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    Clinical Trial Results:
    A double-blind, randomized, placebo-controlled study to investigate the efficacy and safety of cannabidiol (GWP42003-P, CBD) as add-on therapy in patients with tuberous sclerosis complex who experience inadequately-controlled seizures

    Summary
    EudraCT number
    		 2015-002154-12
    Trial protocol
    		 ES   GB   PL   NL  
    Global end of trial date
    11 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Dec 2021
    First version publication date
    26 Dec 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GWEP1521 Open-Label Extension
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02544750
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 GWEP1521 - Open Label Extension: NCT02544750, GWEP1521 - Double Blind Phase: NCT02544763
    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 Switchboard, GW Research Ltd, 0044 1223266800, info@gwpharm.com
    Scientific contact
    GW Research Ltd Switchboard, GW Research Ltd, 0044 1223266800, info@gwpharm.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001964-PIP01-16
    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
    26 Aug 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Double-Blinded Phase (DBP): To evaluate the efficacy of GWP42003-P as add-on therapy in reducing the frequency of seizures when compared with placebo in subjects with Tuberous Sclerosis Complex (TSC). Open-label Extension (OLE): To evaluate via the adverse events (AE) profile the long term safety and tolerability of GWP42003-P as add-on therapy in children and adults with TSC who experience inadequately-controlled seizures.
    Protection of trial subjects
    This study was conducted in accordance with International Council on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Apr 2016
    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
    Netherlands: 9
    Country: Number of subjects enrolled
    Poland: 61
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Australia: 24
    Country: Number of subjects enrolled
    United States: 112
    Worldwide total number of subjects
    224
    EEA total number of subjects
    81
    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)
    10
    Children (2-11 years)
    108
    Adolescents (12-17 years)
    48
    Adults (18-64 years)
    58
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 255 subjects were screened; of these 31 were screen failures. A total of 224 subjects were randomized to double-blind treatment. A total of 199 subjects from the DBP were enrolled in the OLE study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DBP: GWP42003-P 25 mg/kg/Day
    Arm description
    		 Subjects were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) orally twice daily (morning and evening administration). Subjects completed a 4-week dose-escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GWP42003-P
    Investigational medicinal product code
    Other name
    Cannabidiol, CBD
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    GWP42003-P was presented as an oral solution containing 100 mg/milliliter (mL) cannabidiol (CBD) dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener and strawberry flavoring.

    Arm title
    		 DBP: GWP42003-P 50 mg/kg/Day
    Arm description
    		 Subjects were randomized to receive GWP42003-P 50 mg/kg/day orally twice daily (morning and evening administration). Subjects completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GWP42003-P
    Investigational medicinal product code
    Other name
    Cannabidiol, CBD
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    GWP42003-P was presented an oral solution containing 100 mg/mL cannabidiol dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener and strawberry flavoring.

    Arm title
    		 DBP: Placebo
    Arm description
    		 Subjects were randomized to receive placebo matched to GWP42003-P orally twice daily (morning and evening administration) for 16 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo solution dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener and strawberry flavoring.

    Number of subjects in period 1
    		DBP: GWP42003-P 25 mg/kg/Day DBP: GWP42003-P 50 mg/kg/Day DBP: Placebo
    Started
    75
    73
    76
    Completed
    65
    61
    75
    Not completed
    10
    12
    1
         Withdrawn by parent/guardian
    1
    1
    1
         Physician decision
    -
    1
    -
         Adverse event, non-fatal
    8
    8
    -
         Met withdrawal criteria
    -
    2
    -
         Difficulties taking IMP
    1
    -
    -
    Period 2
    Period 2 title
    Open Label Phase (OLE)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE)
    Arm description
    		 Subjects who completed the DBP entered a 2-week blinded transition prior to the OLE. During the transition, open-label IMP was titrated up to 25 mg/kg/day whilst blinded IMP was simultaneously tapered down to zero to accommodate those subjects who had been randomized to placebo during the double-blind phase of the study. Transition from the DBP to the OLE were as follows: Subjects receiving placebo during the DBP were titrated up to receive 25 mg/kg/day in OLE phase, subjects receiving 25 mg/kg/day of GWP42003-P during the DBP continued to receive 25 mg/kg/day in OLE phase, subjects receiving 50 mg/kg/day of GWP42003-P during the DBP were tapered (10% per day for 5 days) to receive 25 mg/kg/day of GWP42003-P during OLE. All subjects completed the transition and entered the OLE taking 25 mg/kg/day GWP42003-P.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GWP42003-P
    Investigational medicinal product code
    Other name
    Cannabidiol, CBD
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    GWP42003-P was presented an oral solution containing 100 mg/milliliter (mL) cannabidiol (CBD) dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener and strawberry flavoring.

    Arm title
    		 OLE: Placebo (DBP) then GWP42003-P (OLE)
    Arm description
    		 Subjects who completed the DBP entered a 2-week blinded transition prior to the OLE. During the transition, open-label IMP was titrated up to 25 mg/kg/day whilst blinded IMP was simultaneously tapered down to zero to accommodate those subjects who had been randomized to placebo during the double-blind phase of the study. Transition from the DBP to the OLE were as follows: Subjects receiving placebo during the DBP were titrated up to receive 25 mg/kg/day in OLE phase, subjects receiving 25 mg/kg/day of GWP42003-P during the DBP continued to receive 25 mg/kg/day in OLE phase, subjects receiving 50 mg/kg/day of GWP42003-P during the DBP were tapered (10% per day for 5 days) to receive 25 mg/kg/day of GWP42003-P during OLE. All subjects completed the transition and entered the OLE taking 25 mg/kg/day GWP42003-P.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo then GWP42003-P
    Investigational medicinal product code
    Other name
    Cannabidiol, CBD
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    DBP: Placebo oral solution. OLE: GWP42003-P was presented an oral solution containing 100 mg/mL CBD dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener and strawberry flavoring.

    Number of subjects in period 2 [1]
    		OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Started
    124
    75
    Completed
    22
    12
    Not completed
    102
    63
         Transition To Commercial Product
    1
    -
         Physician decision
    3
    1
         Consent withdrawn by subject
    10
    4
         Adverse event, non-fatal
    8
    10
         Other
    69
    39
         Met withdrawal criteria
    2
    2
         Withdrawal by Parent/Guardian
    8
    7
         Lost to follow-up
    1
    -
    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: Only 199 subjects were transitioned from the DBP to OLE phase. Two subjects did not enter the transition period of the OLE phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DBP: GWP42003-P 25 mg/kg/Day
    Reporting group description
    		 Subjects were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) orally twice daily (morning and evening administration). Subjects completed a 4-week dose-escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.

    Reporting group title
    DBP: GWP42003-P 50 mg/kg/Day
    Reporting group description
    		 Subjects were randomized to receive GWP42003-P 50 mg/kg/day orally twice daily (morning and evening administration). Subjects completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.

    Reporting group title
    DBP: Placebo
    Reporting group description
    		 Subjects were randomized to receive placebo matched to GWP42003-P orally twice daily (morning and evening administration) for 16 weeks.

    Reporting group values
    		 DBP: GWP42003-P 25 mg/kg/Day DBP: GWP42003-P 50 mg/kg/Day DBP: Placebo Total
    Number of subjects
    		 75 73 76 224
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.112 ± 10.8131 12.779 ± 8.5532 13.794 ± 10.6143 -
    Gender categorical
    Units: Subjects
        Female
    		 32 30 31 93
        Male
    		 43 43 45 131
    Number of Tuberous Sclerosis Complex (TSC)-Associated Seizures
    TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that are countable. Intent-to-Treat (ITT) Analysis Set: all subjects who were randomized and dosed with IMP in the trial and had post-Baseline efficacy data. Subject data were analyzed according to the treatment group to which they were randomized.
    Units: Seizures
        median (inter-quartile range (Q1-Q3))
    		 56.0 (21.24 to 101.0) 61.0 (36.00 to 117.0) 54.05 (26.42 to 102.0) -
    Number of Total Seizures
    Total seizures included all seizure types combined. The Baseline Period included all data prior to Day 1. ITT Analysis Set.
    Units: Seizures
        median (inter-quartile range (Q1-Q3))
    		 56.0 (22.58 to 101.0) 70.0 (38.0 to 130.0) 56.48 (27.50 to 138.10) -

    End points

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    End points reporting groups
    Reporting group title
    DBP: GWP42003-P 25 mg/kg/Day
    Reporting group description
    		 Subjects were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) orally twice daily (morning and evening administration). Subjects completed a 4-week dose-escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.

