Pharmacogenetics of Nicotine Addiction Treatment

NCT01314001 | Completed Phase 3 Results DMC

• 2 other identifiers: 811722U01DA020830
• Study Type: interventional
• Target: 1,246
• Locations: 2 countries
• Sites: 4

Brief Summary

The purpose of this research program is to understand how a biomarker called the "nicotine metabolite ratio" (also referred to as NMR) may influence a smoker's ability to quit smoking.

Conditions

Nicotine Addiction

Keywords

Tobacco, Smoking, Varenicline, Nicotine Patch

Outcome Measures

Primary Outcomes (1)

• 7-day Point Prevalence Quit Rate at End-of-Treatment (EOT)

  The percentage of ITT subjects who were verified as abstinent. Abstinence was defined as no self-reported smoking (not even a puff) for at least 7 days before the telephone assessment, with in-person verification for those self-reporting abstinence. In-person verification consisted of breath carbon monoxide analysis, with a reading of 8 parts-per-million or less confirming abstinence. Subjects who were lost to follow-up were considered smokers.

  Week 11

Secondary Outcomes (5)

• 7-day Point Prevalence Quit Rate at 6-month Follow up Survey

  Week 24

• Total Side-Effect Severity Index at Pre-Quit

  Pre-Quit (Week -1/Baseline)

• Total Side-Effect Severity Index at Target Quit Date

  Target Quit Date (Week 0)

• Total Side-Effect Severity Index at Week 1

  Week 1

• Total Side-Effect Severity Index at Week 4

  Week 4

Study Arms (6)

Placebo (Slow Metabolizers)

PLACEBO COMPARATOR

Subjects in this arm are those identified as slow metabolizers of nicotine (based on their NMR) and will take placebo pills daily for twelve weeks \& wear a placebo patch daily for eleven weeks. The placebo pill will look identical to the active varenicline tablets; however, they will not contain any active medication. Subjects will follow the same drug regimen as those in the active varenicline arm. The placebo patch will look identical to the active transdermal nicotine patches; however, they do not contain actual nicotine. Subjects will follow the same regimen as those in the active transdermal nicotine arm. All subjects in this arm will receive smoking cessation counseling during their sessions.

Drug: Placebo

Varenicline (Slow Metabolizers)

ACTIVE COMPARATOR

Subjects in this arm are those identified as slow metabolizers of nicotine (based on their NMR) and will take active varenicline pills daily for twelve weeks \& wear a placebo patch daily for eleven weeks. When taking the active varenicline, subjects will follow the same treatment regimen per the manufacturer. The placebo patch will look identical to the active transdermal nicotine patches; however, they do not contain actual nicotine. Subjects will follow the same regimen as those in the active transdermal nicotine arm. All subjects in this arm will receive smoking cessation counseling during their sessions.

Drug: Varenicline

Transdermal Nicotine (Slow Metabolizers)

ACTIVE COMPARATOR

Subjects in this arm are those identified as slow metabolizers of nicotine (based on their NMR) and will take placebo pills daily for twelve weeks \& will wear an active transdermal nicotine patch daily for eleven weeks. The placebo pill will look identical to the active varenicline tablets; however, they will not contain any active medication. Subjects will follow the same drug regimen as those in the active varenicline arm. When wearing the active transdermal nicotine, subjects will follow the same treatment regimen per the manufacturer. All subjects in this arm will receive smoking cessation counseling during their sessions.

Drug: Transdermal Nicotine

Placebo (Normal Metabolizers)

PLACEBO COMPARATOR

Subjects in this arm are those identified as normal metabolizers of nicotine (based on their NMR) and will take placebo pills daily for twelve weeks \& wear a placebo patch daily for eleven weeks. The placebo pill will look identical to the active varenicline tablets; however, they will not contain any active medication. Subjects will follow the same drug regimen as those in the active varenicline arm. The placebo patch will look identical to the active transdermal nicotine patches; however, they do not contain actual nicotine. Subjects will follow the same regimen as those in the active transdermal nicotine arm. All subjects in this arm will receive smoking cessation counseling during their sessions.

Drug: Placebo

Varenicline (Normal Metabolizers)

ACTIVE COMPARATOR

Subjects in this arm are those identified as normal metabolizers of nicotine (based on their NMR) and will take active varenicline pills daily for twelve weeks \& wear a placebo patch daily for eleven weeks. When taking the active varenicline, subjects will follow the same treatment regimen per the manufacturer. The placebo patch will look identical to the active transdermal nicotine patches; however, they do not contain actual nicotine. Subjects will follow the same regimen as those in the active transdermal nicotine arm. All subjects in this arm will receive smoking cessation counseling during their sessions.

Drug: Varenicline

Transdermal Nicotine (Normal Metabolizers)

ACTIVE COMPARATOR

Subjects in this arm are those identified as normal metabolizers of nicotine (based on their NMR) and will take placebo pills daily for twelve weeks \& will wear an active transdermal nicotine patch daily for eleven weeks. The placebo pill will look identical to the active varenicline tablets; however, they will not contain any active medication. Subjects will follow the same drug regimen as those in the active varenicline arm. When wearing the active transdermal nicotine, subjects will follow the same treatment regimen per the manufacturer. All subjects in this arm will receive smoking cessation counseling during their sessions.

