Trial Outcomes & Findings for Study Evaluating The Safety And Efficacy Of Varenicline and Bupropion For Smoking Cessation In Subjects With And Without A History Of Psychiatric Disorders (NCT NCT01456936)

Last Updated: 2016-06-10

Results Overview

The primary safety endpoint is the occurrence of at least one treatment emergent "severe" adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent "moderate" or "severe" adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

8144 participants

Primary outcome timeframe

Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Results posted on

2016-06-10

Participant Flow

A total of 11,186 participants were screened for participation in the study, of which 3042 participants were considered to be screen failures, leaving 8144 participants eligible for study participation (efficacy population). 86 participants (1.1%) did not receive study drug. A total of 8058 participants received study drug (safety population).

Participants were classified into 2 cohorts: participants without diagnosis of psychiatric disorder and participants with a stable diagnosis of psychiatric disorder confirmed by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID) 4th edition conducted at screening.

Participant milestones

Participant milestones
Measure	Varenicline Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg daily once (QD) x 3 days, 0.5 mg twice daily (BID) x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Overall Study STARTED	2037	2034	2038	2035
Overall Study Randomized and Treated	2016	2006	2022	2014
Overall Study COMPLETED	1598	1586	1557	1552
Overall Study NOT COMPLETED	439	448	481	483

Reasons for withdrawal

Reasons for withdrawal
Measure	Varenicline Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg daily once (QD) x 3 days, 0.5 mg twice daily (BID) x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Overall Study Other reason	41	30	36	33
Overall Study No longer meets eligibility criteria	4	8	6	5
Overall Study Protocol Violation	4	2	5	5
Overall Study Pregnancy	1	0	0	1
Overall Study Insufficient clinical response	4	4	14	13
Overall Study No longer willing to participate	195	218	224	248
Overall Study Lost to Follow-up	135	126	144	127
Overall Study Medication error	0	1	0	1
Overall Study Adverse event (study drug)	25	21	26	17
Overall Study Adverse event (study drug unrelated)	9	7	9	9
Overall Study Death	0	3	1	3
Overall Study Randomized but not treated	21	28	16	21

Baseline Characteristics

Study Evaluating The Safety And Efficacy Of Varenicline and Bupropion For Smoking Cessation In Subjects With And Without A History Of Psychiatric Disorders

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Varenicline 1.0 mg BID n=2016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion n=2006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2022 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2014 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.	Total n=8058 Participants Total of all reporting groups
Age, Continuous	46.5 Years STANDARD_DEVIATION 12.4 • n=5 Participants	46.3 Years STANDARD_DEVIATION 12.6 • n=7 Participants	46.8 Years STANDARD_DEVIATION 12.2 • n=5 Participants	46.4 Years STANDARD_DEVIATION 12.2 • n=4 Participants	46.5 Years STANDARD_DEVIATION 12.3 • n=21 Participants
Sex: Female, Male Female	1114 Participants n=5 Participants	1116 Participants n=7 Participants	1141 Participants n=5 Participants	1138 Participants n=4 Participants	4509 Participants n=21 Participants
Sex: Female, Male Male	902 Participants n=5 Participants	890 Participants n=7 Participants	881 Participants n=5 Participants	876 Participants n=4 Participants	3549 Participants n=21 Participants

PRIMARY outcome

Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=2016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=2006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2022 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2014 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Occurrence of Neuropsychiatric (NPS) Adverse Events (AE) - the Primary Study Endpoint Non-psychiatric cohort (N= 990, 989, 1006, 999)	1.3 percentage of participants	2.2 percentage of participants	2.5 percentage of participants	2.4 percentage of participants
Occurrence of Neuropsychiatric (NPS) Adverse Events (AE) - the Primary Study Endpoint Psychiatric cohort (N= 1026, 1017, 1016, 1015)	6.5 percentage of participants	6.7 percentage of participants	5.2 percentage of participants	4.9 percentage of participants
Occurrence of Neuropsychiatric (NPS) Adverse Events (AE) - the Primary Study Endpoint Overall (N= 2016, 2006, 2022, 2014)	4.0 percentage of participants	4.5 percentage of participants	3.9 percentage of participants	3.7 percentage of participants

PRIMARY outcome

Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=2016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=2006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2022 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2014 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Estimated NPS AE Rate (%), by Cohort Non-psychiatric cohort (N=3984)	1.25 percentage of participants Interval 0.6 to 1.9	2.44 percentage of participants Interval 1.52 to 3.36	2.31 percentage of participants Interval 1.37 to 3.25	2.52 percentage of participants Interval 1.58 to 3.46
Estimated NPS AE Rate (%), by Cohort Psychiatric cohort (N= 4074)	6.42 percentage of participants Interval 4.91 to 7.93	6.62 percentage of participants Interval 5.09 to 8.15	5.20 percentage of participants Interval 3.84 to 6.56	4.83 percentage of participants Interval 3.51 to 6.16

SECONDARY outcome

Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

The safety endpoint is the occurrence of at least one treatment emergent "severe" adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent "moderate" or "severe" adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Each of these 16 components is reported below.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=990 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=989 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=999 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Anxiety (severe)	0 participants	1 participants	0 participants	3 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Depression (severe)	1 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Feeling abnormal (severe only)	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Hostility (severe)	0 participants	1 participants	1 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Agitation (moderate and severe)	10 participants	11 participants	19 participants	11 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Aggression (moderate and severe)	3 participants	3 participants	2 participants	3 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Delusions (moderate and severe)	0 participants	0 participants	1 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Hallucinations (moderate and severe)	1 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Mania (moderate and severe)	0 participants	1 participants	2 participants	2 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Panic (moderate and severe)	0 participants	4 participants	1 participants	3 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Paranoia (moderate and severe)	0 participants	1 participants	0 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Psychosis (moderate and severe)	0 participants	0 participants	1 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Homicidal ideation (moderate and severe)	0 participants	0 participants	1 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Suicidal behavior (moderate and severe)	0 participants	1 participants	1 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Suicidal ideation (moderate and severe)	0 participants	1 participants	2 participants	3 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort Suicide (moderate and severe)	0 participants	0 participants	0 participants	1 participants

