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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Vemurafenib (RO5185426) Adjuvant Therapy in Patients with Surgically Resected, Cutaneous BRAF-Mutant Melanoma at High Risk for Recurrence

    Summary
    EudraCT number
    		 2011-004011-24
    Trial protocol
    		 GB   AT   SE   CZ   DE   FR   BE   IT   ES   NL   EE   PT   IE   PL  
    Global end of trial date
    13 Jul 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    27 Jul 2019
    First version publication date
    21 Jun 2018
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GO27826
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01667419
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    13 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of vemurafenib adjuvant treatment administered over a 52-week period in subjects with completely resected BRAF V600 mutation−positive, cutaneous melanoma, as measured by disease-free survival (DFS).
    Protection of trial subjects
    Subjects (or legally authorized representative) were required to read and sign an informed consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Sep 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 42
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    South Africa: 9
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    United States: 51
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Italy: 93
    Country: Number of subjects enrolled
    United Kingdom: 41
    Country: Number of subjects enrolled
    Russian Federation: 39
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    Poland: 20
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Ukraine: 18
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Israel: 15
    Country: Number of subjects enrolled
    Serbia: 15
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Ireland: 9
    Country: Number of subjects enrolled
    Croatia: 7
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    Switzerland: 1
    Worldwide total number of subjects
    498
    EEA total number of subjects
    277
    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)
    424
    From 65 to 84 years
    74
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Adult subjects with completely resected, BRAF V600 mutation-positive melanoma were included in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 Vemurafenib
    Arm description
    		 Subjects with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib, 960 milligrams (mg) twice daily, in 28-day cycles, for up to 52 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vemurafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib, 960 mg twice daily, in 28-day cycles, for up to 52 weeks.

    Arm title
    		 Cohort 1 Placebo
    Arm description
    		 Subjects with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks.

    Arm title
    		 Cohort 2 Vemurafenib
    Arm description
    		 Subjects with Stage IIIC cutaneous melanoma received vemurafenib, 960 mg twice daily, in 28-day cycles, for up to 52 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vemurafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with Stage IIIC cutaneous melanoma received vemurafenib, 960 mg twice daily, in 28-day cycles, for up to 52 weeks.

    Arm title
    		 Cohort 2 Placebo
    Arm description
    		 Subjects with Stage IIIC cutaneous melanoma received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with Stage IIIC cutaneous melanoma received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks.

    Number of subjects in period 1
    		Cohort 1 Vemurafenib Cohort 1 Placebo Cohort 2 Vemurafenib Cohort 2 Placebo
    Started
    157
    157
    93
    91
    Completed
    114
    110
    57
    52
    Not completed
    43
    47
    36
    39
         Adverse event, serious fatal
    18
    33
    25
    26
         Consent withdrawn by subject
    16
    8
    9
    8
         Reason Not Specified
    1
    -
    -
    -
         Non-compliance
    -
    -
    -
    1
         Lost to follow-up
    7
    6
    2
    4
         Protocol deviation
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 Vemurafenib
    Reporting group description
    		 Subjects with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib, 960 milligrams (mg) twice daily, in 28-day cycles, for up to 52 weeks

    Reporting group title
    Cohort 1 Placebo
    Reporting group description
    		 Subjects with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks

    Reporting group title
    Cohort 2 Vemurafenib
    Reporting group description
    		 Subjects with Stage IIIC cutaneous melanoma received vemurafenib, 960 mg twice daily, in 28-day cycles, for up to 52 weeks

    Reporting group title
    Cohort 2 Placebo
    Reporting group description
    		 Subjects with Stage IIIC cutaneous melanoma received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks

    Reporting group values
    		 Cohort 1 Vemurafenib Cohort 1 Placebo Cohort 2 Vemurafenib Cohort 2 Placebo Total
    Number of subjects
    		 157 157 93 91 498
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.7 ( 12.4 ) 49.6 ( 12.7 ) 51.6 ( 14.1 ) 49.1 ( 12.9 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 73 69 41 32 215
        Male
    		 84 88 52 59 283
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 12 2 8 3 25
        Not Hispanic or Latino
    		 138 148 79 80 445
        Unknown or Not Reported
    		 7 7 6 8 28
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 150 150 84 81 465
        Other
    		 1 2 1 2 6
        Multiple
    		 0 0 1 0 1
        Unknown
    		 6 5 7 8 26

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 Vemurafenib
    Reporting group description
    		 Subjects with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib, 960 milligrams (mg) twice daily, in 28-day cycles, for up to 52 weeks

    Reporting group title
    Cohort 1 Placebo
    Reporting group description
    		 Subjects with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks

    Reporting group title
    Cohort 2 Vemurafenib
    Reporting group description
    		 Subjects with Stage IIIC cutaneous melanoma received vemurafenib, 960 mg twice daily, in 28-day cycles, for up to 52 weeks

    Reporting group title
    Cohort 2 Placebo
    Reporting group description
    		 Subjects with Stage IIIC cutaneous melanoma received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks

    Primary: Disease-Free Survival (DFS) as Assessed Using Contrast-Enhanced Magnetic Resonance Imaging (MRI) or Contrast Enhanced Computed Tomography (CT)

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    End point title
    		 Disease-Free Survival (DFS) as Assessed Using Contrast-Enhanced Magnetic Resonance Imaging (MRI) or Contrast Enhanced Computed Tomography (CT)
    End point description
    DFS was defined as the time from randomization until the date of the first local, regional, or distant melanoma recurrence, occurrence of new primary melanoma, or death from any cause. The ITT population included all subjects enrolled in the study, whether or not they had received study medication. Here, 99999 = not estimable due to low number of events.
    End point type
    Primary
    End point timeframe
    From randomization until the date of the first local, regional, or distant melanoma recurrence, occurrence of new primary melanoma, or death from any cause (up to the April 17, 2017 data cut-off, approximately 4.5 years)
    End point values
    		 Cohort 1 Vemurafenib Cohort 1 Placebo Cohort 2 Vemurafenib Cohort 2 Placebo
    Number of subjects analysed
    45
    72
    52
    53
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    36.9 (21.4 to 99999)
    23.1 (18.6 to 26.5)
    15.4 (11.1 to 35.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Cohort 1 Vemurafenib v Cohort 1 Placebo
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.78
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Cohort 2 Vemurafenib v Cohort 2 Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2598
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.18

    Secondary: Distant Metastasis-Free Survival (DMFS) as Assessed Using Contrast-Enhanced MRI or Contrast Enhanced CT

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    End point title
    		 Distant Metastasis-Free Survival (DMFS) as Assessed Using Contrast-Enhanced MRI or Contrast Enhanced CT
    End point description
    DMFS was defined as the time from randomization until the date of diagnosis of distant (i.e. non-locoregional) metastases or death from any cause. The ITT population included all subjects enrolled in the study, whether or not they had received study medication. Here, 99999 = not estimable due to low number of events.
    End point type
    Secondary
    End point timeframe
    From randomization until the date of diagnosis of distant (i.e., non-locoregional) metastases or death from any cause (up to the April 17, 2017 data cut-off, approximately 4.5 years)
    End point values
    		 Cohort 1 Vemurafenib Cohort 1 Placebo Cohort 2 Vemurafenib Cohort 2 Placebo
    Number of subjects analysed
    34
    52
    38
    37
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (36.9 to 99999)
    37.2 (22.1 to 99999)
    30.7 (24.5 to 99999)
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Cohort 1 Vemurafenib v Cohort 1 Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0133
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.9
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Cohort 2 Vemurafenib v Cohort 2 Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6815
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.44

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from randomization until the date of death from any cause. The ITT population included all subjects enrolled in the study, whether or not they had received study medication. Here, 99999 = not estimable due to low number of events.
    End point type
    Secondary
    End point timeframe
    From randomization until the date of death from any cause (up to the July 13, 2018 data cut-off, approximately 6 years)
    End point values
    		 Cohort 1 Vemurafenib Cohort 1 Placebo Cohort 2 Vemurafenib Cohort 2 Placebo
    Number of subjects analysed
    18
    33
    25
    25
    Units: months
        median (confidence interval 95%)
    99999 (60.0 to 99999)
    99999 (99999 to 99999)
    59.9 (54.6 to 59.9)
    99999 (52.6 to 99999)
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Cohort 1 Vemurafenib v Cohort 1 Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0274
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.94
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Cohort 2 Vemurafenib v Cohort 2 Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8597
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.66

    Secondary: Percentage of Subjects With Adverse Events

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    End point title
    		 Percentage of Subjects With Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The safety population included all subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    From randomization up to data cut-off (up to 3-July-2018, approximately 6 years)
    End point values
    		 Cohort 1 Vemurafenib Cohort 1 Placebo Cohort 2 Vemurafenib Cohort 2 Placebo
    Number of subjects analysed
    154
    156
    93
    91
    Units: percentage of subjects
        number (not applicable)
    99.4
    88.5
    100.0
    89.0
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) 30-Item Quality of Life Questionnaire (QLQ-C30) Score

