A Randomized Controlled Trial of Cannabidiol (GWP42003-P, CBD) for Seizures in Tuberous Sclerosis Complex (GWPCARE6)

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02544763
• Collaborator: (none)
• Enrollment: 224
• Locations: 44
• Arms: 3
• Actual Duration (Months): 34.7
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This trial consists of 2 parts: a double-blinded phase and an open-label extension phase. The blinded phase only will be described in this record. Participants will receive 1 of 2 doses of GWP42003-P or matching placebo. The primary clinical hypothesis is that there will be a difference between GWP42003-P and placebo in their effect on seizure frequency.

Condition or Disease	Intervention/Treatment	Phase
Tuberous Sclerosis Complex; Seizures	Drug: GWP42003-P; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 224 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Randomized, Placebo-controlled Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P, CBD) as Add-on Therapy in Patients With Tuberous Sclerosis Complex Who Experience Inadequately-controlled Seizures
• Actual Study Start Date: Apr 6, 2016
• Actual Primary Completion Date: Jan 22, 2019
• Actual Study Completion Date: Feb 26, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 25 mg/kg/day GWP42003-P 100 mg/mL GWP42003-P oral solution taken twice daily (morning and evening).	Drug: GWP42003-P; Yellow oily solution containing cannabidiol dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring.; Other Names: Cannabidiol CBD
Experimental: 50 mg/kg/day GWP42003-P 100 mg/mL GWP42003-P oral solution taken twice daily (morning and evening).	Drug: GWP42003-P; Yellow oily solution containing cannabidiol dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring.; Other Names: Cannabidiol CBD
Placebo Comparator: Placebo Placebo oral solution matching 100 mg/mL GWP42003-P.	Drug: Placebo; Yellow oily solution containing the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring.

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline in the Number of Tuberous Sclerosis Complex (TSC)-Associated Seizures During the Treatment Period (Maintenance and Titration) [Baseline; up to Week 16]

   TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that are countable. Percent change from Baseline was calculated as the (post-Baseline value minus the Baseline value) divided by the Baseline value x 100.

Secondary Outcome Measures

1. Number of Participants Considered Treatment Responders During the Treatment Period (Maintenance and Titration) [Baseline; up to Week 16]

   Treatment responders are defined as those participants with a ≥ 50% reduction in TSC-associated seizure frequency. TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that are countable. Participants who withdrew from the trial during the treatment period are considered non-responders.

2. Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit [Baseline; up to Week 16]

   The combined caregiver and participant summary uses either the caregiver or participant version if only one version was completed, or the caregiver version if both caregiver and participant versions were completed. The CGIC comprised the following question, to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): "Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment)." The SGIC comprised the following question, to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): "Since you started treatment, please assess the status of your overall condition (comparing your condition now to your condition before treatment)."

3. Percent Change From Baseline in Total Seizures During the Treatment Period (Maintenance and Titration) [Baseline; up to Week 16]

   Total seizures included all seizure types combined. Percent change from Baseline was calculated as the (post-Baseline value minus the Baseline value) divided by the Baseline value x 100.

4. Number of Participants With Any Severe Treatment-emergent Adverse Event (TEAE) [up to approximately Week 22]

   A TEAE was defined as an AE with a start date on or after the first dose of IMP during the Blinded Phase up to and including the date of first dose of the Open-label Extension (OLE) Phase (OLE Day 1).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Participant has a well-documented clinical history of epilepsy.

• Participant has a clinical diagnosis of Tuberous Sclerosis Complex (TSC) according to the criteria agreed by the 2012 International TSC Consensus Conference.

• All medications or interventions for epilepsy (including ketogenic diet and any neurostimulation devices for epilepsy) must have been stable for 1 month prior to screening and the participant is willing to maintain a stable regimen throughout the trial.

Key Exclusion Criteria:

• Participant has a history of pseudo-seizures.

• Participant has clinically significant unstable medical conditions other than epilepsy.

• Participant has an illness in the 4 weeks prior to screening or randomization, other than epilepsy, which in the opinion of the investigator could affect seizure frequency.

• Participant has undergone general anesthetic in the 4 weeks prior to screening or randomization.

• Participant has undergone surgery for epilepsy in the 6 months prior to screening.

• Participant is being considered for epilepsy surgery or any procedure involving general anesthesia.

