A Dose-ranging Pharmacokinetics and Safety Study of GWP42003-P in Children With Dravet Syndrome (GWPCARE1)

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02091206
• Collaborator: (none)
• Enrollment: 34
• Locations: 11
• Arms: 4
• Actual Duration (Months): 4.5
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

To evaluate the safety and pharmacokinetics (PK) of multiple doses of GWP42003-P compared with placebo in children with Dravet syndrome.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy; Dravet Syndrome	Drug: GWP42003-P 5 mg/kg/day Dose; Drug: Placebo control; Drug: GWP42003-P 10 mg/kg/day Dose; Drug: GWP42003-P 20 mg/kg/day Dose	Phase 2

Detailed Description

This multi-center study consisted of 2 parts: Part A and Part B. Only Part A is described in this record. Part A was a randomized, double-blind 21-day treatment study period. Participants were randomized to one of 3 doses of active drug or placebo at a 4:1 ratio.

Participants who satisfied all inclusion and none of the exclusion criteria were assigned a unique participant number and then began a 28-day baseline observation period.

Eligible participants were then randomly assigned to receive one of 3 dose levels of GWP42003-P: 5 milligrams (mg) per kilogram (kg) per day, 10 mg/kg/day, 20 mg/kg/day, or matching placebo.

There were three groups of ten participants. In each group, participants were randomly assigned so that eight participants received active treatment and two participants received placebo. Participants received GWP42003-P or placebo for a 21-day exposure period, which consisted of a titration period, followed by a stable dose period.

A PK assessment took place after the first single dose of GWP42003-P. There was a second PK assessment after 21 days of consecutive dosing with GWP42003-P. Participants who took clobazam (CLB) as an adjunctive treatment were asked to take their usual dose 2 hours prior to attending the clinic. The same recommendation was made for other concomitant antiepileptic drugs (AEDs), if applicable. This was so that the pre-treatment (with GWP42003-P) plasma concentrations of CLB, its major metabolite N-desmethylclobazam, and any other concomitant AEDs could be measured, and the impact of GWP42003-P treatment on these levels evaluated. Interim clinic visits to (primarily) evaluate safety and adherence to the titration regimen took place at 7 and 14 days of treatment.

After 21 days of treatment, all participants commenced a 10-day down-titration taper period. An independent Data Safety Monitoring Committee reviewed unblinded safety and PK data and recommended the target dose (up to 20 mg/kg/day) for Part B of the study and for an open label extension study. Once the safety review of Part A data had taken place, participants had the option of entering the open label extension study.

A follow-up telephone call was made 28 days after the end of dosing for participants who did not enter the open label extension study within this time-frame.

Throughout the 21-day treatment period and the 10-day taper period, there were regular safety telephone calls (approximately every 2 days) to check participant status. Weekly safety telephone calls were made during the 28-day follow-up period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 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: Oct 22, 2014
• Actual Primary Completion Date: Mar 9, 2015
• Actual Study Completion Date: Mar 9, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GWP42003-P 5 mg/kg/day Dose Participants received GWP42003-P 5 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 5 mg/kg/day over 3 days and remained at this dose for the rest of the 21-day treatment period (19 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Drug: GWP42003-P 5 mg/kg/day Dose; GWP42003-P was an oral solution containing 25 mg/milliliter (mL) cannabidiol (CBD) or 100 mg/mL 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). Participants were randomly assigned to receive either 5, 10 or 20 mg/kg/day.; Other Names: Cannabidiol Epidiolex
Experimental: GWP42003-P 10 mg/kg/day Dose Participants received GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at this dose for the rest of the 21-day treatment period (15 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Drug: GWP42003-P 10 mg/kg/day Dose; GWP42003-P was an oral solution containing 25 mg/mL CBD or 100 mg/mL 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). Participants were randomly assigned to receive either 5, 10 or 20 mg/kg/day.; Other Names: Cannabidiol Epidiolex
Experimental: GWP42003-P 20 mg/kg/day Dose Participants received GWP42003-P 20 mg/kg/day 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 rest of the 21-day treatment period (11 days). The 21-day treatment 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 25 mg/mL CBD or 100 mg/mL 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). Participants were randomly assigned to receive either 5, 10 or 20 mg/kg/day.; Other Names: Cannabidiol Epidiolex
Placebo Comparator: Placebo Participants received placebo (0 mg/mL CBD), volume matched to one of the 3 dose levels (5, 10, or 20 mg/kg/day), administered orally, half in the morning and half in the evening for 21 days. To maintain the blinded aspect of the study, participants titrated the placebo dose over 3 to 11 days according to the matched investigational medicinal product (IMP) group (3, 7, and 11 days for the 5, 10, or 20 mg/kg/day GWP42003-P groups, respectively) and remained at this dose for the rest of the 21-day treatment period. The 21-day treatment 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. Number Of Participants Who Experienced Severe Treatment-Emergent Adverse Events (TEAEs) [Baseline (Day 1) through Safety follow-up visit (Day 60)]

