Trial Outcomes & Findings for A Study to Assess Changes in Cigarette Consumption During a Switch to Very Low Nicotine Cigarettes (NCT NCT03571724)

NCT ID: NCT03571724

Last Updated: 2020-09-16

Results Overview

Primary objective is to measure a change in cigarette consumption behavior before, during and after switching from usual brand to to VLN cigarettes. Subjects will record their cigarette consumption daily in an electronic diary. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).All 142 randomized subjects were included in the ITT population based on product use. Out of these, 71 subjects were included in the PP Population and 71 were excluded. All excluded subjects had a ratio of \[plasma cotinine/CPD VLN\]/\[plasma cotinine/CPD baseline\] \> 0.2. It was pre-specified to exclude participants with a ratio \>0.2 as they were considered non-compliant.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 142 participants
• Primary outcome timeframe: Assessed daily from Week -1 to Week 6; Week -1, Week 2, and Week 6 reported
• Results posted on: 2020-09-16

Participant Flow

A total of 142 smokers were recruited from two sites in the United States; Celerion, Lincoln Nebraska and High Point Clinical Trials Center, High Point, North Carolina. The participants were recruited via social media, print, TV, radio, referrals.

Subjects may have been excluded from the study if there was evidence of any of the exclusion criteria during the study as noted, in the opinion of the Investigator.

Participant milestones

Measure	Non-Menthol Very Low Nicotine Cigarettes Subjects will be switched from their usual brand to smoke Very Low Nicotine king size cigarettes Non-Menthol Very Low Nicotine Cigarettes: King size non-menthol cigarettes containing 0.4mg nicotine /g tobacco	Menthol Very Low Nicotine Cigarettes Subjects will be switched from their usual brand to smoke Very Low Nicotine king size Menthol cigarettes Menthol Very Low Nicotine Cigarettes: King size menthol cigarettes containing 0.4mg nicotine /g tobacco	Usual Brand Non-Metholated Subjects continue to smoke their usual brand non-Menthol cigarettes	Usual Brand Metholated Subjects continue to smoke their usual brand Menthol cigarettes
Week -1 (Prior to Switching) STARTED	0	0	72	70
Week -1 (Prior to Switching) Topography	0	0	18	18
Week -1 (Prior to Switching) PK Nicotine	0	0	12	12
Week -1 (Prior to Switching) COMPLETED	0	0	72	70
Week -1 (Prior to Switching) NOT COMPLETED	0	0	0	0
Week 1-6 STARTED	50	50	22	20
Week 1-6 COMPLETED	43	42	19	20
Week 1-6 NOT COMPLETED	7	8	3	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Study to Assess Changes in Cigarette Consumption During a Switch to Very Low Nicotine Cigarettes

Baseline characteristics by cohort

Measure	Non-Menthol Very Low Nicotine Cigarettes n=50 Participants Subjects will be switched from their usual brand to smoke Very Low Nicotine king size cigarettes Non-Menthol Very Low Nicotine Cigarettes: King size non-menthol cigarettes containing 0.4mg nicotine /g tobacco	Menthol Very Low Nicotine Cigarettes n=50 Participants Subjects will be switched from their usual brand to smoke Very Low Nicotine king size Menthol cigarettes Menthol Very Low Nicotine Cigarettes: King size menthol cigarettes containing 0.4mg nicotine /g tobacco	Usual Brand Non-Mentholated n=22 Participants Subjects will continue to use their usual brand non-menthol cigarettes	Usual Brand Mentholated n=20 Participants Subjects will continue to use their usual brand menthol cigarettes	Total n=142 Participants Total of all reporting groups
Age, Continuous	45.9 years STANDARD_DEVIATION 10.85 • n=5 Participants	40.5 years STANDARD_DEVIATION 9.34 • n=7 Participants	45.8 years STANDARD_DEVIATION 12.39 • n=5 Participants	42.7 years STANDARD_DEVIATION 10.82 • n=4 Participants	43.5 years STANDARD_DEVIATION 10.76 • n=21 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	22 Participants n=7 Participants	9 Participants n=5 Participants	10 Participants n=4 Participants	60 Participants n=21 Participants
Sex: Female, Male Male	31 Participants n=5 Participants	28 Participants n=7 Participants	13 Participants n=5 Participants	10 Participants n=4 Participants	82 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	4 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	49 Participants n=5 Participants	49 Participants n=7 Participants	21 Participants n=5 Participants	19 Participants n=4 Participants	138 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	29 Participants n=7 Participants	2 Participants n=5 Participants	12 Participants n=4 Participants	46 Participants n=21 Participants
Race (NIH/OMB) White	44 Participants n=5 Participants	17 Participants n=7 Participants	18 Participants n=5 Participants	8 Participants n=4 Participants	87 Participants n=21 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	4 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Region of Enrollment United States	50 participants n=5 Participants	50 participants n=7 Participants	22 participants n=5 Participants	20 participants n=4 Participants	142 participants n=21 Participants
Cigarettes Per Day (CPD)	19.8 Cigarettes per day STANDARD_DEVIATION 6.92 • n=5 Participants	15.4 Cigarettes per day STANDARD_DEVIATION 6.19 • n=7 Participants	18.2 Cigarettes per day STANDARD_DEVIATION 3.85 • n=5 Participants	17.1 Cigarettes per day STANDARD_DEVIATION 6.16 • n=4 Participants	17.6 Cigarettes per day STANDARD_DEVIATION 6.39 • n=21 Participants

PRIMARY outcome

Timeframe: Assessed daily from Week -1 to Week 6; Week -1, Week 2, and Week 6 reported

Population: Cigarettes per Day were calculated as the average cigarettes smoked per day in each week.

