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    Clinical Trial Results:
    An open label extension study to investigate the safety of cannabidiol (GWP42003-P; CBD) in children and adults with inadequately controlled Dravet or Lennox-Gastaut Syndromes

    Summary
    EudraCT number
    2014-001834-27
    Trial protocol
    GB   ES   PL   NL   FR  
    Global end of trial date
    24 Sep 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Apr 2021
    First version publication date
    08 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GWEP1415
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02224573
    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
    Medical Enquiries, GW Research Ltd, medinfo@gwpharm.com
    Scientific contact
    Medical Enquiries, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was conducted to evaluate the long-term safety and tolerability of GWP42003-P, as adjunctive treatment, in children and adults with inadequately controlled Dravet Syndrome or Lennox-Gastaut Syndrome.
    Protection of trial subjects
    This trial was conducted in accordance with the ethical principles that have their origin in the World Medical Association (WMA) Declaration of Helsinki, adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and subsequent amendments. This trial was also designed to comply with International Council for Harmonisation (ICH) E6 Guideline for good clinical practice (EMA/CHMP/ICH/135/1995) and the European Clinical Trial Directive 2001/20/EC. The ICH-adopted guidelines and other relevant international guidelines, recommendations, and requirements were taken into account as comprehensively as possible, as long as they did not violate country-specific law.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Jun 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 24
    Country: Number of subjects enrolled
    Poland: 70
    Country: Number of subjects enrolled
    Spain: 71
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    United States: 460
    Worldwide total number of subjects
    681
    EEA total number of subjects
    182
    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)
    373
    Adolescents (12-17 years)
    179
    Adults (18-64 years)
    129
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects who completed the double-blind, placebo-controlled, clinical studies with GWP42003-P (Core Studies: GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) were eligible for enrollment.

    Period 1
    Period 1 title
    Treatment Phase
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dravet Syndrome
    Arm description
    Subjects with Dravet Syndrome who completed double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies: GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], and GWEP1424 [NCT02224703]) were titrated up to 10 to 20 milligrams per kilogram per day (mg/kg/day) GWP42003-P using a recommended titration schedule during the Titration Period. Subjects continued at this dose during the Maintenance Period. The maximum dose subjects could receive was 30 mg/kg/day.
    Arm type
    Experimental

    Investigational medicinal product name
    GWP42003-P
    Investigational medicinal product code
    GWP42003-P
    Other name
    EPIDIOLEX, cannabidiol, CBD-OS
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    100 milligrams per milliliter (mg/mL) cannabidiol (CBD) in sesame oil with anhydrous ethanol, added sweetener (sucralose) and strawberry flavoring

    Arm title
    Lennox-Gastaut Syndrome
    Arm description
    Subjects with Lennox-Gastaut Syndrome who completed double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies: GWEP1414 [NCT02224560] and GWEP1423 [NCT02224690]) were titrated up to 10 to 20 milligrams per kilogram per day (mg/kg/day) GWP42003-P using a recommended titration schedule during the Titration Period. Subjects continued at this dose during the Maintenance Period. The maximum dose subjects could receive was 30 mg/kg/day.
    Arm type
    Experimental

    Investigational medicinal product name
    GWP42003-P
    Investigational medicinal product code
    GWP42003-P
    Other name
    EPIDIOLEX, cannabidiol, CBD-OS
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    100 milligrams per milliliter (mg/mL) cannabidiol (CBD) in sesame oil with anhydrous ethanol, added sweetener (sucralose) and strawberry flavoring

    Number of subjects in period 1
    Dravet Syndrome Lennox-Gastaut Syndrome
    Started
    315
    366
    Completed
    170
    243
    Not completed
    145
    123
         Caregiver Asked to Stop IMP
    -
    1
         Started on Other IMP
    1
    -
         Subject Discontinued IMP
    -
    1
         Lack of efficacy
    15
    8
         Began Commerical Product
    1
    -
         Lack of Efficacy per Subject/Caregiver
    3
    3
         Met Withdrawal Criteria
    5
    7
         Subject Did Not Return for Visits
    -
    1
         Continued Compassionate Use
    1
    -
         Lack of Efficiency
    2
    1
         Subject Began Protocol-Excluded Treatment
    -
    1
         Subject Moved
    2
    -
         Withdrawal by Subject or Parent/Guardian
    62
    48
         Refused Medication
    1
    1
         Adverse event, non-fatal
    26
    38
         Placed in Group Home
    -
    1
         Pursued Other Trials
    1
    -
         Withdrawn by the Investigator
    23
    11
         Lost to follow-up
    2
    1
    Period 2
    Period 2 title
    Taper Phase
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dravet Syndrome
    Arm description
    Subjects with Dravet Syndrome who completed double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies: GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], and GWEP1424 [NCT02224703]) were titrated up to 10 to 20 milligrams per kilogram per day (mg/kg/day) GWP42003-P using a recommended titration schedule during the Titration Period. Subjects continued at this dose during the Maintenance Period. The maximum dose subjects could receive was 30 mg/kg/day.
    Arm type
    Experimental

    Investigational medicinal product name
    GWP42003-P
    Investigational medicinal product code
    Other name
    EPIDIOLEX, cannabidiol, CBD-OS
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    100 milligrams per milliliter (mg/mL) cannabidiol (CBD) in sesame oil with anhydrous ethanol, added sweetener (sucralose) and strawberry flavoring

    Arm title
    Lennox-Gastaut Syndrome
    Arm description
    Subjects with Lennox-Gastaut Syndrome who completed double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies: GWEP1414 [NCT02224560] and GWEP1423 [NCT02224690]) were titrated up to 10 to 20 milligrams per kilogram per day (mg/kg/day) GWP42003-P using a recommended titration schedule during the Titration Period. Subjects continued at this dose during the Maintenance Period. The maximum dose subjects could receive was 30 mg/kg/day.
    Arm type
    Experimental

    Investigational medicinal product name
    GWP42003-P
    Investigational medicinal product code
    Other name
    EPIDIOLEX, cannabidiol, CBD-OS
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    100 milligrams per milliliter (mg/mL) cannabidiol (CBD) in sesame oil with anhydrous ethanol, added sweetener (sucralose) and strawberry flavoring

    Number of subjects in period 2 [1]
    Dravet Syndrome Lennox-Gastaut Syndrome
    Started
    79
    71
    Completed
    76
    67
    Not completed
    3
    4
         Completed Incorrect Number of Taper Days
    1
    -
         Hospitalization/Dose Reduction
    1
    -
         Withdrawal by Subject or Parent/Guardian
    -
    3
         Adverse event, non-fatal
    1
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all subjects completing the Treatment Phase continued to the Taper Phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dravet Syndrome
    Reporting group description
    Subjects with Dravet Syndrome who completed double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies: GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], and GWEP1424 [NCT02224703]) were titrated up to 10 to 20 milligrams per kilogram per day (mg/kg/day) GWP42003-P using a recommended titration schedule during the Titration Period. Subjects continued at this dose during the Maintenance Period. The maximum dose subjects could receive was 30 mg/kg/day.

