Project 2: Strategies for Reducing Nicotine Content in Cigarettes

The main goal of this project is to compare two different approaches to reducing levels of nicotine in cigarettes: an immediate reduction in nicotine content in cigarettes to non-addictive levels or a gradual reduction in nicotine content in cigarettes to non-addictive levels. These two approaches will then be contrasted to a group that continues to smoke cigarettes with nicotine content similar to conventional cigarettes.

Study Overview

• Status: Completed
• Conditions: Tobacco Smoking; Nicotine Dependence
• Intervention / Treatment: Behavioral: Normal Nicotine Control Group; Behavioral: Immediate Nicotine Reduction Group; Behavioral: Gradual Nicotine Reduction Group

Detailed Description

This project will be conducted to compare product use patterns and biomarkers of exposure between smokers who are assigned to a) gradual reduction in reduced nicotine content (RNC) cigarettes; b) immediate reduction to very low nicotine content (VLNC) cigarettes or c) normal nicotine content (NNC) cigarettes. The outcomes from this study will provide information on different approaches to reducing levels of nicotine in cigarettes and will determine the approach with the most optimal outcomes taking into account the balance between overall risk reduction (possibly maximized by abrupt switching) and compliance and acceptability (possibly maximized by gradual reduction of RNC cigarettes).

• Study Type: Interventional
• Enrollment (Anticipated): 1250
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • Florida
    • Tampa, Florida, United States, 33617
      • Moffitt Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University
  • Minnesota
    • Duluth, Minnesota, United States, 55812
      • University of Minnesota Medical School Duluth
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
  • Oregon
    • Eugene, Oregon, United States, 97403
      • Oregon Research Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Texas
    • Houston, Texas, United States, 77030
      • MDAnderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18+
2. Daily smokers who smoke an average of at least five cigarettes per day for at least 1 year
3. Breath CO levels > 8 ppm (if ≤ 8 ppm, then NicAlert Strip level must indicate regular smoking)

Exclusion Criteria:

1. Planned quit date in the next 30 days
2. Currently seeking treatment for smoking cessation
3. Currently using nicotine replacement therapies or other pharmacotherapies as cessation aid (non-cessation intermittent use acceptable)
4. A quit attempt in the past 30 days resulting in greater than 3 days of abstinence
5. Using other tobacco products or e-cigarettes more than 9 days in the past 30 days
6. Significant unstable medical conditions (Any significant change in a serious medical condition occurring during the past 3 months including, cardiovascular disease, COPD, and cancer, as determined by the licensed medical professional at each site)
7. Unstable psychiatric conditions (Any significant change in psychiatric symptoms during the past 3 months as determined by the licensed medical professional at each site)
8. Schizophrenia and schizoaffective disorder
9. Psychiatric medication changes (e.g., new prescriptions, changes in dosages, or discontinuation of medications) in the past 3 months that was a result of negative changes in symptoms.

10. Positive toxicology screen for any of the following drugs: cocaine, opiates, methadone, benzodiazepines, barbiturates, amphetamines, methamphetamines, and PCP

    1. Marijuana will be tested for but will not be an exclusionary criterion.
    2. Participants with valid prescriptions for opiates, benzodiazepines, barbiturates, amphetamines or methadone will not be excluded.
    3. Participants failing the toxicology screen will be allowed to re-screen once.

11. Blood alcohol level > 0.01

    a. Participants failing the blood alcohol screen will be allowed to re-screen once.

12. Binge drinking alcohol (more than 9 days in the past 30 days, 4/5 drinks per day (female/male))
13. Pregnant, trying to become pregnant or breastfeeding
14. Predominant use of 'roll your own cigarettes'
15. CO reading >80 ppm

16. Systolic BP greater than or equal to 160

    a. Participants failing for blood pressure will be allowed to re-screen once.

17. Diastolic BP greater than or equal to 100

    a. Participants failing for blood pressure will be allowed to re-screen once.

18. Systolic BP below 90 and symptomatic (dizziness, extreme fatigue, difficulty thinking, inability to stand or walk, feeling faint)

    a. Participants failing for blood pressure will be allowed to re-screen once.

19. Diastolic BP below 50 and symptomatic (dizziness, extreme fatigue, difficulty thinking, inability to stand or walk, feeling faint)

    a. Participants failing for blood pressure will be allowed to re-screen once.

20. Heart rate greater than or equal to 105 bpm

    a. Participants failing for heart rate will be allowed to re-screen once.

21. Heart rate lower than 45 bpm and symptomatic (dizziness, extreme fatigue, difficulty thinking, inability to stand or walk, feeling faint)

    a. Participants failing for heart rate will be allowed to re-screen once.

22. Indicating any suicidal ideation in the past month, suicide attempts in the past 5 years (if within past 5 to 10 years, requires physician approval), or score of >4 on the MINI suicide subscale
23. Household member enrolled in the study concurrently.
24. Inability to independently read and comprehend the consent form and other written study materials and measures because participants are required to complete parts of the protocol at home independently.
25. Participated in prior study that involved reduced nicotine content cigarettes.
26. Having participated in a research study during the past three months in a study that would impact baseline smoking or response to study products.

