Tobacco SmokingPhase 3NCT03272685
Impact of Very Low Nicotine Content Cigarettes in a Complex Marketplace
A Phase 3 study testing Very Low Nicotine Content Cigarettes and Normal Nicotine Content Cigarettes in people with Tobacco Smoking and Nicotine Dependence, run by University of Minnesota at 6 sites in United States.
Trial summary
This project will examine the impact of very low nicotine content (VLNC) cigarettes in a complex tobacco and nicotine product marketplace. We will compare the number of cigarettes smoked and cigarette-free days in an experimental marketplace that contains VLNC cigarettes versus normal nicotine content (NNC) cigarettes. Read more about this study
- Who is it for?
- Ages 21 years and olderHealthy volunteers can take part
- Conditions the study is for
- Tobacco Smoking, Nicotine Dependence
- What is being tested?
- Very Low Nicotine Content Cigarettes and Normal Nicotine Content Cigarettes
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 799 participants
- Where
- 6 sitesUnited States
- Study dates
- 1 Jun 2018to 10 Jan 2023
- 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 21 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Male or female;
- 18/21 (legal age to purchase tobacco at site);
- Biochemically confirmed smoker.
Who cannot join
- Unstable health condition;
- Unstable medications;
- Pregnant or nursing.
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
United States6 sites
The Center for Addiction Science and Technology
Durham, North Carolina, 27705
Tobacco Research Programs
Minneapolis, Minnesota, 55414
Center for Interdisciplinary Research on Nicotine Addiction
Philadelphia, Pennsylvania, 19104
Brown University Center for Alcohol and Addiction Studies School of Public Health
Providence, Rhode Island, 02912
Tobacco Research Center
San Francisco, California, 94110
Wake Forest Tobacco Control Center of Excellence
Winston-Salem, North Carolina, 27175
About this study
Official title: Impact of Very Low Nicotine Content Cigarettes in a Complex Marketplace Part of "Evaluating New Nicotine Standards for Cigarettes"
This project will examine the impact of very low nicotine content (VLNC) cigarettes in a complex tobacco and nicotine product marketplace. We will compare the number of cigarettes smoked and cigarette-free days in an experimental marketplace that contains VLNC cigarettes versus normal nicotine content (NNC) cigarettes.
Read the detailed description
This randomized, open label, controlled, multi-site study will simulate a "real world" tobacco environment by providing participants access to an experimental marketplace where they will be given vouchers for a specified number of points that can be exchanged for study cigarettes (varying in nicotine content described below) and non-combusted tobacco/nicotine products (smokeless tobacco, snus, electronic cigarette, medicinal nicotine replacement) and at the end of the study can exchange unspent points for money.
Subjects (N=200 in each group) will be randomly assigned to: 1) very low nicotine content cigarettes (VLNC; 0.4 mg nicotine/g tobacco) along with non-combusted tobacco/nicotine products or 2) normal nicotine content cigarettes (NNC; 15.8 mg nicotine/g tobacco) along with non-combusted tobacco/nicotine products.
Smokers will undergo an orientation visit for screening and then enter a three phase experimental trial:
- Phase 1 - Baseline: Two week baseline assessment period during usual brand cigarette smoking.
- Phase 2 - Marketplace Adaptation: Two week period where subjects have access to the marketplace that provides their preferred usual brand cigarettes and selected non-combusted tobacco products to allow the subject to adjust to the marketplace prior to randomization;
- Phase 3 - Intervention: Randomization to a marketplace with access to either VLNC or NNC cigarettes plus non-combusted products for a 12 week period.
Biomarker samples are collected at baseline, end of Phase 2 and end of week Phase 3 (week 12).
- Conditions
- Tobacco Smoking, Nicotine Dependence
- Being tested
- Very Low Nicotine Content Cigarettes, Normal Nicotine Content Cigarettes
- Keywords
- Reduced nicotine cigarettes, Alternative nicotine products, Biomarkers of tobacco exposure
- Medical subject headings
- Tobacco Smoking, Tobacco Use Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Very Low Nicotine Content CigarettesDrug
Also called Reduced Nicotine Content Cigarettes
0.4 mg nicotine/g tobacco; 9 mg tar
Normal Nicotine Content CigarettesDrug
Also called Conventional Nicotine Content Cigarettes
15.8 mg nicotine/g tobacco; 9 mg tar
| Study group | Role | What they receive |
|---|---|---|
| Very Low Nicotine Content Cigarettes | Experimental | Very Low Nicotine Content Cigarettes (0.4 mg nicotine/g tobacco; 9 mg of tar): Median nicotine content, averaged across menthol and non-menthol cigarettes: Receives: Drug: Very Low Nicotine Content Cigarettes |
| Normal Nicotine Content Cigarettes | Active comparator | Normal (Conventional) Nicotine Content (15.8 mg nicotine/g tobacco; 9 mg of tar): Median nicotine content, averaged across menthol and non-menthol cigarettes Receives: Drug: Normal Nicotine Content Cigarettes |
What is being measured
The primary outcome is the main question the study is designed to answer.
