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    Clinical Trial Results:
    A double-blind, placebo-controlled two-part study to investigate the dose-ranging safety and pharmacokinetics, followed by the efficacy and safety of cannabidiol (GWP42003-P) in children and young adults with Dravet syndrome.

    Summary
    EudraCT number
    2014-000995-24
    Trial protocol
    GB   PL  
    Global end of trial date
    26 Nov 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Sep 2018
    First version publication date
    27 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GWEP1332
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02091206
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    NCT02091206: NCT number for GWEP1332A, NCT02091375: NCT Number for GWEP1332B
    Sponsors
    Sponsor organisation name
    GW Research Ltd.
    Sponsor organisation address
    Sovereign House, Vision Park, Chivers Way, Histon, Cambridge, United Kingdom, CB24 9BZ
    Public contact
    Alternate contact: medinfo@greenwichbiosciences.com, GW Research Ltd., medinfo@gwpharm.com
    Scientific contact
    Alternate contact: medinfo@greenwichbiosciences.com, GW Research Ltd., medinfo@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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part A: To evaluate the safety of multiple doses of GWP42003-P compared with placebo with respect to: • Incidence, type and severity of adverse events (AEs). • Effect on vital signs, physical examination parameters including weight. • Effect on 12-lead electrocardiogram (ECG) findings. • Effect on laboratory parameters. • Changes in seizure frequency. Part B: • To assess the efficacy of GWP42003-P as an adjunctive antiepileptic treatment compared with placebo, with respect to the percentage change from baseline during the treatment period of the study in convulsive seizure frequency.
    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
    22 Oct 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 102
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    France: 18
    Worldwide total number of subjects
    154
    EEA total number of subjects
    52
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    110
    Adolescents (12-17 years)
    41
    Adults (18-64 years)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    This multi-center study consisted of 2 parts: Part A was a randomized, double-blind 21-day treatment study period. Part B was a randomized, double-blind, placebo-controlled, 14-week treatment study period that enrolled an entirely new group of participants, and those who failed the entry criteria for Part A were eligible to take part in Part B.

    Period 1
    Period 1 title
    Parts A and B Combined (BL + treatment) (overall period)
    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
    Part A GWP42003-P 5 mg/kg/day Dose
    Arm description
    Participants received GWP42003-P 5 milligrams per kilogram per day (mg/kg/day) administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 5 mg/kg/day over 3 days and remained at this dose for the rest of the 21-day treatment period (19 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.
    Arm type
    Experimental

    Investigational medicinal product name
    GWP42003-P
    Investigational medicinal product code
    Other name
    Cannibidiol, CBD, Epidiolex
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    GWP42003-P was presented an oral solution containing 25 or 100 mg/milliliter (mL) cannabidiol (CBD) dissolved in the excipients sesame oil and anhydrous ethanol (79 mg/mL) with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).

    Arm title
    Part A GWP42003-P 10 mg/kg/day Dose
    Arm description
    Participants received GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at this dose for the rest of the 21-day treatment period (15 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.
    Arm type
    Experimental

    Investigational medicinal product name
    GWP42003-P
    Investigational medicinal product code
    Other name
    Cannibidiol, CBD, Epidiolex
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    GWP42003-P was presented an oral solution containing 25 or 100 mg/mL CBD dissolved in the excipients sesame oil and anhydrous ethanol (79 mg/mL) with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).

    Arm title
    Part A GWP42003-P 20 mg/kg/day Dose
    Arm description
    Part A Participants received GWP42003-P 20 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the rest of the 21-day treatment period (11 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.
    Arm type
    Experimental

    Investigational medicinal product name
    GWP42003-P
    Investigational medicinal product code
    Other name
    Cannibidiol, CBD, Epidiolex
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    GWP42003-P was presented an oral solution containing 25 or 100 mg/mL CBD dissolved in the excipients sesame oil and anhydrous ethanol (79 mg/mL) with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).

    Arm title
    Part A Placebo
    Arm description
    Participants received placebo (0 mg/mL CBD), volume-matched to one of the 3 dose levels (5, 10, or 20 mg/kg/day), administered orally, half in the morning and half in the evening for 21 days. To maintain the blinded aspect of the study, participants titrated the placebo dose over 3 to 11 days according to the matched investigational medicinal product (IMP) group (3, 7, and 11 days for the 5, 10, or 20 mg/kg/day GWP42003-P groups, respectively) and remained at this dose for the rest of the 21-day treatment period. The 21-day treatment period was followed by a 10-day taper (10% per day of the matched dose) period.
    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
    Participants received placebo (0 mg/mL CBD) dissolved in the excipients sesame oil and anhydrous ethanol (79 mg/mL) with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).