   A TEAE was defined as an adverse event (AE) with an onset date on or after the first dose of IMP. If an AE had a partial onset date and it was unclear from the partial date (or the stop date) whether the AE started prior to or following the first dose of IMP then the AE was considered a TEAE. The number of participants who experienced one or more severe TEAEs after dosing on Day 1 through the Safety Follow-up Visit (Day 60) is presented. A summary of serious and all other non-serious AEs regardless of causality is located in the Adverse Events module.

Secondary Outcome Measures

1. Area Under The Concentration-Time Curve Calculated To The Last Observable Concentration At Time T (AUC0-t) For CBD And Its Metabolites At Days 1 And 22 [Predose and 2-6 hours postdose on Days 1 and 22]

   AUC0-t for CBD and its major metabolites, 6-hydroxy-CBD (6-OH-CBD), 7-hydroxy-CBD (7-OH-CBD), and 7-carboxy-CBD (7-COOH-CBD) were calculated using blood samples collected before and after IMP dosing on Days 1 and 22. One sample was collected predose, 2 to 3 hours postdose, and 4 to 6 hours postdose for CBD and its metabolites. Results are presented for participants who received GWP42003-P at 5, 10, or 20 mg/kg/day during the study and for participants with a numeric result for the given evaluation.

2. Mean Percentage Change From Baseline To End Of Treatment In Plasma Clobazam (CLB) And N-Desmethylclobazam (N-CLB) Concentrations [Predose on Days 1 and 22]

   Plasma concentrations of CLB and N-CLB were measured on Days 1 and 22. Participants were instructed to take their daily dose of CLB 2 hours prior to the anticipated pre-IMP blood specimen collection on both days. Blood samples were collected prior to administration of IMP. Results are presented for a subgroup of participants who took CLB during the study and had PK samples analyzed at both PK sampling visits (Days 1 and 22).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 10 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Participants were male or female aged between 4 and 10 years (inclusive).

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

• Participants took one or more AEDs at a dose which had been stable for at least 4 weeks.

• Participants had experienced fewer than 4 convulsive seizures (tonic-clonic, tonic, clonic, atonic seizures) during the 28-day baseline period.

• All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation [VNS]) were stable for four weeks prior to screening and participants were willing to maintain a stable regimen throughout the study. The ketogenic diet and VNS treatments were not counted as an AED.

Key Exclusion Criteria:

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

• Participants had clinically relevant abnormalities in the 12-lead electrocardiogram measured at screening or randomization.

• Participants were currently using or had in the past used recreational or medicinal cannabis, or synthetic CBD based medications (including Sativex®) within the 3 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 IMP.

• Participants who had been part of a clinical trial involving another investigational product in the previous 6 months.

