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Study To Evaluate Cardiac Assessments Following Different Treatments Of Smoking Cessation Medications In Subjects With And Without Psychiatric Disorders. (CATS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01574703
Recruitment Status : Completed
First Posted : April 10, 2012
Results First Posted : December 29, 2016
Last Update Posted : December 29, 2016
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label)
Condition: Smoking Cessation
Interventions: Drug: placebo
Drug: varenicline tartrate
Drug: bupropion hydrochloride
Drug: Nicotine Replacement Therapy Patch

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Of the 6293 participants who completed the parent study NCT01456936 as per protocol, a total of 4595 participants enrolled into this study NCT01574703 from 132 centers in 16 countries.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
This is a non-treatment extension study of parent study NCT01456936. No study drug was provided in this extension phase. However, cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline(N=2016), bupropion(N=2006),NRT(N=2022), or placebo(N=2014) in a triple-dummy design were analyzed in this study.

Reporting Groups
  Description
Varenicline This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline in a triple-dummy design were analyzed as part of this study.
Bupropion This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received bupropion in a triple-dummy design were analyzed as part of this study.
Nicotine Replacement Therapy (NRT) Patch This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.
Placebo This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received placebo in a triple-dummy design were analyzed as part of this study.

Participant Flow:   Overall Study
    Varenicline   Bupropion   Nicotine Replacement Therapy (NRT) Patch   Placebo
STARTED   1192   1166   1116   1121 
COMPLETED   1067   1054   1011   1007 
NOT COMPLETED   125   112   105   114 
Adverse Event                0                2                1                1 
Protocol Violation                0                0                0                1 
Unspecified Reason                27                15                20                16 
Withdrawal by Subject                53                52                36                61 
Met Withdrawal Criteria                0                1                1                0 
Lost to Follow-up                43                41                46                35 
Death                2                1                1                0 



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The term Baseline visit refers to the Baseline (Week 0) visit of the parent study NCT01456936. The safety population included all participants who received at least one dose of study drug in NCT01456936 parent study. The below Baseline characteristics (age, gender) are presented for all participants who entered study NCT01574703.

Reporting Groups
  Description
Varenicline This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline in a triple-dummy design were analyzed as part of this study.
Bupropion This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received bupropion in a triple-dummy design were analyzed as part of this study.
NRT Patch This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.
Placebo This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received placebo in a triple-dummy design were analyzed as part of this study.
Total Total of all reporting groups

Baseline Measures
   Varenicline   Bupropion   NRT Patch   Placebo   Total 
Overall Participants Analyzed 
[Units: Participants]
 1192   1166   1116   1121   4595 
Age 
[Units: Years]
Mean (Standard Deviation)
 48.1  (12.2)   47.7  (12.5)   48.3  (11.9)   47.5  (12.2)   47.9  (12.2) 
Gender 
[Units: Participants]
Count of Participants
         
Female      659  55.3%      648  55.6%      623  55.8%      621  55.4%      2551  55.5% 
Male      533  44.7%      518  44.4%      493  44.2%      500  44.6%      2044  44.5% 


  Outcome Measures

1.  Primary:   Time to Occurrence of Major Adverse Cardiovascular Event (MACE) During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.   [ Time Frame: Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks). ]

Measure Type Primary
Measure Title Time to Occurrence of Major Adverse Cardiovascular Event (MACE) During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Measure Description This is an adjudicated endpoint. MACE is defined as a cardiovascular death, a non-fatal myocardial infarction or a non-fatal stroke evaluated during the treatment phase (up to date of last dose of study drug). The measure type mentioned in the outcome data table is Hazard Ratio relative to Placebo.
Time Frame Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks).  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study NCT01456936.

Reporting Groups
  Description
Varenicline This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline in a triple-dummy design were analyzed as part of this study.
Bupropion This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received bupropion in a triple-dummy design were analyzed as part of this study.
NRT Patch This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.
Placebo This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received placebo in a triple-dummy design were analyzed as part of this study.

Measured Values
   Varenicline   Bupropion   NRT Patch   Placebo 
Participants Analyzed   2016   2006   2022   2014 
Time to Occurrence of Major Adverse Cardiovascular Event (MACE) During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936. 
[Units: Unitless]
Number (95% Confidence Interval)
 0.29 
 (0.05 to 1.68) 
 0.50 
 (0.10 to 2.50) 
 0.29 
 (0.05 to 1.70) 
 NA [1] 
[1] Hazard ratio relative to Placebo.


Statistical Analysis 1 for Time to Occurrence of Major Adverse Cardiovascular Event (MACE) During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.37
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis for overall treatment comparison.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value for the treatment effect from the Log-Rank test stratified by Cohort.



