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    Clinical Trial Results:
    A Twelve-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Ranging Study With Follow-Up Evaluating The Safety And Efficacy of Varenicline For Smoking Cessation in Healthy Adolescent Smokers

    Summary
    EudraCT number
    		 2018-000761-37
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    18 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2018
    First version publication date
    29 Jul 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    A3051073
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01312909
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CHANTIX: Alias Study Number
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy, safety, and tolerability of varenicline compared with placebo in adolescent smokers aged 12-19 years.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 Brief (up to 10 minutes of duration) age-appropriate smoking cessation counseling, in accordance with Public Health Service (PHS) guidelines was provided by a trained counselor at each clinic visit and at each telephone contact, starting with the baseline visit till end of the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Apr 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Georgia: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 28
    Country: Number of subjects enrolled
    Russian Federation: 64
    Country: Number of subjects enrolled
    Taiwan: 25
    Country: Number of subjects enrolled
    United States: 187
    Worldwide total number of subjects
    312
    EEA total number of subjects
    0
    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)
    234
    Adults (18-64 years)
    78
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study consisted of 3 phases: Screening (3 weeks before first dose of study drug); treatment (from Week 2 to Week 12 after a 2-week titration) and non-treatment follow-up (Week 13 through Week 52).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Varenicline High Dose
    Arm description
    		 Subjects received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Subjects with a body weight less than or equal to (<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Varenicline
    Investigational medicinal product code
    CP-526,555
    Other name
    Chantix/Champix
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily

    Arm title
    		 Varenicline Low Dose
    Arm description
    		 Subjects received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Subjects with a body weight <= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Varenicline
    Investigational medicinal product code
    CP-526,555
    Other name
    Chantix/Champix
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Varenicline 0.5 mg tablet orally, twice daily

    Arm title
    		 Placebo
    Arm description
    		 Subjects received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two tablets of placebo (matched to Varenicline) orally, twice daily

    Number of subjects in period 1
    		Varenicline High Dose Varenicline Low Dose Placebo
    Started
    109
    103
    100
    Treated
    108
    100
    99
    Completed
    67
    67
    53
    Not completed
    42
    36
    47
         Consent withdrawn by subject
    8
    10
    7
         Entrance criteria not met
    -
    -
    2
         Randomized but not treated
    1
    3
    1
         Adverse event
    1
    -
    3
         Unspecified
    9
    6
    11
         Lost to follow-up
    21
    17
    20
         Protocol deviation
    2
    -
    2
         Insufficient clinical response
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Varenicline High Dose
    Reporting group description
    		 Subjects received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Subjects with a body weight less than or equal to (<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.

    Reporting group title
    Varenicline Low Dose
    Reporting group description
    		 Subjects received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Subjects with a body weight <= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.

    Reporting group values
    		 Varenicline High Dose Varenicline Low Dose Placebo Total
    Number of subjects
    		 109 103 100 312
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 80 78 76 234
        Adults (18-64 years)
    		 29 25 24 78
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    Here the data provided is for N=307 subjects of safety analysis set (subjects who took at least 1 dose of randomized study medication, including partial doses).
    Units: years
        arithmetic mean (standard deviation)
    		 16.0 ± 2.0 16.0 ± 1.7 15.8 ± 1.8 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 39 38 37 114
        Male
    		 70 65 63 198
    Race/Ethnicity, Customized
    Here the data provided is for N=307 subjects of safety analysis set (subjects who took at least 1 dose of randomized study medication, including partial doses).
    Units: Subjects
        White|
    		 81 73 74 228
        Black|
    		 9 9 5 23
        Asian|
    		 16 18 19 53
        Other|
    		 2 0 1 3
        Unknown
    		 1 3 1 5

    End points

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    End points reporting groups
    Reporting group title
    Varenicline High Dose
    Reporting group description
    		 Subjects received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Subjects with a body weight less than or equal to (<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.

    Reporting group title
    Varenicline Low Dose
    Reporting group description
    		 Subjects received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Subjects with a body weight <= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.

    Primary: 4-Week Continuous Abstinence Rate: Percentage of Subjects Who Remained Abstinent From Week 9 Through Week 12

