life threatening 0 1 0.6
- Hospitalisation or prolongation of hospitalisation 18 6.2 18 10.2
- Medically important 37 12.8 25 14.4
Maximum severity
Mild 139 48.3 78 44.8
Moderate 112 38.5 77 44.3
Severe 38 13.2 19 10.9
Relationship to study treatment
Definitely 0 4 2.3
Probably 9 3.1 1 0.6
Possibly 108 37.2 10 5.7
Not related 171 59.4 159 91.4
Adverse events over 6 months
Intervention Usual care
n % n %
Total participants 204 134
Total events 288 174
Serious and definitely, probably or
possibly related to study treatment
- Mild
- Moderate
- Severe
0
4
4
0
1
2
Incidence Rate Ratio
1.67, 95% CI 1.38 - 2.01, p < 0.001
Adverse events over six months
Intervention Usual care
Severity Related* Not related Related* Not related
n % n % n % n %
Mild 58 49.6 81 47.4 7 46.7 71 44.7
Moderate 42 35.9 69 40.4 5 33.3 72 45.3
Severe 17 14.5 21 12.3 3 20 16 10.1
In intervention group
Severe and related: 17 events in 9 people. Headache, body rash,
trouble sleeping, vivid dreams, stomach cramps, nausea, racing
heart, dizziness, constipation, diarrhoea, very dry mouth
In the usual care group
Severe and related: 3 events in 3 people. One person had a
depressive event, one high blood pressure and one body rash
*Related: definitely, probably or possibly related to study treatment
Incidence Rate Ratio
1.67, 95% CI 1.38 - 2.01, p < 0.001
Most frequent adverse events
Intervention Usual care
Nausea and vomiting (R11) 30 2
Sleep disorders (G47·0/G47·8) 28 2
Symptoms/signs involving the circulatory
and respiratory systems (R00-R09) 9 6
Depressive episode, unspecified (F32·9) 8 5
Non-infective gastroenteritis and colitis,
unspecified (K52·9) 8 2
Headache (R51) 8 0
Dizziness and giddiness (R42) 8 4
Malaise and fatigue (R53) 6 0
Somnolence (R40·0) 5 0
Excluding signs and symptoms of cold and influenza. ICD 10AM codes
provided.
Cost data
• Still to be analysed
• Low cost compared to other smoking cessation
medications
• Low cost per quality adjusted life year – Estimated for smokers aged 35-54 years to be $162, 95% CI $106-
$363 (where $1=£0.62, €0.74).
[Stapleton J, West R. Nicotine Tob Res 2012; 14: 463-71].
Strengths and limitations
• Strengths
– Large, well conducted
– Broad entry criteria to help ensure generalisable findings
• Limitations
– Quitline callers more motivated to quit
– Adverse events were self-reported, although they were
reviewed by a medical practitioner
– Differing access to medication – did it lead to better
compliance?
– Expectancy
– Quitting not biochemically verified
– Preloading?
Limitations
“Verification of self-reported abstinence was
not undertaken”
• Dispersed population, budget constraints, at one month people in the
usual care group would be using NRT.
• Biochemical verification in two previous cessation trials (n=2500)
• 79% of those who reported abstinence were biochemically confirmed
abstainers.
• ‘Verified’ continuous abstinence rates at 1 month
• 209, 32% cytisine vs 160, 25% usual care
• crude RR 1·31, 95% CI: 1·10-1·56
• RD 7·48, 95% CI: 2·62-12·34
• p=0·0026
In summary….
• Cytisine is not only as least as good as NRT, it’s
better
– Delayed time to relapse
– Reduced symptoms of withdrawal slightly better than NRT
– In those still smoking, it reduced smoking satisfaction,
reward and craving
– Medication compliance was higher
• More adverse events, but majority were mild-
moderate and self-limiting
• Protocol paper:
– Walker N, Howe C, Bullen C, McRobbie H, Glover M,
Parag V, et al. Study protocol for a non-inferiority trial of
cytisine versus nicotine replacement therapy in people
motivated to stop smoking. BMC Public Health 2011;
11(880): 880.
• Paper in preparation
• Acknowledgements – Participants, Quitline and NIHI staff, members of the
DSMC