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    Clinical Trial Results:
    A Phase 3b Multicenter, Double-Blind, Randomized, Placebo-Controlled, 2-Way Crossover Study of Pregabalin in the Treatment of Fibromyalgia With Concurrent Antidepressant Therapy for Comorbid Depression

    Summary
    EudraCT number
    		 2011-002480-19
    Trial protocol
    		 ES   IT  
    Global end of trial date
    22 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 May 2016
    First version publication date
    25 Jul 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    A0081275
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01432236
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 East 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer Clinical Trials.gov Call Centre, Pfizer Inc, 001 8007181021, clinicaltrials.govcallcenter@pfizer.com
    Scientific contact
    Pfizer Clinical Trials.gov Call Centre, Pfizer Inc, 001 8007181021, clinicaltrials.govcallcenter@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
    07 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of pregabalin compared with placebo in subjects with fibromyalgia and comorbid depression currently on a stable selective serotonin reuptake inhibitor (SSRI) or serotonin noradrenalin reuptake inhibitor (SNRI) primarily being used to treat the depression.
    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 Conference on  Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Nov 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    United States: 120
    Country: Number of subjects enrolled
    Canada: 22
    Worldwide total number of subjects
    193
    EEA total number of subjects
    51
    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)
    180
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 In this double blind, crossover study, a total of 197 subjects were randomized to either pregabalin/placebo or placebo/pregabalin treatment sequence. Of these, 193 took at least one dose of study medication. Four randomized subjects never took study medication. Randomized subjects were recruited from 4 countries at 38 study centers.

    Pre-assignment
    Screening details
    		 Subjects with mean Numeric Rating Scale (NRS) pain score of greater than or equal to (>=) 4 at baseline, meeting all other inclusion/exclusion criteria were randomly assigned to receive double blind treatment with either pregabalin followed by placebo with background antidepressant or placebo followed by pregabalin with background antidepressant.

    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
    No

    Arm title
    		 Pregabalin/Placebo
    Arm description
    		 Subjects were randomized in a 1:1 ratio to double-blind treatment with pregabalin for 6 weeks (3 weeks dose optimization and 3 weeks fixed dose) in period 1 followed by placebo in period 2 with background antidepressants. There was a 2-week single-blind taper/washout period between treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pregabalin
    Investigational medicinal product code
    Other name
    Lyrica
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Pregabalin was administered as immediate release (IR) capsule with a starting dose of 150 milligram per day (mg/day) and increased up to 300 - 450 mg/day during the dose optimization process.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to pregabalin.

    Arm title
    		 Placebo/Pregabalin
    Arm description
    		 Subjects were randomized in a 1:1 ratio to double-blind treatment with placebo for 6 weeks in period 1 followed by pregabalin in period 2 (3 weeks dose optimization and 3 weeks fixed dose) with background antidepressants. There was a 2-week single-blind taper or washout period between treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to pregabalin.

    Investigational medicinal product name
    Pregabalin
    Investigational medicinal product code
    Other name
    Lyrica
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Pregabalin was administered as IR capsule with a starting dose of 150 mg/day and increased up to 300 - 450 mg/day during the dose optimization process.

    Number of subjects in period 1
    		Pregabalin/Placebo Placebo/Pregabalin
    Started
    96
    97
    Completed
    70
    79
    Not completed
    26
    18
         Consent withdrawn by subject
    4
    5
         Protocol violation
    1
    1
         Adverse event
    11
    5
         Unspecified
    3
    4
         Lost to follow-up
    2
    2
         Lack of efficacy
    5
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pregabalin/Placebo
    Reporting group description
    		 Subjects were randomized in a 1:1 ratio to double-blind treatment with pregabalin for 6 weeks (3 weeks dose optimization and 3 weeks fixed dose) in period 1 followed by placebo in period 2 with background antidepressants. There was a 2-week single-blind taper/washout period between treatment periods.

    Reporting group title
    Placebo/Pregabalin
    Reporting group description
    		 Subjects were randomized in a 1:1 ratio to double-blind treatment with placebo for 6 weeks in period 1 followed by pregabalin in period 2 (3 weeks dose optimization and 3 weeks fixed dose) with background antidepressants. There was a 2-week single-blind taper or washout period between treatment periods.

    Reporting group values
    		 Pregabalin/Placebo Placebo/Pregabalin Total
    Number of subjects
    		 96 97 193
    Age categorical
    Units: Subjects
        Below 18 Years
    		 0 0 0
        18-44 years
    		 22 29 51
        45-64 years
    		 69 60 129
        65 years or above
    		 5 8 13
    Gender categorical
    Units: Subjects
        Female
    		 87 93 180
        Male
    		 9 4 13

    End points

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    End points reporting groups
    Reporting group title
    Pregabalin/Placebo
    Reporting group description
    		 Subjects were randomized in a 1:1 ratio to double-blind treatment with pregabalin for 6 weeks (3 weeks dose optimization and 3 weeks fixed dose) in period 1 followed by placebo in period 2 with background antidepressants. There was a 2-week single-blind taper/washout period between treatment periods.

    Reporting group title
    Placebo/Pregabalin
    Reporting group description
    		 Subjects were randomized in a 1:1 ratio to double-blind treatment with placebo for 6 weeks in period 1 followed by pregabalin in period 2 (3 weeks dose optimization and 3 weeks fixed dose) with background antidepressants. There was a 2-week single-blind taper or washout period between treatment periods.

    Subject analysis set title
    All Subjects
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects were included in this analysis.

