Nicotine AddictionPhase 3NCT01314001
Pharmacogenetics of Nicotine Addiction Treatment
A Phase 3 study testing Varenicline and Transdermal Nicotine in people with Nicotine Addiction, run by University of Pennsylvania at 4 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Nicotine Addiction
- What is being tested?
- Varenicline and Transdermal Nicotine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,246 participants
- Where
- 4 sitesin 2 countries
- Study dates
- Dec 2010to Sep 2014
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
- Alcohol/Drug Exclusion Criteria
Show all 44Show fewer
- 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.
- Medical Exclusion Criteria
- 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).
- Uncontrolled hypertension (determined as a Systolic Blood pressure (SBP) reading greater than 160 and/or a Diastolic Blood Pressure (DBP) greater than 100).
- Serious or unstable disease within the past 6 months.
- History (last 6 months) of abnormal heart rhythms, tachycardia and cardiovascular disease (stroke, angina, heart attack) may result in ineligibility. These conditions will be evaluated on a case by case basis by the Study Physician.
- Inability to provide a blood sample to be used to assess nicotine metabolite ratio.
- Psychiatric Exclusion Criteria (as determined by self report \& MINI)
- Current diagnosis of major depression. Persons with a history of major depression, if stable for 6 months or longer, are eligible, provided they are not excluded based on medications (below).
- Any suicide risk score on MINI or self-reported suicide attempt on telephone screen.
- Current or past hypomanic/manic episode.
- History or current diagnosis of Post Traumatic Stress Disorder (PTSD).
- History or current diagnosis of psychotic disorder, bipolar disorder, schizophrenia.
- Medication Exclusion Criteria
- Current use or recent discontinuation (within the last 14-days) of:
- Smoking cessation medication (e.g. Zyban, Wellbutrin, Wellbutrin SR, Chantix); NOTE: Once participants are found eligible for the study, they are instructed to use the smoking cessation medication provided to them by the study staff. If a subject reports an isolated (non-daily) instance of using a non-study smoking cessation medication, the study physician and PI will evaluate the situation and determine if it is safe for the subject to continue participation.
- Anti-psychotic medications.
- Certain medications used to treat depression, including Wellbutrin, Monoamine Oxidase Inhibitors (MAOIs), and tricyclic antidepressants.
- Prescription stimulants (e.g. Provigil, Ritalin, Adderall).
- Current use of:
- Nicotine replacement therapy (NRT); NOTE: Once participants are found eligible for the study, they are told they should only use the NRT provided to them by the study staff. If a subject reports an isolated (non-daily) instance of NRT use during the study, they may be permitted to continue.
- Tagamet (cimetidine).
- Heart medications such as digoxin, quinidine, nitroglycerin; use of these medications may result in ineligibility and will therefore be evaluated on a case-by-case basis by the Study Physician.
- Anti-coagulants (e.g., Coumadin, Warfarin).
- Daily use of:
- Opiate-containing medications for chronic pain; if a participant reports taking an opiate-containing medication every day for the 14 days prior to the telephone screen and/or Intake Session, the participant will be ineligible.
- Rescue Inhalers (e.g. albuterol, proventil, ventolin, or maxair)
- General Exclusion
- Any medical condition, illness, disorder or concomitant medication that could compromise participant safety or treatment, as determined by the Principal Investigator and/or Study Physician.
- Inability to provide informed consent or complete any of the study tasks as determined by the Principal Investigator and/or Study Physician.
Trial locations and contacts
4 sites in 2 countries.
4 sites in 2 countries
United States3 sites
University at Buffalo - State University of New York
Buffalo, New York, 14260
MD Anderson Cancer Center, University of Texas
Houston, Texas, 77230
Center for Interdisciplinary Research on Nicotine Addiction, University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Canada1 site
Centre for Addiction and Mental Health, University of Toronto
Toronto, Ontario, M5T1RH
About this study
Official title: Pharmacogenetics of Nicotine Addiction Treatment (PNAT)
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.