    Reporting group title
    DBP: GWP42003-P 50 mg/kg/Day
    Reporting group description
    		 Subjects were randomized to receive GWP42003-P 50 mg/kg/day orally twice daily (morning and evening administration). Subjects completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.

    Reporting group title
    DBP: Placebo
    Reporting group description
    		 Subjects were randomized to receive placebo matched to GWP42003-P orally twice daily (morning and evening administration) for 16 weeks.
    Reporting group title
    OLE: GWP42003-P (DBP) then GWP42003-P (OLE)
    Reporting group description
    		 Subjects who completed the DBP entered a 2-week blinded transition prior to the OLE. During the transition, open-label IMP was titrated up to 25 mg/kg/day whilst blinded IMP was simultaneously tapered down to zero to accommodate those subjects who had been randomized to placebo during the double-blind phase of the study. Transition from the DBP to the OLE were as follows: Subjects receiving placebo during the DBP were titrated up to receive 25 mg/kg/day in OLE phase, subjects receiving 25 mg/kg/day of GWP42003-P during the DBP continued to receive 25 mg/kg/day in OLE phase, subjects receiving 50 mg/kg/day of GWP42003-P during the DBP were tapered (10% per day for 5 days) to receive 25 mg/kg/day of GWP42003-P during OLE. All subjects completed the transition and entered the OLE taking 25 mg/kg/day GWP42003-P.

    Reporting group title
    OLE: Placebo (DBP) then GWP42003-P (OLE)
    Reporting group description
    		 Subjects who completed the DBP entered a 2-week blinded transition prior to the OLE. During the transition, open-label IMP was titrated up to 25 mg/kg/day whilst blinded IMP was simultaneously tapered down to zero to accommodate those subjects who had been randomized to placebo during the double-blind phase of the study. Transition from the DBP to the OLE were as follows: Subjects receiving placebo during the DBP were titrated up to receive 25 mg/kg/day in OLE phase, subjects receiving 25 mg/kg/day of GWP42003-P during the DBP continued to receive 25 mg/kg/day in OLE phase, subjects receiving 50 mg/kg/day of GWP42003-P during the DBP were tapered (10% per day for 5 days) to receive 25 mg/kg/day of GWP42003-P during OLE. All subjects completed the transition and entered the OLE taking 25 mg/kg/day GWP42003-P.

    Primary: DBP: Percent Change From Baseline in the Number of Tuberous Sclerosis Complex (TSC)-Associated Seizures During the DBP Treatment Period (Maintenance and Titration)

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    End point title
    		 DBP: Percent Change From Baseline in the Number of Tuberous Sclerosis Complex (TSC)-Associated Seizures During the DBP Treatment Period (Maintenance and Titration)
    End point description
    TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that are countable. Percent change from Baseline was calculated as the (post-Baseline value minus the Baseline value) divided by the Baseline value x 100. Intent-to-Treat (ITT) Analysis Set: all subjects who were randomized and dosed with investigational medicinal product (IMP) in the trial and had post-Baseline efficacy data. Data were analyzed according to the treatment group to which subjects were randomized.
    End point type
    Primary
    End point timeframe
    DBP: Baseline; up to Week 16
    End point values
    		 DBP: GWP42003-P 25 mg/kg/Day DBP: GWP42003-P 50 mg/kg/Day DBP: Placebo
    Number of subjects analysed
    75
    73
    76
    Units: Percent change
        median (inter-quartile range (Q1-Q3))
    -43.36 (-67.8 to -13.6)
    -36.55 (-67.0 to -5.5)
    -20.08 (-47.1 to 3.1)
    Statistical analysis title
    		 GWP42003-P 25 mg/kg/Day vs Placebo
    Comparison groups
    DBP: GWP42003-P 25 mg/kg/Day v DBP: Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0009
    Method
    		 Mixed model analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    0.699
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.567
         upper limit
    		 0.861
    Statistical analysis title
    		 GWP42003-P 50 mg/kg/Day vs Placebo
    Comparison groups
    DBP: GWP42003-P 50 mg/kg/Day v DBP: Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0018
    Method
    		 Mixed model analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    0.715
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 0.881

    Primary: OLE: Number of Subjects With Any Treatment-emergent Adverse Events (TEAE)

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    End point title
    		 OLE: Number of Subjects With Any Treatment-emergent Adverse Events (TEAE) [1]
    End point description
    An AE was defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which occurred following screening and at any point up to the post-treatment safety follow-up visit, which may or may not be related to the IMP. Analysis was performed in OLE Safety Analysis Set population defined as all subjects who received at least 1 dose of IMP in the OLE phase of the study.
    End point type
    Primary
    End point timeframe
    OLE: up to approximately 4 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned for this endpoint.
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
    117
    75
    No statistical analyses for this end point

    Primary: OLE: Number of Subjects With Related TEAEs, Serious AEs, Discontinuations and Deaths

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    End point title
    		 OLE: Number of Subjects With Related TEAEs, Serious AEs, Discontinuations and Deaths [2]
    End point description
    An AE was defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which occurred following screening and at any point up to the post-treatment safety follow-up visit, which may or may not be related to the IMP. An AE was considered serious if it: (1) was fatal; (2) was life-threatening; (3) required inpatient hospitalization or prolonged existing hospitalization; (4) was persistently or significantly disabling or incapacitating; (5) was a congenital anomaly/birth defect; or (6) was a medically significant event that, based upon appropriate medical judgment, may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed above. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Primary
    End point timeframe
    OLE: up to approximately 4 years
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned for this endpoint.
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
        Treatment-Related TEAEs
    80
    60
        TEAEs Leading to Permanent Discontinuation
    11
    7
        Serious TEAEs
    38
    18
        Deaths
    1
    0
    No statistical analyses for this end point

    Primary: OLE: Number of Subjects With TEAEs by Severity

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    End point title
    		 OLE: Number of Subjects With TEAEs by Severity [3]
    End point description
    An AE was defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which occurred following screening and at any point up to the post-treatment safety follow-up visit, which may or may not be related to the IMP. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Primary
    End point timeframe
    OLE: up to approximately 4 years
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned for this endpoint.
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
        Mild
    35
    16
        Moderate
    63
    48
        Severe
    19
    11
    No statistical analyses for this end point

    Secondary: DBP: Number of Subjects Considered Treatment Responders During the DBP Treatment Period (Maintenance and Titration)

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    End point title
    		 DBP: Number of Subjects Considered Treatment Responders During the DBP Treatment Period (Maintenance and Titration)
    End point description
    Treatment responders were defined as those subjects with a ≥ 50% reduction in TSC-associated seizure frequency. TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that were countable. Subjects who withdrew from the trial during the treatment period were considered non-responders. ITT Analysis Set population.
    End point type
    Secondary
    End point timeframe
    DBP: Baseline; up to Week 16
    End point values
    		 DBP: GWP42003-P 25 mg/kg/Day DBP: GWP42003-P 50 mg/kg/Day DBP: Placebo
    Number of subjects analysed
    75
    73
    76
    Units: Subjects
        Responders
    27
    29
    17
        Non-responders
    48
    44
    59
    Statistical analysis title
    		 GWP42003-P 25 mg/kg/Day, Placebo
    Comparison groups
    DBP: GWP42003-P 25 mg/kg/Day v DBP: Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0692 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 4
    Notes
    [4] - The p-value was calculated from a Cochran-Mantel-Haenszel test stratified by age group (1-6, 7-11, 12-17 and 18-65 years).
    Statistical analysis title
    		 GWP42003-P 50 mg/kg/Day, Placebo
    Comparison groups
    DBP: Placebo v DBP: GWP42003-P 50 mg/kg/Day
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0245 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.12
         upper limit
    		 4.67
    Notes
    [5] - The p-value was calculated from a Cochran-Mantel-Haenszel test stratified by age group (1-6, 7-11, 12-17 and 18-65 years).

