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    Clinical Trial Results:
    SATIVEX® AS ADD-ON THERAPY VS. FURTHER OPTIMIZED FIRST-LINE ANTISPASTICS: THE SAVANT TRIAL

    Summary
    EudraCT number
    2015-004451-40
    Trial protocol
    CZ   AT  
    Global end of trial date
    23 May 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    02 May 2018
    First version publication date
    02 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    H15/02
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Almirall Hermal GmbH
    Sponsor organisation address
    Ronda General Mitre 151, Barcelona, Spain, 08022
    Public contact
    Carlos Vila Silván, Almirall S.A., +34 932 913 490, carlos.vila@almirall.com
    Scientific contact
    Carlos Vila Silván, Almirall S.A., +34 932 913 490, carlos.vila@almirall.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
    23 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of Sativex (tetrahydrocannabinol [THC]:cannabidiol [CBD] oromucosal spray) as add-on therapy compared to further optimized standard antispastic therapy with oral baclofen and/or tizanidine and/or dantrolene (mono- or combination therapy) in subjects with moderate to severe spasticity due to multiple sclerosis (MS) who have not gained adequate relief through 2 optimized standard antispastic drugs.
    Protection of trial subjects
    The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki that are consistent with International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Apr 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Czech Republic: 190
    Worldwide total number of subjects
    191
    EEA total number of subjects
    191
    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)
    185
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in 14 centers in the Czech Republic and 1 center in Austria between 25 April 2016 (first subject first visit) and 23 May 2017 (last subject last visit).

    Pre-assignment
    Screening details
    A total of 210 subjects were screened, 191 entered the study and 190 received treatment while 15 were screen failure, 2 withdrawn consent, 2 withdrawn due to technical reasons and 1 due to non-TEAE.

    Period 1
    Period 1 title
    Phase A
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject

    Arms
    Arm title
    Phase A: Sativex
    Arm description
    Subjects received up-titrated Sativex up to 12 sprays per day for 4 weeks as add-on to their optimized standard antispastic medication (oral baclofen and/or tizanidine and/or dantrolene) until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.
    Arm type
    Experimental

    Investigational medicinal product name
    Sativex
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Subjects received oromucosal spray of Sativex for 4 weeks.

    Number of subjects in period 1
    Phase A: Sativex
    Started
    191
    Treated
    190
    Completed
    134
    Not completed
    57
         Protocol deviation
    1
         Noncompliance with study drug
    1
         Physician decision
    1
         Lack of efficacy
    49
         Adverse event, non-fatal
    4
         Not treated
    1
    Period 2
    Period 2 title
    Washout Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Phase A: Sativex Washout
    Arm description
    Subjects who qualified as Sativex initial responders received their underlying optimized standard antispastic medication (oral baclofen and/or tizanidine and/or dantrolene) but not Sativex. The washout phase was to last for a minimum of 1 week and a maximum of 4 weeks, until the subject’s Phase A-improvement in MS spasticity numerical rating scale (NRS) score had been reduced by at least 80%.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Phase A: Sativex Washout
    Started
    134
    Completed
    106
    Not completed
    28
         Technical problems
    2
         Adverse event, non-fatal
    1
         Failed to meet Inclusion criteria
    22
         Consent withdrawn by subject
    3
    Period 3
    Period 3 title
    Phase B
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase B: Sativex
    Arm description
    Subjects who were initial responders and whose Phase A-improvement in MS spasticity NRS score had been reduced by at least 80% during the washout phase received up-titrated Sativex to the dose identified during Phase A as being their optimal dose (up to 12 sprays per day) for 12 weeks as add-on to their optimized standard antispastic medication until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.
    Arm type
    Experimental

    Investigational medicinal product name
    Sativex
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Subjects received oromucosal spray (up to 12 sprays per day) of optimal dose of Sativex for 12 weeks.

    Arm title
    Phase B: Placebo
    Arm description
    Subjects who were initial responders and whose Phase A-improvement in MS spasticity NRS score had been reduced by at least 80% during the washout phase received matched placebo for 12 weeks as add-on to their optimized standard antispastic medication until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Subjects received matched placebo for 12 weeks.

    Number of subjects in period 3
    Phase B: Sativex Phase B: Placebo
    Started
    53
    53
    Completed
    50
    46
    Not completed
    3
    7
         Protocol deviation
    -
    1
         Physician decision
    -
    1
         Consent withdrawn by subject
    3
    4
         Didn't meet inclusion criteria#14 (screen failure)
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase A: Sativex
    Reporting group description
    Subjects received up-titrated Sativex up to 12 sprays per day for 4 weeks as add-on to their optimized standard antispastic medication (oral baclofen and/or tizanidine and/or dantrolene) until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.

    Reporting group values
    Phase A: Sativex Total
    Number of subjects
    191 191
    Age categorical
    Units: Subjects
    Age continuous
    Phase A safety set included all screened subjects who took at least 1 dose of study medication.
    Units: years
        arithmetic mean (standard deviation)
    51.3 ± 10.2 -
    Gender categorical
    Units: Subjects
        Female
    134 134
        Male
    57 57

    End points

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    End points reporting groups
    Reporting group title
    Phase A: Sativex
    Reporting group description
    Subjects received up-titrated Sativex up to 12 sprays per day for 4 weeks as add-on to their optimized standard antispastic medication (oral baclofen and/or tizanidine and/or dantrolene) until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.
    Reporting group title
    Phase A: Sativex Washout
    Reporting group description
    Subjects who qualified as Sativex initial responders received their underlying optimized standard antispastic medication (oral baclofen and/or tizanidine and/or dantrolene) but not Sativex. The washout phase was to last for a minimum of 1 week and a maximum of 4 weeks, until the subject’s Phase A-improvement in MS spasticity numerical rating scale (NRS) score had been reduced by at least 80%.
    Reporting group title
    Phase B: Sativex
    Reporting group description
    Subjects who were initial responders and whose Phase A-improvement in MS spasticity NRS score had been reduced by at least 80% during the washout phase received up-titrated Sativex to the dose identified during Phase A as being their optimal dose (up to 12 sprays per day) for 12 weeks as add-on to their optimized standard antispastic medication until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.

