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    Clinical Trial Results:
    The efficacy, safety and tolerability of Sativex as an adjunctive treatment to existing anti-spasticity medications in children aged 8 to 18 years with spasticity due to cerebral palsy or traumatic central nervous system injury who have not responded adequately to their existing anti-spasticity medications: a parallel group randomised, double-blind, placebo-controlled study followed by a 24-week open label extension phase.

    Summary
    EudraCT number
    		 2012-003771-18
    Trial protocol
    		 GB   CZ  
    Global end of trial date
    23 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2018
    First version publication date
    04 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GWSP08258
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01898520
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GW Research Ltd
    Sponsor organisation address
    Sovereign House, Vision Park, Chivers Way, Histon, Cambridge, United Kingdom, CB24 9BZ
    Public contact
    GW Research Ltd, Alternate contact: medinfo@greenwichbiosciences.com, medinfo@gwpharm.com
    Scientific contact
    GW Research Ltd, Alternate contact: medinfo@greenwichbiosciences.com, medinfo@gwpharm.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000181-PIP01-08
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of Sativex on spasticity in a population of children and adolescents aged from 8 to 18 years with cerebral palsy (CP) or traumatic central nervous system (CNS) injury.
    Protection of trial subjects
    This trial was conducted in compliance with International Conference on Harmonisation Good Clinical Practice guidelines for conducting, recording, and reporting trials, as well as for archiving essential documents. Consistent with ethical principles for the protection of human research participants, no study procedures were performed on study participants until written consent had been obtained from them. The informed consent form, protocol, and amendments for this trial were submitted to and approved by the Institutional Review Board or Ethics Committee at each participating trial site.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    United Kingdom: 61
    Country: Number of subjects enrolled
    Czech Republic: 4
    Worldwide total number of subjects
    72
    EEA total number of subjects
    65
    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)
    35
    Adolescents (12-17 years)
    37
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In order to be eligible for the trial, participants had to be to be suffering from spasticity due to CP or traumatic CNS injury.

    Pre-assignment
    Screening details
    		 Participants were 8 to 18 years old with CP or traumatic CNS injury, were under treatment for spasticity for ≥1 year and had reached a stage of non-progressive spasticity, had Gross Motor Function Classification Scale Level III - V, and had a Modified Ashworth Scale (MAS) score of ≥2 in at least one muscle group.

    Period 1
    Period 1 title
    Randomised Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sativex (Randomised Phase)
    Arm description
    		 Sativex was presented as an oromucosal spray. Sativex was administered by participants or caregivers to the sub-lingual or oral mucosa up to a maximum of 12 sprays per day, for 12 weeks. Each actuation delivered 100 μL (2.7 milligrams [mg] delta-9-tetrahydrocannabinol [THC] and 2.5 mg cannabidiol [CBD]). Sativex was administered as per the following titration schedule (subject to tolerability): Week 1: 1 spray every evening; Week 2: 1 spray twice daily (morning and evening); Weeks 3-4: 1 spray 3 times a day (morning, noon, and evening); Weeks 5 -6: 2 sprays 3 times a day; Weeks 7-8: 3 sprays 3 times a day; Weeks 9-12: 4 sprays 3 times a day. The maximum number of sprays at each stage of titration did not have to be reached. Participants were permitted to stop titrating at any well tolerated dose of 1–12 sprays per day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sativex
    Investigational medicinal product code
    Other name
    Nabiximols, THC:CBD spray, GW-1000-02
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Sativex was presented as an oromucosal spray in an amber plastic coated glass vial. Sativex contained THC (27 mg/mL) and CBD (25 mg/mL) in ethanol:propylene glycol (50:50) with peppermint oil (0.05%) as flavouring. Each actuation delivered 100 μL (2.7 mg THC and 2.5 mg CBD) and was administered sublingually or to oral mucosa. In those participants whose disabilities made this difficult, a caregiver administered the medication. If participants complained of oral discomfort, they were advised to apply the spray to varying sites in the mouth and were not to continue spraying onto sore or inflamed mucous membranes. If lesions were observed or persistent soreness was reported, the dosing of Sativex was to be stopped until complete resolution occurred.

