GWPCARE2 A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P) in Children and Young Adults With Dravet Syndrome

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02224703
• Collaborator: (none)
• Enrollment: 199
• Locations: 38
• Arms: 3
• Actual Duration (Months): 35.9
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To investigate the potential antiepileptic effects of cannabidiol (GWP42003-P) in children and young adults with Dravet syndrome.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy; Dravet Syndrome	Drug: GWP42003-P; Drug: Placebo Control	Phase 3

Detailed Description

This study was a 2:2:1:1 randomized, double-blind, 14-week comparison of two dose levels of GWP42003-P (10 milligram/kilogram [mg/kg]/day and 20 mg/kg/day) versus placebo (10 mg/kg/day dose-volume equivalent and 20 mg/kg/day dose-volume equivalent; presented as pooled placebo in the study). A 28-day screening period prior to randomization (to establish baseline parameters) preceded the treatment period, which consisted of a 2-week titration period followed by a 12-week maintenance period. The study aimed to determine the efficacy, safety, and tolerability of GWP42003-P compared with placebo. 20 mg/kg/day was recommended by the Data Safety Monitoring Committee (DSMC) after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (NCT02091206). The first participant did not enroll into this study until the DSMC reviewed the safety data from Part A of study GWEP1332 (NCT02091206).

Following study completion, all participants were invited to continue to receive GWP42003-P in a separate open-label extension study (GWEP1415; NCT02224573).

Study Design

• Study Type: Interventional
• Actual Enrollment: 199 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P) in Children and Young Adults With Dravet Syndrome.
• Actual Study Start Date: Apr 13, 2015
• Actual Primary Completion Date: Apr 9, 2018
• Actual Study Completion Date: Apr 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 10 mg/kg/day GWP42003-P GWP42003-P oral solution (100 mg/milliliter [mL] cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 10 mg/kg/day dose was defined as 50% of the 20 mg/kg/day dose.	Drug: GWP42003-P; Other Names: Cannabidiol CBD Epidiolex
Experimental: 20 mg/kg/day GWP42003-P GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 20 mg/kg/day dose was recommended by the DSMC after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (NCT02091206).	Drug: GWP42003-P; Other Names: Cannabidiol CBD Epidiolex
Placebo Comparator: Placebo Control Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent.	Drug: Placebo Control; Other Names: Placebo

Outcome Measures

Primary Outcome Measures

1. Change In Convulsive Seizures During The Treatment Period Compared To Baseline [Baseline to Day 99 or Early Termination (ET)]

   Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic. Participants or their caregivers recorded the number and type of convulsive seizures each day from screening until completion of dosing using an interactive voice response system (IVRS) diary. The primary endpoint was analyzed using negative binomial regression on the sum of the convulsive seizure counts during the treatment period, based on the ITT analysis set. Baseline included all available data prior to Day 1. Data reported as the ratio of geometric least squares mean in convulsive seizures and expressed as a percentage reduction.

Secondary Outcome Measures

1. Change In Total Seizures During The Treatment Period Compared To Baseline [Baseline to Day 99 or ET]

   Total seizures were defined as the combination of convulsive and non-convulsive seizures. Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic seizures. Non-convulsive seizures were defined as myoclonic, countable partial, other partial, or absence seizures. Participants or their caregivers recorded the number and type of convulsive seizures and non-convulsive seizures each day from screening until completion of dosing using an IVRS diary. Change compared to baseline was calculated as per the primary outcome measure. Data reported as the ratio of geometric least squares mean in total seizures and expressed as a percentage reduction.

2. Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period [Baseline to Day 99 or ET]

   Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic. Participants or their caregivers recorded the number and type of convulsive seizures each day from screening until completion of dosing using an IVRS diary. Baseline included all available data prior to Day 1 (28-day average). Percentage change from baseline was calculated as: ([frequency during the treatment period - frequency during baseline]/frequency during baseline) x 100. The frequency during each period was based on 28-day averages and calculated as: (number of seizures in the period/number of reported days in the IVRS period) x 28. Baseline included all available data prior to Day 1 (28-day average).

