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    Clinical Trial Results:
    NEUROPHYSIOLOGIC STUDY AIMED AT EVALUATING ON EFFECT OF SATIVEX® ON SPASTICITY IN PROGRESSIVE MULTIPLE SCLEROSIS

    Summary
    EudraCT number
    		 2011-002258-30
    Trial protocol
    		 IT  
    Global end of trial date
    30 Aug 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jun 2016
    First version publication date
    02 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M/SATIVX/01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01538225
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Almirall S.A.
    Sponsor organisation address
    General Mitre 151 , Barcelona, Spain,
    Public contact
    Global Medical Affairs, ALMIRALL S.A., 0034 932913490, carlos.vila@almirall.com
    Scientific contact
    Global Medical Affairs, ALMIRALL S.A., 0034 932913490, 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
    13 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Aug 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of Sativex (THC:CBD 1:1 ratio oromucosal spray) compared to placebo in modifying neurophysiological measures of spasticity (H/M ratio scores at baseline and at week 4) in patients affected by lower limbs spasticity in Progressive Multiple Sclerosis
    Protection of trial subjects
    Insurance policy available. Informed consent and informative sheet for patients about study procedures. Telephone conntacts at weeks 2 and 8 for Sativex dose fixation. Presential visits at weeks 0, 4, 6, 10.
    Background therapy
    		 Approved antispastic medication
    Evidence for comparator
    		 Not applicable, Placebo comparator
    Actual start date of recruitment
    19 Apr 2012
    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
    Italy: 44
    Worldwide total number of subjects
    44
    EEA total number of subjects
    44
    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)
    43
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Following the protocol selection criteria

    Pre-assignment
    Screening details
    		 Patients fulfilling the protocol selection criteria, including Sativex approved label requirements and providing informed consent. Subjects affected by Secondary or Primary-Progressive MS. Sativex has been gradually titrated. Subjects recieved in a random order each treatment (Sativex/Placebo) during 2 subsequent 4-weeks period divided by a washout

    Pre-assignment period milestones
    Number of subjects started
    		 44
    Number of subjects completed
    		 44

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 4 weeks Sativex and 4 weeks Placebo
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sativex and Placebo
    Investigational medicinal product code
    Other name
    THC:CDB oromucosal spray, Namiximols (USAN name)
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Spray containing, for 100 microliters, 2.7mg THC and 2.5mg CBD OR Placebo gradually titrated during the first 2 weeks of treatment, increasing the number of sprays until they reached and individualized sprayed dose (maximum 12 sprays)

    Arm title
    		 4 weeks Placebo and 4 weeks Sativex
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sativex and Placebo
    Investigational medicinal product code
    Other name
    THC:CBD oromucosal spray, Namiximols (USAN name)
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Spray containing, for 100 microliters, 2.7mg THC and 2.5mg CBD OR Placebo gradually titrated during the first 2 weeks of treatment, increasing the number of sprays until they reached and individualized sprayed dose (maximum 12 sprays)

    Number of subjects in period 1
    		4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex
    Started
    22
    22
    Completed
    17
    21
    Not completed
    5
    1
         Adverse event, non-fatal
    2
    -
         Intolerance to TMS
    -
    1
         Serious Adverse Event, non-fatal
    1
    -
         Personal Reasons
    1
    -
         Starting neurorehabilitation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    4 weeks Sativex and 4 weeks Placebo
    Reporting group description
    		 -

    Reporting group title
    4 weeks Placebo and 4 weeks Sativex
    Reporting group description
    		 -

    Reporting group values
    		 4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex Total
    Number of subjects
    		 22 22 44
    Age categorical
    Units: Subjects
        Aged 18 years or above
    		 22 22 44
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.5 ( 7.8 ) 47.6 ( 8.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 12 8 20
        Male
    		 10 14 24

    End points

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    End points reporting groups
    Reporting group title
    4 weeks Sativex and 4 weeks Placebo
    Reporting group description
    		 -

    Reporting group title
    4 weeks Placebo and 4 weeks Sativex
    Reporting group description
    		 -

    Primary: The treatment effect on the H reflex/Motor response ratio (H/M ratio)

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    End point title
    		 The treatment effect on the H reflex/Motor response ratio (H/M ratio)
    End point description
    End point type
    Primary
    End point timeframe
    H/M ratio scores at baseline and at week 4 for each treatment
    End point values
    		 4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex
    Number of subjects analysed
    15
    19
    Units: H/M ratio value
    arithmetic mean (standard deviation)
        Baseline sativex
    0.37 ( 0.19 )
    0.3 ( 0.18 )
        After 4 weeks sativex treatment
    0.34 ( 0.17 )
    0.29 ( 0.16 )
        Baseline placebo
    0.31 ( 0.17 )
    0.31 ( 0.18 )
        After 4 weeks placebo treatment
    0.32 ( 0.18 )
    0.29 ( 0.15 )
    Statistical analysis title
    		 H reflex/Motor response H/M ratio values evolution
    Comparison groups
    4 weeks Sativex and 4 weeks Placebo v 4 weeks Placebo and 4 weeks Sativex
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.405
    Method
    		 T-test
    Confidence interval
    Notes
    [1] - There was no significant difference between change from baseline to week 4 in the H/M ratio score (p=0.405) under treatment with Sativex or placebo. No significant effect of sequence of treatment was observed

