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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled study to investigate the efficacy and safety of cannabidiol (GWP42003-P; CBD) as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in children and adults

    Summary
    EudraCT number
    2014-002940-42
    Trial protocol
    GB   ES  
    Global end of trial date
    19 May 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    GWEP1414
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02224560
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GW Research Ltd.
    Sponsor organisation address
    Sovereign House, Vision Park, Chivers Way, Histon, Cambridge, United Kingdom, CB24 9BZ
    Public contact
    GW Research Ltd., Alternate contact: medinfo@greenwichbiosciences.com, medinfo@gwpharm.com
    Scientific contact
    GW Research Ltd., Alternate contact: medinfo@greenwichbiosciences.com, medinfo@gwpharm.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-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
    19 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    19 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of GWP42003-P as adjunctive treatment in reducing the number of drop seizures when compared with placebo in participants with Lennox-Gastaut syndrome (LGS).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation 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. No study procedures were performed on study candidates until written consent had been obtained from the participant’s parent(s)/legal representative(s) and, if appropriate, written assent had been obtained from the participant. The informed consent form, protocol, and amendments for this study were submitted to and approved by the institutional review board or independent ethics committee at each participating study site.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Jun 2015
    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 Kingdom: 11
    Country: Number of subjects enrolled
    United States: 181
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Spain: 32
    Worldwide total number of subjects
    225
    EEA total number of subjects
    44
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    99
    Adolescents (12-17 years)
    59
    Adults (18-64 years)
    67
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The dose levels of 10 and 20 milligram (mg) per kilogram (kg) per day (mg/kg/day) were recommended by the Data Safety Monitoring Committee (DSMC) of study GWEP1332 Part A (NCT02091206) after assessment of safety and pharmacokinetic data. Participants of GWEP1414 were not enrolled until the DSMC had reviewed the safety data of GWEP1332 Part A.

    Period 1
    Period 1 title
    Baseline, Treatment, and Follow-up (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
    GWP42003-P 20 mg/kg/day Dose
    Arm description
    Participants received GWP42003-P 20 milligrams (mg) per kilogram (kg) per day (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 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
    Cannabidiol, CBD, Epidiolex
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    GWP42003-P was presented as an oral solution containing 100 mg/milliliter (mL) cannabidiol (CBD) 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
    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 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.
    Arm type
    Experimental

    Investigational medicinal product name
    GWP42003-P
    Investigational medicinal product code
    Other name
    Cannabidiol, CBD, Epidiolex
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    GWP42003-P was presented as an oral solution containing 100 mg/mL CBD 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
    Placebo
    Arm description
    Participants received placebo (0 mg/mL CBD) volume matched to 1 of the 2 dose levels (10 or 20 mg/kg/day), 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 7 to 11 days according to the matched investigational medicinal product (IMP) group (7 or 11 days for the 10 or 20 mg/kg/day GWP42003-P groups, respectively) 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
    Placebo control
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was presented as an oral solution containing 0 mg/mL CBD 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
    GWP42003-P 20 mg/kg/day Dose GWP42003-P 10 mg/kg/day Dose Placebo
    Started
    76
    73
    76
    Intent to Treat (ITT) Analysis Set
    76
    73
    76
    Completed
    67
    71
    74
    Not completed
    9
    2
    2
         Protocol deviation
    1
    -
    -
         Withdrawal by Subject
    2
    -
    1
         Met withdrawal criteria
    1
    -
    -
         Adverse event
    4
    1
    1
         Withdrawn by investigator
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline, Treatment, and Follow-up
    Reporting group description
    ITT Analysis Set: Received at least 1 dose of IMP with at least 1 post-baseline efficacy endpoint measurement. Participants were analyzed according to the treatment group to which they were randomized.

    Reporting group values
    Baseline, Treatment, and Follow-up Total
    Number of subjects
    225 225
    Age categorical
    Units: Subjects
        Children (2-11 years)
    99 99
        Adolescents (12-17 years)
    59 59
        Adults (18-64 years)
    67 67
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    15.6 ± 9.8 -
    Gender categorical
    Units: Subjects
        Female
    96 96
        Male
    129 129
    Subject analysis sets

    Subject analysis set title
    GWP42003-P 20 mg/kg/day Dose-ITT Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received at least 1 dose of IMP with at least 1 post-baseline efficacy endpoint measurement; analyzed according to the treatment group to which they were randomized (GWP42003-P 20 mg/kg/day).

    Subject analysis set title
    GWP42003-P 10 mg/kg/day-ITT Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received at least 1 dose of IMP with at least 1 post-baseline efficacy endpoint measurement; analyzed according to the treatment group to which they were randomized (GWP42003-P 10 mg/kg/day).