    Arm title
    Part B GWP42003-P 20 mg/kg/day Dose
    Arm description
    Participants received 20 milligrams (mg) per kilogram (kg) per day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the open-label extension (OLE) study, the maintenance period was followed by a 10-day taper (10% per day) period.
    Arm type
    Experimental

    Investigational medicinal product name
    GWP42003-P
    Investigational medicinal product code
    Other name
    Cannibidiol, CBD, Epidiolex
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    GWP42003-P was presented an oral solution containing 100 mg/mL CBD dissolved in the excipients sesame oil and anhydrous ethanol (79 mg/mL) with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).

    Arm title
    Part B Placebo
    Arm description
    Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
    Arm type
    Placebo

    Investigational medicinal product name
    Part B Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo (0 mg/mL CBD) dissolved in the excipients sesame oil and anhydrous ethanol (79 mg/mL) with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).

    Number of subjects in period 1
    Part A GWP42003-P 5 mg/kg/day Dose Part A GWP42003-P 10 mg/kg/day Dose Part A GWP42003-P 20 mg/kg/day Dose Part A Placebo Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Started
    10
    8
    9
    7
    61
    59
    Safety Analysis Set
    10
    8
    9
    7
    61
    59
    Completed
    10
    7
    8
    7
    52
    56
    Not completed
    0
    1
    1
    0
    9
    3
         Withdrawn by investigator
    -
    -
    -
    -
    1
    -
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    1
         Adverse event, non-fatal
    -
    1
    -
    -
    8
    1
         Met withdrawal criteria
    -
    -
    1
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A GWP42003-P 5 mg/kg/day Dose
    Reporting group description
    Participants received GWP42003-P 5 milligrams per kilogram per day (mg/kg/day) administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 5 mg/kg/day over 3 days and remained at this dose for the rest of the 21-day treatment period (19 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.

    Reporting group title
    Part A GWP42003-P 10 mg/kg/day Dose
    Reporting group description
    Participants received GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at this dose for the rest of the 21-day treatment period (15 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.

    Reporting group title
    Part A GWP42003-P 20 mg/kg/day Dose
    Reporting group description
    Part A Participants received GWP42003-P 20 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the rest of the 21-day treatment period (11 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.

    Reporting group title
    Part A Placebo
    Reporting group description
    Participants received placebo (0 mg/mL CBD), volume-matched to one of the 3 dose levels (5, 10, or 20 mg/kg/day), administered orally, half in the morning and half in the evening for 21 days. To maintain the blinded aspect of the study, participants titrated the placebo dose over 3 to 11 days according to the matched investigational medicinal product (IMP) group (3, 7, and 11 days for the 5, 10, or 20 mg/kg/day GWP42003-P groups, respectively) and remained at this dose for the rest of the 21-day treatment period. The 21-day treatment period was followed by a 10-day taper (10% per day of the matched dose) period.

    Reporting group title
    Part B GWP42003-P 20 mg/kg/day Dose
    Reporting group description
    Participants received 20 milligrams (mg) per kilogram (kg) per day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the open-label extension (OLE) study, the maintenance period was followed by a 10-day taper (10% per day) period.

    Reporting group title
    Part B Placebo
    Reporting group description
    Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.

    Reporting group values
    Part A GWP42003-P 5 mg/kg/day Dose Part A GWP42003-P 10 mg/kg/day Dose Part A GWP42003-P 20 mg/kg/day Dose Part A Placebo Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo Total
    Number of subjects
    10 8 9 7 61 59 154
    Age categorical
    Units: Subjects
        Children (2-11 years)
    10 8 9 7 38 38 110
        Adolescents (12-17 years)
    0 0 0 0 22 19 41
        Adults (18-64 years)
    0 0 0 0 1 2 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    7.150 ± 1.8955 7.368 ± 2.1229 8.671 ± 1.7957 6.978 ± 0.9476 9.736 ± 4.7309 9.779 ± 4.8505 -
    Gender categorical
    Units: Subjects
        Female
    5 5 6 2 26 32 76
        Male
    5 3 3 5 35 27 78

    End points

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    End points reporting groups
    Reporting group title
    Part A GWP42003-P 5 mg/kg/day Dose
    Reporting group description
    Participants received GWP42003-P 5 milligrams per kilogram per day (mg/kg/day) administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 5 mg/kg/day over 3 days and remained at this dose for the rest of the 21-day treatment period (19 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.

    Reporting group title
    Part A GWP42003-P 10 mg/kg/day Dose
    Reporting group description
    Participants received GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at this dose for the rest of the 21-day treatment period (15 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.

    Reporting group title
    Part A GWP42003-P 20 mg/kg/day Dose
    Reporting group description
    Part A Participants received GWP42003-P 20 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the rest of the 21-day treatment period (11 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.