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    End point title
    		 4-Week Continuous Abstinence Rate: Percentage of Subjects Who Remained Abstinent From Week 9 Through Week 12
    End point description
    The percentage of subjects who, at each visit from Week 9 through Week 12, reported no smoking and no use of other nicotine-containing products since the last study visit (on the Nicotine Use Inventory) and at each of these visits were confirmed to have quit based on urine cotinine less than 200 nanograms/milliliter (ng/mL). The full analysis set included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Week 9 through Week 12
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    109
    103
    100
    Units: percentage of subjects
        number (not applicable)
    20.2
    27.2
    18.0
    Statistical analysis title
    		 Varenicline High Dose Vs. Placebo
    Statistical analysis description
    Odds ratios and p-values were obtained from a logistic regression model with terms treatment, age strata, body weight strata and pooled center.
    Comparison groups
    Varenicline High Dose v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.6337 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 2.37
    Notes
    [1] - A testing order was used to control type I error. 1mg Varenicline twice daily group was tested against placebo first, and if statistically significant difference was observed, the 0.5 mg Varenicline twice daily group was tested against placebo.
    [2] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Varenicline Low Dose Vs. Placebo
    Statistical analysis description
    Odds ratios and p-values were obtained from a logistic regression model with terms treatment, age strata, body weight strata and pooled center.
    Comparison groups
    Varenicline Low Dose v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.1114 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 3.39
    Notes
    [3] - A testing order was used to control type I error. 1mg Varenicline twice daily group was tested against placebo first, and if statistically significant difference was observed, the 0.5 mg Varenicline twice daily group was tested against placebo.
    [4] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects With 7-Day Point Prevalence of Smoking Abstinence at Weeks 12, 24 and 52

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    End point title
    		 Percentage of Subjects With 7-Day Point Prevalence of Smoking Abstinence at Weeks 12, 24 and 52
    End point description
    The percentage of subjects who reported no smoking and no use of other nicotine-containing products (treatment phase) or tobacco products (non-treatment phase) on the Nicotine Use Inventory in the 7 days prior to the study visits or telephone contacts at Week 12,24 and 52.The full analysis set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24 and 52
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    109
    103
    100
    Units: percentage of subjects
    number (not applicable)
        Week 12
    31.2
    37.9
    23.0
        Week 24
    31.2
    35.9
    23.0
        Week 52
    28.4
    35.0
    20.0
    Statistical analysis title
    		 Varenicline High Dose Vs. Placebo
    Statistical analysis description
    Week 12: Odds ratios and p-values were obtained from separate logistic regression models of treatment, pooled center, age strata and body weight strata.
    Comparison groups
    Varenicline High Dose v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5793
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 2.38
    Statistical analysis title
    		 Varenicline Low Dose Vs. Placebo
    Statistical analysis description
    Week 12: Odds ratios and p-values were obtained from separate logistic regression models of treatment, pooled center, age strata and body weight strata.
    Comparison groups
    Varenicline Low Dose v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0932
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 3.51
    Statistical analysis title
    		 Varenicline High Dose Vs. Placebo
    Statistical analysis description
    Week 24: Odds ratios and p-values were obtained from separate logistic regression models of treatment, pooled center, age strata and body weight strata.
    Comparison groups
    Varenicline High Dose v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5647
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 2.5
    Statistical analysis title
    		 Varenicline Low Dose Vs. Placebo
    Statistical analysis description
    Week 24: Odds ratios and p-values were obtained from separate logistic regression models of treatment, pooled center, age strata and body weight strata.
    Comparison groups
    Varenicline Low Dose v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2917
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 2.96
    Statistical analysis title
    		 Varenicline High Dose Vs. Placebo
    Statistical analysis description
    Week 52: Odds ratios and p-values were obtained from separate logistic regression models of treatment, pooled center, age strata and body weight strata.
    Comparison groups
    Varenicline High Dose v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5616
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 2.69
    Statistical analysis title
    		 Varenicline Low Dose Vs. Placebo
    Statistical analysis description
    Week 52: Odds ratios and p-values were obtained from separate logistic regression models of treatment, pooled center, age strata and body weight strata.
    Comparison groups
    Varenicline Low Dose v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.13
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 3.78

    Secondary: Change From Baseline in Daily Number of Cigarettes Smoked at Weeks 12, 24, and 52