    Secondary: DBP: Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Subject Global Impression of Change (PGIC) Score

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    End point title
    		 DBP: Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Subject Global Impression of Change (PGIC) Score
    End point description
    Combined caregiver and subject summary uses either caregiver or subject version if only one version was completed, or caregiver version if both caregiver and subject versions were completed. CGIC comprised following question, to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): "Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment)." SGIC comprised the following question, to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): "Since you started treatment, please assess the status of your overall condition (comparing your condition now to your condition before treatment)." ITT Analysis Set. Here ''n" signifies subjects analysed in each arm.
    End point type
    Secondary
    End point timeframe
    DBP: Baseline; up to Week 16
    End point values
    		 DBP: GWP42003-P 25 mg/kg/Day DBP: GWP42003-P 50 mg/kg/Day DBP: Placebo
    Number of subjects analysed
    75
    73
    76
    Units: score on a scale
    arithmetic mean (standard deviation)
        Caregiver (n=66,66,72)
    3.0 ± 1.34
    3.1 ± 1.40
    3.5 ± 0.93
        Combined Caregiver and Subject (n=70,69,66)
    3.0 ± 1.35
    3.2 ± 1.45
    3.5 ± 0.96
        Subject (n=6,4,4)
    3.3 ± 1.51
    4.5 ± 1.73
    2.8 ± 1.26
    Statistical analysis title
    		 GWP42003-P 25 mg/kg/Day, Placebo
    Comparison groups
    DBP: GWP42003-P 25 mg/kg/Day v DBP: Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0074 [6]
    Method
    		 nominal
    Parameter type
    		 Ordinal logistic regression
    Point estimate
    2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.24
         upper limit
    		 4.07
    Notes
    [6] - The global impression of change was analyzed using an ordinal logistic regression model with treatment group as a fixed factor.
    Statistical analysis title
    		 GWP42003-P 50 mg/kg/Day, Placebo
    Comparison groups
    DBP: Placebo v DBP: GWP42003-P 50 mg/kg/Day
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.058 [7]
    Method
    		 nominal
    Parameter type
    		 Ordinal logistic regression
    Point estimate
    1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 3.2
    Notes
    [7] - The global impression of change was analyzed using an ordinal logistic regression model with treatment group as a fixed factor.

    Secondary: DBP: Percent Change From Baseline in Total Seizures During the Treatment Period (Maintenance and Titration)

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    End point title
    		 DBP: Percent Change From Baseline in Total Seizures During the Treatment Period (Maintenance and Titration)
    End point description
    Total seizures included all seizure types combined. Percent change from Baseline was calculated as the (post-Baseline value minus the Baseline value) divided by the Baseline value x 100. ITT Analysis Set population.
    End point type
    Secondary
    End point timeframe
    DBP: Baseline; up to Week 16
    End point values
    		 DBP: GWP42003-P 25 mg/kg/Day DBP: GWP42003-P 50 mg/kg/Day DBP: Placebo
    Number of subjects analysed
    75
    73
    76
    Units: Percent change
        arithmetic mean (standard deviation)
    -34.71 ± 46.150
    -35.14 ± 42.530
    -19.63 ± 35.137
    Statistical analysis title
    		 GWP42003-P 25 mg/kg/Day, Placebo
    Comparison groups
    DBP: GWP42003-P 25 mg/kg/Day v DBP: Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0013
    Method
    		 Mixed model analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    0.709
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.576
         upper limit
    		 0.873
    Statistical analysis title
    		 GWP42003-P 50 mg/kg/Day, Placebo
    Comparison groups
    DBP: Placebo v DBP: GWP42003-P 50 mg/kg/Day
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0018
    Method
    		 Mixed model analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    0.716
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.582
         upper limit
    		 0.882

    Secondary: DBP: Number of Subjects With Any Severe Treatment-emergent Adverse Events (TEAE)

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    End point title
    		 DBP: Number of Subjects With Any Severe Treatment-emergent Adverse Events (TEAE)
    End point description
    A TEAE was defined as an AE with a start date on or after the first dose of IMP during the DBP up to and including the date of first dose of the OLE Phase (OLE Day 1). Safety Analysis Set: all subjects randomized to treatment who received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    DBP: Up to approximately Week 22
    End point values
    		 DBP: GWP42003-P 25 mg/kg/Day DBP: GWP42003-P 50 mg/kg/Day DBP: Placebo
    Number of subjects analysed
    75
    73
    76
    Units: Subjects
    7
    9
    1
    No statistical analyses for this end point

    Secondary: OLE: Percent Change from Baseline in the TSC-associated Seizures During the OLE Treatment Period

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    End point title
    		 OLE: Percent Change from Baseline in the TSC-associated Seizures During the OLE Treatment Period
    End point description
    TSC-associated seizures include: focal motor seizures without impairment of consciousness or awareness; focal seizures with impairment of consciousness or awareness; focal seizures evolving to bilateral generalized convulsive seizures and tonic-clonic, tonic, clonic or atonic seizures. OLE last 12 weeks was defined as all available data from 12 weeks prior to the earliest of the OLE completion date or the last call to IVRS. Seizure scores were averaged per 28 days. Percent change from Baseline was calculated as the (post-Baseline value minus the Baseline value) divided by the Baseline value x 100. A negative change from baseline indicates improvement. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Secondary
    End point timeframe
    OLE: Baseline, OLE Treatment Period (up to 209 weeks), Last 12 weeks of study treatment
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Frequency of Seizure
    median (inter-quartile range (Q1-Q3))
        Last 12 Weeks
    -62.95 (-95.26 to -12.44)
    -58.53 (-82.01 to -9.58)
        OLE Treatment Period
    -55.66 (-86.47 to -12.33)
    -46.76 (-78.17 to -15.69)
    No statistical analyses for this end point

    Secondary: OLE: Number of Subjects Considered Treatment Responders During the OLE Treatment Period

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    End point title
    		 OLE: Number of Subjects Considered Treatment Responders During the OLE Treatment Period
    End point description
    Treatment responders were defined as those subjects with a ≥ 50% reduction from baseline in TSC-associated seizure frequency, during the treatment period, for subjects who had not withdrawn from the trial during the treatment period. TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that were countable. Subjects who withdrew from the trial during the treatment period were considered non-responders. OLE Safety Analysis Set population.
    End point type
    Secondary
    End point timeframe
    OLE: Baseline; up to 209 weeks
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
        ≥ 25% reduction: Yes
    86
    53
        ≥ 25% reduction: No
    38
    22
        ≥ 50% reduction: Yes
    70
    36
        ≥ 50% reduction: No
    54
    39
        ≥ 75% reduction: Yes
    43
    22
        ≥ 75% reduction: No
    81
    53
        100% reduction: Yes
    5
    0
        100% reduction: No
    119
    75
    No statistical analyses for this end point

    Secondary: OLE: Number of Subjects Experiencing a Worsening, no change, or improvements in TSC-associated seizure frequency

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    End point title
    		 OLE: Number of Subjects Experiencing a Worsening, no change, or improvements in TSC-associated seizure frequency
    End point description
    Treatment responders were defined as those subjects with a ≥ 50% reduction from baseline in TSC-associated seizure frequency, during the treatment period, for subjects who had not withdrawn from the trial during the treatment period. Worsening was categorized as experienced a > 25% worsening; experienced −25% to +25% no change; experienced 25% to 50% improvement; experienced 50% to 75% improvement; and experienced > 75% improvement. TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that were countable. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Secondary
    End point timeframe
    OLE treatment period (Approx 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
        > 25% worsening
    8
    7
        −25 to +25% no change
    24
    15
        25 to 50% improvement
    16
    17
        50 to 75% improvement
    27
    14
        > 75% improvement
    43
    22
    No statistical analyses for this end point