    Reporting group title
    Lennox-Gastaut Syndrome
    Reporting group description
    Subjects with Lennox-Gastaut Syndrome who completed double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies: GWEP1414 [NCT02224560] and GWEP1423 [NCT02224690]) were titrated up to 10 to 20 milligrams per kilogram per day (mg/kg/day) GWP42003-P using a recommended titration schedule during the Titration Period. Subjects continued at this dose during the Maintenance Period. The maximum dose subjects could receive was 30 mg/kg/day.

    Reporting group values
    Dravet Syndrome Lennox-Gastaut Syndrome Total
    Number of subjects
    315 366 681
    Age categorical
    Units: Subjects
        Children (2-11 years)
    216 157 373
        Adolescents (12-17 years)
    90 89 179
        Adults (18-64 years)
    9 120 129
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9.737 ± 4.4434 15.906 ± 9.5392 -
    Gender categorical
    Units: Subjects
        Female
    159 168 327
        Male
    156 198 354
    Race
    Not Applicable = Not applicable as per country-specific data protection law.
    Units: Subjects
        White/Caucasian
    269 325 594
        Black/African American
    10 15 25
        American Indian/Alaska Native
    1 0 1
        Asian
    6 10 16
        Not Applicable
    15 1 16
        Caucasian/Asian
    1 1 2
        Hispanic/Caucasian
    1 2 3
        White and Black Caribbean
    1 0 1
        Biracial
    2 1 3
        Caucasian and African American
    3 1 4
        Mulatto
    1 0 1
        North African
    1 0 1
        South American
    1 0 1
        Latino
    1 5 6
        Eurasian
    1 0 1
        Anglo-Indian
    1 0 1
        Indian
    0 2 2
        Unknown
    0 2 2
        Arab
    0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Dravet Syndrome
    Reporting group description
    Subjects with Dravet Syndrome who completed double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies: GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], and GWEP1424 [NCT02224703]) were titrated up to 10 to 20 milligrams per kilogram per day (mg/kg/day) GWP42003-P using a recommended titration schedule during the Titration Period. Subjects continued at this dose during the Maintenance Period. The maximum dose subjects could receive was 30 mg/kg/day.

    Reporting group title
    Lennox-Gastaut Syndrome
    Reporting group description
    Subjects with Lennox-Gastaut Syndrome who completed double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies: GWEP1414 [NCT02224560] and GWEP1423 [NCT02224690]) were titrated up to 10 to 20 milligrams per kilogram per day (mg/kg/day) GWP42003-P using a recommended titration schedule during the Titration Period. Subjects continued at this dose during the Maintenance Period. The maximum dose subjects could receive was 30 mg/kg/day.
    Reporting group title
    Dravet Syndrome
    Reporting group description
    Subjects with Dravet Syndrome who completed double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies: GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], and GWEP1424 [NCT02224703]) were titrated up to 10 to 20 milligrams per kilogram per day (mg/kg/day) GWP42003-P using a recommended titration schedule during the Titration Period. Subjects continued at this dose during the Maintenance Period. The maximum dose subjects could receive was 30 mg/kg/day.

    Reporting group title
    Lennox-Gastaut Syndrome
    Reporting group description
    Subjects with Lennox-Gastaut Syndrome who completed double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies: GWEP1414 [NCT02224560] and GWEP1423 [NCT02224690]) were titrated up to 10 to 20 milligrams per kilogram per day (mg/kg/day) GWP42003-P using a recommended titration schedule during the Titration Period. Subjects continued at this dose during the Maintenance Period. The maximum dose subjects could receive was 30 mg/kg/day.

    Primary: Number of subjects with any treatment-emergent adverse event (TEAE) occuring in ≥5% of subjects in any treatment group

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    End point title
    Number of subjects with any treatment-emergent adverse event (TEAE) occuring in ≥5% of subjects in any treatment group [1]
    End point description
    TEAEs, defined as AEs that started, worsened in severity or seriousness, following the first dose of investigational medicinal product in this study, are reported. Any AEs that continued from the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) were only classified as treatment emergent if they worsened in this study.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    315 [2]
    366 [3]
    Units: subjects
        Total subjects affected by any TEAE
    306
    353
        Diarrhoea
    135
    140
        Vomiting
    63
    107
        Constipation
    20
    43
        Nausea
    16
    32
        Pyrexia
    124
    126
        Fatigue
    39
    38
        Upper respiratory tract infection
    78
    104
        Nasopharyngitis
    78
    58
        Sinusitis
    38
    49
        Pneumonia
    35
    51
        Ear infection
    35
    50
        Influenza
    37
    45
        Urinary tract infection
    19
    51
        Pharyngitis streptococcal
    26
    27
        Gastroenteritis viral
    15
    30
        Otitis media
    21
    22
        Bronchitis
    15
    23
        Viral upper respiratory tract infection
    11
    20
        Gastroenteritis
    16
    7
        Fall
    22
    23
        Laceration
    8
    35
        Contusion
    15
    25
        Weight decreased
    21
    61
        Alanine aminotransferase increased
    37
    30
        Aspartate aminotransferase increased
    38
    19
        Gamma-glutamyltransferase increased
    32
    20
        Decreased appetite
    99
    93
        Convulsion
    79
    141
        Somnolence
    87
    107
        Status epilepticus
    47
    42
        Lethargy
    21
    34
        Headache
    18
    26
        Sedation
    16
    27
        Drooling
    11
    21
        Abnormal behaviour
    34
    23
        Insomnia
    16
    40
        Irritability
    26
    29
        Aggression
    20
    30
        Agitation
    9
    19
        Cough
    42
    63
        Nasal congestion
    13
    46
        Rhinorrhoea
    20
    19
        Pneumonia aspiration
    4
    22
        Hypoxia
    2
    21
    Notes
    [2] - Safety Analysis Set
    [3] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Number of subjects with clinically significant changes in the indicated vital sign values from the pre-randomization Baseline of the Core Study at any time post-dose