    Subject analysis set title
    Pregabalin
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects were randomized in a 1:1 ratio to double-blind treatment with pregabalin for 6 weeks (3 weeks dose optimization and 3 weeks fixed dose) in period 1 followed by placebo in period 2 with background antidepressants. Pregabalin was administered as immediate release (IR) capsule with a starting dose of 150 mg/day and increased up to 300 - 450 mg/day during the dose optimization process. There was a 2-week single-blind taper/washout period between treatment periods.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects were randomized in a 1:1 ratio to double-blind treatment with placebo for 6 weeks in period 1 followed by pregabalin in period 2 (3 weeks dose optimization and 3 weeks fixed dose) with background antidepressants. Pregabalin was administered as immediate release (IR) capsule with a starting dose of 150 mg/day and increased up to 300 - 450 mg/day during the dose optimization process in period 2. There was a 2-week single-blind taper/washout period between treatment periods

    Primary: Mean Numeric Rating Scale (NRS) Pain Score at End of Period

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    End point title
    		 Mean Numeric Rating Scale (NRS) Pain Score at End of Period
    End point description
    The daily pain diary consists of an 11-point numeric scale (NRS) ranging from 0 (“no pain”) to 10 (“worst possible pain”). Subjects describe their pain during the past 24 hours by choosing the appropriate number between 0 and 10. The endpoint mean pain scores for Period 1 and Period 2 are defined as the mean of the last 7 non-missing daily diary pain ratings while taking study medication in the double-blind phase during Period 1 and Period 2, respectively. ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Primary
    End point timeframe
    End of each period, at Weeks 6, Week 14
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    179
    173
    Units: Units on a scale
        least squares mean (standard error)
    4.84 ( 0.15 )
    5.45 ( 0.16 )
    Statistical analysis title
    		 Mean NRS Pain Score at End of Period
    Statistical analysis description
    Analysis was done using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 -0.31
    Notes
    [1] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 181, not 352.
    [2] - Primary analysis was two-sided and performed at the 0.05 significance level. Satterthwaite’s approximation was used to estimate denominator degrees of freedom.

    Secondary: Fibromyalgia Impact Questionnaire (FIQ) Score at Baseline

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    End point title
    		 Fibromyalgia Impact Questionnaire (FIQ) Score at Baseline
    End point description
    This was a 20-item subjects reported outcome instrument. It contained 10 subscales, which were combined to yield a total score. The first 11 questions were related specifically to physical functioning subscale, ranging from 0 to 10. The remaining 9 questions assessed pain, fatigue, stiffness, difficulty working, and symptoms of anxiety and depression ranging from 0 to 10. The higher values indicated greater impairment. All 20 were combined to form a total score ranging from 0 to 100, provides an estimation of fibromyalgia impact with higher scores indicating more impairment. The severity categorizations for the FIQ are: less than 40 (mild), 40-60 (moderate), and above 60 (severe). ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Pregabalin/Placebo Placebo/Pregabalin
    Number of subjects analysed
    96
    97
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Total (N=96, 96)
    63.83 ( 11.58 )
    62.75 ( 12.51 )
        Physical Impairment (N=96, 97)
    4.58 ( 2.1 )
    4.44 ( 2.14 )
        Feel Good (N=96, 97)
    7.78 ( 2.47 )
    7.43 ( 2.32 )
        Work Missed (N=96, 97)
    3.38 ( 2.88 )
    3.49 ( 3.21 )
        Do Work (N=96, 97)
    6.61 ( 2.03 )
    6.38 ( 2.21 )
        Pain (N=96, 96)
    6.98 ( 1.25 )
    7.09 ( 1.32 )
        Fatigue (N=96, 97)
    8.17 ( 1.37 )
    8.08 ( 1.58 )
        Rested (N=96, 97)
    7.9 ( 1.51 )
    7.82 ( 1.96 )
        Stiffness (N=96, 97)
    7.56 ( 1.56 )
    7.64 ( 1.58 )
        Anxiety (N=96, 97)
    5.65 ( 2.73 )
    5.6 ( 2.59 )
        Depression (N=96, 97)
    5.23 ( 2.64 )
    4.84 ( 2.55 )
    No statistical analyses for this end point