Cigarettes Per Day (CPD)
The mean cigarettes (study and non-study cigarettes) smoked per day based on 7 days Daily Interactive Voice Response (IVR) data at the end of Phase 3 (experimental marketplace with study cigarettes) compared to Phase 2 (experimental marketplace with usual brand cigarettes).
Measured: 7 days prior to week 12 visit
Number of Smoke-free Days
Rate of smoke-free days, defined as no cigarettes smoked in the past 24 hours calculated as the proportion of smoke-free days out of the total number of days in Phase 3.
Number of smoke free days based on the interactive voice response (IVR)
Measured: day 1 of study until day before week 12 visit
Secondary outcomes (3)
Percent Change in 2-cyanoethyl-mercapturic Acid (CEMA)
Change in CEMA (biomarker for the mercapturic acid acrylonitrile) from end of Phase 2 (experimental marketplace with usual brand cigarettes) to end of Phase 3 (experimental marketplace with study cigarettes).
Measured: The last visit in Phase 2 is the end of the baseline
Study Cigarettes Per Day
The mean study cigarettes smoked per day based on 7 days Daily Interactive Voice Response (IVR) data at the end of Phase 3 (experimental marketplace with study cigarettes) compared to Phase 2 (experimental marketplace with usual brand cigarettes).
Measured: 12 weeks (Phase 3) on study cigarettes
Seven Day Point-prevalence CO-verified Abstinence
Total cigarettes per day equal to 0 for all 7 days before the week 12 visit and carbon monoxide (CO) ≤ 6ppm at week 12.
Measured: 7 days before week 12 visit
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Sep 2017
- Study start1 Jun 2018
- Primary completion30 Sep 2022
- Study completion10 Jan 2023
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 (3)Papers the sponsor has linked to this study.
- Other trials for Tobacco SmokingStudies of the same condition, open and under way.
- More trials run by University of MinnesotaThe 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
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Phase III randomized, open label, multi-center study that will examine the impact of very low nicotine content (VLNC) cigarettes using an experimental marketplace that contains tobacco and nicotine products, simulating a real world environment. There are three phases: Phase 1 is smoking usual brand cigarettes. Phase 2 is access to a marketplace with usual brand cigarettes and other non-combusted nicotine and tobacco products. Phase 3 involves access to a marketplace with study cigarettes and other non-combusted nicotine and tobacco products.
- Masking
- None (open label)
- Enrolment
- 799 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Minnesota
- Sponsor type
- University, hospital or other
- Collaborators
- Duke University, University of California, San Francisco, Wake Forest University, University of Pennsylvania, Brown University
- Responsible party
- Sponsor
- Investigators
- Dorothy Hatsukami, PHD, Principal investigator, University of Minnesota
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03272685
- Sponsor's protocol ID
- 2017NTLS107
- Status last verified
- Jul 2024
- First submitted
- 10 Aug 2017
- Last updated
- 20 Aug 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Intend to share findings from this research through publications and presentations. Institutions and individuals wishing to access any resources or data must contact the Principal Investigator (Hatsukami). Data will be available in two formats. One will be a summary of the data, with graphs and tables, posted as pdf files and as raw individual-level data for analysis. Data generated by this grant will be made to outside investigators, according to NIH Guidance. When data are shared, there will be no limits placed on how the data will be used. Users will agree, however, that the recipient must not transfer the data to other users and that the data are only to be used for research purposes. A record of transfer of data and a copy of the dataset that was distributed will be kept by University of Minnesota.
Publications
Benowitz NL, Hu J, Luo X, McClernon FJ, Tidey J, Strasser AA, Colby S, Donny EC, Hatsukami DK. Titration of nicotine intake in smokers switching to reduced nicotine content cigarettes with access to alternative nicotine systems: Secondary analysis of a randomized clinical trial. Addiction. 2026 Jul;121(7):1899-1906. doi: 10.1111/add.70385. Epub 2026 Mar 19.
