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

Where to from here?

Placebo NRT Varenicline

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

Non-inferiority (RD)

0 -5 5

Cytisine: 9.32 (4.16-14.48)

10

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)

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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