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    End point title
    Number of subjects with clinically significant changes in the indicated vital sign values from the pre-randomization Baseline of the Core Study at any time post-dose [4]
    End point description
    Clinical significance was determined by the investigator. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. SBP = Systolic Blood Pressure; DBP = Diastolic Blood Pressure; mmHg = millimeters of mercury. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of investigational medicinal product (IMP). Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    315 [5]
    366 [6]
    Units: subjects
        Sitting SBP < -20 mmHg
    59
    88
        Sitting SBP > 20 mmHg
    96
    120
        Sitting DBP < -10 mmHg
    139
    176
        Sitting DBP > 10 mmHg
    166
    191
        Pulse Rate < -15 beats per minute
    176
    192
        Pulse Rate > 15 beats per minute
    150
    179
        Weight ≤ -7 %
    47
    106
        Weight ≥ 7%
    213
    223
    Notes
    [5] - Safety Analysis Set
    [6] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in body mass index

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in body mass index [7]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    243 [8]
    294 [9]
    Units: kilograms per meters squared (kg/m^2)
        arithmetic mean (standard deviation)
    0.42 ± 2.701
    0.05 ± 5.863
    Notes
    [8] - Safety Analysis Set
    [9] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Number of subjects with clinically significant electrocardiogram (ECG) values at the pre-randomization Baseline of the Core Study and at any time post-dose

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    End point title
    Number of subjects with clinically significant electrocardiogram (ECG) values at the pre-randomization Baseline of the Core Study and at any time post-dose [10]
    End point description
    Clinical significance was determined by the investigator. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. QTcB = corrected QT interval with Bazette correction. msec = milliseconds. The time frame represents the duration for which subjects were enrolled in GWEP1415.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    315 [11]
    366 [12]
    Units: subjects
        QTcB > 450 msec, Baseline
    13
    21
        QTcB > 450 msec, any time post-dose
    62
    120
        QTcB > 480 msec, Baseline
    2
    4
        QTcB > 480 msec, any time post-dose
    10
    40
        QTcB > 500 msec, Baseline
    2
    2
        QTcB > 500 msec, any time post-dose
    7
    20
    Notes
    [11] - Safety Analysis Set
    [12] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Number of subjects with the indicated responses to questions regarding suicidal ideation and behavior using the Children’s Columbia-Suicide Severity Rating Scale (Children’s C-SSRS) at Day 1 and at any time post-dose

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    End point title
    Number of subjects with the indicated responses to questions regarding suicidal ideation and behavior using the Children’s Columbia-Suicide Severity Rating Scale (Children’s C-SSRS) at Day 1 and at any time post-dose [13]
    End point description
    The C-SSRS questionnaire is a brief, standardized measure that uniquely assesses the essential information (behavior, ideation, lethality, and severity) and distinguishes between suicidal occurrences and non-suicidal self-injury. Analysis was conducted in members of the safety analysis set defined as all subjects who took at least 1 dose of IMP.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    315 [14]
    366 [15]
    Units: subjects
        Any suicidality, Day 1
    1
    1
        Any suicidality, any time post-dose
    1
    2
        Suicidal ideation, Day 1
    0
    1
        Suicidal ideation, any time post-dose
    1
    2
        Suicidal behavior, Day 1
    1
    0
        Suicidal behavior, any time post-dose
    1
    0
        Complete suicidality, any time post-dose
    1
    0
    Notes
    [14] - Safety Analysis Set
    [15] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean Cannabis Withdrawal Scale Score at End of Taper, the Post-Taper Safety Call, and at Safety Follow-up

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    End point title
    Mean Cannabis Withdrawal Scale Score at End of Taper, the Post-Taper Safety Call, and at Safety Follow-up [16]
    End point description
    The Cannabinoid Withdrawal Scale is a 19-item scale, with each item (withdrawal symptom) measured on a 0 to 10 numerical rating scale (0 = Not at all; 5 = Moderately; 10 = Extremely). Scores are calculated as the sum of the 19 items for each measure (each separate score has a theoretical maximum of 190). Higher scores indicate more withdrawal symptoms and an increased negative impact to quality of life. The subject/caregiver was asked to record the extent to which each withdrawal symptom was experienced in the last 24 hours and also to rate the negative impact on normal daily activities. L24S = Last 24 Hours Score. NIS = Negative Impact on Normal Daily Activity Score. The End of Treatment visit occurred after a maximum of 4 years of treatment. The End of Taper occurred up to 10 days after the End of Treatment visit. The Safety Call and Safety Follow-up occurred 2 and 4 weeks, respectively, after the End of Taper. Only subjects with available data were analyzed.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    315 [17]
    366 [18]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        L24S, End of Taper, n=5, 11
    9.8 ± 10.64
    4.9 ± 14.00
        L24S, Post-Taper Safety Call, n=5, 8
    3.4 ± 4.72
    0.0 ± 0.00
        L24S, Safety Follow-Up, n=5, 11
    2.4 ± 3.36
    4.9 ± 12.27
        NIS, End of Taper, n=6, 18
    9.5 ± 12.03
    5.1 ± 10.96
        NIS, Post-Taper Safety Call, n=3, 13
    16.3 ± 3.79
    1.2 ± 3.00
        NIS, Safety Follow-Up, n=3, 10
    5.3 ± 9.24
    1.8 ± 3.82
    Notes
    [17] - Safety Analysis Set
    [18] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean Pediatric Cannabinoid Withdrawal Scale (PCWS) Score at the End of Treatment, the End of Taper, the Post-Taper Safety Call, and at Safety Follow-up

