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    Clinical Trial Results:
    A PHASE 4, RANDOMIZED, DOUBLE BLIND, ACTIVE AND PLACEBO CONTROLLED, MULTICENTER STUDY EVALUATING THE NEUROPSYCHIATRIC SAFETY AND EFFICACY OF 12 WEEKS VARENICLINE TARTRATE 1 MG BID AND BUPROPION HYDROCHLORIDE 150 MG BID FOR SMOKING CESSATION IN SUBJECTS WITH AND WITHOUT A HISTORY OF PSYCHIATRIC DISORDERS

    Summary
    EudraCT number
    2010-022914-15
    Trial protocol
    ES   DE   DK   FI   BG   SK  
    Global end of trial date
    13 Jan 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    A3051123
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01456936
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 East 42nd Street, New York, NY, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc.,, +1 8007181021, 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
    29 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Safety Objectives: 1. To characterize the neuropsychiatric safety profiles of varenicline and bupropion by estimating the differences from placebo in the incidence of the primary neuropsychiatric AE endpoint for subjects: a. With a diagnosis of psychiatric disorder; b. Without a diagnosis of psychiatric disorder. 2. To characterize the differences in the neuropsychiatric safety profiles of varenicline and bupropion as compared with placebo between these sub-populations (cohorts). Efficacy: Abstinence from Smoking Main Efficacy Objective: To compare smoking abstinence rates of varenicline and bupropion relative to placebo for the last 4 weeks of treatment and continuously through Week 24, as measured by CO-confirmed continuous abstinence rate (CAR) CAR9-12 and CAR9-24, respectively, separately for subjects with and without a diagnosis of psychiatric disorder.
    Protection of trial subjects
    All parties will ensure protection of subject personal data and will not include partcipant names on any sponsor forms, reports, publications, or in any other disclosures, except where required by laws. In case of data transfer, Pfizer will maintain high standards of confidentiality and protection of subject personal data. The informed consent form must be in compliance with ICH GCP, local regulatory requirements, and legal requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Nov 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety, Regulatory reason
    Long term follow-up duration
    3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 202
    Country: Number of subjects enrolled
    South Africa: 295
    Country: Number of subjects enrolled
    Spain: 237
    Country: Number of subjects enrolled
    United States: 4207
    Country: Number of subjects enrolled
    Argentina: 329
    Country: Number of subjects enrolled
    Australia: 55
    Country: Number of subjects enrolled
    Brazil: 21
    Country: Number of subjects enrolled
    Bulgaria: 490
    Country: Number of subjects enrolled
    Canada: 277
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    Denmark: 113
    Country: Number of subjects enrolled
    Finland: 501
    Country: Number of subjects enrolled
    Germany: 876
    Country: Number of subjects enrolled
    Mexico: 187
    Country: Number of subjects enrolled
    New Zealand: 125
    Country: Number of subjects enrolled
    Russian Federation: 126
    Worldwide total number of subjects
    8058
    EEA total number of subjects
    2419
    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)
    7529
    From 65 to 84 years
    529
    85 years and over
    0

    Subject disposition

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

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

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Varenicline
    Arm description
    Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, Nicotine Replacement Therapy (NRT) in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg daily once (QD) x 3 days, 0.5 mg twice daily (BID) x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.
    Arm type
    Experimental

    Investigational medicinal product name
    Varenicline tartrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The titration had two steps: 0.5 mg once daily for 3 days, 0.5 mg twice daily for 4 days and 1 mg twice daily for 11 weeks.

    Arm title
    Bupropion
    Arm description
    Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.
    Arm type
    Experimental

    Investigational medicinal product name
    Buproprion hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg daily once for 3 days and 150 mg twice daily for remainder of treatment period.

    Arm title
    NRT patch
    Arm description
    Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.
    Arm type
    Active comparator

    Investigational medicinal product name
    Nicotine replacement therapy patch
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    1 mg daily once for 3 days, 1 mg daily twice for 4 days, 21 mg per day for 7 weeks, 14 mg per day for 2 weeks and 7 mg for 2 weeks for a toal of 11 weeks of treatment

    Arm title
    Placebo
    Arm description
    Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet, Transdermal patch
    Routes of administration
    Oral use, Transdermal use
    Dosage and administration details
    Matching placebo for varenicline, buproprion and NRT

    Number of subjects in period 1
    Varenicline Bupropion NRT patch Placebo
    Started
    2016
    2006
    2022
    2014
    Completed
    1598
    1586
    1557
    1552
    Not completed
    418
    420
    465
    462
         Medication error
    -
    1
    -
    1
         Protocol deviation
    4
    2
    5
    5
         No longer meets eligibility criteria
    4
    8
    6
    5
         Adverse event (study drug unrelated)
    9
    7
    9
    9
         Pregnancy
    1
    -
    -
    1
         Other reason
    41
    30
    36
    33
         Adverse event, serious fatal
    -
    3
    1
    3
         Adverse event (study drug)
    25
    21
    26
    17
         Insufficient clinical response
    4
    4
    14
    13
         No longer willing to participate
    195
    218
    224
    248
         Lost to follow-up
    135
    126
    144
    127

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Varenicline
    Reporting group description
    Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, Nicotine Replacement Therapy (NRT) in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg daily once (QD) x 3 days, 0.5 mg twice daily (BID) x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.

    Reporting group title
    Bupropion
    Reporting group description
    Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.

    Reporting group title
    NRT patch
    Reporting group description
    Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.

    Reporting group title
    Placebo
    Reporting group description
    Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.

    Reporting group values
    Varenicline Bupropion NRT patch Placebo Total
    Number of subjects
    2016 2006 2022 2014 8058
    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)
    1884 1859 1887 1899 7529
        From 65-84 years
    132 147 135 115 529
        85 years and over
    0 0 0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    46.5 ± 12.4 46.35 ± 12.6 46.85 ± 12.15 46.4 ± 12.15 -
    Gender, Male/Female
    Units: Participants
        Female
    1114 1116 1141 1138 4509
        Male
    902 890 881 876 3549

    End points

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    End points reporting groups
    Reporting group title
    Varenicline
    Reporting group description
    Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, Nicotine Replacement Therapy (NRT) in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg daily once (QD) x 3 days, 0.5 mg twice daily (BID) x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.

    Reporting group title
    Bupropion
    Reporting group description
    Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.

    Reporting group title
    NRT patch
    Reporting group description
    Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.

    Reporting group title
    Placebo
    Reporting group description
    Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.

    Primary: Occurrence of neuropsychiatric (NPS) adverse events (AE) - the primary study endpoint

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    End point title
    Occurrence of neuropsychiatric (NPS) adverse events (AE) - the primary study endpoint
    End point description
    The primary safety endpoint is the occurrence of at least one treatment emergent “severe” adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent “moderate” or “severe” adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Primary
    End point timeframe
    Treatment emergent is first dose date to last dose date (upto 12 weeks) plus 30 days
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: percentage of participants
    number (not applicable)
        Non-psychiatric cohort (N= 990, 989, 1006, 999)
    1.3
    2.2
    2.5
    2.4
        Psychiatric cohort (N= 1026, 1017, 1016, 1015)
    6.5
    6.7
    5.2
    4.9
        Overall (N= 2016, 2006, 2022, 2014)
    4
    4.5
    3.9
    3.7
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The reduced (final) statistical model included treatment group, cohort and region, plus the 2-way interaction of treatment by cohort. Other interactions not included due to lack of significance. Region reduced to 2-level to address event sparseness issue.
    Comparison groups
    Bupropion v Varenicline v NRT patch v Placebo
    Number of subjects included in analysis
    8058
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0652 [1]
    Method
    Regression, Linear
    Confidence interval
    Notes
    [1] - For the reduced model at 10% level (typical for interaction assessment due to inherently poor power), there was a significant interaction between treatment and cohort. No multiplicity adjustments were utilized.