Read the detailed description
Smoking is an enormous public health problem with a great need for research to improve treatment outcomes. Our prior data indicates that the cytochrome P450 2A6 (CYP2A6) enzyme is critical in the metabolic inactivation of nicotine, and also influences smoking behavior and response to therapies. With a vision toward translation of our research to practice, we have characterized a genetically-informed biomarker of CYP2A6 activity, specifically the nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine), which reflects both CYP2A6 genetic variation and environmental influences on CYP2A6 activity. The NMR is measured non-invasively in smokers with established reliability, stability, analytic validity, and efficacy as a predictor of the ability to quit smoking and treatment response in multiple retrospective trials. Translation of these findings to clinical practice requires validation in a prospective clinical trial comparing alternative therapies for smoking cessation. Thus, the proposed trial is a prospective, stratified, placebo-controlled, multi-center clinical trial of alternative therapies for smoking cessation treatment in approximately 1,200 smokers. Randomization to placebo (PLA), transdermal nicotine (TN), or varenicline (VAR) will be stratified prospectively based on the nicotine metabolite ratio (NMR). Abstinence from smoking at the end of treatment will be the primary outcome. Quit rate at 6-month follow-up is a secondary outcome. To facilitate translation to practice, analysis of the cost-effectiveness of our proposed approach will also be completed. The proposed research provides the next critical step to validate a genetically-informed diagnostic tool, the NMR, which clinicians can use in the future to optimize treatment decisions for their patients who wish to quit smoking.
- Conditions
- Nicotine Addiction
- Being tested
- Varenicline, Placebo, Transdermal Nicotine
- Keywords
- Tobacco, Smoking, Varenicline, Nicotine Patch
- Medical subject headings
- Tobacco Use Disorder, Smoking
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VareniclineDrug
Also called Chantix
Day 1-3: 0.5mg once daily orally Day 4-7: 0.5mg twice daily orally Day 8-84: 1.0mg twice daily orally
PlaceboDrug
Also called Placebo pills, Placebo patches
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
Transdermal NicotineDrug
Also called Nicoderm CQ, Nicotine Patch
Week 1-6: 21mg nicotine patch Week 7-8: 14mg nicotine patch Week 9-11: 7mg nicotine patch
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Transdermal Nicotine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Week 11
Secondary outcomes (5)
7-day Point Prevalence Quit Rate at 6-month Follow up Survey
The percentage of ITT subjects who were verified as abstinent at the 6-month follow up survey. 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.
Measured: Week 24
Total Side-Effect Severity Index at Pre-Quit
The mean side-effect severity score by treatment group (placebo vs. nicotine patch vs. varenicline) and by NMR group (slow metabolizers vs. normal metabolizers).
Side-effect severity was calculated using a Side Effects Checklists (SEC). 29 common side-effects associated with transdermal nicotine or varenicline treatment were rated by participants on a 0 (none) to 3 (severe) scale. For each participant at this timepoint, these scores were summed to calculate a total score, with a range of 0 to 87; a higher score indicated a higher severity of side-effects.
Measured: Pre-Quit (Week -1/Baseline)
Total Side-Effect Severity Index at Target Quit Date
The mean side-effect severity score by treatment group (placebo vs. nicotine patch vs. varenicline) and by NMR group (slow metabolizers vs. normal metabolizers).
Side-effect severity was calculated using a Side Effects Checklists (SEC). 29 common side-effects associated with transdermal nicotine or varenicline treatment were rated by participants on a 0 (none) to 3 (severe) scale. For each participant at this timepoint, these scores were summed to calculate a total score, with a range of 0 to 87; a higher score indicated a higher severity of side-effects.
Measured: Target Quit Date (Week 0)
Total Side-Effect Severity Index at Week 1
The mean side-effect severity score by treatment group (placebo vs. nicotine patch vs. varenicline) and by NMR group (slow metabolizers vs. normal metabolizers).
