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

    Summary
    EudraCT number
    2014-002939-34
    Trial protocol
    GB   ES   NL   PL  
    Global end of trial date
    09 Apr 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Aug 2019
    First version publication date
    11 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GWEP1424
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02224703
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GW Research Ltd.
    Sponsor organisation address
    Sovereign House, Vision Park, Chivers Way, Histon, Cambridge, United Kingdom, CB24 9BZ
    Public contact
    GW Research Ltd., Alternate contact: medinfo@greenwichbiosciences.com, +44 1223 238170, medinfo@gwpharm.com
    Scientific contact
    GW Research Ltd., Alternate contact: medinfo@greenwichbiosciences.com, +44 1223 238170, 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
    09 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of GWP42003-P as an adjunctive antiepileptic treatment compared with placebo, with respect to the change during the treatment period of the study compared to baseline in convulsive seizure frequency. The dose response effect between 2 GWP42003-P dose levels and placebo was also explored. Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic and nonconvulsive seizures as myoclonic, countable partial, other partial, or absence.
    Protection of trial subjects
    This study was designed, conducted, recorded, and reported in accordance with ethical principles that have their origin in the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, and are consistent with International Council on Harmonisation Good Clinical Practice guidelines and in accordance with applicable local, federal, and regulatory agency regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Apr 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    United States: 94
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Netherlands: 25
    Country: Number of subjects enrolled
    Poland: 25
    Worldwide total number of subjects
    199
    EEA total number of subjects
    89
    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)
    137
    Adolescents (12-17 years)
    59
    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
    A total of 43 sites screened participants and 38 sites (23 in the United States, 7 in Spain, 3 in Poland, 2 in Australia, 1 in Israel, and 2 in the Netherlands) randomized participants into the trial. Two sites selected (1 in Israel and 1 in the United States) did not screen any participants.

    Pre-assignment
    Screening details
    To assess eligibility, participants 2–18 years of age with Dravet syndrome had to be taking 1 or more antiepileptic drugs (AEDs) at a dose that had been stable for at least 4 weeks were screened. A total of 285 participants were screened, of which 199 were randomized.

    Period 1
    Period 1 title
    Double-Blind Period (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
    10 mg/kg/Day GWP42003-P
    Arm description
    GWP42003-P oral solution (100 milligrams/milliliter [mg/mL] cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 10 mg/kilogram (kg)/day dose was defined as 50% of the 20 mg/kg/day dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Cannabidiol
    Investigational medicinal product code
    GWP42003-P
    Other name
    Epidiolex, CBD
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    GWP42003-P was taken orally twice daily as directed by the investigator. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at the target dose for the treatment period.

    Arm title
    20 mg/kg/Day GWP42003-P
    Arm description
    GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 20 mg/kg/day dose was recommended by the Data Safety Monitoring Committee (DSMC) after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (2014-000995-24).
    Arm type
    Experimental

    Investigational medicinal product name
    Cannabidiol
    Investigational medicinal product code
    GWP42003-P
    Other name
    Epidiolex, CBD
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    GWP42003-P was taken orally twice daily as directed by the investigator. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at the target dose for the treatment period.

    Arm title
    Placebo Control
    Arm description
    Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was taken orally twice daily as directed by the investigator.

    Number of subjects in period 1
    10 mg/kg/Day GWP42003-P 20 mg/kg/Day GWP42003-P Placebo Control
    Started
    67
    67
    65
    Received at Least 1 Dose of Study Drug
    66
    67
    65
    Intent to Treat (ITT) Analysis Set
    66
    67
    65
    Completed
    64
    61
    65
    Not completed
    3
    6
    0
         Advised by medical monitor
    1
    -
    -
         Consent withdrawn by parent or guardian
    -
    1
    -
         Lack of efficacy
    1
    -
    -
         Adverse event, non-fatal
    -
    5
    -
         Withdrawn by investigator
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    10 mg/kg/Day GWP42003-P
    Reporting group description
    GWP42003-P oral solution (100 milligrams/milliliter [mg/mL] cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 10 mg/kilogram (kg)/day dose was defined as 50% of the 20 mg/kg/day dose.