SECONDARY outcome

Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=1026 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=1017 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=1015 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Anxiety (severe)	5 participants	4 participants	6 participants	2 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Depression (severe)	6 participants	4 participants	7 participants	6 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Feeling abnormal (severe only)	0 participants	1 participants	0 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Hostility (severe)	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Agitation (moderate and severe)	25 participants	29 participants	21 participants	22 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Aggression (moderate and severe)	14 participants	9 participants	7 participants	8 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Delusions (moderate and severe)	1 participants	1 participants	1 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Hallucinations (moderate and severe)	5 participants	4 participants	2 participants	2 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Mania (moderate and severe)	7 participants	9 participants	3 participants	6 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Panic (moderate and severe)	7 participants	16 participants	13 participants	7 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Paranoia (moderate and severe)	1 participants	0 participants	0 participants	2 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Psychosis (moderate and severe)	4 participants	2 participants	3 participants	1 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Homicidal ideation (moderate and severe)	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Suicidal behavior (moderate and severe)	1 participants	1 participants	0 participants	1 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Suicidal ideation (moderate and severe)	5 participants	2 participants	3 participants	2 participants
Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort Suicide (moderate and severe)	0 participants	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

The NPS AE composite results (as previously described) are for the two cohorts combined and are presented below.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=2016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=2006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2022 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2014 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Suicidal Ideation	5 participants	3 participants	5 participants	5 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Anxiety	5 participants	5 participants	6 participants	5 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Depression	7 participants	4 participants	7 participants	6 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Feeling Abnormal	0 participants	1 participants	0 participants	0 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Hostility	0 participants	1 participants	1 participants	0 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Agitation	35 participants	40 participants	40 participants	33 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Aggression	17 participants	12 participants	9 participants	11 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Delusions	1 participants	1 participants	2 participants	0 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Hallucination	6 participants	4 participants	2 participants	2 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Mania	7 participants	10 participants	5 participants	8 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Panic Disorder	7 participants	20 participants	14 participants	10 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Paranoia	1 participants	1 participants	0 participants	2 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Psychosis	4 participants	2 participants	4 participants	1 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Homicidal Ideation	0 participants	0 participants	1 participants	0 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Suicidal Behavior	1 participants	2 participants	1 participants	1 participants
Occurrence of the Components of NPS AE Primary Endpoint (Overall) Suicide	0 participants	0 participants	0 participants	1 participants

SECONDARY outcome

Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=2016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=2006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2022 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2014 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Occurrence of Severe-only NPS AEs in the Primary Endpoint, by Cohort Psychiatric cohort (N= 1026, 1017, 1016, 1015)	1.4 percentage of participants	1.4 percentage of participants	1.4 percentage of participants	1.3 percentage of participants
Occurrence of Severe-only NPS AEs in the Primary Endpoint, by Cohort Overall (N= 2016, 2006, 2022, 2014)	0.7 percentage of participants	0.9 percentage of participants	0.8 percentage of participants	0.9 percentage of participants
Occurrence of Severe-only NPS AEs in the Primary Endpoint, by Cohort Non-psychiatric cohort (N= 990, 989, 1006, 999)	0.1 percentage of participants	0.4 percentage of participants	0.3 percentage of participants	0.5 percentage of participants

SECONDARY outcome

Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=990 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=989 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=999 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Anxiety	0 participants	1 participants	0 participants	3 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Depression	1 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Feeling abnormal	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Hostility	0 participants	1 participants	1 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Agitation	0 participants	0 participants	2 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Aggression	1 participants	1 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Delusions	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Hallucinations	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Mania	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Panic	0 participants	1 participants	1 participants	1 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Paranoia	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Psychosis	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Homicidal ideation	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Suicidal behavior	0 participants	1 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Suicidal ideation	0 participants	0 participants	0 participants	1 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort Suicide	0 participants	0 participants	0 participants	1 participants

SECONDARY outcome

Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=1026 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=1017 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=1015 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Anxiety	5 participants	4 participants	6 participants	2 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Depression	6 participants	4 participants	7 participants	6 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Feeling abnormal	0 participants	1 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Hostility	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Agitation	1 participants	1 participants	4 participants	2 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Aggression	1 participants	1 participants	0 participants	1 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Delusions	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Hallucinations	0 participants	1 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Mania	2 participants	1 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Panic	0 participants	1 participants	0 participants	1 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Paranoia	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Psychosis	0 participants	1 participants	1 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Homicidal ideation	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Suicidal behavior	1 participants	1 participants	0 participants	1 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Suicidal ideation	1 participants	0 participants	1 participants	0 participants
Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort Suicide	0 participants	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

