CompletedNCT02250664P2S2Updated Dec 1, 2022Results posted

Project 2, Study 2: Extended Exposure to Low Nicotine Content Cigarettes in Opioid Abusers

A Phase 1/2 interventional study of Very low nicotine content cigarettes in Tobacco Use Disorder, sponsored by University of Vermont. Completed at 2 sites in United States. Open to participants aged 18 Years to 70 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2022-12-01.

Sponsored by University of Vermont · Phase 1/2, Interventional, and Basic science

Phase: Phase 1/2
Study type: Interventional
Enrollment: 775
Allocation: Randomized
Ages: 18 Years to 70 Years
Sex: All

Study summary

This study will examine extended exposure to cigarettes varying in nicotine content among adults with opioid use disorder. Those with opioid use disorder are at increased risk for smoking, nicotine dependence, and using high nicotine yield cigarettes and are also at significantly increased risk for smoking-related adverse health consequences, including site specific cancers, heart disease, and premature death. Studies testing an innovative regulatory strategy of reducing the nicotine content of cigarettes to a non-addictive level have shown promising beneficial effects (decreased smoking rate, reduced toxicant exposure, and increased cessation) in the general population of smokers. However, these studies have uniformly excluded vulnerable populations like those with opioid use disorder who may respond differently considering their greater vulnerability to smoking and nicotine dependence. Thus, little is known scientifically about how this highly vulnerable subgroup of smokers might respond to a nicotine reduction policy. This project is designed to address that substantial knowledge gap. This same study was also conducted in two additional vulnerable populations under a similar protocol.

Read the detailed description

The primary overall objective of these studies is to evaluate the effects of extended exposure to cigarettes differing in nicotine content in adults with opioid use disorder using a 3-condition, parallel groups design. After a baseline period in which daily smoking rate and other baseline assessments are completed, participants will be randomly assigned to one of three cigarette conditions (nicotine content: 0.04, 2.4, and 15.8 mg nicotine/gram of tobacco) for the 12-week experimental period.

The cigarettes to be used in this study were made under an NIH contract with production being overseen by the Research Triangle Institute (referred to as "Spectrum cigarettes"). NIH currently has approximately 10 million of these cigarettes (of varying types) for research purposes. The cigarettes selected for the study span the range of yields likely to produce the hypothesized effects, as described above. The Spectrum cigarettes are not currently commercially available, although they are similar in many ways to marketed cigarettes (e.g., similar manufacturing, filter, paper, etc.).

The primary overall objective of this study is to evaluate the effects of extended exposure to cigarettes differing in nicotine content in male and female adults with opioid use disorder using a 3-condition, parallel groups design. After a baseline period in which daily smoking rate and other baseline assessments are completed, participants will be randomly assigned to one of three cigarette conditions (nicotine content: 0.04 mg, 2.4 mg, and 15.8 mg nicotine/g of tobacco) for the 12-week experimental period.

Participants will be seen weekly throughout the 12-week experimental period to obtain research cigarettes. Cigarettes smoked per day will be obtained by participants completing daily Interactive Voice Response (IVR) reports of cigarettes in past 24 hours. This daily data will be used to calculate weekly means, with week-12 means serving as the primary outcome.

This same study was conducted in two additional vulnerable populations under a similar protocol, with differences between protocols consisting of data collection specific to that vulnerable population. This included information such as additional assessments of anxiety and depression for individuals with affective disorders or other measures specific to disadvantaged women of reproductive age. In order to explore potential differences across individuals with different vulnerabilities, data from all three studies were combined for analysis. A vulnerable population-by-condition or population-by-condition-by-time interaction term was included in all analyses. In the event that these interaction terms were statistically significant, all pairwise comparisons were conducted using a Bonferroni multiple comparison adjustment.

Conditions studied

Tobacco Use Disorder

Browse trials for

Tobacco Use Disorder 968

Keywords

Biomarkers of exposure
Compensatory smoking
Nicotine dependence
Reduced nicotine cigarettes
Tobacco withdrawal
Women
Health disparities
Vulnerable populations

In context

Tobacco Use Disorder

968 studies on the registry are indexed under Tobacco Use Disorder; 126 are open to participants now.

This study's enrollment of 775 is above the median of 89 across 851 interventional studies indexed under Tobacco Use Disorder.

Browse Tobacco Use Disorder studies →

Lead sponsor

University of Vermont is the lead sponsor of 215 studies on the registry; 28 are open to participants now.