3. Caregiver Global Impression Of Change (CGIC) At The Last Visit [Baseline to Last Visit]

   On Day 1 (prior to receiving study drug), the caregiver was asked to write a brief description of the participant's overall condition as a memory aid for the CGIC questionnaire at subsequent visits. The CGIC questionnaire comprised the following question, to be rated on a 7-point scale: Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment) using the scale below. The markers were: "Very Much Improved"; "Much Improved"; "Slightly Improved"; "No Change"; "Slightly Worse"; "Much Worse"; "Very Much Worse". The CGIC response/score, recorded at each visit, was summarized, on both a categorical and continuous scale, by treatment group. The scores at the last scheduled visit (not including the end of taper or safety follow-up visits) at which participant's last evaluation was performed were analyzed using ordinal logistic regression.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Participant must have been male or female, aged between 2 and 18 years (inclusive).

• Participant must have had a documented history of Dravet syndrome that was not completely controlled by current antiepileptic drugs.

• Participant must have been taking 1 or more antiepileptic drugs at a dose that had been stable for at least 4 weeks.

• All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation) must have been stable for 4 weeks prior to screening and participant was willing to maintain a stable regimen throughout the study.

Key Exclusion Criteria:

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

• Participant had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to screening or randomization, other than epilepsy.

• Participant was currently using or had in the past used recreational cannabis, medicinal cannabis, or synthetic cannabinoid-based medications (including Sativex®) within the 3 months prior to study entry and was unwilling to abstain for the duration for the study.

• Participant had any known or suspected hypersensitivity to cannabinoids or any of the excipients of the investigational medicinal products.

• There were plans for the participant to travel outside their country of residence during the study.

• Any history of suicidal behavior or any suicidal ideation of type four or five on the Columbia-Suicide Severity Rating Scale (Children's) at screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35233
2		Little Rock	Arkansas	United States	72202
3		Los Angeles	California	United States	90027
4		Sacramento	California	United States	95816
5		Hartford	Connecticut	United States	06106
6		Miami	Florida	United States	33155
7		Savannah	Georgia	United States	31404
8		Chicago	Illinois	United States	60611
9		Lexington	Kentucky	United States	40536-0284
10		Louisville	Kentucky	United States	40202
11		Saint Paul	Minnesota	United States	55102
12		Saint Louis	Missouri	United States	63141
13		Omaha	Nebraska	United States	68106
14		Lebanon	New Hampshire	United States	03756
15		Buffalo	New York	United States	14203
16		Chapel Hill	North Carolina	United States	27599
17		Portland	Oregon	United States	97239
18		Philadelphia	Pennsylvania	United States	19104-4399
19		Charleston	South Carolina	United States	29425
20		Austin	Texas	United States	78723
21		Fort Worth	Texas	United States	76104
22		Richmond	Virginia	United States	23298-0211
23		Seattle	Washington	United States	98105
24		Heidelberg		Australia	3084
25		Randwick		Australia	NSW 2031
26		Ramat Gan		Israel	52621
27		Heeze		Netherlands	5591 VE
28		Zwolle		Netherlands	8025 BV
29		Kraków		Poland	30-363
30		Warszawa		Poland	04-730
31		Łódź		Poland	93-271
32		Barcelona		Spain	08022
33		Madrid		Spain	28009
34		Madrid		Spain	28034
35		Madrid		Spain	28222
36		Pamplona		Spain	31008
37		Sevilla		Spain	41013
38		Valencia		Spain	46026

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Sep 6, 2018
• Statistical Analysis Plan - Oct 5, 2018

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02224703
• Other Study ID Numbers: GWEP1424; 2014-002939-34
• First Posted: Aug 25, 2014
• Last Update Posted: Aug 1, 2019
• Last Verified: Jul 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Jazz Pharmaceuticals: Cannabidiol; CBD; GWP42003-P; Epidiolex
• Additional relevant MeSH terms: Epilepsies, Myoclonic; Syndrome; Cannabidiol

Study Results

Participant Flow

Recruitment Details	A total of 43 sites screened participants and 38 sites (23 in the United States, 7 in Spain, 3 in Poland, 2 in Australia, 1 in Israel, and 2 in the Netherlands) randomized participants into the trial. Two sites selected (1 in Israel and 1 in the United States) did not screen any participants.
Pre-assignment Detail	To assess eligibility, participants, 2-18 years of age with Dravet syndrome had to be taking 1 or more antiepileptic drugs at a dose which had been stable; and medicated for epilepsy for at least 4 weeks were screened. A total of 285 participants were screened, of which 199 were randomized.