• Participant has been taking felbamate for less than 1 year prior to screening.

• Participant is taking an oral mTOR inhibitor.

• Participant has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the Investigational Medicinal Product (IMP), such as sesame oil.

• Participant has any history of suicidal behavior or any suicidal ideation of type 4 or 5 on the C-SSRS in the last month or at screening.

• Participant is currently using or has in the past used recreational or medicinal cannabis, or cannabinoid-based medications, within the 3 months prior to screening and is unwilling to abstain for the duration for the study.

• Participant has tumor growth which, in the opinion of the Investigator, could affect the primary endpoint.

• Participant has significantly impaired hepatic function at the screening or randomization visit

• Participant has received an IMP within the 12 weeks prior to the screening visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB Epilepsy Center	Birmingham	Alabama	United States	35294
2	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202
3	UCLA-Pediatric Neurology	Los Angeles	California	United States	90095
4	UCSF Benioff Children's Hospital Oakland	Oakland	California	United States	94609
5	University of Colorado Denver	Aurora	Colorado	United States	80045
6	Pediatric Neurology	Miami	Florida	United States	33155
7	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
8	Mid Atlantic Epilepsy & Sleep Centre	Bethesda	Maryland	United States	20817
9	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
10	Mayo Clinic	Rochester	Minnesota	United States	55905
11	Minnesota Epilepsy Group, P.A	Saint Paul	Minnesota	United States	55102
12	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
13	NYU Comprehensive Epilepsy Center	New York	New York	United States	10016
14	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
15	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
16	Oregon Health & Science University	Portland	Oregon	United States	97239
17	WellSpan Paediatric Neurology	Manchester	Pennsylvania	United States	17345
18	Le Bonheur Children's Hospital	Memphis	Tennessee	United States	38103
19	Texas Scottish Rite Hospital for Children	Dallas	Texas	United States	75104
20	Cook Children's Health Care System	Fort Worth	Texas	United States	76104
21	Paediatric Neurology	Salt Lake City	Utah	United States	84113
22	University of Virginia	Charlottesville	Virginia	United States	22903
23	Seattle Children's Hospital	Seattle	Washington	United States	98105
24	Austin Health	Heidelberg		Australia
25	Royal Brisbane and Women's Hospital	Herston		Australia
26	The Royal Melbourne Hospital	Parkville		Australia
27	Sydney Children's Hospital	Randwick		Australia
28	Erasmus MC/Sophia Children's Hospital	Rotterdam		Netherlands
29	UMC Utrecht/ Wilhelmina, Kinderziekenhuis	Utrecht		Netherlands
30	Vitamed Gałaj I Cichomski Spółka Jawna	Bydgoszcz		Poland
31	Centrum Medyczne Plejady	Kraków		Poland
32	Wojewódzki Szpital Specjalistyczny im S. K. Wyszyńskiego SPZOZ	Lublin		Poland
33	Instytut "Pomnik - Centrum Zdrowia Dziecka"	Warsaw		Poland
34	Uniwersyteckie Centrum Kliniczne Warszawskiego Uniwersytetu Medycznego w Warszawie	Warsaw		Poland
35	Centrum Neuropsychiatrii "Neuromed"	Wrocław		Poland
36	Centro Médico Teknon	Barcelona		Spain
37	Clinical Research Unit	Barcelona		Spain
38	Unitat d'Epilèpsia	Barcelona		Spain
39	Hospital Infantil Universitario Niño Jesús	Madrid		Spain
40	Clinica Universidad de Navarra	Pamplona		Spain
41	Cardiff and Vale University Local Health Board	Cardiff		United Kingdom
42	Children and Young Adults' Research Unit	Cardiff		United Kingdom
43	NIHR Clinical Research Facility	London		United Kingdom
44	St George's University Hospitals NHS Foundation Trust	London		United Kingdom

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 23, 2019
• Statistical Analysis Plan - Nov 28, 2019

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02544763
• Other Study ID Numbers: GWEP1521 Blinded Phase; 2015-002154-12
• First Posted: Sep 9, 2015
• Last Update Posted: Oct 6, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Tuberous Sclerosis; Seizures; Sclerosis; Cannabidiol

Study Results

Participant Flow

Pre-assignment Detail	A total of 255 participants were screened; 31 of whom were screen failures. A total of 224 participants were randomized to double-blind treatment.

