Trial Outcomes & Findings for A Study To Evaluate The Efficacy And Safety Of Varenicline Compared To Placebo For Smoking Cessation Through Reduction (NCT NCT01370356)

Last Updated: 2014-09-01

Results Overview

Percentage of participants who remained abstinent from Week 15 to Week 24, inclusive, reporting no smoking and no use of nicotine-containing products since the last study visit or contact on the Nicotine Use Inventory (NUI) and confirmed by expired CO \< 10 ppm at any time point (CO measurements conducted at the clinic visits) during Weeks 15 through 24, inclusive. Missing CO was imputed as negative (CO ≤ 10 ppm).

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

1510 participants

Primary outcome timeframe

Week 15 - 24

Results posted on

2014-09-01

Participant Flow

A total of 1747 participants were screened, whereof 1510 were randomized into the study, and of whom 1493 took at least 1 dose of study drug. Overall, 61 centers in 10 countries received study drug: Australia (4), Canada (6), Czech Republic (6), Germany (6), Egypt (3), United Kingdom (7), Japan (6), Mexico (4), Taiwan (7), and USA (12).

Participant milestones

Participant milestones
Measure	Varenicline Varenicline was titrated to the full dose during the first week (Day 1 - 3: 0.5 mg/day; Day 4 -7: 0.5 mg twice daily \[BID\]). From Week 2 to Week 24, the dose was 1 mg BID. Participants who had difficulties with tolerability were permitted to have the dose lowered temporarily or permanently to 0.5 mg BID. Data below are presented for the treated population.	Placebo Placebo was titrated and administered in the same manner as varenicline and reduction of dosing for difficulties with tolerability was also allowed. Data below are presented for the treated population.
Overall Study STARTED	751	742
Overall Study COMPLETED	559	515
Overall Study NOT COMPLETED	192	227

Reasons for withdrawal

Reasons for withdrawal
Measure	Varenicline Varenicline was titrated to the full dose during the first week (Day 1 - 3: 0.5 mg/day; Day 4 -7: 0.5 mg twice daily \[BID\]). From Week 2 to Week 24, the dose was 1 mg BID. Participants who had difficulties with tolerability were permitted to have the dose lowered temporarily or permanently to 0.5 mg BID. Data below are presented for the treated population.	Placebo Placebo was titrated and administered in the same manner as varenicline and reduction of dosing for difficulties with tolerability was also allowed. Data below are presented for the treated population.
Overall Study Death	1	0
Overall Study Lack of Efficacy	6	28
Overall Study Lost to Follow-up	76	81
Overall Study Withdrawal by Subject	54	59
Overall Study Reason not specified	39	43
Overall Study Protocol Violation	3	3
Overall Study Adverse event (AE) Related to Study Drug	12	9
Overall Study AE Not Related to Study Drug	1	4

Baseline Characteristics

A Study To Evaluate The Efficacy And Safety Of Varenicline Compared To Placebo For Smoking Cessation Through Reduction

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Varenicline n=751 Participants Varenicline was titrated to the full dose during the first week (Day 1 - 3: 0.5 mg/day; Day 4 -7: 0.5 mg BID). From Week 2 to Week 24, the dose was 1 mg BID. Participants who had difficulties with tolerability were permitted to have the dose lowered temporarily or permanently to 0.5 mg BID. One participant was assigned to varenicline as a male but is in fact female. Data below are presented for the treated population.	Placebo n=742 Participants Placebo was titrated and administered in the same manner as varenicline and reduction of dosing for difficulties with tolerability was also allowed. Data below are presented for the treated population.	Total n=1493 Participants Total of all reporting groups
Age, Continuous	44.7 Years STANDARD_DEVIATION 11.8 • n=5 Participants	44.4 Years STANDARD_DEVIATION 12.0 • n=7 Participants	44.6 Years STANDARD_DEVIATION 11.9 • n=5 Participants
Sex: Female, Male Female	330 Participants n=5 Participants	321 Participants n=7 Participants	651 Participants n=5 Participants
Sex: Female, Male Male	421 Participants n=5 Participants	421 Participants n=7 Participants	842 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 15 - 24

Population: The Full Analysis Set was referred to as the Intent-to-Treat (ITT) population and was defined as all randomized participants. The ITT population was the primary analysis set for the efficacy analyses in this study.