    Arm title
    		 Placebo (Randomised Phase)
    Arm description
    		 Placebo was presented as an oromucosal spray. Placebo was administered by participants or caregivers to the sub-lingual or oral mucosa up to a maximum of 12 sprays per day, for 12 weeks. Placebo contained ethanol: propylene glycol (50:50) excipients. Each actuation delivered 100 μL. Placebo was administered as per the following titration schedule (subject to tolerability): Week 1: 1 spray every evening; Week 2: 1 spray twice daily (morning and evening); Weeks 3-4: 1 spray 3 times a day (morning, noon, and evening); Weeks 5 -6: 2 sprays 3 times a day; Weeks 7-8: 3 sprays 3 times a day; Weeks 9-12: 4 sprays 3 times a day. The maximum number of sprays at each stage of titration did not have to be reached. Participants were permitted to stop titrating at any well tolerated dose of 1–12 sprays per day.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    GW-4000-01
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Placebo was presented as an oromucosal spray in an amber plastic coated glass vial. Placebo contained ethanol:propylene glycol (50:50) with peppermint oil (0.05%) as flavouring, and FD&C Yellow No.5 (E102 tartrazine) (0.0260%), FD&C Yellow No.6 (E110 sunset yellow) (0.0038%), FD&C Red No. 40 (E129 Allura red AC) (0.00330%) and FD&C Blue No.1 (E133 Brilliant blue FCF) (0.00058%) as colourant. Each actuation delivered 100 μL of placebo and was administered sublingually or to oral mucosa. In those participants whose disabilities made this difficult, a caregiver administered the medication. If participants complained of oral discomfort, they were advised to apply the spray to varying sites in the mouth and were not to continue spraying onto sore or inflamed mucous membranes. If lesions were observed or persistent soreness was reported, the dosing of placebo was to be stopped until complete resolution occurred.

    Number of subjects in period 1
    		Sativex (Randomised Phase) Placebo (Randomised Phase)
    Started
    47
    25
    Received at least 1 dose of study drug
    47
    25
    Completed
    44
    24
    Not completed
    3
    1
         Withdrawn by investigator
    1
    -
         Consent withdrawn by subject
    -
    1
         Adverse event
    2
    -
    Period 2
    Period 2 title
    Open-Label Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Sativex (OLE Phase)
    Arm description
    		 Following the final assessment of the randomised phase of the trial on Day 84, all participants were invited to participate in the OLE phase. All participants who chose to continue were re-titrated with Sativex using the same titration schedule in the randomization phase. Sativex was presented as an oromucosal spray and was administered by participants or caregivers to the sub-lingual or oral mucosa up to a maximum of 12 sprays per day, for up to 24 weeks. Each actuation delivered 100 μL (2.7 mg THC and 2.5 mg CBD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sativex
    Investigational medicinal product code
    Other name
    Nabiximols, THC:CBD spray, GW-1000-02
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Sativex was presented as an oromucosal spray. Sativex contained THC (27 mg/mL) and CBD (25 mg/mL) in ethanol:propylene glycol (50:50) with peppermint oil (0.05%) as flavouring. Each actuation delivered 100 μL (2.7 mg THC and 2.5 mg CBD) and was administered sublingually or to oral mucosa. In those participants whose disabilities made this difficult, a caregiver administered the medication. If participants complained of oral discomfort, they were advised to apply the spray to varying sites in the mouth and were not to continue spraying onto sore or inflamed mucous membranes. If lesions were observed or persistent soreness was reported, the dosing of Sativex was to be stopped until complete resolution occurred.

    Number of subjects in period 2 [1]
    		Sativex (OLE Phase)
    Started
    67
    Received at least 1 dose of study drug
    67
    Safety Population
    67
    Completed
    54
    Not completed
    13
         Withdrawn by investigator
    1
         Consent withdrawn by subject
    3
         Adverse event
    9
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participation in the OLE phase was optional. One participant who received Sativex in the randomised phase did not continue to the optional OLE phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sativex (Randomised Phase)
    Reporting group description
    		 Sativex was presented as an oromucosal spray. Sativex was administered by participants or caregivers to the sub-lingual or oral mucosa up to a maximum of 12 sprays per day, for 12 weeks. Each actuation delivered 100 μL (2.7 milligrams [mg] delta-9-tetrahydrocannabinol [THC] and 2.5 mg cannabidiol [CBD]). Sativex was administered as per the following titration schedule (subject to tolerability): Week 1: 1 spray every evening; Week 2: 1 spray twice daily (morning and evening); Weeks 3-4: 1 spray 3 times a day (morning, noon, and evening); Weeks 5 -6: 2 sprays 3 times a day; Weeks 7-8: 3 sprays 3 times a day; Weeks 9-12: 4 sprays 3 times a day. The maximum number of sprays at each stage of titration did not have to be reached. Participants were permitted to stop titrating at any well tolerated dose of 1–12 sprays per day.