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    End point title
    		 Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) 30-Item Quality of Life Questionnaire (QLQ-C30) Score
    End point description
    EORTC QLQ-C30 assessments: appetite loss, constipation, diarrhea, dyspnea, fatigue, nausea/vomiting, pain, insomnia, function (cognitive, emotional, physical, role, and social), financial difficulties, and a global health status (GHS)/health-related quality of life (HRQoL). Either a 4-point scale (1 'Not at all' to 4 'Very much' or 7-point scale (1 'very poor' to 7 'Excellent') were used. Scores were averaged and transformed to a 0 - 100 scale. HRQoL subscales: higher scores=higher levels of functioning. Symptom subscales: higher scores=higher levels of symptoms/problems. Changes of 5 - 10 points=considered minimally important difference to subjects. Patient-reported outcome (PRO)-evaluable population: subjects with at least one dose of vemurafenib and with a baseline and at least one post-baseline QLQ-C30 with a score. PT=post-treatment; EOT=End of Treatment; Wks=weeks; C=Cycle; D=Day. 999=1 subject analyzed, therefore, standard deviation not applicable. 99999=0 subjects analyzed.
    End point type
    Secondary
    End point timeframe
    Days 1 and 15 of Cycles 1 and 2; Day 1 of Cycles 3-13; at end of treatment (up to 13 months); every 13 weeks thereafter until recurrence or occurrence of a new primary melanoma (up to the April 17, 2017 data cut-off, approximately 4.5 years)
    End point values
    		 Cohort 1 Vemurafenib Cohort 1 Placebo Cohort 2 Vemurafenib Cohort 2 Placebo
    Number of subjects analysed
    138
    147
    87
    89
    Units: score on a scale
    arithmetic mean (standard deviation)
        App. Loss: C1 D1 (Baseline, n=138,147,86,89)
    3.6 ( 11.2 )
    3.9 ( 14.9 )
    3.5 ( 10.3 )
    3.4 ( 11.3 )
        App. Loss: Change at C1 D8 (n=24,22,16,19)
    2.8 ( 9.4 )
    1.5 ( 7.1 )
    10.4 ( 16.0 )
    0.0 ( 11.1 )
        App. Loss: Change at C1 D15 (n=132,139,79,84)
    16.7 ( 26.5 )
    1.4 ( 12.0 )
    12.2 ( 22.8 )
    1.2 ( 17.5 )
        App. Loss: Change at C1 D22 (n=22,21,15,17)
    7.6 ( 14.3 )
    3.2 ( 10.0 )
    11.1 ( 20.6 )
    3.9 ( 20.0 )
        App. Loss: Change at C2 D1 (n=126,142,82,84)
    9.5 ( 21.0 )
    1.2 ( 10.1 )
    12.2 ( 23.7 )
    1.6 ( 15.4 )
        App. Loss: Change at C2 D15 (n=119,134,79,81)
    9.5 ( 22.2 )
    1.0 ( 12.2 )
    6.8 ( 16.3 )
    0.8 ( 14.9 )
        App. Loss: Change at C3 D1 (n=119,129,80,77)
    10.4 ( 20.7 )
    1.6 ( 10.1 )
    8.3 ( 18.0 )
    0.4 ( 14.8 )
        App. Loss: Change at C4 D1 (n=119,129,78,76)
    9.5 ( 20.9 )
    1.3 ( 12.1 )
    10.3 ( 20.3 )
    2.6 ( 15.2 )
        App. Loss: Change at C5 D1 (n=110,117,72,64)
    13.3 ( 23.5 )
    1.4 ( 12.7 )
    7.4 ( 15.0 )
    -0.5 ( 12.6 )
        App. Loss: Change at C6 D1 (n=106,112,69,63)
    9.7 ( 21.1 )
    2.4 ( 12.4 )
    13.0 ( 21.6 )
    1.1 ( 17.9 )
        App. Loss: Change at C7 D1 (n=106,108,68,59)
    10.7 ( 22.8 )
    1.5 ( 14.0 )
    7.4 ( 16.1 )
    4.0 ( 18.7 )
        App. Loss: Change at C8 D1 (n=105,105,65,53)
    10.2 ( 22.7 )
    1.9 ( 13.7 )
    10.8 ( 18.7 )
    -0.6 ( 12.2 )
        App. Loss: Change at C9 D1 (n=100,101,63,52)
    9.7 ( 25.2 )
    2.3 ( 13.5 )
    7.9 ( 17.7 )
    3.8 ( 15.7 )
        App. Loss: Change at C10 D1 (n=96,97,63,47)
    7.3 ( 18.9 )
    1.7 ( 15.5 )
    4.8 ( 15.7 )
    0.0 ( 12.0 )
        App. Loss: Change at C11 D1 (n=93,93,57,48)
    5.4 ( 19.2 )
    1.8 ( 14.2 )
    4.7 ( 13.3 )
    0.7 ( 12.8 )
        App. Loss: Change at C12 D1 (n=90,91,55,48)
    8.5 ( 20.9 )
    1.5 ( 14.0 )
    7.3 ( 15.3 )
    0.0 ( 11.9 )
        App. Loss: Change at C13 D1 (n=82,89,54,45)
    5.7 ( 17.2 )
    1.9 ( 13.6 )
    6.2 ( 14.6 )
    0.7 ( 11.2 )
        App. Loss: Change at EOT (n=123,125,66,75)
    2.7 ( 16.3 )
    0.8 ( 20.1 )
    5.1 ( 18.7 )
    2.7 ( 18.8 )
        App. Loss: Change at PT 13 Weeks (n=90,74,55,38)
    0.0 ( 13.2 )
    1.8 ( 16.5 )
    -1.2 ( 6.3 )
    1.8 ( 10.8 )
        App. Loss: Change at PT 26 Weeks (n=90,72,47,35)
    0.7 ( 16.6 )
    -1.4 ( 15.3 )
    3.5 ( 17.4 )
    1.0 ( 12.7 )
        App. Loss: Change at PT 39 Weeks (n=79,68,42,33)
    -0.4 ( 12.5 )
    -0.5 ( 7.0 )
    -0.8 ( 9.0 )
    2.0 ( 14.3 )
        App. Loss: Change at PT 52 Weeks (n=76,62,26,25)
    0.4 ( 17.6 )
    0.0 ( 12.1 )
    -1.3 ( 6.5 )
    2.7 ( 9.2 )
        App. Loss: Change at PT 65 Weeks (n=53,38,17,18)
    -1.9 ( 12.1 )
    0.9 ( 14.5 )
    0.0 ( 0.0 )
    5.6 ( 17.1 )
        App. Loss: Change at PT 78 Weeks (n=46,33,15,9)
    -0.7 ( 11.1 )
    2.0 ( 14.3 )
    0.0 ( 0.0 )
    3.7 ( 11.1 )
        App. Loss: Change at PT 91 Weeks (n=32,29,15,12)
    2.1 ( 16.8 )
    2.3 ( 12.4 )
    0.0 ( 0.0 )
    2.8 ( 9.6 )
        App. Loss: Change at PT 104 Weeks (n=27,25,10,9)
    -1.2 ( 11.3 )
    -1.3 ( 6.7 )
    0.0 ( 0.0 )
    -3.7 ( 11.1 )
        App. Loss: Change at PT 117 Weeks (n=22,17,9,5)
    -1.5 ( 12.5 )
    2.0 ( 14.3 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        App. Loss: Change at PT 130 Weeks (n=17,12,5,5)
    0.0 ( 0.0 )
    2.8 ( 17.2 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        App. Loss: Change at PT 143 Weeks (n=7,2,3,2)
    -4.8 ( 12.6 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        App. Loss: Change at PT 156 Weeks (n=3,1,0,2)
    0.0 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    16.7 ( 23.6 )
        App. Loss: Change at PT 169 Weeks (n=2,1,0,0)
    0.0 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        App. Loss: Change at PT 182 Weeks (n=3,0,0,0)
    0.0 ( 0.0 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        App. Loss: Change at PT/Discont. (n=8,1,6,1)
    0.0 ( 0.0 )
    0.0 ( 999 )
    0.0 ( 0.0 )
    0.0 ( 999 )
        Cog. Func. C1 D1 (Baseline, n=138,147,87,89)
    93.0 ( 14.1 )
    92.0 ( 16.2 )
    91.4 ( 17.2 )
    94.9 ( 11.6 )
        Cog. Func.: Change at C1 D8 (n=24,22,16,19)
    -2.1 ( 12.3 )
    1.5 ( 14.5 )
    0.0 ( 10.5 )
    2.6 ( 6.2 )
        Cog. Func.: Change at C1 D15 (n=132,139,78,84)
    -4.3 ( 13.1 )
    0.8 ( 12.6 )
    -3.8 ( 13.4 )
    -0.8 ( 11.5 )
        Cog. Func.: Change at C1 D22 (n=22,21,15,17)
    -0.8 ( 17.4 )
    1.6 ( 11.7 )
    -3.3 ( 9.3 )
    -4.9 ( 14.1 )
        Cog. Func.: Change at C2 D1 (n=127,142,82,84)
    -2.4 ( 14.2 )
    -2.5 ( 14.3 )
    -2.2 ( 12.2 )
    0.0 ( 13.9 )
        Cog. Func.: Change at C2 D15 (n=119,134,80,80)
    -3.8 ( 15.1 )
    -1.1 ( 14.6 )
    -3.1 ( 11.9 )
    -0.4 ( 15.2 )
        Cog. Func.: Change at C3 D1 (n=119,129,81,78)
    -3.6 ( 13.4 )
    -0.6 ( 12.0 )
    -2.5 ( 12.4 )
    -2.1 ( 13.3 )
        Cog. Func.: Change at C4 D1 (n=119,129,78,76)
    -3.8 ( 14.6 )
    -1.3 ( 15.1 )
    -4.9 ( 13.5 )
    -2.9 ( 13.7 )
        Cog. Func.: Change at C5 D1 (n=110,116,72,64)
    -6.2 ( 17.3 )
    -2.0 ( 14.9 )
    -3.9 ( 12.7 )
    -3.6 ( 15.3 )
        Cog. Func.: Change at C6 D1 (n=106,112,69,63)
    -5.7 ( 15.8 )
    -2.1 ( 12.5 )
    -4.1 ( 16.0 )
    -3.4 ( 18.2 )
        Cog. Func.: Change at C7 D1 (n=106,108,68,59)
    -6.3 ( 17.3 )
    -3.1 ( 13.3 )
    -3.9 ( 15.5 )
    -5.6 ( 15.0 )
        Cog. Func.: Change at C8 D1 (n=104,106,65,53)
    -7.4 ( 16.1 )
    -3.6 ( 16.9 )
    -5.1 ( 16.6 )
    -4.7 ( 13.2 )
        Cog. Func.: Change at C9 D1 (n=100,101,63,52)
    -8.2 ( 18.1 )
    -4.6 ( 17.3 )
    -5.8 ( 17.7 )
    -5.4 ( 12.2 )
        Cog. Func.: Change at C10 D1 (n=96,97,63,47)
    -9.0 ( 20.1 )
    -3.6 ( 17.4 )
    -4.5 ( 17.5 )
    -8.2 ( 19.3 )
        Cog. Func.: Change at C11 D1 (n=93,93,57,48)
    -10.6 ( 20.1 )
    -2.9 ( 15.9 )
    -5.0 ( 15.1 )
    -3.8 ( 12.5 )
        Cog. Func.: Change at C12 D1 (n=90,91,55,48)
    -8.7 ( 21.5 )
    -4.0 ( 14.6 )
    -3.9 ( 13.6 )
    -4.5 ( 14.5 )
        Cog. Func.: Change at C13 D1 (n=82,89,54,45)
    -7.7 ( 20.7 )
    -3.9 ( 16.1 )
    -6.5 ( 15.7 )
    -5.2 ( 12.7 )
        Cog. Func.:Change at EOT (n=123,125,67,75)
    -4.9 ( 17.3 )
    -3.5 ( 19.5 )
    -4.0 ( 17.2 )
    -6.9 ( 14.3 )
        Cog. Func.: Change at PT 13 Weeks (n=90,74,56,38)
    -4.4 ( 14.9 )
    -1.6 ( 14.1 )
    -1.5 ( 14.0 )
    -3.5 ( 14.1 )
        Cog. Func.: Change at PT 26 Weeks (n=90,72,47,35)
    -2.8 ( 16.2 )
    -2.5 ( 14.2 )
    -2.1 ( 15.4 )
    -3.8 ( 13.5 )
        Cog. Func.: Change at PT 39 Weeks (n=79,68,41,33)
    -2.1 ( 13.2 )
    -1.0 ( 14.6 )
    -2.0 ( 11.9 )
    -3.0 ( 11.4 )
        Cog. Func.: Change at PT 52 Weeks (n=76,62,27,25)
    -3.5 ( 17.3 )
    -1.9 ( 9.1 )
    1.2 ( 13.0 )
    -7.3 ( 12.8 )
        Cog. Func.: Change at PT 65 Weeks (n=53,38,17,18)
    -4.4 ( 17.3 )
    -3.9 ( 15.2 )
    -1.0 ( 12.5 )
    -4.6 ( 11.2 )
        Cog. Func.: Change at PT 78 Weeks (n=46,33,15,9)
    -2.5 ( 17.2 )
    -3.5 ( 19.4 )
    -1.1 ( 14.7 )
    -7.4 ( 12.1 )
        Cog. Func.: Change at PT 91 Weeks (n=33,29,15,12)
    -2.5 ( 16.2 )
    -2.3 ( 15.9 )
    3.3 ( 11.3 )
    -5.6 ( 13.0 )
        Cog. Func.: Change at PT 104 Weeks (n=27,25,10,9)
    1.2 ( 14.6 )
    -4.0 ( 16.9 )
    3.3 ( 13.1 )
    -5.6 ( 11.8 )
        Cog. Func.: Change at PT 117 Weeks (n=22,17,8,5)
    1.5 ( 12.5 )
    0.0 ( 10.2 )
    -2.1 ( 5.9 )
    -6.7 ( 14.9 )
        Cog. Func.: Change at PT 130 Weeks (n=17,12,5,5)
    -3.9 ( 15.1 )
    -1.4 ( 15.0 )
    0.0 ( 0.0 )
    -6.7 ( 14.9 )
        Cog. Func.: Change at PT 143 Weeks (n=7,2,3,2)
    4.8 ( 18.5 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
    -8.3 ( 11.8 )
        Cog. Func.: Change at PT 156 Weeks (n=3,1,0,2)
    11.1 ( 19.2 )
    0.0 ( 999 )
    99999 ( 99999 )
    -16.7 ( 23.6 )
        Cog. Func.: Change at PT 169 Weeks (n=2,1,0,0)
    16.7 ( 23.6 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cog. Func.: Change at PT 182 Weeks (n=3,0,0,0)
    11.1 ( 19.2 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cog. Func.: Change at PT/Discont. (n=8,1,6,1)
    -2.1 ( 16.5 )
    0.0 ( 999 )
    -5.6 ( 8.6 )
    0.0 ( 999 )
        Constip.: C1 D1 (Baseline, n=138,146,87,88)
    3.1 ( 10.6 )
    5.7 ( 16.3 )
    4.6 ( 12.6 )
    5.7 ( 15.3 )
        Constip.: Change at C1 D8 (n=23,22,16,19)
    -2.9 ( 13.9 )
    0.0 ( 0.0 )
    -2.1 ( 8.3 )
    -5.3 ( 12.5 )
        Constip.: Change at C1 D15 (n=130,138,80,83)
    2.1 ( 17.0 )
    0.7 ( 13.0 )
    1.7 ( 13.9 )
    -0.4 ( 16.9 )
        Constip.: Change at C1 D22 (n=21,21,15,17)
    -1.6 ( 19.7 )
    1.6 ( 7.3 )
    0.0 ( 12.6 )
    -3.9 ( 16.2 )
        Constip.: Change at C2 D1 (n=124,141,82,83)
    1.1 ( 12.7 )
    1.4 ( 10.4 )
    1.6 ( 13.8 )
    -0.4 ( 16.9 )
        Constip.: Change at C2 D15 (n=117,133,79,79)
    1.4 ( 14.8 )
    0.0 ( 13.0 )
    0.0 ( 11.9 )
    -1.3 ( 15.5 )
        Constip.: Change at C3 D1 (n=115,127,79,77)
    -1.2 ( 12.4 )
    1.0 ( 13.9 )
    0.4 ( 12.5 )
    -1.7 ( 18.7 )
        Constip.: Change at C4 D1 (n=118,127,78,75)
    0.6 ( 11.5 )
    0.5 ( 16.8 )
    0.0 ( 10.7 )
    -2.2 ( 14.8 )
        Constip.: Change at C5 D1 (n=107,116,71,64)
    -0.6 ( 9.1 )
    0.3 ( 16.7 )
    3.8 ( 14.4 )
    -3.1 ( 17.5 )
        Constip.: Change at C6 D1 (n=104,112,68,63)
    0.6 ( 13.1 )
    1.8 ( 16.6 )
    5.4 ( 16.9 )
    -3.7 ( 20.0 )
        Constip.: Change at C7 D1 (n=106,108,67,59)
    3.1 ( 18.1 )
    1.5 ( 19.0 )
    3.0 ( 12.6 )
    -4.0 ( 15.3 )
        Constip.: Change at C8 D1 (n=103,106,64,53)
    1.9 ( 14.6 )
    1.6 ( 16.2 )
    4.2 ( 15.1 )
    -1.9 ( 17.8 )
        Constip.: Change at C9 D1 (n=97,101,62,52)
    1.4 ( 11.7 )
    -2.3 ( 13.5 )
    3.2 ( 14.4 )
    -0.6 ( 20.3 )
        Constip.: Change at C10 D1 (n=96,97,62,47)
    1.4 ( 10.7 )
    -1.4 ( 12.7 )
    1.6 ( 11.2 )
    -4.3 ( 17.9 )
        Constip.: Change at C11 D1 (n=92,93,56,48)
    2.2 ( 14.7 )
    0.0 ( 16.3 )
    2.4 ( 14.0 )
    -4.9 ( 15.4 )
        Constip.: Change at C12 D1 (n=90,91,54,48)
    4.8 ( 19.1 )
    -1.8 ( 14.4 )
    3.1 ( 13.4 )
    -3.5 ( 14.2 )
        Constip.: Change at C13 D1 (n=81,89,54,45)
    4.1 ( 18.5 )
    0.0 ( 18.8 )
    0.0 ( 11.2 )
    -3.7 ( 19.1 )
        Constip.: Change at EOT (n=122,124,67,74)
    3.3 ( 15.1 )
    2.4 ( 19.1 )
    4.5 ( 17.3 )
    -1.4 ( 17.8 )
        Constip.: Change at PT 13 Weeks (n=88,74,56,38)
    0.4 ( 17.1 )
    -0.5 ( 17.0 )
    6.0 ( 16.9 )
    0.9 ( 21.2 )
        Constip.: Change at PT 26 Weeks (n=89,71,47,35)
    -0.4 ( 13.8 )
    -0.9 ( 13.8 )
    2.8 ( 9.4 )
    -1.0 ( 18.9 )
        Constip.: Change at PT 39 Weeks (n=77,67,41,33)
    0.4 ( 14.8 )
    -0.5 ( 13.6 )
    2.4 ( 13.7 )
    -4.0 ( 16.2 )