    Secondary: FIQ Score at End of Period

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    End point title
    		 FIQ Score at End of Period
    End point description
    This was a 20-item subject reported outcome instrument. It contained 10 subscales, which were combined to yield a total score. The first 11 questions were related specifically to physical functioning subscale, ranging from 0 to 10. The remaining 9 questions assessed pain, fatigue, stiffness, difficulty working, and symptoms of anxiety and depression ranging from 0 to 10. The higher values indicated greater impairment. All 20 were combined to form a total score ranging from 0 to 100, provides an estimation of fibromyalgia impact with higher scores indicating more impairment. The severity categorizations for the FIQ are: less than 40 (mild), 40-60 (moderate), and above 60 (severe). ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation. 'N' for each category represents subjects that were actually treated with pregabalin and placebo during the study.
    End point type
    Secondary
    End point timeframe
    End of each period, at Weeks 6, Week 14
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    181
    177
    Units: Units on a scale
    least squares mean (standard error)
        Total (N=176, 172)
    43.78 ( 1.42 )
    50.38 ( 1.43 )
        Physical impairment (N=176, 173)
    3.35 ( 0.17 )
    3.77 ( 0.17 )
        Feel good (N=176, 173)
    4.69 ( 0.23 )
    5.53 ( 0.23 )
        Work missed (N=176 , 173)
    2.02 ( 0.21 )
    2.62 ( 0.21 )
        Do work (N=176, 172)
    4.56 ( 0.2 )
    5.31 ( 0.2 )
        Pain (N=176, 173)
    4.91 ( 0.17 )
    5.54 ( 0.17 )
        Fatigue (N=176, 173)
    6.32 ( 0.19 )
    6.76 ( 0.19 )
        Rested (N=176, 173)
    5.64 ( 0.19 )
    6.41 ( 0.19 )
        Stiffness (N=176, 173)
    5.24 ( 0.19 )
    5.95 ( 0.19 )
        Anxiety (N=176, 173)
    3.8 ( 0.2 )
    4.35 ( 0.21 )
        Depression (N=176, 173)
    3.2 ( 0.2 )
    4.13 ( 0.2 )
    Statistical analysis title
    		 FIQ Total Score
    Statistical analysis description
    Analysis was performed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.33
         upper limit
    		 -3.87
    Notes
    [3] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 181, not 358.
    [4] - Analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.
    Statistical analysis title
    		 Physical Impairment
    Statistical analysis description
    Analysis was performed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0078 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.74
         upper limit
    		 -0.11
    Notes
    [5] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 181, not 358.
    [6] - Analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.
    Statistical analysis title
    		 Feel Good
    Statistical analysis description
    Analysis was performed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0014 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.36
         upper limit
    		 -0.33
    Notes
    [7] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 181, not 358.
    [8] - Analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.
    Statistical analysis title
    		 Work Missed
    Statistical analysis description
    Analysis was performed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within- subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.005 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 -0.18
    Notes
    [9] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 181, not 358.
    [10] - Analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.
    Statistical analysis title
    		 Do Work
    Statistical analysis description
    Analysis was performed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0002 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.14
         upper limit
    		 -0.36
    Notes
    [11] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 181, not 358.
    [12] - Analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.
    Statistical analysis title
    		 Pain
    Statistical analysis description
    Analysis was performed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.0006 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 -0.28
    Notes
    [13] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 181, not 358.
    [14] - Analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.
    Statistical analysis title
    		 Fatigue
    Statistical analysis description
    Analysis was performed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.0315 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.85
         upper limit
    		 -0.04
    Notes
    [15] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 181, not 358.
    [16] - Analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.
    Statistical analysis title
    		 Rested
    Statistical analysis description
    Analysis was performed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.0003 [18]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.17
         upper limit
    		 -0.35
    Notes
    [17] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 181, not 358.
    [18] - Analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.
    Statistical analysis title
    		 Stiffness
    Statistical analysis description
    Analysis was performed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.0007 [20]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.11
         upper limit
    		 -0.31
    Notes
    [19] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 181, not 358.
    [20] - Analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.
    Statistical analysis title
    		 Anxiety
    Statistical analysis description
    Analysis was performed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.0048 [22]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.93
         upper limit
    		 -0.17
    Notes
    [21] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 181, not 358.
    [22] - Analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.
    Statistical analysis title
    		 Depression
    Statistical analysis description
    Analysis was performed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.0001 [24]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.32
         upper limit
    		 -0.53
    Notes
    [23] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 181, not 358.
    [24] - Analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.

    Secondary: Patient Global Impression of Change (PGIC) at the End of Period 1

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    End point title
    		 Patient Global Impression of Change (PGIC) at the End of Period 1
    End point description
    PGIC: Subject rated instrument to measure subject's change in overall status from baseline to the end of period 1 (Week 6) on a 7-point scale; range from 1 (very much improved) to 7 (very much worse). ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    End of Period 1 at Week 6
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    93
    93
    Units: Percentage of subjects
    number (not applicable)
        Very much improved
    10.8
    4.3
        Much improved
    35.5
    25.8
        Minimally improved
    28
    40.9
        No change
    17.2
    21.5
        Minimally worse
    4.3
    6.5
        Much worse
    3.2
    1.1
        Very much worse
    1.1
    0
    Statistical analysis title
    		 PGIC at the End of Period 1
    Statistical analysis description
    The PGIC variable was analyzed using Cochran Mantel-Haenszel (CMH) test with modified ridit transformation.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0637 [25]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [25] - This analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.

    Secondary: Percentage of Subjects with Greater than or Equal to (>=)30 Percent (%) and >=50% Pain Reduction Based on Daily Pain

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    End point title
    		 Percentage of Subjects with Greater than or Equal to (>=)30 Percent (%) and >=50% Pain Reduction Based on Daily Pain
    End point description
    Subject with at least a 30% reduction in mean pain score from baseline (at randomization) to the endpoint at the end of each period (Visit 6 and 12) was considered a 30% responder, for the respective period. Similarly, a subject with at least a 50% reduction in mean pain score from baseline (at randomization) to the endpoint at the end of each period (Visit 6 and 12) was considered a 50% responder, for the respective period. ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Visits 2, 6, 12
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    179
    173
    Units: Percentage of subjects
    number (not applicable)
        30% Responders
    45.3
    27.7
        50% Responders
    26
    15.8
    Statistical analysis title
    		 For 30 Percent Responders
    Statistical analysis description
    Analysis was conducted using a logistic regression model using sequence, period, and treatment as fixed factors and subject within sequence and within subject error as random factors. Log link transformation was used for the model.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.0007 [27]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [26] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 179, not 352.
    [27] - This secondary analyses was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.
    Statistical analysis title
    		 For 50 Percent Responders
    Statistical analysis description
    Analysis was conducted using a logistic regression model using sequence, period, and treatment as fixed factors and subject within sequence and within subject error as random factors. Log link transformation was used for the model.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.0205 [29]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [28] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 179, not 352.
    [29] - This secondary analyses was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.

