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    Clinical Trial Results:
    A PHASE 4, NON-TREATMENT FOLLOW-UP FOR CARDIAC ASSESSMENTS FOLLOWING USE OF SMOKING CESSATION TREATMENTS IN SUBJECTS WITH AND WITHOUT A HISTORY OF PSYCHIATRIC DISORDERS.

    Summary
    EudraCT number
    2011-005513-37
    Trial protocol
    DE   ES   FI   BG   DK   SK  
    Global end of trial date
    10 Jul 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Jul 2016
    First version publication date
    24 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A3051148
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01574703
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 East 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the cardiovascular safety assessment in Study 2010-022914-15 and continuing into Study 2011-005513-37 was to characterize the cardiovascular safety profiles of varenicline and bupropion compared to placebo.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants, as well as the general principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences 2002). A signed and dated informed consent was required before any screening procedures were done. The study investigators explained the nature, purpose, and risks of the study to each participant. Each participant was informed that he/she could withdraw from the study at any time and for any reason. Each participant was given sufficient time to consider the implications of the study before deciding whether to participate. Participants who chose to participate signed an informed consent document.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Nov 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 179
    Country: Number of subjects enrolled
    South Africa: 213
    Country: Number of subjects enrolled
    Spain: 134
    Country: Number of subjects enrolled
    United States: 2241
    Country: Number of subjects enrolled
    Argentina: 134
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Brazil: 12
    Country: Number of subjects enrolled
    Bulgaria: 352
    Country: Number of subjects enrolled
    Canada: 153
    Country: Number of subjects enrolled
    Chile: 16
    Country: Number of subjects enrolled
    Denmark: 54
    Country: Number of subjects enrolled
    Finland: 349
    Country: Number of subjects enrolled
    Germany: 377
    Country: Number of subjects enrolled
    Mexico: 157
    Country: Number of subjects enrolled
    New Zealand: 105
    Country: Number of subjects enrolled
    Russian Federation: 106
    Worldwide total number of subjects
    4595
    EEA total number of subjects
    1445
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    4220
    From 65 to 84 years
    375
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Of the 6293 participants who completed the parent study 2010-022914-15 as per protocol, a total of 4595 participants enrolled into this study 2011-005513-37 from 132 centers in 16 countries.

    Pre-assignment
    Screening details
    This is a non-treatment extension study of parent study 2010-022914-15.No study drug was provided in the extension phase. However,cardiovascular events that occurred during parent study 2010-022914-15 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.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor
    Blinding implementation details
    Randomization took place during the parent study.The blinding in effect during the parent study 2010-022914-15 remained in place during this Study 2011-005513-37.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Varenicline
    Arm description
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study 2010-022914-15 when participants received varenicline in a triple-dummy design were analyzed as part of this study.
    Arm type
    Experimental

    Investigational medicinal product name
    Varenicline
    Investigational medicinal product code
    CP-526,555
    Other name
    Champix
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, cardiovascular events that occurred during parent study 2010-022914-15 when participants received varenicline in a triple-dummy design were analyzed as part of this study.

    Arm title
    Bupropion
    Arm description
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, cardiovascular events that occurred during parent study 2010-022914-15 when participants received bupropion in a triple-dummy design were analyzed as part of this study.
    Arm type
    Experimental

    Investigational medicinal product name
    Bupropion
    Investigational medicinal product code
    Other name
    Zyban Bupropion hydrochloride
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, cardiovascular events that occurred during parent study 2010-022914-15 when participants received bupropion in a triple-dummy design were analyzed as part of this study.

    Arm title
    Nicotine Replacement Therapy (NRT) patch
    Arm description
    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 2010-022914-15 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.
    Arm type
    Experimental

    Investigational medicinal product name
    NRT patch
    Investigational medicinal product code
    Transdermal nicotine Patch (NRT)
    Other name
    Nicotine
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    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 2010-022914-15 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.

    Arm title
    Placebo
    Arm description
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, cardiovascular events that occurred during parent study 2010-022914-15 when participants received placebo in a triple-dummy design were analyzed as part of this study.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, cardiovascular events that occurred during parent study 2010-022914-15 when participants received placebo in a triple-dummy design were analyzed as part of this study.