        Constip.: Change at PT 52 Weeks (n=75,62,27,25)
    0.0 ( 13.4 )
    0.0 ( 14.8 )
    0.0 ( 9.2 )
    0.0 ( 13.6 )
        Constip.: Change at PT 65 Weeks (n=53,37,17,18)
    3.8 ( 14.1 )
    3.6 ( 21.9 )
    2.0 ( 14.3 )
    0.0 ( 11.4 )
        Constip.: Change at PT 78 Weeks (n=46,33,15,9)
    -1.4 ( 9.8 )
    6.1 ( 25.6 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        Constip.: Change at PT 91 Weeks (n=31,28,15,12)
    -4.3 ( 11.4 )
    6.0 ( 18.3 )
    2.2 ( 8.6 )
    0.0 ( 14.2 )
        Constip.: Change at PT 104 Weeks (n=26,25,10,9)
    1.3 ( 14.8 )
    4.0 ( 14.7 )
    -3.3 ( 10.5 )
    0.0 ( 16.7 )
        Constip.: Change at PT 117 Weeks (n=20,17,9,5)
    -6.7 ( 13.7 )
    9.8 ( 19.6 )
    0.0 ( 0.0 )
    -6.7 ( 14.9 )
        Constip.: Change at PT 130 Weeks (n=16,12,5,5)
    -8.3 ( 14.9 )
    5.6 ( 13.0 )
    0.0 ( 23.6 )
    -6.7 ( 14.9 )
        Constip.: Change at PT 143 Weeks (n=7,2,3,2)
    -9.5 ( 16.3 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        Constip.: Change at PT 156 Weeks (n=3,1,0,2)
    0.0 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    -16.7 ( 23.6 )
        Constip.: Change at PT 169 Weeks (n=2,1,0,0)
    0.0 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Constip.: Change at PT 182 Weeks (n=3,0,0,0)
    -11.1 ( 19.2 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Constip.: Change at PT/Discont.(n=8,1,6,1)
    0.0 ( 0.0 )
    0.0 ( 999 )
    0.0 ( 0.0 )
    0.0 ( 999 )
        Diarrhoea: C1 D1 (Baseline, n=138,147,87,89)
    4.1 ( 13.0 )
    5.4 ( 17.5 )
    3.8 ( 13.9 )
    4.1 ( 16.5 )
        Diarrhoea: Change at C1 D8 (n=24,22,16,19)
    4.2 ( 11.3 )
    0.0 ( 10.3 )
    -4.2 ( 20.6 )
    -8.8 ( 24.4 )
        Diarrhoea: Change at C1 D15 (n=132,139,77,84)
    2.5 ( 21.3 )
    -0.7 ( 14.7 )
    1.7 ( 19.4 )
    -1.6 ( 17.1 )
        Diarrhoea: Change at C1 D22 (n=22,21,15,17)
    3.0 ( 9.8 )
    -1.6 ( 16.6 )
    -2.2 ( 23.5 )
    -9.8 ( 25.7 )
        Diarrhoea: Change at C2 D1 (n=127,142,82,84)
    1.3 ( 19.9 )
    -0.9 ( 16.3 )
    4.9 ( 21.7 )
    0.0 ( 20.0 )
        Diarrhoea: Change at C2 D15 (n=119,134,80,80)
    1.7 ( 21.2 )
    -1.5 ( 19.1 )
    0.4 ( 17.2 )
    0.0 ( 16.8 )
        Diarrhoea: Change at C3 D1 (n=119,129,81,78)
    3.4 ( 21.9 )
    -0.3 ( 18.4 )
    3.3 ( 19.4 )
    -0.9 ( 15.2 )
        Diarrhoea: Change at C4 D1 (n=119,129,78,76)
    3.9 ( 23.0 )
    0.3 ( 19.8 )
    5.6 ( 18.2 )
    -2.6 ( 18.7 )
        Diarrhoea: Change at C5 D1 (n=110,116,72,64)
    7.6 ( 23.7 )
    -1.4 ( 20.3 )
    2.8 ( 20.0 )
    -3.6 ( 18.9 )
        Diarrhoea: Change at C6 D1 (n=106,112,69,63)
    7.2 ( 25.2 )
    -0.6 ( 20.0 )
    7.2 ( 24.8 )
    -2.6 ( 19.2 )
        Diarrhoea: Change at C7 D1 (n=106,108,68,59)
    9.4 ( 24.2 )
    -1.5 ( 21.6 )
    4.9 ( 22.5 )
    -4.5 ( 18.0 )
        Diarrhoea: Change at C8 D1 (n=104,106,65,52)
    5.1 ( 19.6 )
    -0.9 ( 21.3 )
    5.6 ( 20.9 )
    -3.2 ( 16.5 )
        Diarrhoea: Change at C9 D1 (n=100,101,62,52)
    7.7 ( 25.0 )
    0.7 ( 24.5 )
    4.3 ( 19.5 )
    -1.9 ( 23.3 )
        Diarrhoea: Change at C10 D1 (n=96,97,62,47)
    6.9 ( 21.6 )
    -0.3 ( 22.3 )
    5.9 ( 23.8 )
    -2.1 ( 18.9 )
        Diarrhoea: Change at C11 D1 (n=93,93,57,48)
    6.1 ( 19.6 )
    1.1 ( 23.3 )
    4.7 ( 23.1 )
    -0.7 ( 20.0 )
        Diarrhoea: Change at C12 D1 (n=90,91,55,47)
    7.4 ( 25.4 )
    -0.7 ( 23.3 )
    7.9 ( 24.8 )
    -0.7 ( 19.0 )
        Diarrhoea: Change at C13 D1 (n=82, 89,54,45)
    8.5 ( 24.5 )
    0.4 ( 25.4 )
    8.0 ( 28.9 )
    -1.5 ( 20.0 )
        Diarrhoea: Change at EOT (n=123,125,67,75)
    0.8 ( 21.5 )
    0.0 ( 20.7 )
    -1.0 ( 16.4 )
    -1.8 ( 18.9 )
        Diarrhoea: Change at PT 13 Weeks (n=90,74,56,38)
    -0.4 ( 15.4 )
    -1.8 ( 24.0 )
    0.0 ( 18.0 )
    0.0 ( 15.5 )
        Diarrhoea: Change at PT 26 Weeks (n=89,72,47,35)
    -2.2 ( 16.5 )
    -3.2 ( 24.5 )
    0.7 ( 8.5 )
    -1.9 ( 19.7 )
        Diarrhoea: Change at PT 39 Weeks (n=79,68,41,33)
    -1.7 ( 15.9 )
    -4.9 ( 23.2 )
    1.6 ( 14.8 )
    0.0 ( 18.6 )
        Diarrhoea: Change at PT 52 Weeks (n=75,62,27,25)
    -1.8 ( 17.2 )
    -3.8 ( 23.5 )
    -1.2 ( 21.6 )
    0.0 ( 19.2 )
        Diarrhoea: Change at PT 65 Weeks (n=53,38,17,18)
    0.0 ( 19.6 )
    -6.1 ( 29.9 )
    2.0 ( 8.1 )
    -7.4 ( 24.4 )
        Diarrhoea: Change at PT 78 Weeks (n=46,33,15,9)
    -0.7 ( 20.5 )
    -7.1 ( 29.8 )
    0.0 ( 0.0 )
    -3.7 ( 11.1 )
        Diarrhoea: Change at PT 91 Weeks (n=33,29,15,12)
    4.0 ( 16.2 )
    -9.2 ( 25.0 )
    0.0 ( 0.0 )
    -8.3 ( 28.9 )
        Diarrhoea: Change at PT 104 Weeks (n=27,25,10,9)
    0.0 ( 9.2 )
    -5.3 ( 28.3 )
    3.3 ( 10.5 )
    -11.1 ( 33.3 )
        Diarrhoea: Change at PT 117 Weeks (n=22,17,8,5)
    0.0 ( 10.3 )
    -11.8 ( 31.0 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        Diarrhoea: Change at PT 130 Weeks (n=17,12,5,5)
    -2.0 ( 8.1 )
    -2.8 ( 43.7 )
    6.7 ( 14.9 )
    13.3 ( 18.3 )
        Diarrhoea: Change at PT 143 Weeks (n=7,2,3,2)
    0.0 ( 0.0 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        Diarrhoea: Change at PT 156 Weeks (n=3,1,0,2)
    0.0 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    0.0 ( 0.0 )
        Diarrhoea: Change at PT 169 Weeks (n=2,1,0,0)
    0.0 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Diarrhoea: Change at PT 182 Weeks (n=3,0,0,0)
    0.0 ( 0.0 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Diarrhoea: Change at PT/Discont. (n=8,1,6,1)
    0.0 ( 17.8 )
    -33.3 ( 999 )
    0.0 ( 0.0 )
    0.0 ( 999 )
        Dyspnoea: C1 D1 (Baseline, (n=138,147,87,89)
    3.6 ( 10.4 )
    4.8 ( 12.9 )
    5.0 ( 12.0 )
    3.0 ( 10.8 )
        Dyspnoea: Change at C1 D8 (n=24,22,16,19)
    4.2 ( 11.3 )
    -1.5 ( 7.1 )
    4.2 ( 16.7 )
    -1.8 ( 7.6 )
        Dyspnoea: Change at C1 D15 (n=132,139,80,84)
    6.3 ( 18.9 )
    0.2 ( 8.5 )
    2.9 ( 15.2 )
    1.2 ( 12.1 )
        Dyspnoea: Change at C1 D22 (n=21,21,15,17)
    4.8 ( 12.0 )
    -1.6 ( 7.3 )
    0.0 ( 17.8 )
    0.0 ( 0.0 )
        Dyspnoea: Change at C2 D1 (n=126,142,83,84)
    1.9 ( 13.5 )
    0.2 ( 11.6 )
    4.8 ( 20.9 )
    3.2 ( 14.3 )
        Dyspnoea: Change at C2 D15 (n=119,134,80,81)
    2.8 ( 16.0 )
    1.0 ( 13.5 )
    4.6 ( 18.9 )
    4.1 ( 17.0 )
        Dyspnoea: Change at C3 D1 (n=119,129,81,78)
    3.4 ( 17.0 )
    1.8 ( 13.4 )
    3.7 ( 18.3 )
    3.8 ( 12.0 )
        Dyspnoea: Change at C4 D1 (n=119,129,78,76)
    3.1 ( 15.6 )
    3.1 ( 14.7 )
    3.0 ( 18.8 )
    1.8 ( 14.3 )
        Dyspnoea: Change at C5 D1 (n=110,116,72,64)
    5.2 ( 14.4 )
    4.0 ( 14.7 )
    3.7 ( 19.0 )
    3.1 ( 15.4 )
        Dyspnoea: Change at C6 D1 (n=106,112,69,63)
    3.8 ( 16.8 )
    2.4 ( 13.9 )
    3.9 ( 19.4 )
    2.1 ( 15.7 )
        Dyspnoea: Change at C7 D1 (n=106,108,68,59)
    5.3 ( 16.7 )
    3.7 ( 17.3 )
    3.9 ( 17.8 )
    2.8 ( 12.8 )
        Dyspnoea: Change at C8 D1 (n=104,106,65,53)
    4.2 ( 16.5 )
    4.1 ( 17.6 )
    2.6 ( 14.8 )
    3.1 ( 13.5 )
        Dyspnoea: Change at C9 D1 (n=100,101,63,52)
    5.7 ( 17.1 )
    5.3 ( 16.8 )
    2.1 ( 16.8 )
    4.5 ( 18.7 )
        Dyspnoea: Change at C10 D1 (n=96,97,63,47)
    5.2 ( 20.1 )
    4.5 ( 16.4 )
    6.3 ( 18.8 )
    3.5 ( 12.5 )
        Dyspnoea: Change at C11 D1 (n=93,93,57,48)
    5.7 ( 19.4 )
    5.0 ( 19.0 )
    7.0 ( 20.6 )
    3.5 ( 14.2 )
        Dyspnoea: Change at C12 D1 (n=90,91,55,48)
    6.7 ( 24.1 )
    5.5 ( 18.1 )
    3.6 ( 18.9 )
    5.6 ( 15.9 )
        Dyspnoea: Change at C13 D1 (n=82,89,54,45)
    6.5 ( 19.2 )
    4.9 ( 15.5 )
    4.9 ( 19.9 )
    5.9 ( 14.7 )
        Dyspnoea: Change at EOT (n=123,125,67,75)
    4.1 ( 14.5 )
    2.4 ( 19.9 )
    3.0 ( 18.1 )
    6.2 ( 16.2 )
        Dyspnoea: Change at PT 13 Weeks (n=90,74,55,38)
    3.0 ( 17.1 )
    3.2 ( 16.7 )
    3.0 ( 16.1 )
    2.6 ( 12.0 )
        Dyspnoea: Change at PT 26 Weeks (n=90,72,47,35)
    4.8 ( 16.2 )
    1.4 ( 16.3 )
    3.5 ( 19.9 )
    -1.0 ( 5.6 )
        Dyspnoea: Change at PT 39 Weeks (n=79,68,42,33)
    1.7 ( 14.0 )
    2.5 ( 13.3 )
    4.8 ( 18.9 )
    3.0 ( 12.8 )
        Dyspnoea: Change at PT 52 Weeks (n=76,62,27,25)
    1.8 ( 15.3 )
    3.8 ( 16.1 )
    2.5 ( 15.8 )
    5.3 ( 15.8 )
        Dyspnoea: Change at PT 65 Weeks (n=53,38,17,18)
    3.8 ( 14.1 )
    6.1 ( 15.2 )
    -3.9 ( 11.1 )
    1.9 ( 7.9 )
        Dyspnoea: Change at PT 78 Weeks (n=46,33,15,9)
    4.3 ( 13.3 )
    7.1 ( 18.2 )
    0.0 ( 21.8 )
    0.0 ( 16.7 )
        Dyspnoea: Change at PT 91 Weeks (n=33,29,15,12)
    3.0 ( 9.7 )
    5.7 ( 12.8 )
    -2.2 ( 15.3 )
    0.0 ( 14.2 )
        Dyspnoea: Change at PT 104 Weeks (n=27,25,10,8)
    0.0 ( 16.0 )
    6.7 ( 16.7 )
    0.0 ( 22.2 )
    8.3 ( 15.4 )
        Dyspnoea: Change at PT 117 Weeks (n=22,17,9,5)
    0.0 ( 14.5 )
    5.9 ( 13.1 )
    -3.7 ( 20.0 )
    6.7 ( 14.9 )
        Dyspnoea: Change at PT 130 Weeks (n=17,12,5,5)
    -2.0 ( 8.1 )
    0.0 ( 0.0 )
    0.0 ( 23.6 )
    13.3 ( 18.3 )
        Dyspnoea: Change at PT 143 Weeks (n=7,2,3,2)
    9.5 ( 25.2 )
    0.0 ( 0.0 )
    -11.1 ( 19.2 )
    0.0 ( 0.0 )
        Dyspnoea: Change at PT 156 Weeks (n=3,1,0,2)
    0.0 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    16.7 ( 23.6 )
        Dyspnoea: Change at PT 169 Weeks (n=2,1,0,0)
    0.0 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Dyspnoea: Change at PT 182 Weeks (n=3,0,0,0)
    0.0 ( 0.0 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Dyspnoea: Change at PT/Discont. (n=8,1,6,1)
    0.0 ( 0.0 )
    0.0 ( 999 )
    0.0 ( 0.0 )
    0.0 ( 999 )
        Emot. func.: C1 D1 (Baseline, n=138,147,87,89)
    83.8 ( 15.1 )
    86.1 ( 16.4 )
    81.6 ( 21.5 )
    84.5 ( 17.4 )
        Emot. func.: Change at C1 D8 (n=24,22,16,19)
    -4.5 ( 15.5 )
    1.9 ( 12.0 )
    3.6 ( 11.4 )
    1.8 ( 14.0 )
        Emot. func.: Change at C1 D15 (n=132,139,78,84)
    -5.2 ( 18.0 )
    1.9 ( 12.3 )
    -1.0 ( 16.6 )
    3.8 ( 12.0 )
        Emot. func.: Change at C1 D22 (n=22,21,15,17)
    -6.4 ( 20.6 )
    2.4 ( 9.9 )
    -0.6 ( 12.8 )
    -0.5 ( 17.3 )
        Emot. func.: Change at C2 D1 (n=127,142,82,84)
    -1.2 ( 16.0 )
    2.5 ( 13.2 )
    -1.0 ( 17.5 )
    4.0 ( 12.7 )
        Emot. func.: Change at C2 D15 (n=119,134,80,80)
    0.2 ( 18.7 )
    2.0 ( 15.4 )
    -0.5 ( 11.7 )
    3.8 ( 13.6 )
        Emot. func.: Change at C3 D1 (n=119,129,81,78)
    -0.1 ( 17.3 )
    2.3 ( 13.2 )
    -0.8 ( 16.8 )
    3.5 ( 13.9 )
        Emot. func.: Change at C4 D1 (n=119,129,78,76)
    -2.7 ( 18.9 )
    1.8 ( 15.1 )
    -1.2 ( 15.9 )
    2.4 ( 14.9 )
        Emot. func.: Change at C5 D1 (n=110,116,72,64)
    -3.5 ( 19.8 )
    -0.2 ( 18.4 )
    -0.8 ( 15.4 )
    3.0 ( 14.4 )
        Emot. func.: Change at C6 D1 (n=106,112,69,63)
    -2.8 ( 17.5 )
    -0.7 ( 16.7 )
    -2.6 ( 16.0 )
    1.4 ( 18.7 )
        Emot. func.: Change at C7 D1 (n=106,108,68,59)
    -3.0 ( 18.5 )
    0.5 ( 16.4 )
    -2.3 ( 16.1 )
    -0.5 ( 14.4 )
        Emot. func.: Change at C8 D1 (n=104,106,65,53)
    -3.5 ( 20.0 )
    -0.9 ( 15.5 )
    -1.9 ( 15.9 )
    0.2 ( 13.1 )
        Emot. func.: Change at C9 D1 (n=100,101,63,52)
    -1.6 ( 22.1 )
    -0.9 ( 17.0 )
    0.1 ( 15.8 )
    -0.2 ( 16.1 )
        Emot. func.: Change at C10 D1 (n=96,97,63,47)
    -1.0 ( 20.5 )
    -1.1 ( 14.3 )
    -0.1 ( 16.5 )
    0.0 ( 14.6 )
        Emot. func.: Change at C11 D1 (n=93,93,57,48)
    0.0 ( 19.6 )
    0.5 ( 14.1 )
    1.2 ( 15.7 )
    0.7 ( 14.3 )
        Emot. func.: Change at C12 D1 (n=90,91,55,48)
    -2.3 ( 20.0 )
    -2.2 ( 16.4 )
    1.1 ( 14.6 )
    -1.6 ( 14.1 )
        Emot. func.: Change at C13 D1 (n=82,89,54,45)
    -2.0 ( 20.4 )
    -2.5 ( 18.6 )
    0.2 ( 16.5 )
    0.2 ( 13.5 )
        Emot. func.: Change at EOT (n=123,125,67,75)
    1.5 ( 18.8 )
    -2.0 ( 19.6 )
    2.2 ( 22.2 )
    -4.4 ( 19.9 )
        Emot. func.: Change at PT 13 Weeks (n=90,74,56,38)
    3.2 ( 17.4 )
    -1.0 ( 19.5 )
    6.4 ( 16.7 )
    3.5 ( 13.8 )
        Emot. func.: Change at PT 26 Weeks (n=90,72,47,35)
    4.9 ( 18.3 )
    -1.4 ( 14.1 )
    3.0 ( 18.2 )
    1.2 ( 16.2 )
        Emot. func.: Change at PT 39 Weeks (n=79,68,41,33)
    2.5 ( 15.5 )
    -0.2 ( 14.9 )
    4.1 ( 19.0 )
    2.3 ( 12.9 )
        Emot. func.: Change at PT 52 Weeks (n=76,62,27,25)
    2.4 ( 17.8 )
    -0.7 ( 16.3 )
    9.0 ( 16.8 )
    1.7 ( 14.2 )
        Emot. func.: Change at PT 65 Weeks (n=53,38,17,18)
    1.1 ( 17.9 )
    -2.0 ( 17.5 )
    10.3 ( 17.1 )
    3.7 ( 16.0 )
        Emot. func.: Change at PT 78 Weeks (n=46,33,15,9)
    2.9 ( 14.6 )
    -1.8 ( 22.1 )
    8.9 ( 16.2 )
    1.9 ( 10.8 )
        Emot. func.: Change at PT 91 Weeks (n=33,29,15,12)