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    End point title
    Mean Pediatric Cannabinoid Withdrawal Scale (PCWS) Score at the End of Treatment, the End of Taper, the Post-Taper Safety Call, and at Safety Follow-up [19]
    End point description
    The PCWS was administered to subjects aged 4 to 17 (inclusive) that was developed from the 19-item validated CWS (adults) to assess mood, behavioral, and physical symptoms associated with cannabis. The total score was calculated as the sum of 10 items (rated on a 4-point scale: 0 = none; 1 = a little bit; 2 = quite a bit; 3 = a lot) and has a theoretical maximum of 30. Higher scores indicate more withdrawal symptoms and an increased negative impact to quality of life. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. The End of Treatment visit occurred after a maximum of 4 years (208 weeks from Visit 1) of treatment. The End of Taper occurred up to 10 days after the End of Treatment visit. The Safety Call and Safety Follow-up occurred 2 and 4 weeks, respectively, after the End of Taper. 9999 = standard deviation was not calculated for a single subject.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    315 [20]
    366 [21]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        End of Treatment, n=1, 1
    4.0 ± 9999
    6.0 ± 9999
        End of Taper, n=74, 46
    2.9 ± 3.77
    2.1 ± 2.78
        Post-Taper Safety Call, n=55, 25
    2.4 ± 3.50
    2.0 ± 2.72
        Safety Follow-Up, n=68, 34
    1.9 ± 2.72
    1.8 ± 2.28
    Notes
    [20] - Safety Analysis Set
    [21] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in red blood cells (RBCs)

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in red blood cells (RBCs) [22]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    268 [23]
    307 [24]
    Units: 10^12 cells per Liter (L)
        arithmetic mean (standard deviation)
    -0.068 ± 0.3297
    -0.059 ± 0.3424
    Notes
    [23] - Safety Analysis Set
    [24] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in hemoglobin

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in hemoglobin [25]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    268 [26]
    307 [27]
    Units: grams per Liter (g/L)
        arithmetic mean (standard deviation)
    -1.6 ± 9.08
    -2.4 ± 11.14
    Notes
    [26] - Safety Analysis Set
    [27] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in hematocrit

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in hematocrit [28]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [28] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    268 [29]
    307 [30]
    Units: percentage of RBCs in whole blood (L/L)
        arithmetic mean (standard deviation)
    -0.0105 ± 0.02938
    -0.0110 ± 0.02983
    Notes
    [29] - Subject Analysis Set
    [30] - Subject Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in erythrocyte mean corpuscular volume

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in erythrocyte mean corpuscular volume [31]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    268 [32]
    307 [33]
    Units: femtoliters (fL)
        arithmetic mean (standard deviation)
    -1.0 ± 5.10
    -1.3 ± 5.01
    Notes
    [32] - Safety Analysis Set
    [33] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in erythrocyte mean corpuscular hemoglobin

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in erythrocyte mean corpuscular hemoglobin [34]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [34] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    268 [35]
    307 [36]
    Units: picograms (pg)
        arithmetic mean (standard deviation)
    0.10 ± 1.482
    -0.15 ± 1.926
    Notes
    [35] - Safety Analysis Set
    [36] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in platelets, white blood cells, basophils, eosinophils, lymphocytes, monocytes, and neutrophils

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in platelets, white blood cells, basophils, eosinophils, lymphocytes, monocytes, and neutrophils [37]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    315 [38]
    366 [39]
    Units: 10^9 cells/L
    arithmetic mean (standard deviation)
        Platelets, n=266, 304
    5.4 ± 64.84
    5.0 ± 70.47
        White blood cells, n= 268, 307
    -0.52 ± 2.531
    -0.09 ± 2.052
        Basophils, n=268, 305
    0.00 ± 0.041
    0.01 ± 0.040
        Eosinophils, n=268, 305
    -0.02 ± 0.159
    -0.02 ± 0.165
        Lymphocytes, n=268, 305
    -0.31 ± 0.988
    -0.14 ± 0.778
        Monocytes, n=268, 305
    -0.05 ± 0.276
    0.01 ± 0.245
        Neutrophils, n=268, 305
    -0.16 ± 2.041
    0.05 ± 1.878
    Notes
    [38] - Safety Analysis Set
    [39] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in the percentage of basophils, eosinophils, lymphocytes, monocytes, and neutrophils in white blood cells (WBCs)

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in the percentage of basophils, eosinophils, lymphocytes, monocytes, and neutrophils in white blood cells (WBCs) [40]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [40] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    268 [41]
    305 [42]
    Units: percentage in WBCs
    arithmetic mean (standard deviation)
        Basophils/WBCs
    0.08 ± 0.284
    0.12 ± 0.287
        Eosinophils/WBCs
    -0.10 ± 2.064
    -0.24 ± 2.104
        Lymphocytes/WBCs
    -1.32 ± 12.396
    -1.32 ± 11.193
        Monocytes/WBCs
    -0.05 ± 3.125
    0.18 ± 2.600
        Neutrophils/WBCs
    1.47 ± 12.982
    1.27 ± 12.245
    Notes
    [41] - Safety Analysis Set
    [42] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in sodium, potassium, blood urea nitrogen, glucsose, calcium, and high-density lipoprotein (HDL) cholesterol

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in sodium, potassium, blood urea nitrogen, glucsose, calcium, and high-density lipoprotein (HDL) cholesterol [43]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [43] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    315 [44]
    366 [45]
    Units: millimoles per Liter (mmol/L)
    arithmetic mean (standard deviation)
        Sodium, n=277, 311
    -0.4 ± 3.25
    -0.8 ± 2.70
        Potassium, n=274, 307
    -0.06 ± 0.372
    -0.08 ± 0.407
        Blood urea nitrogen, n=276, 309
    -0.08 ± 1.571
    0.00 ± 1.555
        Glucose, n=275, 307
    -0.06 ± 1.026
    0.06 ± 1.288
        Calcium, n=277, 311
    -0.050 ± 0.1148
    -0.054 ± 0.1218
        HDL cholesterol, n=277, 311
    0.06 ± 0.372
    0.12 ± 0.320
    Notes
    [44] - Safety Analysis Set
    [45] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in creatinine (Jaffe), creatinine (enzymatic), and bilirubin

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in creatinine (Jaffe), creatinine (enzymatic), and bilirubin [46]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [46] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    315 [47]
    366 [48]
    Units: micromoles per Liter (µmol/L)
    arithmetic mean (standard deviation)
        Creatinine, Jaffe, n=268, 311
    7.0 ± 9.32
    7.1 ± 10.86
        Creatinine, enzymatic, n=148, 140
    3.8 ± 8.83
    4.0 ± 9.44
        Bilirubin, n=276, 309
    0.48 ± 2.339
    0.45 ± 2.626
    Notes
    [47] - Safety Analysis Set
    [48] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in creatinine clearance (Schwartz) and creatinine clearance (Cockcroft-Gault)