    Reporting group title
    Placebo (Randomised Phase)
    Reporting group description
    		 Placebo was presented as an oromucosal spray. Placebo was administered by participants or caregivers to the sub-lingual or oral mucosa up to a maximum of 12 sprays per day, for 12 weeks. Placebo contained ethanol: propylene glycol (50:50) excipients. Each actuation delivered 100 μL. Placebo was administered as per the following titration schedule (subject to tolerability): Week 1: 1 spray every evening; Week 2: 1 spray twice daily (morning and evening); Weeks 3-4: 1 spray 3 times a day (morning, noon, and evening); Weeks 5 -6: 2 sprays 3 times a day; Weeks 7-8: 3 sprays 3 times a day; Weeks 9-12: 4 sprays 3 times a day. The maximum number of sprays at each stage of titration did not have to be reached. Participants were permitted to stop titrating at any well tolerated dose of 1–12 sprays per day.

    Reporting group values
    		 Sativex (Randomised Phase) Placebo (Randomised Phase) Total
    Number of subjects
    		 47 25 72
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 22 13 35
        Adolescents (12-17 years)
    		 25 12 37
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.58 ± 3.340 11.90 ± 2.390 -
    Gender categorical
    Units: Subjects
        Female
    		 18 10 28
        Male
    		 29 15 44

    End points

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    End points reporting groups
    Reporting group title
    Sativex (Randomised Phase)
    Reporting group description
    		 Sativex was presented as an oromucosal spray. Sativex was administered by participants or caregivers to the sub-lingual or oral mucosa up to a maximum of 12 sprays per day, for 12 weeks. Each actuation delivered 100 μL (2.7 milligrams [mg] delta-9-tetrahydrocannabinol [THC] and 2.5 mg cannabidiol [CBD]). Sativex was administered as per the following titration schedule (subject to tolerability): Week 1: 1 spray every evening; Week 2: 1 spray twice daily (morning and evening); Weeks 3-4: 1 spray 3 times a day (morning, noon, and evening); Weeks 5 -6: 2 sprays 3 times a day; Weeks 7-8: 3 sprays 3 times a day; Weeks 9-12: 4 sprays 3 times a day. The maximum number of sprays at each stage of titration did not have to be reached. Participants were permitted to stop titrating at any well tolerated dose of 1–12 sprays per day.

    Reporting group title
    Placebo (Randomised Phase)
    Reporting group description
    		 Placebo was presented as an oromucosal spray. Placebo was administered by participants or caregivers to the sub-lingual or oral mucosa up to a maximum of 12 sprays per day, for 12 weeks. Placebo contained ethanol: propylene glycol (50:50) excipients. Each actuation delivered 100 μL. Placebo was administered as per the following titration schedule (subject to tolerability): Week 1: 1 spray every evening; Week 2: 1 spray twice daily (morning and evening); Weeks 3-4: 1 spray 3 times a day (morning, noon, and evening); Weeks 5 -6: 2 sprays 3 times a day; Weeks 7-8: 3 sprays 3 times a day; Weeks 9-12: 4 sprays 3 times a day. The maximum number of sprays at each stage of titration did not have to be reached. Participants were permitted to stop titrating at any well tolerated dose of 1–12 sprays per day.
    Reporting group title
    Sativex (OLE Phase)
    Reporting group description
    		 Following the final assessment of the randomised phase of the trial on Day 84, all participants were invited to participate in the OLE phase. All participants who chose to continue were re-titrated with Sativex using the same titration schedule in the randomization phase. Sativex was presented as an oromucosal spray and was administered by participants or caregivers to the sub-lingual or oral mucosa up to a maximum of 12 sprays per day, for up to 24 weeks. Each actuation delivered 100 μL (2.7 mg THC and 2.5 mg CBD).

