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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
    		 2014-002941-23
    Trial protocol
    		 NL   PL  
    Global end of trial date
    18 Mar 2016

    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
    GWEP1423
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02224690
    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, GW Research Ltd., medinfo@gwpharm.com
    Scientific contact
    GW Research Ltd., 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
    24 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    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 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. 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
    28 Apr 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
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 38
    Country: Number of subjects enrolled
    United States: 128
    Worldwide total number of subjects
    171
    EEA total number of subjects
    43
    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)
    76
    Adolescents (12-17 years)
    37
    Adults (18-64 years)
    58
    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 level of 20 milligram per kilogram per day (mg/kg/day) was recommended by the Data Safety Monitoring Committee (DSMC) of study GWEP1332 Part A (NCT02091206) after assessment of safety/pharmacokinetic data. The investigational medicinal product (IMP) was given daily in 2 doses to align with the preferred regimen for anti-epileptic drugs.

    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 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 liquid, 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
    		 Placebo
    Arm description
    		 Participants received placebo (0 mg/mL CBD), volume matched to the 20 mg/kg/day dose, 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) period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    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 Placebo
    Started
    86
    85
    Intent to Treat (ITT) Analysis Set
    86
    85
    Safety Analysis Set
    86
    85
    Completed
    72
    84
    Not completed
    14
    1
         Use of G-tube
    1
    -
         Adverse Event
    8
    1
         Did not meet eligibility criteria
    1
    -
         Met Withdrawal Criteria
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GWP42003-P 20 mg/kg/day Dose
    Reporting group description
    		 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 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
    Placebo
    Reporting group description
    		 Participants received placebo (0 mg/mL CBD), volume matched to the 20 mg/kg/day dose, 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) period.

    Reporting group values
    		 GWP42003-P 20 mg/kg/day Dose Placebo Total
    Number of subjects
    		 86 85 171
    Age categorical
    Units: Subjects
        2-11 years
    		 37 39 76
        12-17 years
    		 19 18 37
        18-64 years
    		 30 28 58
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.478 ± 8.685 15.284 ± 9.7945 -
    Gender categorical
    Units: Subjects
        Female
    		 41 42 83
        Male
    		 45 43 88

    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 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
    Placebo
    Reporting group description
    		 Participants received placebo (0 mg/mL CBD), volume matched to the 20 mg/kg/day dose, 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) period.

    Subject analysis set title
    GWP42003-P 20 mg/kg/day Dose-ITT 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 received (GWP42003-P 20 mg/kg/day).

    Subject analysis set title
    Placebo-ITT 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 received (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) * 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)
    End point values
    		 GWP42003-P 20 mg/kg/day Dose-ITT Set Placebo-ITT Set
    Number of subjects analysed
    86
    85
    Units: percentage change
        median (inter-quartile range (Q1-Q3))
    -43.90 (-69.62 to 1.93)
    -21.80 (-45.72 to 1.74)
    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 Set v Placebo-ITT Set
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0135
    Method
    		 Wilcoxon rank sum test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -17.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.32
         upper limit
    		 -4.09

    Secondary: Participants With ≥50% Reduction From Baseline in Drop Seizure Frequency During The Treatment Period

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    End point title
    		 Participants With ≥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 Set Placebo-ITT Set
    Number of subjects analysed
    86
    86
    Units: Participants
    38
    20
    Statistical analysis title
    		 Number Of 50% Responders 20 mg/kg/day
    Comparison groups
    GWP42003-P 20 mg/kg/day Dose-ITT Set v Placebo-ITT Set
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0043 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.33
         upper limit
    		 4.97
    Notes
    [1] - Calculated using a Cochran-Mantel-Haenszel 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 Set Placebo-ITT Set
    Number of subjects analysed
    86
    85
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    -41.24 (-62.85 to -13.00)
    -13.70 (-45.00 to 7.27)
    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 Set v Placebo-ITT Set
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005
    Method
    		 Wilcoxon rank sum test
    Parameter type
    		 Median difference (final values)
    Point estimate
    -21.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.26
         upper limit
    		 -9.37

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

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    End point title
    		 Subject/Caregiver Global Impression Of Change (S/CGIC)
    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 Set Placebo-ITT Set
    Number of subjects analysed
    86
    85
    Units: Participants
        Very Much Improved
    15
    5
        Much Improved
    14
    9
        Slightly Improved
    20
    15
        No Change
    27
    43
        Slightly Worse
    7
    9
        Much Worse
    1
    2
        Very Much Worse
    0
    2
    Statistical analysis title
    		 Subject/Caregiver Global Impression Of Change
    Statistical analysis description
    The odds ratio represents the odds of participant recording a lower score (improvement) on a continuous scale.
    Comparison groups
    GWP42003-P 20 mg/kg/day Dose-ITT Set v Placebo-ITT Set
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0012
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.45
         upper limit
    		 4.47
    Notes
    [2] - 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: All participants randomized to treatment who received at least 1 dose of IMP. Participants were analyzed according to the treatment group to which they received.
    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 Set
    Reporting group description
    		 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 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- Safety Set
    Reporting group description
    		 Participants received placebo (0 mg/mL CBD), volume matched to the 20 mg/kg/day dose, 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) period.