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

• Participants were previously randomized into this study. In particular, participants participating in Part A of the study cannot enter Part B.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Miami	Florida	United States	33155
2		Atlanta	Georgia	United States	30328
3		Chicago	Illinois	United States	60611
4		Iowa City	Iowa	United States	52242
5		Boston	Massachusetts	United States	02114
6		Winston-Salem	North Carolina	United States	27408
7		Columbus	Ohio	United States	43205
8		Houston	Texas	United States	77030
9		Edinburgh		United Kingdom	EH9 1LF
10		Liverpool		United Kingdom	L12 2AP
11		London		United Kingdom	WC1N 3JH

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, Greenwood S, Morrison G, Sommerville K; GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018 Apr 3;90(14):e1204-e1211. doi: 10.1212/WNL.0000000000005254. Epub 2018 Mar 14.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02091206
• Other Study ID Numbers: GWEP1332 Part A; 2014-002941-23
• First Posted: Mar 19, 2014
• Last Update Posted: Aug 24, 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 5 mg/kg/Day Dose	GWP42003-P 10 mg/kg/Day Dose	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received GWP42003-P 5 milligrams (mg) per kilogram (kg) per day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 5 mg/kg/day over 3 days and remained at this dose for the rest of the 21-day treatment period (19 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at this dose for the rest of the 21-day treatment period (15 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received GWP42003-P 20 mg/kg/day 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 rest of the 21-day treatment period (11 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/milliliter [mL] cannabidiol [CBD]), volume matched to one of the 3 dose levels (5, 10, or 20 mg/kg/day), administered orally, half in the morning and half in the evening for 21 days. To maintain the blinded aspect of the study, participants titrated the placebo dose over 3 to 11 days according to the matched investigational medicinal product (IMP) group (3, 7, and 11 days for the 5, 10, or 20 mg/kg/day GWP42003-P groups, respectively) and remained at this dose for the rest of the 21-day treatment period. The 21-day treatment period was followed by a 10-day taper (10% per day of the matched dose) period.
Period Title: Treatment Period
STARTED	10	8	9	7
Safety Analysis Set	10	8	9	7
COMPLETED	10	7	8	7
NOT COMPLETED	0	1	1	0
Period Title: Treatment Period
STARTED	10	7	8	7
COMPLETED	9	7	8	5
NOT COMPLETED	1	0	0	2

Baseline Characteristics

Arm/Group Title	GWP42003-P 5 mg/kg/Day Dose	GWP42003-P 10 mg/kg/Day Dose	GWP42003-P 20 mg/kg/Day Dose	Placebo	Total
Arm/Group Description	Participants received GWP42003-P 5 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 5 mg/kg/day over 3 days and remained at this dose for the rest of the 21-day treatment period (19 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at this dose for the rest of the 21-day treatment period (15 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received GWP42003-P 20 mg/kg/day 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 rest of the 21-day treatment period (11 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume matched to one of the 3 dose levels (5, 10, or 20 mg/kg/day), administered orally, half in the morning and half in the evening for 21 days. To maintain the blinded aspect of the study, participants titrated the placebo dose over 3 to 11 days according to the matched IMP group (3, 7, and 11 days for the 5, 10, or 20 mg/kg/day GWP42003-P groups, respectively) and remained at this dose for the rest of the 21-day treatment period. The 21-day treatment period was followed by a 10-day taper (10% per day of the matched dose) period.	Total of all reporting groups
Overall Participants	10	8	9	7	34
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	7.150 (1.8955)	7.368 (2.1229)	8.671 (1.7957)	6.978 (0.9476)	7.568 (1.8300)
Sex: Female, Male (Count of Participants)
Female	5 50%	5 62.5%	6 66.7%	2 28.6%	18 52.9%
Male	5 50%	3 37.5%	3 33.3%	5 71.4%	16 47.1%

Outcome Measures

1. Primary Outcome

Title	Number Of Participants Who Experienced Severe Treatment-Emergent Adverse Events (TEAEs)
Description	A TEAE was defined as an adverse event (AE) with an onset date on or after the first dose of IMP. If an AE had a partial onset date and it was unclear from the partial date (or the stop date) whether the AE started prior to or following the first dose of IMP then the AE was considered a TEAE. The number of participants who experienced one or more severe TEAEs after dosing on Day 1 through the Safety Follow-up Visit (Day 60) is presented. A summary of serious and all other non-serious AEs regardless of causality is located in the Adverse Events module.
Time Frame	Baseline (Day 1) through Safety follow-up visit (Day 60)

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 treatment they received. Only participants for whom it had been confirmed that they did not take any IMP were excluded from the safety analysis set.