    Reporting group title
    20 mg/kg/Day GWP42003-P
    Reporting group description
    GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 20 mg/kg/day dose was recommended by the Data Safety Monitoring Committee (DSMC) after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (2014-000995-24).

    Reporting group title
    Placebo Control
    Reporting group description
    Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent.

    Reporting group values
    10 mg/kg/Day GWP42003-P 20 mg/kg/Day GWP42003-P Placebo Control Total
    Number of subjects
    67 67 65 199
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    47 47 43 137
        Adolescents (12-17 years)
    20 18 21 59
        Adults (18-64 years)
    0 2 1 3
        From 65-84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9.208 ± 4.2479 9.263 ± 4.3060 9.617 ± 4.5757 -
    Gender categorical
    Units: Subjects
        Female
    40 31 34 105
        Male
    27 36 31 94
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    0 0 1 1
        Asian
    0 1 4 5
        Black or African American
    1 0 4 5
        White
    58 64 55 177
        Other
    8 2 1 11

    End points

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    End points reporting groups
    Reporting group title
    10 mg/kg/Day GWP42003-P
    Reporting group description
    GWP42003-P oral solution (100 milligrams/milliliter [mg/mL] cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 10 mg/kilogram (kg)/day dose was defined as 50% of the 20 mg/kg/day dose.

    Reporting group title
    20 mg/kg/Day GWP42003-P
    Reporting group description
    GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 20 mg/kg/day dose was recommended by the Data Safety Monitoring Committee (DSMC) after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (2014-000995-24).

    Reporting group title
    Placebo Control
    Reporting group description
    Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent.

    Primary: Change In Convulsive Seizures During The Treatment Period Compared To Baseline

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    End point title
    Change In Convulsive Seizures During The Treatment Period Compared To Baseline
    End point description
    Convulsive seizures were defined as tonic–clonic, tonic, clonic, or atonic. Participants or their caregivers recorded the number and type of convulsive seizures each day from screening until completion of dosing using an interactive voice response system (IVRS) diary. The primary end point was analyzed using negative binomial regression on the sum of the convulsive seizure counts during the treatment period, based on the ITT analysis set. Baseline included all available data prior to Day 1. Data reported as the ratio of geometric least squares mean in convulsive seizures and expressed as a percentage reduction.
    End point type
    Primary
    End point timeframe
    Baseline to Day 99 or Early Termination (ET)
    End point values
    10 mg/kg/Day GWP42003-P 20 mg/kg/Day GWP42003-P Placebo Control
    Number of subjects analysed
    66
    67
    65
    Units: Percentage reduction
        number (confidence interval 95%)
    48.7 (37.9 to 57.6)
    45.7 (34.2 to 55.2)
    26.9 (11.9 to 39.4)
    Statistical analysis title
    20 mg/kg/Day GWP42003-P, Placebo Control
    Statistical analysis description
    Model includes total number of seizures as a response variable and age group, time (baseline and treatment period), treatment, and treatment by time interaction as fixed effects, and participant as a random effect. Log-transformed number of days in which seizures were reported by period is included as an offset. Null hypothesis was that the ratio of GWP42003-P to placebo would be 1.
    Comparison groups
    20 mg/kg/Day GWP42003-P v Placebo Control
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0299
    Method
    Negative binomial regression
    Parameter type
    Treatment Ratio
    Point estimate
    0.743
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.568
         upper limit
    0.971
    Statistical analysis title
    10 mg/kg/Day GWP42003-P, Placebo Control
    Statistical analysis description
    Model includes total number of seizures as a response variable and age group, time (baseline and treatment period), treatment, and treatment by time interaction as fixed effects, and participant as a random effect. Log-transformed number of days in which seizures were reported by period is included as an offset. Null hypothesis was that the ratio of GWP42003-P to placebo would be 1.
    Comparison groups
    10 mg/kg/Day GWP42003-P v Placebo Control
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0095
    Method
    Negative binomial regression
    Parameter type
    Treatment Ratio
    Point estimate
    0.702
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.538
         upper limit
    0.916