    Number of subjects in period 1
    Varenicline Bupropion Nicotine Replacement Therapy (NRT) patch Placebo
    Started
    1192
    1166
    1116
    1121
    Completed
    1067
    1054
    1011
    1007
    Not completed
    125
    112
    105
    114
         Protocol deviation
    -
    -
    -
    1
         Death
    2
    1
    1
    -
         Unspecified Reason
    27
    15
    20
    16
         Met Withdrawal Criteria
    -
    1
    1
    -
         Consent withdrawn by subject
    53
    52
    36
    61
         Adverse Event
    -
    2
    1
    1
         Lost to follow-up
    43
    41
    46
    35

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Varenicline
    Reporting group description
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study 2010-022914-15 when participants received varenicline in a triple-dummy design were analyzed as part of this study.

    Reporting group title
    Bupropion
    Reporting group description
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, cardiovascular events that occurred during parent study 2010-022914-15 when participants received bupropion in a triple-dummy design were analyzed as part of this study.

    Reporting group title
    Nicotine Replacement Therapy (NRT) patch
    Reporting group description
    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 2010-022914-15 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.

    Reporting group title
    Placebo
    Reporting group description
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, cardiovascular events that occurred during parent study 2010-022914-15 when participants received placebo in a triple-dummy design were analyzed as part of this study.

    Reporting group values
    Varenicline Bupropion Nicotine Replacement Therapy (NRT) patch Placebo Total
    Number of subjects
    1192 1166 1116 1121 4595
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    1093 1064 1018 1045 4220
        From 65-84 years
    99 102 98 76 375
        85 years and over
    0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    48.1 ± 12.2 47.7 ± 12.5 48.3 ± 11.9 47.5 ± 12.2 -
    Gender, Male/Female
    Units: Participants
        Female
    659 648 623 621 2551
        Male
    533 518 493 500 2044
    Subject analysis sets

    Subject analysis set title
    Varenicline
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety analysis set is defined as all participants that receive at least one partial dose of study drug during the parent study (i.e., the Safety analysis set for 2010-022914-15).

    Subject analysis set title
    Bupropion
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety analysis set is defined as all participants that receive at least one partial dose of study drug during the parent study (i.e., the Safety analysis set for 2010-022914-15).

    Subject analysis set title
    NRT patch
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety analysis set is defined as all participants that receive at least one partial dose of study drug during the parent study (i.e., the Safety analysis set for 2010-022914-15).

    Subject analysis set title
    Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety analysis set is defined as all participants that receive at least one partial dose of study drug during the parent study (i.e., the Safety analysis set for 2010-022914-15).

    Subject analysis sets values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects
    2016
    2006
    2022
    2014
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    1884
    1859
    1887
    1899
        From 65-84 years
    132
    147
    135
    115
        85 years and over
    0
    0
    0
    0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    46.5 ± 12.4
    46.3 ± 12.6
    46.9 ± 12.2
    46.4 ± 12.1
    Gender, Male/Female
    Units: Participants
        Female
    1114
    1114
    1139
    1138
        Male
    902
    892
    883
    876

    End points

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    End points reporting groups
    Reporting group title
    Varenicline
    Reporting group description
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, Cardiovascular events that occurred during parent study 2010-022914-15 when participants received varenicline in a triple-dummy design were analyzed as part of this study.

    Reporting group title
    Bupropion
    Reporting group description
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, cardiovascular events that occurred during parent study 2010-022914-15 when participants received bupropion in a triple-dummy design were analyzed as part of this study.

    Reporting group title
    Nicotine Replacement Therapy (NRT) patch
    Reporting group description
    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 2010-022914-15 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.

    Reporting group title
    Placebo
    Reporting group description
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, cardiovascular events that occurred during parent study 2010-022914-15 when participants received placebo in a triple-dummy design were analyzed as part of this study.

    Subject analysis set title
    Varenicline
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety analysis set is defined as all participants that receive at least one partial dose of study drug during the parent study (i.e., the Safety analysis set for 2010-022914-15).

