ORIGINAL INVESTIGATION Smoking Cessation With Varenicline, a Selective ␣4␤2 Nicotinic Receptor Partial Agonist Results From a 7-Week, Randomized, Placebo- and Bupropion-Controlled Trial With 1-Year Follow-up Mitchell Nides, PhD; Cheryl Oncken, MD, MPH; David Gonzales, PhD; Stephen Rennard, MD; Eric J. Watsky, MD; Rich Anziano, MS; Karen R. Reeves, MD; for the Varenicline Study Group Background: Currently available smoking cessation cline tartrate, 1.0 mg twice daily (48.0%; PϽ.001) and 1.0 therapies have limited success rates. Varenicline tar- mg once daily (37.3%; PϽ.001), than for placebo (17.1%). trate is a novel, selective nicotinic receptor partial ago- The bupropion rate was 33.3% (P=.002 vs placebo). The car- nist developed specifically for smoking cessation. This bon monoxide–confirmed continuous quit rates from week study evaluated the efficacy, tolerability, and safety of 3 4 to week 52 were significantly higher in the varenicline tar- varenicline doses for smoking cessation. Bupropion hy- trate, 1.0 mg twice daily, group compared with the placebo drochloride was included as an active control. group(14.4%vs4.9%;P=.002).Thebupropionratewas6.3% (P=.60 vs placebo). Discontinuation owing to treatment- Methods: A phase 2, multicenter, randomized, double- emergent adverse events was 15.9% for bupropion, 11.2% blind, placebo-controlled study of healthy smokers (18-65 to14.3%forvarenicline,and9.8%forplacebo.Nodose-related years old). Subjects were randomized to varenicline tar- increases occurred in adverse events for varenicline. trate, 0.3 mg once daily (n=128), 1.0 mg once daily (n=128), or 1.0 mg twice daily (n=127), for 6 weeks plus Conclusions: Varenicline tartrate demonstrated both placebo for 1 week; to 150-mg sustained-release bupro- short-term (1 mg twice daily and 1 mg once daily) and pion hydrochloride twice daily (n=128) for 7 weeks; or long-term efficacy (1 mg twice daily) vs placebo. Vareni- to placebo (n=127) for 7 weeks. cline was well tolerated and may provide a novel therapy to aid smoking cessation. Results: During the treatment phase, the continuous quit rates for any 4 weeks were significantly higher for vareni- Arch Intern Med. 2006;166:1561-1568 IGARETTE SMOKING RE- Varenicline tartrate is a novel, nonnico- mains the world’s lead- tine agent developed expressly for smok- ing cause of preventable ing cessation. It is a selective nicotinic ace- death,1 contributing to 5 tylcholine receptor partial agonist that ␣ ␤ Author Affiliations: million premature deaths binds specifically at the 4 2 nicotinic re- 2 10 ␣ ␤ Los Angeles Clinical Trials, in 2000, which is estimated to increase ceptor subtype. The 4 2 receptor is C 1 Los Angeles, Calif (Dr Nides); to 10 million by 2020. Surveys show that thought to mediate the rewarding prop- Department of Medicine, most smokers want to quit,3 but most at- erties of nicotine by modulating the re- University of Connecticut tempts are unaided, with success rates of lease of dopamine in the nucleus accum- Health Center, Farmington only 3% to 5% at 1 year.3 Current phar- bens.11-13 Cytisine, a plant-derived ␣4␤2 (Dr Oncken); Smoking macotherapies, such as nicotine replace- Cessation Center, Department ment therapy (NRT), bupropion hydro- of Medicine, Oregon Health & chloride, and nortriptyline hydrochloride, See also pages 1547, Science University, Portland (Dr Gonzales); Pulmonary 1553, and 1571 Division, University of CME course available at Nebraska Medical Center, www.archinternmed.com partial agonist used for many years as a Omaha (Dr Rennard); and smoking cessation aid in eastern Eu- 14 Pfizer Global Research and have shown moderate success, typically rope, provided a structural starting point Development, Pfizer Global doubling short-term quit rates vs pla- for the development of the higher- Pharmaceuticals, Groton, Conn cebo,4-7 with success at 1 year averaging affinity varenicline. The agonist effect of (Drs Watsky and Reeves and oral varenicline on dopamine release is Mr Anziano). approximately 7% to 30%, depending on Group Information: The the level of adjunctive behavioral coun- 35% to 60% of that observed with nico- 8,9 10 members of the Varenicline seling. Consequently, additional, more tine, theoretically sufficient to attenu- Study Group are listed at the efficacious smoking cessation medica- ate craving and withdrawal without pro- end of this article. tions are needed. ducing its own dependence syndrome. The (REPRINTED) ARCH INTERN MED/ VOL 166, AUG 14/28, 2006 WWW.ARCHINTERNMED.COM 1561 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 slower release of dopamine with varenicline compared during the previous year, without a period of abstinence of more with smoking would also reduce any potential for abuse.10 than 3 months. Exclusion criteria were major depression re- Varenicline also has a competitive antagonist effect on quiring treatment within the past year; history of panic disor- nicotine due to a substantially higher affinity for the ␣4␤2 der, psychosis, or bipolar