Drug: Transdermal Nicotine

Interventions

Varenicline DRUG

Day 1-3: 0.5mg once daily orally Day 4-7: 0.5mg twice daily orally Day 8-84: 1.0mg twice daily orally

Also known as: Chantix

Varenicline (Normal Metabolizers); Varenicline (Slow Metabolizers)

Placebo DRUG

Day 1-3: 0.5mg once daily orally Day 4-7: 0.5mg twice daily orally Day 8-84: 1.0mg twice daily orally Week 1 - 6: 21mg placebo patch Week 7 - 8: 14mg placebo patch Week 9 - 11: 7mg placebo patch

Also known as: Placebo pills, Placebo patches

Placebo (Normal Metabolizers); Placebo (Slow Metabolizers)

Transdermal Nicotine DRUG

Week 1-6: 21mg nicotine patch Week 7-8: 14mg nicotine patch Week 9-11: 7mg nicotine patch

Also known as: Nicoderm CQ, Nicotine Patch

Transdermal Nicotine (Normal Metabolizers); Transdermal Nicotine (Slow Metabolizers)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Eligible participants will be males and females
• Between the ages of 18-65.
• Smoke at least 10 cigarettes/day for the past 6 months.
• Provide a baseline Carbon Monoxide (CO) reading greater than 10ppm at the Intake Session.
• Are seeking smoking cessation treatment.
• Plan to live in the area for the next 12 months.
• Fluent English speaker.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the combined consent and Health Insurance Portability and Accountability Act (HIPAA) form. All subjects must consent to use a medically accepted method of birth control (e.g., condoms and spermicide, oral contraceptive, Depo-Provera injection, contraceptive patch, tubal ligation) or abstain from sexual intercourse during the time they are taking study medication (pills and patches) and for at least one month after the medication period ends. All female subjects of child-bearing potential should not be pregnant for the duration of the study.

You may not qualify if:

• Smoking Behavior
• Regular (daily) use of chewing tobacco, snuff or snus.
• Current enrollment or plans to enroll in another smoking cessation or research program in the next 12 months.
• Plan to use other nicotine substitutes or smoking cessation treatments in the next 12 months.
• Provide a baseline CO reading less than or equal to 10ppm at the Intake Session.
• History (within the last year) or currently receiving treatment for substance abuse (e.g., alcohol, opioids, cocaine, marijuana, or stimulants), excluding nicotine.
• Current use of cocaine and/or methamphetamines (urine drug screen at the Intake Session).
• Current alcohol consumption that exceeds greater than 25 standard drinks/week.
• Current alcohol abuse or dependence.
• Current non-alcoholic psychoactive substance abuse or dependence.
• Women who are pregnant, planning a pregnancy, or lactating.
• History of epilepsy or a seizure disorder.
• Current medical problems for which transdermal nicotine is contraindicated including:
• Allergy to latex.
• History of kidney and/or liver disease, including transplant (self-report).

Sponsors & Collaborators

• University of Pennsylvania: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (4)

University at Buffalo - State University of New York

Buffalo, New York, 14260, United States

Location

Center for Interdisciplinary Research on Nicotine Addiction, University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

MD Anderson Cancer Center, University of Texas

Houston, Texas, 77230, United States

Location

Centre for Addiction and Mental Health, University of Toronto

Toronto, Ontario, M5T1RH, Canada

Location

Related Publications (13)

• Tonkin SS, Betts JM, Dowd AN, Mahoney MC, Cinciripini PM, Schnoll RA, George TP, Tyndale RF, Hawk LW Jr. Daily Cigarette Abstinence and Smoking Rate With Varenicline: Relationships With Treatment, Craving, and Affect During the First Week of the Quit Attempt. Nicotine Tob Res. 2025 Nov 23;27(12):2328-2332. doi: 10.1093/ntr/ntaf095.

  PMID: 40358028 DERIVED

• Chenoweth MJ, Kim YJ, Nollen NL, Hawk LW Jr, Mahoney MC, Lerman C, Knight J, Tyndale RF. Genetic Prediction of Smoking Cessation Medication Side Effects: A Genome-Wide Investigation of Abnormal Dreams on Varenicline. Clin Pharmacol Ther. 2024 Jun;115(6):1277-1281. doi: 10.1002/cpt.3210. Epub 2024 Feb 19.

  PMID: 38369951 DERIVED

• Chenoweth MJ, Lerman C, Knight J, Tyndale RF. Influence of CYP2A6 Genetic Variation, Nicotine Dependence Severity, and Treatment on Smoking Cessation Success. Nicotine Tob Res. 2023 May 22;25(6):1207-1211. doi: 10.1093/ntr/ntac268.

  PMID: 36789481 DERIVED

• Tonkin SS, Colder C, Mahoney MC, Swan GE, Cinciripini P, Schnoll R, George TP, Tyndale RF, Hawk LW. Evaluating Treatment Mechanisms of Varenicline: Mediation by Affect and Craving. Nicotine Tob Res. 2022 Oct 26;24(11):1803-1810. doi: 10.1093/ntr/ntac138.

