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Varenicline, an 42 Nicotinic Acetylcholine
Receptor Partial Agonist, vs Sustained-Release
Bupropion and Placebo for Smoking Cessation
A Randomized Controlled Trial
Context The ␣4␤2 nicotinic acetylcholine receptors (nAChRs) are linked to the re-
inforcing effects of nicotine and maintaining smoking behavior. Varenicline, a novel ␣4␤2 nAChR partial agonist, may be beneficial for smoking cessation.
Objective To assess efficacy and safety of varenicline for smoking cessation com-
pared with sustained-release bupropion (bupropion SR) and placebo.
Design, Setting, and Participants Randomized, double-blind, parallel-group, pla-
cebo- and active-treatment–controlled, phase 3 clinical trial conducted at 19 US cen- ters from June 19, 2003, to April 22, 2005. Participants were 1025 generally healthysmokers (Ն10 cigarettes/d) with fewer than 3 months of smoking abstinence in the past year, 18 to 75 years old, recruited via advertising.
Intervention Participants were randomly assigned in a 1:1:1 ratio to receive brief
counseling and varenicline titrated to 1 mg twice per day (n=352), bupropion SR ti- trated to 150 mg twice per day (n=329), or placebo (n=344) orally for 12 weeks,with 40 weeks of nondrug follow-up.
Main Outcome Measures Primary outcome was the exhaled carbon monoxide–
ALTHOUGHNEARLY41%OF confirmed4-weekrateofcontinuousabstinencefromsmokingforweeks9through 12. A secondary outcome was the continuous abstinence rate for weeks 9 through 24 Results For weeks 9 through 12, the 4-week continuous abstinence rates were 44.0%
for varenicline vs 17.7% for placebo (odds ratio [OR], 3.85; 95% confidence interval [CI], 2.70-5.50; PϽ.001) and vs 29.5% for bupropion SR (OR, 1.93; 95% CI, 1.40- 2.68; PϽ.001). Bupropion SR was also significantly more efficacious than placebo (OR,2.00; 95% CI, 1.38-2.89; PϽ.001). For weeks 9 through 52, the continuous absti- nence rates were 21.9% for varenicline vs 8.4% for placebo (OR, 3.09; 95% CI, 1.95- 4.91; PϽ.001) and vs 16.1% for bupropion SR (OR, 1.46; 95% CI, 0.99-2.17; P=.057).
Varenicline reduced craving and withdrawal and, for those who smoked while receiv- ing study drug, smoking satisfaction. No sex differences in efficacy for varenicline were observed. Varenicline was safe and generally well tolerated, with study drug discon- of quitting generally twice those of pla- tinuation rates similar to those for placebo. The most common adverse events for par- ticipants receiving active-drug treatment were nausea (98 participants receiving vareni- cline [28.1%]) and insomnia (72 receiving bupropion SR [21.9%]).
Conclusion Varenicline was significantly more efficacious than placebo for smok-
role of the ␣4␤2 nicotinic acetylcho- ing cessation at all time points and significantly more efficacious than bupropion SR at the end of 12 weeks of drug treatment and at 24 weeks.
Trial Registration Identifier: NCT00141206
Author Affiliations and Members of the Varenicline
Cessation Center, Department of Medicine, Oregon Phase 3 Study Group are listed at the end of this
Health & Science University, 3181 SW Sam Jackson Park See also pp 56, 64, and 94.
Rd, CR 115, Portland, OR 97239 (gonzales@ohsu Corresponding Author: David Gonzales, PhD, Smoking
2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 5, 2006—Vol 296, No. 1 47
VARENICLINE VS BUPROPION AND PLACEBO FOR SMOKING CESSATION available therapies. Partial agonists at this nAChR could stimulate the release of suf- or unstable disease within 6 months; sei- zure risk; diabetes mellitus requiring in- ing effects of smoked nicotine. The ␣4␤2 clinically significant cardiovascular dis- to take doses at least 8 hours apart.