Of its 16 completed or terminated interventional studies of FDA-regulated products, 9 (56%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 70 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

Inclusion criteria

Men and women ages 18-70, who are currently receiving methadone or buprenorphine maintenance treatment for opioid dependence.
Report smoking ≥ 5 cigarettes per day.
Provide an intake breath carbon monoxide (CO) sample >8 ppm.
Be without current (within the past year) serious mental disorder that would interfere with study results or completion as determined by the licensed medical professional or PI.
Be sufficiently literate to complete the research-related tasks.
Be in good physical health without serious illness or change in health or medication (not including methadone or buprenorphine dose) in the past three months as determined by the license medical professional at each site.
Not pregnant or nursing, and report using oral, implant, injection or barrier contraceptives, or report being surgically sterile, or post menopausal.
Report no significant use of other tobacco or nicotine products within the past month (more than 9 days in the past 30).
Participants must be maintained on a stable methadone or buprenorphine dose for the past month, with no evidence of regular illicit-drug abuse (\<30% positive specimens in the past 30 days).
1. Consent to confirm dose and drug abstinence with the participant's opioid clinic will be obtained at screening and we will monitor any changes in dose throughout the study.
2. Participants must provide at least three urine samples within the last 30 days. If they do not have three they will be asked to come in and provide a sample. They may leave up to two samples per week with at least one full day between samples.

Exclusion criteria

Exclusion Criteria:

Any prior regular use (used as primary cigarette outside of laboratory) of Spectrum cigarettes (i.e., research cigarettes with reduced nicotine content).
Exclusive use of roll-your-own cigarettes.
Planning to quit smoking in the next 30 days.
A quit attempt in the past 30 days resulting in greater than 3 days of abstinence.
Currently taking anticonvulsant medications.
Positive toxicology screen for illicit drugs not including Marijuana ( participants with valid prescriptions will not be excluded and participants with a positive toxicology screen will be allowed to re-screen once).
Not currently enrolled in a treatment program for opioid dependence and/or not currently stable on their methadone or buprenorphine dose.
Breath alcohol level > 0.01 ( participants with a positive screen will be allowed to re-screen once).
Self-report of binge drinking alcohol (more than 9 days in the past 30 days, 4/5 drinks in a 2 hour period in females/males),
Blood pressure is greater than or equal to 160/100 mmHg or below 90/50 mmHg (participants outside the range will be allowed to re-screen once).
a. Participants failing for blood pressure will be allowed to re-screen once.
Breath CO > 80 ppm.
Heart rate is greater than or equal to 115 bpm or less than 45 bpm ( participants outside the range will be allowed to re-screen once).
Currently seeking treatment for smoking cessation.
Have used nicotine replacement, bupropion or other pharmacotherapies as cessation aids in the past month (bupropion will be allowed for treatment of depression).
Current symptoms of psychosis or dementia, or mania.
Suicidal ideation in the past month. 17.) Suicide attempt in the past 6 months. 18.) Participation in another research study in the past 30 days.

Study design

Phase: Phase 1 / Phase 2
Primary purpose: Basic science
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Double (Participant, Investigator)
Enrollment: 775 participants (actual)

Study arms

Experimental
0.8 mg nicotine
0.8 mg nicotine very low nicotine content cigarettes
Other: Very low nicotine content cigarettes
Experimental
0.12 mg nicotine
0.12 mg nicotine very low nicotine content cigarettes
Other: Very low nicotine content cigarettes
Experimental
0.03 mg nicotine
0.03 mg nicotine very low nicotine content cigarettes
Other: Very low nicotine content cigarettes

Interventions

OtherVery low nicotine content cigarettes
Very low nicotine content cigarettes

What researchers measure

Primary outcomes

Cigarettes Per Day (CPD)
Participant reported number of cigarettes smoked per day at Week 12
Time frame: 12 weeks

Results

Posted Dec 1, 2022

Participant flow

Participant flow — Overall Study
Milestone	0.8 mg Nicotine	0.12 mg Nicotine	0.03 mg Nicotine
Started	254	235	286
Completed	218	190	224
Not completed	36	45	62
Withdrew: Lost to follow-up	18	28	33
Withdrew: Personal reasons	7	8	14
Withdrew: Adverse event	6	3	8
Withdrew: Incarcerated	2	1	2
Withdrew: Withdrawal by subject	0	1	2
Withdrew: Death	0	1	1
Withdrew: Physician decision	1	3	1
Withdrew: Protocol violation	1	0	1
Withdrew: Reason unknown	1	0	0