    Secondary: OLE: Percent Change from Baseline in Total Seizure Frequency

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    End point title
    		 OLE: Percent Change from Baseline in Total Seizure Frequency
    End point description
    Total seizures include all seizure types i.e. combination of TSC-associated and other seizures. Percent change from Baseline was calculated as the (post-Baseline value minus the Baseline value) divided by the Baseline value x 100. A negative change from baseline indicates improvement. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Secondary
    End point timeframe
    OLE: Baseline; OLE treatment period (up to 209 weeks)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Percentage change
        median (inter-quartile range (Q1-Q3))
    -55.18 (-84.21 to -11.95)
    -46.76 (-76.22 to -19.77)
    No statistical analyses for this end point

    Secondary: OLE: Change from Baseline in Number of TSC-associated Seizure-Free Days

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    End point title
    		 OLE: Change from Baseline in Number of TSC-associated Seizure-Free Days
    End point description
    Seizure information was collected daily during the double-blind phase but weekly during the OLE phase. Therefore, the change in number of TSC-associated-seizure-free days could not be calculated for the OLE phase.
    End point type
    Secondary
    End point timeframe
    OLE: Baseline; OLE treatment period (up to approx 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: Days
        number (not applicable)
    Notes
    [8] - Change in number of TSC-associated-seizure-free days could not be calculated.
    [9] - Change in number of TSC-associated-seizure-free days could not be calculated.
    No statistical analyses for this end point

    Secondary: OLE: Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score

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    End point title
    		 OLE: Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score
    End point description
    The combined caregiver and participant summary uses either the caregiver or participant version if only one version was completed, or the caregiver version if both caregiver and participant versions were completed. The CGIC comprised the following question, to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): "Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment)." The SGIC comprised the following question, to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): "Since you started treatment, please assess the status of your overall condition (comparing your condition now to your condition before treatment)." Analysis was performed in OLE Safety Analysis Set.
    End point type
    Secondary
    End point timeframe
    OLE: Baseline; OLE End of Treatment (up to 209 weeks)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: score on a scale
    arithmetic mean (standard deviation)
        Caregiver (n=39,25)
    3.2 ± 1.58
    3.4 ± 1.12
        Subject (n=3,3)
    4.0 ± 0.0
    2.7 ± 1.53
        Combined Caregiver and Subject (n=40,28)
    3.2 ± 1.56
    3.3 ± 1.16
    No statistical analyses for this end point

    Secondary: OLE: Change from Baseline in Physician Global Impression of Change (PGIC) Score

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    End point title
    		 OLE: Change from Baseline in Physician Global Impression of Change (PGIC) Score
    End point description
    The PGIC comprised the following question, rated on a seven-point scale: “Very Much Improved”; “Much Improved”; “Slightly Improved”; “No Change”; “Slightly Worse”; “Much Worse”; “Very Much Worse”, which assess the change in the subject's general functional abilities. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed in OLE Safety Analysis Set population. Here 'N', signifies the number of subjects evaluable at the specified time point for this outcome measure.
    End point type
    Secondary
    End point timeframe
    OLE: Baseline; OLE Last Visit (up to approx 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    118
    72
    Units: Score on a scale
        arithmetic mean (standard deviation)
    2.8 ± 1.22
    3.0 ± 1.19
    No statistical analyses for this end point

    Secondary: OLE: Change from Baseline in Quality of Life in Childhood Epilepsy (QOLCE) Score

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    End point title
    		 OLE: Change from Baseline in Quality of Life in Childhood Epilepsy (QOLCE) Score
    End point description
    Quality of life (QOL) was measured using the QOLCE questionnaire which has good construct validity, internal consistency, test-retest reliability, and sensitivity to epilepsy severity. Each subscale consists of a number of questions in addition to a ‘distress’ item. The raw score for each question and the ‘distress’ item was converted to a 0-100 score. A final subscale weighted score was calculated where higher scores reflect better quality of life; lower ones, worse quality of life. The overall QOL score was calculated by taking the mean of the subscale scores. Baseline was defined as Day 1 of the DBP. Analysis was performed in OLE Safety Analysis Set population. Here 'N', signifies the number of subjects evaluable at the specified time point for this outcome measure.
    End point type
    Secondary
    End point timeframe
    OLE: Baseline, OLE treatment period (up to approx 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    20
    14
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -3.4 ± 13.90
    -5.6 ± 13.03
    No statistical analyses for this end point

    Secondary: OLE: Change from Baseline in Quality of Life in Epilepsy (QOLIE-31-P) Score

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    End point title
    		 OLE: Change from Baseline in Quality of Life in Epilepsy (QOLIE-31-P) Score
    End point description
    Quality of life (QOL) was measured using the QOLIE-31-P questionnaire. Each subscale consists of a number of questions in addition to a ‘distress’ item. The raw score for each question and the ‘distress’ item was converted to a 0-100 score. A final subscale weighted score was calculated where higher scores reflect better quality of life; lower ones, worse quality of life. The overall quality of life score was calculated by taking the mean of the subscale scores. The total score was calculated as: (Sum of all subscale weighted scores ÷ Sum of all subscale ‘distress’ item converted scores) × 100. Baseline was defined as Day 1 of the double-blind phase. Analysis was performed in OLE Safety Analysis Set population. Here 'N', signifies the number of subjects evaluable at the specified time point for this outcome measure.
    End point type
    Secondary
    End point timeframe
    OLE: Baseline; OLE End of Treatment (up to approx 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    5
    4
    Units: score on a scale
        arithmetic mean (standard deviation)
    -14.8 ± 20.60
    -1.8 ± 13.12
    No statistical analyses for this end point

    Secondary: OLE: Change from Baseline in Other Seizure Frequency

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    End point title
    		 OLE: Change from Baseline in Other Seizure Frequency
    End point description
    Other seizures include absence, myoclonic, partial sensory seizures, and infantile or epileptic spasms. Baseline period includes all data prior to Day 1 of the double-blind phase. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A negative change from baseline indicates improvement. Analysis was performed in OLE Safety Analysis Set population. Here 'N', signifies the number of subjects evaluable at the specified time point for this outcome measure.
    End point type
    Secondary
    End point timeframe
    OLE: Baseline; OLE treatment period (Approx 209 weeks)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    30
    15
    Units: Percentage change
        median (inter-quartile range (Q1-Q3))
    -84.43 (-100.0 to -59.61)
    -99.0 (-100.0 to -47.11)
    No statistical analyses for this end point

    Secondary: OLE: Change from Baseline in Serum Insulin-like Growth Factor-1 (IGF-1) levels

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    End point title
    		 OLE: Change from Baseline in Serum Insulin-like Growth Factor-1 (IGF-1) levels
    End point description
    Serum IGF-1 concentrations were determined. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed in OLE Safety Analysis Set population. Here 'N', signifies the number of subjects evaluable at the specified time point for this outcome measure.
    End point type
    Secondary
    End point timeframe
    OLE: Baseline; OLE End of Treatment (up to approximately 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    30
    17
    Units: nanomole(s)/litre
        arithmetic mean (standard deviation)
    -0.54 ± 9.069
    -1.0 ± 9.057
    No statistical analyses for this end point

    Secondary: OLE: Number of Subjects with Indicated Tanner stages

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    End point title
    		 OLE: Number of Subjects with Indicated Tanner stages
    End point description
    For all adolescent subjects (10-17 years of age), the onset and progression of pubertal changes were assessed by Tanner staging. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Secondary
    End point timeframe
    OLE treatment period (up to 209 weeks)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
        Tanner Stage 1
    0
    2
        Tanner Stage 2
    7
    1
        Tanner Stage 3
    3
    1
        Tanner Stage 4
    2
    2
        Tanner Stage 5
    4
    2
    No statistical analyses for this end point