    Secondary: Subjective Sleep Questionnaire - Mean Sleep Quality at End of Period

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    End point title
    		 Subjective Sleep Questionnaire - Mean Sleep Quality at End of Period
    End point description
    Subjective sleep questionnaire-mean sleep quality at end of each period (Week 6 and Week 14) included 5 items: subjects report latency (how long it took them to fall asleep), how many hours they slept, the number of times they woke up, the total wake time after sleep onset, and then rate the quality of their sleep (NRS) for the previous night. Subjective rating of quality of sleep during the past night was done by selecting a number between 0 (very poor) and 10 (excellent). Mean sleep quality was calculated as the mean of the last seven days, the potential range of responses was therefore 0-10. ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    End of each period, at Weeks 6 and 14
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    179
    173
    Units: Units on a scale
        least squares mean (standard error)
    6.15 ( 0.14 )
    5.57 ( 0.14 )
    Statistical analysis title
    		 Subjective Sleep Questionnaire
    Statistical analysis description
    Analyzed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 < 0.0001 [31]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.84
    Notes
    [30] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 179, not 352.
    [31] - This was done using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.

    Secondary: Subjective Sleep Questionnaire - Mean Subjective Wake After Sleep Onset at End of Period

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    End point title
    		 Subjective Sleep Questionnaire - Mean Subjective Wake After Sleep Onset at End of Period
    End point description
    Subjective sleep questionnaire included, subjects report latency (how long it took them to fall asleep), how many hours they slept, the number of times they woke up, the total wake time after sleep onset, and then rate the quality of their sleep (numeric rating scale) for the previous night. Subjective wake after sleep onset was the subjective estimate of the total amount of time the subject was awake after initial sleep onset until final awakening. ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    End of each period, at Weeks 6 and 14
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    179
    173
    Units: Minutes
        least squares mean (standard error)
    33.38 ( 2.73 )
    41.18 ( 2.76 )
    Statistical analysis title
    		 Subjective Sleep Questionnaire
    Statistical analysis description
    Analyzed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 = 0.0018 [33]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.66
         upper limit
    		 -2.96
    Notes
    [32] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 179, not 352.
    [33] - This was done using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.

    Secondary: Subjective Sleep Questionnaire - Mean Latency to Sleep Onset at End of Period

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    End point title
    		 Subjective Sleep Questionnaire - Mean Latency to Sleep Onset at End of Period
    End point description
    Subjective sleep questionnaire included, subjects report latency (how long it took them to fall asleep), how many hours they slept, the number of times they woke up, the total wake time after sleep onset, and then rate the quality of their sleep (numeric rating scale) for the previous night. Subjective latency to sleep onset was the subjective estimate of the amount of time to fall asleep after lights out. ITT population defined, as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    End of each period, at Weeks 6 and 14
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    179
    173
    Units: Minutes
        least squares mean (standard error)
    33.54 ( 2.68 )
    39.33 ( 2.71 )
    Statistical analysis title
    		 Subjective Sleep Questionnaire
    Statistical analysis description
    Analyzed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 = 0.0117 [35]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.29
         upper limit
    		 -1.31
    Notes
    [34] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 179, not 352.
    [35] - This was done using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.

    Secondary: Subjective Sleep Questionnaire - Mean Subjective Total Sleep Time at End of Period

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    End point title
    		 Subjective Sleep Questionnaire - Mean Subjective Total Sleep Time at End of Period
    End point description
    Subjective Sleep Questionnaire included, subjects report latency (how long it took them to fall asleep), how many hours they slept, the number of times they woke up, the total wake time after sleep onset, and then rate the quality of their sleep (numeric rating scale) for the previous night. Subjective total sleep time was the subjective estimate of the total amount of time the subject was asleep after lights out until final awakening. ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    End of each period, at Weeks 6 and 14
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    179
    173
    Units: Minutes
        least squares mean (standard error)
    422.98 ( 5.42 )
    414.63 ( 5.48 )
    Statistical analysis title
    		 Subjective Sleep Questionnaire
    Statistical analysis description
    Analyzed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [36]
    P-value
    		 = 0.0511 [37]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 16.74
    Notes
    [36] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 179, not 352.
    [37] - This was done using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.

    Secondary: Subjective Sleep Questionnaire - Parameter Estimates for Subjective Number of Awakenings Per Night After Sleep Onset at End of Period

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    End point title
    		 Subjective Sleep Questionnaire - Parameter Estimates for Subjective Number of Awakenings Per Night After Sleep Onset at End of Period
    End point description
    Subjective sleep questionnaire included, subjects report latency (how long it took them to fall asleep), how many hours they slept, the number of times they woke up, the total wake time after sleep onset, and then rate the quality of their sleep (numeric rating scale) for the previous night. Subjective number of awakenings after sleep onset was the subjective estimate of the total number of times the subject awakened during the night until final awakening. ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    End of each period, at Weeks 6 and 14
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    179
    173
    Units: Number of times awakened
        least squares mean (standard error)
    0.48 ( 0.07 )
    0.61 ( 0.07 )
    Statistical analysis title
    		 Subjective Sleep Questionnaire
    Statistical analysis description
    Analyzed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors. Analyzed as a count variable using a generalized linear model assuming a Poisson distribution and utilizing a log link transformation.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [38]
    P-value
    		 = 0.1139 [39]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 0.03
    Notes
    [38] - For 'number of subjects included in the analysis' field: In cross over studies, each subject received both treatments. Total number of subjects were 179, not 352.
    [39] - This was done using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.