Primary objective is to measure a change in cigarette consumption behavior before, during and after switching from usual brand to to VLN cigarettes. Subjects will record their cigarette consumption daily in an electronic diary. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).All 142 randomized subjects were included in the ITT population based on product use. Out of these, 71 subjects were included in the PP Population and 71 were excluded. All excluded subjects had a ratio of [plasma cotinine/CPD VLN]/[plasma cotinine/CPD baseline] > 0.2. It was pre-specified to exclude participants with a ratio >0.2 as they were considered non-compliant.

Outcome measures

Measure	Very Low Nicotine Mentholated n=17 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=12 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=29 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=20 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated n=22 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined n=42 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Cigarettes Per Day Week -1	14.75 Cigarettes Per Day (CPD) Standard Deviation 6.198	17.19 Cigarettes Per Day (CPD) Standard Deviation 4.727	15.76 Cigarettes Per Day (CPD) Standard Deviation 5.676	16.29 Cigarettes Per Day (CPD) Standard Deviation 5.809	16.80 Cigarettes Per Day (CPD) Standard Deviation 4.015	16.55 Cigarettes Per Day (CPD) Standard Deviation 4.895
Cigarettes Per Day Week 2	15.66 Cigarettes Per Day (CPD) Standard Deviation 7.860	23.32 Cigarettes Per Day (CPD) Standard Deviation 9.717	18.90 Cigarettes Per Day (CPD) Standard Deviation 9.341	15.47 Cigarettes Per Day (CPD) Standard Deviation 4.425	16.17 Cigarettes Per Day (CPD) Standard Deviation 4.475	15.84 Cigarettes Per Day (CPD) Standard Deviation 4.411
Cigarettes Per Day Week 6	14.43 Cigarettes Per Day (CPD) Standard Deviation 9.435	21.20 Cigarettes Per Day (CPD) Standard Deviation 8.219	17.98 Cigarettes Per Day (CPD) Standard Deviation 9.265	14.69 Cigarettes Per Day (CPD) Standard Deviation 4.877	15.89 Cigarettes Per Day (CPD) Standard Deviation 5.356	15.29 Cigarettes Per Day (CPD) Standard Deviation 5.092

SECONDARY outcome

Timeframe: -1 week, and at 2 and 6 weeks.

Population: Summary of Urinary NNAL Mass Excreted (ng/24 hour) by Study Product Group and Study Week (ITT Population)

Total 24 hour urine will be collected to evaluate changes in NNAL (4-methylnitrosamino)-1-3-pyridyl)-1-butanone biomarker) before, during, and after switching to VLN cigarettes. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=49 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=99 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=21 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated n=20 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined n=41 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Biomarkers of Exposure - Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1 Butanol (NNAL) Week -1	582.855 ng/24 hour Standard Deviation 288.3650	423.752 ng/24 hour Standard Deviation 185.6953	502.500 ng/24 hour Standard Deviation 253.6974	614.06 ng/24 hour Standard Deviation 353.9198	479.979 ng/24 hour Standard Deviation 203.2470	548.658 ng/24 hour Standard Deviation 294.7134
Biomarkers of Exposure - Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1 Butanol (NNAL) Week 2	313.911 ng/24 hour Standard Deviation 176.1390	214.139 ng/24 hour Standard Deviation 131.4077	266.766 ng/24 hour Standard Deviation 163.6124	581.039 ng/24 hour Standard Deviation 312.7864	458.036 ng/24 hour Standard Deviation 203.4045	521.037 ng/24 hour Standard Deviation 269.1556
Biomarkers of Exposure - Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1 Butanol (NNAL) Week 6	377.057 ng/24 hour Standard Deviation 217.6683	240.970 ng/24 hour Standard Deviation 173.1282	309.833 ng/24 hour Standard Deviation 207.3562	614.717 ng/24 hour Standard Deviation 416.6105	431.458 ng/24 hour Standard Deviation 173.9915	517.997 ng/24 hour Standard Deviation 321.7481

SECONDARY outcome

Timeframe: -1 week, and at 2 and 6 weeks.

Population: Summary of Urinary NNAL Mass Excreted (ng/24 hour) by Study Product Group and Study Week (ITT Population)

Total 24 hour urine will be collected to evaluate changes in NNN before, during, and after switching to VLN cigarettes. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=49 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=99 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=21 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated n=20 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined n=41 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Biomarkers of Exposure - Total N-Nitrosonornicotine (NNN) Week -1	20.070 ng/24 hour Standard Deviation 14.4934	12.370 ng/24 hour Standard Deviation 7.9412	16.181 ng/24 hour Standard Deviation 12.2224	22.614 ng/24 hour Standard Deviation 24.4627	13.641 ng/24 hour Standard Deviation 11.1026	18.237 ng/24 hour Standard Deviation 19.4522
Biomarkers of Exposure - Total N-Nitrosonornicotine (NNN) Week 2	14.246 ng/24 hour Standard Deviation 11.6548	9.052 ng/24 hour Standard Deviation 10.2762	11.792 ng/24 hour Standard Deviation 11.2701	20.809 ng/24 hour Standard Deviation 21.2301	12.024 ng/24 hour Standard Deviation 9.0103	16.523 ng/24 hour Standard Deviation 16.8430
Biomarkers of Exposure - Total N-Nitrosonornicotine (NNN) Week 6	14.803 ng/24 hour Standard Deviation 11.4754	6.382 ng/24 hour Standard Deviation 4.5544	10.643 ng/24 hour Standard Deviation 9.6904	22.095 ng/24 hour Standard Deviation 25.7769	9.359 ng/24 hour Standard Deviation 6.0602	15.373 ng/24 hour Standard Deviation 19.0844

SECONDARY outcome

Timeframe: -1 week, and at 2 and 6 weeks.