    Secondary: OLE: Number of Subjects with Suicidal Ideation and Behavior

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    End point title
    		 OLE: Number of Subjects with Suicidal Ideation and Behavior
    End point description
    Suicidality was assessed either by using the C-SSRS/Children’s C-SSRS or, in subjects with profound cognitive impairment, by the investigator’s clinical judgment. Common items from the Adult and Child C-SSRS questionnaires were combined for this summary. Suicidal Ideation: Wish to be dead; Non-specific active suicidal thoughts; Active suicidal ideation with any methods (not plan) without intent to act; Active suicidal ideation with some intent to act, without specific plan; Active suicidal ideation with specific plan and intent. Suicidal Behavior: Actual attempt; Interrupted attempt; Aborted attempt; Preparatory acts or behavior; Suicidal behavior; Completed suicide. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Secondary
    End point timeframe
    OLE treatment period (up to approx 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
        Suicidal Ideation
    0
    0
        Suicidal Behavior
    0
    0
    No statistical analyses for this end point

    Secondary: OLE: Number of Subjects with Clinically Significant Laboratory Abnormalities

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    End point title
    		 OLE: Number of Subjects with Clinically Significant Laboratory Abnormalities
    End point description
    Blood and urine samples were collected at the scheduled visits for hematology, biochemistry, and urinalysis. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Secondary
    End point timeframe
    OLE treatment period (up to approx 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Secondary: OLE: Number of Subjects Who Reported Hospitalizations

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    End point title
    		 OLE: Number of Subjects Who Reported Hospitalizations
    End point description
    The number of inpatient hospitalizations due to epilepsy were reported. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Secondary
    End point timeframe
    OLE treatment period (Approx 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
    28
    10
    No statistical analyses for this end point

    Secondary: OLE: Number of Subjects with Clinically Significant 12-Lead Electrocardiogram (ECG)

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    End point title
    		 OLE: Number of Subjects with Clinically Significant 12-Lead Electrocardiogram (ECG)
    End point description
    12-lead ECG recordings were performed after 5 minutes in supine position. A physician reviewed the ECG and any abnormal findings considered to indicate significant medical history or AEs were recorded appropriately on the CRF. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Secondary
    End point timeframe
    OLE treatment period (up to approx 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Secondary: OLE: Number of Subjects with Drug Abuse Based on Study Medication Use and Behavior Survey

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    End point title
    		 OLE: Number of Subjects with Drug Abuse Based on Study Medication Use and Behavior Survey
    End point description
    All subjects/caregivers were interviewed and a Study Medication Use and Behavior Survey was completed which consisted of 17 questions regarding the use of the IMP. Of the 17 questions, 14 were marked unanimously as ‘never,’ ‘no desire,’ or ‘not at all’ including all those relating to routes of administration and diversion. For the remaining 3 questions, relating to drug dosage, dose impact, withdrawal syndrome, and desired use, the number of responses which were marked as anything other than ‘never,’ ‘no,’ or ‘not at all’. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Secondary
    End point timeframe
    OLE treatment period (Approx 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
        Used more than the maximum daily dose
    0
    2
        Took additional dose to improve relief of seizures
    0
    1
        Took additional dose to treat other symptoms
    0
    1
        Develop new emotional or psychological issues
    3
    1
        Expressed concern over medication use
    8
    5
        Interference with normal activities
    7
    3
        Lead to problems with the police
    1
    0
        Had to be less honest to anybody about drug use
    1
    0
        How often stopped taking study medications
    1
    3
        Sign and symptoms consistent to withdrawal symptom
    1
    1
        Took additional study medication by accident
    0
    1
    No statistical analyses for this end point

    Secondary: OLE: Number of Female Subjects with Abnormal Changes Related to Menstrual Cycle

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    End point title
    		 OLE: Number of Female Subjects with Abnormal Changes Related to Menstrual Cycle
    End point description
    Caregivers of female subjects were asked if the subject was menstruating and details were recorded. Analysis was performed in OLE Safety Analysis Set population. Here, 'N' signifies the number of female subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    OLE treatment period (up to 209 weeks)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    51
    30
    Units: Subjects
        Changes in Menstrual Cycle
    1
    1
        Abnormalities Related to Menstrual Cycle
    1
    0
    No statistical analyses for this end point

    Secondary: OLE: Number of Subjects with Clinically Significant Changes in Indicated Physical Examination Parameters

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    End point title
    		 OLE: Number of Subjects with Clinically Significant Changes in Indicated Physical Examination Parameters
    End point description
    A physical examination was performed at the screening to ensure that the subject was eligible to enter the trial. Physical examinations included height and body weight measurements. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Secondary
    End point timeframe
    OLE treatment period (up to approx 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
        Weight <= -7 %
    6
    4
        Weight >= 7 %
    16
    8
        Height
    0
    0
    No statistical analyses for this end point

    Secondary: OLE: Number of Subjects with Clinically Significant Changes in Indicated Vital Signs

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    End point title
    		 OLE: Number of Subjects with Clinically Significant Changes in Indicated Vital Signs
    End point description
    Vital sign measurements included body temperature, pulse rate, respiration rate, including blood pressure taken in a sitting position at rest for 5 minutes. Analysis was performed in OLE Safety Analysis Set population.
    End point type
    Secondary
    End point timeframe
    OLE treatment period (up to approx 4 years)
    End point values
    		 OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Number of subjects analysed
    124
    75
    Units: Subjects
        Sitting Systolic Blood Pressure < -20 mmHg
    3
    3
        Sitting Systolic Blood Pressure > 20 mmHg
    2
    2
        Sitting Diastolic Blood Pressure < -10 mmHg
    7
    2
        Sitting Diastolic Blood Pressure > 10 mmHg
    8
    9
        Pulse Rate < -10 beats/min
    13
    7
        Pulse Rate > 10 beats/min
    9
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    DBP: From the start of treatment up to Week 22; OLE: From the start of treatment up to 4 years.
    Adverse event reporting additional description
    Safety Analysis Set, comprised of subjects randomized to treatment who received at least 1 dose of IMP. Treatment-emergent adverse events were defined as adverse events with a start date on or after the first dose of IMP throughout the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    DBP: GWP42003-P 25 mg/kg/Day
    Reporting group description
    		 Subjects were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) orally twice daily (morning and evening administration). Subjects completed a 4-week dose-escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.

    Reporting group title
    DBP: GWP42003-P 50 mg/kg/Day
    Reporting group description
    		 Subjects were randomized to receive GWP42003-P 50 mg/kg/day orally twice daily (morning and evening administration). Subjects completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.

    Reporting group title
    DBP: Placebo
    Reporting group description
    		 Subjects were randomized to receive placebo matched to GWP42003-P orally twice daily (morning and evening administration) for 16 weeks.

    Reporting group title
    OLE: GWP42003-P (DBP) then GWP42003-P (OLE)
    Reporting group description
    		 Subjects who completed the DBP entered a 2-week blinded transition prior to the OLE. During the transition, open-label IMP was titrated up to 25 mg/kg/day whilst blinded IMP was simultaneously tapered down to zero to accommodate those subjects who had been randomized to placebo during the double-blind phase of the study. Transition from the DBP to the OLE were as follows: Subjects receiving placebo during the DBP were titrated up to receive 25 mg/kg/day in OLE phase, subjects receiving 25 mg/kg/day of GWP42003-P during the DBP continued to receive 25 mg/kg/day in OLE phase, subjects receiving 50 mg/kg/day of GWP42003-P during the DBP were tapered (10% per day for 5 days) to receive 25 mg/kg/day of GWP42003-P during OLE. All subjects completed the transition and entered the OLE taking 25 mg/kg/day GWP42003-P.