The NPS AE endpoint was the occurrence of at least 1 treatment-emergent "severe" AE of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least 1 treatment-emergent "severe" AE of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=2016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=2006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2022 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2014 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Hostility	0 participants	1 participants	1 participants	0 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Anxiety	5 participants	5 participants	6 participants	5 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Depression	7 participants	4 participants	7 participants	6 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Feeling Abnormal	0 participants	1 participants	0 participants	0 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Agitation	1 participants	1 participants	6 participants	2 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Aggression	2 participants	2 participants	0 participants	1 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Delusions	0 participants	0 participants	0 participants	0 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Hallucination	0 participants	1 participants	0 participants	0 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Mania	2 participants	1 participants	0 participants	0 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Panic Disorder	0 participants	2 participants	1 participants	2 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Paranoia	1 participants	1 participants	0 participants	2 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Psychosis	4 participants	2 participants	4 participants	1 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Suicidal Behavior	1 participants	2 participants	0 participants	1 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Suicidal Ideation	1 participants	0 participants	1 participants	0 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Suicide	0 participants	0 participants	0 participants	1 participants
Occurrence of the Components of Severe-only NPS AE Endpoint (Overall) Homicidal Ideation	0 participants	0 participants	1 participants	0 participants

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

The HADS is a subject self-reporting scale completed in person at clinic visits at Baseline and Weeks 1 through 6, 8, 10, 12, 13, 16, 20, and 24. It contains 14 individual item responses ranging in increasing severity from 0 (normal) to 3 (most severe) for a total range of 0 to 42. Of the 14 items, 7 assess anxiety and 7 assess depression, providing 2 subscales with ranges of 0 to 21. For each subscale, 0 to 7 is considered normal, while 15 to 21 represents severe symptoms.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=990 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=989 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=999 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 1 (N= 984, 972, 989, 992)	3.26 Units on a scale Standard Deviation 3.92	3.58 Units on a scale Standard Deviation 4.25	3.06 Units on a scale Standard Deviation 3.87	3.38 Units on a scale Standard Deviation 4.20
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 2 (N= 961, 954, 963, 970)	2.91 Units on a scale Standard Deviation 3.86	3.07 Units on a scale Standard Deviation 3.96	2.84 Units on a scale Standard Deviation 3.85	3.20 Units on a scale Standard Deviation 4.25
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 3 (N= 935, 930, 936, 941)	2.61 Units on a scale Standard Deviation 3.85	2.64 Units on a scale Standard Deviation 3.82	2.63 Units on a scale Standard Deviation 3.93	2.77 Units on a scale Standard Deviation 3.94
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 4 (N= 923, 916, 934, 923)	2.40 Units on a scale Standard Deviation 3.66	2.36 Units on a scale Standard Deviation 3.57	2.46 Units on a scale Standard Deviation 3.80	2.77 Units on a scale Standard Deviation 4.21
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 5 (N= 911, 897, 906, 902)	2.29 Units on a scale Standard Deviation 3.51	2.24 Units on a scale Standard Deviation 3.52	2.32 Units on a scale Standard Deviation 3.86	2.48 Units on a scale Standard Deviation 3.92
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 6 (N= 899, 893, 909, 897)	2.23 Units on a scale Standard Deviation 3.56	2.18 Units on a scale Standard Deviation 3.57	2.40 Units on a scale Standard Deviation 3.87	2.48 Units on a scale Standard Deviation 3.97
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 8 (N= 868, 861, 877, 877)	2.17 Units on a scale Standard Deviation 3.60	2.16 Units on a scale Standard Deviation 3.70	2.28 Units on a scale Standard Deviation 3.60	2.64 Units on a scale Standard Deviation 4.29
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 10 (N= 853, 844, 852, 846)	2.29 Units on a scale Standard Deviation 3.89	1.96 Units on a scale Standard Deviation 3.24	2.33 Units on a scale Standard Deviation 3.80	2.57 Units on a scale Standard Deviation 4.41
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 12 (N= 772, 768, 750, 742)	2.07 Units on a scale Standard Deviation 3.48	1.83 Units on a scale Standard Deviation 3.21	2.01 Units on a scale Standard Deviation 3.51	2.46 Units on a scale Standard Deviation 4.10
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 13 (N= 797, 796, 789, 807)	2.11 Units on a scale Standard Deviation 3.74	1.85 Units on a scale Standard Deviation 3.22	2.01 Units on a scale Standard Deviation 3.47	2.38 Units on a scale Standard Deviation 4.27
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 16 (N= 784, 797, 775, 789)	2.05 Units on a scale Standard Deviation 3.47	1.90 Units on a scale Standard Deviation 3.43	2.09 Units on a scale Standard Deviation 3.61	2.34 Units on a scale Standard Deviation 3.98
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 20 (N= 771, 785, 762, 772)	2.10 Units on a scale Standard Deviation 3.54	1.93 Units on a scale Standard Deviation 3.36	1.97 Units on a scale Standard Deviation 3.53	2.31 Units on a scale Standard Deviation 4.15
Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort Week 24 (N= 758, 748, 737, 758)	2.01 Units on a scale Standard Deviation 3.49	1.87 Units on a scale Standard Deviation 3.47	2.01 Units on a scale Standard Deviation 3.45	2.25 Units on a scale Standard Deviation 4.04