Population: Summary of Urinary S-PMA Mass Excreted (µg/24 hour) by Study Product Group and Study Week (ITT Population)

Total 24 hour urine will be collected to evaluate changes in S-PMA (benzene biomarker) before, during, and after switching to VLN cigarettes. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=49 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=99 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=21 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated n=20 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined n=41 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Biomarkers of Exposure - S-phenylmercapturic Acid (S-PMA) Week -1	7.144 µg/24 hour Standard Deviation 5.9255	6.561 µg/24 hour Standard Deviation 3.8833	6.850 µg/24 hour Standard Deviation 4.9823	7.935 µg/24 hour Standard Deviation 3.8120	8.239 µg/24 hour Standard Deviation 7.3290	8.083 µg/24 hour Standard Deviation 5.7274
Biomarkers of Exposure - S-phenylmercapturic Acid (S-PMA) Week 2	8.160 µg/24 hour Standard Deviation 7.8142	6.734 µg/24 hour Standard Deviation 4.7617	7.486 µg/24 hour Standard Deviation 6.5560	7.561 µg/24 hour Standard Deviation 3.7582	7.731 µg/24 hour Standard Deviation 5.9223	7.644 µg/24 hour Standard Deviation 4.8713
Biomarkers of Exposure - S-phenylmercapturic Acid (S-PMA) Week 6	7.282 µg/24 hour Standard Deviation 6.4350	5.589 µg/24 hour Standard Deviation 3.6334	6.446 µg/24 hour Standard Deviation 5.2792	7.261 µg/24 hour Standard Deviation 4.4329	6.845 µg/24 hour Standard Deviation 5.2829	7.042 µg/24 hour Standard Deviation 4.8353

SECONDARY outcome

Timeframe: -1 week, and at 2 and 6 weeks.

Population: Summary of Urinary 3-HPMA Mass Excreted (µg/24 hour) by Study Product Group and Study Week (ITT Population)

Total 24 hour urine will be collected to evaluate changes in 3-HPMA (acrolein biomarker) before, during, and after switching to VLN cigarettes. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=49 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=99 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=21 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated n=20 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined n=41 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Biomarkers of Exposure - 3-hydroxypropylmercapturic Acid (3-HPMA) Week -1	1795.719 µg/24 hour Standard Deviation 708.6089	1644.113 µg/24 hour Standard Deviation 500.1249	1719.151 µg/24 hour Standard Deviation 613.8453	1910.675 µg/24 hour Standard Deviation 772.7715	1520.921 µg/24 hour Standard Deviation 605.2480	1720.551 µg/24 hour Standard Deviation 715.1892
Biomarkers of Exposure - 3-hydroxypropylmercapturic Acid (3-HPMA) Week 2	1706.862 µg/24 hour Standard Deviation 901.3990	1204.530 µg/24 hour Standard Deviation 543.2655	1469.496 µg/24 hour Standard Deviation 790.9739	1710.747 µg/24 hour Standard Deviation 732.7759	1329.844 µg/24 hour Standard Deviation 319.7909	1524.940 µg/24 hour Standard Deviation 595.1580
Biomarkers of Exposure - 3-hydroxypropylmercapturic Acid (3-HPMA) Week 6	1481.693 µg/24 hour Standard Deviation 694.6765	1035.064 µg/24 hour Standard Deviation 475.3512	1261.069 µg/24 hour Standard Deviation 634.0203	1815.382 µg/24 hour Standard Deviation 828.3606	1336.103 µg/24 hour Standard Deviation 297.2953	1562.429 µg/24 hour Standard Deviation 673.6060

SECONDARY outcome

Timeframe: -1 week, and at 2 and 6 weeks.

Population: Summary of Urinary 1-OHP Mass Excreted (ng/24 hour) by Study Product Group and Study Week (ITT Population)

Total 24 hour urine will be collected to evaluate changes in 1-OHP before, during, and after switching to VLN cigarettes. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=49 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=99 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=21 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated n=20 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined n=41 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Biomarkers of Exposure - 1-hydroxy Pyrene(1-OHP) Week -1	334.920 ng/24 hour Standard Deviation 167.7463	315.203 ng/24 hour Standard Deviation 160.6678	324.962 ng/24 hour Standard Deviation 163.6689	314.736 ng/24 hour Standard Deviation 90.9545	316.566 ng/24 hour Standard Deviation 140.5579	315.629 ng/24 hour Standard Deviation 116.2823
Biomarkers of Exposure - 1-hydroxy Pyrene(1-OHP) Week 2	262.756 ng/24 hour Standard Deviation 157.8692	214.010 ng/24 hour Standard Deviation 117.020	239.722 ng/24 hour Standard Deviation 141.4377	289.071 ng/24 hour Standard Deviation 97.7694	263.305 ng/24 hour Standard Deviation 101.9363	276.502 ng/24 hour Standard Deviation 99.4242
Biomarkers of Exposure - 1-hydroxy Pyrene(1-OHP) Week 6	278.998 ng/24 hour Standard Deviation 178.6065	203.396 ng/24 hour Standard Deviation 122.0693	241.652 ng/24 hour Standard Deviation 157.0509	299.312 ng/24 hour Standard Deviation 118.7805	274.171 ng/24 hour Standard Deviation 128.5495	286.043 ng/24 hour Standard Deviation 122.9241

SECONDARY outcome

Timeframe: -1 week, and at 2 and 6 weeks.