Outcome measures

PrimaryCigarettes Per Day (CPD)

Participant reported number of cigarettes smoked per day at Week 12

Time frame:: 12 weeks
Reported as:: Least squares mean · cigarettes per day

Cigarettes Per Day (CPD)
cigarettes per day	0.8 mg Nicotine	0.12 mg Nicotine	0.03 mg Nicotine
Cigarettes Per Day (CPD)	25.28 ± 0.77	19.95 ± 0.80	17.74 ± 0.74

Statistical analysis

0.8 mg Nicotine vs 0.12 mg Nicotine · ANCOVA · p = <0.0001 (The p-value is Bonferroni-corrected for multiple comparisons with a priori threshold of significance P \< 0.0167) · Mean difference (net): -5.33 · 95% CI -7.41 to -3.26Group difference = 0.12 mg nicotine - 0.8 mg nicotine
0.8 mg Nicotine vs 0.03 mg Nicotine · ANOVA · p = <0.0001 (The p-value is Bonferroni-corrected for multiple comparisons with a priori threshold of significance P \< 0.0167) · Mean difference (net): -7.54 · 95% CI -9.51 to -5.57

Adverse events

Collected over 12 weeks. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
0.8 mg Nicotine	0/254 (0%)	13/254 (5.1%)	241/254 (94.9%)
0.12 mg Nicotine	1/235 (0.4%)	4/235 (1.7%)	203/235 (86.4%)
0.03 mg Nicotine	1/286 (0.3%)	13/286 (4.5%)	226/286 (79%)

Most frequent serious events

Showing 10 of 14

Most frequent serious events
Event	0.8 mg Nicotine	0.12 mg Nicotine	0.03 mg Nicotine
Infections and infestationsInfections and infestations	3/254	1/235	1/286
Nervous system disordersNervous system disorders	0/254	0/235	3/286
Sudden onset of chest pain due to not enough blood going to the heartCardiac disorders	2/254	1/235	0/286
Psychiatric disordersPsychiatric disorders	2/254	1/235	2/286
Injury, poisoning and procedural complicationsInjury, poisoning and procedural complications	0/254	0/235	2/286
Skin graft to wound on legSkin and subcutaneous tissue disorders	0/254	1/235	0/286
Blurred visionEye disorders	1/254	0/235	0/286
Metabolism and nutrition disordersMetabolism and nutrition disorders	1/254	0/235	1/286
Tenosynovitis of the HandMusculoskeletal and connective tissue disorders	1/254	0/235	0/286
Acute renal failureRenal and urinary disorders	1/254	0/235	0/286

Most frequent other events

Most frequent other events
Event	0.8 mg Nicotine	0.12 mg Nicotine	0.03 mg Nicotine
Infections and infestationsInfections and infestations	89/254	79/235	92/286
Respiratory, thoracic, and mediastinal disordersRespiratory, thoracic and mediastinal disorders	78/254	72/235	84/286
Gastrointestinal disordersGastrointestinal disorders	63/254	49/235	77/286
General disordersGeneral disorders	58/254	46/235	67/286
Nervous system disordersNervous system disorders	49/254	38/235	46/286
Musculoskeletal and connective tissue disordersMusculoskeletal and connective tissue disorders	42/254	27/235	33/286
Vascular disordersVascular disorders	20/254	22/235	25/286
Surgical and medical proceduresSurgical and medical procedures	23/254	16/235	26/286
Injury, poisoning, and procedural complicationsInjury, poisoning and procedural complications	22/254	13/235	17/286

Baseline characteristics

Age, Continuous
Age, Continuous(years)	0.8 mg Nicotine	0.12 mg Nicotine	0.03 mg Nicotine	Total
Mean	35.90 ± 10.82	35.18 ± 11.13	35.65 ± 11.21	35.59 ± 11.05

Sex: Female, Male
Sex: Female, Male(Participants)	0.8 mg Nicotine	0.12 mg Nicotine	0.03 mg Nicotine	Total
Female	184	167	200	551
Male	70	68	86	224

Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)	0.8 mg Nicotine	0.12 mg Nicotine	0.03 mg Nicotine	Total
Non-Latino White	207	183	240	630
Non-Latino Black	24	25	19	68
Latino	7	8	8	23
Non-Latino Other	12	18	16	46
Unknown	4	1	3	8