    Secondary: Hospital Anxiety and Depression Scale (HADS) at Baseline

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    End point title
    		 Hospital Anxiety and Depression Scale (HADS) at Baseline
    End point description
    HADS: Subject rated questionnaire with 2 subscales. HADS-A (anxiety) assesses state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); HADS-D (depression) assesses state of lost interest and diminished pleasure response (lowering of hedonic tone). Each subscale comprised of 7 items with range 0 (no presence of anxiety or depression) to 3 (severe feeling of anxiety or depression). Total score 0 to 21 for each subscale; higher score indicates greater severity of anxiety and depression symptoms. ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Pregabalin/Placebo Placebo/Pregabalin
    Number of subjects analysed
    96
    97
    Units: Units on a scale
    arithmetic mean (standard deviation)
        HADS-A (anxiety)
    8.67 ( 3.95 )
    7.97 ( 3.77 )
        HADS-D (depression)
    8.34 ( 3.59 )
    7.73 ( 3.64 )
    No statistical analyses for this end point

    Secondary: HADS at End of Period

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    End point title
    		 HADS at End of Period
    End point description
    HADS: Subject rated questionnaire with 2 subscales. HADS-A (anxiety) assesses state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); HADS-D (depression) assesses state of lost interest and diminished pleasure response (lowering of hedonic tone). Each subscale comprised of 7 items with range 0 (no presence of anxiety or depression) to 3 (severe feeling of anxiety or depression). Total score 0 to 21 for each subscale; higher score indicates greater severity of anxiety and depression symptoms. ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Week 6, Week 14
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    176
    173
    Units: Units on a scale
    least squares mean (standard error)
        HADS-A (anxiety)
    6.01 ( 0.28 )
    6.96 ( 0.28 )
        HADS-D (depression)
    6.17 ( 0.31 )
    7.05 ( 0.31 )
    Statistical analysis title
    		 For HADS-A (anxiety)
    Statistical analysis description
    Analyzed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [40]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 -0.5
    Notes
    [40] - Two-sided test with α=0.05 was used. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.
    Statistical analysis title
    		 For HADS-D (depression)
    Statistical analysis description
    Analyzed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [41]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.37
         upper limit
    		 -0.39
    Notes
    [41] - Two-sided test with α=0.05 was used. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.

    Secondary: Mean EuroQoL 5-Dimensions (EQ-5D) Score at Baseline

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    End point title
    		 Mean EuroQoL 5-Dimensions (EQ-5D) Score at Baseline
    End point description
    EQ-5D is a standardized, subject-administered measure of health outcome. It provides a descriptive profile for 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), using 3 levels (no, moderate, or extreme problems) and a single index value characterizing current health status using a 100-point visual analog scale (0=worst, 100=best). EQ-5D summary index is obtained with a formula that weights each level of the dimensions. The index-based score is interpreted along a continuum of 0 (death) to 1 (perfect health). ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Pregabalin/Placebo Placebo/Pregabalin
    Number of subjects analysed
    96
    97
    Units: Units on a scale
        arithmetic mean (standard deviation)
    0.4 ( 0.31 )
    0.37 ( 0.33 )
    No statistical analyses for this end point

    Secondary: EQ-5D score at End of Period

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    End point title
    		 EQ-5D score at End of Period
    End point description
    EQ-5D is a standardized, subject-administered measure of health outcome. It provides a descriptive profile for 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), using 3 levels (no, moderate, or extreme problems) and a single index value characterizing current health status using a 100-point visual analog scale (0=worst, 100=best). EQ-5D summary index is obtained with a formula that weights each level of the dimensions. The index-based score is interpreted along a continuum of 0 (death) to 1 (perfect health). ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    End of each period, at Weeks 6 and 14
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    176
    172
    Units: Units on a scale
        least squares mean (standard error)
    0.58 ( 0.02 )
    0.56 ( 0.02 )
    Statistical analysis title
    		 For EQ-5D Score at End of Period
    Statistical analysis description
    Analyzed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subjectt within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3854 [42]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.06
    Notes
    [42] - Two-sided test with α=0.05 was used. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.

    Other pre-specified: PGIC at the End of Period 2

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    End point title
    		 PGIC at the End of Period 2
    End point description
    PGIC: subject rated instrument to measure subjects's change in overall status from baseline to the end of period 2 (Week 14) on a 7-point scale; range from 1 (very much improved) to 7 (very much worse). Because of the crossover design and PGIC recall period (since starting study medication), the Period 1 PGIC data were felt to provide the clearest comparison across treatments, whereas Period 2 PGIC data were felt to have a more complex interpretation. Thus PGIC at End of Period 2 was separately analyzed from PGIC at End of Period 1. ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Other pre-specified
    End point timeframe
    End of Period 2 at Week 14
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    82
    81
    Units: Percentage of subjects
    number (not applicable)
        Very much improved
    18.3
    8.6
        Much improved
    34.1
    25.9
        Minimally improved
    28
    38.3
        No change
    11
    14.8
        Minimally worse
    6.1
    8.6
        Much worse
    1.2
    2.5
        Very much worse
    1.2
    1.2
    Statistical analysis title
    		 For PGIC at the End of Period 2
    Statistical analysis description
    The PGIC variable was analyzed using CMH test with modified ridit transformation.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.116 [43]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [43] - This analysis was conducted using a two-sided test with α=0.05. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.

    Other pre-specified: Mean Patient Static Global Assessment (PSGA) Score at Baseline

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    End point title
    		 Mean Patient Static Global Assessment (PSGA) Score at Baseline
    End point description
    PSGA was a single-item self-rated instrument that measured the subject’s overall status on an 11-point NRS ranging from 0 (very poor) to 10 (very good). ITT population defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Pregabalin/Placebo Placebo/Pregabalin
    Number of subjects analysed
    96
    97
    Units: Units on a scale
        arithmetic mean (standard deviation)
    4.35 ( 2.04 )
    4.46 ( 1.92 )
    No statistical analyses for this end point

    Other pre-specified: Mean PSGA score at End of Period

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    End point title
    		 Mean PSGA score at End of Period
    End point description
    PSGA was a single-item self-rated instrument that measured the subject’s overall status on an 11-point numeric rating scale (NRS) ranging from 0 (very poor) to 10 (very good). ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Other pre-specified
    End point timeframe
    End of each period, at Weeks 6 and 14
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    176
    172
    Units: Units on a scale
        least squares mean (standard error)
    5.83 ( 0.17 )
    5.27 ( 0.17 )
    Statistical analysis title
    		 Mean PSGA Score at End of Period
    Statistical analysis description
    Analyzed using a linear mixed effects model including sequence, period, and treatment as fixed factors and subject within sequence and within-subject error as random factors.
    Comparison groups
    Pregabalin v Placebo
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0085 [44]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.97
    Notes
    [44] - Two-sided test with α=0.05 was used. No corrections to alpha to control for potential inflation of Type I error resulting from multiple comparisons were made.

