Antiepileptic Efficacy Study of GWP42003-P in Children and Young Adults With Dravet Syndrome (GWPCARE1)

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02091375
• Collaborator: (none)
• Enrollment: 120
• Locations: 22
• Arms: 2
• Actual Duration (Months): 7.9
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.7

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 20 mg/kg/day Dose; Drug: Placebo control	Phase 3

Detailed Description

GWEP1332 Part B recruited an entirely new group of participants than GWEP1332 Part A. Participants who failed the entry criteria for Part A were eligible to take part in Part B.

Part B was a 1:1 randomized, double-blind, placebo-controlled, 14-week comparison of GWP42003-P versus placebo. The aim of Part B was to assess the antiepileptic efficacy of GWP42003-P as an adjunctive antiepileptic treatment compared with placebo, with respect to the percentage change from baseline during the treatment period of the study in convulsive seizure frequency in children and young adults.

Following the establishment of initial eligibility and baseline measurements, participants entered Part B and began a 28-day baseline observation period.

Eligible participants were then randomized to receive either GWP42003-P or placebo on a 1:1 basis and titrated up to the target dose that was identified in Part A (up to 20 milligrams [mg] per kilogram [kg] per day), which was confirmed following completion of Part A by an independent Data Safety Monitoring Committee who reviewed unblinded safety and pharmacokinetic data from Part A.

Participants received investigational medicinal product for 14 weeks, consisting of a titration period followed by a 12-week maintenance period.

Efficacy and safety were monitored at various clinic visits and via telephone. After 14 weeks of treatment, all participants were offered the option of entering an open label extension (OLE) study. Entry was within seven days of the final treatment visit. Participants who did not immediately enter the OLE study commenced a down-titration taper period lasting up to 10 days. The taper period was interrupted if the participant wished to enter the open label extension study within the seven-day timeframe.

For participants who opted not to enter the OLE study, a follow-up telephone call was made 28 days after the end of dosing and weekly safety telephone calls were made during the 28-day follow-up period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double Blind, Placebo Controlled Two-part Study to Investigate the Dose-ranging Safety and Pharmacokinetics, Followed by the Efficacy and Safety of Cannabidiol (GWP42003-P) in Children and Young Adults With Dravet Syndrome
• Actual Study Start Date: Mar 30, 2015
• Actual Primary Completion Date: Nov 26, 2015
• Actual Study Completion Date: Nov 26, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GWP42003-P 20 mg/kg/day Dose Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Drug: GWP42003-P 20 mg/kg/day Dose; GWP42003-P was an oral solution containing 100 mg/milliliter (mL) cannabidiol (CBD) dissolved in the excipients, sesame oil and anhydrous ethanol (79 mg/mL), with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).; Other Names: Cannabidiol Epidiolex
Placebo Comparator: Placebo Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.	Drug: Placebo control; Placebo oral solution contained the excipients, sesame oil and anhydrous ethanol (79 mg/mL), with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).; Other Names: Placebo

Outcome Measures

Primary Outcome Measures

1. Percentage Change From Baseline In Convulsive Seizure Frequency During The Treatment Period [Baseline to End of Treatment (EOT) (Day 99) or Early Termination (ET)]

   Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an interactive voice response system (IVRS) diary. Percentage change from baseline was calculated as: ([frequency during the treatment period - frequency during baseline]/frequency during baseline) * 100. The frequency during each period was based on 28-day averages and calculated as: (number of seizures in the period/number of reported days in the IVRS period) * 28. Baseline included all available data prior to Day 1 (28-day average). Negative percentages show an improvement from baseline.

Secondary Outcome Measures

1. Number Of Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period [Baseline to EOT (Day 99) or ET]

   Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure.

2. Number of Participants With A ≥25%, ≥75% Or 100% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period [Baseline to EOT (Day 99) or ET]

   Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure.

3. Percentage Change From Baseline In Non-Convulsive Seizure Frequency During The Treatment Period [Baseline to EOT (Day 99) or ET]

   Non-convulsive seizures (myoclonic, partial, or absence) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure. Only participants with non-convulsive seizures during the baseline period were included. Negative percentages show an improvement from baseline.