    1.8 ( 16.8 )
    0.0 ( 17.3 )
    13.3 ( 16.6 )
    -0.7 ( 20.6 )
        Emot. func.: Change at PT 104 Weeks (n=27,25,10,9)
    6.5 ( 14.3 )
    -7.0 ( 21.9 )
    4.2 ( 13.2 )
    1.9 ( 20.7 )
        Emot. func.: Change at PT 117 Weeks (n=22,17,8,5)
    7.2 ( 12.7 )
    -2.9 ( 14.7 )
    0.0 ( 16.7 )
    3.3 ( 29.8 )
        Emot. func.: Change at PT 130 Weeks (n=17,12,5,5)
    8.7 ( 12.8 )
    -4.9 ( 15.3 )
    3.3 ( 20.1 )
    1.7 ( 32.5 )
        Emot. func.: Change at PT 143 Weeks (n=7,2,3,2)
    0.0 ( 18.0 )
    -4.2 ( 5.9 )
    0.0 ( 25.0 )
    -16.7 ( 23.6 )
        Emot. func.: Change at PT 156 Weeks (n=3,1,0,2)
    22.2 ( 9.6 )
    0.0 ( 999 )
    99999 ( 99999 )
    4.2 ( 53.0 )
        Emot. func.: Change at PT 169 Weeks (n=2,1,0,0)
    25.0 ( 11.8 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Emot. func.: Change at PT 182 Weeks (n=3,0,0,0)
    16.7 ( 16.7 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Emot. func.: Change at PT/Discont. (n=8,1,6,1)
    -5.2 ( 28.1 )
    0.0 ( 999 )
    1.4 ( 11.1 )
    8.3 ( 999 )
        Fatigue: C1 D1 (Baseline, n=138,147,87,89)
    13.2 ( 14.7 )
    16.1 ( 19.4 )
    15.5 ( 18.2 )
    14.7 ( 18.6 )
        Fatigue: Change at C1 D8 (n=24,22,16,19)
    7.9 ( 19.0 )
    -0.3 ( 9.8 )
    7.6 ( 13.3 )
    5.3 ( 10.1 )
        Fatigue: Change at C1 D15 (n=132,139,80,84)
    22.6 ( 26.1 )
    2.3 ( 14.2 )
    18.2 ( 27.0 )
    3.4 ( 13.1 )
        Fatigue: Change at C1 D22 (n=22,21,15,17)
    15.2 ( 21.3 )
    -1.9 ( 14.4 )
    17.0 ( 21.4 )
    9.2 ( 15.8 )
        Fatigue: Change at C2 D1 (n=127,142,83,84)
    13.2 ( 22.0 )
    2.5 ( 15.2 )
    13.7 ( 24.2 )
    2.5 ( 14.5 )
        Fatigue: Change at C2 D15 (n=119,134,80,81)
    15.2 ( 23.5 )
    1.5 ( 18.2 )
    10.7 ( 19.9 )
    2.1 ( 16.5 )
        Fatigue: Change at C3 D1 (n=119,129,81,78)
    14.1 ( 22.5 )
    1.5 ( 16.4 )
    12.6 ( 23.1 )
    4.7 ( 15.9 )
        Fatigue: Change at C4 D1 (n=119,129,78,76)
    12.6 ( 21.7 )
    2.0 ( 18.4 )
    13.3 ( 23.1 )
    3.2 ( 18.1 )
        Fatigue: Change at C5 D1 (n=110,117,72,64)
    14.2 ( 23.7 )
    1.9 ( 16.1 )
    13.6 ( 18.9 )
    4.7 ( 17.2 )
        Fatigue: Change at C6 D1 (n=106,112,69,63)
    11.9 ( 21.6 )
    1.5 ( 17.4 )
    13.8 ( 22.2 )
    3.0 ( 18.7 )
        Fatigue: Change at C7 D1 (n=106,108,68,59)
    13.1 ( 21.0 )
    0.2 ( 18.3 )
    13.2 ( 23.2 )
    6.0 ( 17.7 )
        Fatigue: Change at C8 D1 (n=105,106,65,53)
    14.1 ( 23.9 )
    3.9 ( 21.9 )
    12.7 ( 22.7 )
    5.0 ( 15.5 )
        Fatigue: Change at C9 D1 (n=100,101,63,52)
    16.3 ( 25.3 )
    2.7 ( 20.5 )
    13.7 ( 24.1 )
    6.0 ( 21.3 )
        Fatigue: Change at C10 D1 (n=96,97,63,47)
    11.3 ( 22.6 )
    3.4 ( 18.7 )
    11.3 ( 25.0 )
    3.3 ( 16.2 )
        Fatigue: Change at C11 D1 (n=93,93,57,48)
    11.5 ( 22.7 )
    2.7 ( 18.2 )
    10.7 ( 20.9 )
    7.6 ( 18.4 )
        Fatigue: Change at C12 D1 (n=90,91,55,48)
    10.3 ( 23.8 )
    2.1 ( 16.2 )
    10.7 ( 22.5 )
    3.2 ( 17.0 )
        Fatigue: Change at C13 D1 (n=82,89,54,45)
    11.1 ( 23.1 )
    4.0 ( 19.0 )
    13.4 ( 26.6 )
    4.7 ( 15.6 )
        Fatigue: Change at EOT (n=123,125,67,75)
    6.5 ( 21.3 )
    2.2 ( 24.2 )
    3.3 ( 21.9 )
    6.4 ( 20.9 )
        Fatigue: Change at PT 13 Weeks (n=90,74,56,38)
    1.6 ( 18.4 )
    0.7 ( 19.8 )
    -1.2 ( 19.0 )
    1.5 ( 14.9 )
        Fatigue: Change at PT 26 Weeks (n=90,72,47,35)
    2.5 ( 18.4 )
    1.0 ( 15.5 )
    0.5 ( 21.6 )
    -1.3 ( 18.8 )
        Fatigue: Change at PT 39 Weeks (n=79,68,42,33)
    -1.0 ( 16.9 )
    0.7 ( 17.2 )
    -0.5 ( 18.2 )
    -0.3 ( 12.6 )
        Fatigue: Change at PT 52 Weeks (n=76,62,27,25)
    1.6 ( 16.7 )
    1.7 ( 17.6 )
    -1.2 ( 14.6 )
    1.3 ( 20.6 )
        Fatigue: Change at PT 65 Weeks (n=53,38,17,18)
    1.3 ( 16.5 )
    4.4 ( 18.5 )
    -4.6 ( 11.8 )
    -1.2 ( 17.8 )
        Fatigue: Change at PT 78 Weeks (n=46,33,15,9)
    2.4 ( 16.2 )
    4.7 ( 20.8 )
    -4.4 ( 10.1 )
    -4.9 ( 18.5 )
        Fatigue: Change at PT 91 Weeks (n=33,29,15,12)
    -0.8 ( 16.3 )
    3.8 ( 18.8 )
    -3.7 ( 15.5 )
    -2.8 ( 26.0 )
        Fatigue: Change at PT 104 Weeks (n=27,25,10,9)
    -1.2 ( 14.6 )
    8.9 ( 18.7 )
    -1.1 ( 17.7 )
    -1.2 ( 29.1 )
        Fatigue: Change at PT 117 Weeks (n=22,17,9,5)
    -3.0 ( 13.4 )
    4.2 ( 19.2 )
    -7.4 ( 15.7 )
    0.0 ( 28.3 )
        Fatigue: Change at PT 130 Weeks (n=17,12,5,5)
    -0.7 ( 15.5 )
    6.5 ( 19.2 )
    -4.4 ( 16.9 )
    0.0 ( 33.3 )
        Fatigue: Change at PT 143 Weeks (n=7,2,3,2)
    -1.6 ( 14.9 )
    5.6 ( 7.9 )
    -3.7 ( 17.0 )
    16.7 ( 23.6 )
        Fatigue: Change at PT 156 Weeks (n=3,1,0,2)
    -11.1 ( 11.1 )
    0.0 ( 999 )
    99999 ( 99999 )
    33.3 ( 15.7 )
        Fatigue: Change at PT 169 Weeks (n=2,1,0,0)
    -16.7 ( 7.9 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Fatigue: Change at PT 182 Weeks (n=3,0,0,0)
    -14.8 ( 6.4 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Fatigue: Change at PT/Discont. (n=8,1,6,1)
    6.9 ( 16.7 )
    -22.2 ( 999 )
    -11.1 ( 25.3 )
    0.0 ( 999 )
        Fin. diff.: C1 D1 (Baseline, n=137,147,87,88)
    12.4 ( 25.2 )
    20.9 ( 30.0 )
    16.5 ( 30.4 )
    15.9 ( 26.3 )
        Fin. diff.: Change at C1 D8 (n=24,22,16,19)
    -9.7 ( 25.0 )
    -3.0 ( 14.2 )
    2.1 ( 8.3 )
    -7.0 ( 17.8 )
        Fin. diff.: Change at C1 D15 (n=131,139,78,84)
    1.5 ( 17.5 )
    -1.9 ( 20.0 )
    0.0 ( 15.2 )
    -4.4 ( 21.2 )
        Fin. diff.: Change at C1 D22 (n=22,21,15,17)
    -1.5 ( 26.2 )
    -3.2 ( 14.5 )
    0.0 ( 0.0 )
    0.0 ( 20.4 )
        Fin. diff.: Change at C2 D1 (n=126,141,82,83)
    0.0 ( 17.9 )
    -3.1 ( 21.0 )
    0.8 ( 16.5 )
    -4.4 ( 19.3 )
        Fin. diff.: Change at C2 D15 (n=119,134,80,79)
    1.1 ( 20.8 )
    -2.2 ( 20.1 )
    -0.4 ( 17.2 )
    -7.2 ( 20.4 )
        Fin. diff.: Change at C3 D1 (n=119,129,80,77)
    0.3 ( 21.5 )
    -5.2 ( 24.1 )
    1.3 ( 20.2 )
    -5.6 ( 19.8 )
        Fin. diff.: Change at C4 D1 (n=119,129,78,75)
    -0.8 ( 23.6 )
    -2.8 ( 24.3 )
    -0.4 ( 19.7 )
    -5.8 ( 18.5 )
        Fin. diff.: Change at C5 D1 (n=110,116,72,64)
    1.2 ( 23.0 )
    -5.5 ( 26.7 )
    2.3 ( 18.0 )
    -7.8 ( 23.6 )
        Fin. diff.: Change at C6 D1 (n=106,112,69,63)
    -0.6 ( 22.5 )
    -7.4 ( 26.4 )
    2.9 ( 20.4 )
    -5.8 ( 22.0 )
        Fin. diff.: Change at C7 D1 (n=106,107,68,59)
    1.9 ( 26.8 )
    -5.6 ( 26.1 )
    4.9 ( 27.2 )
    -5.6 ( 21.6 )
        Fin. diff.: Change at C8 D1 (n=104,106,65,53)
    -0.6 ( 23.2 )
    -4.7 ( 27.0 )
    4.1 ( 26.7 )
    -3.1 ( 20.9 )
        Fin. diff.: Change at C9 D1 (n=100,101,63,52)
    2.0 ( 24.1 )
    -8.9 ( 23.0 )
    4.2 ( 23.6 )
    -5.8 ( 20.6 )
        Fin. diff.: Change at C10 D1 (n=96,97,63,47)
    1.0 ( 23.4 )
    -8.6 ( 25.1 )
    2.6 ( 22.6 )
    -6.4 ( 20.4 )
        Fin. diff.: Change at C11 D1 (n=93,93,57,48)
    1.4 ( 21.4 )
    -7.5 ( 21.5 )
    0.6 ( 20.4 )
    -8.3 ( 22.3 )
        Fin. diff.: Change at C12 D1 (n=89,90,55,48)
    -0.4 ( 24.4 )
    -6.3 ( 23.9 )
    0.0 ( 26.4 )
    -6.3 ( 23.5 )
        Fin. diff.: Change at C13 D1 (n=82,89,54,45)
    1.2 ( 23.7 )
    -6.0 ( 22.2 )
    -1.9 ( 27.8 )
    -8.1 ( 24.8 )
        Fin. diff.: Change at EOT (n=122,125,67,75)
    2.5 ( 23.1 )
    -3.7 ( 26.5 )
    -2.5 ( 23.4 )
    -0.9 ( 23.9 )
        Fin. diff.: Change at PT 13 Weeks (n=90,74,56,38)
    0.4 ( 26.2 )
    -5.9 ( 24.3 )
    -10.1 ( 27.6 )
    -8.8 ( 25.3 )
        Fin. diff.: Change at PT 26 Weeks (n=89,72,47,35)
    -3.0 ( 22.3 )
    -6.0 ( 18.8 )
    -5.7 ( 26.3 )
    -7.6 ( 25.7 )
        Fin. diff.: Change at PT 39 Weeks (n=78,68,41,33)
    -1.7 ( 22.1 )
    -7.8 ( 25.8 )
    -2.4 ( 28.3 )
    -8.1 ( 26.4 )
        Fin. diff.: Change at PT 52 Weeks (n=75,62,27,25)
    -2.2 ( 21.5 )
    -5.4 ( 21.1 )
    -11.1 ( 24.5 )
    -1.3 ( 32.6 )
        Fin. diff.: Change at PT 65 Weeks (n=52,38,17,18)
    2.6 ( 26.3 )
    -6.1 ( 30.9 )
    -9.8 ( 19.6 )
    -7.4 ( 31.4 )
        Fin. diff.: Change at PT 78 Weeks (n=45,33,15,9)
    2.2 ( 27.9 )
    -8.1 ( 31.2 )
    -11.1 ( 20.6 )
    0.0 ( 16.7 )
        Fin. diff.: Change at PT 91 Weeks (n=31,29,15,12)
    0.0 ( 27.2 )
    -10.3 ( 29.7 )
    -11.1 ( 20.6 )
    -11.1 ( 32.8 )
        Fin. diff.: Change at PT 104 Weeks (n=26,25,10,9)
    -2.6 ( 18.7 )
    -8.0 ( 30.9 )
    -13.3 ( 23.3 )
    -18.5 ( 37.7 )
        Fin. diff.: Change at PT 117 Weeks (n=22,17,8,5)
    -6.1 ( 22.1 )
    -5.9 ( 24.3 )
    -4.2 ( 11.8 )
    -13.3 ( 18.3 )
        Fin. diff.: Change at PT 130 Weeks (n=17,12,5,5)
    -7.8 ( 27.7 )
    -5.6 ( 31.2 )
    0.0 ( 0.0 )
    -20.0 ( 29.8 )
        Fin. diff.: Change at PT 143 Weeks (n=7,2,3,2)
    4.8 ( 40.5 )
    16.7 ( 23.6 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        Fin. diff.: Change at PT 156 Weeks (n=3,1,0,2)
    -22.2 ( 38.5 )
    0.0 ( 999 )
    99999 ( 99999 )
    -16.7 ( 23.6 )
        Fin. diff.: Change at PT 169 Weeks (n=2,1,0,0)
    0.0 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Fin. diff.: Change at PT 182 Weeks (n=3,0,0,0)
    -22.2 ( 38.5 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Fin. diff.: Change at PT/Discont. (n=8,1,6,1)
    0.0 ( 17.8 )
    0.0 ( 999 )
    0.0 ( 0.0 )
    0.0 ( 999 )
        Naus./vom.: C1 D1 (Baseline, n=138,147,87,89)
    1.4 ( 5.1 )
    1.8 ( 9.6 )
    1.9 ( 7.4 )
    1.3 ( 5.2 )
        Naus./vom.: Change at C1 D8 (n=24,22,16,19)
    4.2 ( 8.9 )
    0.8 ( 6.3 )
    5.2 ( 8.0 )
    3.5 ( 8.9 )
        Naus./vom.: Change at C1 D15 (n=132,139,80,84)
    9.8 ( 16.9 )
    1.8 ( 6.9 )
    8.8 ( 17.0 )
    1.2 ( 7.7 )
        Naus./vom.: Change at C1 D22 (n=22,21,15,17)
    6.1 ( 12.1 )
    0.8 ( 6.4 )
    5.6 ( 10.3 )
    2.9 ( 8.8 )
        Naus./vom.: Change at C2 D1 (n=127,142,83,84)
    5.2 ( 12.9 )
    0.9 ( 5.9 )
    4.6 ( 11.1 )
    1.4 ( 7.9 )
        Naus./vom.: Change at C2 D15 (n=119,134,80,81)
    6.3 ( 14.1 )
    1.1 ( 8.5 )
    2.9 ( 9.1 )
    1.6 ( 10.4 )
        Naus./vom.: Change at C3 D1 (n=119,129,81,78)
    5.7 ( 13.1 )
    1.6 ( 7.3 )
    4.5 ( 9.9 )
    1.3 ( 8.4 )
        Naus./vom.: Change at C4 D1 (n=119,129,78,76)
    5.6 ( 13.6 )
    1.9 ( 11.7 )
    6.6 ( 14.3 )
    1.3 ( 10.8 )
        Naus./vom.: Change at C5 D1 (n=110,117,72,64)
    7.3 ( 16.4 )
    2.6 ( 9.2 )
    5.1 ( 10.7 )
    -0.5 ( 7.8 )
        Naus./vom.: Change at C6 D1 (n=106,112,69,63)
    5.3 ( 13.1 )
    2.4 ( 9.7 )
    6.3 ( 12.2 )
    -0.5 ( 7.9 )
        Naus./vom.: Change at C7 D1 (n=106,108,68,59)
    4.7 ( 11.7 )
    2.0 ( 7.8 )
    4.2 ( 11.3 )
    0.6 ( 6.9 )
        Naus./vom.: Change at C8 D1 (n=105,106,65,53)
    4.6 ( 11.9 )
    1.1 ( 9.0 )
    5.9 ( 15.7 )
    2.5 ( 12.4 )
        Naus./vom.: Change at C9 D1 (n=100,101,63,52)
    5.5 ( 15.7 )
    2.5 ( 10.4 )
    4.0 ( 10.2 )
    0.3 ( 7.0 )
        Naus./vom.: Change at C10 D1 (n=96,97,63,47)
    5.2 ( 13.1 )
    0.9 ( 10.3 )
    4.8 ( 10.6 )
    0.4 ( 6.5 )
        Naus./vom.: Change at C11 D1 (n=93,93,57,48)
    3.4 ( 10.9 )
    2.0 ( 8.5 )
    3.2 ( 8.6 )
    -0.3 ( 5.4 )
        Naus./vom.: Change at C12 D1 (n=90,91,55,48)
    4.3 ( 12.6 )
    1.3 ( 7.9 )
    4.8 ( 10.5 )
    3.5 ( 13.7 )
        Naus./vom.: Change at C13 D1 (n=82,89,54,45)
    2.8 ( 11.7 )
    1.7 ( 7.1 )
    3.4 ( 9.9 )
    2.2 ( 9.8 )
        Naus./vom.: Change at EOT (n=123,125,67,75)
    0.9 ( 6.5 )
    0.3 ( 12.5 )
    1.5 ( 11.9 )
    3.8 ( 13.9 )
        Naus./vom.: Change at PT 13 Weeks (n=90,74,56,38)
    0.2 ( 6.4 )
    1.8 ( 8.5 )
    0.6 ( 6.3 )
    0.9 ( 6.7 )
        Naus./vom.: Change at PT 26 Weeks (n=90,72,47,35)
    2.2 ( 8.7 )
    0.7 ( 15.7 )
    0.7 ( 10.4 )
    -1.0 ( 3.9 )
        Naus./vom.: Change at PT 39 Weeks (n=79,68,42,33)
    0.2 ( 5.7 )
    0.2 ( 6.1 )
    1.6 ( 8.1 )
    1.5 ( 6.4 )
        Naus./vom.: Change at PT 52 Weeks (n=76,62,27,25)
    0.9 ( 6.0 )
    0.3 ( 4.8 )
    0.0 ( 4.6 )
    0.7 ( 3.3 )
        Naus./vom.: Change at PT 65 Weeks (n=53,38,17,18)
    0.0 ( 5.7 )
    3.5 ( 12.9 )
    -1.0 ( 4.0 )
    2.8 ( 8.6 )
        Naus./vom.: Change at PT 78 Weeks (n=46,33,15,9)
    0.4 ( 5.5 )
    2.0 ( 11.6 )
    -1.1 ( 4.3 )
    1.9 ( 5.6 )
        Naus./vom.: Change at PT 91 Weeks (n=32,29,15,12)
    1.6 ( 6.5 )
    2.3 ( 8.6 )
    -1.1 ( 4.3 )
    1.4 ( 4.8 )
        Naus./vom.:Change at PT 104 Weeks (n=27,25,10,9)
    1.9 ( 10.7 )
    0.0 ( 4.8 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        Naus./vom.:Change at PT 117 Weeks (n=22,17,9,5)
    -1.5 ( 4.9 )
    4.9 ( 9.8 )
    -1.9 ( 5.6 )
    0.0 ( 0.0 )
        Naus./vom.:Change at PT 130 Weeks (n=17,12,5,5)