Arm/Group Title	GWP42003-P 25 mg/kg/Day	GWP42003-P 50 mg/kg/Day	Placebo
Arm/Group Description	Participants were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive GWP42003-P 50 mg/kg/day (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive placebo matched to GWP42003-P (via oral twice daily [morning and evening] administration) for 16 weeks.
Period Title: Overall Study
STARTED	75	73	76
COMPLETED	65	61	75
NOT COMPLETED	10	12	1

Baseline Characteristics

Arm/Group Title	GWP42003-P 25 mg/kg/Day	GWP42003-P 50 mg/kg/Day	Placebo	Total
Arm/Group Description	Participants were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive GWP42003-P 50 mg/kg/day (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive placebo matched to GWP42003-P (via oral twice daily [morning and evening] administration) for 16 weeks.	Total of all reporting groups
Overall Participants	75	73	76	224
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.112 (10.8131)	12.915 (8.5324)	13.918 (10.6302)	13.659 (10.0324)
Sex: Female, Male (Count of Participants)
Female	32 42.7%	30 41.1%	31 40.8%	93 41.5%
Male	43 57.3%	42 57.5%	44 57.9%	129 57.6%
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian	68 90.7%	65 89%	66 86.8%	199 88.8%
Black/African American	2 2.7%	3 4.1%	0 0%	5 2.2%
American Indian/Alaska Native	1 1.3%	0 0%	0 0%	1 0.4%
Asian	1 1.3%	0 0%	3 3.9%	4 1.8%
Biracial Causasian-African American	1 1.3%	0 0%	0 0%	1 0.4%
Latin	1 1.3%	0 0%	0 0%	1 0.4%
Arabic	1 1.3%	0 0%	0 0%	1 0.4%
Caucasian/Asian	0 0%	1 1.4%	0 0%	1 0.4%
Hispanic/Latino	0 0%	2 2.7%	0 0%	2 0.9%
Hispanic	0 0%	1 1.4%	3 3.9%	4 1.8%
Hispanic And Caucasian	0 0%	0 0%	1 1.3%	1 0.4%
Anglo Indian	0 0%	0 0%	1 1.3%	1 0.4%
Black, White, American Indian	0 0%	0 0%	1 1.3%	1 0.4%
Number of Tuberous Sclerosis Complex (TSC)-Associated Seizures (seizures) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [seizures]	77.95 (83.390)	92.95 (89.782)	89.22 (101.778)	86.66 (91.841)
Number of Total Seizures (seizures) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [seizures]	80.87 (84.676)	108.06 (115.699)	118.32 (211.868)	102.44 (148.495)

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in the Number of Tuberous Sclerosis Complex (TSC)-Associated Seizures During the Treatment Period (Maintenance and Titration)
Description	TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that are countable. Percent change from Baseline was calculated as the (post-Baseline value minus the Baseline value) divided by the Baseline value x 100.
Time Frame	Baseline; up to Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Analysis Set: all participants who were randomized and dosed with investigational medicinal product (IMP) in the trial and had post-Baseline efficacy data. Participant data were analyzed according to the treatment group to which they were randomized.

Arm/Group Title	GWP42003-P 25 mg/kg/Day	GWP42003-P 50 mg/kg/Day	Placebo
Arm/Group Description	Participants were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive GWP42003-P 50 mg/kg/day (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive placebo matched to GWP42003-P (via oral twice daily [morning and evening] administration) for 16 weeks.
Measure Participants	75	73	76
Median (Inter-Quartile Range) [percent change]	-43.36	-36.55	-20.08

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 25 mg/kg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percentage reduction
	Estimated Value	48.6
	Confidence Interval	(2-Sided) 95%; 40.4 to 55.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 50 mg/kg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percentage reduction
	Estimated Value	47.5
	Confidence Interval	(2-Sided) 95%; 39.0 to 54.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percentage reduction
	Estimated Value	26.5
	Confidence Interval	(2-Sided) 95%; 14.9 to 36.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 25 mg/kg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0009
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment ratio
	Estimated Value	0.699
	Confidence Interval	(2-Sided) 95%; 0.567 to 0.861
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 50 mg/kg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0018
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment ratio
	Estimated Value	0.715
	Confidence Interval	(2-Sided) 95%; 0.580 to 0.881
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants Considered Treatment Responders During the Treatment Period (Maintenance and Titration)
Description	Treatment responders are defined as those participants with a ≥ 50% reduction in TSC-associated seizure frequency. TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that are countable. Participants who withdrew from the trial during the treatment period are considered non-responders.
Time Frame	Baseline; up to Week 16