Side-effect severity was calculated using a Side Effects Checklists (SEC). 29 common side-effects associated with transdermal nicotine or varenicline treatment were rated by participants on a 0 (none) to 3 (severe) scale. For each participant at this timepoint, these scores were summed to calculate a total score, with a range of 0 to 87; a higher score indicated a higher severity of side-effects.
Measured: Week 1
Total Side-Effect Severity Index at Week 4
The mean side-effect severity score by treatment group (placebo vs. nicotine patch vs. varenicline) and by NMR group (slow metabolizers vs. normal metabolizers).
Side-effect severity was calculated using a Side Effects Checklists (SEC). 29 common side-effects associated with transdermal nicotine or varenicline treatment were rated by participants on a 0 (none) to 3 (severe) scale. For each participant at this timepoint, these scores were summed to calculate a total score, with a range of 0 to 87; a higher score indicated a higher severity of side-effects.
Measured: Week 4
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Mar 2011 (estimated)
- Study startDec 2010
- Primary completionDec 2013
- Study completionSep 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Nicotine AddictionStudies of the same condition, open and under way.
- More trials run by University of PennsylvaniaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 1,246 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pennsylvania
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Drug Abuse (NIDA)
- Responsible party
- Sponsor
- Investigators
- Caryn Lerman, PhD, Principal investigator, University of PennsylvaniaRachel F Tyndale, PhD, Principal investigator, University of Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01314001
- Sponsor's protocol ID
- 811722
- Other IDs
- U01DA020830
- Status last verified
- Feb 2016
- First submitted
- 10 Mar 2011
- Last updated
- 3 Mar 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 40358028Chenoweth MJ, Lerman C, Knight J, Tyndale RF. Sex dependent genetic architecture of biochemically verified tobacco use. Psychiatry Res. 2025 Jun;348:116465. doi: 10.1016/j.psychres.2025.116465. Epub 2025 Mar 26.
PubMed 40174410Chenoweth 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.
PubMed 38369951Chenoweth 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.
PubMed 36789481Tonkin 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.
PubMed 35639828Chenoweth 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.
PubMed 33713409El-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.
PubMed 33300144Peng 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.
PubMed 31502736Ashare 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.
PubMed 30946162Robinson 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.
PubMed 30614717Peng 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.
PubMed 29986268Hamilton 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.
PubMed 25732567Lerman 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.
PubMed 25588294Chenoweth 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.
PubMed 25012994
Study at a glance
From the registry record, last updated by the sponsor on 3 Mar 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacogenetics of Nicotine Addiction Treatment (PNAT)
- ClinicalTrials.gov ID
- NCT01314001
- Acronym / sponsor ID
- 811722
- Conditions
- Nicotine Addiction
- Keywords
- Tobacco, Smoking, Varenicline, Nicotine Patch
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,246 participants (actual)
- Lead sponsor
- University of PennsylvaniaUniversity, hospital or other
- Collaborators
- National Institute on Drug Abuse (NIDA)
- Study start
- Dec 2010
- Primary completion
- Dec 2013 (actual)
- Study completion
- Sep 2014 (actual)
- First posted
- 14 Mar 2011 (estimated)
- Results
- Posted 3 Mar 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Smoking is an enormous public health problem with a great need for research to improve treatment outcomes. Our prior data indicates that the cytochrome P450 2A6 (CYP2A6) enzyme is critical in the metabolic inactivation of nicotine, and also influences smoking behavior and response to therapies. With a vision toward translation of our research to practice, we have characterized a genetically-informed biomarker of CYP2A6 activity, specifically the nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine), which reflects both CYP2A6 genetic variation and environmental influences on CYP2A6 activity. The NMR is measured non-invasively in smokers with established reliability, stability, analytic validity, and efficacy as a predictor of the ability to quit smoking and treatment response in multiple retrospective trials. Translation of these findings to clinical practice requires validation in a prospective clinical trial comparing alternative therapies for smoking cessation. Thus, the proposed trial is a prospective, stratified, placebo-controlled, multi-center clinical trial of alternative therapies for smoking cessation treatment in approximately 1,200 smokers. Randomization to placebo (PLA), transdermal nicotine (TN), or varenicline (VAR) will be stratified prospectively based on the nicotine metabolite ratio (NMR). Abstinence from smoking at the end of treatment will be the primary outcome. Quit rate at 6-month follow-up is a secondary outcome. To facilitate translation to practice, analysis of the cost-effectiveness of our proposed approach will also be completed. The proposed research provides the next critical step to validate a genetically-informed diagnostic tool, the NMR, which clinicians can use in the future to optimize treatment decisions for their patients who wish to quit smoking.