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

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    End point title
    		 Number of Subjects With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) at Baseline
    End point description
    C-SSRS assessed whether subjects experienced following: completed suicide (1), suicide attempt (2) (response of “Yes” on “actual attempt”), preparatory acts toward imminent suicidal behavior (3) (“Yes” on “preparatory acts or behavior”), suicidal ideation (4) (“Yes” on “wish to be dead”, “non-specific 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 suicidal behavior or ideation, self-injurious behavior (7) (“Yes” on “Has subject engaged in non-suicidal self-injurious behavior”). ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 Pregabalin/Placebo Placebo/Pregabalin
    Number of subjects analysed
    96
    97
    Units: Subjects
    number (not applicable)
        Wish to be Dead
    3
    1
        Non-Specific Thoughts
    0
    1
        Without Intent to Act
    0
    0
        Some Intent to Act
    0
    0
        Specific Plan and Intent
    0
    0
        Actual Attempt
    0
    0
        Non-Suicidal Self-Injurious Behavior
    0
    0
        Interrupted Attempt
    0
    0
        Aborted Attempt
    0
    0
        Preparatory Acts or Behavior
    0
    0
        Suicidal Behavior Present
    0
    0
        Completed Suicide
    0
    0
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects With Categorical Scores on the Columbia Suicidality Severity Rating Scale (C-SSRS) at Post-Baseline
    End point description
    C-SSRS assessed whether subjects experienced following: completed suicide (1), suicide attempt (2) (response of Yes on “actual attempt”), preparatory acts toward imminent suicidal behavior (3) (Yes on “preparatory acts or behavior”), suicidal ideation (4) (Yes on “wish to be dead”, “non-specific 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 suicidal behavior or ideation, self-injurious behavior (7) (Yes on “Has subject engaged in non-suicidal self-injurious behavior”). Below table indicated 1 subject treated with Pregabalin reported preparatory act. On study unblinding it was clarified that preparatory act occurred while subject was taking placebo. ITT population, defined as all subject who were randomized, treated (ie, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Other pre-specified
    End point timeframe
    From Visit 3 to Visit 14
    End point values
    		 Pregabalin Placebo
    Number of subjects analysed
    181
    177
    Units: Subjects
    number (not applicable)
        Wish to be Dead
    10
    8
        Non-Specific Thoughts
    3
    1
        Without Intent to Act
    2
    0
        Some Intent to Act
    0
    0
        Specific Plan and Intent
    0
    0
        Actual Attempt
    0
    0
        Non-Suicidal Self-Injurious Behavior
    0
    0
        Interrupted Attempt
    0
    0
        Aborted Attempt
    0
    0
        Preparatory Acts or Behavior
    1
    0
        Suicidal Behavior Present
    1
    0
        Completed Suicide
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Work Productivity and Activity Index-Specific Health Problem (WPAI-SHP) Questionnaire at Baseline

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    End point title
    		 Work Productivity and Activity Index-Specific Health Problem (WPAI-SHP) Questionnaire at Baseline
    End point description
    WPAI-SHP assessed work productivity and impairment. It was a subject-rated, six-item questionnaire regarding current employment, hours missed and actually worked, and degree to which a specified health problem affected work productivity and regular activities over the past 7 days. Subscale scores included percent work time missed due to the health problem; percent impairment while working due to problem; percent overall work impairment due to problem; and percent activity impairment due to problem. Each subscale score was expressed as an impairment percentage (0-100) where higher numbers indicated greater impairment and less productivity. ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 All Subjects
    Number of subjects analysed
    193
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Percent Absenteeism (N= 86)
    15.22 ( 25.36 )
        Percent Presenteeism (N= 83)
    53.98 ( 21.52 )
        Percent Overall Work Impairment (N= 82)
    57.96 ( 23.42 )
        Percent Activity Impairment (N=193)
    64.97 ( 18.77 )
    No statistical analyses for this end point

    Other pre-specified: Health Utilization Assessment (Total Office Visits, Number of Hospitalizations and Number of Emergency Room Visits) at Baseline

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    End point title
    		 Health Utilization Assessment (Total Office Visits, Number of Hospitalizations and Number of Emergency Room Visits) at Baseline
    End point description
    The healthcare utilization assessment was used to capture healthcare utilization data at Baseline. This assessment contained 10 questions related to aspects of healthcare services. ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation. Here "99999" in the mean and standard deviation of number of hospitalizations, signifies not available (NA). Mean and standard deviation were not calculated as no subject was evaluated for this time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 All Subjects
    Number of subjects analysed
    193
    Units: Visits
    arithmetic mean (standard deviation)
        Total office visits (N= 193)
    5.01 ( 6.6 )
        Number of hospitalizations (N= 0)
    99999 ( 99999 )
        Number of emergency room visits (N= 12)
    1.83 ( 1 )
    No statistical analyses for this end point

    Other pre-specified: Health Utilization Assessment (Time for Help No Payment) at Baseline