    Subject analysis set title
    Placebo-ITT Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received at least 1 dose of IMP with at least 1 post-baseline efficacy endpoint measurement; analyzed according to the treatment group to which they were randomized (Placebo).

    Subject analysis sets values
    GWP42003-P 20 mg/kg/day Dose-ITT Analysis Set GWP42003-P 10 mg/kg/day-ITT Analysis Set Placebo-ITT Analysis Set
    Number of subjects
    76
    73
    76
    Age categorical
    Units: Subjects
        Children (2-11 years)
    34
    32
    33
        Adolescents (12-17 years)
    20
    19
    20
        Adults (18-64 years)
    22
    22
    23
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    16.0 ± 10.8
    15.4 ± 9.5
    15.3 ± 9.3
    Gender categorical
    Units: Subjects
        Female
    31
    33
    32
        Male
    45
    40
    44

    End points

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    End points reporting groups
    Reporting group title
    GWP42003-P 20 mg/kg/day Dose
    Reporting group description
    Participants received GWP42003-P 20 milligrams (mg) per kilogram (kg) per day (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 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
    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 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
    Placebo
    Reporting group description
    Participants received placebo (0 mg/mL CBD) volume matched to 1 of the 2 dose levels (10 or 20 mg/kg/day), 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 7 to 11 days according to the matched investigational medicinal product (IMP) group (7 or 11 days for the 10 or 20 mg/kg/day GWP42003-P groups, respectively) 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.

    Subject analysis set title
    GWP42003-P 20 mg/kg/day Dose-ITT Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received at least 1 dose of IMP with at least 1 post-baseline efficacy endpoint measurement; analyzed according to the treatment group to which they were randomized (GWP42003-P 20 mg/kg/day).

    Subject analysis set title
    GWP42003-P 10 mg/kg/day-ITT Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received at least 1 dose of IMP with at least 1 post-baseline efficacy endpoint measurement; analyzed according to the treatment group to which they were randomized (GWP42003-P 10 mg/kg/day).

    Subject analysis set title
    Placebo-ITT Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received at least 1 dose of IMP with at least 1 post-baseline efficacy endpoint measurement; analyzed according to the treatment group to which they were randomized (Placebo).

    Primary: Percentage Change From Baseline In Drop Seizure Frequency During The Treatment Period

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    End point title
    Percentage Change From Baseline In Drop Seizure Frequency During The Treatment Period
    End point description
    Drop seizures were recorded by the participant or caregiver using an interactive voice response system (IVRS) diary. Drop seizures were defined as the subset of tonic-clonic, tonic or atonic seizures that were reported as drop seizures in the IVRS. 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). 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)
    End point values
    GWP42003-P 20 mg/kg/day Dose-ITT Analysis Set GWP42003-P 10 mg/kg/day-ITT Analysis Set Placebo-ITT Analysis Set
    Number of subjects analysed
    76
    73
    76
    Units: percentage change
        median (inter-quartile range (Q1-Q3))
    -41.86 (-72.4 to -1.3)
    -37.16 (-63.8 to -5.6)
    -17.17 (-37.1 to 0.9)
    Statistical analysis title
    Change From Baseline In Drop Seizures 20 mg/kg/day
    Statistical analysis description
    The P-value was calculated by using the Wilcoxon rank-sum test; the point estimate and confidence intervals were calculated by using the Hodges–Lehmann approach.
    Comparison groups
    GWP42003-P 20 mg/kg/day Dose-ITT Analysis Set v Placebo-ITT Analysis Set
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0047
    Method
    Wilcoxon rank-sum test
    Parameter type
    Median difference (final values)
    Point estimate
    -21.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -34.79
         upper limit
    -6.67
    Statistical analysis title
    Change From Baseline In Drop Seizures 10 mg/kg/day
    Statistical analysis description
    The P-value was calculated by using the Wilcoxon rank-sum test; the point estimate and confidence intervals were calculated by using the Hodges–Lehmann approach.
    Comparison groups
    GWP42003-P 10 mg/kg/day-ITT Analysis Set v Placebo-ITT Analysis Set
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0016
    Method
    Wilcoxon rank-sum test
    Parameter type
    Median difference (final values)
    Point estimate
    -19.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -31.24
         upper limit
    -7.69

