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

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ClinicalTrials.gov Identifier: NCT01456936
Recruitment Status : Completed
First Posted : October 21, 2011
Results First Posted : May 2, 2016
Last Update Posted : June 10, 2016
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Smoking Cessation
Interventions Drug: Placebo
Drug: varenicline tartrate
Drug: bupropion hydrochloride
Drug: Nicotine Replacement Therapy Patch
Enrollment 8144
Recruitment Details 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).
Pre-assignment Details 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.
Arm/Group Title Varenicline Bupropion NRT Patch Placebo
Hide Arm/Group Description 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. 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. 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. 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.
Period Title: Overall Study
Started 2037 2034 2038 2035
Randomized and Treated 2016 2006 2022 2014
Completed 1598 1586 1557 1552
Not Completed 439 448 481 483
Reason Not Completed
Other reason             41             30             36             33
No longer meets eligibility criteria             4             8             6             5
Protocol Violation             4             2             5             5
Pregnancy             1             0             0             1
Insufficient clinical response             4             4             14             13
No longer willing to participate             195             218             224             248
Lost to Follow-up             135             126             144             127
Medication error             0             1             0             1
Adverse event (study drug)             25             21             26             17
Adverse event (study drug unrelated)             9             7             9             9
Death             0             3             1             3
Randomized but not treated             21             28             16             21
Arm/Group Title Varenicline 1.0 mg BID Bupropion NRT Patch Placebo Total
Hide Arm/Group Description 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. 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. 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. 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 of all reporting groups
Overall Number of Baseline Participants 2016 2006 2022 2014 8058
Hide Baseline Analysis Population Description
The safety analysis population contained all treated participants i.e. who received at least one partial dose of study medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 2016 participants 2006 participants 2022 participants 2014 participants 8058 participants
46.5  (12.4) 46.3  (12.6) 46.8  (12.2) 46.4  (12.2) 46.5  (12.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2016 participants 2006 participants 2022 participants 2014 participants 8058 participants
Female
1114
  55.3%
1116
  55.6%
1141
  56.4%
1138
  56.5%
4509
  56.0%
Male
902
  44.7%
890
  44.4%
881
  43.6%
876
  43.5%
3549
  44.0%
1.Primary Outcome
Title Occurrence of Neuropsychiatric (NPS) Adverse Events (AE) - the Primary Study Endpoint
Hide Description 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.
Time Frame Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 2016 2006 2022 2014
Measure Type: Number
Unit of Measure: percentage of participants
Non-psychiatric cohort (N= 990, 989, 1006, 999) 1.3 2.2 2.5 2.4
Psychiatric cohort (N= 1026, 1017, 1016, 1015) 6.5 6.7 5.2 4.9
Overall (N= 2016, 2006, 2022, 2014) 4.0 4.5 3.9 3.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Varenicline 1.0 mg BID, Bupropion 150 mg BID, NRT Patch, Placebo
Comments The reduced (final) statistical model included treatment group, cohort and region, plus the 2-way interaction of treatment by cohort. Other interactions not included due to lack of significance. Region reduced to 2-level to address event sparseness issue.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0652
Comments An interaction between treatment and cohort was considered significant at 10% level. No multiplicity adjustments were utilized.
Method Regression, Linear
Comments A generalized linear regression analysis based on the safety analysis set was used to evaluate incidence of NPS AE as the primary analysis.
2.Primary Outcome
Title Estimated NPS AE Rate (%), by Cohort
Hide Description 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. Estimated NPS AE rate (%) was calculated based on least-squares means analysis.
Time Frame Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 2016 2006 2022 2014
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percentage of participants
Non-psychiatric cohort (N=3984)
1.25
(0.60 to 1.90)
2.44
(1.52 to 3.36)
2.31
(1.37 to 3.25)
2.52
(1.58 to 3.46)
Psychiatric cohort (N= 4074)
6.42
(4.91 to 7.93)
6.62
(5.09 to 8.15)
5.20
(3.84 to 6.56)
4.83
(3.51 to 6.16)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Varenicline 1.0 mg BID, Placebo
Comments Non-psychiatric cohort
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -1.28
Confidence Interval (2-Sided) 95%
-2.40 to -0.15
Estimation Comments Risk difference for varenicline versus placebo from estimation model.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Bupropion 150 mg BID, Placebo
Comments Non-psychiatric cohort
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -0.08
Confidence Interval (2-Sided) 95%
-1.37 to 1.21
Estimation Comments Risk difference for bupropion 150 mg BID versus placebo from estimation model.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection NRT Patch, Placebo
Comments Non-psychiatric cohort
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -0.21
Confidence Interval (2-Sided) 95%
-1.54 to 1.12
Estimation Comments Risk difference for NRT versus placebo from estimation model.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Varenicline 1.0 mg BID, Placebo
Comments Psychiatric cohort
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 1.59
Confidence Interval (2-Sided) 95%
-0.42 to 3.59
Estimation Comments Risk difference for varenicline versus placebo from estimation model
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Bupropion 150 mg BID, Placebo
Comments Psychiatric cohort
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 1.78
Confidence Interval (2-Sided) 95%
-0.24 to 3.81
Estimation Comments Risk difference for bupropion 150 mg BID versus placebo from estimation model.