Population: Summary of Urinary Tneq Mass Excreted (mg/24 hour) by Study Product Group and Study Week (ITT Population)

Total 24 hour urine will be collected to evaluate changes in total nicotine equivalents before, during, and after switching to VLN cigarettes. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=49 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=99 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=21 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated n=20 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined n=41 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Biomarkers of Exposure - Total Nicotine Equivalents Week -1	17.511 mg/24 hour Standard Deviation 6.1103	15.885 mg/24 hour Standard Deviation 5.3291	16.690 mg/24 hour Standard Deviation 5.7580	17.732 mg/24 hour Standard Deviation 6.3013	15.928 mg/24 hour Standard Deviation 5.9611	16.852 mg/24 hour Standard Deviation 6.1291
Biomarkers of Exposure - Total Nicotine Equivalents Week 2	5.404 mg/24 hour Standard Deviation 4.5528	3.616 mg/24 hour Standard Deviation 3.5530	4.559 mg/24 hour Standard Deviation 4.1858	16.962 mg/24 hour Standard Deviation 6.2675	15.279 mg/24 hour Standard Deviation 4.7106	16.141 mg/24 hour Standard Deviation 5.5594
Biomarkers of Exposure - Total Nicotine Equivalents Week 6	9.150 mg/24 hour Standard Deviation 6.1240	6.800 mg/24 hour Standard Deviation 5.2118	7.989 mg/24 hour Standard Deviation 5.7792	17.530 mg/24 hour Standard Deviation 7.3994	14.418 mg/24 hour Standard Deviation 5.5176	15.888 mg/24 hour Standard Deviation 6.5703

SECONDARY outcome

Timeframe: Week -1, and at 2 and 6 weeks.

Population: Summary of Blood COHb (% Saturation) by Study Product Group and Study Week (ITT Population)

Blood will be drawn to evaluate COHb before, during, and after switching to VLN cigarettes. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=100 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=22 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated n=20 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined n=42 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Biomarkers of Exposure - Carboxyhemoglobin (COHb) Week -1	6.20 % Saturation Standard Deviation 1.801	5.69 % Saturation Standard Deviation 1.526	5.95 % Saturation Standard Deviation 1.680	5.25 % Saturation Standard Deviation 1.294	5.41 % Saturation Standard Deviation 1.322	5.33 % Saturation Standard Deviation 1.294
Biomarkers of Exposure - Carboxyhemoglobin (COHb) Week 2	7.10 % Saturation Standard Deviation 2.794	5.55 % Saturation Standard Deviation 2.167	6.36 % Saturation Standard Deviation 2.618	5.40 % Saturation Standard Deviation 1.206	5.59 % Saturation Standard Deviation 2.060	5.49 % Saturation Standard Deviation 1.659
Biomarkers of Exposure - Carboxyhemoglobin (COHb) Week 6	5.97 % Saturation Standard Deviation 1.930	4.63 % Saturation Standard Deviation 1.898	5.31 % Saturation Standard Deviation 2.019	5.56 % Saturation Standard Deviation 1.323	4.61 % Saturation Standard Deviation 1.259	5.07 % Saturation Standard Deviation 1.361

SECONDARY outcome

Timeframe: Week -1, and at 2 and 6 weeks.

Population: Blood was drawn to evaluate cotinine levels before, during, and after switching to VLN cigarettes at Week -1, Week 2 and Week 6.

Blood will be drawn to evaluate cotinine levels before, during, and after switching to VLN cigarettes. The baseline data were collected for participants at Week -1, and Week -1 data are reported per pre-switch Arms/Group assignment.

Outcome measures

Measure	Very Low Nicotine Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=70 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=72 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Biomarkers of Exposure -Cotinine Week -1	—	—	242.0 ng/mL Standard Deviation 111.1681285	221.4 ng/mL Standard Deviation 85.32850957	—	—
Biomarkers of Exposure -Cotinine Week 2	58.8 ng/mL Standard Deviation 58.5318519	58.7 ng/mL Standard Deviation 60.58382526	223.9 ng/mL Standard Deviation 100.5596713	195.8 ng/mL Standard Deviation 77.043868	—	—
Biomarkers of Exposure -Cotinine Week 6	102.0 ng/mL Standard Deviation 76.3105523	110.1 ng/mL Standard Deviation 102.5119239	207.2 ng/mL Standard Deviation 81.7796209	187.7 ng/mL Standard Deviation 71.86818497	—	—

SECONDARY outcome

Timeframe: Week -1, and at 2 and 6 weeks.

Population: Plasma Nicotine Pharmacokinetic Parameters (Cmax) Following use of VLN Non-Mentholated, VLN Mentholated, UB Non-Mentholated, UB Mentholated Cigarettes (Pharmacokinetic Population from ITT).

Blood samples will be drawn at -5, 2, 5, 7, 10, 12, 15, 20, 30, 45, 60, 90, 120, 150 and 180 minutes relative to the start of cigarette smoking a single cigarette for determination of C-max at weeks -1, 2 and 6. The baseline data were collected for participants at Week -1, and Week -1 data are reported per pre-switch Arms/Group assignment.

Outcome measures

Measure	Very Low Nicotine Mentholated n=12 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=10 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=12 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=12 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Nicotine Pharmacokinetics - Maximum Nicotine Concentration (C-Max) Week -1	—	—	13.28 ng/mL Standard Deviation 5.9925	12.98 ng/mL Standard Deviation 5.3932	—	—
Nicotine Pharmacokinetics - Maximum Nicotine Concentration (C-Max) Week 2	0.3264 ng/mL Standard Deviation 0.15367	0.3561 ng/mL Standard Deviation 0.20204	—	—	—	—
Nicotine Pharmacokinetics - Maximum Nicotine Concentration (C-Max) Week 6	0.4026 ng/mL Standard Deviation 0.15292	0.3259 ng/mL Standard Deviation 0.16294	—	—	—	—

SECONDARY outcome

Timeframe: Week -1, and at 2 and 6 weeks.