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

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    End point title
    Number Of Participants With A ≥50% Reduction From Baseline In Drop Seizure Frequency During The Treatment Period
    End point description
    Drop seizures were recorded by the participant or caregiver using an IVRS diary. Drop seizures included the subset of tonic-clonic, tonic, or atonic seizures that were reported as drop seizures in 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
    End point values
    GWP42003-P 20 mg/kg/day Dose-ITT Analysis Set GWP42003-P 10 mg/kg/day-ITT Analysis Set Placebo-ITT Analysis Set
    Number of subjects analysed
    76
    73
    76
    Units: participants
    30
    26
    11
    Statistical analysis title
    Number of 50% Responders 20 mg/kg/day
    Comparison groups
    GWP42003-P 20 mg/kg/day Dose-ITT Analysis Set v Placebo-ITT Analysis Set
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.75
         upper limit
    8.47
    Notes
    [1] - Calculated using a Cochran-Mantel-Haenszel (CMH) test stratified by age group (2-5, 6-11, 12-17 and 18-55 years)
    Statistical analysis title
    Number of 50% Responders 10 mg/kg/day
    Comparison groups
    GWP42003-P 10 mg/kg/day-ITT Analysis Set v Placebo-ITT Analysis Set
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.47
         upper limit
    7.26
    Notes
    [2] - Calculated using a CMH test stratified by age group (2-5, 6-11, 12-17 and 18-55 years)

    Secondary: Percentage Change From Baseline In Total Seizure Frequency During The Treatment Period

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    End point title
    Percentage Change From Baseline In Total Seizure Frequency During The Treatment Period
    End point description
    Total seizures included the sum of all seizures (tonic-clonic, tonic, atonic, clonic, myoclonic, countable partial, other partial, and absence seizures) recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure. Negative percentages show an improvement from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Day 99) or ET
    End point values
    GWP42003-P 20 mg/kg/day Dose-ITT Analysis Set GWP42003-P 10 mg/kg/day-ITT Analysis Set Placebo-ITT Analysis Set
    Number of subjects analysed
    76
    73
    76
    Units: percentage change
        median (inter-quartile range (Q1-Q3))
    -38.40 (-64.6 to -0.7)
    -36.44 (-64.5 to -10.8)
    -18.47 (-39.0 to 0.5)
    Statistical analysis title
    Change in Total Seizure Frequency 20 mg/kg/day
    Statistical analysis description
    The P-value was calculated by using the Wilcoxon rank-sum test; the point estimate and confidence intervals were calculated by using the Hodges–Lehmann approach.
    Comparison groups
    GWP42003-P 20 mg/kg/day Dose-ITT Analysis Set v Placebo-ITT Analysis Set
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0091
    Method
    Wilcoxon rank-sum test
    Parameter type
    Median difference (final values)
    Point estimate
    -18.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -31.8
         upper limit
    -4.43
    Statistical analysis title
    Change in Total Seizure Frequency 10 mg/kg/day
    Statistical analysis description
    The P-value was calculated by using the Wilcoxon rank-sum test; the point estimate and confidence intervals were calculated by using the Hodges–Lehmann approach.
    Comparison groups
    GWP42003-P 10 mg/kg/day-ITT Analysis Set v Placebo-ITT Analysis Set
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0015
    Method
    Wilcoxon rank-sum test
    Parameter type
    Median difference (final values)
    Point estimate
    -19.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -30.37
         upper limit
    -7.47

    Secondary: Subject/Caregiver Global Impression Of Change (S/CGIC) Assessment

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    End point title
    Subject/Caregiver Global Impression Of Change (S/CGIC) Assessment
    End point description
    The S/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 S/CGIC questionnaire at subsequent visits. If both a CGIC and SGIC were completed then the CGIC was used; if only a CGIC was completed then the CGIC was used; if only a SGIC was completed then the SGIC was used. 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
    End point values
    GWP42003-P 20 mg/kg/day Dose-ITT Analysis Set GWP42003-P 10 mg/kg/day-ITT Analysis Set Placebo-ITT Analysis Set
    Number of subjects analysed
    75
    73
    75
    Units: participants
        Very Much Improved
    6
    9
    1
        Much Improved
    15
    14
    8
        Slightly Improved
    22
    25
    24
        No Change
    25
    21
    35
        Slightly Worse
    6
    3
    4
        Much Worse
    1
    1
    3
        Very Much Worse
    0
    0
    0
    Statistical analysis title
    S/CGIC 20 mg/kg/day
    Statistical analysis description
    The OR represents the odds of participant recording a lower score (improvement) on a continuous scale.
    Comparison groups
    GWP42003-P 20 mg/kg/day Dose-ITT Analysis Set v Placebo-ITT Analysis Set
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0439 [3]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.02
         upper limit
    3.3
    Notes
    [3] - Ordinal logistic regression model with treatment group as a fixed factor.
    Statistical analysis title
    S/CGIC 10 mg/kg/day
    Statistical analysis description
    The OR represents the odds of participant recording a lower score (improvement) on a continuous scale.
    Comparison groups
    GWP42003-P 10 mg/kg/day-ITT Analysis Set v Placebo-ITT Analysis Set
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002 [4]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.41
         upper limit
    4.66
    Notes
    [4] - Ordinal logistic regression model with treatment group as a fixed factor