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=1026 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=1017 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=1015 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
HADS Total Score, Psychiatric History Cohort Week 3 (N= 947, 961, 945, 926)	5.99 Units on a scale Standard Deviation 6.21	6.51 Units on a scale Standard Deviation 6.39	6.30 Units on a scale Standard Deviation 6.55	6.02 Units on a scale Standard Deviation 6.10
HADS Total Score, Psychiatric History Cohort Week 1 (N= 1026, 1017, 1015, 1015)	6.76 Units on a scale Standard Deviation 6.14	7.58 Units on a scale Standard Deviation 6.87	6.82 Units on a scale Standard Deviation 6.33	6.70 Units on a scale Standard Deviation 5.94
HADS Total Score, Psychiatric History Cohort Week 2 (N= 1005, 1004, 996, 995)	6.42 Units on a scale Standard Deviation 6.36	6.99 Units on a scale Standard Deviation 6.47	6.64 Units on a scale Standard Deviation 6.55	6.42 Units on a scale Standard Deviation 6.17
HADS Total Score, Psychiatric History Cohort Week 4 (N= 935, 938, 929, 908)	5.87 Units on a scale Standard Deviation 6.39	6.36 Units on a scale Standard Deviation 6.55	6.16 Units on a scale Standard Deviation 6.51	6.04 Units on a scale Standard Deviation 6.31
HADS Total Score, Psychiatric History Cohort Week 5 (N= 918, 918, 914, 895)	5.58 Units on a scale Standard Deviation 6.32	6.03 Units on a scale Standard Deviation 6.41	5.82 Units on a scale Standard Deviation 6.44	5.80 Units on a scale Standard Deviation 6.31
HADS Total Score, Psychiatric History Cohort Week 6 (N= 917, 914, 912, 874)	5.39 Units on a scale Standard Deviation 6.14	5.87 Units on a scale Standard Deviation 6.41	5.62 Units on a scale Standard Deviation 6.22	5.75 Units on a scale Standard Deviation 6.26
HADS Total Score, Psychiatric History Cohort Week 8 (N= 887, 893, 878, 859)	5.43 Units on a scale Standard Deviation 6.24	5.96 Units on a scale Standard Deviation 6.68	5.63 Units on a scale Standard Deviation 6.36	5.63 Units on a scale Standard Deviation 6.26
HADS Total Score, Psychiatric History Cohort Week 10 (N= 864, 865, 864, 823)	5.38 Units on a scale Standard Deviation 6.35	5.72 Units on a scale Standard Deviation 6.50	5.64 Units on a scale Standard Deviation 6.30	5.55 Units on a scale Standard Deviation 6.38
HADS Total Score, Psychiatric History Cohort Week 12 (N= 790, 803, 798, 749)	5.17 Units on a scale Standard Deviation 6.09	5.66 Units on a scale Standard Deviation 6.63	5.44 Units on a scale Standard Deviation 6.30	5.42 Units on a scale Standard Deviation 6.13
HADS Total Score, Psychiatric History Cohort Week 13 (N= 813, 812, 814, 763)	5.06 Units on a scale Standard Deviation 6.11	5.44 Units on a scale Standard Deviation 6.54	5.36 Units on a scale Standard Deviation 6.20	5.09 Units on a scale Standard Deviation 5.96
HADS Total Score, Psychiatric History Cohort Week 16 (N= 795, 805, 791, 748)	5.26 Units on a scale Standard Deviation 6.35	5.62 Units on a scale Standard Deviation 6.68	5.44 Units on a scale Standard Deviation 6.34	5.37 Units on a scale Standard Deviation 6.38
HADS Total Score, Psychiatric History Cohort Week 20 (N= 784, 784, 763, 737)	5.17 Units on a scale Standard Deviation 6.02	5.54 Units on a scale Standard Deviation 6.44	5.46 Units on a scale Standard Deviation 6.18	5.26 Units on a scale Standard Deviation 6.22
HADS Total Score, Psychiatric History Cohort Week 24 (N= 770, 764, 758, 729)	5.21 Units on a scale Standard Deviation 6.27	5.69 Units on a scale Standard Deviation 6.64	5.57 Units on a scale Standard Deviation 6.32	5.04 Units on a scale Standard Deviation 5.97

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=2016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=2006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2021 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2014 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
HADS Total Score (Overall) Week 1 (N= 1989, 1976, 1985, 1987)	5.03 Units on a scale Standard Deviation 5.45	5.61 Units on a scale Standard Deviation 6.07	4.95 Units on a scale Standard Deviation 5.58	5.05 Units on a scale Standard Deviation 5.41
HADS Total Score (Overall) Week 2 (N= 1938, 1937, 1931, 1929)	4.68 Units on a scale Standard Deviation 5.55	5.06 Units on a scale Standard Deviation 5.73	4.74 Units on a scale Standard Deviation 5.70	4.80 Units on a scale Standard Deviation 5.53
HADS Total Score (Overall) Week 3 (N= 1882, 1891, 1881, 1867)	4.31 Units on a scale Standard Deviation 5.44	4.60 Units on a scale Standard Deviation 5.63	4.48 Units on a scale Standard Deviation 5.71	4.38 Units on a scale Standard Deviation 5.37
HADS Total Score (Overall) Week 4 (N= 1858, 1854, 1863, 1831)	4.15 Units on a scale Standard Deviation 5.50	4.39 Units on a scale Standard Deviation 5.65	4.31 Units on a scale Standard Deviation 5.64	4.39 Units on a scale Standard Deviation 5.60
HADS Total Score (Overall) Week 5 (N= 1829, 1815, 1820, 1797)	3.94 Units on a scale Standard Deviation 5.37	4.16 Units on a scale Standard Deviation 5.52	4.08 Units on a scale Standard Deviation 5.59	4.14 Units on a scale Standard Deviation 5.51
HADS Total Score (Overall) Week 6 (N= 1816, 1807, 1821, 1771)	3.82 Units on a scale Standard Deviation 5.27	4.05 Units on a scale Standard Deviation 5.52	4.01 Units on a scale Standard Deviation 5.42	4.09 Units on a scale Standard Deviation 5.48
HADS Total Score (Overall) Week 8 (N= 1755, 1754, 1755, 1736)	3.82 Units on a scale Standard Deviation 5.36	4.10 Units on a scale Standard Deviation 5.75	3.96 Units on a scale Standard Deviation 5.43	4.12 Units on a scale Standard Deviation 5.56
HADS Total Score (Overall) Week 10 (N= 1717, 1709, 1716, 1669)	3.85 Units on a scale Standard Deviation 5.49	3.86 Units on a scale Standard Deviation 5.48	4.00 Units on a scale Standard Deviation 5.47	4.04 Units on a scale Standard Deviation 5.67
HADS Total Score (Overall) Week 12 (N= 1562, 1571, 1548, 1491)	3.64 Units on a scale Standard Deviation 5.21	3.79 Units on a scale Standard Deviation 5.58	3.78 Units on a scale Standard Deviation 5.42	3.95 Units on a scale Standard Deviation 5.42
HADS Total Score (Overall) Week 13 (N= 1610, 1608, 1603, 1570)	3.60 Units on a scale Standard Deviation 5.29	3.66 Units on a scale Standard Deviation 5.47	3.71 Units on a scale Standard Deviation 5.32	3.70 Units on a scale Standard Deviation 5.34
HADS Total Score (Overall) Week 16 (N= 1579, 1602, 1566, 1537)	3.67 Units on a scale Standard Deviation 5.37	3.77 Units on a scale Standard Deviation 5.63	3.78 Units on a scale Standard Deviation 5.44	3.82 Units on a scale Standard Deviation 5.50
HADS Total Score (Overall) Week 20 (N= 1555, 1569, 1525, 1509)	3.65 Units on a scale Standard Deviation 5.18	3.73 Units on a scale Standard Deviation 5.44	3.72 Units on a scale Standard Deviation 5.33	3.75 Units on a scale Standard Deviation 5.47
HADS Total Score (Overall) Week 24 (N= 1528, 1512, 1495, 1487)	3.62 Units on a scale Standard Deviation 5.33	3.80 Units on a scale Standard Deviation 5.64	3.82 Units on a scale Standard Deviation 5.41	3.62 Units on a scale Standard Deviation 5.27