    Subject analysis set title
    Bupropion
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety analysis set is defined as all participants that receive at least one partial dose of study drug during the parent study (i.e., the Safety analysis set for 2010-022914-15).

    Subject analysis set title
    NRT patch
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety analysis set is defined as all participants that receive at least one partial dose of study drug during the parent study (i.e., the Safety analysis set for 2010-022914-15).

    Subject analysis set title
    Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety analysis set is defined as all participants that receive at least one partial dose of study drug during the parent study (i.e., the Safety analysis set for 2010-022914-15).

    Primary: Time to occurrence of major adverse cardiovascular event (MACE) during treatment period (up to date of last dose of study drug) in study 2010-022914-15.

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    End point title
    Time to occurrence of major adverse cardiovascular event (MACE) during treatment period (up to date of last dose of study drug) in study 2010-022914-15.
    End point 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. The term Baseline visit refers to the Baseline (Week 0) visit of the parent study 2010-022914-15. The safety population included all participants who received at least one dose of study drug in 2010-022914-15 parent study.
    End point type
    Primary
    End point timeframe
    Baseline to last dose of study drug.
    End point values
    Varenicline Bupropion NRT patch
    Number of subjects analysed
    2016
    2006
    2022
    Units: Unitless
        number (confidence interval 95%)
    0.29 (0.05 to 1.68)
    0.5 (0.1 to 2.5)
    0.29 (0.05 to 1.7)
    Statistical analysis title
    Statistical analysis for overall treatment groups
    Comparison groups
    Varenicline v Bupropion v NRT patch
    Number of subjects included in analysis
    6044
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.37 [1]
    Method
    Logrank
    Confidence interval
    Notes
    [1] - P-value for the treatment effect from the Log-Rank test stratified by Cohort.

    Secondary: Time to MACE up to date of last dose of study drug plus 30 days follow-up in study 2010-022914-15.

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    End point title
    Time to MACE up to date of last dose of study drug plus 30 days follow-up in study 2010-022914-15.
    End point 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 relative to Placebo. The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study 2010-022914-15.
    End point type
    Secondary
    End point timeframe
    Baseline to last dose of study drug plus 30 days.
    End point values
    Varenicline Bupropion NRT patch
    Number of subjects analysed
    2016
    2006
    2022
    Units: Unitless
        number (confidence interval 95%)
    0.29 (0.05 to 1.7)
    0.51 (0.1 to 2.51)
    0.5 (0.1 to 2.48)
    Statistical analysis title
    Statistical analysis for overall treatment groups
    Comparison groups
    Varenicline v Bupropion v NRT patch
    Number of subjects included in analysis
    6044
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.53 [2]
    Method
    Logrank
    Confidence interval
    Notes
    [2] - P-value for the treatment effect from the Log-Rank test stratified by Cohort.

    Secondary: Time to MACE until the end of study 2011-005513-37.

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    End point title
    Time to MACE until the end of study 2011-005513-37.
    End point 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. The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study 2010-022914-15.
    End point type
    Secondary
    End point timeframe
    Baseline until end of study (end of study is defined as last visit in study 2011-005513-37, or in study 2010-022914-15 for those participants not enrolled into study 2011-005513-37).
    End point values
    Varenicline Bupropion NRT patch
    Number of subjects analysed
    2016
    2006
    2022
    Units: Unitless
        number (confidence interval 95%)
    0.39 (0.12 to 1.27)
    1.09 (0.42 to 2.83)
    0.75 (0.26 to 2.13)
    Statistical analysis title
    Statistical analysis for overall treatment groups
    Comparison groups
    Varenicline v Bupropion v NRT patch
    Number of subjects included in analysis
    6044
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.34 [3]
    Method
    Logrank
    Confidence interval
    Notes
    [3] - P-value for the treatment effect from the Log-Rank test stratified by Cohort.

    Secondary: Incidence of MACE assessed during treatment period (up to date of last dose of study drug) in study 2010-022914-15.