    Secondary: Change In Total Seizures During The Treatment Period Compared To Baseline

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    End point title
    Change In Total Seizures During The Treatment Period Compared To Baseline
    End point description
    Total seizures were defined as the combination of convulsive and non-convulsive seizures. Convulsive seizures were defined as tonic–clonic, tonic, clonic, or atonic seizures. Non-convulsive seizures were defined as myoclonic, countable partial, other partial, or absence seizures. Participants or their caregivers recorded the number and type of convulsive seizures and non-convulsive seizures each day from screening until completion of dosing using an IVRS diary. Change compared to baseline was calculated as per the primary outcome measure. Data reported as the ratio of geometric least squares mean in total seizures and expressed as a percentage reduction.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 99 or ET
    End point values
    10 mg/kg/Day GWP42003-P 20 mg/kg/Day GWP42003-P Placebo Control
    Number of subjects analysed
    66
    67
    65
    Units: Percentage reduction
        number (confidence interval 95%)
    56.4 (47.8 to 63.6)
    47.3 (36.9 to 56.0)
    29.7 (16.0 to 41.1)
    Statistical analysis title
    20 mg/kg/Day GWP42003-P, Placebo Control
    Statistical analysis description
    Model includes total number of seizures as a response variable and age group, time (baseline and treatment period), treatment, and treatment by time interaction as fixed effects, and participant as a random effect. Log-transformed number of days in which seizures were reported by period is included as an offset.
    Comparison groups
    Placebo Control v 20 mg/kg/Day GWP42003-P
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0255
    Method
    Negative binomial regression
    Parameter type
    Treatment Ratio
    Point estimate
    0.749
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.581
         upper limit
    0.965
    Statistical analysis title
    10 mg/kg/Day GWP42003-P, Placebo Control
    Statistical analysis description
    Model includes total number of seizures as a response variable and age group, time (baseline and treatment period), treatment, and treatment by time interaction as fixed effects, and participant as a random effect. Log-transformed number of days in which seizures were reported by period is included as an offset.
    Comparison groups
    10 mg/kg/Day GWP42003-P v Placebo Control
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Negative binomial regression
    Parameter type
    Treatment Ratio
    Point estimate
    0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.481
         upper limit
    0.799

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

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    End point title
    Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period
    End point description
    Convulsive seizures were defined as tonic–clonic, tonic, clonic, or atonic. Participants or their caregivers recorded the number and type of convulsive seizures each day from screening until completion of dosing using an IVRS diary. Baseline included all available data prior to Day 1 (28-day average). Percentage change from baseline was calculated as: ([frequency during the treatment period - frequency during baseline]/frequency during baseline) x 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) x 28. Baseline included all available data prior to Day 1 (28-day average).
    End point type
    Secondary
    End point timeframe
    Baseline to Day 99 or ET
    End point values
    10 mg/kg/Day GWP42003-P 20 mg/kg/Day GWP42003-P Placebo Control
    Number of subjects analysed
    66 [1]
    67 [2]
    65 [3]
    Units: Participants
    29
    33
    17
    Notes
    [1] - ITT
    [2] - ITT
    [3] - ITT
    Statistical analysis title
    20 mg/kg/Day GWP42003-P, Placebo Control
    Comparison groups
    20 mg/kg/Day GWP42003-P v Placebo Control
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0069 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.32
         upper limit
    5.7
    Notes
    [4] - P-value calculated from a Cochran–Mantel–Haenszel test stratified by age group (2–5, 6–12, and 13–18 years).
    Statistical analysis title
    10 mg/kg/Day GWP42003-P, Placebo Control
    Comparison groups
    10 mg/kg/Day GWP42003-P v Placebo Control
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0332 [5]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.06
         upper limit
    4.62
    Notes
    [5] - P-value calculated from a Cochran–Mantel–Haenszel test stratified by age group (2–5, 6–12, and 13–18 years).