Arm/Group Title	10 mg/kg/Day GWP42003-P	20 mg/kg/Day GWP42003-P	Placebo Control
Arm/Group Description	GWP42003-P oral solution (100 milligrams/milliliter [mg/mL] cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 10 mg/kilogram (kg)/day dose was defined as 50% of the 20 mg/kg/day dose.	GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring).The 20 mg/kg/day dose was recommended by the Data Safety Monitoring Committee (DSMC) after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (NCT02091206).	Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent.
Period Title: Overall Study
STARTED	67	67	65
Received at Least 1 Dose of Study Drug	66	67	65
Safety Analysis Set	64	69	65
Intent to Treat (ITT) Analysis Set	66	67	65
COMPLETED	64	61	65
NOT COMPLETED	3	6	0

Baseline Characteristics

Arm/Group Title	10 mg/kg/Day GWP42003-P	20 mg/kg/Day GWP42003-P	Placebo Control	Total
Arm/Group Description	GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 10 mg/kg/day dose was defined as 50% of the 10 mg/kg/day dose.	GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 20 mg/kg/day dose was recommended by the DSMC after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (NCT02091206).	Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent.	Total of all reporting groups
Overall Participants	64	69	65	198
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	9.169 (4.1744)	9.245 (4.3792)	9.617 (4.5757)	9.343 (4.3626)
Sex: Female, Male (Count of Participants)
Female	38 59.4%	32 46.4%	34 52.3%	104 52.5%
Male	26 40.6%	37 53.6%	31 47.7%	94 47.5%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	1 1.5%	1 0.5%
Asian	0 0%	1 1.4%	4 6.2%	5 2.5%
Black or African American	1 1.6%	0 0%	4 6.2%	5 2.5%
White	55 85.9%	66 95.7%	55 84.6%	176 88.9%
Other	8 12.5%	2 2.9%	1 1.5%	11 5.6%
Region of Enrollment (participants) [Number]
Australia	6 9.4%	4 5.8%	3 4.6%	13 6.6%
Israel	0 0%	1 1.4%	2 3.1%	3 1.5%
Netherlands	9 14.1%	7 10.1%	9 13.8%	25 12.6%
Poland	8 12.5%	11 15.9%	6 9.2%	25 12.6%
Spain	12 18.8%	14 20.3%	13 20%	39 19.7%
United States	29 45.3%	32 46.4%	32 49.2%	93 47%

Outcome Measures

1. Primary Outcome

Title	Change In Convulsive Seizures During The Treatment Period Compared To Baseline
Description	Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic. Participants or their caregivers recorded the number and type of convulsive seizures each day from screening until completion of dosing using an interactive voice response system (IVRS) diary. The primary endpoint was analyzed using negative binomial regression on the sum of the convulsive seizure counts during the treatment period, based on the ITT analysis set. Baseline included all available data prior to Day 1. Data reported as the ratio of geometric least squares mean in convulsive seizures and expressed as a percentage reduction.
Time Frame	Baseline to Day 99 or Early Termination (ET)

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) analysis set: All participants who were randomized and dosed in the trial and had post-baseline efficacy data.

Arm/Group Title	10 mg/kg/Day GWP42003-P	20 mg/kg/Day GWP42003-P	Placebo Control
Arm/Group Description	GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 10 mg/kg/day dose was defined as 50% of the 20 mg/kg/day dose.	GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 20 mg/kg/day dose was recommended by the DSMC after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (NCT02091206).	Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent.
Measure Participants	66	67	65
Geometric Least Squares Mean (95% Confidence Interval) [percentage reduction]	48.7	45.7	26.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	20 mg/kg/Day GWP42003-P, Placebo Control
	Comments	Model includes 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. Log-transformed number of days in which seizures were reported by period is included as an offset. Null hypothesis was that the ratio of GWP42003-P to placebo would be 1.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0299
	Comments
	Method	Negative binomial regression
	Comments
Method of Estimation	Estimation Parameter	Treatment Ratio
	Estimated Value	0.743
	Confidence Interval	(2-Sided) 95%; 0.568 to 0.971
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10 mg/kg/Day GWP42003-P, Placebo Control
	Comments	Model includes 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. Log-transformed number of days in which seizures were reported by period is included as an offset. Null hypothesis was that the ratio of GWP42003-P to placebo would be 1.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0095
	Comments
	Method	Negative binomial regression
	Comments
Method of Estimation	Estimation Parameter	Treatment Ratio
	Estimated Value	0.702
	Confidence Interval	(2-Sided) 95%; 0.538 to 0.916
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change In Total Seizures During The Treatment Period Compared To Baseline
Description	Total seizures were defined as the combination of convulsive and non-convulsive seizures. Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic seizures. Non-convulsive seizures were defined as myoclonic, countable partial, other partial, or absence seizures. Participants or their caregivers recorded the number and type of convulsive seizures and non-convulsive seizures each day from screening until completion of dosing using an IVRS diary. Change compared to baseline was calculated as per the primary outcome measure. Data reported as the ratio of geometric least squares mean in total seizures and expressed as a percentage reduction.
Time Frame	Baseline to Day 99 or ET