    Reporting group title
    Part A Placebo
    Reporting group description
    Participants received placebo (0 mg/mL CBD), volume-matched to one of the 3 dose levels (5, 10, or 20 mg/kg/day), administered orally, half in the morning and half in the evening for 21 days. To maintain the blinded aspect of the study, participants titrated the placebo dose over 3 to 11 days according to the matched investigational medicinal product (IMP) group (3, 7, and 11 days for the 5, 10, or 20 mg/kg/day GWP42003-P groups, respectively) and remained at this dose for the rest of the 21-day treatment period. The 21-day treatment period was followed by a 10-day taper (10% per day of the matched dose) period.

    Reporting group title
    Part B GWP42003-P 20 mg/kg/day Dose
    Reporting group description
    Participants received 20 milligrams (mg) per kilogram (kg) per day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the open-label extension (OLE) study, the maintenance period was followed by a 10-day taper (10% per day) period.

    Reporting group title
    Part B Placebo
    Reporting group description
    Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.

    Primary: Part A: Number Of Participants Who Experienced Severe Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Part A: Number Of Participants Who Experienced Severe Treatment-Emergent Adverse Events (TEAEs) [1] [2]
    End point description
    A TEAE was defined as an AE with an onset date on or after the first dose of investigational medicinal product (IMP). If an AE had a partial onset date and it was unclear from the partial date (or the stop date) whether the AE started prior to or following the first dose of IMP then the AE was considered a TEAE. The number of participants who experienced one or more severe TEAEs after dosing on Day 1 through the Safety Follow-up Visit (Day 60) is shown. A summary of serious and all other non-serious AEs regardless of causality is located in the Adverse Events module.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) through Safety follow-up visit (Day 60)
    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: Quantitative statistical analyses were not performed on safety endpoints for Part A of the study.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part A of the study only. Severe TEAE data are not presented for Part B.
    End point values
    Part A GWP42003-P 5 mg/kg/day Dose Part A GWP42003-P 10 mg/kg/day Dose Part A GWP42003-P 20 mg/kg/day Dose Part A Placebo
    Number of subjects analysed
    10
    8
    9
    7
    Units: Participants
    2
    1
    0
    1
    No statistical analyses for this end point

    Primary: Part B: Percentage Change From Baseline In Convulsive Seizure Frequency During The Treatment Period

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    End point title
    Part B: Percentage Change From Baseline In Convulsive Seizure Frequency During The Treatment Period [3]
    End point description
    Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an interactive voice response system (IVRS) diary. Percentage change from baseline was calculated as: ([frequency during the treatment period - frequency during baseline]/frequency during baseline) * 100. The frequency during each period was based on 28-day averages and calculated as: (number of seizures in the period/number of reported days in the IVRS period) * 28. Baseline included all available data prior to Day 1 (28-day average). Negative percentages show an improvement from baseline.
    End point type
    Primary
    End point timeframe
    Baseline to End of Treatment (EOT) (Day 99) or Early Termination (ET)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part B of the study only. Change in convulsive seizure frequency data are not presented for Part A.
    End point values
    Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Number of subjects analysed
    61
    59
    Units: Percent change
        median (inter-quartile range (Q1-Q3))
    -38.94 (-69.53 to -4.83)
    -13.29 (-52.53 to 20.20)
    Statistical analysis title
    GWP42003-P 20 mg/kg/Day Dose, Placebo
    Comparison groups
    Part B GWP42003-P 20 mg/kg/day Dose v Part B Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0123 [4]
    Method
    Wilcoxon rank-sum test
    Parameter type
    Median difference (final values)
    Point estimate
    -22.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -41.06
         upper limit
    -5.43
    Notes
    [4] - The Wilcoxon test was used to calculate the p value, while the point estimate and confidence intervals were calculated using the Hodges–Lehmann approach.

    Secondary: Part A: Area Under The Concentration-Time Curve Calculated To The Last Observable Concentration At Time T (AUC0-t) For CBD And Its Metabolites At Days 1 And 22