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    End point title
    		 Change From Baseline in Daily Number of Cigarettes Smoked at Weeks 12, 24, and 52
    End point description
    The reduction in the number of the cigarettes smoked was calculated by subtracting the reported average number of cigarettes smoked per day in the past 7 days at Weeks 12, 24 and 52 from the average number of cigarettes smoked per day in the past 7 days reported at the baseline visit. The full analysis set included all randomized subjects. The longitudinal model includes all subjects regardless of observed visits.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, and 52
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    109
    103
    100
    Units: cigarettes smoked per day
    least squares mean (standard error)
        Change at Week 12|
    -8.56 ± 0.43
    -8.20 ± 0.44
    -8.01 ± 0.46
        Change at Week 24|
    -6.93 ± 0.44
    -7.31 ± 0.45
    -6.59 ± 0.48
        Change at Week 52|
    -6.80 ± 0.45
    -7.74 ± 0.46
    -6.98 ± 0.48
    Statistical analysis title
    		 Varenicline High Dose Vs. Placebo
    Statistical analysis description
    Week 12: Analysis was performed using longitudinal repeated measures model with the change from baseline average number of Cigarettes Smoked as the dependent variable, including terms treatment, visit, age strata, body weight strata, pooled center, baseline measure and treatment by visit interaction.
    Comparison groups
    Varenicline High Dose v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.354
    Method
    		 Longitudinal repeated measures model
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    -0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.69
         upper limit
    		 0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58
    Statistical analysis title
    		 Varenicline Low Dose Vs. Placebo
    Statistical analysis description
    Week 12: Analysis was performed using longitudinal repeated measures model with the change from baseline average number of Cigarettes Smoked as the dependent variable, including terms treatment, visit, age strata, body weight strata, pooled center, baseline measure and treatment by visit interaction.
    Comparison groups
    Varenicline Low Dose v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7574
    Method
    		 Longitudinal repeated measures model
    Parameter type
    		 LS mean difference
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.35
         upper limit
    		 0.98
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.59
    Statistical analysis title
    		 Varenicline High Dose Vs. Placebo
    Statistical analysis description
    Week 24: Analysis was performed using longitudinal repeated measures model with the change from baseline average number of Cigarettes Smoked as the dependent variable, including terms treatment, visit, age strata, body weight strata, pooled center, baseline measure and treatment by visit interaction.
    Comparison groups
    Varenicline High Dose v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5676
    Method
    		 Longitudinal repeated measures model
    Parameter type
    		 LS mean difference
    Point estimate
    -0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.53
         upper limit
    		 0.84
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6
    Statistical analysis title
    		 Varenicline Low Dose Vs. Placebo
    Statistical analysis description
    Week 24: Analysis was performed using longitudinal repeated measures model with the change from baseline average number of Cigarettes Smoked as the dependent variable, including terms treatment, visit, age strata, body weight strata, pooled center, baseline measure and treatment by visit interaction.
    Comparison groups
    Varenicline Low Dose v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2356
    Method
    		 Longitudinal repeated measures model
    Parameter type
    		 LS mean difference
    Point estimate
    -0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.92
         upper limit
    		 0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.61
    Statistical analysis title
    		 Varenicline High Dose Vs. Placebo
    Statistical analysis description
    Week 52: Analysis was performed using longitudinal repeated measures model with the change from baseline average number of Cigarettes Smoked as the dependent variable, including terms treatment, visit, age strata, body weight strata, pooled center, baseline measure and treatment by visit interaction.
    Comparison groups
    Varenicline High Dose v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.773
    Method
    		 Longitudinal repeated measures model
    Parameter type
    		 LS mean difference
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.03
         upper limit
    		 1.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.62
    Statistical analysis title
    		 Varenicline Low Dose Vs. Placebo
    Statistical analysis description
    Week 52: Analysis was performed using longitudinal repeated measures model with the change from baseline average number of Cigarettes Smoked as the dependent variable, including terms treatment, visit, age strata, body weight strata, pooled center, baseline measure and treatment by visit interaction.
    Comparison groups
    Varenicline Low Dose v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2166
    Method
    		 Longitudinal repeated measures model
    Parameter type
    		 LS mean difference
    Point estimate
    -0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.99
         upper limit
    		 0.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.62

    Secondary: Continuous Abstinence Rate: Percentage of Subjects Who Remained Abstinent From Week 9 Through Week 24 and Week 52

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    End point title
    		 Continuous Abstinence Rate: Percentage of Subjects Who Remained Abstinent From Week 9 Through Week 24 and Week 52
    End point description
    The percentage of subjects who, at each visit from Week 9 to 52 (inclusive), reported no smoking and no use of other nicotine-containing products (Weeks 9-12) or tobacco products (Weeks 13-52) since the last study visit/last contact (on the Nicotine Use Inventory) and at any of the study visits were confirmed to have quit based on urine cotinine less than 200 ng/mL. The full analysis set included all randomized subjects. The longitudinal model included all subjects regardless of observed visits.
    End point type
    Secondary
    End point timeframe
    Week 9 through Week 24; Week 9 through Week 52
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    109
    103
    100
    Units: percentage of subjects
    number (not applicable)
        Week 9 through Week 24
    10.1
    24.3
    13.0
        Week 9 through Week 52
    8.3
    20.4
    9.0
    Statistical analysis title
    		 Varenicline High Dose Vs. Placebo
    Statistical analysis description
    Week 9 through Week 24: Odds ratios and p-values were obtained from a logistic regression model including the main effects of treatment, pooled center, age strata and body weight strata.
    Comparison groups
    Varenicline High Dose v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6133
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.9
    Statistical analysis title
    		 Varenicline Low Dose Vs. Placebo
    Statistical analysis description
    Week 9 through Week 24: Odds ratios and p-values were obtained from a logistic regression model including the main effects of treatment, pooled center, age strata and body weight strata.
    Comparison groups
    Varenicline Low Dose v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0335
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.07
         upper limit
    		 4.79
    Statistical analysis title
    		 Varenicline High Dose Vs. Placebo
    Statistical analysis description
    Week 9 through Week 52: Odds ratios and p-values were obtained from a logistic regression model including the main effects of treatment, pooled center, age strata and body weight strata.
    Comparison groups
    Varenicline High Dose v Placebo
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9874
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 2.65
    Statistical analysis title
    		 Varenicline Low Dose Vs. Placebo
    Statistical analysis description
    Week 9 through Week 52: Odds ratios and p-values were obtained from a logistic regression model including the main effects of treatment, pooled center, age strata and body weight strata.
    Comparison groups
    Varenicline Low Dose v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0188
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 6.55