vided a structural starting point for the pulmonary disease; history of cancer (ex- tion); given Clearing the Air: Quit Smok- tine, high-affinity ␣4␤2 partial ago- ing Today,14 a smoking cessation self- nist9-11 developed specifically for smok- clinically significant allergic reactions.
process; and instructed to take their first pressive disorder within the past year re- was scheduled for day 8 (week 1 visit).
one of these studies are reported here.
tions in the Public Health Service Clini- Study Design
center, double-blind, parallel-group, pla- 52, with phone visits at weeks 16, 20, 28, Practices Guidelines at 19 centers in the Interventions
Study Population
self-identification of race (white, black, were titrated as follows: varenicline 0.5 48 JAMA, July 5, 2006—Vol 296, No. 1 (Reprinted)
2006 American Medical Association. All rights reserved.
Statistical Analysis
peated at weeks 2 and 12 or at early ter- Smoking Status
Measures of Craving, Withdrawal,
and Reinforcing Effects of Smoking
considered abstinent if, at the next non- at baseline and each clinic visit to con- products since the prior study visit.
tability, anxiety, difficulty concentrat- ing, restlessness, increased appetite, and Study End Points
the study were assumed to be smokers.
pectations of positive effects. The Modi- dently at each clinic or telephone visit.
ing (not even a puff) or use of any nico- administered by all participants at base- treatment (prior to target quit date), and Adverse Events
2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 5, 2006—Vol 296, No. 1 49
varenicline vs placebo followed byvarenicline vs bupropion SR. All sig- nificance tests were 2-tailed using anoverall level of significance of ␣=.05.
the logistic regression model reportedfor each treatment comparison. Treat-ment comparisons for 7-day point prevalence abstinence were con-ducted at weeks 12, 24, and 52 usingthe logistic regression model. Labora- by frequencies of events and meanchanges from baseline.
visit through the first 7 weeks of treat- ment. The analysis was based on a re-peated-measures model with treat- effect and P values were obtained by contrasting the average over week 1through week 7. SAS version 8.2 (SASInstitute Inc, Cary, NC) was used for *“Lack of efficacy” was recorded if the primary reason for discontinuation was a report by the participant that Participant Disposition
their assigned treatment (blinded varenicline, sustained-release bupropion [bupropion SR], or placebo) wasnot effective for them.
Of 1483 participants screened, 1025
were eligible, randomly assigned to re-
ceive treatment, and included in the
analysis (FIGURE 1). The 52-week study
Table 1. Baseline Participant Characteristics
Bupropion SR
No. of cigarettes/d in past mo, mean (SD) ment of 84 days in each of the 3 groups.
Abbreviations: bupropion SR, sustained-release bupropion; NRT, nicotine replacement therapy.
groups (TABLE 1). Overall, 54% of par-
*Range, 0 to 10. Higher scores indicate greater dependence.
ticipants were men and 79% were white.
50 JAMA, July 5, 2006—Vol 296, No. 1 (Reprinted)
2006 American Medical Association. All rights reserved.
and Smoking Satisfaction
80% had at least 1 prior attempt to quit, (PϽ.001), enjoyment of respiratory tract sensations (PϽ.001), and crav- TABLE 2. As assessed by subscales of the
ing relief (PϽ.001) after smoking, with Continuous Abstinence
placebo (PϽ.001). The effect size of the Figure 2. Continuous Abstinence Rates
(OR, 3.85; 95% CI, 2.70-5.50; PϽ.001) (FIGURE 2). Bupropion SR was also su-
(P=.01), but the effect size was small.27 1.38-2.89; PϽ.001). The continuous significantly higher with varenicline than with placebo (P=.04), but the effect size 5.60; PϽ.001) and vs bupropion SR fect restlessness or appetite but signifi- 2.33; P = .007). The continuous absti- The Ns shown in the key are the denominators used for all 3 periods. PϽ.001 for all comparisons except varenicline vs sustained-release bupropion (bupro-pion SR) at weeks 9 through 24 (P = .007), vareni- total craving score was significantly less cline vs bupropion SR at weeks 9 through 52 (P=.057), 3.09; 95% CI, 1.95-4.91; PϽ.001) but for both varenicline (PϽ.001) and bu- and bupropion SR vs placebo at weeks 9 through 52 propion SR (P=.001). The effect size for (P=.001).