Population: Plasma Nicotine Pharmacokinetic Parameters (Tmax) Following Use of VLN Non-Mentholated, VLN Mentholated, UB Mentholated and UB Non-Mentholated Cigarettes (Pharmacokinetic Population from ITT).

Blood samples will be drawn at -5, 2, 5, 7, 10, 12, 15, 20, 30, 45, 60, 90, 120, 150 and 180 minutes relative to the start of cigarette smoking a single cigarette for determination of T-Max at weeks -1, 2 and 6. The baseline data were collected for participants at Week -1, and Week -1 data are reported per pre-switch Arms/Group assignment.

Outcome measures

Measure	Very Low Nicotine Mentholated n=12 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=10 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=12 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=12 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Nicotine Pharmacokinetics - Peak Nicotine Time (T-Max) Week -1	—	—	13.60 hr Standard Deviation 5.2610	0.1408 hr Standard Deviation 0.041525	—	—
Nicotine Pharmacokinetics - Peak Nicotine Time (T-Max) Week 2	0.1154 hr Standard Deviation 0.040675	0.1430 hr Standard Deviation 0.063681	—	—	—	—
Nicotine Pharmacokinetics - Peak Nicotine Time (T-Max) Week 6	0.1446 hr Standard Deviation 0.084195	0.2895 hr Standard Deviation 0.43017	—	—	—	—

SECONDARY outcome

Timeframe: Week -1, and at 2 and 6 weeks.

Population: Plasma Nicotine Pharmacokinetic Parameters (AUC0-180) Following Use of VLN Non-Mentholated, VLN Mentholated, UB Mentholated and UB Non-Mentholated Filtered Cigarettes (Pharmacokinetic Population from ITT).

Blood samples will be drawn at -5, 2, 5, 7, 10, 12, 15, 20, 30, 45, 60, 90, 120, 150 and 180 minutes relative to the start of cigarette smoking a single cigarette for determination of AUC at weeks -1, 2 and 6. The baseline data were collected for participants at Week -1, and Week -1 data are reported per pre-switch Arms/Group assignment.

Outcome measures

Measure	Very Low Nicotine Mentholated n=12 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=10 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=12 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=12 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Nicotine Pharmacokinetics - Area Under Nicotine Concentration Curve (AUC) Week -1	—	—	13.60 mg*hr/mL Standard Deviation 5.2610	13.18 mg*hr/mL Standard Deviation 4.0648	—	—
Nicotine Pharmacokinetics - Area Under Nicotine Concentration Curve (AUC) Week 2	0.2006 mg*hr/mL Standard Deviation 0.19107	0.2264 mg*hr/mL Standard Deviation 0.20588	—	—	—	—
Nicotine Pharmacokinetics - Area Under Nicotine Concentration Curve (AUC) Week 6	0.2620 mg*hr/mL Standard Deviation 0.15446	0.2348 mg*hr/mL Standard Deviation 0.20330	—	—	—	—

SECONDARY outcome

Timeframe: -1 week, and at 2 and 6 weeks.

Population: Summary of Puffing Topography Parameters by Study Product Group and Study Week (ITT Population). Puff topography was conducted in a randomly-selected subset of 18 non-menthol and 18 menthol cigarette smokers at a single site. The randomly-selected subjects have been assigned to switch to smoking very low nicotine (VLN) cigarettes.

Puff duration will be measured before, during, and after switching to VLN cigarettes. Topography will be measured during an ad libitum smoking session. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=18 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=18 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=36 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Smoking Topography - Puff Duration Week -1	23.494 seconds Standard Deviation 7.9301	27.783 seconds Standard Deviation 7.6979	25.639 seconds Standard Deviation 8.0036	—	—	—
Smoking Topography - Puff Duration Week 2	23.282 seconds Standard Deviation 8.1071	24.559 seconds Standard Deviation 6.9773	23.940 seconds Standard Deviation 7.4545	—	—	—
Smoking Topography - Puff Duration Week 6	21.966 seconds Standard Deviation 7.0242	22.122 seconds Standard Deviation 6.4746	22.039 seconds Standard Deviation 6.6636	—	—	—

SECONDARY outcome

Timeframe: -1 week, and at 2 and 6 weeks.

Population: Summary of Puffing Topography Parameters by Study Product Group and Study Week (ITT Population). Puff topography was conducted in a randomly-selected subset of 18 non-menthol and 18 menthol cigarette smokers at a single site. The randomly-selected subjects have been assigned to switch to smoking very low nicotine (VLN) cigarettes.

Puff volume will be measured before, during, and after switching to VLN cigarettes. Topography will be measured during an ad libitum smoking session. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=18 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=18 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=36 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Smoking Topography - Puff Volume Week -1	50.7496 mL Standard Deviation 12.88508	57.8934 mL Standard Deviation 23.65244	54.3215 mL Standard Deviation 19.11782	—	—	—
Smoking Topography - Puff Volume Week 2	44.6595 mL Standard Deviation 13.48557	49.7368 mL Standard Deviation 13.17315	47.2751 mL Standard Deviation 13.36612	—	—	—
Smoking Topography - Puff Volume Week 6	47.9733 mL Standard Deviation 13.25475	46.7513 mL Standard Deviation 11.63150	47.4005 mL Standard Deviation 12.33536	—	—	—

SECONDARY outcome

Timeframe: -1 week, and at 2 and 6 weeks.

Population: Summary of Puffing Topography Parameters by Study Product Group and Study Week (ITT Population). Puff topography was conducted in a randomly-selected subset of 18 non-menthol and 18 menthol cigarette smokers at a single site. The randomly-selected subjects have been assigned to switch to smoking very low nicotine (VLN) cigarettes.