2.  Secondary:   Time to MACE up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.   [ Time Frame: Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks) plus 30 days. ]

Measure Type Secondary
Measure Title Time to MACE up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Measure Description This is an adjudicated endpoint. MACE is defined as a cardiovascular death, a non-fatal myocardial infarction or a non-fatal stroke evaluated during the treatment phase (up to date of last dose of study drug) plus 30 days follow-up. The measure type mentioned in the outcome data table is Hazard Ratio.
Time Frame Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks) plus 30 days.  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study NCT01456936.

Reporting Groups
  Description
Varenicline This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline in a triple-dummy design were analyzed as part of this study.
Bupropion This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received bupropion in a triple-dummy design were analyzed as part of this study.
NRT Patch This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.
Placebo This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received placebo in a triple-dummy design were analyzed as part of this study.

Measured Values
   Varenicline   Bupropion   NRT Patch   Placebo 
Participants Analyzed   2016   2006   2022   2014 
Time to MACE up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936. 
[Units: Unitless]
Number (95% Confidence Interval)
 0.29 
 (0.05 to 1.70) 
 0.51 
 (0.10 to 2.51) 
 0.50 
 (0.10 to 2.48) 
 NA [1] 
[1] Hazard ratio relative to Placebo.


Statistical Analysis 1 for Time to MACE up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.53
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis for overall treatment comparison.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value for the treatment effect from the Log-Rank test stratified by Cohort.



3.  Secondary:   Time to MACE Until the End of Study NCT01574703.   [ Time Frame: Baseline until end of study (end of study is defined as last visit in study NCT01574703 [up to Week 52], or in study NCT01456936 [up to 24 Weeks] for those participants not enrolled into study NCT01574703). ]

Measure Type Secondary
Measure Title Time to MACE Until the End of Study NCT01574703.
Measure Description This is an adjudicated endpoint. MACE is defined as a cardiovascular death, a non-fatal myocardial infarction or a non-fatal stroke evaluated until end of study. The measure type mentioned in the outcome data table is Hazard Ratio.
Time Frame Baseline until end of study (end of study is defined as last visit in study NCT01574703 [up to Week 52], or in study NCT01456936 [up to 24 Weeks] for those participants not enrolled into study NCT01574703).  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study NCT01456936.

Reporting Groups
  Description
Varenicline This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline in a triple-dummy design were analyzed as part of this study.
Bupropion This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received bupropion in a triple-dummy design were analyzed as part of this study.
NRT Patch This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.
Placebo This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received placebo in a triple-dummy design were analyzed as part of this study.

Measured Values
   Varenicline   Bupropion   NRT Patch   Placebo 
Participants Analyzed   2016   2006   2022   2014 
Time to MACE Until the End of Study NCT01574703. 
[Units: Unitless]
Number (95% Confidence Interval)
 0.39 
 (0.12 to 1.27) 
 1.09 
 (0.42 to 2.83) 
 0.75 
 (0.26 to 2.13) 
 NA [1] 
[1] Hazard ratio relative to Placebo.


Statistical Analysis 1 for Time to MACE Until the End of Study NCT01574703.
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.34
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis for overall treatment comparison.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value for the treatment effect from the Log-Rank test stratified by Cohort.



4.  Secondary:   Incidence of MACE Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.   [ Time Frame: Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks). ]

Measure Type Secondary
Measure Title Incidence of MACE Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Measure Description This is an adjudicated endpoint. MACE is defined as a cardiovascular death, a non-fatal myocardial infarction or a non-fatal stroke evaluated during the treatment phase (up to date of last dose of study drug).
Time Frame Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks).  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study NCT01456936.

Reporting Groups
  Description
Varenicline This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline in a triple-dummy design were analyzed as part of this study.
Bupropion This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received bupropion in a triple-dummy design were analyzed as part of this study.
NRT Patch This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.
Placebo This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received placebo in a triple-dummy design were analyzed as part of this study.