Arm/Group Title	GWP42003-P 5 mg/kg/Day Dose	GWP42003-P 10 mg/kg/Day Dose	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received GWP42003-P 5 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 5 mg/kg/day over 3 days and remained at this dose for the rest of the 21-day treatment period (19 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at this dose for the rest of the 21-day treatment period (15 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received GWP42003-P 20 mg/kg/day 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 rest of the 21-day treatment period (11 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume matched to one of the 3 dose levels (5, 10, or 20 mg/kg/day), administered orally, half in the morning and half in the evening for 21 days. To maintain the blinded aspect of the study, participants titrated the placebo dose over 3 to 11 days according to the matched IMP group (3, 7, and 11 days for the 5, 10, or 20 mg/kg/day GWP42003-P groups, respectively) and remained at this dose for the rest of the 21-day treatment period. The 21-day treatment period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	10	8	9	7
Count of Participants [Participants]	2 20%	1 12.5%	0 0%	1 14.3%

2. Secondary Outcome

Title	Area Under The Concentration-Time Curve Calculated To The Last Observable Concentration At Time T (AUC0-t) For CBD And Its Metabolites At Days 1 And 22
Description	AUC0-t for CBD and its major metabolites, 6-hydroxy-CBD (6-OH-CBD), 7-hydroxy-CBD (7-OH-CBD), and 7-carboxy-CBD (7-COOH-CBD) were calculated using blood samples collected before and after IMP dosing on Days 1 and 22. One sample was collected predose, 2 to 3 hours postdose, and 4 to 6 hours postdose for CBD and its metabolites. Results are presented for participants who received GWP42003-P at 5, 10, or 20 mg/kg/day during the study and for participants with a numeric result for the given evaluation.
Time Frame	Predose and 2-6 hours postdose on Days 1 and 22

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 treatment they received. Only participants for whom it had been confirmed that they did not take any IMP were excluded from the safety analysis set.

Arm/Group Title	GWP42003-P 5 mg/kg/Day Dose	GWP42003-P 10 mg/kg/Day Dose	GWP42003-P 20 mg/kg/Day Dose
Arm/Group Description	Participants received GWP42003-P 5 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 5 mg/kg/day over 3 days and remained at this dose for the rest of the 21-day treatment period (19 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at this dose for the rest of the 21-day treatment period (15 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received GWP42003-P 20 mg/kg/day 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 rest of the 21-day treatment period (11 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.
Measure Participants	10	8	9
Day 1 CBD	70.61 (20.38)	66.35 (120.8)	73.69 (96.64)
Day 22 CBD	240.8 (100.8)	721.8 (79.92)	962.6 (93.43)
Day 1 6-OH-CBD	3.27 (132)	2.79 (87.7)	5.16 (57.2)
Day 22 6-OH-CBD	9.33 (119)	26.3 (82.9)	58.6 (90.1)
Day 1 7-OH-CBD	21.9 (57.0)	18.4 (299)	30.2 (105)
Day 22 7-OH-CBD	131 (107)	244 (120)	508 (96.0)
Day 1 7-COOH-CBD	297 (97.3)	125 (1750)	195 (573)
Day 22 7-COOH-CBD	4190 (81.20)	9220 (178)	15500 (148)

3. Secondary Outcome

Title	Mean Percentage Change From Baseline To End Of Treatment In Plasma Clobazam (CLB) And N-Desmethylclobazam (N-CLB) Concentrations
Description	Plasma concentrations of CLB and N-CLB were measured on Days 1 and 22. Participants were instructed to take their daily dose of CLB 2 hours prior to the anticipated pre-IMP blood specimen collection on both days. Blood samples were collected prior to administration of IMP. Results are presented for a subgroup of participants who took CLB during the study and had PK samples analyzed at both PK sampling visits (Days 1 and 22).
Time Frame	Predose on Days 1 and 22

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 treatment they received. Only participants for whom it had been confirmed that they did not take any IMP were excluded from the safety analysis set.