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) analysis set: All participants who were randomized and dosed in the trial and had post-baseline efficacy data.

Arm/Group Title	10 mg/kg/Day GWP42003-P	20 mg/kg/Day GWP42003-P	Placebo Control
Arm/Group Description	GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 10 mg/kg/day dose was defined as 50% of the 10 mg/kg/day dose.	GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 20 mg/kg/day dose was recommended by the DSMC after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (NCT02091206).	Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent.
Measure Participants	66	67	65
Geometric Least Squares Mean (95% Confidence Interval) [percentage reduction]	56.4	47.3	29.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	20 mg/kg/Day GWP42003-P, Placebo Control
	Comments	Model includes 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. Log-transformed number of days in which seizures were reported by period is included as an offset.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0255
	Comments
	Method	Negative binomial regression
	Comments
Method of Estimation	Estimation Parameter	Treatment Ratio
	Estimated Value	0.749
	Confidence Interval	(2-Sided) 95%; 0.581 to 0.965
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10 mg/kg/Day GWP42003-P, Placebo Control
	Comments	Model includes 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. Log-transformed number of days in which seizures were reported by period is included as an offset.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Negative binomial regression
	Comments
Method of Estimation	Estimation Parameter	Treatment Ratio
	Estimated Value	0.620
	Confidence Interval	(2-Sided) 95%; 0.481 to 0.799
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period
Description	Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic. Participants or their caregivers recorded the number and type of convulsive seizures each day from screening until completion of dosing using an IVRS diary. Baseline included all available data prior to Day 1 (28-day average). Percentage change from baseline was calculated as: ([frequency during the treatment period - frequency during baseline]/frequency during baseline) x 100. The frequency during each period was based on 28-day averages and calculated as: (number of seizures in the period/number of reported days in the IVRS period) x 28. Baseline included all available data prior to Day 1 (28-day average).
Time Frame	Baseline to Day 99 or ET

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) analysis set: All participants who were randomized and dosed in the trial and had post-baseline efficacy data.

Arm/Group Title	10 mg/kg/Day GWP42003-P	20 mg/kg/Day GWP42003-P	Placebo Control
Arm/Group Description	GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 10 mg/kg/day dose was defined as 50% of the 10 mg/kg/day dose.	GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 20 mg/kg/day dose was recommended by the DSMC after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (NCT02091206).	Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent.
Measure Participants	66	67	65
Count of Participants [Participants]	29 45.3%	33 47.8%	17 26.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	20 mg/kg/Day GWP42003-P, Placebo Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0069
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value calculated from a Cochran-Mantel-Haenszel test stratified by age group (2-5, 6-12, and 13-18 years).
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.74
	Confidence Interval	(2-Sided) 95%; 1.32 to 5.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10 mg/kg/Day GWP42003-P, Placebo Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0332
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value calculated from a Cochran-Mantel-Haenszel test stratified by age group (2-5, 6-12, and 13-18 years).
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.21
	Confidence Interval	(2-Sided) 95%; 1.06 to 4.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Caregiver Global Impression Of Change (CGIC) At The Last Visit
Description	On Day 1 (prior to receiving study drug), the caregiver was asked to write a brief description of the participant's overall condition as a memory aid for the CGIC questionnaire at subsequent visits. The CGIC questionnaire comprised the following question, to be rated on a 7-point scale: Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment) using the scale below. The markers were: "Very Much Improved"; "Much Improved"; "Slightly Improved"; "No Change"; "Slightly Worse"; "Much Worse"; "Very Much Worse". The CGIC response/score, recorded at each visit, was summarized, on both a categorical and continuous scale, by treatment group. The scores at the last scheduled visit (not including the end of taper or safety follow-up visits) at which participant's last evaluation was performed were analyzed using ordinal logistic regression.
Time Frame	Baseline to Last Visit