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in creatinine clearance (Schwartz) and creatinine clearance (Cockcroft-Gault) [49]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. mL/min/1.73 m^2 = milliliters per minute per 1.73 meters squared. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [49] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    315 [50]
    366 [51]
    Units: mL/min/1.73 m^2
    arithmetic mean (standard deviation)
        Creatinine Clearance, Schwartz, n=247, 185
    0.3 ± 4.41
    0.0 ± 0.00
        Creatinine Clearance, Cockcroft-Gault, n=7, 103
    0.0 ± 0.00
    -0.6 ± 5.94
    Notes
    [50] - Safety Analysis Set
    [51] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and gamma glutamyl transferase

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and gamma glutamyl transferase [52]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [52] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    315 [53]
    366 [54]
    Units: Units/L
    arithmetic mean (standard deviation)
        Alkaline phosphatase, n=277, 311
    -40.9 ± 88.18
    -40.1 ± 73.62
        Aspartate aminotransferase, n=274, 308
    4.0 ± 26.14
    2.8 ± 26.62
        Alanine aminotransferase, n=275, 308
    7.0 ± 39.24
    9.5 ± 43.96
        Gamma glutamyl transferase, n=276, 309
    8.7 ± 42.35
    4.9 ± 45.65
    Notes
    [53] - Safety Analysis Set
    [54] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in albumin and protein

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in albumin and protein [55]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [55] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    315 [56]
    366 [57]
    Units: grams (g)/L
    arithmetic mean (standard deviation)
        Albumin, n=277, 311
    -0.2 ± 3.43
    -0.9 ± 3.31
        Protein, n=277, 311
    -1.2 ± 5.83
    -2.0 ± 5.75
    Notes
    [56] - Safety Analysis Set
    [57] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in prolactin

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in prolactin [58]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [58] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    276 [59]
    309 [60]
    Units: µInternational Units/milliliter (µIU/mL)
        arithmetic mean (standard deviation)
    0.43 ± 132.613
    10.43 ± 230.439
    Notes
    [59] - Safety Analysis Set
    [60] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in prothrombin time

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in prothrombin time [61]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [61] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    256 [62]
    282 [63]
    Units: seconds
        arithmetic mean (standard deviation)
    -0.08 ± 0.740
    -0.09 ± 0.706
    Notes
    [62] - Safety Analysis Set
    [63] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in prothrombin international normalized ratio

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in prothrombin international normalized ratio [64]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [64] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    256 [65]
    282 [66]
    Units: ratio
        arithmetic mean (standard deviation)
    -0.012 ± 0.0784
    -0.010 ± 0.0736
    Notes
    [65] - Safety Analysis Set
    [66] - Safety Analysis Set
    No statistical analyses for this end point

    Primary: Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in insulin-like growth factor-1

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    End point title
    Mean change from the pre-randomization Baseline of the Core Study to the end of treatment in insulin-like growth factor-1 [67]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Pre-randomization Baseline of the Core Study (GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], GWEP1424 [NCT02224703], GWEP1414 [NCT02224560], and GWEP1423 [NCT02224690]) is defined as Baseline of the double-blind, placebo-controlled, clinical studies with GWP42003-P. Analysis was conducted in members of the Safety Analysis Set, comprised of all subjects who received at least 1 dose of IMP. Only subjects with available data were analyzed. Data for change from Baseline at pre-randomization of the Core Study are presented; however, the time frame represents the duration for which subjects were enrolled in GWEP1415. No data from the Core Studies are presented in this report.
    End point type
    Primary
    End point timeframe
    up to a maximum of 6 years
    Notes
    [67] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    Dravet Syndrome Lennox-Gastaut Syndrome
    Number of subjects analysed
    69 [68]
    142 [69]
    Units: nanomoles (nmol)/L
        arithmetic mean (standard deviation)
    -0.28 ± 12.701
    1.10 ± 15.970
    Notes
    [68] - Safety Analysis Set
    [69] - Safety Analysis Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to a maximum of 6 years
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs), defined as AEs that started, worsened in severity or seriousness, following the first dose of investigational medicinal product in this study, are reported. Any AEs that continued from the Core Study were only classified as treatment emergent if they worsened in this study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Lennox-Gastaut Syndrome
    Reporting group description
    Subjects with Lennox-Gastaut Syndrome who completed double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies: GWEP1414 [NCT02224560] and GWEP1423 [NCT02224690]) were titrated up to 10 to 20 milligrams per kilogram per day (mg/kg/day) GWP42003-P using a recommended titration schedule during the Titration Period. Subjects continued at this dose during the Maintenance Period. The maximum dose subjects could receive was 30 mg/kg/day.

    Reporting group title
    Dravet Syndrome
    Reporting group description
    Subjects with Dravet Syndrome who completed double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies: GWEP1332A [NCT02091206], GWEP1332B [NCT02091375], and GWEP1424 [NCT02224703]) were titrated up to 10 to 20 milligrams per kilogram per day (mg/kg/day) GWP42003-P using a recommended titration schedule during the Titration Period. Subjects continued at this dose during the Maintenance Period. The maximum dose subjects could receive was 30 mg/kg/day.