Outcome Measure Data

Analysis Population Description

ITT Analysis Set

Arm/Group Title	GWP42003-P 25 mg/kg/Day	GWP42003-P 50 mg/kg/Day	Placebo
Arm/Group Description	Participants were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive GWP42003-P 50 mg/kg/day (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive placebo matched to GWP42003-P (via oral twice daily [morning and evening] administration) for 16 weeks.
Measure Participants	75	73	76
Responders	27 36%	29 39.7%	17 22.4%
Non-responders	48 64%	44 60.3%	59 77.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 25 mg/kg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0692
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The p-value was calculated from a Cochran-Mantel-Haenszel test stratified by age group (1-6, 7-11, 12-17 and 18-65 years).
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.95
	Confidence Interval	(2-Sided) 95%; 0.95 to 4.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 50 mg/kg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0245
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The p-value was calculated from a Cochran-Mantel-Haenszel test stratified by age group (1-6, 7-11, 12-17 and 18-65 years).
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.29
	Confidence Interval	(2-Sided) 95%; 1.12 to 4.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit
Description	The combined caregiver and participant summary uses either the caregiver or participant version if only one version was completed, or the caregiver version if both caregiver and participant versions were completed. The CGIC comprised the following question, to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): "Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment)." The SGIC comprised the following question, to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): "Since you started treatment, please assess the status of your overall condition (comparing your condition now to your condition before treatment)."
Time Frame	Baseline; up to Week 16

Outcome Measure Data

Analysis Population Description

ITT Analysis Set. Only participants with available data were analyzed. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Arm/Group Title	GWP42003-P 25 mg/kg/Day	GWP42003-P 50 mg/kg/Day	Placebo
Arm/Group Description	Participants were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive GWP42003-P 50 mg/kg/day (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive placebo matched to GWP42003-P (via oral twice daily [morning and evening] administration) for 16 weeks.
Measure Participants	75	73	76
Caregiver	3.0 (1.34)	3.1 (1.40)	3.5 (0.93)
Combined Caregiver and Participant	3.0 (1.35)	3.2 (1.45)	3.5 (0.96)
Participant	3.3 (1.51)	4.5 (1.73)	2.8 (1.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 25 mg/kg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0074
	Comments
	Method	nominal
	Comments	The global impression of change was analyzed using an ordinal logistic regression model with treatment group as a fixed factor.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.25
	Confidence Interval	(2-Sided) 95%; 1.24 to 4.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 50 mg/kg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0580
	Comments
	Method	nominal
	Comments	The global impression of change is analyzed using an ordinal logistic regression model with treatment group as a fixed factor.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.77
	Confidence Interval	(2-Sided) 95%; 0.98 to 3.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percent Change From Baseline in Total Seizures During the Treatment Period (Maintenance and Titration)
Description	Total seizures included all seizure types combined. Percent change from Baseline was calculated as the (post-Baseline value minus the Baseline value) divided by the Baseline value x 100.
Time Frame	Baseline; up to Week 16