Measured Values
   Varenicline   Bupropion   NRT Patch   Placebo 
Participants Analyzed   2016   2006   2022   2014 
Incidence of MACE Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936. 
[Units: Percentage of participants]
 0.05   0.10   0.05   0.20 


Statistical Analysis 1 for Incidence of MACE Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] Varenicline vs. Bupropion
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.8375
Risk Difference (RD) [5] -0.49
95% Confidence Interval -5.22 to 4.23
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and Bupropion.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Incidence of MACE Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] Varenicline vs. NRT Patch
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.9780
Risk Difference (RD) [5] -0.07
95% Confidence Interval -5.20 to 5.05
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and NRT patch.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Incidence of MACE Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] Varenicline vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.6142
Risk Difference (RD) [5] -1.13
95% Confidence Interval -5.54 to 3.27
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Incidence of MACE Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] Bupropion vs. NRT Patch
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.8602
Risk Difference (RD) [5] 0.42
95% Confidence Interval -4.28 to 5.13
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Bupropion and NRT patch.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Incidence of MACE Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] Bupropion vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.7217
Risk Difference (RD) [5] -0.64
95% Confidence Interval -4.15 to 2.88
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Bupropion and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 6 for Incidence of MACE Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] NRT Patch vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.6322
Risk Difference (RD) [5] -1.06
95% Confidence Interval -5.41 to 3.28
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between NRT patch and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.



5.  Secondary:   Incidence of MACE + Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.   [ Time Frame: Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks). ]

Measure Type Secondary
Measure Title Incidence of MACE + Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Measure Description This is an adjudicated endpoint. MACE + is defined as any MACE or a new onset or worsening peripheral vascular disease (PVD) requiring intervention, a need for coronary revascularization, or hospitalization for unstable angina.
Time Frame Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks).  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study NCT01456936.

Reporting Groups
  Description
Varenicline This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline in a triple-dummy design were analyzed as part of this study.
Bupropion This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received bupropion in a triple-dummy design were analyzed as part of this study.
NRT Patch This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.
Placebo This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received placebo in a triple-dummy design were analyzed as part of this study.

Measured Values
   Varenicline   Bupropion   NRT Patch   Placebo 
Participants Analyzed   2016   2006   2022   2014 
Incidence of MACE + Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936. 
[Units: Percentage of participants]
 0.25   0.20   0.10   0.25 


Statistical Analysis 1 for Incidence of MACE + Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] Varenicline vs. Bupropion
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.9687
Risk Difference (RD) [5] -0.07
95% Confidence Interval -3.48 to 3.34
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and Bupropion.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Incidence of MACE + Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] Varenicline vs. NRT Patch
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.7905
Risk Difference (RD) [5] 0.56
95% Confidence Interval -3.58 to 4.70
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and NRT patch.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Incidence of MACE + Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] Varenicline vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.8962
Risk Difference (RD) [5] -0.21
95% Confidence Interval -3.36 to 2.94
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Incidence of MACE + Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] Bupropion vs. NRT Patch
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.7767
Risk Difference (RD) [5] 0.63
95% Confidence Interval -3.72 to 4.98
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Bupropion and NRT patch.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Incidence of MACE + Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] Bupropion vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.9260
Risk Difference (RD) [5] -0.14
95% Confidence Interval -3.13 to 2.85
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Bupropion and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 6 for Incidence of MACE + Assessed During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936.
Groups [1] NRT Patch vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.7113
Risk Difference (RD) [5] -0.77
95% Confidence Interval -4.85 to 3.31
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between NRT patch and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.



6.  Secondary:   Incidence of MACE Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.   [ Time Frame: Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks) plus 30 days follow-up. ]

Measure Type Secondary
Measure Title Incidence of MACE Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Measure Description This is an adjudicated endpoint. MACE is defined as a cardiovascular death, a non-fatal myocardial infarction or a non-fatal stroke evaluated during the treatment phase (up to date of last dose of study drug) plus 30 days follow-up.
Time Frame Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks) plus 30 days follow-up.  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study NCT01456936.

Reporting Groups
  Description
Varenicline This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline in a triple-dummy design were analyzed as part of this study.
Bupropion This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received bupropion in a triple-dummy design were analyzed as part of this study.
NRT Patch This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.
Placebo This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received placebo in a triple-dummy design were analyzed as part of this study.

Measured Values
   Varenicline   Bupropion   NRT Patch   Placebo 
Participants Analyzed   2016   2006   2022   2014 
Incidence of MACE Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936. 
[Units: Percentage of participants]
 0.05   0.10   0.10   0.20 


Statistical Analysis 1 for Incidence of MACE Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] Varenicline vs. Bupropion
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.8117
Risk Difference (RD) [5] -0.57
95% Confidence Interval -5.27 to 4.13
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and Bupropion.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Incidence of MACE Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] Varenicline vs. NRT Patch
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.7303
Risk Difference (RD) [5] -0.78
95% Confidence Interval -5.21 to 3.65
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and NRT patch.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Incidence of MACE Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] Varenicline vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.5946
Risk Difference (RD) [5] -1.20
95% Confidence Interval -5.60 to 3.21
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Incidence of MACE Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] Bupropion vs. NRT Patch
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.9200
Risk Difference (RD) [5] -0.21
95% Confidence Interval -4.27 to 3.85
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Bupropion and NRT patch.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Incidence of MACE Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] Bupropion vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.7236
Risk Difference (RD) [5] -0.62
95% Confidence Interval -4.09 to 2.84
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Bupropion and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 6 for Incidence of MACE Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] NRT Patch vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.8201
Risk Difference (RD) [5] -0.42
95% Confidence Interval -4.01 to 3.17
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between NRT patch and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.