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) analysis set: All participants who were randomized and dosed in the trial and had post-baseline efficacy data.

Arm/Group Title	10 mg/kg/Day GWP42003-P	20 mg/kg/Day GWP42003-P	Placebo Control
Arm/Group Description	GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 10 mg/kg/day dose was defined as 50% of the 10 mg/kg/day dose.	GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 20 mg/kg/day dose was recommended by the DSMC after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (NCT02091206).	Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent.
Measure Participants	66	66	65
Very Much Improved	13 20.3%	11 15.9%	1 1.5%
Much Improved	11 17.2%	10 14.5%	8 12.3%
Slightly Improved	21 32.8%	19 27.5%	18 27.7%
No Change	18 28.1%	17 24.6%	32 49.2%
Slightly Worse	2 3.1%	5 7.2%	4 6.2%
Much Worse	1 1.6%	3 4.3%	2 3.1%
Very Much Worse	0 0%	1 1.4%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	20 mg/kg/Day GWP42003-P, Placebo Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0279
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.02
	Confidence Interval	(2-Sided) 95%; 1.08 to 3.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Proportional odds modelling was carried out by including treatment group as a fixed factor. The estimated OR tested the null hypothesis that OR was equal to 1.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10 mg/kg/Day GWP42003-P, Placebo Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.93
	Confidence Interval	(2-Sided) 95%; 1.56 to 5.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	Proportional odds modelling was carried out by including treatment group as a fixed factor. The estimated OR tested the null hypothesis that OR was equal to 1.