    Reporting group title
    Phase B: Placebo
    Reporting group description
    Subjects who were initial responders and whose Phase A-improvement in MS spasticity NRS score had been reduced by at least 80% during the washout phase received matched placebo for 12 weeks as add-on to their optimized standard antispastic medication until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.

    Subject analysis set title
    Phase B: Intent To Treat (ITT) population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    ITT set included all randomized subjects in Phase B who took at least 1 dose of study medication and had at least a baseline and 1 post-dose efficacy value (N=106).

    Primary: Percentage of Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Responders After 12 Weeks of Randomized Treatment in Phase B

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    End point title
    Percentage of Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Responders After 12 Weeks of Randomized Treatment in Phase B
    End point description
    MS Spasticity was measured based on a scale of 0 to 10, 0 as “No spasticity” and 10 as “Worst possible spasticity”. A responder was defined as a subject who achieved an improvement in NRS score of greater than or equal to (>=) 30% (i.e. clinically important difference [CID]) from baseline.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [1]
    53 [2]
    Units: Percentage of responders
    number (not applicable)
        Logistic Regression Analysis (LOCF)
    77.4
    32.1
        Generalized Linear Mixed Models (GLMM) Analysis
    67.9
    30.2
    Notes
    [1] - Phase B: ITT
    [2] - Phase B: ITT
    Statistical analysis title
    LOCF: Phase B- Sativex vs Placebo
    Statistical analysis description
    The adjusted statistics were computed using Logistic regression model with Phase B baseline mean value as co-variate and treatment group as factor.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Regression, Logistic
    Parameter type
    Adjusted Odds ratio
    Point estimate
    7.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.953
         upper limit
    16.738
    Statistical analysis title
    GLMM Analysis: Phase B- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    6.842
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.75
         upper limit
    17.023

    Secondary: Percentage of Subjects Who Achieve an Improvement From Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Score of Greater Than or Equal to (>=) 30% Clinically Important Difference (CID) After 4 and 8 Weeks of Treatment

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    End point title
    Percentage of Subjects Who Achieve an Improvement From Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Score of Greater Than or Equal to (>=) 30% Clinically Important Difference (CID) After 4 and 8 Weeks of Treatment
    End point description
    MS Spasticity was measured based on a scale of 0 to 10, 0 as “No spasticity” and 10 as “Worst possible spasticity”.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 8
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [3]
    53 [4]
    Units: Percentage of subjects
    number (not applicable)
        Week 4
    66.0
    32.1
        Week 8
    71.7
    28.3
    Notes
    [3] - Phase B: ITT
    [4] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as covariate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0013
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    4.017
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.747
         upper limit
    9.233
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as covariate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted Odds ratio
    Point estimate
    6.663
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.736
         upper limit
    16.225

    Secondary: Percentage of Subjects Who Achieve an Improvement From Phase B Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Score of Greater Than 18% Minimum Clinically Important Difference (MCID) After 4, 8 and 12 Weeks of Treatment

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    End point title
    Percentage of Subjects Who Achieve an Improvement From Phase B Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Score of Greater Than 18% Minimum Clinically Important Difference (MCID) After 4, 8 and 12 Weeks of Treatment
    End point description
    MS Spasticity was measured based on a scale of 0 to 10, 0 as “No spasticity” and 10 as “Worst possible spasticity”.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [5]
    53 [6]
    Units: Percentage of subjects
    number (not applicable)
        Week 4
    81.1
    45.3
        Week 8
    83.0
    34.0
        Week 12
    77.4
    35.8
    Notes
    [5] - Phase B: ITT
    [6] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0007
    Method
    Mixed models analysis
    Parameter type
    Adjusted Odds ratio
    Point estimate
    4.911
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.999
         upper limit
    12.064
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted Odds ratio
    Point estimate
    10.186
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.687
         upper limit
    28.139
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted Odds ratio
    Point estimate
    9.353
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.381
         upper limit
    25.875
    Notes
    [7] - General Linear Mixed Model for binary repeated data with Phase B baseline mean value as covariate and treatment, week and treatment by week interaction as fixed effect factors.