Outcome Measure Data

Analysis Population Description

ITT Analysis Set

Arm/Group Title	GWP42003-P 25 mg/kg/Day	GWP42003-P 50 mg/kg/Day	Placebo
Arm/Group Description	Participants were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive GWP42003-P 50 mg/kg/day (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive placebo matched to GWP42003-P (via oral twice daily [morning and evening] administration) for 16 weeks.
Measure Participants	75	73	76
Mean (Standard Deviation) [percent change]	-34.71 (46.150)	-35.14 (42.530)	-19.63 (35.137)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 25 mg/kg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments	Model includes the total number of seizures as a response variable and age group, time (Baseline and treatment period), treatment and treatment by time interaction as fixed effects and participant as a random effect. The log transformed number of days seizures were reported by period is included as an offset.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percentage reduction
	Estimated Value	0.519
	Confidence Interval	(2-Sided) 95%; 0.447 to 0.602
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 50 mg/kg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percentage reduction
	Estimated Value	0.524
	Confidence Interval	(2-Sided) 95%; 0.452 to 0.607
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percentage reduction
	Estimated Value	0.731
	Confidence Interval	(2-Sided) 95%; 0.632 to 0.846
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 25 mg/kg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0013
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment ratio
	Estimated Value	0.709
	Confidence Interval	(2-Sided) 95%; 0.576 to 0.873
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 50 mg/kg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0018
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment ratio
	Estimated Value	0.716
	Confidence Interval	(2-Sided) 95%; 0.582 to 0.882
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants With Any Severe Treatment-emergent Adverse Event (TEAE)
Description	A TEAE was defined as an AE with a start date on or after the first dose of IMP during the Blinded Phase up to and including the date of first dose of the Open-label Extension (OLE) Phase (OLE Day 1).
Time Frame	up to approximately Week 22

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: all participants randomized to treatment who received at least 1 dose of IMP

Arm/Group Title	GWP42003-P 25 mg/kg/Day	GWP42003-P 50 mg/kg/Day	Placebo
Arm/Group Description	Participants were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive GWP42003-P 50 mg/kg/day (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.	Participants were randomized to receive placebo matched to GWP42003-P (via oral twice daily [morning and evening] administration) for 16 weeks.
Measure Participants	75	73	76
Count of Participants [Participants]	7 9.3%	9 12.3%	1 1.3%