    Primary: Estimated NPS AE rate (%), by cohort

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    End point title
    Estimated NPS AE rate (%), by cohort
    End point description
    The primary safety endpoint is the occurrence of at least one treatment emergent “severe” adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent “moderate” or “severe” adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Primary
    End point timeframe
    Treatment emergent is first dose date to last dose date (upto 12 weeks) plus 30 days
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: Units on scale
    least squares mean (confidence interval 100%)
        Non-psychiatric cohort (N=3984)
    1.25 (0.6 to 1.9)
    2.44 (1.52 to 3.36)
    2.31 (1.37 to 3.25)
    2.52 (1.58 to 3.46)
        Psychiatric cohort (N= 4074)
    6.42 (4.91 to 7.93)
    6.62 (5.09 to 8.15)
    5.2 (3.84 to 6.56)
    4.83 (3.51 to 6.16)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Non-psychiatric cohort
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    4030
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Regression, Linear
    Parameter type
    Risk difference (RD)
    Point estimate
    -1.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.4
         upper limit
    -0.15
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Non-psychiatric
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    4020
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Regression, Linear
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.37
         upper limit
    1.21
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Non-psychiatric cohort
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    4036
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Regression, Linear
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.54
         upper limit
    1.12
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Psychiatric cohort
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    4030
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Regression, Linear
    Parameter type
    Risk difference (RD)
    Point estimate
    1.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.42
         upper limit
    3.59
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Psychiatric cohort
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    4020
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Regression, Linear
    Parameter type
    Risk difference (RD)
    Point estimate
    1.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.24
         upper limit
    3.81
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Psychiatric cohort
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    4036
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Regression, Linear
    Parameter type
    Risk difference (RD)
    Point estimate
    0.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.53
         upper limit
    2.26

    Secondary: Occurrence of the components of the NPS AE primary endpoint, non-psychiatric history cohort

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    End point title
    Occurrence of the components of the NPS AE primary endpoint, non-psychiatric history cohort
    End point description
    The safety endpoint is the occurrence of at least one treatment emergent “severe” adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent “moderate” or “severe” adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Each of these 16 components is reported below. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Treatment emergent is first dose date to last dose date (upto 12 weeks) plus 30 days
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    990
    989
    1006
    999
    Units: participants
        Anxiety (severe)
    0
    1
    0
    3
        Depression (severe)
    1
    0
    0
    0
        Feeling abnormal (severe only)
    0
    0
    0
    0
        Hostility (severe)
    0
    1
    1
    0
        Agitation (moderate and severe)
    10
    11
    19
    11
        Aggression (moderate and severe)
    3
    3
    2
    3
        Delusions (moderate and severe)
    0
    0
    1
    0
        Hallucinations (moderate and severe)
    1
    0
    0
    0
        Mania (moderate and severe)
    0
    1
    2
    2
        Panic (moderate and severe)
    0
    4
    1
    3
        Paranoia (moderate and severe)
    0
    1
    0
    0
        Psychosis (moderate and severe)
    0
    0
    1
    0
        Homicidal ideation (moderate and severe)
    0
    0
    1
    0
        Suicidal behavior (moderate and severe)
    0
    1
    1
    0
        Suicidal ideation (moderate and severe)
    0
    1
    2
    3
        Suicide (moderate and severe)
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Occurrence of the components of the NPS AE primary endpoint, psychiatric history cohort

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    End point title
    Occurrence of the components of the NPS AE primary endpoint, psychiatric history cohort
    End point description
    The safety endpoint is the occurrence of at least one treatment emergent “severe” adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent “moderate” or “severe” adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Each of these 16 components is reported below. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Treatment emergent is first dose date to last dose date (upto 12 weeks) plus 30 days
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    1026
    1017
    1016
    1015
    Units: participants
        Anxiety (severe)
    5
    4
    6
    2
        Depression (severe)
    6
    4
    7
    6
        Feeling abnormal (severe only)
    0
    1
    0
    0
        Hostility (severe)
    0
    0
    0
    0
        Agitation (moderate and severe)
    25
    29
    21
    22
        Aggression (moderate and severe)
    14
    9
    7
    8
        Delusions (moderate and severe)
    1
    1
    1
    0
        Hallucinations (moderate and severe)
    5
    4
    2
    2
        Mania (moderate and severe)
    7
    9
    3
    6
        Panic (moderate and severe)
    7
    16
    13
    7
        Paranoia (moderate and severe)
    1
    0
    0
    2
        Psychosis (moderate and severe)
    4
    2
    3
    1
        Homicidal ideation (moderate and severe)
    0
    0
    0
    0
        Suicidal behavior (moderate and severe)
    1
    1
    0
    1
        Suicidal ideation (moderate and severe)
    5
    2
    3
    2
        Suicide (moderate and severe)
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Occurrence of the components of NPS AE Primary Endpoint (Overall)

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    End point title
    Occurrence of the components of NPS AE Primary Endpoint (Overall)
    End point description
    The NPS AE composite results (as previously described) are for the two cohorts combined and are presented below. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Treatment emergent is first dose date to last dose date (upto 12 weeks) plus 30 days
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: participants
        Anxiety
    5
    5
    6
    5
        Depression
    7
    4
    7
    6
        Feeling Abnormal
    0
    1
    1
    0
        Hostility
    0
    1
    1
    0
        Agitation
    35
    40
    40
    33
        Aggression
    17
    12
    9
    11
        Delusions
    1
    1
    2
    0
        Hallucination
    6
    4
    2
    2
        Mania
    7
    10
    5
    8
        Panic Disorder
    7
    20
    14
    10
        Paranoia
    1
    1
    0
    2
        Psychosis
    4
    2
    4
    1
        Homicidal Ideation
    0
    0
    1
    0
        Suicidal Behavior
    1
    2
    1
    1
        Suicidal Ideation
    5
    3
    5
    5
        Suicide
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Occurrence of severe-only NPS AEs in the primary endpoint, by cohort

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    End point title
    Occurrence of severe-only NPS AEs in the primary endpoint, by cohort
    End point description
    The primary safety endpoint is the occurrence of at least one treatment emergent “severe” adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent “moderate” or “severe” adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Treatment emergent is first dose date to last dose date (upto 12 weeks) plus 30 days
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: percentage of participants
    number (not applicable)
        Non-psychiatric cohort (N= 990, 989, 1006, 999)
    0.1
    0.4
    0.3
    0.5
        Psychiatric cohort (N= 1026, 1017, 1016, 1015)
    1.4
    1.4
    1.4
    1.3
        Overall (N= 2016, 2006, 2022, 2014)
    0.7
    0.9
    0.8
    0.9
    No statistical analyses for this end point

    Secondary: Occurrence of the components of the observed severe-only NPS AE primary endpoint, non-psychiatric history cohort