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    End point title
    Incidence of MACE assessed during treatment period (up to date of last dose of study drug) in study 2010-022914-15.
    End point 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 safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study 2010-022914-15.
    End point type
    Secondary
    End point timeframe
    Baseline to last dose of study drug.
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: percentage of participants
        number (not applicable)
    0.05
    0.1
    0.05
    0.2
    Statistical analysis title
    Statistical analysis b/w Varenicline and Bupropion
    Comparison groups
    Varenicline v Bupropion
    Number of subjects included in analysis
    4022
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8375 [4]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.22
         upper limit
    4.23
    Notes
    [4] - 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.
    Statistical analysis title
    Statistical analysis b/w Varenicline and NRT
    Comparison groups
    Varenicline v NRT patch
    Number of subjects included in analysis
    4038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.978 [5]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.2
         upper limit
    5.05
    Notes
    [5] - 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.
    Statistical analysis title
    Statistical analysis b/w Varenicline and Placebo
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    4030
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6142 [6]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.54
         upper limit
    3.27
    Notes
    [6] - 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.
    Statistical analysis title
    Statistical analysis b/w Bupropion and NRT
    Comparison groups
    Bupropion v NRT patch
    Number of subjects included in analysis
    4028
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8602 [7]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.28
         upper limit
    5.13
    Notes
    [7] - 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.
    Statistical analysis title
    Statistical analysis b/w Bupropion and Placebo
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    4020
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7217 [8]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.15
         upper limit
    2.88
    Notes
    [8] - 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.
    Statistical analysis title
    Statistical analysis b/w NRT patch and Placebo
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    4036
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6322 [9]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.41
         upper limit
    3.28
    Notes
    [9] - 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.

    Secondary: Incidence of MACE+ assessed during treatment period (up to date of last dose of study drug) in study 2010-022914-15.

    Close Top of page
    End point title
    Incidence of MACE+ assessed during treatment period (up to date of last dose of study drug) in study 2010-022914-15.
    End point 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. The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study 2010-022914-15.
    End point type
    Secondary
    End point timeframe
    Baseline to last dose of study drug.
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: percentage of participants
        number (not applicable)
    0.25
    0.2
    0.1
    0.25
    Statistical analysis title
    Statistical analysis b/w Varenicline and Bupropion
    Comparison groups
    Varenicline v Bupropion
    Number of subjects included in analysis
    4022
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9687 [10]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.48
         upper limit
    3.34
    Notes
    [10] - 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.
    Statistical analysis title
    Statistical analysis b/w Varenicline and NRT
    Comparison groups
    Varenicline v NRT patch
    Number of subjects included in analysis
    4038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7905 [11]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.58
         upper limit
    4.7
    Notes
    [11] - 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.
    Statistical analysis title
    Statistical analysis b/w Varenicline and Placebo
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    4030
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8962 [12]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.36
         upper limit
    2.94
    Notes
    [12] - 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.
    Statistical analysis title
    Statistical analysis b/w Bupropion and NRT
    Comparison groups
    Bupropion v NRT patch
    Number of subjects included in analysis
    4028
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7767 [13]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.72
         upper limit
    4.98
    Notes
    [13] - 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.
    Statistical analysis title
    Statistical analysis b/w Bupropion and Placebo
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    4020
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.926 [14]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.13
         upper limit
    2.85
    Notes
    [14] - 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.
    Statistical analysis title
    Statistical analysis b/w NRT and Placebo
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    4036
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7113 [15]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.85
         upper limit
    3.31
    Notes
    [15] - 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.

    Secondary: Incidence of MACE assessed up to date of last dose of study drug plus 30 days follow-up in study 2010-022914-15.