  PMID: 35639828 DERIVED

• Chenoweth MJ, Lerman C, Knight J, Tyndale RF. A Genome-Wide Association Study of Nausea Incidence in Varenicline-Treated Cigarette Smokers. Nicotine Tob Res. 2021 Aug 29;23(10):1805-1809. doi: 10.1093/ntr/ntab044.

  PMID: 33713409 DERIVED

• El-Boraie A, Chenoweth MJ, Pouget JG, Benowitz NL, Fukunaga K, Mushiroda T, Kubo M, Nollen NL, Sanderson Cox L, Lerman C, Knight J, Tyndale RF. Transferability of Ancestry-Specific and Cross-Ancestry CYP2A6 Activity Genetic Risk Scores in African and European Populations. Clin Pharmacol Ther. 2021 Oct;110(4):975-985. doi: 10.1002/cpt.2135. Epub 2021 Jan 1.

  PMID: 33300144 DERIVED

• Peng AR, Swardfager W, Benowitz NL, Ahluwalia JS, Lerman C, Nollen NL, Tyndale RF. Impact of early nausea on varenicline adherence and smoking cessation. Addiction. 2020 Jan;115(1):134-144. doi: 10.1111/add.14810. Epub 2019 Nov 5.

  PMID: 31502736 DERIVED

• Ashare RL, Thompson M, Leone F, Metzger D, Gross R, Mounzer K, Tyndale RF, Lerman C, Mahoney MC, Cinciripini P, George TP, Collman RG, Schnoll R. Differences in the rate of nicotine metabolism among smokers with and without HIV. AIDS. 2019 May 1;33(6):1083-1088. doi: 10.1097/QAD.0000000000002127.

  PMID: 30946162 DERIVED

• Robinson JD, Li L, Chen M, Lerman C, Tyndale RF, Schnoll RA, Hawk LW, George TP, Benowitz NL, Cinciripini PM. Evaluating the temporal relationships between withdrawal symptoms and smoking relapse. Psychol Addict Behav. 2019 Mar;33(2):105-116. doi: 10.1037/adb0000434. Epub 2019 Jan 7.

  PMID: 30614717 DERIVED

• Peng AR, Schnoll R, Hawk LW Jr, Cinciripini P, George TP, Lerman C, Tyndale RF. Predicting smoking abstinence with biological and self-report measures of adherence to varenicline: Impact on pharmacogenetic trial outcomes. Drug Alcohol Depend. 2018 Sep 1;190:72-81. doi: 10.1016/j.drugalcdep.2018.04.035. Epub 2018 Jun 26.

  PMID: 29986268 DERIVED

• Hamilton DA, Mahoney MC, Novalen M, Chenoweth MJ, Heitjan DF, Lerman C, Tyndale RF, Hawk LW Jr. Test-Retest Reliability and Stability of the Nicotine Metabolite Ratio Among Treatment-Seeking Smokers. Nicotine Tob Res. 2015 Dec;17(12):1505-9. doi: 10.1093/ntr/ntv031. Epub 2015 Mar 1.

  PMID: 25732567 DERIVED

• Lerman C, Schnoll RA, Hawk LW Jr, Cinciripini P, George TP, Wileyto EP, Swan GE, Benowitz NL, Heitjan DF, Tyndale RF; PGRN-PNAT Research Group. Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2015 Feb;3(2):131-138. doi: 10.1016/S2213-2600(14)70294-2. Epub 2015 Jan 12.

  PMID: 25588294 DERIVED

• Chenoweth MJ, Novalen M, Hawk LW Jr, Schnoll RA, George TP, Cinciripini PM, Lerman C, Tyndale RF. Known and novel sources of variability in the nicotine metabolite ratio in a large sample of treatment-seeking smokers. Cancer Epidemiol Biomarkers Prev. 2014 Sep;23(9):1773-82. doi: 10.1158/1055-9965.EPI-14-0427. Epub 2014 Jul 10.

  PMID: 25012994 DERIVED

MeSH Terms

Conditions

Tobacco Use Disorder; Smoking

Interventions

Varenicline; Tobacco Use Cessation Devices; Nicotine

Condition Hierarchy (Ancestors)

Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Behavior

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Quinoxalines; Therapeutics; Solanaceous Alkaloids; Alkaloids; Pyridines; Heterocyclic Compounds, 1-Ring

Limitations and Caveats

A limitation is that few Hispanics or Asians were included.

Results Point of Contact

• Title: Paul M. Sanborn, M.S.
• Organization: University of Pennsylvania

sanborn@mail.med.upenn.edu

215-746-7150

Study Officials

• Caryn Lerman, PhD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

• Rachel F Tyndale, PhD

  University of Toronto

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 10, 2011
• First Posted: March 14, 2011
• Study Start: December 1, 2010
• Primary Completion: December 1, 2013
• Study Completion: September 1, 2014
• Last Updated: March 3, 2016
• Results First Posted: March 3, 2016

Record last verified: 2016-02

Locations

US (3); CA (1)