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    End point title
    Occurrence of the components of the observed severe-only NPS AE primary endpoint, non-psychiatric history cohort
    End point description
    The safety endpoint is the occurrence of at least one treatment emergent “severe” adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent “moderate” or “severe” adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Treatment emergent is first dose date to last dose date (upto 12 weeks) plus 30 days
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    990
    989
    1006
    999
    Units: participants
        Anxiety
    0
    1
    0
    3
        Depression
    1
    0
    0
    0
        Feeling abnormal
    0
    0
    0
    0
        Hostility
    0
    1
    1
    0
        Agitation
    0
    0
    2
    0
        Aggression
    1
    1
    0
    0
        Delusions
    0
    0
    0
    0
        Hallucinations
    0
    0
    0
    0
        Mania
    0
    0
    0
    0
        Panic
    0
    1
    1
    1
        Paranoia
    0
    0
    0
    0
        Psychosis
    0
    0
    0
    0
        Homicidal ideation
    0
    0
    0
    0
        Suicidal behavior
    0
    1
    0
    0
        Suicidal ideation
    0
    0
    0
    1
        Suicide
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Occurrence of the components of the observed severe-only NPS AE primary endpoint, psychiatric history cohort

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    End point title
    Occurrence of the components of the observed severe-only NPS AE primary endpoint, psychiatric history cohort
    End point description
    The safety endpoint is the occurrence of at least one treatment emergent “severe” adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent “moderate” or “severe” adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Treatment emergent is first dose date to last dose date (upto 12 weeks) plus 30 days
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    1026
    1017
    1016
    1015
    Units: Participants
        Anxiety
    5
    4
    6
    2
        Depression
    6
    4
    7
    6
        Feeling abnormal
    0
    1
    0
    0
        Hostility
    0
    0
    0
    0
        Agitation
    1
    1
    4
    2
        Aggression
    1
    1
    0
    1
        Delusions
    0
    0
    0
    0
        Hallucinations
    0
    1
    0
    0
        Mania
    2
    1
    0
    0
        Panic
    0
    1
    0
    1
        Paranoia
    0
    0
    0
    0
        Psychosis
    0
    1
    1
    0
        Homicidal ideation
    0
    0
    0
    0
        Suicidal behavior
    1
    1
    0
    1
        Suicidal ideation
    1
    0
    1
    0
        Suicide
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Occurrence of the components of severe-only NPS AE endpoint (overall)

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    End point title
    Occurrence of the components of severe-only NPS AE endpoint (overall)
    End point description
    The NPS AE endpoint was the occurrence of at least 1 treatment-emergent “severe” AE of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least 1 treatment-emergent “severe” AE of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Treatment emergent is first dose date to last dose date (upto 12 weeks) plus 30 days
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: participants
        Anxiety
    5
    5
    6
    5
        Depression
    7
    4
    7
    6
        Feeling Abnormal
    0
    1
    0
    0
        Hostility
    0
    1
    1
    0
        Agitation
    1
    1
    6
    2
        Aggression
    2
    2
    0
    1
        Delusions
    0
    1
    0
    0
        Hallucination
    0
    1
    0
    0
        Mania
    2
    1
    0
    0
        Panic Disorder
    0
    2
    1
    2
        Paranoia
    1
    1
    0
    2
        Psychosis
    4
    2
    4
    1
        Suicidal Behavior
    1
    2
    0
    1
        Suicidal Ideation
    1
    0
    1
    0
        Suicide
    0
    0
    0
    1
        Homicidal Ideation
    0
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Hospital Anxiety and Depression Scale (HADS) Total Score, non-psychiatric history cohort

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    End point title
    Hospital Anxiety and Depression Scale (HADS) Total Score, non-psychiatric history cohort
    End point description
    The HADS is a subject self-reporting scale completed in person at clinic visits at Baseline and Weeks 1 through 6, 8, 10, 12, 13, 16, 20, and 24. It contains 14 individual item responses ranging in increasing severity from 0 (normal) to 3 (most severe) for a total range of 0 to 42. Of the 14 items, 7 assess anxiety and 7 assess depression, providing 2 subscales with ranges of 0 to 21. For each subscale, 0 to 7 is considered normal, while 15 to 21 represents severe symptoms.The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    990
    989
    1006
    999
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 1 (N= 984, 972, 989, 992)
    3.26 ± 3.92
    3.58 ± 4.25
    3.06 ± 3.87
    3.38 ± 4.2
        Week 2 (N= 961, 954, 963, 970)
    2.91 ± 3.86
    3.07 ± 3.96
    2.84 ± 3.85
    3.2 ± 4.25
        Week 3 (N= 935, 930, 936, 941)
    2.61 ± 3.85
    2.64 ± 3.82
    2.63 ± 3.93
    2.77 ± 3.94
        Week 4 (N= 923, 916, 934, 923)
    2.4 ± 3.66
    2.36 ± 3.57
    2.46 ± 3.8
    2.77 ± 4.21
        Week 5 (N= 911, 897, 906, 902)
    2.29 ± 3.51
    2.24 ± 3.52
    2.32 ± 3.86
    2.48 ± 3.92
        Week 6 (N= 899, 893, 909, 897)
    2.23 ± 3.56
    2.18 ± 3.57
    2.4 ± 3.87
    2.48 ± 3.97
        Week 8 (N= 868, 861, 877, 877)
    2.17 ± 3.6
    2.16 ± 3.7
    2.28 ± 3.6
    2.64 ± 4.29
        Week 10 (N= 853, 844, 852, 846)
    2.29 ± 3.89
    1.96 ± 3.24
    2.33 ± 3.8
    2.57 ± 4.41
        Week 12 (N= 772, 768, 750, 742)
    2.07 ± 3.48
    1.83 ± 3.21
    2.01 ± 3.51
    2.46 ± 4.1
        Week 13 (N= 797, 796, 789, 807)
    2.11 ± 3.74
    1.85 ± 3.22
    2.01 ± 3.47
    2.38 ± 4.27
        Week 16 (N= 784, 797, 775, 789)
    2.05 ± 3.47
    1.9 ± 3.43
    2.09 ± 3.61
    2.34 ± 3.98
        Week 20 (N= 771, 785, 762, 772)
    2.1 ± 3.54
    1.93 ± 3.36
    1.97 ± 3.53
    2.31 ± 4.15
        Week 24 (N= 758, 748, 737, 758)
    2.01 ± 3.49
    1.87 ± 3.47
    2.01 ± 3.45
    2.25 ± 4.04
    No statistical analyses for this end point

    Secondary: HADS Total Score, psychiatric history cohort

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    End point title
    HADS Total Score, psychiatric history cohort
    End point description
    The HADS is a subject self-reporting scale completed in person at clinic visits at Baseline and Weeks 1 through 6, 8, 10, 12, 13, 16, 20, and 24. It contains 14 individual item responses ranging in increasing severity from 0 (normal) to 3 (most severe) for a total range of 0 to 42. Of the 14 items, 7 assess anxiety and 7 assess depression, providing 2 subscales with ranges of 0 to 21. For each subscale, 0 to 7 is considered normal, while 15 to 21 represents severe symptoms. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    1026
    1017
    1016
    1015
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 1 (N= 1026, 1017, 1015, 1015)
    6.76 ± 6.14
    7.58 ± 6.87
    6.82 ± 6.33
    6.7 ± 5.94
        Week 2 (N= 1005, 1004, 996, 995)
    6.42 ± 6.36
    6.99 ± 6.47
    6.64 ± 6.55
    6.42 ± 6.17
        Week 3 (N= 947, 961, 945, 926)
    5.99 ± 6.21
    6.51 ± 6.39
    6.3 ± 6.55
    6.02 ± 6.1
        Week 4 (N= 935, 938, 929, 908)
    5.87 ± 6.39
    6.36 ± 6.55
    6.16 ± 6.51
    6.04 ± 6.31
        Week 5 (N= 918, 918, 914, 895)
    5.58 ± 6.32
    6.03 ± 6.41
    5.82 ± 6.44
    5.8 ± 6.31
        Week 6 (N= 917, 914, 912, 874)
    5.39 ± 6.14
    5.87 ± 6.41
    5.62 ± 6.22
    5.75 ± 6.26
        Week 8 (N= 887, 893, 878, 859)
    5.43 ± 6.24
    5.96 ± 6.68
    5.63 ± 6.36
    5.63 ± 6.26
        Week 10 (N= 864, 865, 864, 823)
    5.38 ± 6.35
    5.72 ± 6.5
    5.64 ± 6.3
    5.55 ± 6.38
        Week 12 (N= 790, 803, 798, 749)
    5.17 ± 6.09
    5.66 ± 6.63
    5.44 ± 6.3
    5.42 ± 6.13
        Week 13 (N= 813, 812, 814, 763)
    5.06 ± 6.11
    5.44 ± 6.54
    5.36 ± 6.2
    5.09 ± 5.96
        Week 16 (N= 795, 805, 791, 748)
    5.26 ± 6.35
    5.62 ± 6.68
    5.44 ± 6.34
    5.37 ± 6.38
        Week 20 (N= 784, 784, 763, 737)
    5.17 ± 6.02
    5.54 ± 6.44
    5.46 ± 6.18
    5.26 ± 6.22
        Week 24 (N= 770, 764, 758, 729)
    5.21 ± 6.27
    5.69 ± 6.64
    5.57 ± 6.32
    5.04 ± 5.97
    No statistical analyses for this end point