    Close Top of page
    End point title
    Incidence of MACE assessed up to date of last dose of study drug plus 30 days follow-up in study 2010-022914-15.
    End point 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 safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study 2010-022914-15.
    End point type
    Secondary
    End point timeframe
    Baseline to last dose of study drug plus 30 days follow-up.
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: percentage of participants
        number (not applicable)
    0.05
    0.1
    0.1
    0.2
    Statistical analysis title
    Statistical analysis b/w Varenicline and Bupropion
    Comparison groups
    Varenicline v Bupropion
    Number of subjects included in analysis
    4022
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8117 [16]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.27
         upper limit
    4.13
    Notes
    [16] - 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.
    Statistical analysis title
    Statistical analysis b/w Varenicline and NRT
    Comparison groups
    Varenicline v NRT patch
    Number of subjects included in analysis
    4038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7303 [17]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.21
         upper limit
    3.65
    Notes
    [17] - 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.
    Statistical analysis title
    Statistical analysis b/w Varenicline and Placebo
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    4030
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5946 [18]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.6
         upper limit
    3.21
    Notes
    [18] - 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.
    Statistical analysis title
    Statistical analysis b/w Bupropion and NRT
    Comparison groups
    Bupropion v NRT patch
    Number of subjects included in analysis
    4028
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.92 [19]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.27
         upper limit
    3.85
    Notes
    [19] - 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.
    Statistical analysis title
    Statistical analysis b/w Bupropion and Placebo
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    4020
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7236 [20]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.09
         upper limit
    2.84
    Notes
    [20] - 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.
    Statistical analysis title
    Statistical analysis b/w NRT patch and Placebo
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    4036
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8201 [21]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.01
         upper limit
    3.17
    Notes
    [21] - 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.

    Secondary: Incidence of MACE+ assessed up to date of last dose of study drug plus 30 days follow-up in study 2010-022914-15.

    Close Top of page
    End point title
    Incidence of MACE+ assessed up to date of last dose of study drug plus 30 days follow-up in study 2010-022914-15.
    End point 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. The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study 2010-022914-15.
    End point type
    Secondary
    End point timeframe
    Baseline to last dose of study drug plus 30 days follow-up.
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: percentage of participants
        number (not applicable)
    0.25
    0.2
    0.15
    0.35
    Statistical analysis title
    Statistical analysis b/w Varenicline and Bupropion
    Comparison groups
    Varenicline v Bupropion
    Number of subjects included in analysis
    4022
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8932 [22]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.22
         upper limit
    2.81
    Notes
    [22] - 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.
    Statistical analysis title
    Statistical analysis b/w Varenicline and NRT
    Comparison groups
    Varenicline v NRT patch
    Number of subjects included in analysis
    4038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8747 [23]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.09
         upper limit
    2.63
    Notes
    [23] - 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.
    Statistical analysis title
    Statistical analysis b/w Varenicline and Placebo
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    4030
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.671 [24]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.35
         upper limit
    2.15
    Notes
    [24] - 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.
    Statistical analysis title
    Statistical analysis b/w Bupropion and NRT
    Comparison groups
    Bupropion v NRT patch
    Number of subjects included in analysis
    4028
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9886 [25]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.32
         upper limit
    3.27
    Notes
    [25] - 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.
    Statistical analysis title
    Statistical analysis b/w Bupropion and Placebo
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    4020
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7631 [26]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.92
         upper limit
    2.14
    Notes
    [26] - 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.
    Statistical analysis title
    Statistical analysis b/w NRT patch and Placebo
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    4036
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8022 [27]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.23
         upper limit
    2.5
    Notes
    [27] - 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.

    Secondary: Incidence of MACE assessed until end of study 2011-005513-37.