4. Caregiver Global Impression Of Change In Seizure Duration (CGICSD) [Baseline to EOT (Day 99) or ET]

   Seizure duration was assessed qualitatively using the CGICSD. Caregivers were asked "Since the patient started treatment, please assess the average duration of the patient's seizures (comparing their condition now to their condition before treatment)"; responses included decrease, no change, or increase in average duration. For each seizure type, only participants with at least 1 seizure for the corresponding seizure type, reported at any time during the study, were included.

5. Number Of Participants Using Rescue Medication [Baseline to EOT (Day 99) or ET]

   The use of rescue medication was recorded by the participant or caregiver using a paper diary.

6. Number Of Participants With Inpatient Hospitalizations Due To Epilepsy [Baseline to Safety Follow-up (Day 137)]

   Inpatient hospitalizations due to epilepsy were recorded by the participant or caregiver and through the serious adverse events (SAE) reporting process.

7. Change From Baseline In Sleep Disruption 0 To 10 Numerical Rating Scale (0 to 10 NRS) Score [Baseline to Last Visit (Day 99) or ET]

   The sleep disruption 0 to 10 NRS questionnaire was completed by the participant's caregiver. The caregiver was asked 'On a scale of '0 to 10', please indicate the number that best describes your child's sleep disruption in the last week.' The markers ranged from 0 = 'slept extremely well' to 10 = 'unable to sleep at all'. The change from baseline in the sleep disruption 0 to 10 numerical rating scale score was analyzed using an analysis of covariance (ANCOVA) model with baseline and age group (2 to 5 years, 6 to 12 years and 13 to 18 years) as covariates and treatment group as a fixed factor. A negative change from baseline represents an improvement in sleep. Last visit for endpoints assessed at clinic visits was defined as the last scheduled visit (not including the end of taper or safety follow-up visits) at which participant's last evaluation was performed.

8. Change From Baseline In Epworth Sleepiness Scale (ESS) Score [Baseline to Last Visit (Day 99) or ET]

   The ESS questionnaire was completed by the participant's caregiver. The change from baseline in the ESS score was analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6- to 2 years and 13 to 18 years) as covariates and treatment group as a fixed factor. The total score was the sum of the 8 item-scores and ranged from 0 to 24. A higher total score represents greater levels of daytime sleepiness.

9. Change From Baseline In Quality Of Life In Childhood Epilepsy (QOLCE) Score [Baseline to EOT (Day 99) or ET]

   The QOLCE questionnaire was completed by the parent or caregiver of participants aged 4 years and above. The change from baseline in the overall quality of life score was analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6 to 12 years and 13 to 18 years) as covariates and treatment group as a fixed factor. Zero represents the lowest or poorest category and 100 represents the highest level of functioning. The overall quality of life score was calculated by taking the mean of the subscale scores.

10. Change From Baseline In Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Score [Baseline to Last Visit (Day 99) or ET]

    The Vineland-II scores (standard scores and adaptive levels for each adaptive behavior domain, the adaptive behavior composite, and the maladaptive behavior index score and level) were assessed by the participant's caregiver. Scores were analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6 to 12 years, and 13 to 18 years) as covariates and treatment group as a fixed factor. Higher scores represent greater levels of functioning except for the maladaptive behavior index, for which a negative change from baseline represents an improvement in condition.

11. Caregiver Global Impression Of Change (CGIC) [Baseline to Last Visit (Day 99) or ET]

    The CGIC was used to assess the participant's overall condition on a 7-point scale using the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse, or very much worse" (1 = very much improved; 7 = very much worse). On Day 1 (prior to starting IMP), the caregiver was asked to write a brief description of the participant's overall condition as a memory aid for the CGIC questionnaire at subsequent visits.

Eligibility Criteria

Criteria

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

Key Inclusion Criteria:

• Participants were male or female aged between 2 and 18 years (inclusive).

• Participants had a documented history of Dravet Syndrome that was not completely controlled by current antiepileptic drugs.

• Participants took one or more antiepileptic drugs at a dose that had been stable for at least four weeks.

• All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation) were stable for four weeks prior to screening and participants were willing to maintain a stable regimen throughout the study.

Key Exclusion Criteria:

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

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

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

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

• Participants had been part of a previous clinical trial involving another investigational product in the previous six months.