PubMed 41852246Said RJ, Carroll DM, Luo X, Hu J, Cao Q, Tessier KM, Bittencourt L, Hatsukami DK; Center for Evaluation of Nicotine in Cigarettes (CENIC). Secondary analysis of a randomized clinical trial of very low nicotine cigarettes: Outcomes across social and demographic groups. Prev Med. 2025 Dec;201:108362. doi: 10.1016/j.ypmed.2025.108362. Epub 2025 Jul 21.
PubMed 40701191Hatsukami DK, Jensen JA, Carroll DM, Luo X, Strayer LG, Cao Q, Hecht SS, Murphy SE, Carmella SG, Denlinger-Apte RL, Colby S, Strasser AA, McClernon FJ, Tidey J, Benowitz NL, Donny EC. Reduced nicotine in cigarettes in a marketplace with alternative nicotine systems: randomized clinical trial. Lancet Reg Health Am. 2024 Jun 3;35:100796. doi: 10.1016/j.lana.2024.100796. eCollection 2024 Jul.
PubMed 38911348
Study at a glance
From the registry record, last updated by the sponsor on 20 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of Very Low Nicotine Content Cigarettes in a Complex Marketplace Part of "Evaluating New Nicotine Standards for Cigarettes"
- ClinicalTrials.gov ID
- NCT03272685
- Acronym / sponsor ID
- 2017NTLS107
- Conditions
- Tobacco Smoking, Nicotine Dependence
- Keywords
- Reduced nicotine cigarettes, Alternative nicotine products, Biomarkers of tobacco exposure
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 799 participants (actual)
- Lead sponsor
- University of MinnesotaUniversity, hospital or other
- Collaborators
- Duke University, University of California, San Francisco, Wake Forest University, University of Pennsylvania, Brown University
- Study start
- 1 Jun 2018 (actual)
- Primary completion
- 30 Sep 2022 (actual)
- Study completion
- 10 Jan 2023 (actual)
- First posted
- 5 Sep 2017 (actual)
- Results
- Posted 20 Aug 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This project will examine the impact of very low nicotine content (VLNC) cigarettes in a complex tobacco and nicotine product marketplace. We will compare the number of cigarettes smoked and cigarette-free days in an experimental marketplace that contains VLNC cigarettes versus normal nicotine content (NNC) cigarettes.
Detailed description
This randomized, open label, controlled, multi-site study will simulate a "real world" tobacco environment by providing participants access to an experimental marketplace where they will be given vouchers for a specified number of points that can be exchanged for study cigarettes (varying in nicotine content described below) and non-combusted tobacco/nicotine products (smokeless tobacco, snus, electronic cigarette, medicinal nicotine replacement) and at the end of the study can exchange unspent points for money.
Subjects (N=200 in each group) will be randomly assigned to: 1) very low nicotine content cigarettes (VLNC; 0.4 mg nicotine/g tobacco) along with non-combusted tobacco/nicotine products or 2) normal nicotine content cigarettes (NNC; 15.8 mg nicotine/g tobacco) along with non-combusted tobacco/nicotine products.
Smokers will undergo an orientation visit for screening and then enter a three phase experimental trial:
- Phase 1 - Baseline: Two week baseline assessment period during usual brand cigarette smoking.
- Phase 2 - Marketplace Adaptation: Two week period where subjects have access to the marketplace that provides their preferred usual brand cigarettes and selected non-combusted tobacco products to allow the subject to adjust to the marketplace prior to randomization;
- Phase 3 - Intervention: Randomization to a marketplace with access to either VLNC or NNC cigarettes plus non-combusted products for a 12 week period.
Biomarker samples are collected at baseline, end of Phase 2 and end of week Phase 3 (week 12).
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Phase III randomized, open label, multi-center study that will examine the impact of very low nicotine content (VLNC) cigarettes using an experimental marketplace that contains tobacco and nicotine products, simulating a real world environment. There are three phases: Phase 1 is smoking usual brand cigarettes. Phase 2 is access to a marketplace with usual brand cigarettes and other non-combusted nicotine and tobacco products. Phase 3 involves access to a marketplace with study cigarettes and other non-combusted nicotine and tobacco products.
| Arm | Type | Receives |
|---|---|---|
| Very Low Nicotine Content Cigarettes | Experimental | Drug: Very Low Nicotine Content CigarettesVery Low Nicotine Content Cigarettes (0.4 mg nicotine/g tobacco; 9 mg of tar): Median nicotine content, averaged across menthol and non-menthol cigarettes: |
| Normal Nicotine Content Cigarettes | Active comparator | Drug: Normal Nicotine Content CigarettesNormal (Conventional) Nicotine Content (15.8 mg nicotine/g tobacco; 9 mg of tar): Median nicotine content, averaged across menthol and non-menthol cigarettes |
Who may qualify
- Ages
- 21 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Male or female;
- 18/21 (legal age to purchase tobacco at site);
- Biochemically confirmed smoker.