    Primary: Change From Baseline In Spasticity Severity 0-10 Numerical Rating Scale (NRS) Score To End Of Treatment (EOT) (12-Week Randomised Phase)

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    End point title
    		 Change From Baseline In Spasticity Severity 0-10 Numerical Rating Scale (NRS) Score To End Of Treatment (EOT) (12-Week Randomised Phase)
    End point description
    The spasticity 0-10 NRS was completed daily at bedtime using a study diary. The primary caregiver was asked the following question: “This question is about your child’s muscles and how soft or tight/hard they have felt today. Think carefully about how your child’s muscles have felt today and circle a number from 0 to 10 that best describes this, where: 0 = ‘my child’s muscles have felt totally relaxed’ and 10 = ‘my child’s muscles have felt the tightest/hardest they have ever felt’”. Baseline was defined as the average of the assessments recorded on Day −7 to Day −1, inclusive. EOT was the average of the last 7 days of diary data up to the earliest of Day 84, the last dose of IMP and the last day with relevant efficacy data. Least Squares Means (LS Means) were calculated using an analysis of covariance (ANCOVA) with baseline score as a covariate and treatment as fixed effect. A reduction in score indicates an improvement in condition
    End point type
    Primary
    End point timeframe
    Baseline, EOT (12-Week Randomised Phase)
    End point values
    		 Sativex (Randomised Phase) Placebo (Randomised Phase)
    Number of subjects analysed
    47
    25
    Units: units on a scale
        least squares mean (standard error)
    -1.812 ± 0.2807
    -1.645 ± 0.3854
    Statistical analysis title
    		 Change in Spasticity Severity NRS Score
    Statistical analysis description
    Change from baseline was compared between groups using ANCOVA with baseline score as a covariate and treatment as a fixed effect. A 2-sided significance test was used in all comparisons at the 5% level of significance. All participants who were treated and received IMP were included and analysed according to their randomised treatment.
    Comparison groups
    Sativex (Randomised Phase) v Placebo (Randomised Phase)
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7291
    Method
    		 ANCOVA
    Parameter type
    		 LSM difference
    Point estimate
    -0.166
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.119
         upper limit
    		 0.787
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4777

    Secondary: Change From Baseline In Modified Tardieu Scale (MTS) Score Of The Worst Affected Limb To EOT (12-Week Randomised Phase)

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    End point title
    		 Change From Baseline In Modified Tardieu Scale (MTS) Score Of The Worst Affected Limb To EOT (12-Week Randomised Phase)
    End point description
    The MTS of the worst affected limb (identified for each participant at Baseline) was assessed. Individuals were positioned in sitting position to test upper extremities and supine position to test lower extremities. MTS was based on the following criteria: • 3 speed definitions of limb movement: V1 (as slow as possible), V2 (falling under gravity), V3 (as fast as possible) • MTS describes R1 and R2: R1 is the angle of muscle reaction; R2 is the full passive range of movement. • R2 was measured at V1 and R1 at V3. R2-R1 = dynamic tone component of the muscle. The relationship between R1 and R2 estimates the relative contributions of spasticity compared to contracture. EOT was defined Day 84. LS Means were calculated using ANCOVA with baseline score as a covariate and treatment as fixed effect; using Last observation carried forward (LOCF) if observations were missing at EOT. A reduction in score indicates an improvement in condition.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (12-Week Randomised Phase)
    End point values
    		 Sativex (Randomised Phase) Placebo (Randomised Phase)
    Number of subjects analysed
    47
    25
    Units: units on a scale
        least squares mean (standard error)
    -6.603 ± 3.4070
    -1.925 ± 4.7281
    No statistical analyses for this end point

    Secondary: Change From Baseline In MAS Score Of The Main Muscle Groups Of The Upper And Lower Limbs To EOT (12-Week Randomised Phase)

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    End point title
    		 Change From Baseline In MAS Score Of The Main Muscle Groups Of The Upper And Lower Limbs To EOT (12-Week Randomised Phase)
    End point description
    This trial assessed the MAS of the main muscle groups of the upper and lower limb using the MAS Examination and Scoring System. The MAS was performed by the same examiner at each clinic visit (where possible), with the participant in the supine position and the participant was requested to relax. If a muscle that primarily flexed a joint was tested, the joint was placed in a maximally flexed position and moved to a position of maximal extension in 1 second (counted ‘one thousand one’). If a muscle that primarily extended a joint was tested, the joint was placed in a maximally extended position and moved to a position of maximal flexion in 1 second (counted ‘one thousand one’). EOT was defined as Day 84. LS Means were calculated using ANCOVA with baseline score as a covariate and treatment as fixed effect; using LOCF if observations were missing at EOT. A reduction in score indicates an improvement in condition.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (12-Week Randomised Phase)
    End point values
    		 Sativex (Randomised Phase) Placebo (Randomised Phase)
    Number of subjects analysed
    47
    25
    Units: units on a scale
        least squares mean (standard error)
    -10.92 ± 1.715
    -10.26 ± 2.303
    No statistical analyses for this end point