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 through Day 137 (Safety Follow-up)
    Adverse event reporting additional description
    Safety Analysis Set: Received at least 1 dose of IMP; analyzed as per actual treatment received. Six participants who were assigned to the GWP42003-P 10 mg/kg/day dose received dosing schedules for GWP42003-P 20 mg/kg/day. For safety analyses, these participants were assigned to the GWP42003-P 20 mg/kg/day group.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    GWP42003-P 20 mg/kg/day Dose-Safety Analysis Set
    Reporting group description
    Participants received at least 1 dose of IMP; analyzed as per actual treatment received. Six participants who were assigned to the GWP42003-P 10 mg/kg/day dose received dosing schedules for GWP42003-P 20 mg/kg/day. For safety analyses, these participants were assigned to the GWP42003-P 20 mg/kg/day group.

    Reporting group title
    GWP42003-P 10 mg/kg/day Dose-Safety Analysis Set
    Reporting group description
    Participants received at least 1 dose of IMP; analyzed as per actual treatment received. Six participants who were assigned to the GWP42003-P 10 mg/kg/day dose received dosing schedules for GWP42003-P 20 mg/kg/day. For safety analyses, these participants were assigned to the GWP42003-P 20 mg/kg/day group.

    Reporting group title
    Placebo-Safety Analysis Set
    Reporting group description
    Participants received at least 1 dose of IMP; analyzed as per actual treatment received.