Region of Enrollment
Region of Enrollment(participants)	0.8 mg Nicotine	0.12 mg Nicotine	0.03 mg Nicotine	Total
United States	254	235	286	775

Cigarettes Per Day
Cigarettes Per Day(Cigarettes Per Day)	0.8 mg Nicotine	0.12 mg Nicotine	0.03 mg Nicotine	Total
Mean	19.63 ± 10.33	19.54 ± 10.56	19.91 ± 10.84	19.71 ± 10.58

Study locations

2 sites

Johns Hopkins University
Baltimore, Maryland 21224, United States
University of Vermont
Burlington, Vermont 05401, United States

References and documents

Publications

Gaalema DE, Snell LM, Tidey JW, Sigmon SC, Heil SH, Lee DC, Bunn JY, Park C, Hughes JR, Higgins ST. Potential effects of nicotine content in cigarettes on use of other substances. Prev Med. 2022 Dec;165(Pt B):107290. doi: 10.1016/j.ypmed.2022.107290. Epub 2022 Oct 5. PubMed 36208817 ↗
Oliver AC, DeSarno M, Irvin CG, Kaminsky D, Tidey JW, Sigmon SC, Heil SH, Gaalema DE, Lee D, Bunn JY, Davis DR, Streck JM, Gallagher T, Higgins ST. Effects of Reduced Nicotine Content Cigarettes on Fractional Exhaled Nitric Oxide and Self-Reported Respiratory Health Outcomes Among Smokers With Psychiatric Conditions or Socioeconomic Disadvantage. Nicotine Tob Res. 2022 Jan 1;24(1):135-140. doi: 10.1093/ntr/ntab145. PubMed 34255068 ↗
Higgins ST, DeSarno M, Bunn JY, Gaalema DE, Leventhal AM, Davis DR, Streck JM, Harfmann RF, Markesich C, Orr E, Sigmon SC, Heil SH, Tidey JW, Lee D, Hughes JR. Cumulative vulnerabilities as a potential moderator of response to reduced nicotine content cigarettes. Prev Med. 2021 Nov;152(Pt 2):106714. doi: 10.1016/j.ypmed.2021.106714. Epub 2021 Jul 7. PubMed 34242666 ↗
Higgins ST, Tidey JW, Sigmon SC, Heil SH, Gaalema DE, Lee D, Hughes JR, Villanti AC, Bunn JY, Davis DR, Bergeria CL, Streck JM, Parker MA, Miller ME, DeSarno M, Priest JS, Cioe P, MacLeod D, Barrows A, Markesich C, Harfmann RF. Changes in Cigarette Consumption With Reduced Nicotine Content Cigarettes Among Smokers With Psychiatric Conditions or Socioeconomic Disadvantage: 3 Randomized Clinical Trials. JAMA Netw Open. 2020 Oct 1;3(10):e2019311. doi: 10.1001/jamanetworkopen.2020.19311. PubMed 33079196 ↗
Higgins ST, DeSarno M, Davis DR, Nighbor T, Streck JM, Adise S, Harfmann R, Nesheim-Case R, Markesich C, Reed D, Tyndale RF, Gaalema DE, Heil SH, Sigmon SC, Tidey JW, Villanti AC, Lee D, Hughes JR, Bunn JY. Relating individual differences in nicotine dependence severity to underpinning motivational and pharmacological processes among smokers from vulnerable populations. Prev Med. 2020 Nov;140:106189. doi: 10.1016/j.ypmed.2020.106189. Epub 2020 Jul 3. PubMed 32628945 ↗

Study documents

Protocol and statistical analysis plan · Feb 9, 2018

Documents are hosted by the registry — open the source record to download them.

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Dec 1, 2022, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT02250664
Lead sponsor: University of Vermont
Collaborators: Johns Hopkins University, National Institute on Drug Abuse (NIDA)
Responsible party: Stephen T. Higgins, PhD (Professor, University of Vermont) — Principal investigator
First posted: Sep 26, 2014
Start date: Oct 2016
Primary completion: Oct 2019
Completion: Oct 2019
Results posted: Dec 1, 2022
Last update: Dec 1, 2022

Study contacts

Stephen T. Higgins, Ph.D.

study director · University of Vermont

Stacey Sigmon, Ph.D.

principal investigator · University of Vermont

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

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