    Secondary: Caregiver Global Impression Of Change (CGIC) At The Last Visit

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    End point title
    Caregiver Global Impression Of Change (CGIC) At The Last Visit
    End point description
    On Day 1 (prior to receiving study drug), 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. The CGIC questionnaire comprised the following question, to be rated on a 7-point scale: Since your child started treatment, please assess the status of your child’s overall condition (comparing their condition now to their condition before treatment) using the scale below. The markers were: “Very Much Improved”; “Much Improved”; “Slightly Improved”; “No Change”; “Slightly Worse”; “Much Worse”; “Very Much Worse”. The CGIC response/score, recorded at each visit, was summarized, on both a categorical and continuous scale, by treatment group. The scores at the last scheduled visit (not including the end of taper or safety follow-up visits) at which participant’s last evaluation was performed were analyzed using ordinal logistic regression.
    End point type
    Secondary
    End point timeframe
    Baseline to Last Visit
    End point values
    10 mg/kg/Day GWP42003-P 20 mg/kg/Day GWP42003-P Placebo Control
    Number of subjects analysed
    66 [6]
    66 [7]
    65 [8]
    Units: Participants
        Very Much Improved
    13
    11
    1
        Much Improved
    11
    10
    8
        Slightly Improved
    21
    19
    18
        No Change
    18
    17
    32
        Slightly Worse
    2
    5
    4
        Much Worse
    1
    3
    2
        Very Much Worse
    0
    1
    0
    Notes
    [6] - ITT
    [7] - ITT
    [8] - ITT
    Statistical analysis title
    20 mg/kg/Day GWP42003-P, Placebo Control
    Comparison groups
    Placebo Control v 20 mg/kg/Day GWP42003-P
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.0279
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.08
         upper limit
    3.78
    Notes
    [9] - Proportional odds modelling was carried out by including treatment group as a fixed factor. The estimated OR tested the null hypothesis that OR was equal to 1.
    Statistical analysis title
    10 mg/kg/Day GWP42003-P, Placebo Control
    Comparison groups
    10 mg/kg/Day GWP42003-P v Placebo Control
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    = 0.0009
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.56
         upper limit
    5.53
    Notes
    [10] - Proportional odds modelling was carried out by including treatment group as a fixed factor. The estimated OR tested the null hypothesis that OR was equal to 1.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 to Day 137.
    Adverse event reporting additional description
    Safety Analysis Set: Received at least 1 dose of study drug and were analyzed per treatment received. Two participants randomized to receive GWP42003-P 10 mg/kg/day titrated above the target dose and were therefore assigned to the GWP42003-P 20 mg/kg/day group for all safety analyses.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    10 mg/kg/Day GWP42003-P
    Reporting group description
    GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 10 mg/kg/day dose was defined as 50% of the 20 mg/kg/day dose.

    Reporting group title
    20 mg/kg/Day GWP42003-P
    Reporting group description
    GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 20 mg/kg/day dose was recommended by the DSMC after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (2014-000995-24).

    Reporting group title
    Placebo Control
    Reporting group description
    Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent.