    0.0 ( 5.9 )
    4.2 ( 10.4 )
    -3.3 ( 7.5 )
    0.0 ( 0.0 )
        Naus./vom.:Change at PT 143 Weeks (n=7,2,3,2)
    -2.4 ( 6.3 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        Naus./vom.:Change at PT 156 Weeks (n=3,1,0,2)
    0.0 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    8.3 ( 11.8 )
        Naus./vom.:Change at PT 169 Weeks (n=2,1,0,0)
    0.0 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Naus./vom.:Change at PT 182 Weeks (n=3,0,0,0)
    0.0 ( 0.0 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Naus./vom.: Change at PT/Discont. (n=8,1,6,1)
    4.2 ( 11.8 )
    0.0 ( 999 )
    8.3 ( 13.9 )
    0.0 ( 999 )
        Pain: C1 D1 (Baseline, n=138,147,87,89)
    11.6 ( 17.5 )
    12.8 ( 21.6 )
    10.9 ( 19.0 )
    14.6 ( 23.9 )
        Pain: Change at C1 D8 (n=24,22,16,19)
    9.7 ( 22.5 )
    -1.5 ( 15.4 )
    10.4 ( 14.8 )
    -3.5 ( 8.9 )
        Pain: Change at C1 D15 (n=132,139,80,84)
    20.8 ( 28.5 )
    0.5 ( 12.4 )
    16.3 ( 28.1 )
    -1.4 ( 14.7 )
        Pain: Change at C1 D22 (n=22,21,15,17)
    15.9 ( 28.9 )
    -3.2 ( 13.6 )
    22.2 ( 18.5 )
    9.8 ( 21.3 )
        Pain: Change at C2 D1 (n=127,142,83,84)
    12.9 ( 26.5 )
    0.5 ( 15.1 )
    15.1 ( 28.9 )
    -3.8 ( 18.0 )
        Pain: Change at C2 D15 (n=119,134,80,81)
    14.3 ( 27.5 )
    2.4 ( 17.2 )
    12.7 ( 23.3 )
    -3.5 ( 18.0 )
        Pain: Change at C3 D1 (n=119,129,81,78)
    11.8 ( 20.2 )
    1.2 ( 16.3 )
    13.2 ( 25.6 )
    -0.6 ( 17.1 )
        Pain: Change at C4 D1 (n=119,129,78,76)
    9.0 ( 22.1 )
    4.0 ( 19.7 )
    12.0 ( 25.9 )
    -2.4 ( 19.6 )
        Pain: Change at C5 D1 (n=110,117,72,64)
    12.7 ( 24.3 )
    1.9 ( 17.6 )
    14.6 ( 21.1 )
    -4.9 ( 20.5 )
        Pain: Change at C6 D1 (n=106,112,69,63)
    8.8 ( 22.7 )
    2.2 ( 18.9 )
    14.5 ( 22.9 )
    -3.7 ( 20.0 )
        Pain: Change at C7 D1 (n=106,108,68,59)
    8.2 ( 21.4 )
    0.9 ( 16.6 )
    8.3 ( 20.5 )
    -2.0 ( 19.1 )
        Pain: Change at C8 D1 (n=105,106,65,53)
    11.0 ( 24.9 )
    3.6 ( 20.1 )
    12.1 ( 23.7 )
    -1.6 ( 18.3 )
        Pain: Change at C9 D1 (n=100,101,63,52)
    12.8 ( 27.5 )
    3.6 ( 21.2 )
    10.3 ( 23.5 )
    -0.3 ( 23.9 )
        Pain: Change at C10 D1 (n=96,97,63,47)
    8.9 ( 22.0 )
    1.9 ( 17.5 )
    11.6 ( 24.6 )
    -3.2 ( 16.9 )
        Pain: Change at C11 D1 (n=93,93,57,48)
    10.0 ( 25.0 )
    2.7 ( 21.3 )
    13.5 ( 26.1 )
    -0.7 ( 24.3 )
        Pain: Change at C12 D1 (n=90,91,55,48)
    12.2 ( 24.6 )
    1.3 ( 19.8 )
    12.7 ( 19.5 )
    -2.1 ( 20.2 )
        Pain: Change at C13 D1 (n=82,89,54,45)
    11.6 ( 23.5 )
    3.4 ( 21.2 )
    16.4 ( 27.4 )
    -1.9 ( 22.0 )
        Pain: Change at EOT (n=123,125,67,75)
    4.9 ( 23.4 )
    4.1 ( 23.3 )
    6.7 ( 21.1 )
    1.6 ( 21.4 )
        Pain: Change at PT 13 Weeks (n=90,74,56,38)
    -0.6 ( 17.6 )
    -0.2 ( 18.2 )
    4.2 ( 19.7 )
    -4.8 ( 23.5 )
        Pain: Change at PT 26 Weeks (n=90,72,47,35)
    1.1 ( 21.8 )
    -1.2 ( 16.6 )
    7.1 ( 24.0 )
    -4.3 ( 19.5 )
        Pain: Change at PT 39 Weeks (n=79,68,42,33)
    0.6 ( 19.9 )
    2.2 ( 22.1 )
    7.5 ( 23.0 )
    -7.6 ( 23.2 )
        Pain: Change at PT 52 Weeks (n=76,62,27,25)
    2.0 ( 18.0 )
    0.0 ( 16.3 )
    9.3 ( 21.8 )
    -1.3 ( 20.4 )
        Pain: Change at PT 65 Weeks (n=53,38,17,18)
    -0.3 ( 19.7 )
    0.9 ( 21.2 )
    6.9 ( 15.7 )
    -4.6 ( 12.5 )
        Pain: Change at PT 78 Weeks (n=46,33,15,9)
    0.7 ( 20.2 )
    2.5 ( 19.6 )
    1.1 ( 14.7 )
    -5.6 ( 8.3 )
        Pain: Change at PT 91 Weeks (n=33,29,15,12)
    -2.5 ( 18.7 )
    4.6 ( 25.9 )
    4.4 ( 14.7 )
    -9.7 ( 21.9 )
        Pain: Change at PT 104 Weeks (n=27,25,10,9)
    -1.2 ( 17.9 )
    11.3 ( 22.4 )
    3.3 ( 13.1 )
    -13.0 ( 21.7 )
        Pain: Change at PT 117 Weeks (n=22,17,9,5)
    -4.5 ( 18.0 )
    8.8 ( 22.9 )
    1.9 ( 13.0 )
    -10.0 ( 25.3 )
        Pain: Change at PT 130 Weeks (n=17,12,5,5)
    2.9 ( 19.8 )
    6.9 ( 31.3 )
    6.7 ( 27.9 )
    -13.3 ( 32.1 )
        Pain: Change at PT 143 Weeks (n=7,2,3,2)
    -2.4 ( 20.2 )
    8.3 ( 11.8 )
    5.6 ( 25.5 )
    0.0 ( 0.0 )
        Pain: Change at PT 156 Weeks (n=3,1,0,2)
    -22.2 ( 19.2 )
    0.0 ( 999 )
    99999 ( 99999 )
    8.3 ( 11.8 )
        Pain: Change at PT 169 Weeks (n=2,1,0,0)
    -8.3 ( 11.8 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Pain: Change at PT 182 Weeks (n=3,0,0,0)
    -22.2 ( 19.2 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Pain: Change at PT/Discont. (n=8,1,6,1)
    12.5 ( 14.8 )
    -33.3 ( 999 )
    -2.8 ( 19.5 )
    0.0 ( 999 )
        Phys. func.: C1 D1 (Baseline, n=138,147,87,89)
    92.7 ( 11.0 )
    92.3 ( 11.6 )
    91.3 ( 13.6 )
    92.7 ( 13.1 )
        Phys. func.: Change at C1 D8 (n=24,22,16,19)
    -4.4 ( 8.7 )
    0.3 ( 4.4 )
    -5.0 ( 6.7 )
    -2.5 ( 11.6 )
        Phys. func.: Change at C1 D15 (n=132,139,80,84)
    -9.7 ( 17.4 )
    -0.2 ( 8.2 )
    -7.4 ( 15.0 )
    -1.5 ( 6.5 )
        Phys. func.: Change at C1 D22 (n=22,21,15,17)
    -10.3 ( 16.6 )
    -0.6 ( 7.0 )
    -10.2 ( 15.3 )
    -2.7 ( 9.7 )
        Phys. func.: Change at C2 D1 (n=127,142,83,84)
    -6.2 ( 14.4 )
    -0.3 ( 9.1 )
    -9.2 ( 16.9 )
    -1.8 ( 8.2 )
        Phys. func.: Change at C2 D15 (n=119,134,80,81)
    -7.1 ( 16.4 )
    -0.7 ( 10.8 )
    -7.6 ( 13.9 )
    -1.4 ( 9.4 )
        Phys. func.: Change at C3 D1 (n=119,129,81,78)
    -6.6 ( 14.8 )
    -0.7 ( 11.0 )
    -7.3 ( 15.0 )
    -2.7 ( 10.4 )
        Phys. func.: Change at C4 D1 (n=119,129,81,78)
    -4.9 ( 13.1 )
    -0.2 ( 10.8 )
    -7.4 ( 13.8 )
    -1.0 ( 10.3 )
        Phys. func.: Change at C5 D1 (n=110,117,72,64)
    -6.1 ( 14.7 )
    -1.0 ( 11.3 )
    -5.6 ( 13.3 )
    -1.8 ( 12.7 )
        Phys. func.: Change at C6 D1 (n=106,112,69,63)
    -4.7 ( 14.5 )
    -0.8 ( 12.1 )
    -7.5 ( 15.2 )
    -0.6 ( 10.0 )
        Phys. func.: Change at C7 D1 (n=106,108,68,59)
    -4.7 ( 13.6 )
    0.4 ( 11.2 )
    -8.0 ( 12.7 )
    0.2 ( 9.5 )
        Phys. func.: Change at C8 D1 (n=105,106,65,53)
    -5.2 ( 13.6 )
    -0.8 ( 13.1 )
    -6.7 ( 12.6 )
    -0.3 ( 11.0 )
        Phys. func.: Change at C9 D1 (n=100,101,63,52)
    -6.7 ( 18.2 )
    -0.5 ( 12.2 )
    -5.5 ( 10.6 )
    -1.5 ( 14.7 )
        Phys. func.: Change at C10 D1 (n=96,97,63,47)
    -4.9 ( 14.0 )
    -1.6 ( 11.8 )
    -6.5 ( 13.2 )
    -1.7 ( 9.9 )
        Phys. func.: Change at C11 D1 (n=93,93,57,48)
    -4.2 ( 14.4 )
    -1.3 ( 10.8 )
    -6.0 ( 12.8 )
    -3.3 ( 13.5 )
        Phys. func.: Change at C12 D1 (n=90,91,55,48)
    -5.4 ( 15.7 )
    -1.6 ( 11.5 )
    -4.8 ( 11.9 )
    -0.6 ( 10.8 )
        Phys. func.: Change at C13 D1 (n=82,89,54,45)
    -4.5 ( 15.0 )
    -3.0 ( 14.7 )
    -5.6 ( 12.4 )
    -1.9 ( 12.3 )
        Phys. func.: Change at EOT (n=123,125,67,75)
    -2.8 ( 13.3 )
    -2.9 ( 16.0 )
    -5.8 ( 13.8 )
    -5.1 ( 14.7 )
        Phys. func.: Change at PT 13 Weeks (n=90,74,56,38)
    0.5 ( 11.3 )
    0.1 ( 9.8 )
    -0.8 ( 10.9 )
    -0.5 ( 12.6 )
        Phys. func.: Change at PT 26 Weeks (n=90,72,47,35)
    -1.9 ( 12.5 )
    0.0 ( 8.5 )
    -4.1 ( 10.5 )
    0.6 ( 12.6 )
        Phys. func.: Change at PT 39 Weeks (n=79,68,42,33)
    0.4 ( 10.7 )
    -1.7 ( 13.5 )
    -3.3 ( 13.4 )
    0.6 ( 8.1 )
        Phys. func.: Change at PT 52 Weeks (n=76,62,27,25)
    -1.4 ( 10.0 )
    -0.5 ( 11.7 )
    -1.4 ( 9.6 )
    -1.1 ( 14.2 )
        Phys. func.: Change at PT 65 Weeks (n=53,38,17,18)
    -0.9 ( 8.6 )
    -2.6 ( 13.6 )
    2.7 ( 9.7 )
    -0.4 ( 10.3 )
        Phys. func.: Change at PT 78 Weeks (n=46,33,15,9)
    -0.5 ( 8.6 )
    -1.0 ( 10.8 )
    2.7 ( 10.0 )
    -3.7 ( 11.6 )
        Phys. func.: Change at PT 91 Weeks (n=33,29,15,12)
    0.2 ( 7.2 )
    -3.4 ( 12.9 )
    -0.9 ( 10.3 )
    0.0 ( 17.5 )
        Phys. func.: Change at PT 104 Weeks (n=27,25,10,9)
    2.5 ( 8.3 )
    -4.9 ( 10.3 )
    1.3 ( 11.2 )
    1.5 ( 18.2 )
        Phys. func.: Change at PT 117 Weeks (n=22,17,9,5)
    1.2 ( 8.1 )
    -7.1 ( 14.2 )
    0.7 ( 13.1 )
    2.7 ( 19.2 )
        Phys. func.: Change at PT 130 Weeks (n=17,12,5,5)
    -1.2 ( 4.2 )
    -5.0 ( 11.4 )
    -2.7 ( 10.1 )
    5.3 ( 20.2 )
        Phys. func.: Change at PT 143 Weeks (n=7,2,3,2)
    0.0 ( 8.6 )
    0.0 ( 0.0 )
    -4.4 ( 20.4 )
    -3.3 ( 4.7 )
        Phys. func.: Change at PT 156 Weeks (n=3,1,0,2)
    2.2 ( 3.8 )
    0.0 ( 999 )
    99999 ( 99999 )
    -6.7 ( 9.4 )
        Phys. func.: Change at PT 169 Weeks (n=2,1,0,0)
    3.3 ( 4.7 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Phys. func.: Change at PT 182 Weeks (n=3,0,0,0)
    2.2 ( 3.8 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Phys. func.: Change at PT/Discont. (n=8,1,6,1)
    -0.8 ( 8.3 )
    0.0 ( 999 )
    10.0 ( 15.6 )
    0.0 ( 999 )
        GHS/QoL: C1 D1 (Baseline, n=138,147,87,89)
    79.0 ( 16.7 )
    77.9 ( 18.4 )
    76.5 ( 20.6 )
    78.8 ( 17.6 )
        GHS/QoL: Change at C1 D8 (n=24,22,16,19)
    -9.4 ( 20.5 )
    0.4 ( 7.5 )
    -9.9 ( 15.9 )
    1.3 ( 6.4 )
        GHS/QoL: Change at C1 D15 (n=132,139,78,83)
    -19.1 ( 24.2 )
    -0.4 ( 11.4 )
    -14.5 ( 20.4 )
    -0.3 ( 11.7 )
        GHS/QoL: Change at C1 D22 (n=22,21,15,17)
    -17.8 ( 27.0 )
    1.2 ( 10.3 )
    -16.7 ( 19.9 )
    0.5 ( 11.2 )
        GHS/QoL: Change at C2 D1 (n=127,142,82,84)
    -9.8 ( 19.7 )
    -1.2 ( 14.5 )
    -10.9 ( 17.6 )
    1.0 ( 10.8 )
        GHS/QoL: Change at C2 D15 (n=118,134,80,80)
    -11.5 ( 21.0 )
    0.2 ( 13.5 )
    -9.5 ( 18.0 )
    -1.4 ( 14.4 )
        GHS/QoL: Change at C3 D1 (n=119,129,81,78)
    -10.6 ( 19.0 )
    -1.0 ( 14.6 )
    -9.4 ( 17.0 )
    -0.9 ( 14.6 )
        GHS/QoL: Change at C4 D1 (n=119,129,78,76)
    -10.2 ( 19.6 )
    -1.0 ( 14.9 )
    -8.4 ( 18.9 )
    -1.8 ( 15.4 )
        GHS/QoL: Change at C5 D1 (n=110,116,72,64)
    -12.0 ( 20.4 )
    -0.1 ( 15.1 )
    -8.9 ( 17.3 )
    0.4 ( 16.6 )
        GHS/QoL: Change at C6 D1 (n=106,112,69,63)
    -8.9 ( 18.9 )
    -2.2 ( 16.1 )
    -12.4 ( 19.3 )
    -0.5 ( 16.5 )
        GHS/QoL: Change at C7 D1 (n=106,108,68,59)
    -10.7 ( 19.4 )
    -1.6 ( 16.8 )
    -11.8 ( 17.9 )
    -2.3 ( 15.8 )
        GHS/QoL: Change at C8 D1 (n=104,106,65,53)
    -10.3 ( 18.3 )
    -1.6 ( 17.6 )
    -11.2 ( 20.5 )
    -3.3 ( 17.0 )
        GHS/QoL: Change at C9 D1 (n=100,101,63,52)
    -11.3 ( 21.9 )
    -0.5 ( 16.9 )
    -8.3 ( 19.7 )
    -1.6 ( 16.6 )
        GHS/QoL: Change at C10 D1 (n=96,97,63,47)
    -7.6 ( 19.1 )
    -0.7 ( 15.9 )
    -9.8 ( 18.7 )
    0.2 ( 15.0 )
        GHS/QoL: Change at C11 D1 (n=93,93,57,48)
    -7.8 ( 19.5 )
    -0.8 ( 15.3 )
    -8.8 ( 18.9 )
    -3.1 ( 18.2 )
        GHS/QoL: Change at C12 D1 (n=90,91,55,48)
    -9.3 ( 20.2 )
    -0.8 ( 16.0 )
    -10.5 ( 17.4 )
    -3.6 ( 18.0 )
        GHS/QoL: Change at C13 D1 (n=82,89,54,45)
    -7.5 ( 17.5 )
    -3.4 ( 19.4 )
    -9.4 ( 18.9 )
    -3.9 ( 15.8 )
        GHS/QoL: Change at EOT (n=123,125,67,75)
    -5.2 ( 19.0 )
    -3.6 ( 19.0 )
    -3.0 ( 18.4 )
    -7.4 ( 21.7 )
        GHS/QoL: Change at PT 13 Weeks (n=90,74,56,38)
    0.1 ( 16.0 )
    -0.1 ( 15.7 )
    -1.0 ( 18.1 )
    0.2 ( 20.0 )
        GHS/QoL: Change at PT 26 Weeks (n=90,72,47,35)
    -2.2 ( 16.2 )
    0.5 ( 14.8 )
    0.4 ( 19.5 )
    0.0 ( 19.7 )
        GHS/QoL: Change at PT 39 Weeks (n=79,68,41,33)
    -4.1 ( 21.6 )
    -0.9 ( 15.2 )
    -0.4 ( 16.9 )
    -1.3 ( 19.9 )
        GHS/QoL: Change at PT 52 Weeks (n=76,62,27,25)
    -2.3 ( 15.6 )
    -0.7 ( 15.3 )
    2.2 ( 13.2 )
    -2.0 ( 23.6 )
        GHS/QoL: Change at PT 65 Weeks (n=53,38,17,18)
    -0.9 ( 17.7 )
    -2.0 ( 15.1 )
    1.5 ( 15.1 )
    -0.5 ( 17.7 )
        GHS/QoL: Change at PT 78 Weeks (n=46,33,15,9)
    -0.9 ( 15.6 )
    -1.5 ( 15.8 )
    1.7 ( 14.8 )
    -0.9 ( 13.5 )
        GHS/QoL: Change at PT 91 Weeks (n=33,29,15,12)
    0.3 ( 17.4 )
    -2.6 ( 17.6 )
    6.1 ( 15.3 )
    -2.1 ( 24.7 )
        GHS/QoL: Change at PT 104 Weeks (n=27,25,10,9)
    1.2 ( 14.9 )
    -4.7 ( 19.4 )
    -3.3 ( 19.3 )
    0.0 ( 29.2 )
        GHS/QoL: Change at PT 117 Weeks (n=22,17,8,5)
    0.4 ( 20.5 )
    2.5 ( 15.0 )
    -1.0 ( 13.7 )
    6.7 ( 21.6 )
        GHS/QoL: Change at PT 130 Weeks (n=16,12,5,5)
    2.1 ( 7.1 )
    -3.5 ( 16.8 )
    -3.3 ( 12.6 )
    5.0 ( 24.0 )
        GHS/QoL: Change at PT 143 Weeks (n=7,2,3,2)
    -1.2 ( 18.9 )
    -4.2 ( 5.9 )
    -11.1 ( 9.6 )
    -8.3 ( 11.8 )
        GHS/QoL: Change at PT 156 Weeks (n=3,1,0,2)
    11.1 ( 4.8 )
    0.0 ( 999 )
    99999 ( 99999 )
    12.5 ( 5.9 )
        GHS/QoL: Change at PT 169 Weeks (n=2,1,0,0)
    8.3 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        GHS/QoL: Change at PT 182 Weeks (n=3,0,0,0)