Adverse Events

Time Frame	up to approximately Week 22
Adverse Event Reporting Description	Baseline data are reported for members of the Safety Analysis Set, comprised of participants randomized to treatment who received at least 1 dose of investigational medicinal product (IMP). Treatment-emergent adverse events are defined as adverse events with a start date on or after the first dose of IMP during the Blinded Phase up to and including the date of the first dose of the Open-label Extension (OLE) Phase (OLE Day 1).
Arm/Group Title	GWP42003-P 25 mg/kg/Day		GWP42003-P 50 mg/kg/Day		Placebo
Arm/Group Description	Participants were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.		Participants were randomized to receive GWP42003-P 50 mg/kg/day (via oral twice daily [morning and evening] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks.		Participants were randomized to receive placebo matched to GWP42003-P (via oral twice daily [morning and evening] administration) for 16 weeks.
All Cause Mortality
	GWP42003-P 25 mg/kg/Day		GWP42003-P 50 mg/kg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0%)		0/73 (0%)		0/76 (0%)
Serious Adverse Events
	GWP42003-P 25 mg/kg/Day		GWP42003-P 50 mg/kg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/75 (21.3%)		10/73 (13.7%)		2/76 (2.6%)
Gastrointestinal disorders
Vomiting	2/75 (2.7%)		0/73 (0%)		0/76 (0%)
Abdominal pain	0/75 (0%)		1/73 (1.4%)		0/76 (0%)
Diarrhoea	0/75 (0%)		1/73 (1.4%)		0/76 (0%)
Nausea	1/75 (1.3%)		0/73 (0%)		0/76 (0%)
General disorders
Fatigue	1/75 (1.3%)		0/73 (0%)		0/76 (0%)
Malaise	1/75 (1.3%)		0/73 (0%)		0/76 (0%)
Hepatobiliary disorders
Liver injury	1/75 (1.3%)		0/73 (0%)		0/76 (0%)
Immune system disorders
Type IV hypersensitivity reaction	1/75 (1.3%)		0/73 (0%)		0/76 (0%)
Infections and infestations
Gastroenteritis viral	2/75 (2.7%)		0/73 (0%)		0/76 (0%)
Pneumonia	1/75 (1.3%)		0/73 (0%)		1/76 (1.3%)
Gastroenteritis	0/75 (0%)		1/73 (1.4%)		0/76 (0%)
Otitis media acute	1/75 (1.3%)		0/73 (0%)		0/76 (0%)
Injury, poisoning and procedural complications
Laceration	0/75 (0%)		1/73 (1.4%)		0/76 (0%)
Toxicity to various agents	0/75 (0%)		1/73 (1.4%)		0/76 (0%)
Investigations
Alanine aminotransferase increased	2/75 (2.7%)		2/73 (2.7%)		0/76 (0%)
Aspartate aminotransferase increased	2/75 (2.7%)		2/73 (2.7%)		0/76 (0%)
Transaminases increased	0/75 (0%)		2/73 (2.7%)		0/76 (0%)
Blood bilirubin increased	1/75 (1.3%)		0/73 (0%)		0/76 (0%)
Metabolism and nutrition disorders
Dehydration	0/75 (0%)		1/73 (1.4%)		0/76 (0%)
Electrolyte imbalance	1/75 (1.3%)		0/73 (0%)		0/76 (0%)
Hypophagia	1/75 (1.3%)		0/73 (0%)		0/76 (0%)
Nervous system disorders
Status epilepticus	2/75 (2.7%)		0/73 (0%)		1/76 (1.3%)
Seizure	1/75 (1.3%)		1/73 (1.4%)		0/76 (0%)
Generalised tonic-clonic seizure	0/75 (0%)		1/73 (1.4%)		0/76 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/75 (1.3%)		0/73 (0%)		0/76 (0%)
Pneumonia aspiration	1/75 (1.3%)		0/73 (0%)		0/76 (0%)
Skin and subcutaneous tissue disorders
Angioedema	0/75 (0%)		1/73 (1.4%)		0/76 (0%)
Rash macular	0/75 (0%)		1/73 (1.4%)		0/76 (0%)
Urticaria	0/75 (0%)		1/73 (1.4%)		0/76 (0%)
Rash	1/75 (1.3%)	1	0/73 (0%)	1	0/76 (0%)	1
Rash erythematous	1/75 (1.3%)		0/73 (0%)		0/76 (0%)
Other (Not Including Serious) Adverse Events
	GWP42003-P 25 mg/kg/Day		GWP42003-P 50 mg/kg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/75 (88%)		71/73 (97.3%)		68/76 (89.5%)
Blood and lymphatic system disorders
Anaemia	5/75 (6.7%)		3/73 (4.1%)		1/76 (1.3%)
Ear and labyrinth disorders
Ear pain	2/75 (2.7%)		1/73 (1.4%)		0/76 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/75 (0%)		3/73 (4.1%)		1/76 (1.3%)