    Secondary: Change From Baseline In Sleep Quality 0-10 NRS Score To EOT (12-Week Randomised Phase)

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    End point title
    		 Change From Baseline In Sleep Quality 0-10 NRS Score To EOT (12-Week Randomised Phase)
    End point description
    Sleep quality was assessed using a 0-10 NRS questionnaire completed at the same time each day, ideally when waking in the morning. This questionnaire was designed to record the level of sleep disturbance. The primary caregiver was asked the following question: “This question is about how badly your child slept last night. Please mark a number from 0 to 10 that indicates how bad your child’s sleep was, where a score of 0 indicated "My child had a night of non-stop sleep" and a score 10 indicated "My child was unable to sleep at all.” EOT is the average of the last 7 days of diary data up to the earliest of Day 84, the last dose of IMP and the last day with relevant efficacy data. LS Means were calculated using ANCOVA with baseline score as a covariate and treatment as fixed effect. A reduction in score indicates an improvement in condition.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (12-Week Randomised Phase)
    End point values
    		 Sativex (Randomised Phase) Placebo (Randomised Phase)
    Number of subjects analysed
    47
    25
    Units: units on a scale
        least squares mean (standard error)
    -1.308 ± 0.2078
    -0.984 ± 0.2855
    No statistical analyses for this end point

    Secondary: Change From Baseline In Paediatric Pain Profile (PPP) Score To EOT (12-Week Randomised Phase)

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    End point title
    		 Change From Baseline In Paediatric Pain Profile (PPP) Score To EOT (12-Week Randomised Phase)
    End point description
    The PPP is a 20-item behaviour rating scale designed to assess pain in children with severe neurological disability. Each item was scored on a 4-point scale of 0 to 3 as occurring ‘not at all’ (zero) to ‘a great deal’ (three) in the given time period. Therefore, the total score ranged from 0 to 60. The questionnaire was designed to be completed by the child’s primary caregiver and was completed at each assessment visit during the trial. EOT was defined as Day 84. LS Means were calculated using ANCOVA with baseline score as a covariate and treatment as fixed effect; using Last observation carried forward (LOCF) if observations were missing at EOT. A reduction in score indicates an improvement in condition.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (12-Week Randomised Phase)
    End point values
    		 Sativex (Randomised Phase) Placebo (Randomised Phase)
    Number of subjects analysed
    47
    25
    Units: units on a scale
    least squares mean (standard error)
        On a Good Day
    -1.6 ± 1.47
    -6.0 ± 2.02
        Most Troublesome Pain
    -16.9 ± 1.59
    -21.8 ± 2.21
        Second Most Troublesome Pain
    -9.0 ± 2.07
    -17.4 ± 2.76
        Third Most Troublesome Pain
    -11.2 ± 5.27
    -24.0 ± 6.15
    No statistical analyses for this end point

    Secondary: Change From Baseline In Cerebral Palsy Quality Of Life (CP QOL) Score To EOT (12-Week Randomised Phase)