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection NRT Patch, Placebo
Comments Psychiatric cohort
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.37
Confidence Interval (2-Sided) 95%
-1.53 to 2.26
Estimation Comments Risk difference for NRT versus placebo from estimation model.
3.Secondary Outcome
Title Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort
Hide Description 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.
Time Frame Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 990 989 1006 999
Measure Type: Number
Unit of Measure: participants
Anxiety (severe) 0 1 0 3
Depression (severe) 1 0 0 0
Feeling abnormal (severe only) 0 0 0 0
Hostility (severe) 0 1 1 0
Agitation (moderate and severe) 10 11 19 11
Aggression (moderate and severe) 3 3 2 3
Delusions (moderate and severe) 0 0 1 0
Hallucinations (moderate and severe) 1 0 0 0
Mania (moderate and severe) 0 1 2 2
Panic (moderate and severe) 0 4 1 3
Paranoia (moderate and severe) 0 1 0 0
Psychosis (moderate and severe) 0 0 1 0
Homicidal ideation (moderate and severe) 0 0 1 0
Suicidal behavior (moderate and severe) 0 1 1 0
Suicidal ideation (moderate and severe) 0 1 2 3
Suicide (moderate and severe) 0 0 0 1
4.Secondary Outcome
Title Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort
Hide Description 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.
Time Frame Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 1026 1017 1016 1015
Measure Type: Number
Unit of Measure: participants
Anxiety (severe) 5 4 6 2
Depression (severe) 6 4 7 6
Feeling abnormal (severe only) 0 1 0 0
Hostility (severe) 0 0 0 0
Agitation (moderate and severe) 25 29 21 22
Aggression (moderate and severe) 14 9 7 8
Delusions (moderate and severe) 1 1 1 0
Hallucinations (moderate and severe) 5 4 2 2
Mania (moderate and severe) 7 9 3 6
Panic (moderate and severe) 7 16 13 7
Paranoia (moderate and severe) 1 0 0 2
Psychosis (moderate and severe) 4 2 3 1
Homicidal ideation (moderate and severe) 0 0 0 0
Suicidal behavior (moderate and severe) 1 1 0 1
Suicidal ideation (moderate and severe) 5 2 3 2
Suicide (moderate and severe) 0 0 0 0
5.Secondary Outcome
Title Occurrence of the Components of NPS AE Primary Endpoint (Overall)
Hide Description The NPS AE composite results (as previously described) are for the two cohorts combined and are presented below.
Time Frame Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 2016 2006 2022 2014
Measure Type: Number
Unit of Measure: participants
Anxiety 5 5 6 5
Depression 7 4 7 6
Feeling Abnormal 0 1 0 0
Hostility 0 1 1 0
Agitation 35 40 40 33
Aggression 17 12 9 11
Delusions 1 1 2 0
Hallucination 6 4 2 2
Mania 7 10 5 8
Panic Disorder 7 20 14 10
Paranoia 1 1 0 2
Psychosis 4 2 4 1
Homicidal Ideation 0 0 1 0
Suicidal Behavior 1 2 1 1
Suicidal Ideation 5 3 5 5
Suicide 0 0 0 1
6.Secondary Outcome
Title Occurrence of Severe-only NPS AEs in the Primary Endpoint, by Cohort
Hide Description 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. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint.
Time Frame Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 2016 2006 2022 2014
Measure Type: Number
Unit of Measure: percentage of participants
Non-psychiatric cohort (N= 990, 989, 1006, 999) 0.1 0.4 0.3 0.5
Psychiatric cohort (N= 1026, 1017, 1016, 1015) 1.4 1.4 1.4 1.3
Overall (N= 2016, 2006, 2022, 2014) 0.7 0.9 0.8 0.9
7.Secondary Outcome
Title Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort
Hide Description 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. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint.
Time Frame Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 990 989 1006 999
Measure Type: Number
Unit of Measure: participants
Anxiety 0 1 0 3
Depression 1 0 0 0
Feeling abnormal 0 0 0 0
Hostility 0 1 1 0
Agitation 0 0 2 0
Aggression 1 1 0 0
Delusions 0 0 0 0
Hallucinations 0 0 0 0
Mania 0 0 0 0
Panic 0 1 1 1
Paranoia 0 0 0 0
Psychosis 0 0 0 0
Homicidal ideation 0 0 0 0
Suicidal behavior 0 1 0 0
Suicidal ideation 0 0 0 1
Suicide 0 0 0 1
8.Secondary Outcome
Title Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort
Hide Description 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. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint.
Time Frame Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 1026 1017 1016 1015
Measure Type: Number
Unit of Measure: participants
Anxiety 5 4 6 2
Depression 6 4 7 6
Feeling abnormal 0 1 0 0
Hostility 0 0 0 0
Agitation 1 1 4 2
Aggression 1 1 0 1
Delusions 0 0 0 0
Hallucinations 0 1 0 0
Mania 2 1 0 0
Panic 0 1 0 1
Paranoia 0 0 0 0
Psychosis 0 1 1 0
Homicidal ideation 0 0 0 0
Suicidal behavior 1 1 0 1
Suicidal ideation 1 0 1 0
Suicide 0 0 0 0
9.Secondary Outcome
Title Occurrence of the Components of Severe-only NPS AE Endpoint (Overall)
Hide Description 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.