    Serious adverse events
    10 mg/kg/Day GWP42003-P 20 mg/kg/Day GWP42003-P Placebo Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 64 (20.31%)
    17 / 69 (24.64%)
    10 / 65 (15.38%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 69 (2.90%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory depression
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Status epilepticus
         subjects affected / exposed
    5 / 64 (7.81%)
    7 / 69 (10.14%)
    8 / 65 (12.31%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 12
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalized tonic-clonic seizure
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 69 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 69 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure cluster
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 69 (0.00%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Unresponsive to stimuli
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 69 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug interaction
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychogenic seizure
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 69 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 64 (4.69%)
    2 / 69 (2.90%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coxsackie viral infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 69 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 69 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 69 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    10 mg/kg/Day GWP42003-P 20 mg/kg/Day GWP42003-P Placebo Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 64 (87.50%)
    60 / 69 (86.96%)
    58 / 65 (89.23%)
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    1 / 64 (1.56%)
    4 / 69 (5.80%)
    0 / 65 (0.00%)
         occurrences all number
    1
    4
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 64 (4.69%)
    8 / 69 (11.59%)
    0 / 65 (0.00%)
         occurrences all number
    3
    9
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 64 (4.69%)
    8 / 69 (11.59%)
    0 / 65 (0.00%)
         occurrences all number
    3
    9
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 64 (6.25%)
    4 / 69 (5.80%)
    3 / 65 (4.62%)
         occurrences all number
    4
    4
    3
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    4 / 65 (6.15%)
         occurrences all number
    0
    1
    4
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    14 / 64 (21.88%)
    16 / 69 (23.19%)
    9 / 65 (13.85%)
         occurrences all number
    17
    20
    9
    Convulsion
         subjects affected / exposed
    3 / 64 (4.69%)
    4 / 69 (5.80%)
    4 / 65 (6.15%)
         occurrences all number
    3
    6
    5
    Tremor
         subjects affected / exposed
    0 / 64 (0.00%)
    4 / 69 (5.80%)
    0 / 65 (0.00%)
         occurrences all number
    0
    4
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    15 / 64 (23.44%)
    14 / 69 (20.29%)
    11 / 65 (16.92%)
         occurrences all number
    21
    22
    15
    Fatigue
         subjects affected / exposed
    5 / 64 (7.81%)
    14 / 69 (20.29%)
    7 / 65 (10.77%)
         occurrences all number
    7
    17
    8
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 64 (1.56%)
    6 / 69 (8.70%)
    2 / 65 (3.08%)
         occurrences all number
    1
    6
    2
    Irritability
         subjects affected / exposed
    3 / 64 (4.69%)
    5 / 69 (7.25%)
    2 / 65 (3.08%)
         occurrences all number
    4
    5
    3
    Abnormal behaviour
         subjects affected / exposed
    0 / 64 (0.00%)
    4 / 69 (5.80%)
    0 / 65 (0.00%)
         occurrences all number
    0
    5
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 64 (17.19%)
    18 / 69 (26.09%)
    8 / 65 (12.31%)
         occurrences all number
    16
    23
    9
    Vomiting
         subjects affected / exposed
    4 / 64 (6.25%)
    11 / 69 (15.94%)
    4 / 65 (6.15%)
         occurrences all number
    4
    13
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 64 (15.63%)
    19 / 69 (27.54%)
    11 / 65 (16.92%)
         occurrences all number
    10
    19
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 64 (6.25%)
    8 / 69 (11.59%)
    5 / 65 (7.69%)
         occurrences all number
    4
    11
    6
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 64 (4.69%)
    4 / 69 (5.80%)
    3 / 65 (4.62%)
         occurrences all number
    3
    4
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 64 (0.00%)
    4 / 69 (5.80%)
    1 / 65 (1.54%)
         occurrences all number
    0
    5
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Oct 2014