Peak Puff Flow Rate will be measured before, during, and after switching to VLN cigarettes. Topography will be measured during an ad libitum smoking session. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=18 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=18 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=36 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Smoking Topography - Peak Puff Flow Rate Week -1	44.3213 mL/sec Standard Deviation 10.85319	45.9639 mL/sec Standard Deviation 20.10163	45.1426 mL/sec Standard Deviation 15.94278	—	—	—
Smoking Topography - Peak Puff Flow Rate Week 2	39.7010 mL/sec Standard Deviation 13.72368	41.4412 mL/sec Standard Deviation 9.94555	40.5975 mL/sec Standard Deviation 11.76950	—	—	—
Smoking Topography - Peak Puff Flow Rate Week 6	43.4274 mL/sec Standard Deviation 14.75467	40.0195 mL/sec Standard Deviation 9.05336	41.8300 mL/sec Standard Deviation 12.34352	—	—	—

SECONDARY outcome

Timeframe: -1 week, and at 2 and 6 weeks.

Population: Summary of Puffing Topography Parameters by Study Product Group and Study Week (ITT Population). Puff topography was conducted in a randomly-selected subset of 18 non-menthol and 18 menthol cigarette smokers at a single site. The randomly-selected subjects have been assigned to switch to smoking very low nicotine (VLN) cigarettes.

Average Puff Flow Rate will be measured before, during, and after switching to VLN cigarettes. Topography will be measured during an ad libitum smoking session. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=18 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=18 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=36 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Smoking Topography - Average Flow Rate Week -1	27.8305 mL/sec Standard Deviation 8.55885	28.5428 mL/sec Standard Deviation 12.99509	28.1866 mL/sec Standard Deviation 10.85056	—	—	—
Smoking Topography - Average Flow Rate Week 2	23.6309 mL/sec Standard Deviation 7.84344	25.4534 mL/sec Standard Deviation 5.68677	24.5698 mL/sec Standard Deviation 6.77219	—	—	—
Smoking Topography - Average Flow Rate Week 6	26.7164 mL/sec Standard Deviation 9.72496	24.1247 mL/sec Standard Deviation 5.15403	25.5016 mL/sec Standard Deviation 7.90798	—	—	—

SECONDARY outcome

Timeframe: -1 week, and at 2 and 6 weeks.

Population: Summary of Puffing Topography Parameters by Study Product Group and Study Week (ITT Population). Puff topography was conducted in a randomly-selected subset of 18 non-menthol and 18 menthol cigarette smokers at a single site. The randomly-selected subjects have been assigned to switch to smoking very low nicotine (VLN) cigarettes.

Inter-puff interval will be measured before, during, and after switching to VLN cigarettes. Topography will be measured during an ad libitum smoking session. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=18 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=18 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=36 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Smoking Topography - Inter-puff Interval Week -1	30.269 sec Standard Deviation 10.2050	29.222 sec Standard Deviation 8.2654	29.746 sec Standard Deviation 9.1677	—	—	—
Smoking Topography - Inter-puff Interval Week 2	24.280 sec Standard Deviation 9.2227	26.624 sec Standard Deviation 12.1134	25.488 sec Standard Deviation 10.7076	—	—	—
Smoking Topography - Inter-puff Interval Week 6	21.044 sec Standard Deviation 7.1810	27.215 sec Standard Deviation 11.4332	23.937 sec Standard Deviation 9.7693	—	—	—

SECONDARY outcome

Timeframe: -1 week, and at 2, 4, and 6 weeks.

Population: Summary of FTCD Score by Study Product Group and Study Week (ITT Population)

Subjects will answer a Fagerstrom Test for Cigarette Dependance (FTCD) questionnaire which contains six items that evaluate the quantity of cigarette consumption, the compulsion to use, and dependence.The Fagerstrom Test for Nicotine Dependence, is scored from 0 to 1 for yes/no items and 0 to 3 for multiple-choice items.The items are summed to yield a total score of 0-10. The higher the total Fagerström score, the greater the patient's physical dependence on nicotine. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=49 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=99 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=20 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated n=22 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined n=42 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Subjective Effects -Fagerstrom Test for Cigarette Dependance (FTCD) Week 6	4.7 score on a scale Standard Deviation 1.65	6.0 score on a scale Standard Deviation 1.68	5.4 score on a scale Standard Deviation 1.78	5.4 score on a scale Standard Deviation 1.98	5.2 score on a scale Standard Deviation 2.04	5.3 score on a scale Standard Deviation 1.99
Subjective Effects -Fagerstrom Test for Cigarette Dependance (FTCD) Week -1	5.2 score on a scale Standard Deviation 1.60	6.0 score on a scale Standard Deviation 1.53	5.6 score on a scale Standard Deviation 1.61	5.2 score on a scale Standard Deviation 1.46	5.4 score on a scale Standard Deviation 1.73	5.3 score on a scale Standard Deviation 1.59
Subjective Effects -Fagerstrom Test for Cigarette Dependance (FTCD) Week 2	5.0 score on a scale Standard Deviation 1.79	6.3 score on a scale Standard Deviation 1.61	5.7 score on a scale Standard Deviation 1.81	5.2 score on a scale Standard Deviation 1.87	4.9 score on a scale Standard Deviation 1.92	5.1 score on a scale Standard Deviation 1.88
Subjective Effects -Fagerstrom Test for Cigarette Dependance (FTCD) Week 4	4.8 score on a scale Standard Deviation 1.44	6.3 score on a scale Standard Deviation 1.71	5.6 score on a scale Standard Deviation 1.76	5.3 score on a scale Standard Deviation 2.02	5.3 score on a scale Standard Deviation 1.85	5.3 score on a scale Standard Deviation 1.92

SECONDARY outcome

Timeframe: Week -1, and at 2, 4, and 6 weeks.