    Secondary: Change From Phase B Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) After 4, 8 and 12 Weeks of Treatment

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    End point title
    Change From Phase B Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) After 4, 8 and 12 Weeks of Treatment
    End point description
    MS Spasticity was measured based on a scale of 0 to 10, 0 as “No spasticity” and 10 as “Worst possible spasticity”.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [8]
    53 [9]
    Units: Score on a scale
    least squares mean (confidence interval 95%)
        Change at Week 4
    -3.04 (-3.58 to -2.50)
    -1.51 (-2.06 to -0.97)
        Change at Week 8
    -3.33 (-3.92 to -2.75)
    -1.54 (-2.12 to -0.95)
        Change at Week 12
    -3.49 (-4.08 to -2.91)
    -1.60 (-2.19 to -1.00)
    Notes
    [8] - Phase B: ITT
    [9] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0001
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -1.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    -0.76
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.63
         upper limit
    -0.97
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.73
         upper limit
    -1.06

    Secondary: Change From Phase B Baseline in the Frequency of Spasm After 4, 8 and 12 Weeks of Treatment

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    End point title
    Change From Phase B Baseline in the Frequency of Spasm After 4, 8 and 12 Weeks of Treatment
    End point description
    Frequency of Spasm was calculated by a daily review (at bedtime) as“number of spasms in the last 24 hours” and gave a best estimate if a large number of spasms occurred. ‘0’ was recorded if no spasms were experienced.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [10]
    53 [11]
    Units: Frequency of spasm
    least squares mean (confidence interval 95%)
        Change at Week 4
    -18.39 (-29.40 to -7.38)
    -15.34 (-26.40 to -4.27)
        Change at Week 8
    -19.82 (-30.91 to -8.73)
    -17.80 (-29.10 to -6.50)
        Change at Week 12
    -20.58 (-31.80 to -9.36)
    -17.75 (-29.10 to -6.41)
    Notes
    [10] - Phase B: ITT
    [11] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7002
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -3.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.67
         upper limit
    12.56
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8016
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -2.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.87
         upper limit
    13.82
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7278
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -2.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.79
         upper limit
    13.14

    Secondary: Change From Phase B Baseline in the Severity of Spasm After 4, 8 and 12 Weeks of Treatment

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    End point title
    Change From Phase B Baseline in the Severity of Spasm After 4, 8 and 12 Weeks of Treatment
    End point description
    Subjects made a qualitative assessment of the severity of the spasms in a 3 levels categorical scale, i.e. mild, moderate, severe. Least square means and 95% confidence interval values of severity score were reported.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [12]
    53 [13]
    Units: Severity of spasms
    least squares mean (confidence interval 95%)
        Change at Week 4
    -0.61 (-0.75 to -0.48)
    -0.34 (-0.47 to -0.21)
        Change at Week 8
    -0.67 (-0.82 to -0.52)
    -0.36 (-0.51 to -0.21)
        Change at Week 12
    -0.72 (-0.87 to -0.58)
    -0.38 (-0.52 to -0.24)
    Notes
    [12] - Phase B: ITT
    [13] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0052
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.46
         upper limit
    -0.08
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.004
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -0.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.52
         upper limit
    -0.1
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0012
    Method
    Mixed Model for Repeated Measure (MMRM).
    Parameter type
    LS Mean Difference
    Point estimate
    -0.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.54
         upper limit
    -0.14

    Secondary: Change From Phase B Baseline in Sleep Disruption 0-10 Numerical Rating Scale (NRS) After 4, 8 and 12 Weeks of Treatment

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    End point title
    Change From Phase B Baseline in Sleep Disruption 0-10 Numerical Rating Scale (NRS) After 4, 8 and 12 Weeks of Treatment
    End point description
    Sleep disruption was measured based on a scale of 0 to 10, 0 as“did not disrupt sleep” and 10 as “completely disrupted (unable to sleep at all)”.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [14]
    53 [15]
    Units: Score on a Scale
    least squares mean (confidence interval 95%)
        Change at Week 4
    -2.77 (-3.28 to -2.27)
    -1.58 (-2.09 to -1.07)
        Change at Week 8
    -3.14 (-3.70 to -2.58)
    -1.62 (-2.18 to -1.05)
        Change at Week 12
    -3.21 (-3.77 to -2.65)
    -1.78 (-2.35 to -1.21)
    Notes
    [14] - Phase B: ITT
    [15] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0014
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.91
         upper limit
    -0.47
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0002
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -1.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.32
         upper limit
    -0.73
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0006
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -1.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.23
         upper limit
    -0.63

    Secondary: Change From Phase B Baseline in the Spasticity Modified Ashworth Scale After 4, 8 and 12 Weeks of Treatment (Overall Score)

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    End point title
    Change From Phase B Baseline in the Spasticity Modified Ashworth Scale After 4, 8 and 12 Weeks of Treatment (Overall Score)
    End point description
    The modified Ashworth scale had 5 categories to classify muscle spasticity by the healthcare professional as- 0) No increase in muscle tone. 1) Slight increase in muscle tone with a catch and release or minimal resistance at end of the range. 2) As 1 but minimal resistance through range following catch. 3) More marked increase in tone through range of motion (ROM). 4) Considerable increase in tone, passive movement is difficult. 5) Affected part rigid in flexion or extension.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [16]
    53 [17]
    Units: Score on a Scale
    least squares mean (confidence interval 95%)
        Change at Week 4
    -0.26 (-0.34 to -0.17)
    -0.02 (-0.11 to 0.07)
        Change at Week 8
    -0.30 (-0.39 to -0.21)
    -0.05 (-0.15 to 0.04)
        Change at Week 12
    -0.30 (-0.39 to -0.21)
    -0.06 (-0.16 to 0.04)
    Notes
    [16] - Phase B: ITT
    [17] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0003
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -0.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.36
         upper limit
    -0.11
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0004
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -0.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.38
         upper limit
    -0.11
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0007
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -0.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.38
         upper limit
    -0.1

    Secondary: Change From Phase B Baseline in Expanded Disability Status Scale (EDSS) Score After 4, 8 and 12 Weeks of Treatment