    Secondary: Resting Motor Thershold (RMT) at First Dorsal Interosseus (FDI)

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    End point title
    		 Resting Motor Thershold (RMT) at First Dorsal Interosseus (FDI)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 4 weeks of treatment
    End point values
    		 4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex
    Number of subjects analysed
    15
    19
    Units: RMT at FDI
    arithmetic mean (standard deviation)
        Baseline Sativex
    60.71 ( 16.31 )
    54.83 ( 12.45 )
        Week 4 Sativex
    61.14 ( 15.58 )
    55.78 ( 14.79 )
        Baseline Placebo
    58.71 ( 13.73 )
    54.26 ( 11.36 )
        Week 4 Placebo
    63.92 ( 13.77 )
    54 ( 11.36 )
    No statistical analyses for this end point

    Secondary: Motor Evoked Potentials (MEP)

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    End point title
    		 Motor Evoked Potentials (MEP)
    End point description
    End point type
    Secondary
    End point timeframe
    Frome baseline to 4 weeks of treatment
    End point values
    		 4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex
    Number of subjects analysed
    15
    19
    Units: MEP value evolution
    arithmetic mean (standard deviation)
        Baseline Sativex
    0.23 ( 0.15 )
    0.32 ( 0.3 )
        week 4 Sativex
    0.24 ( 0.17 )
    0.24 ( 0.16 )
        Baseline Placebo
    0.21 ( 0.1 )
    0.26 ( 0.15 )
        Week 4 Placebo
    0.34 ( 0.42 )
    0.24 ( 0.14 )
    No statistical analyses for this end point

    Secondary: MEP/Muscle potential ratios at APB and AH muscles evolution

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    End point title
    		 MEP/Muscle potential ratios at APB and AH muscles evolution
    End point description
    Motos Evoked Potentials (MEP)/ Muscles potentials ratios at APB (Abductor Pollicis Brevis) and AH (Abductor Hallucis) left (L) and right (R) muscles.
    End point type
    Secondary
    End point timeframe
    From baseline to 4 weeks of treatment
    End point values
    		 4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex
    Number of subjects analysed
    15
    19
    Units: MEP/M
    arithmetic mean (standard deviation)
        Baseline R APB Sativex
    0.21 ( 0.1 )
    0.23 ( 0.19 )
        Week 4 R APB Sativex
    0.21 ( 0.14 )
    0.23 ( 0.17 )
        Baseline L APB Sativex
    0.17 ( 0.13 )
    0.23 ( 0.21 )
        Week 4 L APB Sativex
    0.2 ( 0.14 )
    0.22 ( 0.21 )
        Baseline R AH Sativex
    0.04 ( 0.02 )
    0.06 ( 0.06 )
        Week 4 R AH Sativex
    0.05 ( 0.03 )
    0.08 ( 0.08 )
        Baseline L AH Sativex
    0.04 ( 0.02 )
    0.06 ( 0.04 )
        Week 4 L AH Sativex
    0.04 ( 0.02 )
    0.06 ( 0.04 )
        Baseline R APB Placebo
    0.22 ( 0.13 )
    0.23 ( 0.16 )
        Week 4 R APB Placebo
    0.19 ( 0.12 )
    0.21 ( 0.15 )
        Baseline L APB Placebo
    0.17 ( 0.14 )
    0.22 ( 0.17 )
        Week 4 L APB Placebo
    0.19 ( 0.16 )
    0.24 ( 0.19 )
        Baseline R AH Placebo
    0.04 ( 0.02 )
    0.06 ( 0.03 )
        Week 4 R AH Placebo
    0.04 ( 0.02 )
    0.06 ( 0.03 )
        Baseline L AH Placebo
    0.04 ( 0.02 )
    0.05 ( 0.05 )
        Week 4 L AH Placebo
    0.04 ( 0.02 )
    0.06 ( 0.07 )
    No statistical analyses for this end point

    Secondary: Spasticity Modified Ashworth Scale (MAS)

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    End point title
    		 Spasticity Modified Ashworth Scale (MAS)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 4 weeks of treatment
    End point values
    		 4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex
    Number of subjects analysed
    15
    19
    Units: MAS score evolution
    arithmetic mean (standard deviation)
        Baseline Sativex
    8.03 ( 4.26 )
    6.79 ( 1.87 )
        Week 4 Sativex
    7.67 ( 4.53 )
    6.37 ( 1.74 )
        Baseline Placebo
    7.4 ( 1.4 )
    7 ( 1.63 )
        Week 4 Placebo
    7.33 ( 1.84 )
    6.58 ( 2.01 )
    No statistical analyses for this end point

    Secondary: Spasticity Numeric Rating Scale (NRS)