*Abstinence confirmed by measurement of exhaled 0.99-2.17; P = .057) (Figure 2).
†Clinic and telephone visits: abstinence confirmed bymeasurement of exhaled carbon monoxide at clinic Point Prevalence Abstinence
The 7-day point prevalence absti-
nence rates were significantly higher for
Figure 3. 7-Day Point Prevalence Abstinence
varenicline compared with placebo atweeks 12, 24, and 52 (PϽ.001 at each bupropion SR at week 12 (PϽ.001) and week 24 (P = .01) (FIGURE 3).
Sex and Baseline Comparisons
ing cessation as measured by the week9 through 12 continuous abstinence rate was 42.9% for men and 46% forwomen, with no differences between 3.75; 95% CI, 2.30-6.11; PϽ.001; andwomen: OR, 3.63; 95% CI, 2.21-5.97; The Ns shown in the key are the denominators used for all time points. The 7-day point prevalence rate of PϽ.001). Likewise, analyses of other abstinence at week 12 was 50.3% for the varenicline group vs 21.2% for the placebo group (PϽ.001) and35.9% for the sustained-release bupropion (bupropion SR) group (PϽ.001). At week 24, 33.5% of the vareni- cline group were abstinent vs 14.5% of the placebo group (PϽ.001) and 24.9% of the bupropion SR group (P=.01). At week 52, 28.1% of the varenicline group were abstinent vs 14% of the placebo group (PϽ.001)and 22.8% of the bupropion SR group (P=.13).
2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 5, 2006—Vol 296, No. 1 51
VARENICLINE VS BUPROPION AND PLACEBO FOR SMOKING CESSATION included those that occurred up to 7 days ward compared with placebo (P=.004), reported in at least 5% of participants tak- varenicline (TABLE 3).
placebo (TABLE 4). The incidence of ad-
tion, atrial fibrillation, and chest pain tions due to adverse events were 8.6% for ing varenicline was diagnosed with atrial fibrillation at day 84, with resolution on Safety and Tolerability
participant assigned to placebo died dur- were abdominal pain, atrial fibrillation, Table 2. Measures of Withdrawal and Craving Using MNWS & QSU-brief: Repeated-Measures Analysis of Data for Week 1 through Week 7
Comparison vs Placebo
Mean (SE)†
Difference (SE)
P Value
Effect Size‡
QSU-brief Total Craving Score
Abbreviations: bupropion SR, sustained-release bupropion; CI, confidence interval; MNWS, Minnesota Nicotine Withdrawal Scale; QSU-brief, Brief Questionnaire of Smoking Urges.
*Includes data for all participants who had an assessment for the subscale both at baseline and at least 1 of the visits for weeks 1 through 7.
†Higher scores on the MNWS (range of possible scores, 0-4) indicate greater intensity of symptoms. Higher scores on the QSU-brief (range of possible scores, 1-7) indicate greater ‡Least-square mean difference divided by the pooled SD at baseline.
52 JAMA, July 5, 2006—Vol 296, No. 1 (Reprinted)
2006 American Medical Association. All rights reserved.
VARENICLINE VS BUPROPION AND PLACEBO FOR SMOKING CESSATION Table 3. Measurement of Smoking Reinforcement Using mCEQ: Repeated-Measures Analysis of Data for Week 1 through Week 7 for
Participants Who Smoked
Comparison vs Placebo
Mean (SE)†
Difference (SE)
P Value
Effect Size‡
Enjoyment of respiratory tract sensations Enjoyment of respiratory tract sensations Enjoyment of respiratory tract sensations Abbreviations: bupropion SR, sustained-release bupropion; CI, confidence interval; mCEQ, Modified Cigarette Evaluation Questionnaire.
*Includes data for all participants who had an assessment for the subscale both at baseline and at least 1 of the visits for weeks 1 through 7.