    Secondary: HADS Total Score (overall)

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    End point title
    HADS Total Score (overall)
    End point description
    The HADS is a subject self-reporting scale completed in person at clinic visits at Baseline and Weeks 1 through 6, 8, 10, 12, 13, 16, 20, and 24. It contains 14 individual item responses ranging in increasing severity from 0 (normal) to 3 (most severe) for a total range of 0 to 42. Of the 14 items, 7 assess anxiety and 7 assess depression, providing 2 subscales with ranges of 0 to 21. For each subscale, 0 to 7 is considered normal, while 15 to 21 represents severe symptoms. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 1 (N= 1989, 1976, 1985, 1987)
    5.03 ± 5.45
    5.61 ± 6.07
    4.95 ± 5.58
    5.05 ± 5.41
        Week 2 (N= 1938, 1937, 1931, 1929)
    4.68 ± 5.55
    5.06 ± 5.73
    4.74 ± 5.7
    4.8 ± 5.53
        Week 3 (N= 1882, 1891, 1881, 1867)
    4.31 ± 5.44
    4.6 ± 5.63
    4.48 ± 5.71
    4.38 ± 5.37
        Week 4 (N= 1858, 1854, 1863, 1831)
    4.15 ± 5.5
    4.39 ± 5.65
    4.31 ± 5.64
    4.39 ± 5.6
        Week 5 (N= 1829, 1815, 1820, 1797)
    3.94 ± 5.37
    4.16 ± 5.52
    4.08 ± 5.59
    4.14 ± 5.51
        Week 6 (N= 1816, 1807, 1821, 1771)
    3.82 ± 5.27
    4.05 ± 5.52
    4.01 ± 5.42
    4.09 ± 5.48
        Week 8 (N= 1755, 1754, 1755, 1736)
    3.82 ± 5.36
    4.1 ± 5.75
    3.96 ± 5.43
    4.12 ± 5.56
        Week 10 (N= 1717, 1709, 1716, 1669)
    3.85 ± 5.49
    3.86 ± 5.48
    4 ± 5.47
    4.04 ± 5.67
        Week 12 (N= 1562, 1571, 1548, 1491)
    3.64 ± 5.21
    3.79 ± 5.58
    3.78 ± 5.42
    3.95 ± 5.42
        Week 13 (N= 1610, 1608, 1603, 1570)
    3.6 ± 5.29
    3.66 ± 5.47
    3.71 ± 5.32
    3.7 ± 5.34
        Week 16 (N= 1579, 1602, 1566, 1537)
    3.67 ± 5.37
    3.77 ± 5.63
    3.78 ± 5.44
    3.82 ± 5.5
        Week 20 (N= 1555, 1569, 1525, 1509)
    3.65 ± 5.18
    3.73 ± 5.44
    3.72 ± 5.33
    3.75 ± 5.47
        Week 24 (N= 1528, 1512, 1495, 1487)
    3.62 ± 5.33
    3.8 ± 5.64
    3.82 ± 5.41
    3.62 ± 5.27
    No statistical analyses for this end point

    Secondary: Positive responses for suicidal behavior and/or ideation by Columbia Suicide Severity Rating Scale (C‑SSRS) - non-psychiatric history cohort

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    End point title
    Positive responses for suicidal behavior and/or ideation by Columbia Suicide Severity Rating Scale (C‑SSRS) - non-psychiatric history cohort
    End point description
    The C-SSRS is a semi-structured interview designed to evaluate an individual's degree of suicidal ideation, preparatory acts or behavior to actual attempt, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent". Answers at screening are for lifetime history. Answers for all other visits are since last visit. The scale is also used to record any completed suicides. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    990
    989
    1006
    999
    Units: participants with positive responses
        Suicidal Behavior (Screening lifetime)
    6
    9
    7
    6
        Suicidal Ideation (Screening lifetime)
    48
    43
    50
    49
        Suicidal Behavior (Baseline)
    0
    0
    0
    0
        Suicidal Ideation (Baseline)
    0
    1
    0
    1
        Suicidal Behavior (treatment emergent 12 weeks)
    0
    0
    1
    1
        Suicidal Ideation (treatment emergent 12 weeks)
    7
    4
    3
    6
    No statistical analyses for this end point

    Secondary: Positive responses for suicidal behavior and/or ideation by Columbia Suicide Severity Rating Scale (C‑SSRS) - psychiatric history cohort

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    End point title
    Positive responses for suicidal behavior and/or ideation by Columbia Suicide Severity Rating Scale (C‑SSRS) - psychiatric history cohort
    End point description
    The C-SSRS is a semi-structured interview designed to evaluate an individual's degree of suicidal ideation, preparatory acts or behavior to actual attempt, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent". Answers at screening are for lifetime history. Answers for all other visits are since last visit. The scale is also used to record any completed suicides. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    1026
    1017
    1016
    1015
    Units: participants with positive responses
        Suicidal Behavior (Screening lifetime)
    137
    143
    111
    123
        Suicidal Ideation (Screening lifetime)
    338
    357
    333
    349
        Suicidal Behavior (Baseline)
    0
    0
    0
    1
        Suicidal Ideation (Baseline)
    6
    5
    2
    3
        Suicidal Behavior (treatment emergent 12 weeks)
    0
    1
    0
    2
        Suicidal Ideation (treatment emergent 12 weeks)
    27
    15
    20
    25
    No statistical analyses for this end point

    Secondary: Positive responses for suicidal behavior and/or ideation by Columbia Suicide Severity Rating Scale (C‑SSRS) - overall

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    End point title
    Positive responses for suicidal behavior and/or ideation by Columbia Suicide Severity Rating Scale (C‑SSRS) - overall
    End point description
    The C-SSRS is a semi-structured interview designed to evaluate an individual's degree of suicidal ideation, preparatory acts or behavior to actual attempt, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent". Answers at screening are for lifetime history. Answers for all other visits are since last visit. The scale is also used to record any completed suicides. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: participants with positive responses
        Suicidal Behavior (Screening lifetime)
    143
    152
    118
    129
        Suicidal Ideation (Screening lifetime)
    386
    400
    383
    398
        Suicidal Behavior (Baseline)
    0
    0
    0
    1
        Suicidal Ideation (Baseline)
    6
    6
    2
    4
        Suicidal Behavior (treatment emergent 12 weeks)
    0
    1
    1
    3
        Suicidal Ideation (treatment emergent 12 weeks)
    34
    19
    23
    31
    No statistical analyses for this end point