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    End point title
    Change From Phase B Baseline in Expanded Disability Status Scale (EDSS) Score After 4, 8 and 12 Weeks of Treatment
    End point description
    Expanded disability status scale quantifies disability in 8 functional systems and allows neurologists to assign a Functional System Score. EDSS steps 1.0 to 4.5 refer to subjects with MS who are fully ambulatory. EDSS steps 5.0 to 9.5 are defined by the impairment to ambulation.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [18]
    53 [19]
    Units: Score on a scale
    least squares mean (confidence interval 95%)
        Change at Week 4
    0.00 (-0.02 to 0.02)
    0.00 (-0.02 to 0.02)
        Change at Week 8
    -0.02 (-0.04 to 0.00)
    0.00 (-0.02 to 0.02)
        Change at Week 12
    -0.02 (-0.04 to 0.00)
    -0.01 (-0.04 to 0.01)
    Notes
    [18] - Phase B: ITT
    [19] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9878
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.03
         upper limit
    0.03
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1706
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.05
         upper limit
    0.01
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6259
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.04
         upper limit
    0.03

    Secondary: Change From Phase B Baseline in the Barthel Activities of Daily Living (ADL) Index After 4, 8 and 12 Weeks of Treatment

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    End point title
    Change From Phase B Baseline in the Barthel Activities of Daily Living (ADL) Index After 4, 8 and 12 Weeks of Treatment
    End point description
    The Barthel ADL index analysed the subject´s abilities to perform daily living activities quantitatively. The short form of Barthel ADL index was used in this study, which included 10 elements with a maximum total score of 20. Two elements (grooming and bathing) were on a scale of 0 to 1; 6 elements (bowels, bladder, toilet use, feeding, dressing, and stairs) were on a 0 to 2; and 2 elements (mobility and transfer) were on a scale of 0 to 3. Total possible scores range from 0 to 20, with lower scores indicating increased disability.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [20]
    53 [21]
    Units: Score on a scale
    least squares mean (confidence interval 95%)
        Change at Week 4
    -0.08 (-0.31 to 0.15)
    0.09 (-0.16 to 0.33)
        Change at Week 8
    -0.10 (-0.39 to 0.18)
    0.13 (-0.17 to 0.43)
        Change at Week 12
    0.04 (-0.23 to 0.30)
    0.11 (-0.17 to 0.39)
    Notes
    [20] - Phase B: ITT
    [21] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3273
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    0.17
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2721
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -0.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.65
         upper limit
    0.18
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.709
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.46
         upper limit
    0.31

    Secondary: Percentage of Subjects who Achieve the Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Barthel Activities of Daily Living (ADL) Index After 4, 8 and 12 Weeks of Treatment

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    End point title
    Percentage of Subjects who Achieve the Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Barthel Activities of Daily Living (ADL) Index After 4, 8 and 12 Weeks of Treatment
    End point description
    The Barthel ADL index analysed the subject´s abilities to perform activities of daily living quantitatively. The short form was used in this study, which included 10 elements with a maximum total score of 20. Two elements (grooming and bathing) were on a scale of 0 to 1; 6 elements (bowels, bladder, toilet use, feeding, dressing, and stairs) were on a 0 to 2; and 2 elements (mobility and transfer) were on a scale of 0 to 3. Total possible scores range from 0 to 20, with lower scores indicating increased disability. The MCID of the Barthel ADL index is 1.85 points.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [22]
    53 [23]
    Units: Percentage of subjects
    number (not applicable)
        Week 4
    1.9
    5.7
        Week 8
    3.8
    7.5
        Week 12
    5.7
    5.7
    Notes
    [22] - Phase B: ITT
    [23] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2043
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    0.278
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.038
         upper limit
    2.027
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3249
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    0.413
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.07
         upper limit
    2.434
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8834
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    0.879
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.153
         upper limit
    5.035

    Secondary: Change From Phase B Baseline in Short Form 36 (SF-36) Scores After 4, 8 and 12 Weeks of Treatment