SECONDARY outcome

Timeframe: Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

The C-SSRS is a semi-structured interview designed to evaluate an individual's degree of suicidal ideation, preparatory acts or behavior to actual attempt, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent". Answers at screening are for lifetime history. Answers for all other visits are since last visit.The scale is also used to record any completed suicides.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=990 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=989 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=999 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Non-psychiatric History Cohort Suicidal Behavior (Screening lifetime)	6 participants with positive responses	9 participants with positive responses	7 participants with positive responses	6 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Non-psychiatric History Cohort Suicidal Ideation (Screening lifetime)	48 participants with positive responses	43 participants with positive responses	50 participants with positive responses	49 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Non-psychiatric History Cohort Suicidal Behavior (Baseline)	0 participants with positive responses	0 participants with positive responses	0 participants with positive responses	0 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Non-psychiatric History Cohort Suicidal Ideation (Baseline)	0 participants with positive responses	1 participants with positive responses	0 participants with positive responses	1 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Non-psychiatric History Cohort Suicidal Behavior (treatment emergent 12 weeks)	0 participants with positive responses	0 participants with positive responses	1 participants with positive responses	1 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Non-psychiatric History Cohort Suicidal Ideation (treatment emergent 12 weeks)	7 participants with positive responses	4 participants with positive responses	3 participants with positive responses	6 participants with positive responses

SECONDARY outcome

Timeframe: Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

The C-SSRS is a semi-structured interview designed to evaluate an individual's degree of suicidal ideation, preparatory acts or behavior to actual attempt, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent". Answers at screening are for lifetime history. Answers for all other visits are since last visit. The scale is also used to record any completed suicides.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=1026 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=1017 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=1015 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Psychiatric History Cohort Suicidal Behavior (Screening lifetime)	137 participants with positive responses	143 participants with positive responses	111 participants with positive responses	123 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Psychiatric History Cohort Suicidal Ideation (Screening lifetime)	338 participants with positive responses	357 participants with positive responses	333 participants with positive responses	349 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Psychiatric History Cohort Suicidal Behavior (Baseline)	0 participants with positive responses	0 participants with positive responses	0 participants with positive responses	1 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Psychiatric History Cohort Suicidal Ideation (Baseline)	6 participants with positive responses	5 participants with positive responses	2 participants with positive responses	3 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Psychiatric History Cohort Suicidal Behavior (treatment emergent 12 weeks)	0 participants with positive responses	1 participants with positive responses	0 participants with positive responses	2 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Psychiatric History Cohort Suicidal Ideation (treatment emergent 12 weeks)	27 participants with positive responses	15 participants with positive responses	20 participants with positive responses	25 participants with positive responses

SECONDARY outcome

Timeframe: Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

The C-SSRS is a semi-structured interview designed to evaluate an individual's degree of suicidal ideation, preparatory acts or behavior to actual attempt, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent". Answers at screening are for lifetime history. Answers for all other visits are since last visit. The scale is also used to record any completed suicides.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=2016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=2006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2022 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2014 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Overall Suicidal Behavior (Screening lifetime)	143 participants with positive responses	152 participants with positive responses	118 participants with positive responses	129 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Overall Suicidal Ideation (Screening lifetime)	386 participants with positive responses	400 participants with positive responses	383 participants with positive responses	398 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Overall Suicidal Behavior (Baseline)	0 participants with positive responses	0 participants with positive responses	0 participants with positive responses	1 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Overall Suicidal Ideation (Baseline)	6 participants with positive responses	6 participants with positive responses	2 participants with positive responses	4 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Overall Suicidal Behavior (treatment emergent 12 weeks)	0 participants with positive responses	1 participants with positive responses	1 participants with positive responses	3 participants with positive responses
Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Overall Suicidal Ideation (treatment emergent 12 weeks)	34 participants with positive responses	19 participants with positive responses	23 participants with positive responses	31 participants with positive responses

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.