    Secondary: Clinical Global Impression of Improvement (CGI‑I), "No Change" rating by visit

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    End point title
    Clinical Global Impression of Improvement (CGI‑I), "No Change" rating by visit
    End point description
    The CGI-I is a clinician rated instrument that measures change in participant's psychiatric condition (or lack thereof in the stratum without psychiatric disorders) on a 7 point scale ranging from 1 (very much improved) to 7 (very much worse), with 4 = no change. The ratings were applicable even to those without psychiatric diagnoses (eg, those with no psychiatric symptoms would be rated as "normal, not at all ill" on the CGI-S at baseline and assuming no psychiatric symptoms emerge during the trial, would be rated as "no change" on the CGI-I at follow-up visits). For those participants with a psychiatric diagnosis, the clinician should rate the severity of the mental illness with respect to the clinician's experience with the psychiatric population to which the participant belongs. The safety dataset included all participants who had received at least one partial dose of study medication (N=8058) and was used to analyze all safety endpoints.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014
    Units: percentage of participants
    number (not applicable)
        Week 1 (N= 1986, 1974, 1986, 1982)
    94.2
    93.2
    94.6
    95.1
        Week 2 (N= 1934, 1936, 1927, 1926)
    90.8
    90.8
    90.5
    91.2
        Week 3 (N= 1880, 1892, 1880, 1863)
    88.3
    89.8
    88.7
    87.9
        Week 4 (N= 1860, 1856, 1858, 1834)
    86.6
    88
    87.1
    86.3
        Week 5 (N= 1828, 1816, 1822, 1802)
    85.7
    86.5
    85.5
    85.4
        Week 6 (N= 1816, 1808, 1820, 1773)
    85.2
    86.5
    85.1
    84.1
        Week 8 (N= 1758, 1756, 1755, 1738)
    82.4
    83.6
    82.8
    81.9
        Week 10 (N= 1717, 1707, 1715, 1675)
    80.6
    81.7
    80.4
    79.2
        Week 12 (N= 1558, 1572, 1540, 1492)
    72.9
    75.1
    72.2
    71.3
        Week 13 (N= 1612, 16081602, 1575)
    75.9
    76.7
    75.2
    74.9
        Week 16 (N= 1586, 1606, 1568, 1541)
    74.2
    76.7
    73.9
    73.4
        Week 20 (N= 1563, 1573, 1523, 1510)
    73.4
    75
    72.2
    71.7
        Week 24 (N= 1533, 1515, 1499, 1497)
    71.8
    72.3
    71.1
    71.1
    No statistical analyses for this end point

    Secondary: CO‑confirmed continuous abstinence for Weeks 9 through 12, non-psychiatric history cohort

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    End point title
    CO‑confirmed continuous abstinence for Weeks 9 through 12, non-psychiatric history cohort
    End point description
    A responder to this endpoint requires the answer “no” to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 12 (inclusive). The efficacy population included all randomized participants (N=8144) and was used to analyze all efficacy endpoints.
    End point type
    Secondary
    End point timeframe
    Week 9 through Week 12
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    1005 [2]
    1001 [3]
    1013 [4]
    1009 [5]
    Units: percentage of participants
        number (not applicable)
    38
    26.1
    26.4
    13.7
    Notes
    [2] - The number of participants analyzed here is based on efficacy population (N=8144).
    [3] - The number of participants analyzed here is based on efficacy population (N=8144).
    [4] - The number of participants analyzed here is based on efficacy population (N=8144).
    [5] - The number of participants analyzed here is based on efficacy population (N=8144).
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    2014
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001 [6]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.2
         upper limit
    5
    Notes
    [6] - No multiplicity adjustment.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    2010
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001 [7]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.8
         upper limit
    2.85
    Notes
    [7] - No multiplicity adjustment.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    2022
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001 [8]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.83
         upper limit
    2.9
    Notes
    [8] - No multiplicity adjustment.

    Secondary: CO‑confirmed continuous abstinence for Weeks 9 through 12, psychiatric history cohort

    Close Top of page
    End point title
    CO‑confirmed continuous abstinence for Weeks 9 through 12, psychiatric history cohort
    End point description
    A responder to this endpoint requires the answer “no” to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 12 (inclusive). The efficacy population included all randomized participants (N=8144) and was used to analyze all efficacy endpoints.
    End point type
    Secondary
    End point timeframe
    Week 9 through Week 12
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    1032 [9]
    1033 [10]
    1025 [11]
    1026 [12]
    Units: percentage of participants
        number (not applicable)
    29.2
    19.3
    20.4
    11.4
    Notes
    [9] - The number of participants analyzed here is based on efficacy population (N=8144).
    [10] - The number of participants analyzed here is based on efficacy population (N=8144).
    [11] - The number of participants analyzed here is based on efficacy population (N=8144).
    [12] - The number of participants analyzed here is based on efficacy population (N=8144).
    Statistical analysis title
    Stistical Analysis 1
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    2058
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001 [13]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.56
         upper limit
    4.11
    Notes
    [13] - No multiplicity adjustment.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    2059
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001 [14]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.46
         upper limit
    2.39
    Notes
    [14] - No multiplicity adjustment.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    2051
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001 [15]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.56
         upper limit
    2.55
    Notes
    [15] - No multiplicity adjustment.

    Secondary: CO‑confirmed continuous abstinence for Weeks 9 through 12 (overall)

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    End point title
    CO‑confirmed continuous abstinence for Weeks 9 through 12 (overall)
    End point description
    A responder to this endpoint requires the answer “no” to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 12 (inclusive). The efficacy population included all randomized participants (N=8144) and was used to analyze all efficacy endpoints.
    End point type
    Secondary
    End point timeframe
    Week 9 through Week 12
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006 [16]
    2022
    2014
    Units: Percentage of participants
        number (not applicable)
    33.5
    22.6
    23.4
    12.5
    Notes
    [16] - The number of participants analyzed here is based on efficacy population (N=8144).
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment and region. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    4030
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [17]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.07
         upper limit
    4.24
    Notes
    [17] - No multiplicity adjustment.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment and region. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    4020
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [18]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.75
         upper limit
    2.45
    Notes
    [18] - No multiplicity adjustment.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment and region. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    4036
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [19]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.82
         upper limit
    2.54
    Notes
    [19] - No multiplicity adjustment.

    Secondary: CO-confirmed continuous abstinence from Week 9 through Week 24, non-psychiatric history cohort

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    End point title
    CO-confirmed continuous abstinence from Week 9 through Week 24, non-psychiatric history cohort
    End point description
    A responder to this endpoint requires the answer “no” to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 24 (inclusive). The efficacy population included all randomized participants (N=8144) and was used to analyze all efficacy endpoints.
    End point type
    Secondary
    End point timeframe
    Week 9 through Week 24
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    1005 [20]
    1001 [21]
    1013 [22]
    1009 [23]
    Units: percentage of participants
        number (not applicable)
    25.5
    18.8
    18.5
    10.5
    Notes
    [20] - The number of participants analyzed here is based on efficacy population (N=8144).
    [21] - The number of participants analyzed here is based on efficacy population (N=8144).
    [22] - The number of participants analyzed here is based on efficacy population (N=8144).
    [23] - The number of participants analyzed here is based on efficacy population (N=8144).
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    2014
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [24]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.33
         upper limit
    3.83
    Notes
    [24] - No multiplicity adjustment.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    2010
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [25]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.54
         upper limit
    2.59
    Notes
    [25] - No multiplicity adjustment.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    2022
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [26]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.51
         upper limit
    2.54
    Notes
    [26] - No multiplicity adjustment.