Time Frame Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 2016 2006 2022 2014
Measure Type: Number
Unit of Measure: participants
Anxiety 5 5 6 5
Depression 7 4 7 6
Feeling Abnormal 0 1 0 0
Hostility 0 1 1 0
Agitation 1 1 6 2
Aggression 2 2 0 1
Delusions 0 0 0 0
Hallucination 0 1 0 0
Mania 2 1 0 0
Panic Disorder 0 2 1 2
Paranoia 1 1 0 2
Psychosis 4 2 4 1
Suicidal Behavior 1 2 0 1
Suicidal Ideation 1 0 1 0
Suicide 0 0 0 1
Homicidal Ideation 0 0 1 0
10.Secondary Outcome
Title Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort
Hide Description 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.
Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 990 989 1006 999
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Week 1 (N= 984, 972, 989, 992) 3.26  (3.92) 3.58  (4.25) 3.06  (3.87) 3.38  (4.20)
Week 2 (N= 961, 954, 963, 970) 2.91  (3.86) 3.07  (3.96) 2.84  (3.85) 3.20  (4.25)
Week 3 (N= 935, 930, 936, 941) 2.61  (3.85) 2.64  (3.82) 2.63  (3.93) 2.77  (3.94)
Week 4 (N= 923, 916, 934, 923) 2.40  (3.66) 2.36  (3.57) 2.46  (3.80) 2.77  (4.21)
Week 5 (N= 911, 897, 906, 902) 2.29  (3.51) 2.24  (3.52) 2.32  (3.86) 2.48  (3.92)
Week 6 (N= 899, 893, 909, 897) 2.23  (3.56) 2.18  (3.57) 2.40  (3.87) 2.48  (3.97)
Week 8 (N= 868, 861, 877, 877) 2.17  (3.60) 2.16  (3.70) 2.28  (3.60) 2.64  (4.29)
Week 10 (N= 853, 844, 852, 846) 2.29  (3.89) 1.96  (3.24) 2.33  (3.80) 2.57  (4.41)
Week 12 (N= 772, 768, 750, 742) 2.07  (3.48) 1.83  (3.21) 2.01  (3.51) 2.46  (4.10)
Week 13 (N= 797, 796, 789, 807) 2.11  (3.74) 1.85  (3.22) 2.01  (3.47) 2.38  (4.27)
Week 16 (N= 784, 797, 775, 789) 2.05  (3.47) 1.90  (3.43) 2.09  (3.61) 2.34  (3.98)
Week 20 (N= 771, 785, 762, 772) 2.10  (3.54) 1.93  (3.36) 1.97  (3.53) 2.31  (4.15)
Week 24 (N= 758, 748, 737, 758) 2.01  (3.49) 1.87  (3.47) 2.01  (3.45) 2.25  (4.04)
11.Secondary Outcome
Title HADS Total Score, Psychiatric History Cohort
Hide Description 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.
Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 1026 1017 1016 1015
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Week 1 (N= 1026, 1017, 1015, 1015) 6.76  (6.14) 7.58  (6.87) 6.82  (6.33) 6.70  (5.94)
Week 2 (N= 1005, 1004, 996, 995) 6.42  (6.36) 6.99  (6.47) 6.64  (6.55) 6.42  (6.17)
Week 3 (N= 947, 961, 945, 926) 5.99  (6.21) 6.51  (6.39) 6.30  (6.55) 6.02  (6.10)
Week 4 (N= 935, 938, 929, 908) 5.87  (6.39) 6.36  (6.55) 6.16  (6.51) 6.04  (6.31)
Week 5 (N= 918, 918, 914, 895) 5.58  (6.32) 6.03  (6.41) 5.82  (6.44) 5.80  (6.31)
Week 6 (N= 917, 914, 912, 874) 5.39  (6.14) 5.87  (6.41) 5.62  (6.22) 5.75  (6.26)
Week 8 (N= 887, 893, 878, 859) 5.43  (6.24) 5.96  (6.68) 5.63  (6.36) 5.63  (6.26)
Week 10 (N= 864, 865, 864, 823) 5.38  (6.35) 5.72  (6.50) 5.64  (6.30) 5.55  (6.38)
Week 12 (N= 790, 803, 798, 749) 5.17  (6.09) 5.66  (6.63) 5.44  (6.30) 5.42  (6.13)
Week 13 (N= 813, 812, 814, 763) 5.06  (6.11) 5.44  (6.54) 5.36  (6.20) 5.09  (5.96)
Week 16 (N= 795, 805, 791, 748) 5.26  (6.35) 5.62  (6.68) 5.44  (6.34) 5.37  (6.38)
Week 20 (N= 784, 784, 763, 737) 5.17  (6.02) 5.54  (6.44) 5.46  (6.18) 5.26  (6.22)
Week 24 (N= 770, 764, 758, 729) 5.21  (6.27) 5.69  (6.64) 5.57  (6.32) 5.04  (5.97)
12.Secondary Outcome
Title HADS Total Score (Overall)
Hide Description 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.
Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 2016 2006 2021 2014
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Week 1 (N= 1989, 1976, 1985, 1987) 5.03  (5.45) 5.61  (6.07) 4.95  (5.58) 5.05  (5.41)
Week 2 (N= 1938, 1937, 1931, 1929) 4.68  (5.55) 5.06  (5.73) 4.74  (5.70) 4.80  (5.53)
Week 3 (N= 1882, 1891, 1881, 1867) 4.31  (5.44) 4.60  (5.63) 4.48  (5.71) 4.38  (5.37)
Week 4 (N= 1858, 1854, 1863, 1831) 4.15  (5.50) 4.39  (5.65) 4.31  (5.64) 4.39  (5.60)
Week 5 (N= 1829, 1815, 1820, 1797) 3.94  (5.37) 4.16  (5.52) 4.08  (5.59) 4.14  (5.51)
Week 6 (N= 1816, 1807, 1821, 1771) 3.82  (5.27) 4.05  (5.52) 4.01  (5.42) 4.09  (5.48)
Week 8 (N= 1755, 1754, 1755, 1736) 3.82  (5.36) 4.10  (5.75) 3.96  (5.43) 4.12  (5.56)
Week 10 (N= 1717, 1709, 1716, 1669) 3.85  (5.49) 3.86  (5.48) 4.00  (5.47) 4.04  (5.67)
Week 12 (N= 1562, 1571, 1548, 1491) 3.64  (5.21) 3.79  (5.58) 3.78  (5.42) 3.95  (5.42)
Week 13 (N= 1610, 1608, 1603, 1570) 3.60  (5.29) 3.66  (5.47) 3.71  (5.32) 3.70  (5.34)
Week 16 (N= 1579, 1602, 1566, 1537) 3.67  (5.37) 3.77  (5.63) 3.78  (5.44) 3.82  (5.50)
Week 20 (N= 1555, 1569, 1525, 1509) 3.65  (5.18) 3.73  (5.44) 3.72  (5.33) 3.75  (5.47)
Week 24 (N= 1528, 1512, 1495, 1487) 3.62  (5.33) 3.80  (5.64) 3.82  (5.41) 3.62  (5.27)
13.Secondary Outcome
Title Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C‑SSRS) - Non-psychiatric History Cohort
Hide Description 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.
Time Frame Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 990 989 1006 999
Measure Type: Number
Unit of Measure: participants with positive responses
Suicidal Behavior (Screening lifetime) 6 9 7 6
Suicidal Ideation (Screening lifetime) 48 43 50 49
Suicidal Behavior (Baseline) 0 0 0 0
Suicidal Ideation (Baseline) 0 1 0 1
Suicidal Behavior (treatment emergent 12 weeks) 0 0 1 1
Suicidal Ideation (treatment emergent 12 weeks) 7 4 3 6
14.Secondary Outcome
Title Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C‑SSRS) - Psychiatric History Cohort
Hide Description 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.
Time Frame Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 1026 1017 1016 1015
Measure Type: Number
Unit of Measure: participants with positive responses
Suicidal Behavior (Screening lifetime) 137 143 111 123
Suicidal Ideation (Screening lifetime) 338 357 333 349
Suicidal Behavior (Baseline) 0 0 0 1
Suicidal Ideation (Baseline) 6 5 2 3
Suicidal Behavior (treatment emergent 12 weeks) 0 1 0 2
Suicidal Ideation (treatment emergent 12 weeks) 27 15 20 25
15.Secondary Outcome
Title Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C‑SSRS) - Overall
Hide Description 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.
Time Frame Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 2016 2006 2022 2014
Measure Type: Number
Unit of Measure: participants with positive responses
Suicidal Behavior (Screening lifetime) 143 152 118 129
Suicidal Ideation (Screening lifetime) 386 400 383 398
Suicidal Behavior (Baseline) 0 0 0 1
Suicidal Ideation (Baseline) 6 6 2 4
Suicidal Behavior (treatment emergent 12 weeks) 0 1 1 3
Suicidal Ideation (treatment emergent 12 weeks) 34 19 23 31
16.Secondary Outcome
Title Clinical Global Impression of Improvement (CGI‑I), "No Change" Rating by Visit
Hide Description 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.
Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 2016 2006 2022 2014
Measure Type: Number
Unit of Measure: percentage of participants
Week 1 (N= 1986, 1974, 1986, 1982) 94.2 93.2 94.6 95.1
Week 2 (N= 1934, 1936, 1927, 1926) 90.8 90.8 90.5 91.2
Week 3 (N= 1880, 1892, 1880, 1863) 88.3 89.8 88.7 87.9
Week 4 (N= 1860, 1856, 1858, 1834) 86.6 88.0 87.1 86.3
Week 5 (N= 1828, 1816, 1822, 1802) 85.7 86.5 85.5 85.4
Week 6 (N= 1816, 1808, 1820, 1773) 85.2 86.5 85.1 84.1
Week 8 (N= 1758, 1756, 1755, 1738) 82.4 83.6 82.8 81.9
Week 10 (N= 1717, 1707, 1715, 1675) 80.6 81.7 80.4 79.2
Week 12 (N= 1558, 1572, 1540, 1492) 72.9 75.1 72.2 71.3
Week 13 (N= 1612, 16081602, 1575) 75.9 76.7 75.2 74.9
Week 16 (N= 1586, 1606, 1568, 1541) 74.2 76.7 73.9 73.4
Week 20 (N= 1563, 1573, 1523, 1510) 73.4 75.0 72.2 71.7
Week 24 (N= 1533, 1515, 1499, 1497) 71.8 72.3 71.1 71.1
17.Secondary Outcome
Title CO‑Confirmed Continuous Abstinence for Weeks 9 Through 12, Non-psychiatric History Cohort
Hide Description 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).