    Reporting group title
    OLE: Placebo (DBP) then GWP42003-P (OLE)
    Reporting group description
    		 Subjects who completed the DBP entered a 2-week blinded transition prior to the OLE. During the transition, open-label IMP was titrated up to 25 mg/kg/day whilst blinded IMP was simultaneously tapered down to zero to accommodate those subjects who had been randomized to placebo during the double-blind phase of the study. Transition from the DBP to the OLE were as follows: Subjects receiving placebo during the DBP were titrated up to receive 25 mg/kg/day in OLE phase, subjects receiving 25 mg/kg/day of GWP42003-P during the DBP continued to receive 25 mg/kg/day in OLE phase, subjects receiving 50 mg/kg/day of GWP42003-P during the DBP were tapered (10% per day for 5 days) to receive 25 mg/kg/day of GWP42003-P during OLE. All subjects completed the transition and entered the OLE taking 25 mg/kg/day GWP42003-P.

    Serious adverse events
    		 DBP: GWP42003-P 25 mg/kg/Day DBP: GWP42003-P 50 mg/kg/Day DBP: Placebo OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 75 (21.33%)
    10 / 73 (13.70%)
    2 / 76 (2.63%)
    38 / 124 (30.65%)
    18 / 75 (24.00%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Kidney angiomyolipoma
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue inflammation
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Type IV hypersensitivity reaction
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Alcohol use
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 124 (1.61%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 75 (2.67%)
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anticonvulsant drug level increased
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 75 (2.67%)
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Astrovirus test positive
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eosinophil count increased
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigation
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus test positive
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sapovirus test positive
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    4 / 124 (3.23%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Change in seizure presentation
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epileptic encephalopathy
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postictal state
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sedation
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    12 / 124 (9.68%)
    4 / 75 (5.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 14
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure cluster
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    9 / 124 (7.26%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    2 / 20
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver injury
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash macular
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Adenoiditis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 124 (1.61%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis astroviral
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective myositis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    5 / 124 (4.03%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    16 / 75 (21.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    4 / 124 (3.23%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fluid intake reduced
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 DBP: GWP42003-P 25 mg/kg/Day DBP: GWP42003-P 50 mg/kg/Day DBP: Placebo OLE: GWP42003-P (DBP) then GWP42003-P (OLE) OLE: Placebo (DBP) then GWP42003-P (OLE)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 75 (88.00%)
    71 / 73 (97.26%)
    71 / 76 (93.42%)
    115 / 124 (92.74%)
    75 / 75 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    0
    0
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 75 (2.67%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    2 / 124 (1.61%)
    0 / 75 (0.00%)
         occurrences all number
    2
    1
    0
    2
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 75 (4.00%)
    4 / 73 (5.48%)
    1 / 76 (1.32%)
    7 / 124 (5.65%)
    10 / 75 (13.33%)
         occurrences all number
    3
    4
    1
    7
    13
    Feeling abnormal
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    0
    0
    3
    Gait disturbance
         subjects affected / exposed
    4 / 75 (5.33%)
    3 / 73 (4.11%)
    2 / 76 (2.63%)
    4 / 124 (3.23%)
    1 / 75 (1.33%)
         occurrences all number
    4
    3
    2
    4
    1
    Pyrexia
         subjects affected / exposed
    14 / 75 (18.67%)
    12 / 73 (16.44%)
    6 / 76 (7.89%)
    32 / 124 (25.81%)
    15 / 75 (20.00%)
         occurrences all number
    23
    14
    6
    66
    27
    Immune system disorders
    Immunisation reaction
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    0
    0
    2
    Seasonal allergy
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    0
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    2 / 124 (1.61%)
    1 / 75 (1.33%)
         occurrences all number
    1
    2
    0
    4
    1
    Cough
         subjects affected / exposed
    8 / 75 (10.67%)
    3 / 73 (4.11%)
    5 / 76 (6.58%)
    12 / 124 (9.68%)
    13 / 75 (17.33%)
         occurrences all number
    8
    3
    5
    26
    14
    Epistaxis
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 73 (1.37%)
    2 / 76 (2.63%)
    2 / 124 (1.61%)
    0 / 75 (0.00%)
         occurrences all number
    1
    1
    2
    3
    0
    Nasal congestion
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    3 / 76 (3.95%)
    7 / 124 (5.65%)
    5 / 75 (6.67%)
         occurrences all number
    0
    0
    3
    8
    5
    Oropharyngeal pain
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 73 (2.74%)
    1 / 76 (1.32%)
    6 / 124 (4.84%)
    5 / 75 (6.67%)
         occurrences all number
    0
    2
    1
    7
    6
    Pulmonary congestion
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 124 (2.42%)
    1 / 75 (1.33%)
         occurrences all number
    0
    0
    0
    3
    1
    Respiration abnormal
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    4 / 124 (3.23%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    0
    6
    0
    Rhinorrhoea
         subjects affected / exposed
    3 / 75 (4.00%)
    3 / 73 (4.11%)
    0 / 76 (0.00%)
    6 / 124 (4.84%)
    4 / 75 (5.33%)
         occurrences all number
    3
    3
    0
    6
    5
    Throat irritation
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    0
    0
    2
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 73 (2.74%)
    1 / 76 (1.32%)
    6 / 124 (4.84%)
    5 / 75 (6.67%)
         occurrences all number
    1
    2
    1
    7
    6
    Affect lability
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 124 (2.42%)
    1 / 75 (1.33%)
         occurrences all number
    0
    0
    0
    3
    2
    Aggression
         subjects affected / exposed
    2 / 75 (2.67%)
    2 / 73 (2.74%)
    3 / 76 (3.95%)
    5 / 124 (4.03%)
    9 / 75 (12.00%)
         occurrences all number
    3
    3
    3
    5
    9
    Agitation
         subjects affected / exposed
    2 / 75 (2.67%)
    2 / 73 (2.74%)
    3 / 76 (3.95%)
    7 / 124 (5.65%)
    2 / 75 (2.67%)
         occurrences all number
    2
    2
    3
    8
    3
    Anxiety
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    4 / 124 (3.23%)
    3 / 75 (4.00%)
         occurrences all number
    2
    0
    1
    6
    3
    Insomnia
         subjects affected / exposed
    3 / 75 (4.00%)
    2 / 73 (2.74%)
    5 / 76 (6.58%)
    5 / 124 (4.03%)
    6 / 75 (8.00%)
         occurrences all number
    4
    2
    6
    6
    7
    Intentional self-injury
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    4 / 124 (3.23%)
    0 / 75 (0.00%)
         occurrences all number
    0
    1
    0
    4
    0
    Irritability
         subjects affected / exposed
    4 / 75 (5.33%)
    5 / 73 (6.85%)
    4 / 76 (5.26%)
    9 / 124 (7.26%)
    5 / 75 (6.67%)
         occurrences all number
    4
    6
    5
    10
    6
    Mental status changes
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 124 (2.42%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    Mood altered
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    2 / 75 (2.67%)
         occurrences all number
    0
    1
    0
    1
    2
    Panic attack
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    2 / 76 (2.63%)
    6 / 124 (4.84%)
    4 / 75 (5.33%)
         occurrences all number
    0
    1
    2
    6
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 75 (9.33%)
    14 / 73 (19.18%)
    0 / 76 (0.00%)
    7 / 124 (5.65%)
    5 / 75 (6.67%)
         occurrences all number
    7
    16
    0
    8
    5
    Anticonvulsant drug level increased
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 73 (2.74%)
    1 / 76 (1.32%)
    2 / 124 (1.61%)
    1 / 75 (1.33%)
         occurrences all number
    1
    2
    1
    2
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 75 (8.00%)
    12 / 73 (16.44%)
    0 / 76 (0.00%)
    5 / 124 (4.03%)
    3 / 75 (4.00%)
         occurrences all number
    6
    13
    0
    7
    4