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

• Participants previously randomized into this study. In particular, participants who participated in Part A of the study could not enter Part B.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Miami	Florida	United States	33155
2		Orlando	Florida	United States	32819
3		Atlanta	Georgia	United States	30328
4		Chicago	Illinois	United States	60611
5		Iowa City	Iowa	United States	52242
6		Boston	Massachusetts	United States	02114
7		Rochester	Minnesota	United States	55905
8		New York	New York	United States	10016
9		Winston-Salem	North Carolina	United States	27408
10		Columbus	Ohio	United States	43205
11		Philadelphia	Pennsylvania	United States	19104
12		Houston	Texas	United States	77030
13		Salt Lake City	Utah	United States	84113
14		Marseille		France	13385
15		Paris		France	75015
16		Strasbourg		France	67098
17		Toulouse		France	70034
18		Gdańsk		Poland	80-952
19		Kraków		Poland	30-349
20		Glasgow		United Kingdom	G51 4TF
21		Liverpool		United Kingdom	L12 2AP
22		London		United Kingdom	WC1N 3JH

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S; Cannabidiol in Dravet Syndrome Study Group. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017 May 25;376(21):2011-2020. doi: 10.1056/NEJMoa1611618.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02091375
• Other Study ID Numbers: GWEP1332 Part B; 2014-002941-23
• First Posted: Mar 19, 2014
• Last Update Posted: Aug 27, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Jazz Pharmaceuticals: Cannabidiol; CBD; Epidiolex; GWP42003-P
• Additional relevant MeSH terms: Epilepsies, Myoclonic; Syndrome; Cannabidiol

Study Results

Participant Flow

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 milligrams (mg) per kilogram (kg) per day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the open-label extension (OLE) study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL cannabidiol [CBD]), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Period Title: Overall Study
STARTED	61	59
Safety Analysis Set	61	59
Intention to Treat (ITT) Analysis Set	61	59
COMPLETED	52	56
NOT COMPLETED	9	3

Baseline Characteristics

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo	Total
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period. Participants received at least 1 dose of IMP; analyzed according to the actual treatment received (GWP42003-P).	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period. Participants received at least 1 dose of IMP; analyzed according to the actual treatment received (placebo).	Total of all reporting groups
Overall Participants	61	59	120
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	9.736 (4.7309)	9.779 (4.8505)	9.757 (4.7699)
Sex: Female, Male (Count of Participants)
Female	26 42.6%	32 54.2%	58 48.3%
Male	35 57.4%	27 45.8%	62 51.7%

Outcome Measures

1. Primary Outcome

Title	Percentage Change From Baseline In Convulsive Seizure Frequency During The Treatment Period
Description	Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an interactive voice response system (IVRS) diary. Percentage change from baseline was calculated as: ([frequency during the treatment period - frequency during baseline]/frequency during baseline) * 100. The frequency during each period was based on 28-day averages and calculated as: (number of seizures in the period/number of reported days in the IVRS period) * 28. Baseline included all available data prior to Day 1 (28-day average). Negative percentages show an improvement from baseline.
Time Frame	Baseline to End of Treatment (EOT) (Day 99) or Early Termination (ET)

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all participants in the Part B safety analysis set who had post-baseline efficacy data. Participants were analyzed according to the treatment group to which they were randomized. The ITT analysis set was the primary analysis set for all efficacy outcome measures.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	61	59
Median (Inter-Quartile Range) [percent change]	-38.94	-13.29

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 20 mg/kg/Day Dose, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0123
	Comments
	Method	Wilcoxon rank-sum test
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-22.79
	Confidence Interval	(2-Sided) 95%; -41.06 to -5.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Calculated using the Hodges-Lehmann approach.

2. Secondary Outcome

Title	Number Of Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period
Description	Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure.
Time Frame	Baseline to EOT (Day 99) or ET

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all participants in the Part B safety analysis set who had post-baseline efficacy data. Participants were analyzed according to the treatment group to which they were randomized. The ITT analysis set was the primary analysis set for all efficacy outcome measures.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	61	59
Count of Participants [Participants]	26 42.6%	16 27.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 20 mg/kg/Day Dose, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0784
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by age group (2-5 years, 6-12 years, and 13-18 years).
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.00
	Confidence Interval	(2-Sided) 95%; 0.93 to 4.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With A ≥25%, ≥75% Or 100% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period
Description	Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure.
Time Frame	Baseline to EOT (Day 99) or ET