Time Frame Week 9 through Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 1005 1001 1013 1009
Measure Type: Number
Unit of Measure: percentage of participants
38.0 26.1 26.4 13.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Varenicline 1.0 mg BID, Placebo
Comments The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.00
Confidence Interval (2-Sided) 95%
3.20 to 5.00
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Bupropion 150 mg BID, Placebo
Comments The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.26
Confidence Interval (2-Sided) 95%
1.80 to 2.85
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection NRT Patch, Placebo
Comments The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.30
Confidence Interval (2-Sided) 95%
1.83 to 2.90
Estimation Comments [Not Specified]
18.Secondary Outcome
Title CO‑Confirmed Continuous Abstinence for Weeks 9 Through 12, Psychiatric History Cohort
Hide Description 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).
Time Frame Week 9 through Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 1032 1033 1025 1026
Measure Type: Number
Unit of Measure: percentage of participants
29.2 19.3 20.4 11.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Varenicline 1.0 mg BID, Placebo
Comments The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.24
Confidence Interval (2-Sided) 95%
2.56 to 4.11
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Bupropion 150 mg BID, Placebo
Comments The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.87
Confidence Interval (2-Sided) 95%
1.46 to 2.39
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection NRT Patch, Placebo
Comments The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.00
Confidence Interval (2-Sided) 95%
1.56 to 2.55
Estimation Comments [Not Specified]
19.Secondary Outcome
Title CO‑Confirmed Continuous Abstinence for Weeks 9 Through 12 (Overall)
Hide Description 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).
Time Frame Week 9 through Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 2037 2034 2038 2035
Measure Type: Number
Unit of Measure: percentage of participants
33.5 22.6 23.4 12.5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Varenicline 1.0 mg BID, Placebo
Comments The analysis was done using a logistic regression with terms treatment and region. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.61
Confidence Interval (2-Sided) 95%
3.07 to 4.24
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Bupropion 150 mg BID, Placebo
Comments The analysis was done using a logistic regression with terms treatment and region. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.07
Confidence Interval (2-Sided) 95%
1.75 to 2.45
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection NRT Patch, Placebo
Comments The analysis was done using a logistic regression with terms treatment and region. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.15
Confidence Interval (2-Sided) 95%
1.82 to 2.54
Estimation Comments [Not Specified]
20.Secondary Outcome
Title CO-confirmed Continuous Abstinence From Week 9 Through Week 24, Non-psychiatric History Cohort
Hide Description 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).
Time Frame Week 9 through Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 1005 1001 1013 1009
Measure Type: Number
Unit of Measure: percentage of participants
25.5 18.8 18.5 10.5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Varenicline 1.0 mg BID, Placebo
Comments The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.99
Confidence Interval (2-Sided) 95%
2.33 to 3.83
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Bupropion 150 mg BID, Placebo
Comments The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.00
Confidence Interval (2-Sided) 95%
1.54 to 2.59
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection NRT Patch, Placebo
Comments The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.96
Confidence Interval (2-Sided) 95%
1.51 to 2.54
Estimation Comments [Not Specified]
21.Secondary Outcome
Title CO-confirmed Continuous Abstinence From Week 9 Through Week 24, Psychiatric History Cohort
Hide Description 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).
Time Frame Week 9 through Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 1032 1033 1025 1026
Measure Type: Number
Unit of Measure: percentage of participants
18.3 13.7 13.0 8.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Varenicline 1.0 mg BID, Placebo
Comments The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.50
Confidence Interval (2-Sided) 95%
1.90 to 3.29
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Bupropion 150 mg BID, Placebo
Comments The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.77
Confidence Interval (2-Sided) 95%
1.33 to 2.36
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection NRT Patch, Placebo
Comments The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.65
Confidence Interval (2-Sided) 95%
1.24 to 2.20
Estimation Comments [Not Specified]
22.Secondary Outcome
Title CO-confirmed Continuous Abstinence From Week 9 Through Week 24 (Overall)
Hide Description 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).
Time Frame Week 9 through Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 2037 2034 2038 2035
Measure Type: Number
Unit of Measure: percentage of participants
21.8 16.2 15.7 9.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Varenicline 1.0 mg BID, Placebo
Comments The analysis was done using a logistic regression with terms treatment and region. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.74
Confidence Interval (2-Sided) 95%
2.28 to 3.30
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Bupropion 150 mg BID, Placebo
Comments The analysis was done using a logistic regression with terms treatment and region. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.89
Confidence Interval (2-Sided) 95%
1.56 to 2.29
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection NRT Patch, Placebo
Comments The analysis was done using a logistic regression with terms treatment and region. Region reduced to 2-level for consistency with primary safety model.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments No multiplicity adjustment.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.81
Confidence Interval (2-Sided) 95%
1.49 to 2.19
Estimation Comments [Not Specified]
23.Secondary Outcome
Title 7‑Day Point Prevalence of Abstinence, Non-psychiatric History Cohort
Hide Description

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?