    Secondary: Daily Number of Cigarettes Smoked at Baseline

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    End point title
    		 Daily Number of Cigarettes Smoked at Baseline
    End point description
    The average number of cigarettes smoked per day in the past 7 days reported at the baseline visit.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    109
    103
    100
    Units: cigarettes smoked per day
        arithmetic mean (standard error)
    10.68 ± 0.624
    9.56 ± 0.530
    9.57 ± 0.531
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Treatment-Emergent Adverse Events (AEs)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs)
    End point description
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both non-serious AEs and SAEs. The safety analysis set included all participants who took at least one dose of randomized study medication, including partial doses.
    End point type
    Other pre-specified
    End point timeframe
    First dose up to last dose (up-to Week 12) plus 30 days
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    108
    100
    99
    Units: subjects
    65
    53
    52
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Treatment Emergent Treatment-Related Adverse Events (AEs)

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    End point title
    		 Number of Subjects With Treatment Emergent Treatment-Related Adverse Events (AEs)
    End point description
    Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug.Treatment-emergent were events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.Relatedness to drug was assessed by the investigator(Yes/No). Subjects with multiple occurrences of an AE within a category were counted once within the category.An AE:any untoward medical occurrence attributed to study drug in a subject who received study drug. A serious AE (SAE):an AE resulting in any of the following outcomes or deemed significant for any other reason:death;initial or prolonged inpatient hospitalization;life-threatening experience;persistent or significant disability;congenital anomaly.AEs included both non-serious AEs and SAEs.The safety analysis set included all subjects who took at least one dose of randomized study medication,including partial doses.
    End point type
    Other pre-specified
    End point timeframe
    First dose up to last dose (up-to Week 12) plus 30 days
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    108
    100
    99
    Units: subjects
    46
    28
    27
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Treatment-Emergent Neuropsychiatric Adverse Event Elicited by Neuropsychiatric Adverse Event Interview (NAEI)

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    End point title
    		 Number of Subjects With Treatment-Emergent Neuropsychiatric Adverse Event Elicited by Neuropsychiatric Adverse Event Interview (NAEI)
    End point description
    An AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. SAE: AE causing: death; initial/prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent/significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Solicited AEs collected by semi-structured NAEI inquiring about AEs: depression, anxiety, delusions, hallucinations, paranoia, psychosis, mania, panic, agitation, dissociative states, feeling abnormal, hostility, aggression and homicidal ideation. If a subject had a positive response to any item on the NAEI, investigator determined if it met criteria AE criteria. The safety analysis set included all subjects who took at least one dose of randomized study medication, including partial doses.
    End point type
    Other pre-specified
    End point timeframe
    First dose up to last dose (up-to Week 12) plus 30 days
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    108
    100
    99
    Units: subjects
        Neuropsychiatric AEs
    18
    11
    12
        Neuropsychiatric SAEs
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Number of Subjects With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS)
    End point description
    The C-SSRS (mapped to Columbia Classification Algorithm of Suicide Assessment (C-CASA) categories);was an interview-based instrument to systematically assess suicidal ideation and suicidal behavior.C-SSRS assessed whether participant experienced any of the following:completed suicide;suicide attempt(response of "Yes" on "actual attempt");preparatory acts toward imminent suicidal behavior("Yes" on "preparatory acts or behavior","aborted attempt" or "interrupted attempt"),suicidal ideation("Yes" on "wish to be dead","non-specific (NS) active suicidal thoughts","active suicidal ideation with methods without intent to act or some intent to act,without specific plan or with specific plan and intent,any self-injurious behavior (IB) with no suicidal intent (“Yes”on “Has participant engaged in non-suicidal self-injurious behavior”).Here,number of participants with positive response(response of "yes") to suicidal behavior or/and Ideation,any non-suicidal self-injurious behavior were reported.
    End point type
    Other pre-specified
    End point timeframe
    Screening, Baseline, Week 1 up to Week 12 (treatment-emergent [TE]), thereafter up to Week 52 (last follow-up [FU])
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    108
    100
    99
    Units: subjects
        Screening:Suicidal Behavior or/and Ideation
    2
    3
    2
        Screening:Suicidal Ideation
    2
    3
    2
        Screening: Wish to be Dead
    2
    2
    2
        Screening: Non-Specific Active Suicidal Thoughts
    1
    1
    2
        Screen:Self InjuriousBehavior,no Suicidal Intent
    3
    3
    2
        TE:Suicidal Behavior or/and Ideation(n=105,99,96)
    1
    0
    1
        TE:Suicidal Ideation(n=105,99,96)
    1
    0
    1
        TE: Wish to be Dead(n=105,99,96)
    1
    0
    1
        TE: NS Active Suicidal Thoughts (n=105,99,96)
    0
    0
    1
        TE:Self IB, no Suicidal Intent (n=105,99,96)
    0
    0
    1
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points