The CGI-I is a clinician rated instrument that measures change in participant's psychiatric condition (or lack thereof in the stratum without psychiatric disorders) on a 7 point scale ranging from 1 (very much improved) to 7 (very much worse), with 4 = no change. The ratings were applicable even to those without psychiatric diagnoses (eg, those with no psychiatric symptoms would be rated as "normal, not at all ill" on the CGI-S at baseline and assuming no psychiatric symptoms emerge during the trial, would be rated as "no change" on the CGI-I at follow-up visits). For those participants with a psychiatric diagnosis, the clinician should rate the severity of the mental illness with respect to the clinician's experience with the psychiatric population to which the participant belongs.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=2016 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=2006 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2022 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2014 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 1 (N= 1986, 1974, 1986, 1982)	94.2 percentage of participants	93.2 percentage of participants	94.6 percentage of participants	95.1 percentage of participants
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 2 (N= 1934, 1936, 1927, 1926)	90.8 percentage of participants	90.8 percentage of participants	90.5 percentage of participants	91.2 percentage of participants
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 3 (N= 1880, 1892, 1880, 1863)	88.3 percentage of participants	89.8 percentage of participants	88.7 percentage of participants	87.9 percentage of participants
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 4 (N= 1860, 1856, 1858, 1834)	86.6 percentage of participants	88.0 percentage of participants	87.1 percentage of participants	86.3 percentage of participants
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 5 (N= 1828, 1816, 1822, 1802)	85.7 percentage of participants	86.5 percentage of participants	85.5 percentage of participants	85.4 percentage of participants
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 6 (N= 1816, 1808, 1820, 1773)	85.2 percentage of participants	86.5 percentage of participants	85.1 percentage of participants	84.1 percentage of participants
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 8 (N= 1758, 1756, 1755, 1738)	82.4 percentage of participants	83.6 percentage of participants	82.8 percentage of participants	81.9 percentage of participants
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 10 (N= 1717, 1707, 1715, 1675)	80.6 percentage of participants	81.7 percentage of participants	80.4 percentage of participants	79.2 percentage of participants
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 12 (N= 1558, 1572, 1540, 1492)	72.9 percentage of participants	75.1 percentage of participants	72.2 percentage of participants	71.3 percentage of participants
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 13 (N= 1612, 16081602, 1575)	75.9 percentage of participants	76.7 percentage of participants	75.2 percentage of participants	74.9 percentage of participants
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 16 (N= 1586, 1606, 1568, 1541)	74.2 percentage of participants	76.7 percentage of participants	73.9 percentage of participants	73.4 percentage of participants
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 20 (N= 1563, 1573, 1523, 1510)	73.4 percentage of participants	75.0 percentage of participants	72.2 percentage of participants	71.7 percentage of participants
Clinical Global Impression of Improvement (CGI-I), "No Change" Rating by Visit Week 24 (N= 1533, 1515, 1499, 1497)	71.8 percentage of participants	72.3 percentage of participants	71.1 percentage of participants	71.1 percentage of participants

SECONDARY outcome

Timeframe: Week 9 through Week 12

Population: The full analysis set was defined under the intent-to-treat (ITT) principle as all randomized participants (N=8144) and was used for all efficacy endpoints.

A responder to this endpoint requires the answer "no" to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 12 (inclusive).

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=1005 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=1001 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1013 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=1009 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
CO-Confirmed Continuous Abstinence for Weeks 9 Through 12, Non-psychiatric History Cohort	38.0 percentage of participants	26.1 percentage of participants	26.4 percentage of participants	13.7 percentage of participants

SECONDARY outcome

Timeframe: Week 9 through Week 12

Population: The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.

A responder to this endpoint requires the answer "no" to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 12 (inclusive).

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=1032 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=1033 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1025 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=1026 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
CO-Confirmed Continuous Abstinence for Weeks 9 Through 12, Psychiatric History Cohort	29.2 percentage of participants	19.3 percentage of participants	20.4 percentage of participants	11.4 percentage of participants

SECONDARY outcome

Timeframe: Week 9 through Week 12

Population: The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.

A responder to this endpoint requires the answer "no" to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 12 (inclusive).

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=2037 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=2034 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2038 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2035 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
CO-Confirmed Continuous Abstinence for Weeks 9 Through 12 (Overall)	33.5 percentage of participants	22.6 percentage of participants	23.4 percentage of participants	12.5 percentage of participants

SECONDARY outcome

Timeframe: Week 9 through Week 24

Population: The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.

A responder to this endpoint requires the answer "no" to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 24 (inclusive).

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=1005 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=1001 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1013 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=1009 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
CO-confirmed Continuous Abstinence From Week 9 Through Week 24, Non-psychiatric History Cohort	25.5 percentage of participants	18.8 percentage of participants	18.5 percentage of participants	10.5 percentage of participants

SECONDARY outcome

Timeframe: Week 9 through Week 24

Population: The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.

A responder to this endpoint requires the answer "no" to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 24 (inclusive).

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=1032 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=1033 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1025 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=1026 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
CO-confirmed Continuous Abstinence From Week 9 Through Week 24, Psychiatric History Cohort	18.3 percentage of participants	13.7 percentage of participants	13.0 percentage of participants	8.3 percentage of participants

SECONDARY outcome

Timeframe: Week 9 through Week 24

Population: The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.

A responder to this endpoint requires the answer "no" to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 24 (inclusive).