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    2 / 75 (2.67%)
         occurrences all number
    1
    2
    0
    1
    2
    Blood iron decreased
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    0
    1
    2
    Blood prolactin increased
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 124 (1.61%)
    3 / 75 (4.00%)
         occurrences all number
    0
    0
    0
    2
    4
    Blood triglycerides increased
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    3 / 76 (3.95%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    1
    0
    3
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    2 / 76 (2.63%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    Eosinophil count increased
         subjects affected / exposed
    4 / 75 (5.33%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    1 / 75 (1.33%)
         occurrences all number
    4
    1
    0
    1
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    12 / 75 (16.00%)
    10 / 73 (13.70%)
    0 / 76 (0.00%)
    4 / 124 (3.23%)
    9 / 75 (12.00%)
         occurrences all number
    12
    11
    0
    4
    9
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 75 (0.00%)
    3 / 73 (4.11%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    1 / 75 (1.33%)
         occurrences all number
    0
    3
    0
    1
    1
    International normalised ratio increased
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    1 / 75 (1.33%)
         occurrences all number
    0
    3
    0
    1
    1
    Liver function test increased
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    5 / 75 (6.67%)
         occurrences all number
    0
    0
    0
    1
    10
    Platelet count decreased
         subjects affected / exposed
    3 / 75 (4.00%)
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    3
    2
    0
    0
    1
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    2
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    5 / 75 (6.67%)
    6 / 73 (8.22%)
    0 / 76 (0.00%)
    7 / 124 (5.65%)
    9 / 75 (12.00%)
         occurrences all number
    5
    6
    0
    7
    9
    Weight increased
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    2 / 76 (2.63%)
    3 / 124 (2.42%)
    3 / 75 (4.00%)
         occurrences all number
    1
    0
    2
    3
    5
    White blood cell count decreased
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    3 / 124 (2.42%)
    0 / 75 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    White blood cell count increased
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 124 (2.42%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    3
    0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    4 / 124 (3.23%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    Arthropod bite
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 124 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    1
    0
    2
    Contusion
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 73 (1.37%)
    4 / 76 (5.26%)
    6 / 124 (4.84%)
    4 / 75 (5.33%)
         occurrences all number
    1
    1
    5
    8
    5
    Eye contusion
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    2 / 124 (1.61%)
    2 / 75 (2.67%)
         occurrences all number
    0
    1
    0
    2
    2
    Face injury
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    2 / 124 (1.61%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    1
    2
    2
    Fall
         subjects affected / exposed
    2 / 75 (2.67%)
    4 / 73 (5.48%)
    5 / 76 (6.58%)
    13 / 124 (10.48%)
    8 / 75 (10.67%)
         occurrences all number
    2
    4
    7
    23
    9
    Foot fracture
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 124 (1.61%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Head injury
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    1 / 76 (1.32%)
    4 / 124 (3.23%)
    0 / 75 (0.00%)
         occurrences all number
    0
    1
    2
    5
    0
    Laceration
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    9 / 124 (7.26%)
    4 / 75 (5.33%)
         occurrences all number
    0
    2
    0
    13
    4
    Ligament sprain
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 73 (2.74%)
    1 / 76 (1.32%)
    1 / 124 (0.81%)
    3 / 75 (4.00%)
         occurrences all number
    1
    2
    1
    1
    3
    Lip injury
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 124 (2.42%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Skin abrasion
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 73 (1.37%)
    1 / 76 (1.32%)
    2 / 124 (1.61%)
    3 / 75 (4.00%)
         occurrences all number
    1
    1
    1
    2
    3
    Tooth fracture
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    5 / 124 (4.03%)
    1 / 75 (1.33%)
         occurrences all number
    0
    0
    0
    5
    1
    Upper limb fracture
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    1
    0
    0
    0
    2
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    3 / 75 (4.00%)
    2 / 73 (2.74%)
    2 / 76 (2.63%)
    4 / 124 (3.23%)
    4 / 75 (5.33%)
         occurrences all number
    5
    2
    2
    5
    7
    Balance disorder
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    2 / 76 (2.63%)
    2 / 124 (1.61%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    4
    3
    2
    Dizziness
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 73 (0.00%)
    3 / 76 (3.95%)
    4 / 124 (3.23%)
    4 / 75 (5.33%)
         occurrences all number
    6
    0
    3
    5
    5
    Drooling
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 73 (2.74%)
    2 / 76 (2.63%)
    3 / 124 (2.42%)
    2 / 75 (2.67%)
         occurrences all number
    1
    2
    2
    4
    2
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    4 / 124 (3.23%)
    2 / 75 (2.67%)
         occurrences all number
    0
    1
    0
    4
    2
    Headache
         subjects affected / exposed
    4 / 75 (5.33%)
    2 / 73 (2.74%)
    4 / 76 (5.26%)
    9 / 124 (7.26%)
    5 / 75 (6.67%)
         occurrences all number
    8
    6
    5
    22
    10
    Hypersomnia
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Hypokinesia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    0
    0
    2
    Lethargy
         subjects affected / exposed
    4 / 75 (5.33%)
    3 / 73 (4.11%)
    5 / 76 (6.58%)
    3 / 124 (2.42%)
    4 / 75 (5.33%)
         occurrences all number
    4
    3
    5
    4
    4
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    1 / 124 (0.81%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    1
    1
    2
    Sedation
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    2 / 124 (1.61%)
    3 / 75 (4.00%)
         occurrences all number
    1
    0
    1
    2
    3
    Seizure
         subjects affected / exposed
    4 / 75 (5.33%)
    6 / 73 (8.22%)
    5 / 76 (6.58%)
    32 / 124 (25.81%)
    16 / 75 (21.33%)
         occurrences all number
    4
    7
    6
    49
    23
    Somnolence
         subjects affected / exposed
    10 / 75 (13.33%)
    19 / 73 (26.03%)
    7 / 76 (9.21%)
    15 / 124 (12.10%)
    24 / 75 (32.00%)
         occurrences all number
    10
    21
    8
    21
    29
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 75 (6.67%)
    3 / 73 (4.11%)
    1 / 76 (1.32%)
    4 / 124 (3.23%)
    2 / 75 (2.67%)
         occurrences all number
    5
    3
    1
    4
    2
    Eosinophilia
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    1
    1
    0
    0
    2
    Increased tendency to bruise
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    2 / 76 (2.63%)
    0 / 124 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    0
    2
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 75 (2.67%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    2 / 124 (1.61%)
    2 / 75 (2.67%)
         occurrences all number
    2
    1
    0
    3
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    4 / 124 (3.23%)
    3 / 75 (4.00%)
         occurrences all number
    1
    1
    0
    8
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 75 (0.00%)
    3 / 73 (4.11%)
    1 / 76 (1.32%)
    3 / 124 (2.42%)
    2 / 75 (2.67%)
         occurrences all number
    0
    3
    1
    4
    2
    Constipation
         subjects affected / exposed
    8 / 75 (10.67%)
    5 / 73 (6.85%)
    6 / 76 (7.89%)
    12 / 124 (9.68%)
    9 / 75 (12.00%)
         occurrences all number
    9
    7
    6
    16
    18
    Diarrhoea
         subjects affected / exposed
    23 / 75 (30.67%)
    40 / 73 (54.79%)
    19 / 76 (25.00%)
    50 / 124 (40.32%)
    43 / 75 (57.33%)
         occurrences all number
    36
    54
    26
    97
    91
    Frequent bowel movements
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    4 / 124 (3.23%)
    1 / 75 (1.33%)
         occurrences all number
    1
    0
    0
    4
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    3 / 124 (2.42%)
    0 / 75 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    Nausea
         subjects affected / exposed
    6 / 75 (8.00%)
    2 / 73 (2.74%)
    2 / 76 (2.63%)
    3 / 124 (2.42%)
    4 / 75 (5.33%)
         occurrences all number
    8
    2
    2
    4
    4
    Retching
         subjects affected / exposed
    2 / 75 (2.67%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    3 / 124 (2.42%)