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    End point title
    		 Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points
    End point description
    The HADS is a self-administered questionnaire measuring anxiety. Hospital Anxiety and Depression Scale Anxiety subscale (HADS-A) consisted of 7 items that were assessed on a scale of 0 = no anxiety to 3 = severe feeling of anxiety. Total HADS-A subscale score range from 0 = no anxiety to 21 = severe anxiety; higher scores indicated more severe anxiety. The safety analysis set included all subjects who took at least one dose of randomized study medication, including partial doses. Here, 'n' signifies subjects evaluable for this end point at specified time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 28, 36, 44, and 52
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    108
    100
    99
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=108,100,99)
    2.4 ± 2.05
    1.9 ± 2.06
    2.3 ± 2.26
        Change at Week 1 (n=104,99,94)
    -0.6 ± 1.86
    -0.5 ± 1.53
    -0.3 ± 1.91
        Change at Week 2 (n=102,97,89)
    -1.1 ± 1.95
    -0.7 ± 1.90
    -0.5 ± 2.18
        Change at Week 3 (n=101,91,87)
    -1.2 ± 1.85
    -0.8 ± 1.96
    -1.0 ± 2.09
        Change at Week 4 (n=95,88,87)
    -1.5 ± 1.83
    -0.9 ± 2.31
    -0.9 ± 2.21
        Change at Week 5 (n=92,86,81)
    -1.3 ± 2.03
    -1.0 ± 2.12
    -1.2 ± 2.19
        Change at Week 6 (n=90,84,75)
    -1.5 ± 1.91
    -1.0 ± 2.25
    -1.2 ± 2.31
        Change at Week 7 (n=88,79,73)
    -1.6 ± 2.13
    -1.1 ± 2.41
    -1.2 ± 2.39
        Change at Week 8 (n=88,81,74)
    -1.5 ± 2.11
    -1.1 ± 2.20
    -1.3 ± 1.99
        Change at Week 9 (n=86,77,69)
    -1.4 ± 2.17
    -1.2 ± 2.35
    -1.1 ± 2.13
        Change at Week 10 (n=81,80,70)
    -1.4 ± 2.07
    -1.2 ± 2.44
    -1.1 ± 2.34
        Change at Week 11 (n=83,80,67)
    -1.4 ± 2.00
    -1.2 ± 2.23
    -1.3 ± 2.12
        Change at Week 12 (n=82,77,65)
    -1.4 ± 2.07
    -1.3 ± 2.31
    -1.2 ± 2.15
        Change at Week 13 (n=84,76,65)
    -1.5 ± 2.13
    -1.2 ± 2.17
    -1.2 ± 2.33
        Change at Week 14 (n=79,76,62)
    -1.4 ± 2.33
    -1.2 ± 2.53
    -1.2 ± 2.19
        Change at Week 15 (n=76,74,62)
    -1.7 ± 2.09
    -1.3 ± 2.43
    -1.0 ± 3.35
        Change at Week 16 (n=76,74,61)
    -1.6 ± 2.16
    -1.2 ± 2.44
    -1.1 ± 2.54
        Change at Week 20 (n=78,72,60)
    -1.5 ± 2.28
    -1.2 ± 2.31
    -1.3 ± 2.21
        Change at Week 28 (n=72,69,56)
    -1.5 ± 2.54
    -1.2 ± 2.46
    -1.2 ± 2.38
        Change at Week 36 (n=72,67,53)
    -1.4 ± 2.42
    -1.2 ± 2.51
    -1.3 ± 2.03
        Change at Week 44 (n=70,66,53)
    -1.8 ± 2.21
    -1.2 ± 2.34
    -1.0 ± 1.90
        Change at Week 52 (n=67,67,53)
    -1.6 ± 2.20
    -1.1 ± 2.39
    -1.5 ± 2.06
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points