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    End point title
    Part A: Area Under The Concentration-Time Curve Calculated To The Last Observable Concentration At Time T (AUC0-t) For CBD And Its Metabolites At Days 1 And 22 [5]
    End point description
    AUC0-t for CBD and its major metabolites, 6-hydroxy-CBD (6-OH-CBD), 7-hydroxy-CBD (7-OH-CBD), and 7-carboxy-cannabidiol (7-COOH-CBD) were calculated using blood samples collected before and after IMP dosing on Days 1 and 22. One sample was collected predose, 2 to 3 hours postdose, and 4 to 6 hours postdose for CBD and its metabolites. Results are presented for participants who received GWP42003-P at 5, 10, or 20 mg/kg/day during the study and for participants with a numeric result for the given evaluation. Data presented are geometric means (geometric coefficient of variation [%]).
    End point type
    Secondary
    End point timeframe
    Predose and 2-6 hours postdose on Days 1 and 22
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part A of the study only. PK data are not presented for Part B.
    End point values
    Part A GWP42003-P 5 mg/kg/day Dose Part A GWP42003-P 10 mg/kg/day Dose Part A GWP42003-P 20 mg/kg/day Dose
    Number of subjects analysed
    10 [6]
    8 [7]
    9 [8]
    Units: hours*nanograms/mL
    geometric mean (geometric coefficient of variation)
        Day 1 CBD
    70.61 ± 20.38
    66.35 ± 120.8
    73.69 ± 96.64
        Day 22 CBD
    240.8 ± 100.8
    721.8 ± 79.92
    962.6 ± 93.43
        Day 1 6-OH-CBD
    3.27 ± 132
    2.79 ± 87.7
    5.16 ± 57.2
        Day 22 6-OH-CBD
    9.33 ± 119
    26.3 ± 82.9
    58.6 ± 90.1
        Day 1 7-OH-CBD
    21.9 ± 57.0
    18.4 ± 299
    30.2 ± 105
        Day 22 7-OH-CBD
    131 ± 107
    244 ± 120
    508 ± 96.0
        Day 1 7-COOH-CBD
    297 ± 97.3
    125 ± 1750
    195 ± 573
        Day 22 7-COOH-CBD
    4190 ± 81.20
    9220 ± 178
    15500 ± 148
    Notes
    [6] - CBD (Day 1) 5 (Day 22) 9 6-OH-CBD (1) 3 (22) 8 7-OH-CBD (1) 5 (22) 8 7-COOH-CBD (1) 6 (22) 9
    [7] - CBD (Day 1) 7 (Day 22) 7 6-OH-CBD (1) 5 (22) 7 7-OH-CBD (1) 7 (22) 7 7-COOH-CBD (1) 6 (22) 5
    [8] - CBD (Day 1) 7 (Day 22) 7 6-OH-CBD (1) 5 (22) 6 7-OH-CBD (1) 8 (22) 6 7-COOH-CBD (1) 6 (22) 5
    No statistical analyses for this end point

    Secondary: Part A: Mean Percentage Change From Baseline To End Of Treatment In Plasma Clobazam (CLB) And N-Desmethylclobazam (N-CLB) Concentrations

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    End point title
    Part A: Mean Percentage Change From Baseline To End Of Treatment In Plasma Clobazam (CLB) And N-Desmethylclobazam (N-CLB) Concentrations [9]
    End point description
    Plasma concentrations of CLB and N-CLB were measured on Days 1 and 22. Participants were instructed to take their daily dose of CLB 2 hours prior to the anticipated pre-IMP blood specimen collection on both days. Blood samples were collected prior to administration of IMP. Results are presented for a subgroup of participants who took CLB during the study and had PK samples analyzed at both pharmacokinetics (PK) sampling visits (Days 1 and 22).
    End point type
    Secondary
    End point timeframe
    Predose on Days 1 and 22
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part A of the study only. CLB and N-CLB data are not presented for Part B.
    End point values
    Part A GWP42003-P 5 mg/kg/day Dose Part A GWP42003-P 10 mg/kg/day Dose Part A GWP42003-P 20 mg/kg/day Dose Part A Placebo
    Number of subjects analysed
    6
    6
    5
    5
    Units: percent change
    number (not applicable)
        % change in CLB
    -1.2
    18.0
    29.6
    15.1
        % change in N-CLB
    258.7
    170.7
    228.9
    -5.6
    No statistical analyses for this end point

    Secondary: Part B: Number Of Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period

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    End point title
    Part B: Number Of Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period [10]
    End point description
    Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Day 99) or ET
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part B of the study only. Reduction in seizure frequency data are not presented for Part A.
    End point values
    Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Number of subjects analysed
    61
    59
    Units: Participants
        ≥50% Reduction
    26
    16
    Statistical analysis title
    GWP42003-P 20 mg/kg/Day Dose, Placebo
    Comparison groups
    Part B GWP42003-P 20 mg/kg/day Dose v Part B Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0784
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.93
         upper limit
    4.3

    Secondary: Part B: Number Of Participants with A ≥25%, ≥75%, Or 100% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period

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    End point title
    Part B: Number Of Participants with A ≥25%, ≥75%, Or 100% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period [11]
    End point description
    Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an IVRS. Percentage change from baseline was calculated as per the primary outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Day 99) or ET
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part B of the study only. Convulsive seizure data are not presented for Part A.
    End point values
    Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Number of subjects analysed
    61
    59
    Units: Participants
        ≥25% Reduction
    38
    26
        ≥75% Reduction
    14
    7
        100% Reduction
    3
    0
    No statistical analyses for this end point

    Secondary: Part B: Percentage Change From Baseline In Non-Convulsive Seizure Frequency During The Treatment Period