Time Frame 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 1005 1001 1013 1009
Measure Type: Number
Unit of Measure: percentage of participants
Week 1 1.7 1.0 1.2 1.5
Week 2 20.9 21.3 15.5 11.4
Week 3 30.0 26.6 22.1 13.6
Week 4 34.3 27.7 25.9 14.5
Week 5 38.4 29.8 27.8 14.9
Week 6 41.0 31.4 30.4 15.9
Week 7 44.4 35.2 35.1 19.2
Week 8 42.3 31.0 31.4 16.7
Week 9 47.1 34.9 34.8 19.0
Week 10 42.4 31.0 31.1 16.9
Week 11 46.6 34.1 34.9 20.8
Week 12 44.4 30.5 30.4 17.8
Week 13 41.1 30.7 29.9 17.2
Week 14 44.5 33.5 32.0 20.4
Week 15 43.8 33.2 32.4 21.3
Week 16 37.2 28.5 28.1 18.2
Week 17 40.7 31.9 31.4 20.1
Week 18 40.9 31.3 31.7 20.8
Week 19 39.9 31.2 31.2 20.8
Week 20 35.1 27.5 26.3 18.2
Week 21 38.1 30.3 29.3 20.1
Week 22 38.7 29.9 29.0 20.3
Week 23 37.6 30.6 28.3 20.3
Week 24 33.6 26.0 27.0 17.4
24.Secondary Outcome
Title 7‑Day Point Prevalence of Abstinence, Psychiatric History Cohort
Hide Description

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?

Time Frame 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 1032 1033 1025 1026
Measure Type: Number
Unit of Measure: percentage of participants
Week 1 1.0 1.2 0.7 0.5
Week 2 16.8 14.6 13.0 9.2
Week 3 22.7 18.1 17.9 10.7
Week 4 26.6 21.3 21.1 11.8
Week 5 28.5 21.8 22.4 12.4
Week 6 30.8 22.7 23.3 13.4
Week 7 34.8 25.4 27.5 16.6
Week 8 32.7 22.1 24.6 15.0
Week 9 36.2 26.0 29.4 17.2
Week 10 35.1 24.3 25.0 14.0
Week 11 38.6 27.4 29.4 17.2
Week 12 35.0 23.9 24.9 14.2
Week 13 32.7 22.6 24.0 14.8
Week 14 34.7 25.0 26.8 17.8
Week 15 33.4 25.3 26.0 18.3
Week 16 29.1 21.9 21.8 13.9
Week 17 32.3 24.0 24.8 17.4
Week 18 31.7 24.5 24.7 18.2
Week 19 31.6 24.7 25.1 17.6
Week 20 26.6 20.4 25.1 17.6
Week 21 29.7 23.2 23.7 17.5
Week 22 29.1 22.9 23.6 16.5
Week 23 28.5 23.5 22.2 16.4
Week 24 26.1 20.4 20.1 14.0
25.Secondary Outcome
Title 7‑Day Point Prevalence of Abstinence (Overall)
Hide Description

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?

Time Frame 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set was defined under the ITT principle as all randomized participants (N=8144) and was used for all efficacy endpoints.
Arm/Group Title Varenicline 1.0 mg BID Bupropion 150 mg BID NRT Patch Placebo
Hide Arm/Group Description:
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.
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.
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.
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 Number of Participants Analyzed 2037 2034 2038 2035
Measure Type: Number
Unit of Measure: percentage of participants
Week 1 1.3 1.1 0.9 1.0
Week 2 18.8 17.9 14.2 10.3
Week 3 26.3 22.3 20.0 12.1
Week 4 30.4 24.4 23.5 13.1
Week 5 33.4 25.7 25.1 13.6
Week 6 35.8 26.9 26.8 14.6
Week 7 39.5 30.2 31.3 17.9
Week 8 37.4 26.5 28.0 15.9
Week 9 41.6 30.4 32.1 18.1
Week 10 38.7 27.6 28.0 15.5
Week 11 42.5 30.7 32.1 18.8
Week 12 39.6 27.1 27.6 16.0
Week 13 36.8 26.5 26.9 16.0
Week 14 39.5 29.2 29.4 19.1
Week 15 38.5 29.2 29.2 19.8
Week 16 33.1 25.1 24.9 16.1
Week 17 36.4 27.9 28.1 18.8
Week 18 36.2 27.8 28.2 19.5
Week 19 35.7 27.9 28.1 19.2
Week 20 30.8 23.9 23.7 16.3
Week 21 33.9 26.7 26.5 18.8
Week 22 33.8 26.4 26.3 18.4
Week 23 33.0 27.0 25.3 18.3
Week 24 29.8 23.2 23.6 15.7
Time Frame 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.