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    End point title
    		 Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points
    End point description
    Hospital Anxiety and Depression Scale Depression subscale (HADS-D) consists of 7 items that were assessed on a scale of 0 = no depression to 3 = severe feeling of depression. Total HADS-D subscale score range from 0 = no depression to 21 = severe feeling of depression; higher scores indicated a greater intensity of depression. The safety analysis set included all subjects who took at least one dose of randomized study medication, including partial doses. Here, 'n' signifies subjects evaluable for this end point at specified time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 28, 36, 44, and 52
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    108
    100
    99
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=108,100,99)
    1.5 ± 1.93
    1.4 ± 1.79
    1.4 ± 1.83
        Change at Week 1 (n=104,99,94)
    -0.4 ± 1.43
    -0.2 ± 1.18
    0.1 ± 1.61
        Change at Week 2 (n=102,97,89)
    -0.5 ± 1.57
    -0.2 ± 1.65
    -0.1 ± 1.80
        Change at Week 3 (n=101,91,87)
    -0.5 ± 1.39
    -0.3 ± 1.55
    -0.3 ± 1.79
        Change at Week 4 (n=95,88,87)
    -0.7 ± 1.39
    -0.3 ± 1.79
    -0.4 ± 2.00
        Change at Week 5 (n=92,86,81)
    -0.6 ± 1.66
    -0.3 ± 1.97
    -0.3 ± 1.88
        Change at Week 6 (90,84,75)
    -0.6 ± 1.85
    -0.4 ± 1.60
    -0.5 ± 1.83
        Change at Week 7 (n=88,79,73)
    -0.7 ± 1.52
    -0.5 ± 1.91
    -0.4 ± 2.13
        Change at Week 8 (n=88,81,74)
    -0.8 ± 1.87
    -0.5 ± 1.80
    -0.5 ± 1.80
        Change at Week 9 (n=86,77,69)
    -0.8 ± 1.63
    -0.5 ± 1.85
    -0.5 ± 2.30
        Change at Week 10 (n=81,80,70)
    -0.9 ± 1.67
    -0.7 ± 1.63
    -0.4 ± 2.77
        Change at Week 11 (n=83,80,67)
    -0.7 ± 1.53
    -0.9 ± 1.66
    -0.5 ± 2.11
        Change at Week 12 (n=82,77,65)
    -0.7 ± 1.79
    -0.7 ± 1.72
    -0.6 ± 2.11
        Change at Week 13 (n=84,76,65)
    -0.6 ± 2.16
    -0.7 ± 1.79
    -0.7 ± 1.95
        Change at Week 14 (n=79,76,62)
    -0.8 ± 1.96
    -0.6 ± 1.84
    -0.5 ± 2.22
        Change at Week 15 (n=76,74,62)
    -0.8 ± 1.83
    -0.8 ± 1.84
    -0.3 ± 3.26
        Change at Week 16 (n=76,74,61)
    -0.6 ± 2.09
    -0.6 ± 2.08
    -0.2 ± 2.79
        Change at Week 20 (n=78,72,60)
    -0.8 ± 1.71
    -0.8 ± 1.84
    -0.6 ± 2.24
        Change at Week 28 (n=72,69,56)
    -0.9 ± 1.63
    -0.8 ± 1.90
    -0.5 ± 2.40
        Change at Week 36 (n=72,67,53)
    -0.7 ± 2.19
    -0.8 ± 1.77
    -0.4 ± 2.40
        Change at Week 44 (n=70,66,53)
    -0.9 ± 1.93
    -0.9 ± 1.78
    -0.3 ± 2.44
        Change at Week 52 (n=67,67,53)
    -0.7 ± 1.81
    -0.8 ± 1.67
    -0.6 ± 2.02
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects with Laboratory Abnormalities

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    End point title
    		 Number of Subjects with Laboratory Abnormalities
    End point description
    Criteria for laboratory abnormalities: Lymphocytes Absolute (Abs), Lymphocytes percentage (%), Total Neutrophils (Abs), Neutrophils %: <0.8*LLN or >1.2*ULN; Basophils (Abs), Basophils %Eosinophils (Abs), Eosinophils %, Monocytes (Abs), Monocytes %:> 1.2*ULN; Total Bilirubin milligram per deciliter (mg/dl) >1.5*ULN; alanine aminotransferase: >3.0*ULN; Blood urea nitrogen, Creatinine: >1.3*ULN; Uric acid :> 1.2*ULN. The safety analysis set included all subjects who took at least one dose of randomized study medication, including partial doses. Here, ‘Number of Subjects Analyzed’= subjects evaluable for this end point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    103
    93
    90
    Units: subjects
    35
    33
    26
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Blood Pressure (BP) at Week 12

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    End point title
    		 Change From Baseline in Blood Pressure (BP) at Week 12
    End point description
    Measurement of BP included supine and sitting systolic BP, standing systolic BP, supine and sitting diastolic BP and standing diastolic BP. Blood pressure was taken after subjects rested in a sitting position for 5 minutes. BP was recorded after subjects had been supine for approximately 5 minutes, and then orthostatic blood pressure was recorded immediately when the subject stood. The safety analysis set included all subjects who took at least one dose of randomized study medication, including partial doses. Here, ‘Number of Subjects Analyzed= subjects evaluable for this end point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    77
    77
    59
    Units: millimeters of mercury (mmHg)
    median (full range (min-max))
        Supine Systolic BP:Baseline
    115.0 (85 to 164)
    114.0 (92 to 136)
    109.0 (95 to 142)
        Supine Systolic BP:Change at Week 12
    0.0 (-33 to 25)
    0.0 (-32 to 31)
    0.0 (-35 to 43)
        Sitting Systolic BP:Baseline
    117.0 (90 to 148)
    115.0 (95 to 139)
    113.0 (95 to 135)
        Sitting Systolic BP:Change at Week 12
    -1.0 (-24 to 31)
    0.0 (-30 to 28)
    2.0 (-28 to 28)
        Standing Systolic BP:Baseline
    116.0 (88 to 157)
    115.0 (92 to 155)
    112.0 (90 to 136)
        Standing Systolic BP:Change at Week 12
    0.0 (-30 to 40)
    0.0 (-21 to 53)
    3.0 (-18 to 47)
        Supine Diastolic BP:Baseline
    69.0 (45 to 99)
    66.0 (45 to 84)
    65.0 (50 to 90)
        Supine Diastolic BP:Change at Week 12
    0.0 (-26 to 17)
    0.0 (-20 to 22)
    0.0 (-35 to 21)
        Sitting Diastolic BP:Baseline
    72.0 (50 to 94)
    70.0 (38 to 92)
    69.0 (47 to 87)
        Sitting Diastolic BP:Change at Week 12
    0.0 (-20 to 28)
    -1.0 (-35 to 23)
    1.0 (-18 to 22)
        Standing Diastolic BP:Baseline
    73.0 (57 to 106)
    72.0 (55 to 99)
    70.0 (50 to 92)
        Standing Diastolic BP:Change at Week 12
    0.0 (-28 to 22)
    -1.0 (-43 to 23)
    2.0 (-21 to 20)
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Pulse Rate at Week 12