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    End point title
    Change From Phase B Baseline in Short Form 36 (SF-36) Scores After 4, 8 and 12 Weeks of Treatment
    End point description
    The SF-36 differentiates between physical and mental health and consists of 8 different dimensions (physical functioning, vitality, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health) and is validated for bodily pain and physical function. The SF-36 scores for each dimension could range between 0 and 100. Higher score indicates better functional health and well being.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [24]
    53 [25]
    Units: Score on a scale
    least squares mean (confidence interval 95%)
        Change at Week 4: General health
    3.14 (0.02 to 6.25)
    1.69 (-1.58 to 4.96)
        Change at Week 8: General health
    2.73 (-0.60 to 6.07)
    2.27 (-1.23 to 5.78)
        Change at Week 12: General health
    0.31 (-3.71 to 4.34)
    1.90 (-2.34 to 6.15)
        Change at Week 4: Physical role
    9.05 (5.40 to 12.70)
    4.26 (0.42 to 8.10)
        Change at Week 8: Physical role
    12.25 (8.22 to 16.27)
    5.90 (1.65 to 10.14)
        Change at Week 12: Physical role
    7.44 (2.99 to 11.89)
    4.77 (0.08 to 9.46)
        Change at Week 4: Vitality
    7.93 (4.08 to 11.79)
    2.55 (-1.50 to 6.60)
        Change at Week 8: Vitality
    6.88 (2.83 to 10.92)
    3.98 (-0.27 to 8.24)
        Change at Week 12: Vitality
    8.34 (3.89 to 12.78)
    3.00 (-1.69 to 7.68)
        Change at Week 4: Social functioning
    8.08 (3.28 to 12.89)
    3.49 (-1.56 to 8.54)
        Change at Week 8: Social functioning
    7.90 (2.98 to 12.82)
    5.35 (0.16 to 10.54)
        Change at Week 12: Social functioning
    7.68 (3.12 to 12.24)
    4.27 (-0.54 to 9.08)
        Change at Week 4: Emotional role
    5.85 (0.77 to 10.93)
    7.46 (2.12 to 12.80)
        Change at Week 8: Emotional role
    9.38 (4.42 to 14.33)
    3.84 (-1.40 to 9.07)
        Change at Week 12: Emotional role
    6.21 (1.32 to 11.11)
    4.99 (-0.18 to 10.16)
        Change at Week 4: Mental health
    5.23 (2.19 to 8.26)
    4.34 (1.15 to 7.53)
        Change at Week 8: Mental health
    6.62 (3.02 to 10.23)
    3.85 (0.06 to 7.65)
        Change at Week 12: Mental health
    5.52 (2.09 to 8.95)
    3.38 (-0.23 to 7.00)
        Change at Week 4: Bodily pain
    18.05 (13.81 to 22.28)
    6.02 (1.57 to 10.47)
        Change at Week 8: Bodily pain
    19.52 (14.63 to 24.42)
    9.84 (4.68 to 15.00)
        Change at Week 12: Bodily pain
    19.71 (14.34 to 25.09)
    10.41 (4.74 to 16.08)
        Change at Week 4: Physical functioning
    3.90 (0.87 to 6.93)
    2.63 (-0.55 to 5.82)
        Change at Week 8: Physical functioning
    5.31 (2.05 to 8.57)
    2.68 (-0.75 to 6.12)
        Change at Week 12: Physical functioning
    4.08 (0.57 to 7.59)
    3.65 (-0.05 to 7.35)
    Notes
    [24] - Phase B: ITT
    [25] - Phase B: ITT
    Statistical analysis title
    Week 4: General Health- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.526
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    1.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.07
         upper limit
    5.97
    Statistical analysis title
    Week 8: General Health- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8507
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.38
         upper limit
    5.3
    Statistical analysis title
    Week 12: General Health- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5909
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -1.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.44
         upper limit
    4.26
    Statistical analysis title
    Week 4: Physical role- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0762
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    4.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.51
         upper limit
    10.1
    Statistical analysis title
    Week 8: Physical role- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.034
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    6.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    12.21
    Statistical analysis title
    Week 12: Physical role- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4148
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    2.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    9.13
    Statistical analysis title
    Week 4: Vitality- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0592
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    5.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.21
         upper limit
    10.98
    Statistical analysis title
    Week 8: Vitality- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3306
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    2.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.98
         upper limit
    8.77
    Statistical analysis title
    Week 12: Vitality- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1044
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    5.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.13
         upper limit
    11.8
    Statistical analysis title
    Week 4: Social functioning- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1946
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    4.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.39
         upper limit
    11.57
    Statistical analysis title
    Week 8: Social functioning- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.481
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    2.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.61
         upper limit
    9.71
    Statistical analysis title
    Week 12: Social functioning- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3109
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    3.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.23
         upper limit
    10.04
    Statistical analysis title
    Week 4: Emotional role- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6653
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -1.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.99
         upper limit
    5.76
    Statistical analysis title
    Week 8: Emotional role- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1304
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    5.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.67
         upper limit
    12.75
    Statistical analysis title
    Week 12: Emotional role- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7336
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    1.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.9
         upper limit
    8.35
    Statistical analysis title
    Week 4: Mental health- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6914
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.52
         upper limit
    5.29
    Statistical analysis title
    Week 8: Mental health- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2964
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    2.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.47
         upper limit
    8.01
    Statistical analysis title
    Week 12: Mental health- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3976
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    2.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.85
         upper limit
    7.12
    Statistical analysis title
    Week 4: Bodily pain- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0002
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    12.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.88
         upper limit
    18.18
    Statistical analysis title
    Week 8: Bodily pain- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0082
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    9.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.57
         upper limit
    16.8
    Statistical analysis title
    Week 12: Bodily pain- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0201
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    9.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.49
         upper limit
    17.12
    Statistical analysis title
    Week 4: Physical functioning- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5699
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    1.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.13
         upper limit
    5.66
    Statistical analysis title
    Week 8: Physical functioning- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2746
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    2.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.11
         upper limit
    7.36
    Statistical analysis title
    Week 12: Physical functioning- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.868
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.67
         upper limit
    5.53

    Secondary: Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Short Form 36 Quality of Life (SF-36 Qol) Scale Scores After 4, 8 and 12 Weeks of Treatment in Phase B

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    End point title
    Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Short Form 36 Quality of Life (SF-36 Qol) Scale Scores After 4, 8 and 12 Weeks of Treatment in Phase B
    End point description
    The SF-36 differentiates between physical and mental health and consists of 8 different dimensions (physical functioning, vitality, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health) and is validated for bodily pain and physical function. The SF-36 scores for each dimension could range between 0 and 100. Higher score indicates better functional health and well being.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [26]
    53 [27]
    Units: Percentage of subjects
    number (not applicable)
        Week 4: Bodily pain
    77.4
    35.8
        Week 8: Bodily pain
    79.2
    47.2
        Week 12: Bodily pain
    69.8
    47.2
        Week 4: Physical functioning
    49.1
    34.0
        Week 8: Physical functioning
    52.8
    26.4
        Week 12: Physical functioning
    47.2
    35.8
    Notes
    [26] - Phase B: ITT
    [27] - Phase B: ITT
    Statistical analysis title
    Week 4: Bodily pain- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0008
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    6.264
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.196
         upper limit
    17.871
    Statistical analysis title
    Week 8: Bodily pain- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0016
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    5.078
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.884
         upper limit
    13.685
    Statistical analysis title
    Week 12: Bodily pain- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0543
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    2.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.983
         upper limit
    6.669
    Statistical analysis title
    Week 4: Physical functioning- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2454
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds Ratio
    Point estimate
    1.619
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.714
         upper limit
    3.672
    Statistical analysis title
    Week 8: Physical functioning- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.015
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds Ratio
    Point estimate
    2.948
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.24
         upper limit
    7.01
    Statistical analysis title
    Week 12: Physical functioning- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.424
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds Ratio
    Point estimate
    1.393
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.614
         upper limit
    3.159