Adverse Event Reporting Description 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.
 
Arm/Group Title Varenicline 1.0 mg BID Bupropion NRT Patch Placebo
Hide Arm/Group Description 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. 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. 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. 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.
All-Cause Mortality
Varenicline 1.0 mg BID Bupropion NRT Patch Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Varenicline 1.0 mg BID Bupropion NRT Patch Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   39/2016 (1.93%)   48/2006 (2.39%)   45/2022 (2.23%)   41/2014 (2.04%) 
Cardiac disorders         
Acute myocardial infarction * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Atrial fibrillation * 1  0/2016 (0.00%)  1/2006 (0.05%)  4/2022 (0.20%)  0/2014 (0.00%) 
Cardiac failure * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Coronary artery disease * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Myocardial infarction * 1  1/2016 (0.05%)  0/2006 (0.00%)  1/2022 (0.05%)  1/2014 (0.05%) 
Acute coronary syndrome * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Angina unstable * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Arrhythmia * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Cardiac failure congestive * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  2/2014 (0.10%) 
Cardiovascular disorder * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Coronary artery occlusion * 1  2/2016 (0.10%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Palpitations * 1  1/2016 (0.05%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Endocrine disorders         
Thyrotoxic crisis * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Eye disorders         
Ulcerative keratitis * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Vitreous detachment * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Gastrointestinal disorders         
Colitis ulcerative * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Diverticulum * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Gastritis * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  1/2014 (0.05%) 
Small intestinal obstruction * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Abdominal pain upper * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Oesophagitis * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Pancreatitis * 1  0/2016 (0.00%)  0/2006 (0.00%)  2/2022 (0.10%)  0/2014 (0.00%) 
General disorders         
Chest pain * 1  1/2016 (0.05%)  0/2006 (0.00%)  4/2022 (0.20%)  2/2014 (0.10%) 
Hernia * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Non-cardiac chest pain * 1  0/2016 (0.00%)  2/2006 (0.10%)  1/2022 (0.05%)  1/2014 (0.05%) 
Pyrexia * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Hepatobiliary disorders         
Bile duct stone * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Cholecystitis acute * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Cholelithiasis * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Immune system disorders         
Drug hypersensitivity * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Infections and infestations         
Anal abscess * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Bronchitis * 1  0/2016 (0.00%)  1/2006 (0.05%)  1/2022 (0.05%)  1/2014 (0.05%) 
Pneumonia * 1  1/2016 (0.05%)  0/2006 (0.00%)  2/2022 (0.10%)  0/2014 (0.00%) 
Abscess * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Cellulitis * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Infective exacerbation of chronic obstructive airways disease * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Parotitis * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Post procedural infection * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Pyelonephritis * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Rectal abscess * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Tooth abscess * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Wound infection * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Campylobacter gastroenteritis * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Device related infection * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Diverticulitis * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Herpes zoster * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Oral herpes * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Injury, poisoning and procedural complications         
Alcohol poisoning * 1  1/2016 (0.05%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Ankle fracture * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Burns third degree * 1  1/2016 (0.05%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Fall * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Hip fracture * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Humerus fracture * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Laceration * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Lower limb fracture * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Road traffic accident * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Spinal fracture * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Overdose * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
skull fracture * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Foot fracture * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Hand fracture * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Joint dislocation * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Ligament rupture * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Lumbar vertebral fracture * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Investigations         
Electrocardiogram abnormal * 1  1/2016 (0.05%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Blood pressure increased * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Liver function test abnormal * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Metabolism and nutrition disorders         
Diabetes mellitus * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  2/2014 (0.10%) 
Hyperglycaemia * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Hyperkalaemia * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Hypokalaemia * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Hyponatraemia * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  1/2014 (0.05%) 
Type 2 diabetes mellitus * 1  2/2016 (0.10%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Musculoskeletal and connective tissue disorders         
Arthropathy * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Back pain * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Cervical spinal stenosis * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Fistula * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Intervertebral disc degeneration * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Intervertebral disc protrusion * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Pain in extremity * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Muscular weakness * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Bladder neoplasm * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Lobular breast carcinoma in situ * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Prostate cancer * 1  0/2016 (0.00%)  1/2006 (0.05%)  1/2022 (0.05%)  1/2014 (0.05%) 