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    End point title
    		 Change From Baseline in Pulse Rate at Week 12
    End point description
    Measurement of pulse rate included supine, sitting and standing pulse rate. Pulse rate was taken after subjects rested in a sitting position for 5 minutes. Pulse rate was recorded after subjects had been supine for approximately 5 minutes and then immediately upon standing. The safety analysis set included all subjects who took at least one dose of randomized study medication, including partial doses. Here, ‘Number of Subjects Analyzed= subjects evaluable for this end point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12
    End point values
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Number of subjects analysed
    77
    77
    59
    Units: beats per minute (bpm)
    median (full range (min-max))
        Supine Pulse Rate:Baseline
    75.0 (50 to 111)
    72.0 (50 to 105)
    72.0 (54 to 113)
        Supine Pulse Rate:Change at Week 12
    0.0 (-32 to 44)
    1.0 (-23 to 23)
    3.0 (-30 to 29)
        Sitting Pulse Rate:Baseline
    75.0 (58 to 118)
    75.0 (48 to 113)
    77.0 (58 to 115)
        Sitting Pulse Rate:Change at Week 12
    -1.0 (-22 to 25)
    0.0 (-33 to 30)
    1.0 (-43 to 36)
        Standing Pulse Rate:Baseline
    84.0 (61 to 139)
    85.0 (61 to 119)
    85.0 (63 to 122)
        Standing Pulse Rate:Change at Week 12
    1.0 (-35 to 44)
    -3.0 (-25 to 32)
    -3.0 (-53 to 44)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose up to last dose (up-to Week 12) plus 30 days
    Adverse event reporting additional description
    Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another, or a subject may have experienced both a serious and non-serious event.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Varenicline High Dose
    Reporting group description
    		 Subjects received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Subjects with a body weight less than or equal to (<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.

    Reporting group title
    Varenicline Low Dose
    Reporting group description
    		 Subjects received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Subjects with a body weight <= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.