    Secondary: CO-confirmed continuous abstinence from Week 9 through Week 24, psychiatric history cohort

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    End point title
    CO-confirmed continuous abstinence from Week 9 through Week 24, psychiatric history cohort
    End point description
    A responder to this endpoint requires the answer “no” to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 24 (inclusive). The efficacy population included all randomized participants (N=8144) and was used to analyze all efficacy endpoints.
    End point type
    Secondary
    End point timeframe
    Week 9 through Week 24
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    1032 [27]
    1033 [28]
    1025 [29]
    1026 [30]
    Units: percentage of participants
        number (not applicable)
    18.3
    13.7
    13
    8.3
    Notes
    [27] - The number of participants analyzed here is based on efficacy population (N=8144).
    [28] - The number of participants analyzed here is based on efficacy population (N=8144).
    [29] - The number of participants analyzed here is based on efficacy population (N=8144).
    [30] - The number of participants analyzed here is based on efficacy population (N=8144).
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    2058
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [31]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.9
         upper limit
    3.29
    Notes
    [31] - No multiplicity adjustment.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    2059
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [32]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.33
         upper limit
    2.36
    Notes
    [32] - No multiplicity adjustment.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment, cohort, region, treatment by cohort interaction, and region by cohort interaction. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    2051
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [33]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.24
         upper limit
    2.2
    Notes
    [33] - No multiplicity adjustment.

    Secondary: CO-confirmed continuous abstinence from Week 9 through Week 24 (overall)

    Close Top of page
    End point title
    CO-confirmed continuous abstinence from Week 9 through Week 24 (overall)
    End point description
    A responder to this endpoint requires the answer “no” to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 24 (inclusive). The efficacy population included all randomized participants (N=8144) and was used to analyze all efficacy endpoints.
    End point type
    Secondary
    End point timeframe
    Week 9 through Week 24
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006
    2022
    2014 [34]
    Units: percentage of participants
        number (not applicable)
    21.8
    16.2
    15.7
    9.4
    Notes
    [34] - The number of participants analyzed here is based on efficacy population (N=8144).
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment and region. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    Varenicline v Placebo
    Number of subjects included in analysis
    4030
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [35]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.28
         upper limit
    3.3
    Notes
    [35] - No multiplicity adjustment.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment and region. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    Bupropion v Placebo
    Number of subjects included in analysis
    4020
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [36]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.56
         upper limit
    2.29
    Notes
    [36] - No multiplicity adjustment.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The analysis was done using a logistic regression with terms treatment and region. Region reduced to 2-level for consistency with primary safety model.
    Comparison groups
    NRT patch v Placebo
    Number of subjects included in analysis
    4036
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [37]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.49
         upper limit
    2.19
    Notes
    [37] - No multiplicity adjustment.

    Secondary: 7‑day point prevalence of abstinence, non-psychiatric history cohort

    Close Top of page
    End point title
    7‑day point prevalence of abstinence, non-psychiatric history cohort
    End point description
    A responder to this endpoint requires the answer “no” to both questions 3 and 6 on the Nicotine Use Inventory (NUI) at that specific visit. NUI Question 3 (Baseline through Week 24): Has the participant smoked any cigarettes (even a puff) in the last 7 days? NUI Question 6 (Baseline through Week 12): Has the participant used any other nicotine containing products in the last 7 days? NUI Question 6 (Week 13 through Week 24): Has the participant used any other tobacco products in the last 7 days? The efficacy population included all randomized participants (N=8144) and was used to analyze all efficacy endpoints.
    End point type
    Secondary
    End point timeframe
    24 Weeks
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    1005 [38]
    1001 [39]
    1013 [40]
    1009 [41]
    Units: percentage of participants
    number (not applicable)
        Week 1
    1.7
    1
    1.2
    1.5
        Week 2
    20.9
    21.3
    15.5
    11.4
        Week 3
    30
    26.6
    22.1
    13.6
        Week 4
    34.3
    27.7
    25.9
    14.5
        Week 5
    38.4
    29.8
    27.8
    14.9
        Week 6
    41
    31.4
    30.4
    15.9
        Week 7
    44.4
    35.2
    35.1
    19.2
        Week 8
    42.3
    31
    31.4
    16.7
        Week 9
    47.1
    34.9
    34.8
    19
        Week 10
    42.4
    31
    31.1
    16.9
        Week 11
    46.6
    34.1
    34.9
    20.8
        Week 12
    44.4
    30.5
    30.4
    17.8
        Week 13
    41.1
    30.7
    29.9
    17.2
        Week 14
    44.5
    33.5
    32
    20.4
        Week 15
    43.8
    33.2
    32.4
    21.3
        Week 16
    37.2
    28.5
    28.1
    18.2
        Week 17
    40.7
    31.9
    31.4
    20.1
        Week 18
    40.9
    31.3
    31.7
    20.8
        Week 19
    39.9
    31.2
    31.2
    20.8
        Week 20
    35.1
    27.5
    26.3
    18.2
        Week 21
    38.1
    30.3
    29.3
    20.1
        Week 22
    38.7
    29.9
    29
    20.3
        Week 23
    37.6
    30.6
    28.3
    20.3
        Week 24
    33.6
    26
    27
    17.4
    Notes
    [38] - The number of participants analyzed here is based on efficacy population (N=8144).
    [39] - The number of participants analyzed here is based on efficacy population (N=8144).
    [40] - The number of participants analyzed here is based on efficacy population (N=8144).
    [41] - The number of participants analyzed here is based on efficacy population (N=8144).
    No statistical analyses for this end point

    Secondary: 7‑day point prevalence of abstinence, psychiatric history cohort

    Close Top of page
    End point title
    7‑day point prevalence of abstinence, psychiatric history cohort
    End point description
    A responder to this endpoint requires the answer “no” to both questions 3 and 6 on the Nicotine Use Inventory (NUI) at that specific visit. NUI Question 3 (Baseline through Week 24): Has the participant smoked any cigarettes (even a puff) in the last 7 days? NUI Question 6 (Baseline through Week 12): Has the participant used any other nicotine containing products in the last 7 days? NUI Question 6 (Week 13 through Week 24): Has the participant used any other tobacco products in the last 7 days? The efficacy population included all randomized participants (N=8144) and was used to analyze all efficacy endpoints.
    End point type
    Secondary
    End point timeframe
    24 Weeks
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    1032 [42]
    1033 [43]
    1025 [44]
    1026 [45]
    Units: percentage of participants
    number (not applicable)
        Week 1
    1
    1.2
    0.7
    0.5
        Week 2
    16.8
    14.6
    13
    9.2
        Week 3
    22.7
    18.1
    17.9
    10.7
        Week 4
    26.6
    21.3
    21.1
    11.8
        Week 5
    28.5
    21.8
    22.4
    12.4
        Week 6
    30.8
    22.7
    23.3
    13.4
        Week 7
    34.8
    25.4
    27.5
    16.6
        Week 8
    32.7
    22.1
    24.6
    15
        Week 9
    36.2
    26
    29.4
    17.2
        Week 10
    35.1
    24.3
    25
    14
        Week 11
    38.6
    27.4
    29.4
    17.2
        Week 12
    35
    23.9
    24.9
    14.2
        Week 13
    32.7
    22.6
    24
    14.8
        Week 14
    34.7
    25
    26.8
    17.8
        Week 15
    33.4
    25.3
    26
    18.3
        Week 16
    29.1
    21.9
    21.8
    13.9
        Week 17
    32.3
    24
    24.8
    17.4
        Week 18
    31.7
    24.5
    24.7
    18.2
        Week 19
    31.6
    24.7
    25.1
    17.6
        Week 20
    26.6
    20.4
    25.1
    17.6
        Week 21
    29.7
    23.2
    23.7
    17.5
        Week 22
    29.1
    22.9
    23.6
    16.5
        Week 23
    28.5
    23.5
    22.2
    16.4
        Week 24
    26.1
    20.4
    20.1
    14
    Notes
    [42] - The number of participants analyzed here is based on efficacy population (N=8144).
    [43] - The number of participants analyzed here is based on efficacy population (N=8144).
    [44] - The number of participants analyzed here is based on efficacy population (N=8144).
    [45] - The number of participants analyzed here is based on efficacy population (N=8144).
    No statistical analyses for this end point