    Close Top of page
    End point title
    Incidence of MACE assessed until end of study 2011-005513-37.
    End point 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 safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study 2010-022914-15.
    End point type
    Secondary
    End point timeframe
    Baseline until end of study (end of study is defined as last visit in study 2011-005513-37, or in study 2010-022914-15 for those participants not enrolled into study 2011-005513-37).
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: percentage of participants
        number (not applicable)
    0.15
    0.45
    0.3
    0.4
    Statistical analysis title
    Statistical analysis b/w Varenicline and Bupropion
    Comparison groups
    Varenicline v Bupropion
    Number of subjects included in analysis
    4022
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6441 [28]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.78
         upper limit
    2.96
    Notes
    [28] - 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.
    Statistical analysis title
    Statistical analysis b/w Varenicline and NRT
    Comparison groups
    Varenicline v NRT patch
    Number of subjects included in analysis
    4038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7327 [29]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.63
         upper limit
    3.26
    Notes
    [29] - 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.
    Statistical analysis title
    Statistical analysis b/w Varenicline and Placebo
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    4030
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6109 [30]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.8
         upper limit
    2.82
    Notes
    [30] - 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.
    Statistical analysis title
    Statistical analysis b/w Bupropion and NRT
    Comparison groups
    Bupropion v NRT patch
    Number of subjects included in analysis
    4028
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8707 [31]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    0.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.48
         upper limit
    2.93
    Notes
    [31] - 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.
    Statistical analysis title
    Statistical analysis b/w Bupropion and Placebo
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    4020
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9531 [32]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.63
         upper limit
    2.48
    Notes
    [32] - 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.
    Statistical analysis title
    Statistical analysis b/w NRT patch and Placebo
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    4036
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8262 [33]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.99
         upper limit
    2.39
    Notes
    [33] - 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.

    Secondary: Incidence of MACE+ assessed until end of study 2011-005513-37.

    Close Top of page
    End point title
    Incidence of MACE+ assessed until end of study 2011-005513-37.
    End point 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. The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study 2010-022914-15.
    End point type
    Secondary
    End point timeframe
    Baseline until end of study (end of study is defined as last visit in study 2011-005513-37, or in study 2010-022914-15 for those participants not enrolled into study 2011-005513-37).
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: percentage of participants
        number (not applicable)
    0.5
    0.75
    0.49
    0.6
    Statistical analysis title
    Statistical analysis b/w Varenicline and Bupropion
    Comparison groups
    Varenicline v Bupropion
    Number of subjects included in analysis
    4022
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6105 [34]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.65
         upper limit
    2.01
    Notes
    [34] - 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.
    Statistical analysis title
    Statistical analysis b/w Varenicline and NRT
    Comparison groups
    Varenicline v NRT patch
    Number of subjects included in analysis
    4038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7895 [35]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.65
         upper limit
    2.01
    Notes
    [35] - 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.
    Statistical analysis title
    Statistical analysis b/w Varenicline and Placebo
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    4030
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6804 [36]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.75
         upper limit
    1.8
    Notes
    [36] - 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.
    Statistical analysis title
    Statistical analysis b/w Bupropion and NRT
    Comparison groups
    Bupropion v NRT patch
    Number of subjects included in analysis
    4028
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8127 [37]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    0.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.95
         upper limit
    2.49
    Notes
    [37] - 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.
    Statistical analysis title
    Statistical analysis b/w Bupropion and Placebo
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    4020
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9218 [38]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.04
         upper limit
    2.25
    Notes
    [38] - 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.
    Statistical analysis title
    Statistical analysis b/w NRT patch and Placebo
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    4036
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8841 [39]
    Method
    Regression, Logistic
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.32
         upper limit
    2
    Notes
    [39] - 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.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected at the Week 24 visit of study 2010-022914-15 until the end of study (i.e. Week 52 or date of discontinuation, as applicable).
    Adverse event reporting additional description
    The Safety analysis set was defined as all participants that received at least one partial dose of study drug during the parent study (i.e., the safety analysis set for 2010-022914-15).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Varenicline
    Reporting group description
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, cardiovascular events that occurred during parent study 2010-022914-15 when participants received varenicline in a triple-dummy design were analyzed as part of this study.

    Reporting group title
    Bupropion
    Reporting group description
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, cardiovascular events that occurred during parent study 2010-022914-15 when participants received bupropion in a triple-dummy design were analyzed as part of this study.

    Reporting group title
    NRT patch
    Reporting group description
    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 2010-022914-15 when participants received NRT patch in a triple-dummy design were analyzed as part of this study.

    Reporting group title
    Placebo
    Reporting group description
    This was the non-treatment extension study of parent study 2010-022914-15. No study drug was provided during this extension phase. However, cardiovascular events that occurred during parent study 2010-022914-15 when participants received placebo in a triple-dummy design were analyzed as part of this study.

