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
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Summary
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EudraCT number |
2014-001834-27 |
Trial protocol |
GB ES PL NL FR |
Global end of trial date |
24 Sep 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Apr 2021
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First version publication date |
08 Apr 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
GWEP1415
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02224573 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
GW Research Ltd
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Sponsor organisation address |
Sovereign House, Vision Park, Chivers Way, Histon, Cambridge, United Kingdom, CB24 9BZ
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Public contact |
Medical Enquiries, GW Research Ltd, medinfo@gwpharm.com
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Scientific contact |
Medical Enquiries, GW Research Ltd, medinfo@gwpharm.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001964-PIP01-16 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
24 Sep 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
24 Sep 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Sep 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
11 Jun 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 24
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Country: Number of subjects enrolled |
Poland: 70
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Country: Number of subjects enrolled |
Spain: 71
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Country: Number of subjects enrolled |
United Kingdom: 25
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Country: Number of subjects enrolled |
France: 17
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Country: Number of subjects enrolled |
Australia: 11
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Country: Number of subjects enrolled |
Israel: 3
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Country: Number of subjects enrolled |
United States: 460
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Worldwide total number of subjects |
681
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EEA total number of subjects |
182
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
373
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Adolescents (12-17 years) |
179
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Adults (18-64 years) |
129
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Treatment Phase
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
GWP42003-P
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Other name |
EPIDIOLEX, cannabidiol, CBD-OS
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
100 milligrams per milliliter (mg/mL) cannabidiol (CBD) in sesame oil with anhydrous ethanol, added sweetener (sucralose) and strawberry flavoring
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Arm title
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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
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Investigational medicinal product code |
GWP42003-P
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Other name |
EPIDIOLEX, cannabidiol, CBD-OS
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
100 milligrams per milliliter (mg/mL) cannabidiol (CBD) in sesame oil with anhydrous ethanol, added sweetener (sucralose) and strawberry flavoring
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Period 2
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Period 2 title |
Taper Phase
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Is this the baseline period? |
No | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
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Other name |
EPIDIOLEX, cannabidiol, CBD-OS
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
100 milligrams per milliliter (mg/mL) cannabidiol (CBD) in sesame oil with anhydrous ethanol, added sweetener (sucralose) and strawberry flavoring
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Arm title
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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
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Investigational medicinal product code |
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Other name |
EPIDIOLEX, cannabidiol, CBD-OS
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
100 milligrams per milliliter (mg/mL) cannabidiol (CBD) in sesame oil with anhydrous ethanol, added sweetener (sucralose) and strawberry flavoring
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| 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. |
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Baseline characteristics reporting groups
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Reporting group title |
Dravet Syndrome
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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
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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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Dravet Syndrome
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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
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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
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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
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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. | ||
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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.
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End point type |
Primary
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End point timeframe |
up to a maximum of 6 years
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| 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. |
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| Notes [2] - Safety Analysis Set [3] - Safety Analysis Set |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
up to a maximum of 6 years
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| 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. |
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| Notes [5] - Safety Analysis Set [6] - Safety Analysis Set |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
| Notes [8] - Safety Analysis Set [9] - Safety Analysis Set |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||||||||||||||
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. |
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| Notes [11] - Safety Analysis Set [12] - Safety Analysis Set |
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
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. |
|||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| Notes [14] - Safety Analysis Set [15] - Safety Analysis Set |
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
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. |
|||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| Notes [17] - Safety Analysis Set [18] - Safety Analysis Set |
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
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. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [20] - Safety Analysis Set [21] - Safety Analysis Set |
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
| Notes [23] - Safety Analysis Set [24] - Safety Analysis Set |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
| Notes [26] - Safety Analysis Set [27] - Safety Analysis Set |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
| Notes [29] - Subject Analysis Set [30] - Subject Analysis Set |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
| Notes [32] - Safety Analysis Set [33] - Safety Analysis Set |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
| Notes [35] - Safety Analysis Set [36] - Safety Analysis Set |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||||||||||||||||||||
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. |
||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
| Notes [38] - Safety Analysis Set [39] - Safety Analysis Set |
||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
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. |
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| Notes [41] - Safety Analysis Set [42] - Safety Analysis Set |
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
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. |
|||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| Notes [44] - Safety Analysis Set [45] - Safety Analysis Set |
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
||||||||||||||||||||||
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. |
||||||||||||||||||||||
|
||||||||||||||||||||||
| Notes [47] - Safety Analysis Set [48] - Safety Analysis Set |
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
|||||||||||||||||||
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. |
|||||||||||||||||||
|
|||||||||||||||||||
| Notes [50] - Safety Analysis Set [51] - Safety Analysis Set |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||
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. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [53] - Safety Analysis Set [54] - Safety Analysis Set |
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||
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. |
|||||||||||||||||||
|
|||||||||||||||||||
| Notes [56] - Safety Analysis Set [57] - Safety Analysis Set |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
| Notes [59] - Safety Analysis Set [60] - Safety Analysis Set |
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| No statistical analyses for this end point | |||||||||||||
|
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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. |
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|
|||||||||||||
| Notes [62] - Safety Analysis Set [63] - Safety Analysis Set |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
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. |
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|
|||||||||||||
| Notes [65] - Safety Analysis Set [66] - Safety Analysis Set |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
| Notes [68] - Safety Analysis Set [69] - Safety Analysis Set |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
up to a maximum of 6 years
|
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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.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
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Reporting groups
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Reporting group title |
Lennox-Gastaut Syndrome
|
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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
|
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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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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) |
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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 | |||