27. Currently taking the following anticonvulsant medications:

    1. Phenytoin [Brand Name: Dilantin]
    2. Carbamazepine [Brand Name: Tegretol, Carbatrol, Equetro, Epitol]
    3. Oxcarbazepine [Brand Name: Trileptal]
    4. Primidone [Brand Name: Mysoline]
    5. Phenobarbital

28. Currently taking the following medication:

    1. Bendamustine (Treanda)
    2. Clopidogrel (Plavix)
    3. Clozapine (Clozaril, FazaClo)
    4. Erlotinib (Tarceva)
    5. Flecainide (Tambocor)
    6. Fluvoxamine (Luvox)
    7. Irinotecan (Camptosar)
    8. Olanzapine (Zyprexa)
    9. Ropinirole (Requip)
    10. Tacrine (Cognex)
    11. Theophylline (Theo Dur, etc.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Normal Nicotine Control Group; These subjects will smoke normal nicotine content Spectrum brand cigarettes for 20 weeks.	Behavioral: Normal Nicotine Control Group; Participants will smoke experimental cigarettes for a period of 20-weeks.
Experimental: Immediate Nicotine Reduction Group; This group will immediately be switched to smoking very low nicotine content (VLNC) Spectrum brand cigarettes. They will smoke these cigarettes for 20 weeks.	Behavioral: Immediate Nicotine Reduction Group; Participants will smoke experimental cigarettes for a period of 20-weeks.
Experimental: Gradual Nicotine Reduction Group; This group will smoke progressively lower nicotine content Spectrum brand cigarettes for a period of one month each until they end up smoking the same VLNC cigarettes as the immediate reduction group.	Behavioral: Gradual Nicotine Reduction Group; Participants will smoke experimental cigarettes for a period of 20-weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicant exposure pattern: Expired air carbon monoxide	Between group comparison of expired air carbon monoxide (CO) values at week 20 using baseline CO values as a covariate.	20-week treatment period
Toxicant exposure pattern: Urinary phenanthrene tetroal (Phe)	Between group comparison of urinary phenanthrene tetroal values at week 20 using baseline values as a covariate.	20-week treatment period
Toxicant exposure pattern: Urinary mercapturic acids of acrolein	Between group comparison of urinary mercapturic acid level at week 20 using baseline values as a covariate.	20-week treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nicotine exposure: Total nicotine equivalents (TNE)	Between group comparison of urinary total nicotine equivalents at week 20 using baseline values as a covariate.	End of treatment (Week 20)
Other toxicant exposure: Tobacco specific nitrosamines-Total NNAL and NNN	Between group comparison of urinary total NNAL and NNN levels at week 20 using baseline values as a covariate.	End of treatment (Week 20)
Effect biomarker: C-Reactive protein-high sensitivity as an inflammation biomarker	Between group comparison of C-Reactive protein levels in serum at week 20 using baseline values as a covariate.	End of treatment (Week 20)
Measure of acceptability: Retention in study	Between group comparison of early termination from the study.	End of treatment (Week 20)
Measure of acceptability: Non-compliance	Between group comparison of use of non-study tobacco products.	End of treatment (Week 20)
Effect biomarker: 8-epi-PGF2α as a biomarker for oxidative stress	Between group comparison of 8-epi-PGF2α at week 20 using baseline values as a covariate.	End of treatment (Week 20)
Effect biomarker: White blood cells count as inflammation biomarker	Between group comparison of white blood cell count at week 20 using baseline values as a covariate.	End of treatment (Week 20)
Nicotine exposure: Urinary cotinine	Between group comparison of urinary total nicotine equivalents at week 20 using baseline values as a covariate.	End of treatment (Week 20)

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Eric Donny, PhD, University of Pittsburgh

Publications and helpful links

General Publications

• Hatsukami DK, Luo X, Jensen JA, al'Absi M, Allen SS, Carmella SG, Chen M, Cinciripini PM, Denlinger-Apte R, Drobes DJ, Koopmeiners JS, Lane T, Le CT, Leischow S, Luo K, McClernon FJ, Murphy SE, Paiano V, Robinson JD, Severson H, Sipe C, Strasser AA, Strayer LG, Tang MK, Vandrey R, Hecht SS, Benowitz NL, Donny EC. Effect of Immediate vs Gradual Reduction in Nicotine Content of Cigarettes on Biomarkers of Smoke Exposure: A Randomized Clinical Trial. JAMA. 2018 Sep 4;320(9):880-891. doi: 10.1001/jama.2018.11473.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 14, 2017

Study Registration Dates

• First Submitted: May 12, 2014
• First Submitted That Met QC Criteria: May 13, 2014
• First Posted (Estimate): May 16, 2014

Study Record Updates

• Last Update Posted (Actual): August 15, 2018
• Last Update Submitted That Met QC Criteria: August 13, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: smoking; nicotine reduction
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Tobacco Use Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Ganglionic Stimulants; Nicotinic Agonists; Cholinergic Agonists; Nicotine
• Other Study ID Numbers: U54 DA031659-P2; U54DA031659 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No