    Secondary: Percentage of Subjects With Change From Baseline in Global Assessment Of Clinical Change (7-Item Categorical Scales) by the Subject (SGIC) and the Doctor (PGIC) After 4, 8 and 12 Weeks of Treatment

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    End point title
    Percentage of Subjects With Change From Baseline in Global Assessment Of Clinical Change (7-Item Categorical Scales) by the Subject (SGIC) and the Doctor (PGIC) After 4, 8 and 12 Weeks of Treatment
    End point description
    Subject global impression of change (SGIC) indicated the change in ability to function due to MS. The SGIC was assessed using a 7-point scale: Very much better, Much better, Minimally better, No change, Minimally worse, Much worse and Very much worse. The Physician/doctor Global assessment of clinical change (PGIC) was assessed by the physician, using the same 7-point scale used to assess the SGIC.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [28]
    53 [29]
    Units: Percentage of subjects
    number (not applicable)
        Week 4: SGIC- Very much better
    1.9
    0
        Week 4: SGIC- Much better
    11.3
    1.9
        Week 4: SGIC- Minimally better
    41.5
    15.1
        Week 4: SGIC- No change
    20.8
    39.6
        Week 4: SGIC- Minimally worse
    13.2
    22.6
        Week 4: SGIC- Much worse
    11.3
    11.3
        Week 4: SGIC- Very much worse
    0
    0
        Week 8: SGIC- Very much better
    3.8
    0
        Week 8: SGIC- Much better
    13.2
    9.4
        Week 8: SGIC- Minimally better
    32.1
    13.2
        Week 8: SGIC- No change
    18.9
    34.0
        Week 8: SGIC- Minimally worse
    9.4
    24.5
        Week 8: SGIC- Much worse
    13.2
    3.8
        Week 8: SGIC- Very much worse
    5.7
    1.9
        Week 12: SGIC- Very much better
    0
    0
        Week 12: SGIC- Much better
    15.1
    3.8
        Week 12: SGIC- Minimally better
    28.3
    22.6
        Week 12: SGIC- No change
    32.1
    41.5
        Week 12: SGIC- Minimally worse
    5.7
    17.0
        Week 12: SGIC- Much worse
    13.2
    1.9
        Week 12: SGIC- Very much worse
    1.9
    0
        Week 4: PGIC- Very much better
    0
    0
        Week 4: PGIC- Much better
    20.8
    1.9
        Week 4: PGIC- Minimally better
    37.7
    13.2
        Week 4: PGIC- No change
    15.1
    41.5
        Week 4: PGIC- Minimally worse
    17.0
    24.5
        Week 4: PGIC- Much worse
    9.4
    9.4
        Week 4: PGIC- Very much worse
    0
    0
        Week 8: PGIC- Very much better
    3.8
    0
        Week 8: PGIC- Much better
    11.3
    7.5
        Week 8: PGIC- Minimally better
    34.0
    11.3
        Week 8: PGIC- No change
    26.4
    39.6
        Week 8: PGIC- Minimally worse
    9.4
    26.4
        Week 8: PGIC- Much worse
    11.3
    0
        Week 8: PGIC- Very much worse
    0
    1.9
        Week 12: PGIC- Very much better
    3.8
    0
        Week 12: PGIC- Much better
    11.3
    5.7
        Week 12: PGIC- Minimally better
    32.1
    20.8
        Week 12: PGIC- No change
    35.8
    49.1
        Week 12: PGIC- Minimally worse
    5.7
    9.4
        Week 12: PGIC- Much worse
    7.5
    1.9
        Week 12: PGIC- Very much worse
    0
    0
    Notes
    [28] - Phase B: ITT
    [29] - Phase B: ITT
    Statistical analysis title
    Week 4: SGIC- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for ordinal repeated data with treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0035
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    2.852
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.41
         upper limit
    5.768
    Statistical analysis title
    Week 8: SGIC- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for ordinal repeated data with treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1331
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    1.823
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.833
         upper limit
    3.993
    Statistical analysis title
    Week 12: SGIC- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for ordinal repeated data with treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3515
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    1.384
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.699
         upper limit
    2.741
    Statistical analysis title
    Week 4: PGIC- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for ordinal repeated data with treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0005
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    3.972
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.834
         upper limit
    8.604
    Statistical analysis title
    Week 8: PGIC- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for ordinal repeated data with treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.026
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    2.418
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.111
         upper limit
    5.262
    Statistical analysis title
    Week 12: PGIC- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for ordinal repeated data with treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1615
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    1.623
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.824
         upper limit
    3.198

    Secondary: Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Global Assessment of Clinical Change by the Subject (SGIC) and the Doctor (PGIC) After 4, 8 and 12 Weeks of Treatment (Responder Analysis)