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all participants in the Part B safety analysis set who had post-baseline efficacy data. Participants were analyzed according to the treatment group to which they were randomized. The ITT analysis set was the primary analysis set for all efficacy outcome measures.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	61	59
≥25% Reduction	38 62.3%	26 44.1%
≥75% Reduction	14 23%	7 11.9%
100% Reduction	3 4.9%	0 0%

4. Secondary Outcome

Title	Percentage Change From Baseline In Non-Convulsive Seizure Frequency During The Treatment Period
Description	Non-convulsive seizures (myoclonic, partial, or absence) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure. Only participants with non-convulsive seizures during the baseline period were included. Negative percentages show an improvement from baseline.
Time Frame	Baseline to EOT (Day 99) or ET

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all participants in the Part B safety analysis set who had post-baseline efficacy data. Participants were analyzed according to the treatment group to which they were randomized. The ITT analysis set was the primary analysis set for all efficacy outcome measures.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	37	41
Median (Inter-Quartile Range) [percent change]	-40.16	-34.69

5. Secondary Outcome

Title	Caregiver Global Impression Of Change In Seizure Duration (CGICSD)
Description	Seizure duration was assessed qualitatively using the CGICSD. Caregivers were asked "Since the patient started treatment, please assess the average duration of the patient's seizures (comparing their condition now to their condition before treatment)"; responses included decrease, no change, or increase in average duration. For each seizure type, only participants with at least 1 seizure for the corresponding seizure type, reported at any time during the study, were included.
Time Frame	Baseline to EOT (Day 99) or ET

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all participants in the Part B safety analysis set who had post-baseline efficacy data. Participants were analyzed according to the treatment group to which they were randomized. The ITT analysis set was the primary analysis set for all efficacy outcome measures.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	61	59
Decrease in average duration	17 27.9%	8 13.6%
No change in average duration	32 52.5%	31 52.5%
Increase in average duration	0 0%	2 3.4%
Decrease in average duration	4 6.6%	2 3.4%
No change in average duration	8 13.1%	12 20.3%
Increase in average duration	0 0%	1 1.7%
Decrease in average duration	5 8.2%	3 5.1%
No change in average duration	6 9.8%	3 5.1%
Increase in average duration	0 0%	1 1.7%
Decrease in average duration	2 3.3%	2 3.4%
No change in average duration	1 1.6%	3 5.1%
Increase in average duration	0 0%	2 3.4%
Decrease in average duration	4 6.6%	3 5.1%
No change in average duration	10 16.4%	12 20.3%
Increase in average duration	0 0%	3 5.1%
Decrease in average duration	5 8.2%	2 3.4%
No change in average duration	7 11.5%	9 15.3%
Increase in average duration	0 0%	2 3.4%
Decrease in average duration	0 0%	3 5.1%
No change in average duration	3 4.9%	2 3.4%
Increase in average duration	0 0%	0 0%
Decrease in average duration	4 6.6%	6 10.2%
No change in average duration	11 18%	12 20.3%
Increase in average duration	1 1.6%	1 1.7%

6. Secondary Outcome

Title	Number Of Participants Using Rescue Medication
Description	The use of rescue medication was recorded by the participant or caregiver using a paper diary.
Time Frame	Baseline to EOT (Day 99) or ET

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: included all participants randomized to treatment who received at least 1 dose of IMP. Participants were analyzed according to the actual treatment they received.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	61	59
Count of Participants [Participants]	36 59%	41 69.5%

7. Secondary Outcome

Title	Number Of Participants With Inpatient Hospitalizations Due To Epilepsy
Description	Inpatient hospitalizations due to epilepsy were recorded by the participant or caregiver and through the serious adverse events (SAE) reporting process.
Time Frame	Baseline to Safety Follow-up (Day 137)

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all participants in the Part B safety analysis set who had post-baseline efficacy data. Participants were analyzed according to the treatment group to which they were randomized. The ITT analysis set was the primary analysis set for all efficacy outcome measures.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	61	59
Caregiver/participant-reported	5 8.2%	1 1.7%
Investigator-reported (serious TEAE)	2 3.3%	1 1.7%