disorder; history of anorexia ner- receptor.10 Starting therapy 1 week before the target quit vosa or bulimia; treatment with bupropion within the past year; history of seizures or cardiovascular disease; uncontrolled hy- day could potentially lead to at least partial extinction pertension; history of clinically significant allergic, hemato- of smoking behavior by blocking the rewarding effects logic, renal, endocrine, pulmonary, hepatic, gastrointestinal, 15,16 of smoked nicotine. In addition, the blockade of re- or neurologic disease; alcohol or other drug abuse within the ward could reduce the chance that a “slip” while still un- past year; or use of NRT within the past 3 months. Subjects dergoing treatment would lead to a full-blown relapse. who discontinued use of study medication prematurely were The current study was part of a phase 2 program con- allowed to remain in the study. ducted to select the optimal dose for larger-scale, phase This study was conducted in compliance with the Declara- 3 studies. The primary objectives were to assess the ef- tion of Helsinki. The study protocol and amendments were ap- ficacy, tolerability, and safety of 3 doses of varenicline proved by the institutional review board for each site, and be- administered for 6 weeks. A bupropion arm was in- fore study entry, all subjects signed informed consent forms approved by the sponsor and the site institutional review board. cluded as an active control. EFFICACY ASSESSMENT METHODS Subjects kept daily diaries of the number of cigarettes smoked STUDY DESIGN from baseline through week 7. Exhaled carbon monoxide (CO)levels were measured at each clinic visit through week This randomized, multicenter, double-blind, parallel-group, pla- 52, using a breath CO monitor (Bedfont EC50 Micro III cebo- and active-controlled phase 2 clinical trial was conducted Smokerlyzer, Bedfont USA, Medford, NJ). At each clinic and at 7 US sites from February 21, 2000, to January 3, 2003. Before telephone visit beginning with week 1, subjects were asked the start of the study, a randomization list was computer gener- whether they had smoked in the previous 7 days and since the ated using a method of randomly permuted blocks and a pseudo- previous visit. random number generator. Investigators assigned medication to The primary efficacy measure was the continuous quit rate subjects in numerical order of acceptance into the study. Ran- (CQR) for any 4 weeks, defined as abstinence for any con- domized subjects received 1 of 3 varenicline tartrate dose regi- secutive 28-day period during the treatment phase (deter- mens (0.3 mg once daily, 1.0 mg once daily, or 1.0 mg twice daily), mined by diary data). This measure was chosen to give the sustained-release bupropion hydrochloride (150 mg twice daily), best possibility of detecting an efficacy signal in this early or matched placebo. Varenicline doses were selected on the ba- phase 2 study. Secondary efficacy measures included the sis of tolerability data from phase 1 studies, and subjects were dosed CO-confirmed (Յ10 ppm) 4-week CQR for weeks 4 to 7, as for 6 weeks, receiving blinded placebo during week 7 to pre- well as CQRs from week 4 to weeks 12, 24, and 52. Subjects serve treatment blinding. Bupropion, the primary, non–nicotine- who dropped out for any reason were considered to be smok- based treatment currently prescribed for smoking cessation, was ers at all subsequent time points. Craving was assessed with included as an active control. In accordance with US labeling rec- the urge to smoke item of the Minnesota Nicotine Withdrawal ommendations, bupropion hydrochloride was dosed for 7 weeks, Scale (MNWS)18 and the 10-item Brief Questionnaire of with titration from 150 mg once daily (days 1-3) to 150 mg twice Smoking Urges (QSU-Brief).19 Withdrawal was evaluated daily through week 7. All subjects took study medication for 1 using the remaining 8 items of the MNWS. The MNWS and week before attempting to quit smoking on day 8 of the study. QSU-Brief data were collected daily for the first 2 weeks and During the 7-week treatment phase, subjects visited the study at each weekly visit through week 7. site weekly for efficacy and safety evaluations and up to 10 min- The Modified Cigarette Evaluation Questionnaire (mCEQ) utes of standardized, individual smoking cessation counseling assesses the reinforcing effects of smoking through 12 ques- from trained staff. Subjects were also given the Clearing the Air: tions that collectively make up 5 subscales: smoking satisfac- How to Quit Smoking...andQuit for Keeps17 smoking- tion, psychological reward, enjoyment of respiratory tract sen- cessation booklet at the baseline visit. sations, craving relief, and aversion. Subjects completed the After completing the 7-week treatment phase, subjects mCEQ daily through week 1 and at each weekly visit through had the option to participate in the non–drug treatment the week 7 visit if they had smoked since the previous visit.15,20 phase, which continued through week 52.