    19.4 ( 12.7 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        GHS/QoL: Change at PT/Discont. (n=8,1,6,1)
    -4.2 ( 19.9 )
    0.0 ( 999 )
    0.0 ( 31.2 )
    0.0 ( 999 )
        Role func.: C1 D1 (Baseline, n=138,147,87,89)
    86.7 ( 21.9 )
    87.2 ( 22.5 )
    86.6 ( 22.0 )
    88.6 ( 23.2 )
        Role func.: Change at C1 D8 (n=24,22,16,19)
    -2.8 ( 15.3 )
    -0.8 ( 10.9 )
    -1.0 ( 16.6 )
    4.4 ( 18.3 )
        Role func.: Change at C1 D15 (n=132,139,80,84)
    -19.4 ( 29.1 )
    0.2 ( 16.3 )
    -15.2 ( 27.6 )
    -2.4 ( 19.6 )
        Role func.: Change at C1 D22 (n=22,21,15,17)
    -10.6 ( 28.4 )
    1.6 ( 9.0 )
    -16.7 ( 20.9 )
    -1.0 ( 25.3 )
        Role func.: Change at C2 D1 (n=127,142,83,84)
    -13.0 ( 26.6 )
    0.2 ( 16.6 )
    -13.3 ( 27.5 )
    0.4 ( 17.5 )
        Role func.: Change at C2 D15 (n=119,134,80,81)
    -11.1 ( 25.7 )
    -0.6 ( 18.4 )
    -9.6 ( 21.5 )
    -0.4 ( 17.5 )
        Role func.: Change at C3 D1 (n=119,129,81,78)
    -9.7 ( 25.4 )
    0.4 ( 19.0 )
    -8.2 ( 21.3 )
    -2.1 ( 21.2 )
        Role func.: Change at C4 D1 (n=119,129,78,76)
    -8.4 ( 23.8 )
    0.3 ( 21.3 )
    -9.0 ( 19.7 )
    -1.3 ( 19.0 )
        Role func.: Change at C5 D1 (n=110,117,72,64)
    -11.1 ( 26.0 )
    0.6 ( 20.5 )
    -10.4 ( 22.3 )
    0.8 ( 22.7 )
        Role func.: Change at C6 D1 (n=106,111,69,63)
    -5.8 ( 24.2 )
    -0.5 ( 18.3 )
    -11.6 ( 22.9 )
    0.5 ( 20.1 )
        Role func.: Change at C7 D1 (n=106,108,68,59)
    -9.9 ( 27.6 )
    0.9 ( 21.5 )
    -8.8 ( 24.0 )
    0.3 ( 21.3 )
        Role func.: Change at C8 D1 (n=105,105,65,53)
    -9.2 ( 26.5 )
    -1.9 ( 23.0 )
    -9.5 ( 24.5 )
    -0.3 ( 21.3 )
        Role func.: Change at C9 D1 (n=100,100,63,52)
    -11.2 ( 28.4 )
    0.0 ( 20.7 )
    -7.9 ( 23.5 )
    -1.9 ( 25.7 )
        Role func.: Change at C10 D1 (n=96,97,63,47)
    -8.5 ( 25.5 )
    -1.7 ( 19.3 )
    -7.7 ( 23.2 )
    3.9 ( 22.3 )
        Role func.: Change at C11 D1 (n=93,93,57,48)
    -6.6 ( 24.5 )
    -1.3 ( 19.7 )
    -10.2 ( 25.0 )
    -3.5 ( 24.8 )
        Role func.: Change at C12 D1 (n=90,91,55,48)
    -8.7 ( 26.2 )
    -0.4 ( 17.2 )
    -8.2 ( 25.2 )
    0.3 ( 26.3 )
        Role func.: Change at C13 D1 (n=82,89,54,45)
    -8.1 ( 24.6 )
    -4.5 ( 22.2 )
    -8.3 ( 25.9 )
    -2.2 ( 24.3 )
        Role func.: Change at EOT (n=123,125,67,75)
    -4.7 ( 25.0 )
    -1.3 ( 23.2 )
    -4.2 ( 25.0 )
    -6.0 ( 27.6 )
        Role func.: Change at PT 13 Weeks (n=90,74,56,38)
    2.0 ( 21.8 )
    1.8 ( 17.6 )
    1.2 ( 19.0 )
    5.3 ( 26.9 )
        Role func.: Change at PT 26 Weeks (n=90,72,47,35)
    0.9 ( 24.7 )
    3.0 ( 17.3 )
    0.4 ( 20.1 )
    5.2 ( 24.5 )
        Role func.: Change at PT 39 Weeks (n=79,68,42,33)
    2.7 ( 24.2 )
    0.2 ( 21.1 )
    0.4 ( 21.3 )
    7.1 ( 28.0 )
        Role func.: Change at PT 52 Weeks (n=76,62,27,25)
    2.4 ( 23.8 )
    0.8 ( 20.3 )
    0.6 ( 18.2 )
    4.0 ( 29.0 )
        Role func.: Change at PT 65 Weeks (n=53,38,17,18)
    5.3 ( 19.3 )
    -1.3 ( 16.6 )
    3.9 ( 11.1 )
    7.4 ( 29.3 )
        Role func.: Change at PT 78 Weeks (n=46,33,15,9)
    -1.4 ( 25.5 )
    -4.0 ( 20.0 )
    4.4 ( 11.7 )
    -3.7 ( 13.9 )
        Role func.: Change at PT 91 Weeks (n=33,29,15, 12)
    3.5 ( 27.2 )
    -1.7 ( 17.4 )
    1.1 ( 14.7 )
    16.7 ( 35.5 )
        Role func.: Change at PT 104 Weeks (n=27,25,10,9)
    6.2 ( 22.2 )
    -7.3 ( 20.5 )
    6.7 ( 14.1 )
    14.8 ( 38.6 )
        Role func.: Change at PT 117 Weeks (n=22,17,9,5)
    7.6 ( 26.6 )
    -2.0 ( 10.0 )
    5.6 ( 11.8 )
    26.7 ( 41.8 )
        Role func.: Change at PT 130 Weeks (n=17,12,5,5)
    6.9 ( 21.3 )
    -5.6 ( 14.8 )
    3.3 ( 18.3 )
    23.3 ( 43.5 )
        Role func.: Change at PT 143 Weeks (n=7,2,3,2)
    7.1 ( 18.9 )
    0.0 ( 0.0 )
    11.1 ( 19.2 )
    8.3 ( 11.8 )
        Role func.: Change at PT 156 Weeks (n=3,1,0,2)
    27.8 ( 25.5 )
    0.0 ( 999 )
    99999 ( 99999 )
    16.7 ( 23.6 )
        Role func.: Change at PT 169 Weeks (n=2,1,0,0)
    16.7 ( 23.6 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Role func.: Change at PT 182 Weeks (n=3,0,0,0)
    27.8 ( 25.5 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Role func.: Change at PT/Discont. (n=8,1,6,1)
    -8.3 ( 23.6 )
    0.0 ( 999 )
    11.1 ( 17.2 )
    0.0 ( 999 )
        Soc. func.: C1 D1 (Baseline, (n=138,147,87,89)
    89.6 ( 16.6 )
    88.2 ( 20.8 )
    87.7 ( 21.2 )
    90.4 ( 19.9 )
        Soc. func.: Change at C1 D8 (n=24,22,16,19)
    1.4 ( 18.3 )
    0.8 ( 12.0 )
    2.1 ( 14.8 )
    0.9 ( 8.7 )
        Soc. func.: Change at C1 D15 (n=132,139,78,84)
    -15.0 ( 26.9 )
    0.8 ( 13.8 )
    -7.5 ( 18.9 )
    0.4 ( 13.4 )
        Soc. func.: Change at C1 D22 (n=22,21,15,17)
    -9.1 ( 28.0 )
    5.6 ( 13.3 )
    -5.6 ( 17.4 )
    -2.0 ( 20.3 )
        Soc. func.: Change at C2 D1 (n=127,142,82,84)
    -8.0 ( 22.9 )
    2.2 ( 16.6 )
    -10.2 ( 23.8 )
    3.0 ( 13.7 )
        Soc. func.: Change at C2 D15 (n=118,134,80,80)
    -8.3 ( 21.5 )
    2.7 ( 16.9 )
    -7.7 ( 18.2 )
    4.0 ( 17.0 )
        Soc. func.: Change at C3 D1 (n=119,129,81,78)
    -8.1 ( 21.5 )
    2.3 ( 17.8 )
    -7.4 ( 21.1 )
    1.5 ( 17.9 )
        Soc. func.: Change at C4 D1 (n=119,129,78,76)
    -7.1 ( 21.5 )
    1.7 ( 18.1 )
    -7.5 ( 20.6 )
    1.3 ( 13.5 )
        Soc. func.: Change at C5 D1 (n=110,116,72,64)
    -9.4 ( 21.7 )
    3.3 ( 17.6 )
    -9.5 ( 18.5 )
    2.6 ( 18.6 )
        Soc. func.: Change at C6 D1 (n=106,112,69,63)
    -7.2 ( 22.2 )
    1.9 ( 17.6 )
    -11.4 ( 22.4 )
    0.0 ( 17.2 )
        Soc. func.: Change at C7 D1 (n=106,108,68,59)
    -8.0 ( 22.7 )
    4.5 ( 17.0 )
    -9.6 ( 22.9 )
    0.0 ( 17.2 )
        Soc. func.: Change at C8 D1 (n=104,106,65,53)
    -8.3 ( 23.6 )
    2.2 ( 17.7 )
    -7.9 ( 23.0 )
    0.6 ( 16.0 )
        Soc. func.: Change at C9 D1 (n=100,101,63,52)
    -11.0 ( 26.2 )
    1.7 ( 19.7 )
    -8.2 ( 22.8 )
    -3.8 ( 21.5 )
        Soc. func.: Change at C10 D1 (n=96,97,63,47)
    -8.7 ( 24.9 )
    0.0 ( 16.1 )
    -8.7 ( 23.4 )
    -0.7 ( 16.3 )
        Soc. func.: Change at C11 D1 (n=93,93,57,48)
    -8.6 ( 24.4 )
    1.4 ( 15.1 )
    -9.9 ( 23.1 )
    -2.1 ( 21.6 )
        Soc. func.: Change at C12 D1 (n=90,91,55,48)
    -10.6 ( 24.2 )
    -0.4 ( 15.7 )
    -9.1 ( 22.2 )
    0.0 ( 16.5 )
        Soc. func.: Change at C13 D1 (n=82,89,54,45)
    -8.3 ( 24.2 )
    -1.9 ( 21.1 )
    -10.2 ( 25.2 )
    1.5 ( 17.7 )
        Soc. func.: Change at EOT (n=123,125,67,75)
    -6.1 ( 21.8 )
    1.2 ( 25.8 )
    -5.5 ( 23.3 )
    -3.3 ( 21.2 )
        Soc. func.: Change at PT 13 Weeks (n=90,74,56,38)
    -1.7 ( 18.9 )
    2.7 ( 15.4 )
    1.2 ( 16.2 )
    1.3 ( 19.5 )
        Soc. func.: Change at PT 26 Weeks (n=90,72,47,35)
    -2.6 ( 20.3 )
    4.2 ( 15.0 )
    0.0 ( 13.9 )
    2.4 ( 14.1 )
        Soc. func.: Change at PT 39 Weeks (n=79,68,41,33)
    3.4 ( 16.5 )
    2.7 ( 15.4 )
    0.0 ( 18.3 )
    5.1 ( 17.4 )
        Soc. func.: Change at PT 52 Weeks (n=76,62,27,25)
    -0.7 ( 18.9 )
    1.6 ( 14.7 )
    2.5 ( 13.6 )
    -1.3 ( 18.0 )
        Soc. func.: Change at PT 65 Weeks (n=53,38,17,18)
    2.8 ( 18.7 )
    0.9 ( 16.0 )
    4.9 ( 11.4 )
    0.9 ( 10.7 )
        Soc. func.: Change at PT 78 Weeks (n=46,33,15,9)
    0.7 ( 20.8 )
    6.1 ( 14.3 )
    4.4 ( 13.3 )
    -1.9 ( 13.0 )
        Soc. func.: Change at PT 91 Weeks (n=32,29,15,12)
    2.6 ( 21.6 )
    1.7 ( 20.1 )
    2.2 ( 13.9 )
    2.8 ( 12.0 )
        Soc. func.: Change at PT 104 Weeks (n=27,25,10,9)
    2.5 ( 18.3 )
    0.0 ( 19.2 )
    3.3 ( 10.5 )
    1.9 ( 13.0 )
        Soc. func.: Change at PT 117 Weeks (n=22,17,8,5)
    9.1 ( 15.2 )
    2.0 ( 21.1 )
    -2.1 ( 5.9 )
    3.3 ( 18.3 )
        Soc. func.: Change at PT 130 Weeks (n=17,12,5,5)
    9.8 ( 15.7 )
    6.9 ( 16.6 )
    0.0 ( 0.0 )
    10.0 ( 32.5 )
        Soc. func.: Change at PT 143 Weeks (n=7,2,3,2)
    7.1 ( 18.9 )
    0.0 ( 0.0 )
    0.0 ( 0.0 )
    -8.3 ( 11.8 )
        Soc. func.: Change at PT 156 Weeks (n=3,1,0,2)
    27.8 ( 9.6 )
    0.0 ( 999 )
    99999 ( 99999 )
    0.0 ( 0.0 )
        Soc. func.: Change at PT 169 Weeks (n=2,1,0,0)
    25.0 ( 11.8 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Soc. func.: Change at PT 182 Weeks (n=3,0,0,0)
    27.8 ( 9.6 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Soc. func.: Change at PT/Discont. (n= 8,1,6,1)
    -4.2 ( 21.4 )
    0.0 ( 999 )
    0.0 ( 10.5 )
    0.0 ( 999 )
        Insomnia: C1 D1 (Baseline, n=138,147,87,89)
    18.4 ( 23.2 )
    17.0 ( 25.4 )
    17.2 ( 23.2 )
    18.7 ( 24.6 )
        Insomnia: Change at C1 D8 (n=24,22,16,19)
    11.1 ( 18.8 )
    -3.0 ( 14.2 )
    2.1 ( 22.7 )
    1.8 ( 20.7 )
        Insomnia: Change at C1 D15 (n=132,139,80,84)
    6.8 ( 29.6 )
    1.0 ( 19.6 )
    9.6 ( 26.1 )
    -4.4 ( 21.2 )
        Insomnia: Change at C1 D22 (n=22,21,15,17)
    9.1 ( 27.6 )
    -3.2 ( 23.3 )
    6.7 ( 18.7 )
    -7.8 ( 22.1 )
        Insomnia: Change at C2 D1 (n=127,142,83,84)
    0.8 ( 23.9 )
    -1.2 ( 22.6 )
    2.4 ( 24.8 )
    -5.6 ( 19.9 )
        Insomnia: Change at C2 D15 (n=119,134,80,81)
    5.9 ( 27.7 )
    0.5 ( 25.2 )
    2.1 ( 28.7 )
    -3.7 ( 23.0 )
        Insomnia: Change at C3 D1 (n=119,129,81,78)
    0.6 ( 25.7 )
    -1.3 ( 23.0 )
    -0.4 ( 28.1 )
    -2.6 ( 22.0 )
        Insomnia: Change at C4 D1 (n=119,129,78,75)
    2.2 ( 25.6 )
    -1.0 ( 25.0 )
    3.4 ( 26.1 )
    -4.9 ( 23.1 )
        Insomnia: Change at C5 D1 (n=110,117,72,64)
    2.4 ( 27.4 )
    0.3 ( 23.8 )
    3.2 ( 26.9 )
    -5.7 ( 22.7 )
        Insomnia: Change at C6 D1 (n=106,112,68,63)
    3.1 ( 28.6 )
    1.8 ( 25.6 )
    3.4 ( 26.5 )
    -4.2 ( 24.3 )
        Insomnia: Change at C7 D1 (n=106,108,68,59)
    4.7 ( 26.6 )
    -0.3 ( 25.6 )
    3.4 ( 23.8 )
    -2.3 ( 17.4 )
        Insomnia: Change at C8 D1 (n=104,106,65,53)
    4.2 ( 28.5 )
    0.6 ( 29.1 )
    7.7 ( 29.9 )
    -6.3 ( 18.6 )
        Insomnia: Change at C9 D1 (n=100,101,63,52)
    3.3 ( 27.8 )
    0.7 ( 27.1 )
    6.3 ( 28.6 )
    0.0 ( 21.9 )
        Insomnia: Change at C10 D1 (n=96,97,63,47)
    1.7 ( 22.9 )
    0.7 ( 22.0 )
    4.2 ( 27.1 )
    -1.4 ( 19.6 )
        Insomnia: Change at C11 D1 (n=93,93,57,48)
    0.7 ( 25.0 )
    -0.7 ( 25.5 )
    5.3 ( 32.0 )
    1.4 ( 18.1 )
        Insomnia: Change at C12 D1 (n=89,91,55,48)
    0.7 ( 24.6 )
    0.0 ( 27.7 )
    3.6 ( 29.2 )
    0.0 ( 23.8 )
        Insomnia: Change at C13 D1 (n=82,88,54,45)
    4.1 ( 26.4 )
    3.8 ( 31.7 )
    6.2 ( 29.0 )
    -1.5 ( 22.4 )
        Insomnia: Change at EOT (n=123,125,67,75)
    -3.0 ( 25.3 )
    1.3 ( 28.8 )
    3.5 ( 32.4 )
    0.4 ( 26.6 )
        Insomnia: Change at PT 13 Weeks (n=90,74,56,38)
    -4.4 ( 21.9 )
    -1.8 ( 25.2 )
    -2.4 ( 24.5 )
    -0.9 ( 22.6 )
        Insomnia: Change at PT 26 Weeks (n=90,72,47,35)
    -2.6 ( 21.9 )
    0.5 ( 28.2 )
    -1.4 ( 23.0 )
    -3.8 ( 22.5 )
        Insomnia: Change at PT 39 Weeks (n=79,68,42,33)
    -5.9 ( 23.7 )
    -0.5 ( 29.6 )
    -2.4 ( 27.9 )
    -5.1 ( 23.7 )
        Insomnia: Change at PT 52 Weeks (n=76,62,27,25)
    -3.9 ( 24.3 )
    0.5 ( 26.6 )
    -2.5 ( 26.0 )
    -8.0 ( 26.0 )
        Insomnia: Change at PT 65 Weeks (n=53,38,17,18)
    -6.3 ( 23.6 )
    1.8 ( 21.8 )
    -3.9 ( 33.1 )
    -3.7 ( 22.5 )
        Insomnia: Change at PT 78 Weeks (n=46,33,15,9)
    -2.2 ( 28.5 )
    1.0 ( 30.6 )
    -4.4 ( 27.8 )
    -3.7 ( 26.1 )
        Insomnia: Change at PT 91 Weeks (n=33,29,15,12)
    -4.0 ( 16.2 )
    -1.1 ( 25.9 )
    -4.4 ( 21.3 )
    -2.8 ( 26.4 )
        Insomnia: Change at PT 104 Weeks (n=27,25,10,9)
    -4.9 ( 17.8 )
    4.0 ( 27.8 )
    0.0 ( 22.2 )
    -3.7 ( 11.1 )
        Insomnia: Change at PT 117 Weeks (n=22,17,9,5)
    -9.1 ( 18.3 )
    -7.8 ( 30.1 )
    0.0 ( 16.7 )
    -13.3 ( 29.8 )
        Insomnia: Change at PT 130 Weeks (n=17,12,5,5)
    -7.8 ( 22.1 )
    -8.3 ( 20.7 )
    6.7 ( 27.9 )
    -6.7 ( 14.9 )
        Insomnia: Change at PT 143 Weeks (n=7,2,3,2)
    -14.3 ( 17.8 )
    -16.7 ( 23.6 )
    0.0 ( 33.3 )
    0.0 ( 0.0 )
        Insomnia: Change at PT 156 Weeks (n=3,1,0,2)
    -11.1 ( 19.2 )
    0.0 ( 999 )
    99999 ( 99999 )
    0.0 ( 0.0 )
        Insomnia: Change at PT 169 Weeks (n=2,1,0,0)
    0.0 ( 0.0 )
    0.0 ( 999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Insomnia: Change at PT 182 Weeks (n=3,0,0,0)
    -11.1 ( 19.2 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Insomnia: Change at PT/Discont. (n=8,1,6,1)
    0.0 ( 17.8 )
    0.0 ( 999 )
    5.6 ( 25.1 )
    0.0 ( 999 )
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Vemurafenib