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    End point title
    		 Change From Baseline In Cerebral Palsy Quality Of Life (CP QOL) Score To EOT (12-Week Randomised Phase)
    End point description
    CP QOL-child (4-12 years old) questionnaire assessed the following domains of life: social wellbeing and acceptance, feelings about functioning, participation and physical health, emotional wellbeing and self-esteem, access to services, pain and impact on disability, family health. CP QOL-teen (13-18 years old) questionnaire completed by the participant (if possible) assessed the following domains of life: feelings about functioning, access to services, general wellbeing and participation, communication and physical health, school wellbeing, social wellbeing. Scores from both questionnaires were transformed to a 0–100 scale. Domain scores were calculated by taking the average of the converted question response scores for the questions included in that domain. EOT was Day 84. LS Means were calculated using ANCOVA with baseline score as a covariate and treatment as fixed effect; using LOCF if observations were missing at EOT. Increase in score indicates improvement in condition.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (12-Week Randomised Phase)
    End point values
    		 Sativex (Randomised Phase) Placebo (Randomised Phase)
    Number of subjects analysed
    47
    25
    Units: units on a scale
    least squares mean (standard error)
        CP QOL-Child: Social Wellbeing and Acceptance
    1.155 ± 2.8603
    2.424 ± 3.3030
        CP QOL-Child: Feelings about Functioning
    3.273 ± 1.9984
    5.316 ± 2.4972
        CP QOL-Child: Participation and Physical Health
    4.749 ± 2.5455
    9.101 ± 3.0558
        CP QOL-Child: Emotional Wellbeing and Self-esteem
    -1.088 ± 3.5408
    2.118 ± 4.1104
        CP QOL-Child: Access to Services
    1.760 ± 2.4464
    -1.645 ± 3.0746
        CP QOL-Child: Pain and Impact of Disability
    -3.104 ± 2.9696
    -5.691 ± 3.5527
        CP QOL-Child: Family Health
    -3.243 ± 3.8529
    8.427 ± 4.6147
        CP QOL-Child: Total Score
    0.116 ± 1.7158
    2.198 ± 2.0669
        CP QOL-Teen: Feelings about Functioning
    2.513 ± 2.8097
    1.751 ± 4.6322
        CP QOL-Teen: Access to Services
    5.693 ± 2.2325
    -2.011 ± 3.6795
        CP QOL-Teen: General Wellbeing and Participation
    1.684 ± 2.5737
    3.733 ± 4.2435
        CP QOL-Teen: Communication and Physical Health
    0.817 ± 2.6631
    5.282 ± 4.3968
        CP QOL-Teen: School Wellbeing
    -2.839 ± 3.3714
    7.930 ± 5.5701
        CP QOL-Teen: Social Wellbeing
    -4.560 ± 2.9490
    -1.440 ± 4.8597
        CP QOL-Teen: Total Score
    0.548 ± 1.9262
    2.549 ± 3.1742
        CP QOL: Overall Total Score
    0.649 ± 1.2865
    1.717 ± 1.7568
    No statistical analyses for this end point

    Secondary: Change From Baseline In Comfort Questionnaire Outcome To EOT (12-Week Randomised Phase)

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    End point title
    		 Change From Baseline In Comfort Questionnaire Outcome To EOT (12-Week Randomised Phase)
    End point description
    The comfort questionnaire was completed at the same time each day, that is, bedtime in the evening. The caregiver was asked to reflect on the whole day and record the longest number of minutes at any 1 time during which their child was able to sit in comfort for, without moving position. Baseline was defined as the average of Day −7 to Day −1. EOT was the average of the last 7 days of diary data up to the earliest of Day 84, the last dose of IMP and the last day with relevant efficacy data. LS Means were calculated using ANCOVA with baseline score as a covariate and treatment as fixed effect. An increase in time indicates an improvement in condition.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (12-Week Randomised Phase)
    End point values
    		 Sativex (Randomised Phase) Placebo (Randomised Phase)
    Number of subjects analysed
    47
    25
    Units: minutes
        least squares mean (standard error)
    0.611 ± 0.6905
    0.232 ± 0.9271
    No statistical analyses for this end point

    Secondary: Change From Baseline In Children's Depression Inventory (CDI) 2 Score To EOT (12-Week Randomised Phase)

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    End point title
    		 Change From Baseline In Children's Depression Inventory (CDI) 2 Score To EOT (12-Week Randomised Phase)
    End point description
    The CDI 2 contains 12 items, each of which consists of 3 statements (each scored 0-2 [0=best outcome, 2=worst outcome]). For each item, the participant was asked to select the statement that best describes his or her feelings. The assessment addressed a variety of situations, including schools, child guidance clinics, paediatric practices, and child psychiatric settings. If the participant was unable to complete the questionnaire, the questionnaire was left blank. All CDI 2 forms were administered and scored using the Multi-health System Inc. QuikScore™ format. Each QuikScore form included conversion tables, which were used to convert raw scores to T-scores. EOT was defined as Day 84. LS Means were calculated using ANCOVA with baseline score as a covariate and treatment as fixed effect; using LOCF if observations were missing at EOT. A reduction in T-score indicates an improvement in condition.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (12-Week Randomised Phase)
    End point values
    		 Sativex (Randomised Phase) Placebo (Randomised Phase)
    Number of subjects analysed
    47
    25
    Units: T-score
        least squares mean (standard error)
    -6.4 ± 4.723
    -1.2 ± 4.723
    No statistical analyses for this end point

    Secondary: Change From Baseline In Caregiver QOL (SF-36-II) Score To EOT (12-Week Randomised Phase)