    Secondary: 7‑day point prevalence of abstinence (overall)

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    End point title
    7‑day point prevalence of abstinence (overall)
    End point description
    A responder to this endpoint requires the answer “no” to both questions 3 and 6 on the Nicotine Use Inventory (NUI) at that specific visit. NUI Question 3 (Baseline through Week 24): Has the participant smoked any cigarettes (even a puff) in the last 7 days? NUI Question 6 (Baseline through Week 12): Has the participant used any other nicotine containing products in the last 7 days? NUI Question 6 (Week 13 through Week 24): Has the participant used any other tobacco products in the last 7 days? The efficacy population included all randomized participants (N=8144) and was used to analyze all efficacy endpoints.
    End point type
    Secondary
    End point timeframe
    24 Weeks
    End point values
    Varenicline Bupropion NRT patch Placebo
    Number of subjects analysed
    2016
    2006 [46]
    2022
    2014
    Units: percentage of participants
    number (not applicable)
        Week 1
    1.3
    1.1
    0.9
    1
        Week 2
    18.8
    17.9
    14.2
    10.3
        Week 3
    26.3
    22.3
    20
    12.1
        Week 4
    30.4
    24.4
    23.5
    13.1
        Week 5
    33.4
    25.7
    25.1
    13.6
        Week 6
    35.8
    26.9
    26.8
    14.6
        Week 7
    39.5
    30.2
    31.3
    17.9
        Week 8
    37.4
    26.5
    28
    15.9
        Week 9
    41.6
    30.4
    32.1
    18.1
        Week 10
    38.7
    27.6
    28
    15.5
        Week 11
    42.5
    30.7
    32.1
    18.8
        Week 12
    39.6
    27.1
    27.6
    16
        Week 13
    36.8
    26.5
    26.9
    16
        Week 14
    39.5
    29.2
    29.4
    19.1
        Week 15
    38.5
    29.2
    29.2
    19.8
        Week 16
    33.1
    25.1
    24.9
    16.1
        Week 17
    36.4
    27.9
    28.1
    18.8
        Week 18
    36.2
    27.8
    28.2
    19.5
        Week 19
    35.7
    27.9
    28.1
    19.2
        Week 20
    30.8
    23.9
    23.7
    16.3
        Week 21
    33.9
    26.7
    26.5
    18.8
        Week 22
    33.8
    26.4
    26.3
    18.4
        Week 23
    33
    27
    25.3
    18.3
        Week 24
    29.8
    23.2
    23.6
    15.7
    Notes
    [46] - The number of participants analyzed here is based on efficacy population (N=8144).
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline throughout the study period (16 weeks). Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.
    Adverse event reporting additional description
    Adverse events (AEs) were reported from the time the informed consent was signed throughout the study including 30 days after the last dose of study medication. In addition to the standard collection of volunteered and observed AEs, neuropsychiatric AEs of interest were solicited using the Neuropsychiatric Adverse Event Interview (NAEI).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Varenicline
    Reporting group description
    Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received varenicline titrated to the full dose during the first week in the following manner: 0.5 mg QD x 3 days, 0.5 mg BID x 4 days, then 1 mg BID for 11 weeks. They also received placebo bupropion and NRT patch, dosed in the same manner as the active medication.

    Reporting group title
    Bupropion
    Reporting group description
    Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received bupropion 150 mg QD x 3 days and taken 150 mg BID for the remainder of the treatment period (11 weeks and 4 days). They also received placebo varenicline and NRT patch, dosed in the same manner as the active medication.

    Reporting group title
    NRT patch
    Reporting group description
    Participants were randomized to 1 of the 3 active dosing groups that took active medication of either varenicline, bupropion, NRT in this triple-dummy design. Participants in this arm received NRT started active dosing the morning of the Week 1 visit and received a 21 mg transdermal patch per day x 7 weeks, followed by a 14 mg transdermal patch per day x 2 weeks, and then a 7 mg transdermal patch x 2 weeks for a total of 11 weeks of treatment. They also received placebo varenicline and bupropion, dosed in the same manner as active medication.

    Reporting group title
    Placebo
    Reporting group description
    Participants received matching placebo for varenicline, bupropion, and NRT in this triple-dummy design, and followed the same titration and dosing schedule as for the active treatments noted above.