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    End point title
    		 Plasma Concentration of Vemurafenib [1]
    End point description
    The pharmacokinetic (PK)-evaluable population included all subjects who received at least one dose of vemurafenib and had provided valid PK assessments.
    End point type
    Secondary
    End point timeframe
    Pre-morning dose (0 hour [hr]) and 1 to 4 hrs post-dose on Days 1, 8, 15, and 22 of Cycle 1; pre-morning dose (0 hr) on Days 1 and 15 of Cycle 2; pre-morning dose (0 hr) on Day 1 of Cycles 3-13; at end of treatment (up to 13 months)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to treatment groups receiving vemurafenib.
    End point values
    		 Cohort 1 Vemurafenib Cohort 2 Vemurafenib
    Number of subjects analysed
    149
    92
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (nominal Day 1, n=122,77)
    2880 ( 2770 )
    3050 ( 3010 )
        Cycle 1 Day 8 (n=79,52)
    49900 ( 19800 )
    43400 ( 13600 )
        Cycle 1 Day 15 (n=55,43)
    45300 ( 23000 )
    50200 ( 20500 )
        Cycle 1 Day 22 (n=49,45)
    44000 ( 22400 )
    48800 ( 23700 )
        Cycle 2 Day 1 (n=107,69)
    40200 ( 24100 )
    43800 ( 19400 )
        Cycle 2 Day 15 (n=102,68)
    42400 ( 21700 )
    44200 ( 21200 )
        Cycle 3 Day 1 (n=100,69)
    46700 ( 21500 )
    43700 ( 22000 )
        Cycle 4 Day 1 (n=98,68)
    44800 ( 19300 )
    47400 ( 20100 )
        Cycle 5 Day 1 (n=92,61)
    43100 ( 18800 )
    43700 ( 19400 )
        Cycle 6 Day 1 (n=82,62)
    46000 ( 18900 )
    42000 ( 22000 )
        Cycle 7 Day 1 (n=86,57)
    42800 ( 20500 )
    45200 ( 20500 )
        Cycle 8 Day 1 (n=81,55)
    43600 ( 19900 )
    42600 ( 18900 )
        Cycle 9 Day 1 (n=77,51)
    42900 ( 18400 )
    43000 ( 17700 )
        Cycle 10 Day 1 (n=38,29)
    41000 ( 19000 )
    43900 ( 18500 )
        Cycle 11 Day 1 (n=35,35)
    45900 ( 15300 )
    39700 ( 17600 )
        Cycle 12 Day 1 (n=34,26)
    43700 ( 15200 )
    46600 ( 19800 )
        Cycle 13 Day 1 (n=36,26)
    44000 ( 17200 )
    42600 ( 19900 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to the data cutoff of July 13, 2018 (approximately 6 years).
    Adverse event reporting additional description
    The safety population included all subjects who received at least one dose of study medication.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Cohort 1 Vemurafenib
    Reporting group description
    		 Subjects with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib, 960 mg twice daily, in 28-day cycles, for up to 52 weeks