    Serious adverse events
    Lennox-Gastaut Syndrome Dravet Syndrome
    Total subjects affected by serious adverse events
         subjects affected / exposed
    157 / 366 (42.90%)
    133 / 315 (42.22%)
         number of deaths (all causes)
    12
    6
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    4 / 366 (1.09%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Foot operation
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrostomy
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Child abuse
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drowning
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Effusion
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    11 / 366 (3.01%)
    17 / 315 (5.40%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden unexplained death in epilepsy
         subjects affected / exposed
    4 / 366 (1.09%)
    4 / 315 (1.27%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    0 / 4
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    2 / 366 (0.55%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucinations, mixed
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritability
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    6 / 366 (1.64%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Self injurious behaviour
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep disorder
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular torsion
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear injury
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye contusion
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    3 / 366 (0.82%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Feeding tube complication
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Near drowning
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth avulsion
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    2 / 366 (0.55%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal haemorrhage
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 366 (1.91%)
    7 / 315 (2.22%)
         occurrences causally related to treatment / all
    6 / 7
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ammonia increased
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anticonvulsant drug level increased
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 366 (1.64%)
    10 / 315 (3.17%)
         occurrences causally related to treatment / all
    4 / 6
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature fluctuation
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophil count increased
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 366 (0.82%)
    4 / 315 (1.27%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma output increased
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    6 / 366 (1.64%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    5 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    2 / 366 (0.55%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Norovirus test positive
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen consumption increased
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases abnormal
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    5 / 366 (1.37%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    4 / 366 (1.09%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Rett's disorder
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    10 / 366 (2.73%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choking
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (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
    9 / 366 (2.46%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Increased bronchial secretion
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Increased upper airway secretion
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    16 / 366 (4.37%)
    4 / 315 (1.27%)
         occurrences causally related to treatment / all
    1 / 21
    2 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory alkalosis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    6 / 366 (1.64%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    8 / 366 (2.19%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract inflammation
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restrictive pulmonary disease
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinorrhoea
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia macrocytic
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophilia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 366 (0.00%)
    3 / 315 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral atrophy
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    44 / 366 (12.02%)
    34 / 315 (10.79%)
         occurrences causally related to treatment / all
    3 / 61
    2 / 48
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Depressed level of consciousness
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 366 (0.27%)
    4 / 315 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lethargy
         subjects affected / exposed
    2 / 366 (0.55%)
    3 / 315 (0.95%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Movement disorder
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoclonic epilepsy
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuromyopathy
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postictal state
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sedation
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (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 / 366 (0.27%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    42 / 366 (11.48%)
    47 / 315 (14.92%)
         occurrences causally related to treatment / all
    3 / 81
    5 / 112
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness transient
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye oedema
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 366 (0.82%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 366 (0.82%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 366 (1.37%)
    5 / 315 (1.59%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haematemesis
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    4 / 366 (1.09%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 366 (0.82%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised intraabdominal fluid collection
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 366 (0.82%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth loss
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (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
    13 / 366 (3.55%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 31
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrocalcinosis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    5 / 366 (1.37%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    3 / 366 (0.82%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Excessive granulation tissue
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 366 (0.82%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    5 / 366 (1.37%)
    6 / 315 (1.90%)
         occurrences causally related to treatment / all
    0 / 7
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteral feeding intolerance
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 366 (0.55%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    3 / 366 (0.82%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic alkalosis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic disorder
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site abscess
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 366 (0.55%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon gangrene
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 366 (0.55%)
    4 / 315 (1.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected bites
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective myositis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 366 (0.82%)
    7 / 315 (2.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    5 / 366 (1.37%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    2 / 366 (0.55%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    2 / 366 (0.55%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pertussis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    26 / 366 (7.10%)
    20 / 315 (6.35%)
         occurrences causally related to treatment / all
    0 / 42
    0 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    2 / 366 (0.55%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 366 (0.00%)
    4 / 315 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 366 (0.55%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    2 / 366 (0.55%)
    3 / 315 (0.95%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 366 (1.64%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 366 (0.55%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    2 / 366 (0.55%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection bacterial
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 366 (0.55%)
    3 / 315 (0.95%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    9 / 366 (2.46%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    3 / 366 (0.82%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 366 (0.27%)
    3 / 315 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    West Nile viral infection
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Lennox-Gastaut Syndrome Dravet Syndrome
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    338 / 366 (92.35%)
    292 / 315 (92.70%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    24 / 366 (6.56%)
    15 / 315 (4.76%)
         occurrences all number
    33
    16
    Fall
         subjects affected / exposed
    20 / 366 (5.46%)
    20 / 315 (6.35%)
         occurrences all number
    33
    32
    Laceration
         subjects affected / exposed
    35 / 366 (9.56%)
    8 / 315 (2.54%)
         occurrences all number
    66
    8
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    23 / 366 (6.28%)
    31 / 315 (9.84%)
         occurrences all number
    28
    35
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    18 / 366 (4.92%)
    29 / 315 (9.21%)
         occurrences all number
    18
    34
    Aspartate aminotransferase increased
         subjects affected / exposed
    13 / 366 (3.55%)
    30 / 315 (9.52%)
         occurrences all number
    16
    35
    Weight decreased
         subjects affected / exposed
    58 / 366 (15.85%)
    20 / 315 (6.35%)
         occurrences all number
    63
    20
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    63 / 366 (17.21%)
    42 / 315 (13.33%)
         occurrences all number
    89
    57
    Nasal congestion
         subjects affected / exposed
    46 / 366 (12.57%)
    13 / 315 (4.13%)
         occurrences all number
    70
    21
    Rhinorrhoea
         subjects affected / exposed
    19 / 366 (5.19%)
    19 / 315 (6.03%)
         occurrences all number
    33
    29
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    120 / 366 (32.79%)
    60 / 315 (19.05%)
         occurrences all number
    201
    91
    Drooling
         subjects affected / exposed
    21 / 366 (5.74%)
    11 / 315 (3.49%)
         occurrences all number
    22
    13
    Headache
         subjects affected / exposed
    26 / 366 (7.10%)
    18 / 315 (5.71%)
         occurrences all number
    40
    23
    Lethargy
         subjects affected / exposed
    32 / 366 (8.74%)
    19 / 315 (6.03%)
         occurrences all number
    45
    22
    Sedation
         subjects affected / exposed
    27 / 366 (7.38%)
    16 / 315 (5.08%)
         occurrences all number
    34
    19
    Somnolence
         subjects affected / exposed
    106 / 366 (28.96%)
    86 / 315 (27.30%)
         occurrences all number
    130
    113
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    38 / 366 (10.38%)
    38 / 315 (12.06%)
         occurrences all number
    47
    47
    Pyrexia
         subjects affected / exposed
    123 / 366 (33.61%)
    117 / 315 (37.14%)
         occurrences all number
    280
    298
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    22 / 366 (6.01%)
    32 / 315 (10.16%)
         occurrences all number
    30
    39
    Aggression
         subjects affected / exposed
    29 / 366 (7.92%)
    19 / 315 (6.03%)
         occurrences all number
    35
    28
    Insomnia
         subjects affected / exposed
    40 / 366 (10.93%)
    16 / 315 (5.08%)
         occurrences all number
    48
    23
    Irritability
         subjects affected / exposed
    28 / 366 (7.65%)
    26 / 315 (8.25%)
         occurrences all number
    33
    34
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    41 / 366 (11.20%)
    20 / 315 (6.35%)
         occurrences all number
    59
    25
    Diarrhoea
         subjects affected / exposed
    138 / 366 (37.70%)
    133 / 315 (42.22%)
         occurrences all number
    230
    286
    Nausea
         subjects affected / exposed
    30 / 366 (8.20%)
    16 / 315 (5.08%)
         occurrences all number
    35
    20
    Vomiting
         subjects affected / exposed
    99 / 366 (27.05%)
    63 / 315 (20.00%)
         occurrences all number
    192
    96
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    92 / 366 (25.14%)
    99 / 315 (31.43%)
         occurrences all number
    113
    134
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    23 / 366 (6.28%)
    14 / 315 (4.44%)
         occurrences all number
    30
    18
    Ear infection
         subjects affected / exposed
    50 / 366 (13.66%)
    35 / 315 (11.11%)
         occurrences all number
    101
    61
    Gastroenteritis
         subjects affected / exposed
    6 / 366 (1.64%)
    16 / 315 (5.08%)
         occurrences all number
    6
    24
    Gastroenteritis viral
         subjects affected / exposed
    29 / 366 (7.92%)
    11 / 315 (3.49%)
         occurrences all number
    37
    15
    Influenza
         subjects affected / exposed
    42 / 366 (11.48%)
    31 / 315 (9.84%)
         occurrences all number
    51
    41
    Nasopharyngitis
         subjects affected / exposed
    58 / 366 (15.85%)
    78 / 315 (24.76%)
         occurrences all number
    91
    136
    Otitis media
         subjects affected / exposed
    21 / 366 (5.74%)
    21 / 315 (6.67%)
         occurrences all number
    37
    30
    Pharyngitis streptococcal
         subjects affected / exposed
    26 / 366 (7.10%)
    24 / 315 (7.62%)
         occurrences all number
    49
    37
    Pneumonia
         subjects affected / exposed
    31 / 366 (8.47%)
    22 / 315 (6.98%)
         occurrences all number
    42
    24
    Sinusitis
         subjects affected / exposed
    48 / 366 (13.11%)
    38 / 315 (12.06%)
         occurrences all number
    62
    71
    Upper respiratory tract infection
         subjects affected / exposed
    102 / 366 (27.87%)
    77 / 315 (24.44%)
         occurrences all number
    176
    134
    Urinary tract infection
         subjects affected / exposed
    47 / 366 (12.84%)
    18 / 315 (5.71%)
         occurrences all number
    91
    30
    Viral upper respiratory tract infection
         subjects affected / exposed
    19 / 366 (5.19%)
    9 / 315 (2.86%)
         occurrences all number
    30
    10

