A Placebo-Controlled Trial of Selegiline Hydrochloride for Smoking Cessation

Tony P. George, M.D., Jennifer Vessicchio, M.S.W., Angelo Termine, B.S., Peter Jatlow, M.D., Thomas Kosten, M.D. and Stephanie S. O’Malley,

Ph.D.

Center for Nicotine and Tobacco Use Research at Yale (CENTURY), Department of Psychiatry, Yale University School of Medicine

New Haven, Connecticut USA 06519tony.george@yale.edu

Supported by NIDA (P50-DA-13334)Supported by NIDA (P50-DA-13334)

Introduction• Cigarette smoking rates in the general population are

~23%, and those who continue to smoke have had multiple quit attempt failures [CDC, 2003]

• In spite of nicotine replacement therapies and Bupropion SR (Zyban®), there is a strong need to develop better pharmacological treatments for nicotine dependence.

• Monoamine oxidase B (MAO-B) preferentially metabolizes dopamine, which is an important neurotransmitter in the biology of nicotine dependence.

• Selegiline hydrochloride (L-Deprenyl®) is a MAO-B inhibitor that increases synaptic levels of dopamine. In addition, an unidentified component of tobacco smoke (not nicotine) inhibits MAO-A and B isoforms [Fowler et al., 1996].

Inhibition of MAO-B by Cigarette Smoking [Fowler et al., 1996. Nature. 379: 733-736][Fowler et al., 1996. Nature. 379: 733-736]

Study Aims• To determine if selegiline (10 mg/day)

enhances smoking cessation rates compared to placebo in refractory cigarette smokers.

• To determine the safety and tolerability of selegiline in cigarette smokers.

• To determine if the presence of depressive at the beginning of treatment alters smoking cessation outcomes with selegiline.

Study MethodologyStudy Methodology

• Potential cigarette smoking subjects were recruited from the community through newspaper advertisements and word of mouth.

• Smoked at least 20 cigarettes/day, with a CO level >10 ppm, plasma cotinine > 150 ng/ml and FTND score > 5 (see Table 1).

• Excluded if they met DSM-IV criteria for an Axis I psychiatric disorder and/or alcohol or illicit drug abuse and dependence disorder (besides nicotine or caffeine).

• Subjects with a past history of major depression or current depression were included but could not be prescribed antidepressant drugs.

• Subjects were randomized to selegiline hydrochloride (SEL; 5 mg po bid) or matching placebo, which was begun during Week 1 of the study, for a total of 8 weeks. The quit date was set at the beginning of Week 3. Study medications were tapered during Week 9 of the study.

• All subjects participated in weekly individual therapy for the 8-week trial which emphasized motivational enhancement and relapse-prevention therapies, derived from AHCPR (2000) Guidelines.

Selegiline Smoking Cessation Study Design

Quit Date (Week 3)

SEL (taper to 5 mg qd x 7 days), then d/c

Weekly Individual Therapy (AHCPR)

Week 1(start meds; SEL 5 mg qd)

Week 9Week 2 Maintain at 5 mg po bid x 7 weeks

Week 4 Week 8

6-Month Follow-up

Table 1: Demographic and Baseline Clinical Characteristics of Cigarette Smokers Prescribed Selegiline Hydrochloride versus Placebo (n=40)

Selegiline (n=20) Placebo (n=20)

Age: 49.7±7.0 48.3±10.3 Sex: 8M/12F 7M/13FRace: 15W/5B 15W/3B/2OEducation (years): 13.5 ± 1.6 14.4±3.2Cigarettes/Day: 23.0±10.0 22.4±8.1Smoking Pack-Yearsa: 38.2 +22.1 32.9+16.2Previous Quit Attempts: 9.4±21.7 4.7±2.7 Baseline CO Level (ppm): 21.7±7.3 22.6±9.9FTND Score: 6.6±1.4 6.6±1.8 Plasma Cotinine (ng/ml) 294±99 241±84 Urine Cotinine (ng/ml): 1705±772 1673±770Motivation to Quit (0-4): 3.7±0.8 3.8±0.6History of MDD: 3/20 (15.0%) 7/20 (35.0%)BDI Score: 7.4±5.9 8.4±7.3 _______________________________________________________________ _______ _

W=whiteB=blackO=other raceCO=Carbon MonoxideFTND=Fagerstrom Test for Nicotine DependenceMDD = Major Depressive DisorderBDI=Beck Depression InventoryaSmoking Pack-Years were calculated as average daily smoking multiplied by number of years smoking.p>0.05, all comparisons

George, T.P. et al (2003). Biological Psychiatry. 53: 136-143.