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    End point title
    		 Spasticity Numeric Rating Scale (NRS)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 4 Weeks of treatment
    End point values
    		 4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex
    Number of subjects analysed
    15
    19
    Units: Numeric Rating Scale evolution
    arithmetic mean (standard deviation)
        Baseline Sativex
    7.27 ( 1.16 )
    6.79 ( 1.87 )
        Week 4 Sativex
    6.73 ( 1.58 )
    6.37 ( 1.74 )
        Baseline Placebo
    7.4 ( 1.4 )
    7 ( 1.63 )
        Week 4 Placebo
    7.33 ( 1.84 )
    6.58 ( 2.01 )
    No statistical analyses for this end point

    Secondary: Timed 10 meters walk

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    End point title
    		 Timed 10 meters walk
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 4 weeks of treatment
    End point values
    		 4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex
    Number of subjects analysed
    15
    19
    Units: Seconds
    arithmetic mean (standard deviation)
        Baseline Sativex
    39.5 ( 50.41 )
    20.55 ( 15.55 )
        Week 4 Sativex
    34.99 ( 47.09 )
    22.75 ( 19.36 )
        Baseline Placebo
    36.39 ( 47.74 )
    22.63 ( 20.37 )
        Week 4 Placebo
    34.55 ( 43.44 )
    22.48 ( 20.19 )
    No statistical analyses for this end point

    Secondary: Nine Hole Peg Test (NHPT)

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    End point title
    		 Nine Hole Peg Test (NHPT)
    End point description
    Upper extremity function test
    End point type
    Secondary
    End point timeframe
    From baseline to 4 weeks of treatment
    End point values
    		 4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex
    Number of subjects analysed
    15
    19
    Units: NHPT scores evolution
    arithmetic mean (standard deviation)
        Baseline DH Sativex
    25.95 ( 5.54 )
    25.66 ( 4.19 )
        Week 4 DH Sativex
    27.32 ( 7.77 )
    24.94 ( 4.33 )
        Baseline NDH Sativex
    26.82 ( 3.99 )
    30.26 ( 8.32 )
        Week 4 NDH Sativex
    25.02 ( 2.71 )
    29.42 ( 7.99 )
        Baseline DH Placebo
    25.72 ( 6.51 )
    27.47 ( 4.95 )
        Week 4 DH Placebo
    25.98 ( 7.37 )
    26.02 ( 4.48 )
        Baseline NDH Placebo
    26.37 ( 4.19 )
    31.73 ( 8.23 )
        Week 4 NDH Placebo
    24.42 ( 3.75 )
    30.98 ( 9.37 )
    No statistical analyses for this end point

    Secondary: Pain

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    End point title
    		 Pain
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 4 weeks of treatment
    End point values
    		 4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex
    Number of subjects analysed
    15
    19
    Units: 0-10 Numeric Rating Scale
    arithmetic mean (standard deviation)
        Baseline Sativex
    3.73 ( 3.22 )
    3.16 ( 3.17 )
        Week 4 Sativex
    3.33 ( 3.15 )
    2.63 ( 3 )
        Baseline Placebo
    4.4 ( 3.58 )
    3.84 ( 3.35 )
        Week 4 Placebo
    3.47 ( 2.77 )
    2 ( 2.69 )
    No statistical analyses for this end point

    Secondary: Sleep Quality Numeric Rating Scale (NRS)

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    End point title
    		 Sleep Quality Numeric Rating Scale (NRS)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 4 weeks of treatment
    End point values
    		 4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex
    Number of subjects analysed
    15
    19
    Units: 0-10 Numeric Rating Scale
    arithmetic mean (standard deviation)
        Baseline Sativex
    2 ( 2.73 )
    2.95 ( 2.97 )
        Week 4 Sativex
    1.33 ( 2.89 )
    2.26 ( 3.19 )
        Baseline Placebo
    2.6 ( 3.02 )
    4 ( 3.53 )
        Week 4 Placebo
    2.33 ( 3.24 )
    2.37 ( 2.63 )
    No statistical analyses for this end point

    Secondary: Spasms

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    End point title
    		 Spasms
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 4 weeks of treatment
    End point values
    		 4 weeks Sativex and 4 weeks Placebo 4 weeks Placebo and 4 weeks Sativex
    Number of subjects analysed
    15
    19
    Units: Spasms Frequency Score
    arithmetic mean (standard deviation)
        Baseline Sativex
    5 ( 6.49 )
    4.47 ( 6.5 )
        Week 4 Sativex
    4.28 ( 4.56 )
    2.58 ( 4.84 )
        Baseline Placebo
    4.53 ( 3.85 )
    5 ( 7.87 )
        Week 4 Placebo
    3.73 ( 4.13 )
    3 ( 4.85 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected and reported during two subsequent 4-weeks periods divided by a 2-week washout. The overall duration for each patient was 10 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Adverse events
    Reporting group description
    		 -

    Serious adverse events
    		 Adverse events
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 43 (2.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Adverse events
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 43 (51.16%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Hypertension
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 43 (23.26%)
         occurrences all number
    10
    Vertigo
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Pharyngitis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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