8. Secondary Outcome

Title	Change From Baseline In Sleep Disruption 0 To 10 Numerical Rating Scale (0 to 10 NRS) Score
Description	The sleep disruption 0 to 10 NRS questionnaire was completed by the participant's caregiver. The caregiver was asked 'On a scale of '0 to 10', please indicate the number that best describes your child's sleep disruption in the last week.' The markers ranged from 0 = 'slept extremely well' to 10 = 'unable to sleep at all'. The change from baseline in the sleep disruption 0 to 10 numerical rating scale score was analyzed using an analysis of covariance (ANCOVA) model with baseline and age group (2 to 5 years, 6 to 12 years and 13 to 18 years) as covariates and treatment group as a fixed factor. A negative change from baseline represents an improvement in sleep. Last visit for endpoints assessed at clinic visits was defined as the last scheduled visit (not including the end of taper or safety follow-up visits) at which participant's last evaluation was performed.
Time Frame	Baseline to Last Visit (Day 99) or ET

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all participants in the Part B safety analysis set who had post-baseline efficacy data. Participants were analyzed according to the treatment group to which they were randomized. The ITT analysis set was the primary analysis set for all efficacy outcome measures.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	59	59
Least Squares Mean (95% Confidence Interval) [units on a scale]	-0.7	-0.3

9. Secondary Outcome

Title	Change From Baseline In Epworth Sleepiness Scale (ESS) Score
Description	The ESS questionnaire was completed by the participant's caregiver. The change from baseline in the ESS score was analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6- to 2 years and 13 to 18 years) as covariates and treatment group as a fixed factor. The total score was the sum of the 8 item-scores and ranged from 0 to 24. A higher total score represents greater levels of daytime sleepiness.
Time Frame	Baseline to Last Visit (Day 99) or ET

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all participants in the Part B safety analysis set who had post-baseline efficacy data. Participants were analyzed according to the treatment group to which they were randomized. The ITT analysis set was the primary analysis set for all efficacy outcome measures.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	61	58
Least Squares Mean (95% Confidence Interval) [units on a scale]	0.82	-0.69

10. Secondary Outcome

Title	Change From Baseline In Quality Of Life In Childhood Epilepsy (QOLCE) Score
Description	The QOLCE questionnaire was completed by the parent or caregiver of participants aged 4 years and above. The change from baseline in the overall quality of life score was analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6 to 12 years and 13 to 18 years) as covariates and treatment group as a fixed factor. Zero represents the lowest or poorest category and 100 represents the highest level of functioning. The overall quality of life score was calculated by taking the mean of the subscale scores.
Time Frame	Baseline to EOT (Day 99) or ET

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all participants in the Part B safety analysis set who had post-baseline efficacy data. Participants were analyzed according to the treatment group to which they were randomized. The ITT analysis set was the primary analysis set for all efficacy outcome measures.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	47	44
Least Squares Mean (95% Confidence Interval) [units on a scale]	5.6	4.1

11. Secondary Outcome

Title	Change From Baseline In Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Score
Description	The Vineland-II scores (standard scores and adaptive levels for each adaptive behavior domain, the adaptive behavior composite, and the maladaptive behavior index score and level) were assessed by the participant's caregiver. Scores were analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6 to 12 years, and 13 to 18 years) as covariates and treatment group as a fixed factor. Higher scores represent greater levels of functioning except for the maladaptive behavior index, for which a negative change from baseline represents an improvement in condition.
Time Frame	Baseline to Last Visit (Day 99) or ET

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all participants in the Part B safety analysis set who had post-baseline efficacy data. Participants were analyzed according to the treatment group to which they were randomized. The ITT analysis set was the primary analysis set for all efficacy outcome measures.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	61	59
Communication Domain Standard Score	-0.8	3.0
Daily Living Skills Domain Standard Score	-0.8	-0.8
Socialization Domain Standard Score	-0.6	-0.6
Motor Skills Domain Standard Score	-2.5	1.7
Adaptive Behavior Composite Standard Score	-2.0	0.6
Maladaptive Behavior Index v-Scale Score	-0.3	-0.4

12. Secondary Outcome

Title	Caregiver Global Impression Of Change (CGIC)
Description	The CGIC was used to assess the participant's overall condition on a 7-point scale using the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse, or very much worse" (1 = very much improved; 7 = very much worse). On Day 1 (prior to starting IMP), the caregiver was asked to write a brief description of the participant's overall condition as a memory aid for the CGIC questionnaire at subsequent visits.
Time Frame	Baseline to Last Visit (Day 99) or ET