7.  Secondary:   Incidence of MACE+ Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.   [ Time Frame: Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks) plus 30 days follow-up. ]

Measure Type Secondary
Measure Title Incidence of MACE+ Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Measure Description This is an adjudicated endpoint. MACE + is defined as any MACE or a new onset or worsening PVD requiring intervention, a need for coronary revascularization, or hospitalization for unstable angina.
Time Frame Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks) plus 30 days follow-up.  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study NCT01456936.

Reporting Groups
  Description
Varenicline This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline in a triple-dummy design were analyzed as part of this study.
Bupropion This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received bupropion in a triple-dummy design were analyzed as part of this study.
NRT Patch This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.
Placebo This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received placebo in a triple-dummy design were analyzed as part of this study.

Measured Values
   Varenicline   Bupropion   NRT Patch   Placebo 
Participants Analyzed   2016   2006   2022   2014 
Incidence of MACE+ Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936. 
[Units: Percentage of participants]
 0.25   0.20   0.15   0.35 


Statistical Analysis 1 for Incidence of MACE+ Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] Varenicline vs. Bupropion
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.8932
Risk Difference (RD) [5] -0.21
95% Confidence Interval -3.22 to 2.81
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and Bupropion.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Incidence of MACE+ Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] Varenicline vs. NRT Patch
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.8747
Risk Difference (RD) [5] -0.23
95% Confidence Interval -3.09 to 2.63
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and NRT patch.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Incidence of MACE+ Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] Varenicline vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.6710
Risk Difference (RD) [5] -0.60
95% Confidence Interval -3.35 to 2.15
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Incidence of MACE+ Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] Bupropion vs. NRT Patch
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.9886
Risk Difference (RD) [5] -0.02
95% Confidence Interval -3.32 to 3.27
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Bupropion and NRT patch.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Incidence of MACE+ Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] Bupropion vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.7631
Risk Difference (RD) [5] -0.39
95% Confidence Interval -2.92 to 2.14
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Bupropion and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 6 for Incidence of MACE+ Assessed up to Date of Last Dose of Study Drug Plus 30 Days Follow-up in Study NCT01456936.
Groups [1] NRT Patch vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.8022
Risk Difference (RD) [5] -0.37
95% Confidence Interval -3.23 to 2.50
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between NRT patch and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.



8.  Secondary:   Incidence of MACE Assessed Until End of Study NCT01574703.   [ Time Frame: Baseline until end of study (end of study is defined as last visit in study NCT01574703 [up to Week 52], or in study NCT01456936 [up to 24 Weeks] for those participants not enrolled into study NCT01574703). ]

Measure Type Secondary
Measure Title Incidence of MACE Assessed Until End of Study NCT01574703.
Measure Description This is an adjudicated endpoint. MACE is defined as a cardiovascular death, a non-fatal myocardial infarction or a non-fatal stroke evaluated until end of study.
Time Frame Baseline until end of study (end of study is defined as last visit in study NCT01574703 [up to Week 52], or in study NCT01456936 [up to 24 Weeks] for those participants not enrolled into study NCT01574703).  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study NCT01456936.

Reporting Groups
  Description
Varenicline This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline in a triple-dummy design were analyzed as part of this study.
Bupropion This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received bupropion in a triple-dummy design were analyzed as part of this study.
NRT Patch This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.
Placebo This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received placebo in a triple-dummy design were analyzed as part of this study.

Measured Values
   Varenicline   Bupropion   NRT Patch   Placebo 
Participants Analyzed   2016   2006   2022   2014 
Incidence of MACE Assessed Until End of Study NCT01574703. 
[Units: Percentage of participants]
 0.15   0.45   0.30   0.40 