Population: Summary of QSU-Brief Factor Score by Study Product Group and Study Week (ITT Population)

Subjects will answer a Brief Questionnaire of Smoking Urges (QSU-Brief). QSU is on a scale of 1-7, with 1 being strongly disagree and 7 being strongly agree. The average score of the following is taken to determine the Factor Score 1 and Factor Score 2; Factor 1: Average of Questions 1, 3, 6, 7, and 10; Factor 2: Average of Questions 2, 4, 5, 8, and 9. The score for each factor is calculated by summing the item scores; the total score is calculated by summing all questions together. The higher the score, the greater the urge to smoke. The total score range for this questionnaire is 10-70. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=49 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=99 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=20 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated n=22 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined n=42 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Subjective Effects -Brief Questionnaire of Smoking Urges (QSU-Brief) Week -1	4.2 score on a scale Standard Deviation 1.68	4.3 score on a scale Standard Deviation 1.70	4.3 score on a scale Standard Deviation 1.69	4.51 score on a scale Standard Deviation 1.50	3.8 score on a scale Standard Deviation 1.26	4.1 score on a scale Standard Deviation 1.41
Subjective Effects -Brief Questionnaire of Smoking Urges (QSU-Brief) Week 2	3.7 score on a scale Standard Deviation 1.87	5.4 score on a scale Standard Deviation 1.50	4.5 score on a scale Standard Deviation 1.88	4.3 score on a scale Standard Deviation 1.74	3.7 score on a scale Standard Deviation 1.48	4.0 score on a scale Standard Deviation 1.61
Subjective Effects -Brief Questionnaire of Smoking Urges (QSU-Brief) Week 4	3.8 score on a scale Standard Deviation 1.68	3.9 score on a scale Standard Deviation 1.47	3.8 score on a scale Standard Deviation 1.56	3.8 score on a scale Standard Deviation 1.47	3.7 score on a scale Standard Deviation 1.42	3.7 score on a scale Standard Deviation 1.43
Subjective Effects -Brief Questionnaire of Smoking Urges (QSU-Brief) Week 6	3.4 score on a scale Standard Deviation 1.70	4.4 score on a scale Standard Deviation 1.68	3.9 score on a scale Standard Deviation 1.75	4.1 score on a scale Standard Deviation 1.57	3.5 score on a scale Standard Deviation 1.57	3.8 score on a scale Standard Deviation 1.57

SECONDARY outcome

Timeframe: -1 week, and at 2, 4, and 6 weeks.

Population: Summary of MNWS-R Total Score by Study Product Group and Study Week (ITT Population)

Subjects will answer a MNWS-R questionnaire. The MNWS is considered as the briefest scale among the self-report measures of nicotine withdrawal symptoms currently available. The original MNWS was developed by Hughes and Hatsukami in 1986. It consisted of nine nicotine withdrawal symptoms including craving. The scale was modified to reflect changes made in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for nicotine withdrawal. The total score of the scale range from 0 to 36 depending on participant's rate for the symptoms as not present (0), slight (1), mild (2), moderate (3), and severe (4). A high total score implies high nicotine addiction. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=49 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=99 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=20 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated n=22 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined n=42 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Subjective Effects - Minnesota Nicotine Withdrawal Scale - Revised (MNWS-R) Week -1	8.1 score on a scale Standard Deviation 7.56	13.0 score on a scale Standard Deviation 8.77	10.6 score on a scale Standard Deviation 8.52	10.6 score on a scale Standard Deviation 9.68	9.2 score on a scale Standard Deviation 7.49	9.9 score on a scale Standard Deviation 8.52
Subjective Effects - Minnesota Nicotine Withdrawal Scale - Revised (MNWS-R) Week 2	8.4 score on a scale Standard Deviation 8.53	16.0 score on a scale Standard Deviation 9.74	12.3 score on a scale Standard Deviation 9.88	8.1 score on a scale Standard Deviation 9.02	9.0 score on a scale Standard Deviation 6.94	8.6 score on a scale Standard Deviation 7.90
Subjective Effects - Minnesota Nicotine Withdrawal Scale - Revised (MNWS-R) Week 4	6.5 score on a scale Standard Deviation 7.67	13.5 score on a scale Standard Deviation 10.55	10.1 score on a scale Standard Deviation 9.86	8.4 score on a scale Standard Deviation 8.76	7.8 score on a scale Standard Deviation 7.10	8.1 score on a scale Standard Deviation 7.89
Subjective Effects - Minnesota Nicotine Withdrawal Scale - Revised (MNWS-R) Week 6	5.4 score on a scale Standard Deviation 6.17	13.4 score on a scale Standard Deviation 10.01	9.5 score on a scale Standard Deviation 9.22	7.5 score on a scale Standard Deviation 7.32	8.3 score on a scale Standard Deviation 7.53	7.9 score on a scale Standard Deviation 7.33

SECONDARY outcome

Timeframe: -1 week, and at 2, 4, and 6 weeks.

Population: Summary of Perceived Health Risk Scale by Study Product Group and Study Week (ITT Population)

Subjects will answer a Perceived health risks questionnaire. The subjects indicated their perception of the risk of becoming addicted to the cigarette they were currently using on a scale from 1 to 10. Scale =1 was a very low risk of becoming addicted and Scale =10 was a very high risk of becoming addicted. The baseline data were collected for participants at Week -1, and Week -1 data are reported per post-switch Arms/Group randomization (instead of pre-switch Arms/Group assignment).