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    End point title
    		 Change From Baseline In Caregiver QOL (SF-36-II) Score To EOT (12-Week Randomised Phase)
    End point description
    The SF-36-II is a 36 item questionnaire that measures 8 multi-item dimensions of health: physical functioning (10 items) social functioning (2 items) role limitations due to physical problems (4 items), role limitations due to emotional problems (3 items), mental health (5 items), energy/vitality (4 items), pain (2 items), and general health perception (5 items). There is a further unscaled single item asking respondents about health change over the past year. For each dimension item scores were coded, summed, and transformed on to a scale from 0 (worst possible health state measured by the questionnaire) to 100 (best possible health state). EOT was defined as Day 84. LS Means were calculated using ANCOVA with baseline score as a covariate and treatment as fixed effect; using LOCF if observations were missing at EOT. An increase in score indicates an improvement in condition.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (12-Week Randomised Phase)
    End point values
    		 Sativex (Randomised Phase) Placebo (Randomised Phase)
    Number of subjects analysed
    47
    25
    Units: units on a scale
    least squares mean (standard error)
        Bodily Pain
    1.8 ± 3.14
    -3.7 ± 4.22
        General Health Perception
    -2.5 ± 1.16
    0.6 ± 1.55
        General Mental Health
    2.6 ± 1.95
    2.5 ± 2.62
        Physical Functioning
    -1.2 ± 3.06
    6.5 ± 4.11
        Role Limitations due to Emotional Problems
    2.7 ± 3.08
    12.1 ± 4.13
        Role Limitations due to Physical Health Problems
    0.5 ± 3.78
    11.1 ± 5.07
        Social Functioning
    -0.4 ± 1.72
    -1.8 ± 2.30
        Vitality, Energy or Fatigue
    4.0 ± 1.92
    2.6 ± 2.58
    No statistical analyses for this end point

    Secondary: Caregiver Global Impression Of Change (CGIC) Response On Participants General Functional Capabilities At Last Visit (12-Week Randomised Phase)

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    End point title
    		 Caregiver Global Impression Of Change (CGIC) Response On Participants General Functional Capabilities At Last Visit (12-Week Randomised Phase)
    End point description
    The main caregiver was asked to assess the change in the participant’s condition. At Visit 2 (Baseline) carers were asked to write a brief description of the participant’s general functional abilities. This acted as a memory aid that the carer could refer to when answering the CGIC question at later time points in the trial. The caregiver was asked, ”How have the participant’s general functional abilities changed since Visit 2?” (Baseline). The question was rated on a 7-point scale: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The number of participants for each marker is presented.
    End point type
    Secondary
    End point timeframe
    Last Visit (12-Week Randomised Phase)
    End point values
    		 Sativex (Randomised Phase) Placebo (Randomised Phase)
    Number of subjects analysed
    47
    25
    Units: participants
    number (not applicable)
        Very Much Better
    2
    1
        Much Better
    12
    8
        Minimally Better
    9
    8
        No Change
    17
    7
        Minimally Worse
    4
    1
        Much Worse
    2
    0
        Very Much Worse
    0
    0
    No statistical analyses for this end point

    Secondary: CGIC Response On Participants Ease Of Transfer At EOT (12-Week Randomised Phase)

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    End point title
    		 CGIC Response On Participants Ease Of Transfer At EOT (12-Week Randomised Phase)
    End point description
    The main caregiver was asked to assess the change in the participant’s condition. At Visit 2 (Baseline) carers were asked to write a brief description of the participant’s ease of transfer. This acted as a memory aid that the carer could refer to when answering the CGIC question at later time points in the trial. The caregiver was asked, "How has the participant’s ease of transfer changed since Visit 2?” (Baseline). The question was rated on a 7-point scale: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The number of participants for each marker is presented. EOT was defined as Day 84.
    End point type
    Secondary
    End point timeframe
    EOT (12-Week Randomised Phase)
    End point values
    		 Sativex (Randomised Phase) Placebo (Randomised Phase)
    Number of subjects analysed
    47
    25
    Units: participants
    number (not applicable)
        Very Much Better
    2
    1
        Much Better
    10
    6
        Minimally Better
    10
    8
        No Change
    19
    8
        Minimally Worse
    3
    1
        Much Worse
    1
    0
        Very Much Worse
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After first dose of IMP through Day 266
    Adverse event reporting additional description
    Any adverse changes in the participant’s medical condition, following completion of the consent form, were recorded on the case report form (CRF) as adverse events (AEs). All AEs that occurred during the trial, whether or not attributed to the IMP, observed by the investigator or reported by the participant were recorded in the CRF.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Sativex (Randomised Phase)
    Reporting group description
    		 Safety Analysis Set: All participants who received at least 1 dose of Sativex during the 12-week Randomised Phase.