†Higher scores indicate greater intensity of smoking effects (range of possible scores, 1-7).
‡Least-square mean difference divided by the pooled SD at baseline.
cious for smoking cessation. The end-of-treatment continuous abstinence rate Table 4. Treatment-Emergent Adverse Events (Including Those Not Necessarily Related to
Study Drug)*
for varenicline was nearly 2.5 times that for placebo, was similar for men andwomen, and was sustained through 24 Varenicline
Bupropion SR
more efficacious than bupropion SRthrough 24 weeks.
Most Frequent Adverse Events*
nists to treat addictions28,29 and the pri- tially activating the ␣4␤2 nAChR, crav- Study Drug Treatment Discontinuations Due to Adverse Events‡
Abbreviation: bupropion SR, sustained-release bupropion.
*Treatment-emergent adverse events were defined as adverse events that began or increased in severity during study- drug treatment or up to 7 days after the last dose. Reported events occurred at 5% or more for varenicline and at a higher frequency than reported for placebo.
†Self-described as any change in dreaming, such as vivid dreams or increased frequency of dreaming.
‡Includes participants who discontinued study drug treatment but remained in the study, as well as those who dis-continued the overall study.
2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 5, 2006—Vol 296, No. 1 53
VARENICLINE VS BUPROPION AND PLACEBO FOR SMOKING CESSATION the integrity of the data and the accuracy of the dataanalysis.
Study concept and design: Gonzales, Nides, Billing, Acquisition of data: Gonzales, Rennard, Nides, Oncken,Billing, Gong, Reeves.
throughout the trial, abstinence rates de- Analysis and interpretation of data: Gonzales, Rennard, the increase in point prevalence rate for Nides, Azoulay, Billing, Watsky, Gong, Williams, Reeves.
Drafting of the manuscript: Gonzales, Rennard, Nides, Critical revision of the manuscript for important in-tellectual content: Gonzales, Rennard, Oncken, relatively flat during drug treatment.
Azoulay, Billing, Watsky, Gong, Williams, Reeves.
Statistical analysis: Gonzales, Billing.
Obtained funding: Azoulay, Watsky, Reeves.
Administrative, technical, or material support: tions from earlier trials.17 The trend of Gonzales, Rennard, Watsky, Williams.
Study supervision: Azoulay, Watsky, Gong, Reeves.
Financial Disclosures: Dr Gonzales reports having
received research contracts from Pfizer, Sanofi- cline therapy led to greater long-term ab- Aventis, GlaxoSmithKline, and Nabi Biopharmaceuti- cals; consulting fees and honoraria from Pfizer, Sanofi-Aventis, and GlaxoSmithKline; and owning 5 shares of Pfizer stock. Dr Rennard reports having had or cur- rently having a number of relationships with compa-nies who provide product and/or services relevant to outpatient management of chronic obstructive pulmo- nary disease. These relationships include serving as aconsultant for Adams, Almirall, Altana, Array Bio- pharma, AstraZeneca, Aventis, Biolipox, Centocor, Dey, Critical Therapeutics, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Ono Pharma, Otsuka, RJ Rey-nolds, Roche, Sankyo, Schering-Plough, Scios, and Wyeth; advising regarding clinical trials for Altana, Astra- Zeneca, Aventis, Centocor, GlaxoSmithKline, Novar-tis, Pfizer, and Philip Morris; and speaking at continu- ing medical education programs and performing funded research both at basic and clinical levels for Altana, Astra-Zeneca, Boehringer Ingelheim, GlaxoSmithKline, and Novartis. Dr Nides reports having received research grants, consulting fees, and honoraria from Pfizer, Sanofi-Aventis, and GlaxoSmithKline. Dr Oncken reports hav- ing received research grants, consulting fees, and hono- raria from Pfizer; receiving, at no cost, nicotine CONCLUSIONS
replacement and placebo products from GlaxoSmith-Kline for smoking cessation studies; and receiving hono- Varenicline is an efficacious therapy for raria from Pri-Med. Drs Azoulay, Watsky, Gong, Wil- smoking cessation. In this trial, vareni- liams, and Reeves and Mr Billing report owning Pfizerstock or having stock options in Pfizer.