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    End point title
    Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Global Assessment of Clinical Change by the Subject (SGIC) and the Doctor (PGIC) After 4, 8 and 12 Weeks of Treatment (Responder Analysis)
    End point description
    Subject global impression of change (SGIC) indicated the change in ability to function due to MS. The SGIC was assessed using a 7-point scale: Very much better, Much better, Minimally better, No change, Minimally worse, Much worse and Very much worse. The PGIC was assessed by the physician, using the same 7-point scale used to assess the SGIC.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [30]
    53 [31]
    Units: Percentage of subjects
    number (not applicable)
        Week 4: SGIC
    54.7
    17.0
        Week 8: SGIC
    49.1
    22.6
        Week 12: SGIC
    43.4
    26.4
        Week 4: PGIC
    58.5
    15.1
        Week 8: PGIC
    49.1
    18.9
        Week 12: PGIC
    47.2
    26.4
    Notes
    [30] - Phase B: ITT
    [31] - Phase B: ITT
    Statistical analysis title
    Week 4: SGIC- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0006 [32]
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    5.236
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.077
         upper limit
    13.201
    Notes
    [32] - General Linear Mixed Model for binary repeated data with treatment, week and treatment by week interaction as fixed effect factors.
    Statistical analysis title
    Week 8: SGIC- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0152
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    2.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.238
         upper limit
    7.076
    Statistical analysis title
    Week 12: SGIC- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1568
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    1.849
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.786
         upper limit
    4.345
    Statistical analysis title
    Week 4: PGIC- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0001
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    7.045
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.707
         upper limit
    18.334
    Statistical analysis title
    Week 8: PGIC- Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0045
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    3.777
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.524
         upper limit
    9.363
    Statistical analysis title
    Week 12: PGIC- Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other [33]
    P-value
    = 0.072
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    2.183
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.931
         upper limit
    5.119
    Notes
    [33] - General Linear Mixed Model for binary repeated data with treatment, week and treatment by week interaction as fixed effect factors.

    Secondary: Change From Phase B Baseline in Pain (0-10 NRS) After 4, 8 and 12 Weeks of Treatment

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    End point title
    Change From Phase B Baseline in Pain (0-10 NRS) After 4, 8 and 12 Weeks of Treatment
    End point description
    Pain was measured based on a scale of 0 to 10, 0 as “No pain”and 10 as“Worst possible pain”.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [34]
    53 [35]
    Units: Score on a scale
    least squares mean (confidence interval 95%)
        Change at Week 4
    -2.85 (-3.37 to -2.32)
    -1.65 (-2.18 to -1.12)
        Change at Week 8
    -3.08 (-3.66 to -2.51)
    -1.64 (-2.22 to -1.05)
        Change at Week 12
    -3.21 (-3.81 to -2.62)
    -1.80 (-2.41 to -1.20)
    Notes
    [34] - Phase B: ITT
    [35] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0019
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.94
         upper limit
    -0.45
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0007
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -1.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.26
         upper limit
    -0.62
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0014
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -1.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.26
         upper limit
    -0.56

    Secondary: Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement in Pain (0-10 NRS) After 4, 8 And 12 Weeks of Treatment in Phase B

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    End point title
    Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement in Pain (0-10 NRS) After 4, 8 And 12 Weeks of Treatment in Phase B
    End point description
    Pain was measured based on a scale of 0 to 10, 0 as “No pain”and 10 as“Worst possible pain”.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 8 And Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [36]
    53 [37]
    Units: Percentage of subjects
    number (not applicable)
        Week 4
    77.4
    62.3
        Week 8
    83.0
    54.7
        Week 12
    73.6
    58.5
    Notes
    [36] - Phase B: ITT
    [37] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1104
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.842
         upper limit
    5.236
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0042
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    5.106
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.693
         upper limit
    15.396
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0571
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    2.688
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.97
         upper limit
    7.447

    Secondary: Change From Phase B Baseline in Timed 10 Minute Walk Test, After 4, 8 and 12 Weeks of Treatment

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    End point title
    Change From Phase B Baseline in Timed 10 Minute Walk Test, After 4, 8 and 12 Weeks of Treatment
    End point description
    The timed 10 minute walk test assessed walking speed in meters per second over a short distance.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [38]
    53 [39]
    Units: Meter per second
    least squares mean (confidence interval 95%)
        Change at Week 4
    -2.09 (-3.16 to -1.03)
    -1.10 (-2.25 to 0.05)
        Change at Week 8
    -1.74 (-3.35 to -0.13)
    -1.31 (-3.03 to 0.40)
        Change at Week 12
    -2.79 (-4.25 to -1.32)
    -1.08 (-2.65 to 0.48)
    Notes
    [38] - Phase B: ITT
    [39] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2111
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.56
         upper limit
    0.57
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7158
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.78
         upper limit
    1.92
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1174
    Method
    Mixed Model for Repeated Measure (MMRM)
    Parameter type
    LS Mean Difference
    Point estimate
    -1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.84
         upper limit
    0.44

    Secondary: Percentage of Subjects With a Clinically Important Difference (CID) Improvement in Timed 10m Walk Test, After 4, 8 and 12 Weeks of Treatment