Renal cell carcinoma * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Squamous cell carcinoma of lung * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Transitional cell carcinoma * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Uterine leiomyoma * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Adenocarcinoma of colon * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Breast cancer * 1  2/2016 (0.10%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Invasive ductal breast carcinoma * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Lung neoplasm malignant * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Oesophageal adenocarcinoma * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Nervous system disorders         
Migraine * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Syncope * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Dizziness * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Intracranial aneurysm * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Paraesthesia * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  1/2014 (0.05%) 
Seizure * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Pregnancy, puerperium and perinatal conditions         
Abortion missed * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Ectopic pregnancy * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Psychiatric disorders         
Alcohol abuse * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Depression * 1  1/2016 (0.05%)  1/2006 (0.05%)  1/2022 (0.05%)  0/2014 (0.00%) 
Panic attack * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Suicidal ideation * 1  2/2016 (0.10%)  1/2006 (0.05%)  0/2022 (0.00%)  3/2014 (0.15%) 
Suicide attempt * 1  0/2016 (0.00%)  2/2006 (0.10%)  1/2022 (0.05%)  1/2014 (0.05%) 
Aggression * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Alcohol withdrawal syndrome * 1  1/2016 (0.05%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Alcoholism * 1  0/2016 (0.00%)  3/2006 (0.15%)  1/2022 (0.05%)  0/2014 (0.00%) 
Anxiety * 1  0/2016 (0.00%)  0/2006 (0.00%)  2/2022 (0.10%)  0/2014 (0.00%) 
Anxiety disorder * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Bipolar I disorder * 1  1/2016 (0.05%)  2/2006 (0.10%)  0/2022 (0.00%)  0/2014 (0.00%) 
Bipolar II disorder * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Borderline personality disorder * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Completed suicide * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Emotional disorder * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Hallucination, auditory * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Intentional self-injury * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Mental disorder * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Schizoaffective disorder * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Sleep disorder * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Suicidal behaviour * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Reproductive system and breast disorders         
Bartholin’s cyst * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Menorrhagia * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  1/2014 (0.05%) 
Respiratory, thoracic and mediastinal disorders         
Asthma * 1  0/2016 (0.00%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Dyspnoea * 1  2/2016 (0.10%)  0/2006 (0.00%)  1/2022 (0.05%)  0/2014 (0.00%) 
Pulmonary embolism * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  2/2014 (0.10%) 
Rhinitis allergic * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Skin and subcutaneous tissue disorders         
Angioedema * 1  0/2016 (0.00%)  2/2006 (0.10%)  0/2022 (0.00%)  0/2014 (0.00%) 
Dermatitis atopic * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Psoriasis * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Surgical and medical procedures         
Female sterilisation * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Knee operation * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Therapy change * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Vascular disorders         
Orthostatic hypotension * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Peripheral artery stenosis * 1  0/2016 (0.00%)  0/2006 (0.00%)  2/2022 (0.10%)  0/2014 (0.00%) 
Aortic aneurysm * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Deep vein thrombosis * 1  0/2016 (0.00%)  0/2006 (0.00%)  0/2022 (0.00%)  1/2014 (0.05%) 
Haematoma * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Hypertension * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
Peripheral arterial occlusive disease * 1  0/2016 (0.00%)  1/2006 (0.05%)  0/2022 (0.00%)  0/2014 (0.00%) 
Vascular rupture * 1  1/2016 (0.05%)  0/2006 (0.00%)  0/2022 (0.00%)  0/2014 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (v18.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Varenicline 1.0 mg BID Bupropion NRT Patch Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1158/2016 (57.44%)   1033/2006 (51.50%)   1003/2022 (49.60%)   884/2014 (43.89%) 
Gastrointestinal disorders         
Dry mouth * 1  66/2016 (3.27%)  146/2006 (7.28%)  59/2022 (2.92%)  64/2014 (3.18%) 
Nausea * 1  511/2016 (25.35%)  201/2006 (10.02%)  199/2022 (9.84%)  137/2014 (6.80%) 
General disorders         
Application site pruritus * 1  22/2016 (1.09%)  12/2006 (0.60%)  109/2022 (5.39%)  16/2014 (0.79%) 
Fatigue * 1  124/2016 (6.15%)  57/2006 (2.84%)  75/2022 (3.71%)  83/2014 (4.12%) 
Infections and infestations         
Nasopharyngitis * 1  174/2016 (8.63%)  156/2006 (7.78%)  126/2022 (6.23%)  135/2014 (6.70%) 
Upper respiratory tract infection * 1  109/2016 (5.41%)  104/2006 (5.18%)  97/2022 (4.80%)  115/2014 (5.71%) 
Nervous system disorders         
Headache * 1  245/2016 (12.15%)  186/2006 (9.27%)  233/2022 (11.52%)  199/2014 (9.88%) 
Psychiatric disorders         
Abnormal dreams * 1  201/2016 (9.97%)  131/2006 (6.53%)  251/2022 (12.41%)  92/2014 (4.57%) 
Anxiety * 1  132/2016 (6.55%)  169/2006 (8.42%)  137/2022 (6.78%)  120/2014 (5.96%) 
Insomnia * 1  189/2016 (9.38%)  245/2006 (12.21%)  195/2022 (9.64%)  139/2014 (6.90%) 
Irritability * 1  82/2016 (4.07%)  71/2006 (3.54%)  108/2022 (5.34%)  104/2014 (5.16%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (v18.0)
After database lock and unblinding, one additional participant in the NRT arm of psychiatric cohort was found who had a primary endpoint event (moderate suicidal ideation) which required hospitalization; this event is not included in any analyses.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
Phone: 1-800-718-1021
EMail: ClinicalTrials.gov_Inquiries@pfizer.com
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01456936     History of Changes
Other Study ID Numbers: A3051123
2010-022914-15 ( EudraCT Number )
EAGLES ( Other Identifier: Alias Study Number )
First Submitted: October 14, 2011
First Posted: October 21, 2011
Results First Submitted: January 12, 2016
Results First Posted: May 2, 2016
Last Update Posted: June 10, 2016