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=2037 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=2034 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2038 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2035 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
CO-confirmed Continuous Abstinence From Week 9 Through Week 24 (Overall)	21.8 percentage of participants	16.2 percentage of participants	15.7 percentage of participants	9.4 percentage of participants

SECONDARY outcome

Timeframe: 24 Weeks

Population: The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.

A responder to this endpoint requires the answer "no" to both questions 3 and 6 on the nicotine use inventory at that specific visit. NUI Question 3 (Baseline through Week 24): Has the subject smoked any cigarettes (even a puff) in the last 7 days? NUI Question 6 (Baseline through Week 12): Has the subject used any other nicotine containing products in the last 7 days? NUI Question 6 (Week 13 through Week 24): Has the subject used any other tobacco products in the last 7 days?

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=1005 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=1001 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1013 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=1009 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 1	1.7 percentage of participants	1.0 percentage of participants	1.2 percentage of participants	1.5 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 2	20.9 percentage of participants	21.3 percentage of participants	15.5 percentage of participants	11.4 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 3	30.0 percentage of participants	26.6 percentage of participants	22.1 percentage of participants	13.6 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 4	34.3 percentage of participants	27.7 percentage of participants	25.9 percentage of participants	14.5 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 5	38.4 percentage of participants	29.8 percentage of participants	27.8 percentage of participants	14.9 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 6	41.0 percentage of participants	31.4 percentage of participants	30.4 percentage of participants	15.9 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 7	44.4 percentage of participants	35.2 percentage of participants	35.1 percentage of participants	19.2 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 8	42.3 percentage of participants	31.0 percentage of participants	31.4 percentage of participants	16.7 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 9	47.1 percentage of participants	34.9 percentage of participants	34.8 percentage of participants	19.0 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 10	42.4 percentage of participants	31.0 percentage of participants	31.1 percentage of participants	16.9 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 11	46.6 percentage of participants	34.1 percentage of participants	34.9 percentage of participants	20.8 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 12	44.4 percentage of participants	30.5 percentage of participants	30.4 percentage of participants	17.8 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 13	41.1 percentage of participants	30.7 percentage of participants	29.9 percentage of participants	17.2 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 14	44.5 percentage of participants	33.5 percentage of participants	32.0 percentage of participants	20.4 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 15	43.8 percentage of participants	33.2 percentage of participants	32.4 percentage of participants	21.3 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 16	37.2 percentage of participants	28.5 percentage of participants	28.1 percentage of participants	18.2 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 17	40.7 percentage of participants	31.9 percentage of participants	31.4 percentage of participants	20.1 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 18	40.9 percentage of participants	31.3 percentage of participants	31.7 percentage of participants	20.8 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 19	39.9 percentage of participants	31.2 percentage of participants	31.2 percentage of participants	20.8 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 20	35.1 percentage of participants	27.5 percentage of participants	26.3 percentage of participants	18.2 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 21	38.1 percentage of participants	30.3 percentage of participants	29.3 percentage of participants	20.1 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 22	38.7 percentage of participants	29.9 percentage of participants	29.0 percentage of participants	20.3 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 23	37.6 percentage of participants	30.6 percentage of participants	28.3 percentage of participants	20.3 percentage of participants
7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort Week 24	33.6 percentage of participants	26.0 percentage of participants	27.0 percentage of participants	17.4 percentage of participants

SECONDARY outcome

Timeframe: 24 Weeks

Population: The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=1032 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=1033 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=1025 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=1026 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 1	1.0 percentage of participants	1.2 percentage of participants	0.7 percentage of participants	0.5 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 2	16.8 percentage of participants	14.6 percentage of participants	13.0 percentage of participants	9.2 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 3	22.7 percentage of participants	18.1 percentage of participants	17.9 percentage of participants	10.7 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 4	26.6 percentage of participants	21.3 percentage of participants	21.1 percentage of participants	11.8 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 5	28.5 percentage of participants	21.8 percentage of participants	22.4 percentage of participants	12.4 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 6	30.8 percentage of participants	22.7 percentage of participants	23.3 percentage of participants	13.4 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 7	34.8 percentage of participants	25.4 percentage of participants	27.5 percentage of participants	16.6 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 8	32.7 percentage of participants	22.1 percentage of participants	24.6 percentage of participants	15.0 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 9	36.2 percentage of participants	26.0 percentage of participants	29.4 percentage of participants	17.2 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 10	35.1 percentage of participants	24.3 percentage of participants	25.0 percentage of participants	14.0 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 11	38.6 percentage of participants	27.4 percentage of participants	29.4 percentage of participants	17.2 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 12	35.0 percentage of participants	23.9 percentage of participants	24.9 percentage of participants	14.2 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 13	32.7 percentage of participants	22.6 percentage of participants	24.0 percentage of participants	14.8 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 14	34.7 percentage of participants	25.0 percentage of participants	26.8 percentage of participants	17.8 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 15	33.4 percentage of participants	25.3 percentage of participants	26.0 percentage of participants	18.3 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 16	29.1 percentage of participants	21.9 percentage of participants	21.8 percentage of participants	13.9 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 17	32.3 percentage of participants	24.0 percentage of participants	24.8 percentage of participants	17.4 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 18	31.7 percentage of participants	24.5 percentage of participants	24.7 percentage of participants	18.2 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 19	31.6 percentage of participants	24.7 percentage of participants	25.1 percentage of participants	17.6 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 20	26.6 percentage of participants	20.4 percentage of participants	25.1 percentage of participants	17.6 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 21	29.7 percentage of participants	23.2 percentage of participants	23.7 percentage of participants	17.5 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 22	29.1 percentage of participants	22.9 percentage of participants	23.6 percentage of participants	16.5 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 23	28.5 percentage of participants	23.5 percentage of participants	22.2 percentage of participants	16.4 percentage of participants
7-Day Point Prevalence of Abstinence, Psychiatric History Cohort Week 24	26.1 percentage of participants	20.4 percentage of participants	20.1 percentage of participants	14.0 percentage of participants

SECONDARY outcome

Timeframe: 24 Weeks

Population: The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.