    3 / 75 (4.00%)
         occurrences all number
    3
    1
    0
    4
    3
    Salivary hypersecretion
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 124 (2.42%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Toothache
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    4 / 124 (3.23%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    1
    4
    0
    Vomiting
         subjects affected / exposed
    12 / 75 (16.00%)
    13 / 73 (17.81%)
    7 / 76 (9.21%)
    27 / 124 (21.77%)
    13 / 75 (17.33%)
         occurrences all number
    20
    22
    13
    45
    22
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    3 / 124 (2.42%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    1
    3
    2
    Dermatitis diaper
         subjects affected / exposed
    2 / 75 (2.67%)
    1 / 73 (1.37%)
    1 / 76 (1.32%)
    0 / 124 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    2
    1
    1
    0
    2
    Erythema
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Pruritus
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    2
    0
    0
    0
    2
    Rash
         subjects affected / exposed
    3 / 75 (4.00%)
    7 / 73 (9.59%)
    2 / 76 (2.63%)
    8 / 124 (6.45%)
    4 / 75 (5.33%)
         occurrences all number
    3
    7
    3
    8
    4
    Rash maculo-papular
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 124 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    1
    0
    2
    Urticaria
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    2 / 75 (2.67%)
         occurrences all number
    0
    1
    0
    1
    3
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    2 / 124 (1.61%)
    3 / 75 (4.00%)
         occurrences all number
    1
    1
    0
    2
    3
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    1 / 124 (0.81%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    1
    1
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 75 (2.67%)
    1 / 73 (1.37%)
    1 / 76 (1.32%)
    2 / 124 (1.61%)
    4 / 75 (5.33%)
         occurrences all number
    2
    1
    1
    2
    4
    Conjunctivitis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    8 / 124 (6.45%)
    3 / 75 (4.00%)
         occurrences all number
    2
    0
    0
    9
    3
    Croup infectious
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    1 / 124 (0.81%)
    2 / 75 (2.67%)
         occurrences all number
    1
    0
    2
    1
    2
    Ear infection
         subjects affected / exposed
    2 / 75 (2.67%)
    4 / 73 (5.48%)
    0 / 76 (0.00%)
    6 / 124 (4.84%)
    3 / 75 (4.00%)
         occurrences all number
    2
    4
    0
    10
    5
    Gastroenteritis
         subjects affected / exposed
    3 / 75 (4.00%)
    2 / 73 (2.74%)
    2 / 76 (2.63%)
    4 / 124 (3.23%)
    2 / 75 (2.67%)
         occurrences all number
    3
    2
    3
    9
    3
    Gastroenteritis viral
         subjects affected / exposed
    1 / 75 (1.33%)
    3 / 73 (4.11%)
    3 / 76 (3.95%)
    6 / 124 (4.84%)
    3 / 75 (4.00%)
         occurrences all number
    1
    3
    4
    8
    3
    Influenza
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    11 / 124 (8.87%)
    4 / 75 (5.33%)
         occurrences all number
    0
    0
    1
    11
    5
    Nasopharyngitis
         subjects affected / exposed
    11 / 75 (14.67%)
    11 / 73 (15.07%)
    12 / 76 (15.79%)
    19 / 124 (15.32%)
    16 / 75 (21.33%)
         occurrences all number
    13
    12
    16
    28
    25
    Otitis media
         subjects affected / exposed
    2 / 75 (2.67%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    8 / 124 (6.45%)
    4 / 75 (5.33%)
         occurrences all number
    3
    1
    0
    11
    4
    Pharyngitis
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 73 (2.74%)
    2 / 76 (2.63%)
    8 / 124 (6.45%)
    2 / 75 (2.67%)
         occurrences all number
    1
    2
    2
    13
    2
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 73 (2.74%)
    1 / 76 (1.32%)
    12 / 124 (9.68%)
    4 / 75 (5.33%)
         occurrences all number
    0
    2
    1
    17
    5
    Pneumonia
         subjects affected / exposed
    2 / 75 (2.67%)
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    1 / 124 (0.81%)
    2 / 75 (2.67%)
         occurrences all number
    2
    2
    0
    1
    2
    Respiratory tract infection
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 73 (0.00%)
    2 / 76 (2.63%)
    1 / 124 (0.81%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    2
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    4 / 124 (3.23%)
    1 / 75 (1.33%)
         occurrences all number
    0
    0
    0
    4
    1
    Sinusitis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    7 / 124 (5.65%)
    2 / 75 (2.67%)
         occurrences all number
    1
    0
    1
    8
    2
    Tonsillitis
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    1 / 124 (0.81%)
    2 / 75 (2.67%)
         occurrences all number
    2
    0
    1
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 75 (9.33%)
    7 / 73 (9.59%)
    10 / 76 (13.16%)
    22 / 124 (17.74%)
    10 / 75 (13.33%)
         occurrences all number
    8
    8
    11
    41
    11
    Urinary tract infection
         subjects affected / exposed
    4 / 75 (5.33%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    7 / 124 (5.65%)
    2 / 75 (2.67%)
         occurrences all number
    4
    2
    0
    8
    3
    Viral infection
         subjects affected / exposed
    3 / 75 (4.00%)
    0 / 73 (0.00%)
    2 / 76 (2.63%)
    4 / 124 (3.23%)
    5 / 75 (6.67%)
         occurrences all number
    3
    0
    2
    10
    7
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    4 / 124 (3.23%)
    3 / 75 (4.00%)
         occurrences all number
    1
    0
    1
    5
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 75 (20.00%)
    17 / 73 (23.29%)
    9 / 76 (11.84%)
    22 / 124 (17.74%)
    23 / 75 (30.67%)
         occurrences all number
    16
    19
    9
    26
    29
    Dehydration
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    3 / 124 (2.42%)
    2 / 75 (2.67%)
         occurrences all number
    1
    1
    0
    3
    2
    Diet refusal
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 73 (2.74%)
    0 / 76 (0.00%)
    0 / 124 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Increased appetite
         subjects affected / exposed
    3 / 75 (4.00%)
    3 / 73 (4.11%)
    5 / 76 (6.58%)
    3 / 124 (2.42%)
    0 / 75 (0.00%)
         occurrences all number
    3
    3
    5
    3
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jun 2017
    Incorporated additional updates to the trial design: • Statistical analysis was amended to reflect the re-categorization of secondary endpoints. • Clarification of exclusion criteria relating to mTOR inhibitors to reflect their changing regulatory approval status. • Provision was made to extend the OLE for subjects in the US and Poland. subjects in other countries would be able to access continued supply of investigational medicinal product (IMP) by alternative schemes. • Administration of cannabidiol through a gastrostomy (G)/nasogastric (NG) feeding tube was added as an option after consultation with the medical monitor. • Direction included that subject/caregiver to record information about meals on pharmacokinetic testing days.
    07 Aug 2018
    Incorporated additional updates to the trial design: • An inclusion criterion was added to ensure that eligible subjects must be taking 1 or more AEDs at a dose which had been stable for at least 4 weeks prior to screening. • Inclusion criteria amended to clarify that eligible subjects must have a well-documented clinical history of epilepsy which is not completely controlled by their current AEDs. • Clarification about the 4-hour post-dose 12-lead electrocardiogram (ECG). • Clarification on PK blood samples. • For consistency with the Schedule of Assessments, the protocol has been amended to clarify that eligibility must be assessed at Screening and Randomization according to the criteria. • Clarification that continued use of GWP42003-P following the ‘End of Treatment’ visit of the OLE refers to use of GWP42003-P outside of the GWEP1521 trial. • Clarification that in subjects with profound cognitive impairment aged 6 years or older, where completion of the Columbia-Suicide Severity Rating Scale (C-SSRS) is not appropriate, suicidality is assessed by the investigator’s clinical judgment following interview of the subject. • Clarification that the Study Medication Use and Behavior Survey should be administered at the final dosing visit of the blinded phase and again at the final dosing visit of the OLE. • Clarification that the blinded phase of this study would be locked and unblinded prior to completion of the OLE and that the SAP covering the blinded phase would be finalized prior to unblinding the blinded phase.
    06 Sep 2018
    Incorporated updates to include: • Changes in primary endpoint analysis method and wording • Changes to the proposed sensitivity analyses
    23 Apr 2019
    Incorporated updates to change the order of the hierarchy of testing.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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