Adverse Events

Time Frame	From Day 1 to Day 137.
Adverse Event Reporting Description	Safety Analysis Set: Received at least 1 dose of study drug and were analyzed per treatment received. Two participants randomized to receive GWP42003-P 10 mg/kg/day titrated above the target dose and were therefore assigned to the GWP42003-P 20 mg/kg/day group for all safety analyses.
Arm/Group Title	10 mg/kg/Day GWP42003-P		20 mg/kg/Day GWP42003-P		Placebo Control
Arm/Group Description	GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 10 mg/kg/day dose was defined as 50% of the 10 mg/kg/day dose.		GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring). The 20 mg/kg/day dose was recommended by the DSMC after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (NCT02091206).		Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent.
All Cause Mortality
	10 mg/kg/Day GWP42003-P		20 mg/kg/Day GWP42003-P		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/64 (0%)		0/69 (0%)		0/65 (0%)
Serious Adverse Events
	10 mg/kg/Day GWP42003-P		20 mg/kg/Day GWP42003-P		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/64 (20.3%)		17/69 (24.6%)		10/65 (15.4%)
Gastrointestinal disorders
Constipation	0/64 (0%)		1/69 (1.4%)		0/65 (0%)
General disorders
Pyrexia	1/64 (1.6%)		1/69 (1.4%)		0/65 (0%)
Drug interaction	0/64 (0%)		1/69 (1.4%)		0/65 (0%)
Fatigue	0/64 (0%)		1/69 (1.4%)		0/65 (0%)
Infections and infestations
Pneumonia	3/64 (4.7%)		2/69 (2.9%)		0/65 (0%)
Viral infection	1/64 (1.6%)		1/69 (1.4%)		0/65 (0%)
Coxsackie viral infection	0/64 (0%)		1/69 (1.4%)		0/65 (0%)
Gastroenteritis	0/64 (0%)		1/69 (1.4%)		0/65 (0%)
Sepsis	0/64 (0%)		1/69 (1.4%)		0/65 (0%)
Adenovirus infection	1/64 (1.6%)		0/69 (0%)		0/65 (0%)
Laryngitis	1/64 (1.6%)		0/69 (0%)		0/65 (0%)
Respiratory tract infection	1/64 (1.6%)		0/69 (0%)		0/65 (0%)
Viral upper respiratory tract infection	0/64 (0%)		0/69 (0%)		1/65 (1.5%)
Injury, poisoning and procedural complications
Toxicity to various agents	1/64 (1.6%)		1/69 (1.4%)		0/65 (0%)
Investigations
Alanine aminotransferase increased	0/64 (0%)		1/69 (1.4%)		0/65 (0%)
Aspartate aminotransferase increased	0/64 (0%)		1/69 (1.4%)		0/65 (0%)
Liver function test abnormal	0/64 (0%)		1/69 (1.4%)		0/65 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/64 (1.6%)		1/69 (1.4%)		0/65 (0%)
Nervous system disorders
Status epilepticus	5/64 (7.8%)		7/69 (10.1%)		8/65 (12.3%)
Generalised tonic-clonic seizure	0/64 (0%)		1/69 (1.4%)		0/65 (0%)
Convulsion	3/64 (4.7%)		0/69 (0%)		1/65 (1.5%)
Somnolence	2/64 (3.1%)		0/69 (0%)		0/65 (0%)
Seizure cluster	1/64 (1.6%)		0/69 (0%)		2/65 (3.1%)
Unresponsive to stimuli	1/64 (1.6%)		0/69 (0%)		0/65 (0%)
Psychiatric disorders
Psychogenic seizure	1/64 (1.6%)		0/69 (0%)		0/65 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory depression	0/64 (0%)		1/69 (1.4%)		0/65 (0%)
Respiratory distress	0/64 (0%)		0/69 (0%)		1/65 (1.5%)
Pneumonia aspiration	1/64 (1.6%)		2/69 (2.9%)		0/65 (0%)
Skin and subcutaneous tissue disorders
Rash	0/64 (0%)		1/69 (1.4%)		0/65 (0%)
Other (Not Including Serious) Adverse Events
	10 mg/kg/Day GWP42003-P		20 mg/kg/Day GWP42003-P		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	56/64 (87.5%)		60/69 (87%)		58/65 (89.2%)
Gastrointestinal disorders
Diarrhoea	11/64 (17.2%)		18/69 (26.1%)		8/65 (12.3%)
Vomiting	4/64 (6.3%)		11/69 (15.9%)		4/65 (6.2%)
General disorders
Pyrexia	15/64 (23.4%)		14/69 (20.3%)		11/65 (16.9%)
Fatigue	5/64 (7.8%)		14/69 (20.3%)		7/65 (10.8%)
Infections and infestations
Nasopharyngitis	4/64 (6.3%)		8/69 (11.6%)		5/65 (7.7%)
Upper respiratory tract infection	3/64 (4.7%)		4/69 (5.8%)		3/65 (4.6%)
Urinary tract infection	0/64 (0%)		4/69 (5.8%)		1/65 (1.5%)
Injury, poisoning and procedural complications
Toxicity to various agents	1/64 (1.6%)		4/69 (5.8%)		0/65 (0%)
Investigations
Alanine aminotransferase increased	3/64 (4.7%)		8/69 (11.6%)		0/65 (0%)
Aspartate aminotransferase increased	3/64 (4.7%)		8/69 (11.6%)		0/65 (0%)
Gamma-glutamyltransferase increased	4/64 (6.3%)		4/69 (5.8%)		3/65 (4.6%)
Metabolism and nutrition disorders
Decreased appetite	10/64 (15.6%)		19/69 (27.5%)		11/65 (16.9%)
Nervous system disorders
Somnolence	14/64 (21.9%)		16/69 (23.2%)		9/65 (13.8%)
Convulsion	3/64 (4.7%)		4/69 (5.8%)		4/65 (6.2%)
Tremor	0/64 (0%)		4/69 (5.8%)		0/65 (0%)
Psychiatric disorders
Aggression	1/64 (1.6%)		6/69 (8.7%)		2/65 (3.1%)
Irritability	3/64 (4.7%)		5/69 (7.2%)		2/65 (3.1%)
Abnormal behaviour	0/64 (0%)		4/69 (5.8%)		0/65 (0%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	0/64 (0%)		1/69 (1.4%)		4/65 (6.2%)

Limitations/Caveats

[Not Specified]

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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.