    Reporting group title
    Placebo (Randomised Phase)
    Reporting group description
    		 Safety Analysis Set: All participants who received at least 1 dose of placebo during the 12-week Randomised Phase.

    Reporting group title
    Sativex (OLE Phase)
    Reporting group description
    		 Safety Analysis Set: All participants who received at least 1 dose of Sativex during the 24-week OLE Phase.

    Serious adverse events
    		 Sativex (Randomised Phase) Placebo (Randomised Phase) Sativex (OLE Phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 47 (8.51%)
    3 / 25 (12.00%)
    19 / 67 (28.36%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Body temperature fluctuation
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Shunt malfunction
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 25 (4.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 25 (0.00%)
    5 / 67 (7.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dystonia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 25 (4.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Unresponsive to stimuli
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site erythema
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site swelling
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug interaction
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retching
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 25 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    4 / 67 (5.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anger
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Food aversion
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 25 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thinking abnormal
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 25 (4.00%)
    3 / 67 (4.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 25 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sativex (Randomised Phase) Placebo (Randomised Phase) Sativex (OLE Phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 47 (59.57%)
    17 / 25 (68.00%)
    37 / 67 (55.22%)
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 25 (8.00%)
    5 / 67 (7.46%)
         occurrences all number
    6
    3
    9
    Poor quality sleep
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 25 (4.00%)
    1 / 67 (1.49%)
         occurrences all number
    4
    1
    1
    Somnolence
         subjects affected / exposed
    6 / 47 (12.77%)
    2 / 25 (8.00%)
    4 / 67 (5.97%)
         occurrences all number
    6
    4
    5
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 25 (8.00%)
    2 / 67 (2.99%)
         occurrences all number
    3
    3
    2
    Fatigue
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 25 (8.00%)
    2 / 67 (2.99%)
         occurrences all number
    3
    2
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 25 (12.00%)
    5 / 67 (7.46%)
         occurrences all number
    1
    7
    5
    Diarrhoea
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 25 (8.00%)
    5 / 67 (7.46%)
         occurrences all number
    3
    3
    6
    Oral pain
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 25 (8.00%)
    1 / 67 (1.49%)
         occurrences all number
    1
    2
    1
    Retching
         subjects affected / exposed
    5 / 47 (10.64%)
    0 / 25 (0.00%)
    3 / 67 (4.48%)
         occurrences all number
    6
    0
    4
    Vomiting
         subjects affected / exposed
    6 / 47 (12.77%)
    4 / 25 (16.00%)
    6 / 67 (8.96%)
         occurrences all number
    7
    5
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 25 (8.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    2
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    4 / 47 (8.51%)
    3 / 25 (12.00%)
    2 / 67 (2.99%)
         occurrences all number
    5
    3
    3
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 47 (8.51%)
    2 / 25 (8.00%)
    6 / 67 (8.96%)
         occurrences all number
    5
    3
    7
    Nasopharyngitis
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 25 (4.00%)
    3 / 67 (4.48%)
         occurrences all number
    4
    3
    3
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 47 (8.51%)
    3 / 25 (12.00%)
    11 / 67 (16.42%)
         occurrences all number
    6
    3
    13
    Viral infection
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 25 (8.00%)
    1 / 67 (1.49%)
         occurrences all number
    2
    2
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 25 (4.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    1
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2015
    - A change in an inclusion no longer requires participants to currently be on spasticity therapy as paediatric participants are less likely than adults to continue on medications that are not sufficiently alleviating their symptoms or if side effects occur. The protocol amendment now required participants to have received inadequate efficacy and/or experienced unacceptable side effects from previous or current treatment with at least one of the following medications for spasticity: Baclofen, diazepam (or another benzodiazepine), dantrolene, tizanidine, gabapentin and trihexyphenidyl. - A parental/legal representative can withdraw participant assent/consent. -Before any open-label procedures are performed, the Investigator must reiterate the known adverse reactions to Sativex and ensure participants and parents/legal guardians are fully informed of the trial requirements. The signed informed consent/assent forms can be referred to for this. Participants who decline will receive a follow up telephone call 14 days after the end of treatment to check for AEs and concomitant medication changes. - If a participant does not possess adequate understanding, assent will be taken along with parental/legal representative consent. The investigator should also give consideration to a child's wishes not to participate, or wishes to withdraw at any time during the trial regardless of their level of understanding and regardless of parental/legal representative consent.

    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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