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    End point title
    Part B: Percentage Change From Baseline In Non-Convulsive Seizure Frequency During The Treatment Period [12]
    End point description
    Non-convulsive seizures (myoclonic, partial, or absence) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure. Only participants with non-convulsive seizures during the baseline period were included. Negative percentages show an improvement from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Day 99) or ET
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part B of the study only. Non-convulsive seizure frequency data are not presented for Part A.
    End point values
    Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Number of subjects analysed
    37
    41
    Units: Percent change
        median (inter-quartile range (Q1-Q3))
    -40.16 (-92.1 to -3.6)
    -34.69 (-97.5 to -0.7)
    No statistical analyses for this end point

    Secondary: Part B: Caregiver Global Impression Of Change In Seizure Duration (CGICSD)

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    End point title
    Part B: Caregiver Global Impression Of Change In Seizure Duration (CGICSD) [13]
    End point description
    Seizure duration was assessed qualitatively using the CGICSD. Caregivers were asked “Since the patient started treatment, please assess the average duration of the patient’s seizures (comparing their condition now to their condition before treatment)”; responses included decrease, no change, or increase in average duration. For each seizure type, only participants with at least 1 seizure for the corresponding seizure type, reported at any time during the study, were included.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Day 99) or ET
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part B of the study only. Duration of seizure subtype data are not presented for Part A.
    End point values
    Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Number of subjects analysed
    61
    59
    Units: Participants
        Tonic-Clonic Seizures Number Analyzed
    49
    41
        Tonic-Clonic Seizures Decrease in average duration
    17
    8
        Tonic-Clonic Seizures No change in aver. duration
    32
    31
        Tonic-Clonic Seizures Increase in average duration
    0
    2
        Tonic Seizures Number Analyzed
    12
    15
        Tonic Seizures Decrease in average duration
    4
    2
        Tonic Seizures No change in average duration
    8
    12
        Tonic Seizures Increase in average duration
    0
    1
        Clonic Seizures Number Analyzed
    11
    7
        Clonic Seizures Decrease in average duration
    5
    3
        Clonic Seizures No change in average duration
    6
    3
        Clonic Seizures Increase in average duration
    0
    1
        Atonic Seizures Number Analyzed
    3
    7
        Atonic Seizures Decrease in average duration
    2
    2
        Atonic Seizures No change in average duration
    1
    3
        Atonic Seizures Increase in average duration
    0
    2
        Myoclonic Seizures Number Analyzed
    14
    18
        Myoclonic Seizures Decrease in average duration
    4
    3
        Myoclonic Seizures No change in average duration
    10
    12
        Myoclonic Seizures Increase in average duration
    0
    3
        Countable Partial Seizures Number Analyzed
    12
    13
        Countable Partial Seizures Decrease in aver. dur.
    5
    2
        Countable Partial Seizures No change in aver. dur.
    7
    9
        Countable Partial Seizures Increase in aver. dur.
    0
    2
        Other Partial Seizures Number Analyzed
    3
    5
        Other Partial Seizures Decrease in aver. dur.
    0
    3
        Other Partial Seizures No change in aver. dur.
    3
    2
        Other Partial Seizures Increase in aver. dur.
    0
    0
        Absence Seizures Number Analyzed
    16
    19
        Absence Seizures Decrease in average duration
    4
    6
        Absence Seizures No change in average duration
    11
    12
        Absence Seizures Increase in average duration
    1
    1
    No statistical analyses for this end point

    Secondary: Part B: Number Of Participants Using Rescue Medication

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    End point title
    Part B: Number Of Participants Using Rescue Medication [14]
    End point description
    The use of rescue medication was recorded by the participant or caregiver using a paper diary.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Day 99) or ET
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part B of the study only. Rescue medication data are not presented for Part A.
    End point values
    Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Number of subjects analysed
    61
    59
    Units: Participants
    36
    41
    No statistical analyses for this end point

    Secondary: Part B: Number Of Participants With Inpatient Hospitalizations Due To Epilepsy

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    End point title
    Part B: Number Of Participants With Inpatient Hospitalizations Due To Epilepsy [15]
    End point description
    Inpatient hospitalizations due to epilepsy were recorded by the participant or caregiver and through the serious adverse events (SAE) reporting process.
    End point type
    Secondary
    End point timeframe
    Baseline to Safety Follow-up (Day 137)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part A of the study only. Hospitalization data are not presented for Part B.
    End point values
    Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Number of subjects analysed
    61
    59
    Units: Participants
        Caregiver/participant-reported
    5
    1
        Investigator-reported (serious TEAE)
    2
    1
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline In Sleep Disruption 0 To 10 Numerical Rating Scale (0 to 10 NRS) Score