Arm/Group Title	GWP42003-P 5 mg/kg/Day Dose	GWP42003-P 10 mg/kg/Day Dose	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description	Participants received GWP42003-P 5 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 5 mg/kg/day over 3 days and remained at this dose for the rest of the 21-day treatment period (19 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at this dose for the rest of the 21-day treatment period (15 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received GWP42003-P 20 mg/kg/day 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 rest of the 21-day treatment period (11 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.	Participants received placebo (0 mg/mL CBD), volume matched to one of the 3 dose levels (5, 10, or 20 mg/kg/day), administered orally, half in the morning and half in the evening for 21 days. To maintain the blinded aspect of the study, participants titrated the placebo dose over 3 to 11 days according to the matched IMP group (3, 7, and 11 days for the 5, 10, or 20 mg/kg/day GWP42003-P groups, respectively) and remained at this dose for the rest of the 21-day treatment period. The 21-day treatment period was followed by a 10-day taper (10% per day of the matched dose) period.
Measure Participants	6	6	5	5
% change in CLB	-1.2	18.0	29.6	15.1
% change in N-CLB	258.7	170.7	228.9	-5.6

Adverse Events

Time Frame	Up to Day 60
Adverse Event Reporting Description	All participants randomized to treatment who received at least 1 dose of IMP. Participants were analyzed according to the treatment they received. Only participants for whom it had been confirmed that they did not take any IMP were excluded from the safety analysis set.
Arm/Group Title	GWP42003-P 5 mg/kg/Day Dose		GWP42003-P 10 mg/kg/Day Dose		GWP42003-P 20 mg/kg/Day Dose		Placebo
Arm/Group Description	Participants received GWP42003-P 5 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 5 mg/kg/day over 3 days and remained at this dose for the rest of the 21-day treatment period (19 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.		Participants received GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at this dose for the rest of the 21-day treatment period (15 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.		Participants received GWP42003-P 20 mg/kg/day 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 rest of the 21-day treatment period (11 days). The 21-day treatment period was followed by a 10-day taper (10% per day) period.		Participants received placebo (0 mg/mL CBD), volume matched to one of the 3 dose levels (5, 10, or 20 mg/kg/day), administered orally, half in the morning and half in the evening for 21 days. To maintain the blinded aspect of the study, participants titrated the placebo dose over 3 to 11 days according to the matched IMP group (3, 7, and 11 days for the 5, 10, or 20 mg/kg/day GWP42003-P groups, respectively) and remained at this dose for the rest of the 21-day treatment period. The 21-day treatment period was followed by a 10-day taper (10% per day of the matched dose) period.
All Cause Mortality
	GWP42003-P 5 mg/kg/Day Dose		GWP42003-P 10 mg/kg/Day Dose		GWP42003-P 20 mg/kg/Day Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	GWP42003-P 5 mg/kg/Day Dose		GWP42003-P 10 mg/kg/Day Dose		GWP42003-P 20 mg/kg/Day Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/10 (10%)		2/8 (25%)		1/9 (11.1%)		1/7 (14.3%)
General disorders
Pyrexia	0/10 (0%)		2/8 (25%)		0/9 (0%)		0/7 (0%)
Infections and infestations
Parvovirus Infection	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Viral Infection	0/10 (0%)		0/8 (0%)		0/9 (0%)		1/7 (14.3%)
Nervous system disorders
Convulsion	0/10 (0%)		1/8 (12.5%)		0/9 (0%)		1/7 (14.3%)
Status Epilepticus	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Skin and subcutaneous tissue disorders
Rash Maculo-papular	0/10 (0%)		1/8 (12.5%)		0/9 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	GWP42003-P 5 mg/kg/Day Dose		GWP42003-P 10 mg/kg/Day Dose		GWP42003-P 20 mg/kg/Day Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/10 (80%)		5/8 (62.5%)		7/9 (77.8%)		6/7 (85.7%)