Outcome measures

Measure	Very Low Nicotine Mentholated n=49 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Non-Mentholated n=50 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Very Low Nicotine Combined n=99 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Mentholated n=20 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Non-Mentholated n=22 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.	Usual Brand Combined n=42 Participants Subjects were randomized to one of four study product groups, with menthol cigarette smokers randomized to either their usual brand menthol cigarettes or VLN mentholated cigarettes, and non-menthol cigarette smokers randomized to their usual brand non-menthol cigarettes or VLN non-mentholated cigarettes.
Subjective Effects - Perceived Health Risks Week 6	3.2 units on a scale Standard Deviation 2.89	3.6 units on a scale Standard Deviation 2.79	3.4 units on a scale Standard Deviation 2.83	6.6 units on a scale Standard Deviation 1.70	6.9 units on a scale Standard Deviation 2.54	6.7 units on a scale Standard Deviation 2.12
Subjective Effects - Perceived Health Risks Week -1	7.0 units on a scale Standard Deviation 2.17	7.6 units on a scale Standard Deviation 2.04	7.3 units on a scale Standard Deviation 2.12	6.6 units on a scale Standard Deviation 2.09	7.7 units on a scale Standard Deviation 2.25	7.1 units on a scale Standard Deviation 2.23
Subjective Effects - Perceived Health Risks Week 2	3.4 units on a scale Standard Deviation 2.73	4.0 units on a scale Standard Deviation 3.02	3.7 units on a scale Standard Deviation 2.88	6.8 units on a scale Standard Deviation 2.07	7.0 units on a scale Standard Deviation 2.68	6.9 units on a scale Standard Deviation 2.38
Subjective Effects - Perceived Health Risks Week 4	3.4 units on a scale Standard Deviation 2.86	3.4 units on a scale Standard Deviation 2.55	34 units on a scale Standard Deviation 2.69	6.7 units on a scale Standard Deviation 2.37	7.4 units on a scale Standard Deviation 2.55	7.0 units on a scale Standard Deviation 2.45

Adverse Events

Non-Menthol Very Low Nicotine Cigarettes

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

Menthol Very Low Nicotine Cigarettes

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Usual Brand Non-Metholated

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Usual Brand Metholated

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Measure	Non-Menthol Very Low Nicotine Cigarettes n=50 participants at risk Subjects will be switched from their usual brand to smoke Very Low Nicotine king size cigarettes Non-Menthol Very Low Nicotine Cigarettes: King size non-menthol cigarettes containing 0.4mg nicotine /g tobacco	Menthol Very Low Nicotine Cigarettes n=50 participants at risk Subjects will be switched from their usual brand to smoke Very Low Nicotine king size Menthol cigarettes Menthol Very Low Nicotine Cigarettes: King size menthol cigarettes containing 0.4mg nicotine /g tobacco	Usual Brand Non-Metholated n=22 participants at risk Subjects will be switched from their usual brand to smoke Very Low Nicotine king size non-Menthol cigarettes Non-Menthol Very Low Nicotine Cigarettes: King size non-menthol cigarettes containing 0.4mg nicotine /g tobacco	Usual Brand Metholated n=20 participants at risk Subjects will be switched from their usual brand to smoke Very Low Nicotine king size cigarettes Menthol Very Low Nicotine Cigarettes: King size menthol cigarettes containing 0.4mg nicotine /g tobacco
Injury, poisoning and procedural complications Subarachnoid haemorrhage	2.0% 1/50 • Adverse event data were collected after the start of Week 1 product use through follow-up call at Week 7.	0.00% 0/50 • Adverse event data were collected after the start of Week 1 product use through follow-up call at Week 7.	0.00% 0/22 • Adverse event data were collected after the start of Week 1 product use through follow-up call at Week 7.	0.00% 0/20 • Adverse event data were collected after the start of Week 1 product use through follow-up call at Week 7.

Other adverse events

Measure	Non-Menthol Very Low Nicotine Cigarettes n=50 participants at risk Subjects will be switched from their usual brand to smoke Very Low Nicotine king size cigarettes Non-Menthol Very Low Nicotine Cigarettes: King size non-menthol cigarettes containing 0.4mg nicotine /g tobacco	Menthol Very Low Nicotine Cigarettes n=50 participants at risk Subjects will be switched from their usual brand to smoke Very Low Nicotine king size Menthol cigarettes Menthol Very Low Nicotine Cigarettes: King size menthol cigarettes containing 0.4mg nicotine /g tobacco	Usual Brand Non-Metholated n=22 participants at risk Subjects will be switched from their usual brand to smoke Very Low Nicotine king size non-Menthol cigarettes Non-Menthol Very Low Nicotine Cigarettes: King size non-menthol cigarettes containing 0.4mg nicotine /g tobacco	Usual Brand Metholated n=20 participants at risk Subjects will be switched from their usual brand to smoke Very Low Nicotine king size cigarettes Menthol Very Low Nicotine Cigarettes: King size menthol cigarettes containing 0.4mg nicotine /g tobacco
Nervous system disorders Headache	16.0% 8/50 • Adverse event data were collected after the start of Week 1 product use through follow-up call at Week 7.	12.0% 6/50 • Adverse event data were collected after the start of Week 1 product use through follow-up call at Week 7.	22.7% 5/22 • Adverse event data were collected after the start of Week 1 product use through follow-up call at Week 7.	15.0% 3/20 • Adverse event data were collected after the start of Week 1 product use through follow-up call at Week 7.
Psychiatric disorders Irritability	6.0% 3/50 • Adverse event data were collected after the start of Week 1 product use through follow-up call at Week 7.	10.0% 5/50 • Adverse event data were collected after the start of Week 1 product use through follow-up call at Week 7.	0.00% 0/22 • Adverse event data were collected after the start of Week 1 product use through follow-up call at Week 7.	5.0% 1/20 • Adverse event data were collected after the start of Week 1 product use through follow-up call at Week 7.

Additional Information

Karen E. Delaney

22nd Century Group, Inc.

Phone: 716-270-1523

Email: kdelaney@xxiicentury.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place