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    End point title
    Part B: Change From Baseline In Sleep Disruption 0 To 10 Numerical Rating Scale (0 to 10 NRS) Score [16]
    End point description
    The sleep disruption 0 to 10 NRS questionnaire was completed by the participant’s caregiver. The caregiver was asked ‘On a scale of ‘0 to 10’, please indicate the number that best describes your child’s sleep disruption in the last week.’ The markers ranged from 0 = ‘slept extremely well’ to 10 = ‘unable to sleep at all’. The change from baseline in the sleep disruption 0 to 10 numerical rating scale score was analyzed using an analysis of covariance (ANCOVA) model with baseline and age group (2 to 5 years, 6 to 12 years and 13 to 18 years) as covariates and treatment group as a fixed factor. A negative change from baseline represents an improvement in sleep. Last visit for endpoints assessed at clinic visits was defined as the last scheduled visit (not including the end of taper or safety follow-up visits) at which participant’s last evaluation was performed.
    End point type
    Secondary
    End point timeframe
    Baseline to Last Visit (Day 99) or ET
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part B of the study only. Change In Sleep Disruption NRS data are not presented for Part A.
    End point values
    Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Number of subjects analysed
    59
    59
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -0.7 (-1.5 to 0.1)
    -0.3 (-1.1 to 0.5)
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline In Epworth Sleepiness Scale (ESS) Score

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    End point title
    Part B: Change From Baseline In Epworth Sleepiness Scale (ESS) Score [17]
    End point description
    The ESS questionnaire was completed by the participant’s caregiver. The change from baseline in the ESS score was analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6- to 2 years and 13 to 18 years) as covariates and treatment group as a fixed factor. The total score was the sum of the 8 item-scores and ranged from 0 to 24. A higher total score represents greater levels of daytime sleepiness.
    End point type
    Secondary
    End point timeframe
    Baseline to Last Visit (Day 99) or ET
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part B of the study only. ESS data are not presented for Part A.
    End point values
    Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Number of subjects analysed
    61
    58
    Units: units on a scale
        least squares mean (confidence interval 95%)
    0.82 (-0.36 to 1.99)
    -0.69 (-1.90 to 0.52)
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline In Quality Of Life In Childhood Epilepsy (QOLCE) Score

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    End point title
    Part B: Change From Baseline In Quality Of Life In Childhood Epilepsy (QOLCE) Score [18]
    End point description
    The QOLCE questionnaire was completed by the parent or caregiver of participants aged 4 years and above. The change from baseline in the overall quality of life score was analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6 to 12 years and 13 to 18 years) as covariates and treatment group as a fixed factor. Zero represents the lowest or poorest category and 100 represents the highest level of functioning. The overall quality of life score was calculated by taking the mean of the subscale scores.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Day 99)
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Quantitative statistical analyses were not performed for this endpoint. Descriptive statistics are presented.
    End point values
    Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Number of subjects analysed
    47
    44
    Units: units on a scale
        least squares mean (confidence interval 95%)
    5.6 (1.9 to 9.3)
    4.1 (0.2 to 8.0)
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline In Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Score

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    End point title
    Part B: Change From Baseline In Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Score [19]
    End point description
    The Vineland-II scores (standard scores and adaptive levels for each adaptive behavior domain, the adaptive behavior composite, and the maladaptive behavior index score and level) were assessed by the participant’s caregiver. Scores were analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6 to 12 years, and 13 to 18 years) as covariates and treatment group as a fixed factor. Higher scores represent greater levels of functioning except for the maladaptive behavior index, for which a negative change from baseline represents an improvement in condition.
    End point type
    Secondary
    End point timeframe
    Baseline to Last Visit (Day 99) or ET
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part B of the study only. Vineland Adaptive Behavior Scale data are not presented for Part A.
    End point values
    Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Number of subjects analysed
    61 [20]
    59 [21]
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Communication Domain Standard Score
    -0.8 (-3.2 to 1.5)
    3.0 (0.8 to 5.3)
        Daily Living Skills Domain Standard Score
    -0.8 (-4.0 to 2.4)
    -0.8 (-4.1 to 2.6)
        Socialization Domain Standard Score
    -0.6 (-4.6 to 3.5)
    -0.6 (-4.0 to 2.7)
        Motor Skills Domain Standard Score
    -2.5 (-5.5 to 0.5)
    1.7 (-1.1 to 4.5)
        Adaptive Behavior Composite Standard Score
    -2.0 (-5.2 to 1.1)
    0.6 (-2.1 to 3.3)
        Maladaptive Behavior Index v-Scale Score
    -0.3 (-0.7 to 0.1)
    -0.4 (-0.8 to 0.0)
    Notes
    [20] - Numbers Analysed CDSS 17 DLSDSS 20 SDSS 12 MSDSS 20 ABCSS 12 MBIvSS 47
    [21] - Numbers Analysed CDSS 19 DLSDSS 19 SDSS 16 MSDSS 22 ABCSS 15 MBIvSS 48
    No statistical analyses for this end point