Selegiline versus Placebo: Treatment Retention

8642000.0

0.2

0.4

0.6

0.8

1.0

SEL

PLA

Week in Trial

Pro

port

ion

Rem

ain

ing

in

Tre

atm

en

t

Quit Date

Log Rank Test = 2.27, df =1, p=0.13

Selegiline versus Placebo: Abstinence Outcomes

Trial Endpoint Last Four Weeks Six Month F/U0

25

50

SEL

PLA

Type of Abstinence

Sm

okin

g A

bsti

nen

ce R

ate

(%

)

*

*

*p<0.05 vs. Placebo George, T.P. et al. (2003)

Table 2: Number (Percentage) of Cigarette Smoking Subjects Reporting Adverse Events Prescribed Selegiline Hydrochloride and Placebo During the Trial (n=40)

Adverse Event: Selegiline (n=20) Placebo (n=20)Headache: 8 (40) 9 (45)Anorexia: 3 (15) 2 (10)Constipation: 5 (25) 3 (15)Nausea/Vomiting: 5 (25) 4 (20)Difficulty Falling Asleep: 4 (20) 6 (30)Frequent Night Awakenings: 6 (30) 4 (20)Early Morning Awakenings: 4 (20) 5 (25)Memory Problems: 6 (30) 5 (25)Anxiety/Agitation: 7 (35) 8 (40)Psychotic Symptoms: 0 (0) 1 (5)Dyskinesias: 0 (0) 0 (0)

p>0.05, all comparisons

George, T.P. et al. (2003)

Depressed (Beck Score >10) versus Not Depressed at Baseline: Smoking Abstinence

Yes No0

10

20

30

40

Trial Endpoint

Last Four Weeks

Six-Month Follow-up

Depressed at Trial Baseline

Sm

okin

g A

bsti

nen

ce (

%)

*

* Wald Statistic=1049, df=1, p<0.01

Conclusions• Selegiline hydrochloride (10 mg/day)

significantly enhanced smoking cessation rates compared to placebo in nicotine-dependent cigarette smokers.

• SEL is well-tolerated and safe for use in these patients.

• Current depression (Beck Score>10) at trial baseline is a negative predictor of smoking cessation outcomes with selegiline.

• These preliminary results support the safety and efficacy of an MAO-B inhibitor for smoking cessation.

Future StudiesFuture Studies• Replication of these findings in a larger placebo-Replication of these findings in a larger placebo-

controlled, single-site Phase II trial controlled, single-site Phase II trial [NIH grant 1R01-DA-[NIH grant 1R01-DA-15757-01A1; PI: Tony P. George, M.D., 3/1/04-2/29/08, Priority 15757-01A1; PI: Tony P. George, M.D., 3/1/04-2/29/08, Priority Score 126 from NIDA-E IRG].Score 126 from NIDA-E IRG].

• Special populations – heavy drinkers, women, Special populations – heavy drinkers, women, adolescents.adolescents.

• Pre-clinical studies Pre-clinical studies (self-admnistration, place preference, (self-admnistration, place preference, neurochemical studies to evaluate alternative neurochemical studies to evaluate alternative mechanisms of action to MAO-B inhibition?).mechanisms of action to MAO-B inhibition?).

• Human laboratory studies to evaluate the clinical Human laboratory studies to evaluate the clinical mechanism of action of selegiline, and other selective mechanism of action of selegiline, and other selective MAO-B inhibitors as they become available MAO-B inhibitors as they become available (e.g. (e.g. labazemide).labazemide).