Constipation	8/75 (10.7%)		5/73 (6.8%)		6/76 (7.9%)
Diarrhoea	23/75 (30.7%)		40/73 (54.8%)		19/76 (25%)
Frequent bowel movements	0/75 (0%)		2/73 (2.7%)		0/76 (0%)
Nausea	6/75 (8%)		2/73 (2.7%)		2/76 (2.6%)
Retching	2/75 (2.7%)		1/73 (1.4%)		0/76 (0%)
Vomiting	12/75 (16%)		13/73 (17.8%)		7/76 (9.2%)
General disorders
Fatigue	3/75 (4%)		4/73 (5.5%)		1/76 (1.3%)
Gait disturbance	4/75 (5.3%)		3/73 (4.1%)		2/76 (2.6%)
Pyrexia	14/75 (18.7%)		12/73 (16.4%)		6/76 (7.9%)
Infections and infestations
Bronchitis	2/75 (2.7%)		1/73 (1.4%)		1/76 (1.3%)
Ear infection	2/75 (2.7%)		4/73 (5.5%)		0/76 (0%)
Gastroenteritis	3/75 (4%)		2/73 (2.7%)		2/76 (2.6%)
Gastroenteritis viral	1/75 (1.3%)		3/73 (4.1%)		3/76 (3.9%)
Nasopharyngitis	11/75 (14.7%)		11/73 (15.1%)		12/76 (15.8%)
Otitis media	2/75 (2.7%)		1/73 (1.4%)		0/76 (0%)
Pharyngitis	1/75 (1.3%)		2/73 (2.7%)		2/76 (2.6%)
Pharyngitis streptococcal	0/75 (0%)		2/73 (2.7%)		1/76 (1.3%)
Pneumonia	2/75 (2.7%)		2/73 (2.7%)		0/76 (0%)
Respiratory tract infection	2/75 (2.7%)		0/73 (0%)		2/76 (2.6%)
Tonsillitis	2/75 (2.7%)		0/73 (0%)		1/76 (1.3%)
Upper respiratory tract infection	7/75 (9.3%)		7/73 (9.6%)		10/76 (13.2%)
Urinary tract infection	4/75 (5.3%)		1/73 (1.4%)		0/76 (0%)
Viral infection	3/75 (4%)		0/73 (0%)		2/76 (2.6%)
Injury, poisoning and procedural complications
Fall	2/75 (2.7%)		4/73 (5.5%)		5/76 (6.6%)
Laceration	0/75 (0%)		2/73 (2.7%)		0/76 (0%)
Ligament sprain	1/75 (1.3%)		2/73 (2.7%)		1/76 (1.3%)
Investigations
Alanine aminotransferase increased	7/75 (9.3%)		14/73 (19.2%)		0/76 (0%)
Anticonvulsant drug level increased	1/75 (1.3%)		2/73 (2.7%)		1/76 (1.3%)
Aspartate aminotransferase increased	6/75 (8%)		12/73 (16.4%)		0/76 (0%)
Eosinophil count increased	4/75 (5.3%)		1/73 (1.4%)		0/76 (0%)
Gamma-glutamyltransferase increased	12/75 (16%)		10/73 (13.7%)		0/76 (0%)
Hepatic enzyme increased	0/75 (0%)		3/73 (4.1%)		0/76 (0%)
International normalised ratio increased	0/75 (0%)		2/73 (2.7%)		0/76 (0%)
Platelet count decreased	3/75 (4%)		2/73 (2.7%)		0/76 (0%)
Prothrombin time prolonged	0/75 (0%)		2/73 (2.7%)		0/76 (0%)
Weight decreased	5/75 (6.7%)		6/73 (8.2%)		0/76 (0%)
Metabolism and nutrition disorders
Decreased appetite	15/75 (20%)		17/73 (23.3%)		9/76 (11.8%)
Diet refusal	0/75 (0%)		2/73 (2.7%)		0/76 (0%)
Increased appetite	3/75 (4%)		3/73 (4.1%)		5/76 (6.6%)
Nervous system disorders
Ataxia	3/75 (4%)		2/73 (2.7%)		2/76 (2.6%)
Dizziness	2/75 (2.7%)		0/73 (0%)		3/76 (3.9%)
Drooling	1/75 (1.3%)		2/73 (2.7%)		2/76 (2.6%)
Headache	4/75 (5.3%)		2/73 (2.7%)		4/76 (5.3%)
Hypersomnia	0/75 (0%)		2/73 (2.7%)		0/76 (0%)
Lethargy	4/75 (5.3%)		3/73 (4.1%)		5/76 (6.6%)
Seizure	4/75 (5.3%)		7/73 (9.6%)		5/76 (6.6%)
Somnolence	10/75 (13.3%)		19/73 (26%)		7/76 (9.2%)
Psychiatric disorders
Abnormal behaviour	1/75 (1.3%)		2/73 (2.7%)		1/76 (1.3%)
Aggression	2/75 (2.7%)		2/73 (2.7%)		3/76 (3.9%)
Agitation	1/75 (1.3%)		2/73 (2.7%)		3/76 (3.9%)
Anxiety	2/75 (2.7%)		0/73 (0%)		1/76 (1.3%)
Insomnia	3/75 (4%)		2/73 (2.7%)		5/76 (6.6%)
Irritability	4/75 (5.3%)		5/73 (6.8%)		4/76 (5.3%)
Panic attack	2/75 (2.7%)		0/73 (0%)		0/76 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/75 (1.3%)		2/73 (2.7%)		0/76 (0%)
Cough	8/75 (10.7%)		3/73 (4.1%)		5/76 (6.6%)
Oropharyngeal pain	0/75 (0%)		2/73 (2.7%)		1/76 (1.3%)
Rhinorrhoea	3/75 (4%)		3/73 (4.1%)		0/76 (0%)
Throat irritation	2/75 (2.7%)		0/73 (0%)		0/76 (0%)
Skin and subcutaneous tissue disorders
Dermatitis diaper	2/75 (2.7%)		1/73 (1.4%)		1/76 (1.3%)
Pruritus	2/75 (2.7%)		0/73 (0%)		0/76 (0%)
Rash	3/75 (4%)		7/73 (9.6%)		2/76 (2.6%)
Vascular disorders
Hypertension	2/75 (2.7%)		1/73 (1.4%)		0/76 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.