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jan 2015
    • Added secondary objective/endpoint to evaluate change in duration of subtypes of seizures as assessed by the Subject/Caregiver Global Impression of Change in Seizure Duration (S/CGICSD) • Included the Pediatric Cannabinoid Withdrawal Scale (PCWS) for children 4–17 years of age • Clarified the exclusion criteria addressing previous and current use of cannabinoids and concerning subjects of child bearing potential • Clarified that the safety follow-up period must have been a minimum of 28 days after end of treatment in order to capture sufficient safety data • Clarified the definition of drop seizure of subtypes of seizures and added “countable partial seizures” and “partial seizures” to the definition of terms; in order to aid identification of seizure types • Clarified that the pre-randomization pregnancy test was to be performed using urine rather than serum in order to provide an immediate result for assessment of inclusion/exclusion criteria • Changed maximum dose from 50 milligrams per kilograms per day (mg/kg/day) to 30 mg/kg/day. • Limited maximum treatment to 1 year. The sponsor could look to extend the duration of this study. • Clarified withdrawal criteria to state that subjects with drug-induced liver injury (DILI) were to be withdrawn from the study
    23 Mar 2015
    Amendment in France only: • Documented effects on growth and development in subjecs less than 18 years of age by measurement of height, weight, serum insulin-like growth factor-1 and Tanner Staging (for subjects aged 12–17 [inclusive]) • Included measurement of serum triglycerides in clinical laboratory samples • Limited the maximum duration of prescription of IMP to 28 days • Specified that the IMP was to be stored in a locked cabinet or room designated solely for the storage of narcotics (i.e., containing nothing other) • Specified that any missing/unaccountable or theft or diversion of IMP should be promptly reported to the police authorities, the regional inspectorate of pharmacy and the ANSM. • Clarified that the first dose of IMP was to be taken in the clinic under medical supervision, followed by a two-hour safety observation period • Amended the number of subjects expected to enroll in line with increased sample sizes in each of the Core Studies • Amended the eligibility criterion regarding contraception requirements • Allowed subjects who have had study medication suspended due to an adverse event (AE) to resume dosing prior to complete recovery, provided that the AE was well tolerated
    16 Apr 2015
    Not implemented
    11 Aug 2015
    • Updated dosing following recommendations from the Data Safety Monitoring Committee of Study GWEP1332 Part A • Allowed for additional clinic visits to be scheduled by the Investigator in order to facilitate necessary dose adjustments • Allowed for an interim analysis to be conducted approximately 6 months after the first subject first dose in order to satisfy the Food and Drug Administration (FDA) requirement for an interim analysis to be performed within 6 months of the New Drug Application (NDA) submission • Required additional weekly safety telephone calls when increasing doses above 20 mg/kg/day until stable dosing was achieved • During follow-up of subjects with potential cases of DILI, added further details to state that alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBL), alkaline phosphatase and gamma-glutamyl transferase levels should all be monitored until levels normalized (in the Investigator’s opinion) or returned to Baseline state. • Amended the eligibility criterion regarding impaired hepatic function to bring into line with the criteria for DILI • Allowed Investigators to monitor anti-epileptic drug (AED) plasma concentrations and discuss possible changes in drug dosage with the medical advisor(s) at GW Research Ltd. (GW)
    26 Aug 2015
    Amendment in France only: • Added recommendation of the DSMC of Study GWEP1332 Part A of a target dose of 20 mg/kg/day and titration schedule • Allowed for additional clinic visits to be scheduled by the Investigator in order to facilitate necessary dose adjustments • Allowed for an interim analysis to be conducted approximately 6 months after the first subject first dose in order to satisfy the FDA requirement for an interim analysis to be performed within 6 months of the NDA submission • Required additional weekly safety telephone calls when increasing doses above 20 mg/kg/day until stable dosing was achieved • During follow-up of subjects with potential cases of DILI, added further details to state that ALT, AST, TBL, alkaline phosphatase and gamma-glutamyl transferase levels should all be monitored until levels normalized (in the Investigator’s opinion) or returned to Baseline state • Amended the eligibility criterion regarding impaired hepatic function to bring into line with the criteria for DILI • Allowed Investigators to monitor AED plasma concentrations and discuss possible changes in drug dosage with the medical advisor(s) at GW
    22 Apr 2016
    Amendment in the United States only: • Extended trial duration from 12 months to 24 months • Added IMP dispensing appointments between assessment visits in Year 2 • Simplified the adjustment of concomitant AEDs and deleted the requirement for 6 months of seizure freedom to allow flexibility in reducing or discontinuing AEDs following consultation with the medical monitor • Added information that Investigators should consider when monitoring liver function enzymes during the titration period in subjects taking concomitant medications known to affect liver function • Added that, where permitted by blood volume sampling guidelines, blood samples should have been taken for AED plasma level monitoring • Increased predicted number of subjects to be recruited to the study • Added additional details regarding C-SSRS questionnaire administration • Clarified details regarding liver transaminase monitoring prior to withdrawal • Clarified that subjected needed to have "completed" the treatment period of the Core study to be eligible for the open-label extension study
    19 May 2016