    Serious adverse events
    GWP42003-P 20 mg/kg/day Dose-Safety Analysis Set GWP42003-P 10 mg/kg/day Dose-Safety Analysis Set Placebo-Safety Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 82 (15.85%)
    13 / 67 (19.40%)
    8 / 76 (10.53%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (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
    Injury, poisoning and procedural complications
    Delayed recovery from anaesthesia
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (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
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 67 (1.49%)
    0 / 76 (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
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigation
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 67 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 67 (1.49%)
    0 / 76 (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, thoracic and mediastinal disorders
    Hypoventilation
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 67 (1.49%)
    0 / 76 (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
    Hypoxia
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 67 (1.49%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (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
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 67 (1.49%)
    0 / 76 (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
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (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
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 67 (0.00%)
    0 / 76 (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
    Lethargy
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sedation
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 67 (1.49%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    4 / 82 (4.88%)
    7 / 67 (10.45%)
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device malfunction
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (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
    Pyrexia
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (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
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 67 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 67 (1.49%)
    0 / 76 (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
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (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
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 67 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 67 (1.49%)
    0 / 76 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 67 (1.49%)
    0 / 76 (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
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (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
    Pneumonia
         subjects affected / exposed
    2 / 82 (2.44%)
    3 / 67 (4.48%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 67 (1.49%)
    0 / 76 (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
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (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
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 67 (1.49%)
    0 / 76 (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 syncytial virus infection
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (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
    Tracheobronchitis
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 67 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 67 (0.00%)
    0 / 76 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    GWP42003-P 20 mg/kg/day Dose-Safety Analysis Set GWP42003-P 10 mg/kg/day Dose-Safety Analysis Set Placebo-Safety Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 82 (76.83%)
    36 / 67 (53.73%)
    40 / 76 (52.63%)
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    5 / 82 (6.10%)
    2 / 67 (2.99%)
    7 / 76 (9.21%)
         occurrences all number
    6
    3
    7
    Headache
         subjects affected / exposed
    5 / 82 (6.10%)
    2 / 67 (2.99%)
    3 / 76 (3.95%)
         occurrences all number
    5
    5
    5
    Lethargy
         subjects affected / exposed
    5 / 82 (6.10%)
    3 / 67 (4.48%)
    2 / 76 (2.63%)
         occurrences all number
    5
    3
    2
    Somnolence
         subjects affected / exposed
    25 / 82 (30.49%)
    14 / 67 (20.90%)
    4 / 76 (5.26%)
         occurrences all number
    31
    20
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 82 (9.76%)
    5 / 67 (7.46%)
    2 / 76 (2.63%)
         occurrences all number
    11
    5
    2
    Pyrexia
         subjects affected / exposed
    9 / 82 (10.98%)
    6 / 67 (8.96%)
    12 / 76 (15.79%)
         occurrences all number
    14
    7
    18
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 82 (4.88%)
    4 / 67 (5.97%)
    2 / 76 (2.63%)
         occurrences all number
    5
    4
    2
    Irritability
         subjects affected / exposed
    4 / 82 (4.88%)
    6 / 67 (8.96%)
    2 / 76 (2.63%)
         occurrences all number
    4
    6
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    12 / 82 (14.63%)
    7 / 67 (10.45%)
    6 / 76 (7.89%)
         occurrences all number
    16
    7
    9
    Vomiting
         subjects affected / exposed
    10 / 82 (12.20%)
    4 / 67 (5.97%)
    9 / 76 (11.84%)
         occurrences all number
    19
    5
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    21 / 82 (25.61%)
    11 / 67 (16.42%)
    6 / 76 (7.89%)
         occurrences all number
    23
    13
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 82 (10.98%)
    3 / 67 (4.48%)
    5 / 76 (6.58%)
         occurrences all number
    10
    4
    6
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 82 (12.20%)
    11 / 67 (16.42%)
    11 / 76 (14.47%)
         occurrences all number
    10
    13
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2015
    This amendment addressed the following issues: * Clarified the definition of drop seizures. * Updated secondary objectives to include “Change in duration of subtypes of seizures”. * Updated eligibility criteria for the electroencephalogram. * Clarified criteria for withdrawal. * Updated contact details in line with a change in GW Research Ltd’s business address. * Changed the visit windows. * Included a review of seizure history by the Epilepsy Study Consortium. * Specified that participants would be stratified by age across treatment arms. * Amended wording to allow participants who suspended IMP due to an adverse event to resume dosing prior to complete recovery, provided that the adverse event was well tolerated. * Added recording of additional medical history including antiepileptic drugs (AEDs) and epilepsy-specific genetic testing. * Included additional questionnaires: Subject/Caregiver Global Impression of Change in Seizure Duration (S/CGICSD) and Pediatric Cannabinoid Withdrawal Scale. * Revised ITT analysis set criteria per Food and Drug Administration (FDA) request. * Modified statistical analysis testing of the primary endpoint and additional statistical analysis of the secondary endpoints. * Amended the exclusion criteria to include contraception requirements and previous cannabis use. * Changed the statistical methods dealing with missing data. * Clarified that IMP usage was to be recorded via the paper diary to reduce the IVRS call time. * Incorporated additional assessments: pharmacokinetic, Cognitive Assessment Battery (CAB), Growth and Development measurements, insulin-like growth factor-1 levels, menstruation, and Tanner Staging per FDA request. * Updated references to reflect the latest safety information. * Corrected minor spelling/formatting/consistency issues.
    11 Jun 2015
    This amendment incorporated recommendations received from the United States competent authority (FDA). * Added measurement of serum triglycerides. * Clarified that the EOT visit would also be labeled as the Withdrawal visit. * Added 12-lead electrocardiogram and clinical laboratory assessments at the ‘End of Taper’ visit for participants who withdrew early and tapered IMP and for participants who opted not to enter the OLE study. * Clarified that during the follow-up of participants with potential cases of drug-induced liver injury, the levels of alanine or aspartate aminotransferase, total bilirubin, and alkaline phosphatase should be monitored until levels normalized or returned to normal. * Updated statistical analysis of the primary and secondary endpoints to include the full treatment period. * Updated lower age limit for Tanner Staging to include participants aged 10–17 (inclusive) or earlier if clinically indicated. * Specified that participants would be stratified by 4 age groups (2–5, 6–11, 12–17, and 18–55 years). In addition, the following changes were addressed: * Replaced wording of concomitant AED blood sampling in the event of an adverse event. * Clarification that the growth and development endpoint will only be assessed in participants < 18 years old. * Reclassified effects on menstruation as a safety measure. * Increased the number of participants per treatment group from 40 to 50 and amended the assumption that participants in the placebo group would experience a mean reduction in drop seizure frequency of 10% to 18%. * Replaced “High Dose Level” and “Low Dose Level” with “20 mg/kg/day” and “10 mg/kg/day,” respectively. * Clarified eligibility criteria. * Clarified blood sampling was only to be taken from participants weighing ≥ 20 kg. * Clarified statistical methods and liver function testing. * Removed the Socioeconomic Scale item from the CAB. * Amended responder and sensitivity analysis and the CGIC/CGICSD questionnaires.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/29768152
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