Key exclusion criteria (3 listed)
- Unstable health condition;
- Unstable medications;
- Pregnant or nursing.
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 |
|---|---|---|
| Very Low Nicotine Content CigarettesAlso: Reduced Nicotine Content Cigarettes0.4 mg nicotine/g tobacco; 9 mg tar | Drug | Very Low Nicotine Content Cigarettes |
| Normal Nicotine Content CigarettesAlso: Conventional Nicotine Content Cigarettes15.8 mg nicotine/g tobacco; 9 mg tar | Drug | Normal Nicotine Content Cigarettes |
Primary outcome
Cigarettes Per Day (CPD)
Time frame: 7 days prior to week 12 visit
The mean cigarettes (study and non-study cigarettes) smoked per day based on 7 days Daily Interactive Voice Response (IVR) data at the end of Phase 3 (experimental marketplace with study cigarettes) compared to Phase 2 (experimental marketplace with usual brand cigarettes).
Number of Smoke-free Days
Time frame: day 1 of study until day before week 12 visit
Rate of smoke-free days, defined as no cigarettes smoked in the past 24 hours calculated as the proportion of smoke-free days out of the total number of days in Phase 3. Number of smoke free days based on the interactive voice response (IVR)
3 secondary outcomes
Percent Change in 2-cyanoethyl-mercapturic Acid (CEMA)
Time frame: The last visit in Phase 2 is the end of the baseline
Study Cigarettes Per Day
Time frame: 12 weeks (Phase 3) on study cigarettes
Seven Day Point-prevalence CO-verified Abstinence
Time frame: 7 days before week 12 visit
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Aug 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41852246Benowitz NL, Hu J, Luo X, McClernon FJ, Tidey J, Strasser AA, Colby S, Donny EC, Hatsukami DK. Titration of nicotine intake in smokers switching to reduced nicotine content cigarettes with access to alternative nicotine systems: Secondary analysis of a randomized clinical trial. Addiction. 2026 Jul;121(7):1899-1906. doi: 10.1111/add.70385. Epub 2026 Mar 19.
- Derived from this study: PubMed 40701191Said RJ, Carroll DM, Luo X, Hu J, Cao Q, Tessier KM, Bittencourt L, Hatsukami DK; Center for Evaluation of Nicotine in Cigarettes (CENIC). Secondary analysis of a randomized clinical trial of very low nicotine cigarettes: Outcomes across social and demographic groups. Prev Med. 2025 Dec;201:108362. doi: 10.1016/j.ypmed.2025.108362. Epub 2025 Jul 21.
- Derived from this study: PubMed 38911348Hatsukami DK, Jensen JA, Carroll DM, Luo X, Strayer LG, Cao Q, Hecht SS, Murphy SE, Carmella SG, Denlinger-Apte RL, Colby S, Strasser AA, McClernon FJ, Tidey J, Benowitz NL, Donny EC. Reduced nicotine in cigarettes in a marketplace with alternative nicotine systems: randomized clinical trial. Lancet Reg Health Am. 2024 Jun 3;35:100796. doi: 10.1016/j.lana.2024.100796. eCollection 2024 Jul.
- Individual participant dataSharing planned: Yes. Intend to share findings from this research through publications and presentations. Institutions and individuals wishing to access any resources or data must contact the Principal Investigator (Hatsukami). Data will be available in two formats. One will be a summary of the data, with graphs and tables, posted as pdf files and as raw individual-level data for analysis. Data generated by this grant will be made to outside investigators, according to NIH Guidance. When data are shared, there will be no limits placed on how the data will be used. Users will agree, however, that the recipient must not transfer the data to other users and that the data are only to be used for research purposes. A record of transfer of data and a copy of the dataset that was distributed will be kept by University of Minnesota.
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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.
Dorothy Hatsukami, PHD principal investigator
University of Minnesota
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Very Low Nicotine Content Cigarettes and Normal Nicotine Content Cigarettes in people with Tobacco Smoking and Nicotine Dependence, run by University of Minnesota at 6 sites in United States.
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 3 inclusion and 3 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 20 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United States. 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. 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 20 Aug 2024). 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?
Cigarettes Per Day (CPD) (time frame: 7 days prior to week 12 visit). The study lists 2 primary outcomes in all. 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 NCT03272685, which also lists 3 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 20 Aug 2024.