Outcome measures

Outcome measures
Measure	Varenicline n=760 Participants Varenicline was titrated to the full dose during the first week (Day 1 - 3: 0.5 mg/day; Day 4 -7: 0.5 mg BID). From Week 2 to Week 24, the dose was 1 mg BID. Participants who had difficulties with tolerability were permitted to have the dose lowered temporarily or permanently to 0.5 mg BID.	Placebo n=750 Participants Placebo was titrated and administered in the same manner as varenicline and reduction of dosing for difficulties with tolerability was also allowed.
Percentage of Participants With Carbon Monoxide (CO) Confirmed 10-Week Continuous Abstinence (CA) From Smoking	32.1 percentage of participants	6.9 percentage of participants

SECONDARY outcome

Timeframe: Week 21 - 24

Population: The Full Analysis Set was referred to as the ITT population and was defined as all randomized participants. The ITT population was the primary analysis set for the efficacy analyses in this study.

Percentage of participants who remained abstinent from Week 21 to Week 24, inclusive, reporting no smoking and no use of nicotine-containing products since the last study visit or contact on the NUI and confirmed by expired CO \< 10 ppm at any time point (CO measurements conducted at the clinic visits) during Weeks 21 through 24, inclusive. Missing CO was imputed as negative (CO ≤ 10 ppm).

Outcome measures

Outcome measures
Measure	Varenicline n=760 Participants Varenicline was titrated to the full dose during the first week (Day 1 - 3: 0.5 mg/day; Day 4 -7: 0.5 mg BID). From Week 2 to Week 24, the dose was 1 mg BID. Participants who had difficulties with tolerability were permitted to have the dose lowered temporarily or permanently to 0.5 mg BID.	Placebo n=750 Participants Placebo was titrated and administered in the same manner as varenicline and reduction of dosing for difficulties with tolerability was also allowed.
Percentage of Participants With CO Confirmed 4-Week CA From Smoking	37.8 percentage of participants	12.5 percentage of participants

SECONDARY outcome

Timeframe: Weeks 21 - 52

Percentage of participants who remained abstinent from Week 21 to Week 52, inclusive, reporting no smoking and no use of nicotine-containing products since the last study visit or contact on the NUI and confirmed by expired CO \< 10 ppm at any time point (CO measurements conducted at the clinic visits) during Weeks 21 through 52, inclusive. Missing CO was imputed as negative (CO ≤ 10 ppm).

Outcome measures

Outcome measures
Measure	Varenicline n=760 Participants Varenicline was titrated to the full dose during the first week (Day 1 - 3: 0.5 mg/day; Day 4 -7: 0.5 mg BID). From Week 2 to Week 24, the dose was 1 mg BID. Participants who had difficulties with tolerability were permitted to have the dose lowered temporarily or permanently to 0.5 mg BID.	Placebo n=750 Participants Placebo was titrated and administered in the same manner as varenicline and reduction of dosing for difficulties with tolerability was also allowed.
Percentage of Participants With CO Confirmed Long Term CA From Smoking	27.0 percentage of participants	9.9 percentage of participants

SECONDARY outcome

Timeframe: Week 12, 24, and 52

The 7-day point prevalence of abstinence was defined as being abstinent from smoking and using tobacco products during the last 7 days at Week 12, 24, and 52. The participant's smoking status and other nicotine use was evaluated based on the "last 7 days" questions on the NUI and confirmed by CO expiration. Responders were defined as those, who answered "no" to both questions ("Has the subject smoked any cigarettes (even a puff) in the last 7 days?"; and "Has the subject used any nicotine products and/or other tobacco.... in the last 7 days?") and whose expired CO \< 10 ppm. Missing CO was imputed as negative (CO ≤ 10 ppm).