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Placebo (Slow Metabolizers) | Placebo comparator | Drug: PlaceboSubjects 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. |
| Varenicline (Slow Metabolizers) | Active comparator | Drug: VareniclineSubjects 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. |
| Transdermal Nicotine (Slow Metabolizers) | Active comparator | Drug: Transdermal NicotineSubjects 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. |
| Placebo (Normal Metabolizers) | Placebo comparator | Drug: PlaceboSubjects 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. |
| Varenicline (Normal Metabolizers) | Active comparator | Drug: VareniclineSubjects 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. |
| Transdermal Nicotine (Normal Metabolizers) | Active comparator | Drug: Transdermal NicotineSubjects 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (44 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VareniclineAlso: ChantixDay 1-3: 0.5mg once daily orally Day 4-7: 0.5mg twice daily orally Day 8-84: 1.0mg twice daily orally | Drug | Varenicline (Normal Metabolizers), Varenicline (Slow Metabolizers) |
| PlaceboAlso: Placebo pills, Placebo patchesDay 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 | Drug | Placebo (Normal Metabolizers), Placebo (Slow Metabolizers) |
| Transdermal NicotineAlso: Nicoderm CQ, Nicotine PatchWeek 1-6: 21mg nicotine patch Week 7-8: 14mg nicotine patch Week 9-11: 7mg nicotine patch | Drug | Transdermal Nicotine (Normal Metabolizers), Transdermal Nicotine (Slow Metabolizers) |
Primary outcome
7-day Point Prevalence Quit Rate at End-of-Treatment (EOT)
Time frame: Week 11
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.
5 secondary outcomes
7-day Point Prevalence Quit Rate at 6-month Follow up Survey
Time frame: Week 24
Total Side-Effect Severity Index at Pre-Quit
Time frame: Pre-Quit (Week -1/Baseline)
Total Side-Effect Severity Index at Target Quit Date
Time frame: Target Quit Date (Week 0)
Total Side-Effect Severity Index at Week 1
Time frame: Week 1
Total Side-Effect Severity Index at Week 4
Time frame: Week 4
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Mar 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 40358028Tonkin 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.
- Derived from this study: PubMed 40174410Chenoweth MJ, Lerman C, Knight J, Tyndale RF. Sex dependent genetic architecture of biochemically verified tobacco use. Psychiatry Res. 2025 Jun;348:116465. doi: 10.1016/j.psychres.2025.116465. Epub 2025 Mar 26.
- Derived from this study: PubMed 38369951Chenoweth 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.
- Derived from this study: PubMed 36789481Chenoweth 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.
- Derived from this study: PubMed 35639828Tonkin 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.
- Derived from this study: PubMed 33713409Chenoweth 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.
- Derived from this study: PubMed 33300144El-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.
- Derived from this study: PubMed 31502736Peng 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.
- Derived from this study: PubMed 30946162Ashare 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.
- Derived from this study: PubMed 30614717Robinson 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.
- Derived from this study: PubMed 29986268Peng 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.
- Derived from this study: PubMed 25732567Hamilton 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Caryn Lerman, PhD principal investigator
University of Pennsylvania
Rachel F Tyndale, PhD principal investigator
University of Toronto
4 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Varenicline and Transdermal Nicotine in people with Nicotine Addiction, run by University of Pennsylvania at 4 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 44 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Mar 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Mar 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
7-day Point Prevalence Quit Rate at End-of-Treatment (EOT) (time frame: Week 11). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01314001, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Mar 2016.