    Reporting group title
    Cohort 1 Placebo
    Reporting group description
    		 Subjects with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks

    Reporting group title
    Cohort 2 Vemurafenib
    Reporting group description
    		 Subjects with Stage IIIC cutaneous melanoma received vemurafenib, 960 mg twice daily, in 28-day cycles, for up to 52 weeks

    Reporting group title
    Cohort 2 Placebo
    Reporting group description
    		 Subjects with Stage IIIC cutaneous melanoma received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks

    Serious adverse events
    		 Cohort 1 Vemurafenib Cohort 1 Placebo Cohort 2 Vemurafenib Cohort 2 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 154 (16.88%)
    16 / 156 (10.26%)
    15 / 93 (16.13%)
    10 / 91 (10.99%)
         number of deaths (all causes)
    17
    33
    25
    26
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute promyelocytic leukaemia
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical fibroxanthoma
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    6 / 154 (3.90%)
    7 / 156 (4.49%)
    3 / 93 (3.23%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    2 / 7
    3 / 11
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
    0 / 93 (0.00%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleuritic pain
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    2 / 93 (2.15%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphangiopathies
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Iridocyclitis
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Leukoplakia oral
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis exfoliative
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 154 (1.30%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dupuytren’s contracture
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 154 (0.00%)
    2 / 156 (1.28%)
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Groin infection
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 156 (0.00%)
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperlipasaemia
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
    0 / 93 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 Vemurafenib Cohort 1 Placebo Cohort 2 Vemurafenib Cohort 2 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    150 / 154 (97.40%)
    117 / 156 (75.00%)
    92 / 93 (98.92%)
    67 / 91 (73.63%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    21 / 154 (13.64%)
    2 / 156 (1.28%)
    19 / 93 (20.43%)
    2 / 91 (2.20%)
         occurrences all number
    32
    2
    27
    2
    Seborrhoeic keratosis
         subjects affected / exposed
    13 / 154 (8.44%)
    7 / 156 (4.49%)
    10 / 93 (10.75%)
    1 / 91 (1.10%)
         occurrences all number
    22
    7
    17
    1
    Keratoacanthoma
         subjects affected / exposed
    14 / 154 (9.09%)
    0 / 156 (0.00%)
    10 / 93 (10.75%)
    2 / 91 (2.20%)
         occurrences all number
    20
    0
    16
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    28 / 154 (18.18%)
    5 / 156 (3.21%)
    14 / 93 (15.05%)
    4 / 91 (4.40%)
         occurrences all number
    31
    8
    22
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    18 / 154 (11.69%)
    5 / 156 (3.21%)
    11 / 93 (11.83%)
    3 / 91 (3.30%)
         occurrences all number
    21
    6
    14
    3
    Injury, poisoning and procedural complications
    Sunburn
         subjects affected / exposed
    25 / 154 (16.23%)
    2 / 156 (1.28%)
    19 / 93 (20.43%)
    2 / 91 (2.20%)
         occurrences all number
    33
    2
    35
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    29 / 154 (18.83%)
    32 / 156 (20.51%)
    20 / 93 (21.51%)
    11 / 91 (12.09%)
         occurrences all number
    44
    41
    24
    14
    Dysgeusia
         subjects affected / exposed
    17 / 154 (11.04%)
    4 / 156 (2.56%)
    8 / 93 (8.60%)
    3 / 91 (3.30%)
         occurrences all number
    18
    4
    8
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    52 / 154 (33.77%)
    52 / 156 (33.33%)
    26 / 93 (27.96%)
    18 / 91 (19.78%)
         occurrences all number
    72
    56
    37
    20
    Asthenia
         subjects affected / exposed
    24 / 154 (15.58%)
    13 / 156 (8.33%)
    17 / 93 (18.28%)
    10 / 91 (10.99%)
         occurrences all number
    38
    17
    22
    11
    Pyrexia
         subjects affected / exposed
    28 / 154 (18.18%)
    11 / 156 (7.05%)
    16 / 93 (17.20%)
    7 / 91 (7.69%)
         occurrences all number
    32
    11
    17
    8
    Oedema peripheral
         subjects affected / exposed
    9 / 154 (5.84%)
    8 / 156 (5.13%)
    7 / 93 (7.53%)
    4 / 91 (4.40%)
         occurrences all number
    9
    8
    7
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    59 / 154 (38.31%)
    36 / 156 (23.08%)
    27 / 93 (29.03%)
    9 / 91 (9.89%)
         occurrences all number
    74
    45
    36
    13
    Diarrhoea
         subjects affected / exposed
    38 / 154 (24.68%)
    32 / 156 (20.51%)
    27 / 93 (29.03%)
    9 / 91 (9.89%)
         occurrences all number
    61
    43
    33
    11
    Vomiting
         subjects affected / exposed
    19 / 154 (12.34%)
    9 / 156 (5.77%)
    14 / 93 (15.05%)
    4 / 91 (4.40%)
         occurrences all number
    25
    9
    20
    7
    Constipation
         subjects affected / exposed
    8 / 154 (5.19%)
    11 / 156 (7.05%)
    9 / 93 (9.68%)
    3 / 91 (3.30%)
         occurrences all number
    9
    14
    11
    3
    Abdominal pain
         subjects affected / exposed
    10 / 154 (6.49%)
    7 / 156 (4.49%)
    6 / 93 (6.45%)
    2 / 91 (2.20%)
         occurrences all number
    11
    7
    6
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 154 (9.09%)
    8 / 156 (5.13%)
    6 / 93 (6.45%)
    3 / 91 (3.30%)
         occurrences all number
    17
    9
    7
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    57 / 154 (37.01%)
    20 / 156 (12.82%)
    34 / 93 (36.56%)
    10 / 91 (10.99%)
         occurrences all number
    88
    26
    52
    13
    Alopecia
         subjects affected / exposed
    57 / 154 (37.01%)
    10 / 156 (6.41%)
    37 / 93 (39.78%)
    4 / 91 (4.40%)
         occurrences all number
    57
    10
    39
    4
    Pruritus
         subjects affected / exposed
    44 / 154 (28.57%)
    27 / 156 (17.31%)
    28 / 93 (30.11%)
    3 / 91 (3.30%)
         occurrences all number
    52
    29
    32
    4
    Hyperkeratosis
         subjects affected / exposed
    52 / 154 (33.77%)
    6 / 156 (3.85%)
    35 / 93 (37.63%)
    0 / 91 (0.00%)
         occurrences all number
    80
    8
    51
    0
    Photosensitivity reaction
         subjects affected / exposed
    58 / 154 (37.66%)
    5 / 156 (3.21%)
    26 / 93 (27.96%)
    4 / 91 (4.40%)
         occurrences all number
    84
    6
    31
    5
    Dry skin
         subjects affected / exposed
    32 / 154 (20.78%)
    13 / 156 (8.33%)
    16 / 93 (17.20%)
    5 / 91 (5.49%)
         occurrences all number
    37
    13
    23
    5
    Erythema
         subjects affected / exposed
    20 / 154 (12.99%)
    8 / 156 (5.13%)
    17 / 93 (18.28%)
    6 / 91 (6.59%)
         occurrences all number
    32
    9
    36
    12
    Actinic keratosis
         subjects affected / exposed
    15 / 154 (9.74%)
    8 / 156 (5.13%)
    4 / 93 (4.30%)
    2 / 91 (2.20%)
         occurrences all number
    29
    16
    4
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 154 (5.84%)
    7 / 156 (4.49%)
    12 / 93 (12.90%)
    4 / 91 (4.40%)
         occurrences all number
    9
    7
    13
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    101 / 154 (65.58%)
    37 / 156 (23.72%)
    49 / 93 (52.69%)
    17 / 91 (18.68%)
         occurrences all number
    173
    52
    92
    18
    Pain in extremity
         subjects affected / exposed
    31 / 154 (20.13%)
    15 / 156 (9.62%)
    17 / 93 (18.28%)
    4 / 91 (4.40%)
         occurrences all number
    37
    16
    19
    4
    Myalgia
         subjects affected / exposed
    23 / 154 (14.94%)
    9 / 156 (5.77%)
    9 / 93 (9.68%)
    3 / 91 (3.30%)
         occurrences all number
    25
    11
    9
    4
    Musculoskeletal pain
         subjects affected / exposed
    9 / 154 (5.84%)
    8 / 156 (5.13%)
    8 / 93 (8.60%)
    4 / 91 (4.40%)
         occurrences all number
    13
    8
    11
    5
    Back pain
         subjects affected / exposed
    5 / 154 (3.25%)
    14 / 156 (8.97%)
    7 / 93 (7.53%)
    2 / 91 (2.20%)
         occurrences all number
    6
    16
    7
    2
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    9 / 154 (5.84%)
    10 / 156 (6.41%)
    4 / 93 (4.30%)
    7 / 91 (7.69%)
         occurrences all number
    15
    12
    5
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    17 / 154 (11.04%)
    11 / 156 (7.05%)
    16 / 93 (17.20%)
    2 / 91 (2.20%)
         occurrences all number
    19
    13
    18
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Apr 2012
    - The reporting requirement for serious adverse events (SAEs) and non-SAEs of special interest to the investigators and the sponsors was changed from within 1 working day to within 24 hours of learning of the event. - The inclusion eligibility criteria were revised to reflect the change in randomization date for subjects participating in the trial. Two new criteria were added, specifying a negative blood stool occult test and adequate resection of all visualized polyps found at colonoscopy to the cecum at screening unless a subject had a previous colonoscopy, with or without polyp resection, within 1 year of randomization. - The liver function requirement for assessment of gamma glutamyl transferease (GGT) ≥2.5 the upper limit of normal was deleted, and GGT was deleted from the list of laboratory assessments. - Colonoscopy to the cecum was added to the list of study assessments. Flexible fiberoptic laryngoscopy was included as part of the head and neck evaluation. - An additional two AEs of special interest were added: gastrointestinal polyps and suspected transmission of infectious agent by study drug.
    27 Jun 2012
    - The primary efficacy endpoint, disease-free survival (DFS), was updated to include occurrence of new primary melanoma. - The inclusion criteria were clarified to specify use of the cobas® BRAF V600 Mutation Test as a condition of eligibility.
    25 Mar 2013
    - Language was added to clarify that a computed tomography scan of the head could be performed when a magnetic resonance imaging scan was contraindicated. - For female subjects of childbearing potential and male subjects with partners of childbearing potential, the contraception language was updated to include the need for two effective forms of contraception and also to describe the possible effect of vemurafenib decreasing the plasma exposure of hormonal contraceptives. - The time period within which a subject could be excluded from the study due to a history of a prior invasive malignancy was increased from 3 years to 5 years. - The definition of not having an invasive malignancy at the time of enrollment was clarified to include the pathology results of the screening colonoscopy and the screening Papanicolaou (Pap) smear. - The following exclusion criterion was added: personal history of more than three (>3) adenomatous colorectal polyps or a personal history of adenomatous colorectal polyp(s) >2 centimeters (cm) in size. This also applied to the screening colonoscopy. – The clarification that a current uncorrectable electrolyte disorder that affects serum levels of potassium, calcium, or magnesium was an exclusion criterion was added. - Lipase and amylase were added to the serum chemistry panel. - The prohibited therapy list was expanded to include rifampicin/rifampin, rifabutin, rifapentine, carbamazepine, phenytoin, and phenobarbital. - Collection of information on Fitzpatrick skin type and prior human papilloma virus (HPV) vaccination was added to the dermatology history and monitoring and management sections. - More specific language and closer monitoring of subjects with QTc intervals >500 milliseconds (ms) were added to the guidelines for the assessment and management of QTc abnormalities.
    05 Sep 2013
    - Exclusion criteria were modified as follows: history of or current clinical, radiographic, or pathologic evidence of in-transit metastases satellite or microsatellite lesions.
    20 Dec 2013
    - The requirement for a computed tomography scan of the primary site was removed. - The requirement for immunohistochemical confirmation of melanoma diagnosis was removed from inclusion criteria. Melanoma must have been histologically confirmed. - An exclusion criterion was added to clarify that subjects who had a history of local and/or regional and/or distant melanoma recurrence (excluding first metachronous nodal recurrence) should have been excluded. Note: this did not include subjects who had a new primary melanoma. - The following safety information was added: drug-induced liver injury and neutropenia.
    18 Apr 2014
    - Requirement for mandatory colonoscopy at screening was discontinued, except in select subjects with personal and/or family history or signs/symptoms of colorectal cancer or adenomatous polyps. - Requirement for flexible fiberoptic laryngoscopy was removed. - The requirements for mandatory serum amylase and lipase laboratory testing were removed.
    14 Apr 2015
    - Safety information for the event of hepatic failure was updated. - Potentiation of radiation treatment toxicity was identified as an adverse drug reaction; accordingly, safety information for this event was added. - Pancreatitis was identified as an adverse drug reaction; accordingly, safety information for this event was added. In addition, serum amylase and lipase testing were conducted as part of the workup of any suspected case of pancreatitis, in addition to other appropriate testing (e.g., computed tomography [CT] of the abdomen). - Study design: changed the α level (two sided) from 0.025 for DFS in each independent cohort to 0.05 (two-sided) of the family-wise Type I error rate for two tests of two cohorts; decreased the power for Cohort 1 DFS analysis from 90% to 80%; Cohort 1: approx. 300 subjects (reduced from 500); Cohort 2: approx. 175 subjects (reduced from 225); the number of DFS events required at final DFS analysis was decreased from 190 to 120 in Cohort 1 and from 146 to 120 in Cohort 2; changed the median DFS for the control arm from 26.5 to 24 months in Cohort 1; two OS analyses were proposed for each cohort, one interim analysis and a final analysis; OS landmark rates were clarified to include 1-year, 2-year, and 3-year rates. - End-of-study follow-up was updated from 7 to 6 years after Cycle 1 Day 1 of study treatment. Data cutoff projections were updated to occur approximately 72 months after the first subject enrolled (initiation of enrollment, Q3 2012; final OS analysis cutoff Q4 2018). - Subject-reported outcome language was clarified with regards to outcome measures and the manner in which the results were scored. - The follow-up of subjects with new primary cancers was updated to include all nonmelanoma, new primary cancers including cutaneous squamous cell carcinoma/keratoacanthoma, which was reported to U.S. Food and Drug Administration in accordance with a post-marketing requirement for vemurafenib in the United States.
    14 Mar 2017
    - Protocol GO27826 was amended to change the primary DFS analysis of Cohort 2. - The planned primary DFS analysis of Cohort 2 was revised to be performed at approximately 105 events (reduced from 120 events) to account for a slower than anticipated DFS event rate. The Sponsor made modifications to the study design to minimize the impact of this delay. - A total of 105 DFS events provided approximately 80% power to detect a hazard ratio of 0.58 for the vemurafenib arm versus the placebo arm at an overall two-sided 0.05 significance level. - This change corresponded to an improvement in median DFS from 7.7 months in the placebo arm to 13.3 months in the vemurafenib arm; No changes were made for Cohort 1.

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

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