    Addition of a secondary objective/end point to evaluate change in duration of subtypes of seizures as assessed by the Caregiver Global Impression of Change in Seizure Duration. Clarification of the exclusion criteria addressing previous and current use of cannabinoids. Additional collection of a full record of genetic testing and prior antiepileptic drugs taken as part of the participant’s medical history for safety assessment and to aid/confirm diagnosis of Dravet Syndrome. Clarification that the baseline period must be a minimum of 28 days in order to capture sufficient baseline data. Clarification that the safety follow-up period must be a minimum of 28 days after end of treatment in order to capture sufficient safety data. Clarification of subtypes of seizures and definition of “countable partial seizures” in order to aid identification of seizure types. Clarification that the cognitive assessment battery will only be performed at sites that have the expertise to conduct the test. Pre-randomization pregnancy test to be performed using urine rather than serum in order to provide an immediate result for assessment of inclusion/exclusion criteria. Inclusion of the Pediatric Cannabinoid Withdrawal Scale for children 4–17 years of age.
    20 Nov 2014
    Cases of Drug-Induced Liver Injury must be a criterion for withdrawal from study treatment.
    20 Mar 2015
    Specified participants be stratified by age across treatment arms. Added assessment of growth and development through measurement of height, body weight, serum insulin-like growth factor 1 levels, and Tanner staging. Added measurement of effects of menstruation. Amended statistical methods for analysis of primary and secondary end points. Added blood sampling for pharmacokinetics (PK) analyses of cannabidiol and major metabolites. Added measurement of serum triglycerides in clinical laboratory assessments. Added electrocardiogram and clinical laboratory assessments at the ‘End of Taper’ visit for participants who withdrew early and tapered the investigational medicinal product (IMP) and for participants who opted not to enter the open-label extension. Increased the number of participants per treatment group from 40 to 50 (total increase from 120 to 150) and amended assumption that participants in the placebo group would experience a mean reduction in convulsive seizure frequency of 10 to 18%. Added eligibility criterion excluding participants taking felbamate for <1 year. Felbamate was also listed as a prohibited therapy if taken for <1 year. Clarified use of the Epilepsy study consortium to verify each participant’s seizure subtypes and diagnosis of Dravet syndrome. Amended wording to allow participants who suspended IMP dosing due to an adverse event to resume dosing prior to complete recovery, provided that the adverse event was well tolerated. Added secondary end points to align the protocol with the open-label extension and edited primary and secondary end points to clarify that total number of convulsive and non-convulsive seizures would be measured. Clarified when the Cognitive Assessment Battery should be administered. Clarified that even though participants may achieve target dose before the end of the 2-week titration period, the titration period was 2 weeks to ensure all participants achieved stable dosing.
    29 Jun 2015
    Updated statistical analyses of the primary and secondary end points to include the full treatment period (titration plus maintenance period). Updated the lower age limit for Tanner Staging to include adolescent participants aged 10–17 (inclusive) or earlier if clinically indicated by the onset of menarche or other signs of precocious puberty. Replaced wording of concomitant AED blood sampling in the event of an adverse event with a secondary objective/end point requesting the investigator monitor plasma concomitant AED levels and discuss results with the GW medical monitor. Samples were only to be taken if the risk/benefit outcome was favorable, in the investigator’s opinion. Reclassified effects on menstruation as a safety measure. Amended responder and sensitivity analyses to state the average number of seizures per 28 days rather than per week. Clarified the convulsive seizure inclusion criterion to state that only the first 28 days of the baseline period counted towards a participant’s eligibility. Removed the Socioeconomic Scale test item (parent measure) from the Cognitive Assessment Battery as it was not possible to standardize this end point across different countries. Clarified blood sampling for PK was only to be taken from participants weighing ≥20 kg. Sampling times and windows were also clarified. Clarified the age restriction for Columbia-Suicide Severity Rating Scale suitability to include consideration of developmental delays as well as age.
    23 Feb 2017
    Increased the number of participants per treatment group from 50 to 62 (a total increase from 150 to 186). Changed the statistical analyses of seizure data to use nonparametric rather than parametric methods. Added assessments of plasma and urine concentrations of tetrahydrocannabinol and its major metabolites, and urine concentrations of cannabidiol and its major metabolites. Amended the PK parameters to allow for accurate determination of the defined parameters. Clarified that any clinical symptoms of concern resulting from possible drug-drug interactions should be discussed with the GW medical monitor and if required, adjustments to AEDs would be permitted. Broadened the mode of IMP administration to encompass participants who have difficulty swallowing.

    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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