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all participants in the Part B safety analysis set who had post-baseline efficacy data. Participants were analyzed according to the treatment group to which they were randomized. The ITT analysis set was the primary analysis set for all efficacy outcome measures.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	60	58
Very Much Improved	9 14.8%	4 6.8%
Much Improved	10 16.4%	4 6.8%
Slightly Improved	18 29.5%	12 20.3%
No Change	15 24.6%	31 52.5%
Slightly Worse	3 4.9%	6 10.2%
Much Worse	4 6.6%	1 1.7%
Very Much Worse	1 1.6%	0 0%

Adverse Events

Time Frame	Day 1 (after dosing) to Day 137
Adverse Event Reporting Description	Included all participants randomized to treatment who received at least 1 dose of IMP. Participants were analyzed according to the actual treatment they received.
Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose		Placebo
Arm/Group Description	Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.		Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
All Cause Mortality
	GWP42003-P 20 mg/kg/Day Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	GWP42003-P 20 mg/kg/Day Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/61 (16.4%)		3/59 (5.1%)
Gastrointestinal disorders
Abdominal distension	1/61 (1.6%)		0/59 (0%)
Abdominal pain	1/61 (1.6%)		0/59 (0%)
Gastrointestinal haemorrhage	1/61 (1.6%)		0/59 (0%)
General disorders
Asthenia	1/61 (1.6%)		0/59 (0%)
Fatigue	1/61 (1.6%)		0/59 (0%)
Infections and infestations
Lower respiratory tract infection	1/61 (1.6%)		0/59 (0%)
Oral herpes	1/61 (1.6%)		0/59 (0%)
Pneumonia	1/61 (1.6%)		0/59 (0%)
Investigations
Aspartate aminotransferase increased	1/61 (1.6%)		0/59 (0%)
Gamma-glutamyltransferase	1/61 (1.6%)		0/59 (0%)
Liver function test abnormal	1/61 (1.6%)		0/59 (0%)
Platelet count	1/61 (1.6%)		0/59 (0%)
Weight decreased	1/61 (1.6%)		0/59 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/61 (1.6%)		0/59 (0%)
Hypophagia	1/61 (1.6%)		0/59 (0%)
Nervous system disorders
Status epilepticus	3/61 (4.9%)		3/59 (5.1%)
Convulsion	2/61 (3.3%)		1/59 (1.7%)
Somnolence	3/61 (4.9%)		0/59 (0%)
Hypotonia	1/61 (1.6%)		0/59 (0%)
Lethargy	1/61 (1.6%)		0/59 (0%)
Myoclonus	1/61 (1.6%)		0/59 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/61 (1.6%)		1/59 (1.7%)
Epistaxis	1/61 (1.6%)		0/59 (0%)
Vascular disorders
Hypovolaemic shock	1/61 (1.6%)		0/59 (0%)
Other (Not Including Serious) Adverse Events
	GWP42003-P 20 mg/kg/Day Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/61 (75.4%)		28/59 (47.5%)
Gastrointestinal disorders
Diarrhoea	19/61 (31.1%)		6/59 (10.2%)
Vomiting	9/61 (14.8%)		3/59 (5.1%)
General disorders
Pyrexia	9/61 (14.8%)		5/59 (8.5%)
Fatigue	11/61 (18%)		2/59 (3.4%)
Infections and infestations
Upper respiratory tract infection	7/61 (11.5%)		5/59 (8.5%)
Nasopharyngitis	3/61 (4.9%)		3/59 (5.1%)
Investigations
Gamma-glutamyltransferase increased	4/61 (6.6%)		0/59 (0%)
Transaminases increased	4/61 (6.6%)		0/59 (0%)
Weight decreased	4/61 (6.6%)		0/59 (0%)
Metabolism and nutrition disorders
Decreased appetite	16/61 (26.2%)		3/59 (5.1%)
Nervous system disorders
Somnolence	19/61 (31.1%)		6/59 (10.2%)
Lethargy	7/61 (11.5%)		3/59 (5.1%)
Headache	1/61 (1.6%)		3/59 (5.1%)
Convulsion	5/61 (8.2%)		2/59 (3.4%)
Psychiatric disorders
Irritability	4/61 (6.6%)		0/59 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	4/61 (6.6%)		2/59 (3.4%)

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.