    Serious adverse events
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 100 (1.00%)
    1 / 99 (1.01%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder with mixed disturbance of emotion and conduct
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Varenicline High Dose Varenicline Low Dose Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    65 / 108 (60.19%)
    53 / 100 (53.00%)
    51 / 99 (51.52%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 100 (2.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    2
    0
    Chest pain
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Chills
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Energy increased
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Feeling jittery
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    2
    0
    Malaise
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    1
    0
    Pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 100 (2.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    2
    1
    Immune system disorders
    Multiple allergies
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    0
    2
    Cough
         subjects affected / exposed
    2 / 108 (1.85%)
    2 / 100 (2.00%)
    0 / 99 (0.00%)
         occurrences all number
    2
    2
    0
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Haemoptysis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 100 (1.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 108 (0.93%)
    3 / 100 (3.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    3
    0
    Pharyngeal oedema
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Productive cough
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory disorder
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    1
    0
    Sinus congestion
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 100 (1.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    3
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    8 / 108 (7.41%)
    5 / 100 (5.00%)
    4 / 99 (4.04%)
         occurrences all number
    8
    5
    4
    Adjustment disorder
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Anxiety
         subjects affected / exposed
    6 / 108 (5.56%)
    4 / 100 (4.00%)
    7 / 99 (7.07%)
         occurrences all number
    6
    4
    10
    Agitation
         subjects affected / exposed
    9 / 108 (8.33%)
    5 / 100 (5.00%)
    5 / 99 (5.05%)
         occurrences all number
    11
    5
    5
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Aversion
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 100 (2.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    2
    0
    Depression
         subjects affected / exposed
    3 / 108 (2.78%)
    2 / 100 (2.00%)
    3 / 99 (3.03%)
         occurrences all number
    3
    3
    3
    Dissociation
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Flat affect
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    0
    1
    Grief reaction
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Hallucination
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    1
    0
    2
    Hostility
         subjects affected / exposed
    7 / 108 (6.48%)
    3 / 100 (3.00%)
    4 / 99 (4.04%)
         occurrences all number
    7
    3
    5
    Insomnia
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    0
    Irritability
         subjects affected / exposed
    2 / 108 (1.85%)
    3 / 100 (3.00%)
    1 / 99 (1.01%)
         occurrences all number
    2
    3
    1
    Mania
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    1
    0
    Middle insomnia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Nightmare
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Restlessness
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    0
    1
    Initial insomnia
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Blood pressure orthostatic decreased
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    1
    Body mass index increased
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    0
    2
    White blood cell count decreased
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    2
    1
    0
    Fall
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Foot fracture
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Ligament injury
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Ligament rupture
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    2
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Road traffic accident
         subjects affected / exposed
    0 / 108 (0.00%)
    3 / 100 (3.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    3
    1
    Skin abrasion
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    1
    Wrist fracture
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Disturbance in attention
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    6 / 108 (5.56%)
    7 / 100 (7.00%)
    3 / 99 (3.03%)
         occurrences all number
    6
    7
    3
    Dysgeusia
         subjects affected / exposed
    1 / 108 (0.93%)
    3 / 100 (3.00%)
    2 / 99 (2.02%)
         occurrences all number
    1
    3
    2
    Headache
         subjects affected / exposed
    14 / 108 (12.96%)
    5 / 100 (5.00%)
    8 / 99 (8.08%)
         occurrences all number
    14
    5
    8
    Hypoaesthesia
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Lethargy
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Memory impairment
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Migraine
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    3
    0
    0
    Sinus headache
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Sleep paralysis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    2
    0
    1
    Tension headache
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    0
    2
    Tremor
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    1
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Deafness unilateral
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Otorrhoea
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 108 (2.78%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    3
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 108 (0.93%)
    3 / 100 (3.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    3
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 100 (1.00%)
    2 / 99 (2.02%)
         occurrences all number
    3
    1
    2
    Diarrhoea
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 100 (1.00%)
    3 / 99 (3.03%)
         occurrences all number
    2
    1
    3
    Gastric disorder
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Gastroduodenitis
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 100 (1.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    1
    Haematemesis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    26 / 108 (24.07%)
    19 / 100 (19.00%)
    12 / 99 (12.12%)
         occurrences all number
    31
    22
    14
    Odynophagia
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 100 (2.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    2
    0
    Toothache
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 100 (2.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    3
    1
    Vomiting
         subjects affected / exposed
    14 / 108 (12.96%)
    2 / 100 (2.00%)
    2 / 99 (2.02%)
         occurrences all number
    18
    2
    2
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Dermatitis contact
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    0
    2
    Rash maculo-papular
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary hesitation
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 108 (0.93%)
    2 / 100 (2.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    2
    1
    Back pain
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Costochondritis
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    0
    1
    Folliculitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Furuncle
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 100 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    2
    0
    3
    Gastroenteritis viral
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Gonorrhoea
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 100 (2.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    2
    0
    Laryngitis
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 108 (3.70%)
    3 / 100 (3.00%)
    5 / 99 (5.05%)
         occurrences all number
    6
    3
    5
    Pharyngitis
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 108 (0.93%)
    3 / 100 (3.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    3
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    0
    2
    Respiratory tract infection viral
         subjects affected / exposed
    3 / 108 (2.78%)
    0 / 100 (0.00%)
    3 / 99 (3.03%)
         occurrences all number
    4
    0
    4
    Rhinitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    1
    Sinusitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    0
    2
    0
    Tonsillitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 108 (5.56%)
    5 / 100 (5.00%)
    2 / 99 (2.02%)
         occurrences all number
    6
    5
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 100 (1.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    1
    Viral pharyngitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    0
    1
    Dehydration
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    0
    Increased appetite
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    2
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Mar 2011
    Inconsistency between AE reporting period criteria was modified to make timeframe be “informed consent through last visit”. 24 week endpoints was added to make consistent with other protocols in program. Dosing instructions were clarified. Section 8.2 was changed to correct inconsistency between start of AE collection and AE reporting periods.
    09 Aug 2011
    Modified exclusion criteria to indicate that use of psychoactive or psychotropic drugs in the 6 months prior to screening had to be discussed with the sponsor, rather than be prohibited (in order to allow consideration of ADHD subjects on Ritalin or Adderall).
    23 Nov 2011
    Modified exclusion criteria to indicate that use of psychoactive or psychotropic drugs in the 6 months prior to screening had to be discussed with the sponsor, rather than be prohibited (in order to allow consideration of ADHD subjects on Ritalin or Adderall). Removed specification for use of the COT-One cotinine testing kit.
    20 Jan 2012
    Protocol Summary “Safety Assessments” section wording had been slightly modified to improve quality.
    09 Jul 2012
    In Section 8.3 drug dependency and drug abuse was added as examples of reportable Adverse events (AEs) and removed from signs and symptoms resulting from these. Medication errors were added.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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