Funding/Support: This study was supported by Pfizer
Inc, which provided funding, study drug and pla-cebo, and monitoring.
Role of the Sponsor: The database containing the find-
ings of the 19 individual investigator sites was main- tained by Pfizer Inc, and statistical analyses were per-formed at Pfizer Inc by Mr Billing and by Ann Independent Statistical Analysis: Barbara Pizacani,
PhD, Adjunct Faculty at the School of Nursing at Or-
egon Health & Science University (OHSU) and Epi- demiologist in Program Design and Evaluation Ser- vices for Multnomah Health Department and OrgeonDepartment of Human Services, and Clyde Dent, PhD, of the Program Design and Evaluation Services of Mult- nomah County Health Department and Oregon De- Author Affiliations: Smoking Cessation Center, De-
partment of Human Services, had access to all of the partment of Medicine, Oregon Health & Science Uni- data used in the study and performed an indepen- versity, Portland (Dr Gonzales); Pulmonary Division, dent analysis in consultation with Dr Gonzales. The University of Nebraska Medical Center, Omaha (Dr independent analysis replicated the analyses of the pri- Rennard); Los Angeles Clinical Trials, Los Angeles, Ca- mary and secondary end points reported in the manu- ous abstinence rates.17,18 However, study lif (Dr Nides); Department of Medicine, University of script using cross tabulations, logistic regression, and Connecticut Health Center, Farmington (Dr On- mixed-model procedures. Repeat tabulations for other completion rates in this trial were simi- cken); Pfizer Global Research and Development, Gro- end points were performed. Results for the adverse lar across all treatment groups, and pla- ton, Conn (Drs Azoulay, Watsky, Gong, Williams, and events were also replicated. Results were compa- cebo response rates were similar to prior rable with those obtained by the sponsor. While there Author Contributions: Dr Gonzales had full access to
were several small discrepancies, all were resolved prior all of the data in the study and takes responsibility for to submission of the manuscript and none affected the 54 JAMA, July 5, 2006—Vol 296, No. 1 (Reprinted)
2006 American Medical Association. All rights reserved.
VARENICLINE VS BUPROPION AND PLACEBO FOR SMOKING CESSATION inferences made in the manuscript. Compensation for search Institute, Newport Beach, Calif; Kevin Lawrence sity Hospital, Great Neck, NY; Martin Lewis Throne, Drs Pizacani and Dent was provided by OHSU. Pfizer Kovitz, MD, Tulane University Health Sciences Cen- MD, Radiant Research, Atlanta, Ga; Dan Louis Zim- Inc provided no funds to support the independent ter, New Orleans, La; Lawrence Vincent Larsen, MD, broff, MD, Pacific Clinical Research Medical Group, PhD, Intermountain Clinical Research, Salt Lake City, Varenicline Phase 3 Study Group: Lirio S. Covey, PhD,
Utah; Myra Lee Muramoto, MD, University of Ari- Acknowledgment: We thank Wendy G. Bjornson, MPH,
Social Psychiatry Research Institute, New York, NY; zona Health Sciences, Tucson; Barry Packman, MD, OHSU, for her contribution to the development of the Jeffrey George Geohas, MD, Radiant Research, Chi- Radiant Research, Philadelphia, Pa; Victor Ivar Reus, manuscript and Kelly Stein Marcus, PhD, Cardinal Health, cago, Ill; Elbert D. Glover, PhD, Department of Public MD, University of California, San Francisco; Howard for providing medical editorial review and assisting with and Community Health, University of Maryland, Col- I. Schwartz, MD, Miami Research Associates Inc, Mi- incorporating revisions from the authors and develop- lege Park; Jon F. Heiser, MD, Pharmacology Re- ami, Fla; Arunabh Talwar, MD, North Shore Univer- REFERENCES
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(Reprinted) JAMA, July 5, 2006—Vol 296, No. 1 55


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