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    End point title
    Percentage of Subjects With a Clinically Important Difference (CID) Improvement in Timed 10m Walk Test, After 4, 8 and 12 Weeks of Treatment
    End point description
    The timed 10 m walk test assessed walking speed in meters per second over a short distance.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 8 and Week 12
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [40]
    53 [41]
    Units: Percentage of subjects
    number (not applicable)
        Week 4
    15.1
    11.3
        Week 8
    17.0
    13.2
        Week 12
    18.9
    7.5
    Notes
    [40] - Phase B: ITT
    [41] - Phase B: ITT
    Statistical analysis title
    Week 4: Sativex vs Placebo
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other [42]
    P-value
    = 0.7698
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    1.194
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.358
         upper limit
    3.983
    Notes
    [42] - General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Statistical analysis title
    Week 8: Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7819
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    1.173
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.373
         upper limit
    3.69
    Statistical analysis title
    Week 12: Sativex vs Placebo
    Statistical analysis description
    General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.
    Comparison groups
    Phase B: Sativex v Phase B: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1537
    Method
    Generalized Linear Mixed model
    Parameter type
    Adjusted Odds ratio
    Point estimate
    2.596
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.695
         upper limit
    9.701

    Secondary: Percentage of Subjects With Changes in Concomitant/Underlying Antispastic Standard Therapy Between Visit 4 and Visit 7

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    End point title
    Percentage of Subjects With Changes in Concomitant/Underlying Antispastic Standard Therapy Between Visit 4 and Visit 7
    End point description
    Any changes in concomitant medication - particularly any changes in antispastic medication – during the study period was recorded in the eCRF.
    End point type
    Secondary
    End point timeframe
    Phase B: Start of study drug administration up to 12 weeks
    End point values
    Phase B: Sativex Phase B: Placebo
    Number of subjects analysed
    53 [43]
    53 [44]
    Units: Percentage of subjects
    number (not applicable)
        Baclofen
    3.8
    7.5
        Tizanidine
    0
    0
        Dantrolene
    0
    0
        Benzodiazepine derivatives
    1.9
    0
    Notes
    [43] - Phase B: ITT
    [44] - Phase B: ITT
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration until 20 weeks
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Phase A: Sativex
    Reporting group description
    Subjects received up-titrated Sativex up to 12 sprays per day for 4 weeks as add-on to their optimized standard antispastic medication (oral baclofen and/or tizanidine and/or dantrolene) until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.

    Reporting group title
    Phase B: Sativex
    Reporting group description
    Subjects who were initial responders and whose Phase A-improvement in MS spasticity NRS score had been reduced by at least 80% during the washout phase received up-titrated Sativex to the dose identified during Phase A as being their optimal dose (up to 12 sprays per day) for 12 weeks as add-on to their optimized standard antispastic medication until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.

    Reporting group title
    Phase B: Placebo
    Reporting group description
    Subjects who were initial responders and whose Phase A-improvement in MS spasticity NRS score had been reduced by at least 80% during the washout phase received matched placebo for 12 weeks as addon to their optimized standard antispastic medication until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.

    Reporting group title
    Phase A: Sativex Washout
    Reporting group description
    Subjects who qualified as Sativex initial responders received their underlying optimized standard antispastic medication (oral baclofen and/or tizanidine and/or dantrolene) but not Sativex up to 4 weeks, until the subject’s Phase A-gain in MS spasticity NRS score had been reduced by at least 80%.

    Serious adverse events
    Phase A: Sativex Phase B: Sativex Phase B: Placebo Phase A: Sativex Washout
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 191 (1.05%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
    0 / 134 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Renal and urinary disorders
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 134 (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
    Haematuria
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (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
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Phase A: Sativex Phase B: Sativex Phase B: Placebo Phase A: Sativex Washout
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 191 (24.08%)
    19 / 53 (35.85%)
    8 / 53 (15.09%)
    12 / 134 (8.96%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 191 (1.57%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    2 / 134 (1.49%)
         occurrences all number
    3
    0
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Paraesthesia
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 191 (1.57%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    3
    0
    0
    1
    Asthenia
         subjects affected / exposed
    2 / 191 (1.05%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Administration site pain
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hunger
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    1
    0
    0
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    1
    0
    0
    1
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Reproductive system and breast disorders
    Prostatic neoplasms and hypertrophy
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dry throat
         subjects affected / exposed
    2 / 191 (1.05%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    2 / 134 (1.49%)
         occurrences all number
    2
    0
    0
    2
    Throat tightness
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper respiratory tract inflammation
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 191 (2.09%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    4
    0
    0
    1
    Somnolence
         subjects affected / exposed
    3 / 191 (1.57%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    6
    2
    0
    0
    Dysaesthesia
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    1
    1
    0
    1
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    2
    0
    0
    1
    Disturbance in attention
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypotonia
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Muscle spasticity
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    1
    1
    0
    1
    Dysgeusia
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Tremor
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypogeusia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychomotor skills impaired
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    14 / 191 (7.33%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    15
    1
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 191 (2.09%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    4 / 191 (2.09%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    4
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    3 / 191 (1.57%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    2 / 134 (1.49%)
         occurrences all number
    3
    1
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 191 (1.05%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Oral pain
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatobiliary disorders
    Hepatic cyst
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hydronephrosis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Obstructive nephropathy
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    2 / 191 (1.05%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    1
    0
    0
    1
    Bursitis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    2 / 191 (1.05%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Erysipelas
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    1
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    0
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pulpitis dental
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2016
    - The investigational medicinal product (IMP) was not to be weighed - Subjects were to be withdrawn from the study if they had a relapse of MS. - Systemic corticosteroids were not to be prohibited. - Addition of a secondary efficacy variable: CID improvement in timed 10 minute walk test after 4, 8 and 12 weeks

    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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