    Serious adverse events
    Varenicline Bupropion NRT patch Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 2016 (1.93%)
    48 / 2006 (2.39%)
    45 / 2022 (2.23%)
    41 / 2014 (2.04%)
         number of deaths (all causes)
    0
    3
    2
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    2 / 2022 (0.10%)
    0 / 2014 (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
    Aortic aneurysm
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Deep vein thrombosis
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Haematoma
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Hypertension
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Vascular rupture
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Surgical and medical procedures
    Female sterilisation
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Knee operation
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Therapy change
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobular breast carcinoma in situ
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Prostate cancer
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    1 / 2022 (0.05%)
    1 / 2014 (0.05%)
         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 / 1
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Uterine leiomyoma
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    2 / 2016 (0.10%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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 / 1
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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 / 1
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Ectopic pregnancy
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    4 / 2022 (0.20%)
    2 / 2014 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 2016 (0.00%)
    2 / 2006 (0.10%)
    1 / 2022 (0.05%)
    1 / 2014 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Depression
         subjects affected / exposed
    1 / 2016 (0.05%)
    1 / 2006 (0.05%)
    1 / 2022 (0.05%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 2016 (0.10%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    3 / 2014 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 2016 (0.00%)
    2 / 2006 (0.10%)
    1 / 2022 (0.05%)
    1 / 2014 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 2016 (0.05%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Alcoholism
         subjects affected / exposed
    0 / 2016 (0.00%)
    3 / 2006 (0.15%)
    1 / 2022 (0.05%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    2 / 2022 (0.10%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Bipolar I disorder
         subjects affected / exposed
    1 / 2016 (0.05%)
    2 / 2006 (0.10%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Bipolar II disorder
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Borderline personality disorder
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Completed suicide
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Emotional disorder
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Hallucination, auditory
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Intentional self-injury
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Mental disorder
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Schizoaffective disorder
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Sleep disorder
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Suicidal behaviour
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Reproductive system and breast disorders
    Bartholin’s cyst
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Menorrhagia
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Ankle fracture
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Burns third degree
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Fall
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Hip fracture
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Humerus fracture
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Laceration
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Lower limb fracture
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Road traffic accident
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Spinal fracture
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Overdose
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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 / 1
    0 / 0
    0 / 0
    skull fracture
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Foot fracture
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Hand fracture
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Joint dislocation
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Ligament rupture
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Electrocardiogram abnormal
         subjects affected / exposed
    1 / 2016 (0.05%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Liver function test abnormal
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Atrial fibrillation
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    4 / 2022 (0.20%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Cornoary artery disease
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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 / 2016 (0.05%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    1 / 2014 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Arrhythmia
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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 failure congestive
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    2 / 2014 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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 / 1
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    2 / 2016 (0.10%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Palpitations
         subjects affected / exposed
    1 / 2016 (0.05%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Dyspnoea
         subjects affected / exposed
    2 / 2016 (0.10%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    2 / 2014 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Rhinitis allergic
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Syncope
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Intracranial aneurysm
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Paraesthesia
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Seizure
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Eye disorders
    Ulcerative keratitis
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Vitreous detachment
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Oesophagitis
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Pancreatitis
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    2 / 2022 (0.10%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Cholecystitis acute
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Cholelithiasis
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 2016 (0.00%)
    2 / 2006 (0.10%)
    0 / 2022 (0.00%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis atopic
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Psoriasis
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Back pain
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Fistula
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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 protrusion
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Pain in extremity
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Muscular weakness
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Endocrine disorders
    Thyrotoxic crisis
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    2 / 2014 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    2 / 2016 (0.10%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Hyperkalaemia
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Hypokalaemia
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Bronchitis
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    1 / 2022 (0.05%)
    1 / 2014 (0.05%)
         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
    Pneumonia
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    2 / 2022 (0.10%)
    0 / 2014 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Cellulitis
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Parotitis
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Post procedural infection
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Pyelonephritis
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Rectal abscess
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Tooth abscess
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Wound infection
         subjects affected / exposed
    1 / 2016 (0.05%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    0 / 2022 (0.00%)
    1 / 2014 (0.05%)
         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
    Device related infection
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Diverticulitis
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Herpes zoster
         subjects affected / exposed
    0 / 2016 (0.00%)
    0 / 2006 (0.00%)
    1 / 2022 (0.05%)
    0 / 2014 (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
    Oral herpes
         subjects affected / exposed
    0 / 2016 (0.00%)
    1 / 2006 (0.05%)
    0 / 2022 (0.00%)
    0 / 2014 (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
    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
    1158 / 2016 (57.44%)
    1033 / 2006 (51.50%)
    1003 / 2022 (49.60%)
    884 / 2014 (43.89%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    245 / 2016 (12.15%)
    186 / 2006 (9.27%)
    233 / 2022 (11.52%)
    199 / 2014 (9.88%)
         occurrences all number
    307
    241
    280
    246
    General disorders and administration site conditions
    Application site pruritus
         subjects affected / exposed
    22 / 2016 (1.09%)
    12 / 2006 (0.60%)
    109 / 2022 (5.39%)
    16 / 2014 (0.79%)
         occurrences all number
    24
    12
    113
    16
    Fatigue
         subjects affected / exposed
    124 / 2016 (6.15%)
    57 / 2006 (2.84%)
    75 / 2022 (3.71%)
    83 / 2014 (4.12%)
         occurrences all number
    129
    60
    83
    88
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    201 / 2016 (9.97%)
    131 / 2006 (6.53%)
    251 / 2022 (12.41%)
    92 / 2014 (4.57%)
         occurrences all number
    209
    137
    265
    97
    Anxiety
         subjects affected / exposed
    132 / 2016 (6.55%)
    169 / 2006 (8.42%)
    137 / 2022 (6.78%)
    120 / 2014 (5.96%)
         occurrences all number
    158
    200
    161
    141
    Insomnia
         subjects affected / exposed
    189 / 2016 (9.38%)
    245 / 2006 (12.21%)
    195 / 2022 (9.64%)
    139 / 2014 (6.90%)
         occurrences all number
    206
    261
    213
    152
    Irritability
         subjects affected / exposed
    82 / 2016 (4.07%)
    71 / 2006 (3.54%)
    108 / 2022 (5.34%)
    104 / 2014 (5.16%)
         occurrences all number
    95
    77
    115
    108
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    66 / 2016 (3.27%)
    146 / 2006 (7.28%)
    59 / 2022 (2.92%)
    64 / 2014 (3.18%)
         occurrences all number
    68
    155
    59
    65
    Nausea
         subjects affected / exposed
    511 / 2016 (25.35%)
    201 / 2006 (10.02%)
    199 / 2022 (9.84%)
    137 / 2014 (6.80%)
         occurrences all number
    596
    221
    221
    147
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    174 / 2016 (8.63%)
    156 / 2006 (7.78%)
    126 / 2022 (6.23%)
    135 / 2014 (6.70%)
         occurrences all number
    197
    171
    160
    154
    Upper respiratory tract infection
         subjects affected / exposed
    109 / 2016 (5.41%)
    104 / 2006 (5.18%)
    97 / 2022 (4.80%)
    115 / 2014 (5.71%)
         occurrences all number
    116
    117
    108
    124

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jun 2010
    The protocol was amended to incorporate changes requested by the Food and Drug Adminstration (FDA), to clarify certain protocol aspects, and to correct inconsistencies/typographical errors. The changes requested by FDA were to use a different guidance for suicide risk, clarifying the primary focus of suicide risk assessment was the presence or absence of current significant suicidality.
    28 Jun 2011
    The protocol was amended to incorporate changes requested by the FDA and the European Medical Agency (EMA). In addition, bupropion was added to the title, objectives, and endpoints as an active comparator. The amendment also incorporated changes to the NAEI based on the outcome of the pilot study in a similar subject population. In addition, the amendment provided updates to be in compliance with Pfizer SOPs, clarified certain protocol aspects, and corrected inconsistencies/typographical errors.
    04 Oct 2011
    The protocol was amended to include detailed cardiovascular (CV) medical history, collection of CV events of interest during the study, and a Cardiovascular Event Adjudication Committee. The protocol was also updated to be consistent with updated SOP CT 02 in regards to Section 15.1, Communication of Results to Pfizer.
    10 Oct 2011
    The protocol was amended to incorporate changes requested by the EMA for the countries of Bulgaria, Czech Republic, Denmark, Finland, France, Germany, Slovakia, and Spain. Participants with Bipolar I and II disorders were to be excluded from the study. The medical health professional was defined as a psychiatrist only.
    30 May 2012
    The protocol was amended to incorporate changes based on feedback from the FDA and regulatory agencies in the European Union (EU). Vital signs (pulse rate and blood pressure) were added to all clinic visits. ECG was added to Week 12 and Early Termination (ET) before the Week 12 visit. Section 4.2 Exclusion Criterion #22 was added to exclude participants with skin conditions that could hinder the use of NRT placement. Section 6 (Study Procedures) is updated to include additional vital signs at every clinic visit and ECG at Week 12 or ET12. Section 6.4 (Subject Withdrawal) is updated to include information for Off Treatment in Study (OTIS) participants and all participants were followed until final visit unless they withdrew consent. Section 7.1.1.2 (Physical Examination, Vital Signs and ECG) updated to include vital signs at every clinic visit and ECG as Week 12 or ET12. Section 7.1.15 (Cardiovascular Events of Interest) is 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 are identified, reviewed and adjudicated.
    07 Nov 2012
    The protocol was amended to incorporate changes based on the updated bupropion Company Core Data Sheet dated 18 Sep 2012. Study Period and Nontreatment Follow up Period Pregnancy testing was added to visits at Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16. Partcipant withdrawal added “Study drug will be discontinued immediately for any female partcipant who becomes pregnant during the treatment period of the study. Laboratory section (7.1.14) was updated to include the additional pregnancy testing at clinic visits.

    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.
    After database lock and unblinding, one additional participant in the NRT arm of psychiatric cohort was found who had a primary endpoint event (moderate suicidal ideation) which required hospitalization; this event is not included in any analyses.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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