    Amendment in France only: • Extended trial duration from 12 months to 24 months • Simplified the adjustment of concomitant AEDs and deleted the requirement for 6 months of seizure freedom to allow flexibility in reducing or discontinuing AEDs following consultation with the medical monitor • Added information that Investigators should consider when monitoring liver function enzymes during the titration period in subjects taking concomitant medications known to affect liver function • Added that, where permitted by blood volume sampling guidelines, blood samples should have been taken for AED plasma level monitoring • Increased predicted number of subjects to be recruited to the study • Added additional details regarding C-SSRS questionnaire administration • Clarified details regarding liver transaminase monitoring prior to withdrawal • Clarified that subjected needed to have "completed" the treatment period of the Core study to be eligible for the open-label extension study
    28 Jun 2016
    Amendment in the United States only: Allowed for collection of additional blood samples from patients with Dravet syndrome (DS) taking GWP42003-P to understand more fully the pharmacokinetics (PK) of cannabidiol (CBD) and its metabolites in this subject population
    28 Jul 2016
    Amendment in Poland only: • Extended trial duration from 12 months to 24 months • Added IMP dispensing appointments between assessment visits in Year 2 • Clarified wording around the titration period to enable adjustments if intolerability or increased seizures were observed • Simplified the adjustment of concomitant AEDs and deleted the requirement for 6 months of seizure freedom to allow flexibility in reducing or discontinuing AEDs following consultation with the medical monitor • Added information that Investigators should consider when monitoring liver function enzymes during the titration period in subjects taking concomitant medications known to affect liver function • Added that, where permitted by blood volume sampling guidelines, blood samples should have been taken for AED plasma level monitoring • Increased predicted number of subjects to be recruited to the study • Clarified details regarding liver transaminase monitoring prior to withdrawal • Clarified that subjected needed to have "completed" the treatment period of the Core study to be eligible for the open-label extension study
    29 Mar 2017
    Amendment in France only: • Extended trial duration from 24 months to 36 months • Extended the recommended dose from 20 mg/kg/day to 10-20 mg/kg/day based on the results of trial GWEP1414 for Lennox-Gastaut syndrome • Added the option of administration of CBD through a gastrostomy (G)/nasogastric (NG) feeding tube after consultation with the medical monitor • Allowed for the frequency of dosing to change after consultation with the medical monitor • Added information to the dose titration regimen advising the investigator to consider monitoring hepatic function
    28 Apr 2017
    • Updated secondary objective to include assessment of the total seizures, for all subjects, as well as seizure subtypes • Updated the study design and treatment schema to reflect the correct treatment duration between Visits 10 and the End of Treatment/Withdrawal visit
    03 May 2017
    • Extended the recommended dose from 20 mg/kg/day to 10-20 mg/kg/day • Simplified the adjustment of concomitant AEDs and deleted the requirement for 6 months of seizure freedom to allow flexibility in reducing or discontinuing AEDs following consultation with the medical monitor • Permitted new AEDs in long-term trials, but stated that the investigator should consider whether CBD therapy resulted in an adequate clinical response and if continued participation in the trial was appropriate or if higher CBD doses should have been considered • Added the option of administration of CBD through a G/NG feeding tube after consultation with the medical monitor • Allowed for the frequency of dosing to change after consultation with the medical monitor • Added information that Investigators should consider when monitoring liver function enzymes during the titration period in subjects taking concomitant medications known to affect liver function • Added that, where permitted by blood volume sampling guidelines, blood samples should have been taken for AED plasma level monitoring • Increased predicted number of subjects to be recruited to the study • Clarified details regarding liver transaminase monitoring prior to withdrawal
    29 Aug 2017
    Amendment in Israel only: Extended study duration in Israel to include a second year of treatment
    25 Apr 2018
    Amendment in the United States only: • Extended the trial duration from 3 years to a maximum of 4 years • Updated description of the term “study completion,” to include clarification of when subjects should transition to commercial supply
    26 Apr 2018
    Amendment in France only: Extended the trial duration from 3 years to a maximum of 4 years
    01 May 2018
    Amendment in Poland only: Extended the trial duration from 3 years to a maximum of 4 years
    06 Jun 2018
    Amendment in Israel only: Extended the trial duration from 2 years to a maximum of 3 years
    30 Apr 2019
    Amendment in Israel only: • Extended the trial duration has been extended from 3 years to a maximum of 4 years • Updated Introduction to clarify that GWP42003-P contains not more than 0.1% (weight to weight [w/w]) THC and not 0.15% (w/w) THC
    07 May 2019
    Amendment in Poland only: • Extended the trial duration has been extended from 4 years to a maximum of 5 years • Updated Introduction to clarify that GWP42003-P contains not more than 0.1% (w/w) THC and not 0.1% (w/w) THC
    07 May 2019
    Amendment in France only: • Extended the trial duration has been extended from 4 years to a maximum of 5 years • Updated Introduction to clarify that GWP42003-P contains not more than 0.1% (w/w) THC and not 0.1% (w/w) THC
    11 Jun 2020
    Amendment in Poland only: • Added withdrawal criterion to allow for withdrawal of subjects with significant disease or disorder which, in the opinion of the Investigator, may have either put the subject, other subjects, or site staff at risk, may have influenced the result of the study, or may have affected the subject’s ability to participate in the study • Removed the Study Medication Use and Behavior Survey requirement, as no potential for abuse was expected in the remaining subjects in the study • Specified that evaluations and data collection could be made directly or remotely

    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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