Outcome measures

Outcome measures
Measure	Varenicline 1.0 mg BID n=2037 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion 150 mg BID n=2034 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2038 Participants Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2035 Participants Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
7-Day Point Prevalence of Abstinence (Overall) Week 13	36.8 percentage of participants	26.5 percentage of participants	26.9 percentage of participants	16.0 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 1	1.3 percentage of participants	1.1 percentage of participants	0.9 percentage of participants	1.0 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 2	18.8 percentage of participants	17.9 percentage of participants	14.2 percentage of participants	10.3 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 3	26.3 percentage of participants	22.3 percentage of participants	20.0 percentage of participants	12.1 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 4	30.4 percentage of participants	24.4 percentage of participants	23.5 percentage of participants	13.1 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 5	33.4 percentage of participants	25.7 percentage of participants	25.1 percentage of participants	13.6 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 6	35.8 percentage of participants	26.9 percentage of participants	26.8 percentage of participants	14.6 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 7	39.5 percentage of participants	30.2 percentage of participants	31.3 percentage of participants	17.9 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 8	37.4 percentage of participants	26.5 percentage of participants	28.0 percentage of participants	15.9 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 9	41.6 percentage of participants	30.4 percentage of participants	32.1 percentage of participants	18.1 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 10	38.7 percentage of participants	27.6 percentage of participants	28.0 percentage of participants	15.5 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 11	42.5 percentage of participants	30.7 percentage of participants	32.1 percentage of participants	18.8 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 12	39.6 percentage of participants	27.1 percentage of participants	27.6 percentage of participants	16.0 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 14	39.5 percentage of participants	29.2 percentage of participants	29.4 percentage of participants	19.1 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 15	38.5 percentage of participants	29.2 percentage of participants	29.2 percentage of participants	19.8 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 16	33.1 percentage of participants	25.1 percentage of participants	24.9 percentage of participants	16.1 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 17	36.4 percentage of participants	27.9 percentage of participants	28.1 percentage of participants	18.8 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 18	36.2 percentage of participants	27.8 percentage of participants	28.2 percentage of participants	19.5 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 19	35.7 percentage of participants	27.9 percentage of participants	28.1 percentage of participants	19.2 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 20	30.8 percentage of participants	23.9 percentage of participants	23.7 percentage of participants	16.3 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 21	33.9 percentage of participants	26.7 percentage of participants	26.5 percentage of participants	18.8 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 22	33.8 percentage of participants	26.4 percentage of participants	26.3 percentage of participants	18.4 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 23	33.0 percentage of participants	27.0 percentage of participants	25.3 percentage of participants	18.3 percentage of participants
7-Day Point Prevalence of Abstinence (Overall) Week 24	29.8 percentage of participants	23.2 percentage of participants	23.6 percentage of participants	15.7 percentage of participants

Adverse Events

Varenicline 1.0 mg BID

Serious events: 39 serious events

Other events: 1158 other events

Deaths: 0 deaths

Bupropion

Serious events: 48 serious events

Other events: 1033 other events

Deaths: 0 deaths

NRT Patch

Serious events: 45 serious events

Other events: 1003 other events

Deaths: 0 deaths

Placebo

Serious events: 41 serious events

Other events: 884 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Varenicline 1.0 mg BID n=2016 participants at risk Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.	Bupropion n=2006 participants at risk Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.	NRT Patch n=2022 participants at risk Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.	Placebo n=2014 participants at risk Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
Gastrointestinal disorders Dry mouth	3.3% 66/2016 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	7.3% 146/2006 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	2.9% 59/2022 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	3.2% 64/2014 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.
Gastrointestinal disorders Nausea	25.3% 511/2016 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	10.0% 201/2006 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	9.8% 199/2022 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	6.8% 137/2014 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.
General disorders Application site pruritus	1.1% 22/2016 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	0.60% 12/2006 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	5.4% 109/2022 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	0.79% 16/2014 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.
General disorders Fatigue	6.2% 124/2016 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	2.8% 57/2006 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	3.7% 75/2022 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	4.1% 83/2014 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.
Infections and infestations Nasopharyngitis	8.6% 174/2016 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	7.8% 156/2006 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	6.2% 126/2022 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	6.7% 135/2014 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.
Infections and infestations Upper respiratory tract infection	5.4% 109/2016 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	5.2% 104/2006 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	4.8% 97/2022 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	5.7% 115/2014 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.
Nervous system disorders Headache	12.2% 245/2016 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	9.3% 186/2006 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	11.5% 233/2022 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	9.9% 199/2014 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.
Psychiatric disorders Abnormal dreams	10.0% 201/2016 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	6.5% 131/2006 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	12.4% 251/2022 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	4.6% 92/2014 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.
Psychiatric disorders Anxiety	6.5% 132/2016 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	8.4% 169/2006 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	6.8% 137/2022 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	6.0% 120/2014 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.
Psychiatric disorders Insomnia	9.4% 189/2016 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	12.2% 245/2006 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	9.6% 195/2022 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	6.9% 139/2014 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.
Psychiatric disorders Irritability	4.1% 82/2016 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	3.5% 71/2006 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	5.3% 108/2022 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.	5.2% 104/2014 • From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days. AEs were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview.

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Sponsor has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study participating sites. Investigator may not disclose previously undisclosed confidential other than study results.
Publication restrictions are in place

Restriction type: OTHER