    Secondary: Part B: Caregiver Global Impression Of Change (CGIC)

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    End point title
    Part B: Caregiver Global Impression Of Change (CGIC) [22]
    End point description
    The CGIC was used to assess the participant’s overall condition on a 7-point scale using the markers “very much improved, much improved, slightly improved, no change, slightly worse, much worse, or very much worse” (1 = very much improved; 7 = very much worse). On Day 1 (prior to starting IMP), the caregiver was asked to write a brief description of the participant’s overall condition as a memory aid for the CGIC questionnaire at subsequent visits.
    End point type
    Secondary
    End point timeframe
    Baseline to Last Visit (Day 99) or ET
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint provides data for Part B of the study only. CGIC data are not presented for Part A.
    End point values
    Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Number of subjects analysed
    60
    58
    Units: Participants
        Very Much Improved
    9
    4
        Much Improved
    10
    4
        Slightly Improved
    18
    12
        No Change
    15
    31
        Slightly Worse
    3
    6
        Much Worse
    4
    1
        Very Much Worse
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) up to Day 60 (Part A) or Day 137 (Part B)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Part A GWP42003-P 5 mg/kg/day Dose
    Reporting group description
    Participants received GWP42003-P 5 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 5 mg/kg/day over 3 days and remained at this dose for the rest of the 21-day treatment period (19 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.

    Reporting group title
    Part A GWP42003-P 10 mg/kg/day Dose
    Reporting group description
    Participants received GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at this dose for the rest of the 21-day treatment period (15 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.

    Reporting group title
    Part A GWP42003-P 20 mg/kg/day Dose
    Reporting group description
    Part A Participants received GWP42003-P 20 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the rest of the 21-day treatment period (11 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.

    Reporting group title
    Part A Placebo
    Reporting group description
    Participants received placebo (0 mg/mL CBD), volume matched to one of the 3 dose levels (5, 10, or 20 mg/kg/day), administered orally, half in the morning and half in the evening for 21 days. To maintain the blinded aspect of the study, participants titrated the placebo dose over 3 to 11 days according to the matched IMP group (3, 7, and 11 days for the 5, 10, or 20 mg/kg/day GWP42003-P groups, respectively) and remained at this dose for the rest of the 21-day treatment period. The 21-day treatment period was followed by a 10-day taper (10% per day of the matched dose) period.

    Reporting group title
    Part B GWP42003-P 20 mg/kg/day Dose
    Reporting group description
    Participants received 20 milligrams (mg) per kilogram (kg) per day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.

    Reporting group title
    Part B Placebo
    Reporting group description
    Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.