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    End point title
    		 Health Utilization Assessment (Time for Help No Payment) at Baseline
    End point description
    The healthcare utilization assessment was used to capture healthcare utilization data at Baseline. This assessment contained 10 questions related to aspects of healthcare services. 'Time for help no payment' refers to time other people spent without receiving payment to help with activities the patient cannot perform due to fibromyalgia. ITT population, defined as all subjects who were randomized, treated (i.e, received at least one dose of study medication) and had at least one post-randomization efficacy evaluation.
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 All Subjects
    Number of subjects analysed
    193
    Units: Hours
        arithmetic mean (standard deviation)
    50.37 ( 98.1 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 16
    Adverse event reporting additional description
    The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Pregabalin
    Reporting group description
    		 The below table included subjects who received pregabalin in either treatment period pooled together due to the crossover study design. This crossover study consisted of two double blind 6-week treatment periods where subjects were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period (3 weeks dose optimization and 3 weeks fixed dose for each treatment period). Pregabalin was administered as immediate release (IR) capsule with a starting dose of 150 mg/day and increased up to 300 - 450 mg/day during the dose optimization process. There was a 2-week single-blind taper or washout period between treatment periods.

    Reporting group title
    Placebo
    Reporting group description
    		 The below table included subjects who received placebo in either treatment period pooled together due to the crossover study design. This crossover study consisted of two double blind 6-week treatment periods where subjects were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period (3 weeks dose optimization and 3 weeks fixed dose for each treatment period). There was a 2-week single-blind taper or washout period between treatment periods.