Statistical Analysis 1 for Incidence of MACE Assessed Until End of Study NCT01574703.
Groups [1] Varenicline vs. Bupropion
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.6441
Risk Difference (RD) [5] -0.91
95% Confidence Interval -4.78 to 2.96
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and Bupropion.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Incidence of MACE Assessed Until End of Study NCT01574703.
Groups [1] Varenicline vs. NRT Patch
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.7327
Risk Difference (RD) [5] -0.69
95% Confidence Interval -4.63 to 3.26
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and NRT patch.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Incidence of MACE Assessed Until End of Study NCT01574703.
Groups [1] Varenicline vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.6109
Risk Difference (RD) [5] -0.99
95% Confidence Interval -4.80 to 2.82
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Incidence of MACE Assessed Until End of Study NCT01574703.
Groups [1] Bupropion vs. NRT Patch
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.8707
Risk Difference (RD) [5] 0.22
95% Confidence Interval -2.48 to 2.93
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Bupropion and NRT patch.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Incidence of MACE Assessed Until End of Study NCT01574703.
Groups [1] Bupropion vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.9531
Risk Difference (RD) [5] -0.08
95% Confidence Interval -2.63 to 2.48
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Bupropion and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 6 for Incidence of MACE Assessed Until End of Study NCT01574703.
Groups [1] NRT Patch vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.8262
Risk Difference (RD) [5] -0.30
95% Confidence Interval -2.99 to 2.39
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between NRT patch and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.



9.  Secondary:   Incidence of MACE+ Assessed Until End of Study NCT01574703.   [ Time Frame: Baseline until end of study (end of study is defined as last visit in study NCT01574703 [up to Week 52], or in study NCT01456936 [up to 24 Weeks] for those participants not enrolled into study NCT01574703). ]

Measure Type Secondary
Measure Title Incidence of MACE+ Assessed Until End of Study NCT01574703.
Measure Description This is an adjudicated endpoint. MACE+ is defined as any MACE or a new onset or worsening PVD requiring intervention, a need for coronary revascularization, or hospitalization for unstable angina.
Time Frame Baseline until end of study (end of study is defined as last visit in study NCT01574703 [up to Week 52], or in study NCT01456936 [up to 24 Weeks] for those participants not enrolled into study NCT01574703).  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study NCT01456936.

Reporting Groups
  Description
Varenicline This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline in a triple-dummy design were analyzed as part of this study.
Bupropion This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received bupropion in a triple-dummy design were analyzed as part of this study.
NRT Patch This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.
Placebo This was the non-treatment extension study of parent study NCT01456936. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study NCT01456936 when participants received placebo in a triple-dummy design were analyzed as part of this study.

Measured Values
   Varenicline   Bupropion   NRT Patch   Placebo 
Participants Analyzed   2016   2006   2022   2014 
Incidence of MACE+ Assessed Until End of Study NCT01574703. 
[Units: Percentage of participants]
 0.50   0.75   0.49   0.60 


Statistical Analysis 1 for Incidence of MACE+ Assessed Until End of Study NCT01574703.
Groups [1] Varenicline vs. Bupropion
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.6105
Risk Difference (RD) [5] -0.59
95% Confidence Interval -2.84 to 1.67
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and Bupropion.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Incidence of MACE+ Assessed Until End of Study NCT01574703.
Groups [1] Varenicline vs. NRT Patch
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.7895
Risk Difference (RD) [5] -0.32
95% Confidence Interval -2.65 to 2.01
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and NRT patch.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Incidence of MACE+ Assessed Until End of Study NCT01574703.
Groups [1] Varenicline vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.6804
Risk Difference (RD) [5] -0.48
95% Confidence Interval -2.75 to 1.80
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Varenicline and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Incidence of MACE+ Assessed Until End of Study NCT01574703.
Groups [1] Bupropion vs. NRT Patch
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.8127
Risk Difference (RD) [5] 0.27
95% Confidence Interval -1.95 to 2.49
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Bupropion and NRT patch.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Incidence of MACE+ Assessed Until End of Study NCT01574703.
Groups [1] Bupropion vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.9218
Risk Difference (RD) [5] 0.11
95% Confidence Interval -2.04 to 2.25
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between Bupropion and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 6 for Incidence of MACE+ Assessed Until End of Study NCT01574703.
Groups [1] NRT Patch vs. Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.8841
Risk Difference (RD) [5] -0.16
95% Confidence Interval -2.32 to 2.00
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analysis between NRT patch and Placebo.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-values are for the risk differences of pairwise comparisons based on the logistic regression model with terms Baseline Cardiovascular Risk, treatment, cohort, region, and treatment by cohort interaction.
[5] Other relevant estimation information:
  No text entered.




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information

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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
phone: 1-800-718-1021
e-mail: ClinicalTrials.gov_Inquiries@pfizer.com


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01574703     History of Changes
Other Study ID Numbers: A3051148
2011-005513-37 ( EudraCT Number )
CATS ( Other Identifier: Alias Study Number )
First Submitted: April 6, 2012
First Posted: April 10, 2012
Results First Submitted: July 7, 2016
Results First Posted: December 29, 2016
Last Update Posted: December 29, 2016