Outcome measures

Outcome measures
Measure	Varenicline n=760 Participants Varenicline was titrated to the full dose during the first week (Day 1 - 3: 0.5 mg/day; Day 4 -7: 0.5 mg BID). From Week 2 to Week 24, the dose was 1 mg BID. Participants who had difficulties with tolerability were permitted to have the dose lowered temporarily or permanently to 0.5 mg BID.	Placebo n=750 Participants Placebo was titrated and administered in the same manner as varenicline and reduction of dosing for difficulties with tolerability was also allowed.
Percentage of Participants With 7-Day Point Prevalence of Smoking Cessation Week 12	31.2 percentage of participants	6.7 percentage of participants
Percentage of Participants With 7-Day Point Prevalence of Smoking Cessation Week 24	43.2 percentage of participants	17.5 percentage of participants
Percentage of Participants With 7-Day Point Prevalence of Smoking Cessation Week 52	34.1 percentage of participants	18.3 percentage of participants

SECONDARY outcome

Timeframe: Week 52

The 4-week point prevalence of abstinence was defined as being abstinent from smoking and using tobacco products during the last 4 weeks of the study. The participant's smoking status and other nicotine use was evaluated based on the "last 4 weeks" questions on the NUI and confirmed by CO expiration. Responders were defined as those, who answered "no" to both questions ("Has the subject smoked any cigarettes (even a puff) in the last 4 weeks?"; and "Has the subject used any nicotine products and/or other tobacco.... in the last 4 weeks?") and whose expired CO \< 10 ppm. Missing CO was imputed as negative (CO ≤ 10 ppm).

Outcome measures

Outcome measures
Measure	Varenicline n=760 Participants Varenicline was titrated to the full dose during the first week (Day 1 - 3: 0.5 mg/day; Day 4 -7: 0.5 mg BID). From Week 2 to Week 24, the dose was 1 mg BID. Participants who had difficulties with tolerability were permitted to have the dose lowered temporarily or permanently to 0.5 mg BID.	Placebo n=750 Participants Placebo was titrated and administered in the same manner as varenicline and reduction of dosing for difficulties with tolerability was also allowed.
Percentage of Participants With 4-Week Point Prevalence of Smoking Cessation	32.8 percentage of participants	17.3 percentage of participants

Adverse Events

Varenicline

Serious events: 28 serious events

Other events: 467 other events

Deaths: 0 deaths

Placebo

Serious events: 16 serious events

Other events: 339 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Varenicline n=751 participants at risk Varenicline was titrated to the full dose during the first week (Day 1 - 3: 0.5 mg/day; Day 4 -7: 0.5 mg BID). From Week 2 to Week 24, the dose was 1 mg BID. Participants who had difficulties with tolerability were permitted to have the dose lowered temporarily or permanently to 0.5 mg BID.	Placebo n=742 participants at risk Placebo was titrated and administered in the same manner as varenicline and reduction of dosing for difficulties with tolerability was also allowed.
Gastrointestinal disorders Constipation	5.1% 38/751 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 13/742 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	27.8% 209/751 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	9.0% 67/742 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Fatigue	6.1% 46/751 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.6% 34/742 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Irritability	5.2% 39/751 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.0% 30/742 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Nasopharyngitis	13.0% 98/751 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	12.0% 89/742 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Upper respiratory tract infection	8.4% 63/751 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	8.5% 63/742 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Headache	8.3% 62/751 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.3% 54/742 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Abnormal dreams	11.5% 86/751 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.8% 43/742 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Anxiety	6.9% 52/751 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	8.8% 65/742 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Insomnia	10.7% 80/751 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	6.9% 51/742 • All AEs (serious and nonserious) were recorded from the date of first dose of study drug (Baseline) up to 30 days after the date of last dose of study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Additional Information

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