    Serious adverse events
    		 Pregabalin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 181 (1.66%)
    1 / 177 (0.56%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm malignant
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Detoxification
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Pregabalin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    139 / 181 (76.80%)
    106 / 177 (59.89%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Hot flush
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Hypertension
         subjects affected / exposed
    2 / 181 (1.10%)
    2 / 177 (1.13%)
         occurrences all number
    2
    2
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 177 (1.13%)
         occurrences all number
    1
    2
    Chest discomfort
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 177 (1.13%)
         occurrences all number
    1
    2
    Crying
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Cyst
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Energy increased
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    12 / 181 (6.63%)
    8 / 177 (4.52%)
         occurrences all number
    13
    9
    Feeling abnormal
         subjects affected / exposed
    5 / 181 (2.76%)
    0 / 177 (0.00%)
         occurrences all number
    5
    0
    Feeling drunk
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Feeling hot
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Feeling jittery
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 177 (0.00%)
         occurrences all number
    2
    0
    Gait disturbance
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 177 (0.00%)
         occurrences all number
    3
    0
    Hunger
         subjects affected / exposed
    3 / 181 (1.66%)
    1 / 177 (0.56%)
         occurrences all number
    3
    1
    Inflammation
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Irritability
         subjects affected / exposed
    3 / 181 (1.66%)
    1 / 177 (0.56%)
         occurrences all number
    3
    1
    Malaise
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Mucosal dryness
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    7 / 181 (3.87%)
    3 / 177 (1.69%)
         occurrences all number
    8
    3
    Pain
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 181 (0.00%)
    4 / 177 (2.26%)
         occurrences all number
    0
    4
    Swelling
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal dryness
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal pruritus
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 181 (1.10%)
    1 / 177 (0.56%)
         occurrences all number
    2
    1
    Dyspnoea
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Nasal dryness
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 181 (1.66%)
    5 / 177 (2.82%)
         occurrences all number
    3
    5
    Rhinorrhoea
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    8 / 181 (4.42%)
    7 / 177 (3.95%)
         occurrences all number
    8
    10
    Apathy
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Bradyphrenia
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 177 (0.00%)
         occurrences all number
    2
    0
    Confusional state
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 177 (0.00%)
         occurrences all number
    2
    0
    Depressed mood
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 177 (1.13%)
         occurrences all number
    1
    2
    Depression
         subjects affected / exposed
    5 / 181 (2.76%)
    4 / 177 (2.26%)
         occurrences all number
    5
    4
    Disorientation
         subjects affected / exposed
    5 / 181 (2.76%)
    0 / 177 (0.00%)
         occurrences all number
    5
    0
    Euphoric mood
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Initial insomnia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    13 / 181 (7.18%)
    1 / 177 (0.56%)
         occurrences all number
    14
    1
    Nervousness
         subjects affected / exposed
    3 / 181 (1.66%)
    2 / 177 (1.13%)
         occurrences all number
    3
    2
    Nightmare
         subjects affected / exposed
    1 / 181 (0.55%)
    4 / 177 (2.26%)
         occurrences all number
    1
    4
    Panic attack
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Restlessness
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Suicidal ideation
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 177 (0.00%)
         occurrences all number
    2
    0
    Thinking abnormal
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 181 (0.00%)
    3 / 177 (1.69%)
         occurrences all number
    0
    3
    Eosinophil count increased
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Urine output decreased
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Weight increased
         subjects affected / exposed
    16 / 181 (8.84%)
    3 / 177 (1.69%)
         occurrences all number
    16
    3
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 177 (0.00%)
         occurrences all number
    2
    0
    Fall
         subjects affected / exposed
    4 / 181 (2.21%)
    1 / 177 (0.56%)
         occurrences all number
    4
    1
    Hand fracture
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Laceration
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 177 (1.13%)
         occurrences all number
    0
    2
    Ligament sprain
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Muscle strain
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 177 (0.00%)
         occurrences all number
    3
    0
    Post concussion syndrome
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Road traffic accident
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Skeletal injury
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Tendon rupture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Tooth fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Areflexia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Balance disorder
         subjects affected / exposed
    5 / 181 (2.76%)
    0 / 177 (0.00%)
         occurrences all number
    5
    0
    Burning sensation
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Clumsiness
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 177 (0.00%)
         occurrences all number
    2
    0
    Cognitive disorder
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Disturbance in attention
         subjects affected / exposed
    5 / 181 (2.76%)
    4 / 177 (2.26%)
         occurrences all number
    5
    4
    Dizziness
         subjects affected / exposed
    51 / 181 (28.18%)
    12 / 177 (6.78%)
         occurrences all number
    67
    14
    Dizziness postural
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    14 / 181 (7.73%)
    17 / 177 (9.60%)
         occurrences all number
    4
    20
    Hypersomnia
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 177 (0.00%)
         occurrences all number
    3
    0
    Hyporeflexia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Memory impairment
         subjects affected / exposed
    5 / 181 (2.76%)
    1 / 177 (0.56%)
         occurrences all number
    5
    1
    Mental impairment
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 177 (0.00%)
         occurrences all number
    2
    0
    Migraine
         subjects affected / exposed
    1 / 181 (0.55%)
    3 / 177 (1.69%)
         occurrences all number
    1
    3
    Myoclonus
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    2 / 181 (1.10%)
    1 / 177 (0.56%)
         occurrences all number
    2
    1
    Presyncope
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Repetitive speech
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Sedation
         subjects affected / exposed
    4 / 181 (2.21%)
    2 / 177 (1.13%)
         occurrences all number
    4
    2
    Somnolence
         subjects affected / exposed
    36 / 181 (19.89%)
    8 / 177 (4.52%)
         occurrences all number
    48
    8
    Stupor
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Tension headache
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Neutrophilia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Tinnitus
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Vertigo
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 177 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Dry eye
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 177 (0.00%)
         occurrences all number
    3
    0
    Eye disorder
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    7 / 181 (3.87%)
    3 / 177 (1.69%)
         occurrences all number
    7
    3
    Visual impairment
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Abdominal distension
         subjects affected / exposed
    2 / 181 (1.10%)
    1 / 177 (0.56%)
         occurrences all number
    2
    1
    Abdominal pain
         subjects affected / exposed
    3 / 181 (1.66%)
    3 / 177 (1.69%)
         occurrences all number
    3
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 181 (0.55%)
    4 / 177 (2.26%)
         occurrences all number
    1
    4
    Constipation
         subjects affected / exposed
    19 / 181 (10.50%)
    4 / 177 (2.26%)
         occurrences all number
    20
    4
    Dental caries
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    16 / 181 (8.84%)
    7 / 177 (3.95%)
         occurrences all number
    16
    7
    Dry mouth
         subjects affected / exposed
    12 / 181 (6.63%)
    1 / 177 (0.56%)
         occurrences all number
    12
    1
    Dyspepsia
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Dysphagia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    4 / 181 (2.21%)
    2 / 177 (1.13%)
         occurrences all number
    4
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Lip swelling
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    17 / 181 (9.39%)
    12 / 177 (6.78%)
         occurrences all number
    19
    15
    Odynophagia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Paraesthesia oral
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 177 (0.00%)
         occurrences all number
    3
    0
    Salivary gland pain
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    1 / 181 (0.55%)
    5 / 177 (2.82%)
         occurrences all number
    1
    5
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Night sweats
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 177 (0.00%)
         occurrences all number
    2
    0
    Pruritus
         subjects affected / exposed
    4 / 181 (2.21%)
    4 / 177 (2.26%)
         occurrences all number
    4
    4
    Pruritus generalised
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    1 / 181 (0.55%)
    3 / 177 (1.69%)
         occurrences all number
    1
    3
    Rash generalised
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Haematuria
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Incontinence
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Oliguria
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Pollakiuria
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Urinary retention
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 181 (1.66%)
    2 / 177 (1.13%)
         occurrences all number
    3
    2
    Back pain
         subjects affected / exposed
    3 / 181 (1.66%)
    4 / 177 (2.26%)
         occurrences all number
    3
    4
    Fibromyalgia
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Flank pain
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 177 (0.00%)
         occurrences all number
    2
    0
    Joint swelling
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Medial tibial stress syndrome
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    4 / 181 (2.21%)
    1 / 177 (0.56%)
         occurrences all number
    4
    1
    Muscle twitching
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 177 (0.00%)
         occurrences all number
    3
    0
    Muscular weakness
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    3 / 181 (1.66%)
    3 / 177 (1.69%)
         occurrences all number
    3
    3
    Pain in jaw
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 177 (1.13%)
         occurrences all number
    1
    2
    Bronchitis viral
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Ear infection
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 177 (1.13%)
         occurrences all number
    1
    2
    Folliculitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 181 (0.00%)
    3 / 177 (1.69%)
         occurrences all number
    0
    3
    Gastroenteritis viral
         subjects affected / exposed
    4 / 181 (2.21%)
    2 / 177 (1.13%)
         occurrences all number
    4
    2
    Influenza
         subjects affected / exposed
    3 / 181 (1.66%)
    2 / 177 (1.13%)
         occurrences all number
    3
    2
    Laryngitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 181 (2.76%)
    10 / 177 (5.65%)
         occurrences all number
    5
    10
    Oral herpes
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Pharyngitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Sinusitis
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 177 (1.13%)
         occurrences all number
    1
    2
    Tooth infection
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 181 (2.21%)
    2 / 177 (1.13%)
         occurrences all number
    4
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 181 (1.10%)
    1 / 177 (0.56%)
         occurrences all number
    2
    1
    Vaginal infection
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 177 (1.13%)
         occurrences all number
    1
    2
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 177 (0.00%)
         occurrences all number
    2
    0
    Folate deficiency
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    Food craving
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Hyperlipidaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 177 (0.56%)
         occurrences all number
    1
    1
    Increased appetite
         subjects affected / exposed
    4 / 181 (2.21%)
    0 / 177 (0.00%)
         occurrences all number
    4
    0
    Polydipsia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2012
    Benefit and risk summary was added. Subject withdrawal and adverse event reporting were updated. Pregnancy testing requirements were expanded. Clarifications regarding prohibited and allowable medications 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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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