Eye disorders
Diplopia	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Gastrointestinal disorders
Abdominal Pain Upper	0/10 (0%)		0/8 (0%)		2/9 (22.2%)		0/7 (0%)
Constipation	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Diarrhoea	0/10 (0%)		0/8 (0%)		0/9 (0%)		1/7 (14.3%)
Dry Mouth	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Eructation	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Haematochezia	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Vomiting	1/10 (10%)		1/8 (12.5%)		1/9 (11.1%)		0/7 (0%)
General disorders
Fatigue	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		2/7 (28.6%)
Gait disturbance	0/10 (0%)		1/8 (12.5%)		0/9 (0%)		0/7 (0%)
Influenza like illness	0/10 (0%)		0/8 (0%)		0/9 (0%)		1/7 (14.3%)
Pyrexia	3/10 (30%)		1/8 (12.5%)		0/9 (0%)		0/7 (0%)
Infections and infestations
Erythema infectiosum	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Gastroenteritis	1/10 (10%)		0/8 (0%)		0/9 (0%)		2/7 (28.6%)
Gastroenteritis viral	1/10 (10%)		0/8 (0%)		1/9 (11.1%)		1/7 (14.3%)
Lower respiratory tract infection	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Nasopharyngitis	0/10 (0%)		1/8 (12.5%)		1/9 (11.1%)		1/7 (14.3%)
Otitis media acute	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Pharyngitis streptococcal	1/10 (10%)		0/8 (0%)		0/9 (0%)		1/7 (14.3%)
Pneumonia	0/10 (0%)		1/8 (12.5%)		1/9 (11.1%)		0/7 (0%)
Upper respiratory tract infection	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Viral infection	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Viral rash	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Injury, poisoning and procedural complications
Accident	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Investigations
Aspartate aminotransferase increased	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Electrocardiogram QT prolonged	0/10 (0%)		0/8 (0%)		0/9 (0%)		1/7 (14.3%)
Hepatic enzyme increased	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Liver function test abnormal	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Urine ketone body absent	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Urine ketone body present	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/10 (0%)		1/8 (12.5%)		4/9 (44.4%)		0/7 (0%)
Increased appetite	0/10 (0%)		1/8 (12.5%)		0/9 (0%)		0/7 (0%)
Ketosis	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Nervous system disorders
Ataxia	2/10 (20%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Convulsion	0/10 (0%)		0/8 (0%)		0/9 (0%)		1/7 (14.3%)
Coordination abnormal	0/10 (0%)		1/8 (12.5%)		0/9 (0%)		0/7 (0%)
Dysarthria	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Headache	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Poor quality sleep	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Psychomotor hyperactivity	1/10 (10%)		0/8 (0%)		0/9 (0%)		1/7 (14.3%)
Sedation	2/10 (20%)		0/8 (0%)		2/9 (22.2%)		0/7 (0%)
Somnolence	2/10 (20%)		3/8 (37.5%)		0/9 (0%)		1/7 (14.3%)
Tremor	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Psychiatric disorders
Abnormal behaviour	3/10 (30%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Irritability	0/10 (0%)		1/8 (12.5%)		0/9 (0%)		0/7 (0%)
Mood swings	0/10 (0%)		0/8 (0%)		0/9 (0%)		1/7 (14.3%)
Renal and urinary disorders
Proteinuria	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/10 (0%)		0/8 (0%)		0/9 (0%)		1/7 (14.3%)
Skin and subcutaneous tissue disorders
Dermatitis diaper	0/10 (0%)		0/8 (0%)		0/9 (0%)		1/7 (14.3%)
Erythema	1/10 (10%)		0/8 (0%)		0/9 (0%)		0/7 (0%)
Rash	0/10 (0%)		1/8 (12.5%)		1/9 (11.1%)		0/7 (0%)
Rash papular	0/10 (0%)		0/8 (0%)		1/9 (11.1%)		0/7 (0%)
Urticaria	0/10 (0%)		1/8 (12.5%)		0/9 (0%)		0/7 (0%)

Limitations/Caveats

Analytical issues for 7-OH-CBD related to reference material batch used during analysis. Data are qualitative.

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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.