    Serious adverse events
    Varenicline Bupropion NRT patch Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    34 / 1192 (2.85%)
    39 / 1166 (3.34%)
    43 / 1116 (3.85%)
    41 / 1121 (3.66%)
         number of deaths (all causes)
    2
    1
    1
    0
         number of deaths resulting from adverse events
    1
    0
    0
    0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iliac artery occlusion
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Drug detoxification
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anogenital warts
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast neoplasm
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatosplenic T-cell lymphoma
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma stage II
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 1192 (0.08%)
    1 / 1166 (0.09%)
    1 / 1116 (0.09%)
    2 / 1121 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature baby
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder with depressed mood
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Depressed mood
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    2 / 1192 (0.17%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    2 / 1121 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    0 / 1192 (0.00%)
    2 / 1166 (0.17%)
    1 / 1116 (0.09%)
    2 / 1121 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia, paranoid type
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periorbital haemorrhage
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stab wound
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 1192 (0.00%)
    4 / 1166 (0.34%)
    2 / 1116 (0.18%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    2 / 1116 (0.18%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    2 / 1121 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 1192 (0.17%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 1192 (0.08%)
    1 / 1166 (0.09%)
    2 / 1116 (0.18%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    1 / 1116 (0.09%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Morton’s neuralgia
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Chalazion
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine ophthalmopathy
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 1192 (0.00%)
    2 / 1166 (0.17%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder disorder
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    2 / 1116 (0.18%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis alcoholic
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    1 / 1116 (0.09%)
    2 / 1121 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic fever with renal syndrome
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    1 / 1121 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    3 / 1116 (0.27%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 1192 (0.08%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 1192 (0.08%)
    0 / 1166 (0.00%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 1192 (0.00%)
    1 / 1166 (0.09%)
    0 / 1116 (0.00%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 1192 (0.00%)
    0 / 1166 (0.00%)
    1 / 1116 (0.09%)
    0 / 1121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Varenicline Bupropion NRT patch Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    165 / 1192 (13.84%)
    160 / 1166 (13.72%)
    116 / 1116 (10.39%)
    143 / 1121 (12.76%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    103 / 1192 (8.64%)
    78 / 1166 (6.69%)
    69 / 1116 (6.18%)
    81 / 1121 (7.23%)
         occurrences all number
    123
    81
    83
    97
    Upper respiratory tract infection
         subjects affected / exposed
    63 / 1192 (5.29%)
    84 / 1166 (7.20%)
    48 / 1116 (4.30%)
    63 / 1121 (5.62%)
         occurrences all number
    75
    104
    53
    65

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Nov 2011
    In Amendment 1, the following changes were included; updated the study protocol template from the non interventional template to the interventional template because local regulations in some countries where the study was to be conducted considered certain study procedures an intervention (eg, blood draws). The contents of the protocol were minimally changed to include language applicable to interventional studies.
    05 Jun 2012
    In Amendment 2, incorporated changes based on feedback from the US FDA and to match the most recent protocol template and Pfizer SOPs. The following sections were updated: Vital signs (PR and BP) were added to all clinic visits; Section 6 (Study Procedures) was updated to include additional vital signs at every clinic visit; Section 6.2.1 (Clinic Visits) was updated to add a definition of a visit window; Section 6.3 (Subject Withdrawal) was updated to include information that all subjects would be followed until final visit unless they withdrew consent; Section 7.1 (Physical Examination, Vital Signs and Electrocardiogram) was updated to include vital signs at every clinic visit; Section 7.5 (Cardiovascular Events of Interest) was changed from: Hospitalization for angina pectoris or chest pain to: Hospitalization for unstable angina. Also wording was added to further clarify how events of interest would be identified, reviewed, and adjudicated; Section 8 updated various Adverse Event sections to match the most recent protocol template and Pfizer SOPs; Section 9.2 Efficacy Analysis was changed to Exploratory Efficacy Analyses. This was updated to provide clarification to these exploratory statistical analyses; and Section 15 Publication of Study Results updated to match the most recent protocol template and Pfizer SOPs.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/27116918
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