    Serious adverse events
    Part A GWP42003-P 5 mg/kg/day Dose Part A GWP42003-P 10 mg/kg/day Dose Part A GWP42003-P 20 mg/kg/day Dose Part A Placebo Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 8 (25.00%)
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    10 / 61 (16.39%)
    3 / 59 (5.08%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gamma-glutamyltransferase
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Platelet count
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Vascular disorders
    Hypovolaemic shock
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    2 / 61 (3.28%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status Epilepticus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    3 / 61 (4.92%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    3 / 61 (4.92%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 8 (25.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash Maculo-papular
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infections and infestations
    Parvovirus Infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Viral Infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part A GWP42003-P 5 mg/kg/day Dose Part A GWP42003-P 10 mg/kg/day Dose Part A GWP42003-P 20 mg/kg/day Dose Part A Placebo Part B GWP42003-P 20 mg/kg/day Dose Part B Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
    5 / 8 (62.50%)
    7 / 9 (77.78%)
    6 / 7 (85.71%)
    46 / 61 (75.41%)
    28 / 59 (47.46%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Liver function test abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    1 / 59 (1.69%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    Urine ketone body absent
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Urine ketone body present
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    4 / 61 (6.56%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    Transaminases increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    4 / 61 (6.56%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    Weight decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    4 / 61 (6.56%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    2 / 61 (3.28%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    1
    0
    2
    0
    Convulsion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    5 / 61 (8.20%)
    2 / 59 (3.39%)
         occurrences all number
    0
    0
    0
    1
    5
    3
    Coordination abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    2 / 61 (3.28%)
    0 / 59 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Dysarthria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    2
    0
    1
    5
    Poor quality sleep
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    2 / 61 (3.28%)
    2 / 59 (3.39%)
         occurrences all number
    1
    0
    0
    1
    2
    2
    Sedation
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 8 (0.00%)
    2 / 9 (22.22%)
    0 / 7 (0.00%)
    2 / 61 (3.28%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    2
    0
    2
    0
    Somnolence
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 8 (37.50%)
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    19 / 61 (31.15%)
    6 / 59 (10.17%)
         occurrences all number
    2
    3
    0
    1
    23
    13
    Tremor
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    2 / 61 (3.28%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    Lethargy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    7 / 61 (11.48%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    0
    9
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    2 / 7 (28.57%)
    11 / 61 (18.03%)
    2 / 59 (3.39%)
         occurrences all number
    0
    0
    1
    2
    12
    2
    Gait disturbance
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    3 / 61 (4.92%)
    0 / 59 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    0
    Influenza like illness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    9 / 61 (14.75%)
    5 / 59 (8.47%)
         occurrences all number
    3
    1
    0
    0
    13
    7
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    2 / 9 (22.22%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    2 / 59 (3.39%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    19 / 61 (31.15%)
    6 / 59 (10.17%)
         occurrences all number
    0
    0
    0
    1
    33
    8
    Dry Mouth
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Eructation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    9 / 61 (14.75%)
    3 / 59 (5.08%)
         occurrences all number
    1
    1
    2
    0
    13
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    4 / 61 (6.56%)
    2 / 59 (3.39%)
         occurrences all number
    0
    0
    0
    1
    4
    3
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Erythema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    2 / 61 (3.28%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    1
    0
    3
    1
    Rash papular
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    2 / 61 (3.28%)
    1 / 59 (1.69%)
         occurrences all number
    3
    0
    0
    0
    2
    1
    Irritability
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    4 / 61 (6.56%)
    0 / 59 (0.00%)
         occurrences all number
    0
    1
    0
    0
    6
    0
    Mood swings
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Infections and infestations
    Erythema infectiosum
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 7 (28.57%)
    2 / 61 (3.28%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    2
    2
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    3 / 61 (4.92%)
    3 / 59 (5.08%)
         occurrences all number
    0
    1
    1
    1
    3
    3
    Otitis media acute
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    1 / 61 (1.64%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    2
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    7 / 61 (11.48%)
    5 / 59 (8.47%)
         occurrences all number
    1
    0
    0
    0
    7
    6
    Viral infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    2 / 59 (3.39%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    Viral rash
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    4 / 9 (44.44%)
    0 / 7 (0.00%)
    16 / 61 (26.23%)
    3 / 59 (5.08%)
         occurrences all number
    0
    1
    4
    0
    21
    3
    Increased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    3 / 61 (4.92%)
    0 / 59 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    0
    Ketosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Nov 2014
    Clarification of trial procedures, including the following -Added CGICSD as a secondary assessment and analysis of major metabolites of CBD. -Added a pre-randomization pregnancy test. -Clarified exclusion criteria related to previous use of cannabinoids. -Clarified study procedures, including collection of seizure information for Part A, IMP usage, rescue medication, concomitant anti-epilepsy drugs, and AEs for parts A and B; collection of epilepsy-specific genetic testing and prior anti-epileptic drugs; capturing seizure information and IMP supply; timing of CLB administration -Clarified baseline and safety follow-up periods and visit windows as well as time periods for safety calls and completing case report forms and collection of epilepsy-related hospitalization information -Clarified seizure types and subtypes -Clarified that any AE or drug-induced liver injury could be reason for withdrawal -Clarified when diary information would be collected -Clarified when the taper period would start for participants who terminated early -Added use of diagnostic review and clarified the qualifications for administering the C-SSRS -Clarified when seizures were considered AEs and when AEs should be reviewed by the DSMC
    29 May 2015
    Clarification of trial procedures, including the following: -Revision of endpoint analyses, including Part B primary and secondary endpoints to use the full treatment period (which included titration and maintenance periods); definition of "baseline" for statistical analyses; seizure frequency used in the sensitivity analysis for Part B, new sensitivity analyses for Part B; and details on multiple imputation methods for sensitivity analyses for the primary endpoint in Part B. -Revision/clarification of procedures, including Tanner staging age; monitoring of potential cases of DILI, alanine aminotransferase, aspartate aminotransferase, total bilirubin, and alkaline phosphatase levels until normalized; monitoring of the plasma concentration of concomitant anti-epilepsy drugs and dosage modification if concentrations are altered following administration of IMP; instructions for follow-up for elevated liver enzymes that were not considered DILI; clarification regarding who may participate in the C-SSRS; and collection of seizure count information for Part B. -Clarified assessments including effects of IMP on menstruation cycles and measuring plasma concentrations of anti-epilepsy drugs. -Clarification that only convulsive seizures in the first 28 days of the baseline period would count toward eligibility.

    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.
    In Part A, there were analytical issues for 7-OH-CBD related to reference material batch used during analysis. Data are qualitative.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/29540584
    http://www.ncbi.nlm.nih.gov/pubmed/28538134
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