    Serious adverse events
    		 GWP42003-P 20 mg/kg/day Dose- Safety Set Placebo- Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 86 (23.26%)
    4 / 85 (4.71%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 86 (4.65%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 86 (4.65%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug level increased
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure cluster
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia adenoviral
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 85 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 GWP42003-P 20 mg/kg/day Dose- Safety Set Placebo- Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    53 / 86 (61.63%)
    43 / 85 (50.59%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    12 / 86 (13.95%)
    8 / 85 (9.41%)
         occurrences all number
    13
    8
    Sedation
         subjects affected / exposed
    7 / 86 (8.14%)
    1 / 85 (1.18%)
         occurrences all number
    8
    1
    Convulsion
         subjects affected / exposed
    3 / 86 (3.49%)
    5 / 85 (5.88%)
         occurrences all number
    3
    5
    Headache
         subjects affected / exposed
    2 / 86 (2.33%)
    5 / 85 (5.88%)
         occurrences all number
    2
    7
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    11 / 86 (12.79%)
    7 / 85 (8.24%)
         occurrences all number
    14
    8
    Fatigue
         subjects affected / exposed
    5 / 86 (5.81%)
    2 / 85 (2.35%)
         occurrences all number
    6
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    16 / 86 (18.60%)
    7 / 85 (8.24%)
         occurrences all number
    18
    8
    Vomiting
         subjects affected / exposed
    8 / 86 (9.30%)
    14 / 85 (16.47%)
         occurrences all number
    16
    16
    Constipation
         subjects affected / exposed
    5 / 86 (5.81%)
    4 / 85 (4.71%)
         occurrences all number
    5
    4
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    7 / 86 (8.14%)
    2 / 85 (2.35%)
         occurrences all number
    7
    2
    Cough
         subjects affected / exposed
    5 / 86 (5.81%)
    2 / 85 (2.35%)
         occurrences all number
    5
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    6 / 86 (6.98%)
    1 / 85 (1.18%)
         occurrences all number
    7
    1
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    5 / 86 (5.81%)
    2 / 85 (2.35%)
         occurrences all number
    5
    2
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 86 (2.33%)
    6 / 85 (7.06%)
         occurrences all number
    2
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 86 (12.79%)
    2 / 85 (2.35%)
         occurrences all number
    11
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2014
    • Clarified the definition of drop seizure. • Added a secondary objective/endpoint to evaluate change in duration of subtypes of seizures as assessed by the Combined Subject/Caregiver Global Impression of Change Score. • Clarified the exclusion criteria addressing previous and current use of cannabinoids. • Added additional collection of a full record of epilepsy-specific genetic testing and prior antiepileptic drugs taken as part of the participant’s medical history for safety assessment and to aid/confirm diagnosis of LGS. • Clarified that IMP usage was recorded via the paper diary in order to reduce the IVRS call time. • Clarified that the baseline period must be a minimum of 28 days in order to capture sufficient baseline data. • Clarified that the safety follow-up period must be a minimum of 28 days after EOT in order to capture sufficient safety data. • Clarified the subtypes of seizures and definition of “countable partial seizures” in order to aid identification of seizure types. • Clarified that the pre-randomization pregnancy test was performed using urine rather than serum in order to provide an immediate result for assessment of inclusion/exclusion criteria. • Added the Pediatric Cannabinoid Withdrawal Scale for children 4–17 years of age.
    05 Feb 2015
    • Clarified the definition of drop seizures by removal of ‘clonic’ and ‘myoclonic’ from the definition. • Clarified the criteria for withdrawal. • Added the following assessments to reflect the addition of secondary objectives: Pharmacokinetics, Cognitive Assessment Battery, Growth and Development measurements, Insulin-like growth factor-1 levels, menstruation and Tanner Staging. • Updated references to reflect the latest safety information.
    03 Jun 2015
    • Changed business address. • Added age ranges to participant growth and development monitoring of IGF-1 levels and Tanner Staging. • Reclassified menstruation as a safety measure, rather than an efficacy measure. • Clarified the PK monitoring of CBD and its major metabolites based on participants weight. • Clarified the statistical methods for the primary and secondary endpoints. • Clarified ‘End of Treatment’ visit and withdrawal visit procedures. • Clarified the exclusion criteria relating to hepatic function. • Added clinical laboratory sample measurement of serum triglycerides and blood urea nitrogen. • Added participant stratification by age across treatment arms. • Added follow-up procedures for potential cases of drug-induced liver injury. • Increased participant numbers based on expanded review of published clinical trial data. • Amended responder and sensitivity analysis. • Updated eligibility criteria contraception requirements. • Updated eligibility criteria compliance statement. • Updated the cognitive assessment battery by removing the Socioeconomic Scale test and allowing a +3 day window for completion on a separate day if necessary. • Added antiepileptic drug monitoring as secondary objective/endpoint. • Clarified liver function testing. • Updated recommended target dose and titration regimen based on the Data Safety Monitoring Committee of trial GWEP1332 Part A. • Clarified drop seizure inclusion criteria.
    19 Jun 2015
    • Clarification of eligibility was incorporated. • Clarification of trial procedures • Updated eligibility criteria regarding impaired hepatic function.

    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/29395273
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