Clinical trial NCT02091206: A Dose-ranging Pharmacokinetics and Safety Study of GWP42003-P in Children With Dravet Syndrome (GWPCARE1)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Epilepsy
Dravet Syndrome
Keywords: Cannabidiol
CBD
Epidiolex
GWP42003-P
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2014-03-19
Enrollment: 34
Sex: ALL
Minimum age (years): 4
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number Of Participants Who Experienced Severe Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Baseline (Day 1) through Safety follow-up visit (Day 60)
Secondary outcomes:
measure: 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
timeFrame: Predose and 2-6 hours postdose on Days 1 and 22
measure: Mean Percentage Change From Baseline To End Of Treatment In Plasma Clobazam (CLB) And N-Desmethylclobazam (N-CLB) Concentrations
timeFrame: Predose on Days 1 and 22
Other outcomes:
Locations:
city: Miami
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Iowa City
country: United States
state: Iowa
city: Boston
country: United States
state: Massachusetts
city: Winston-Salem
country: United States
state: North Carolina
city: Columbus
country: United States
state: Ohio
city: Houston
country: United States
state: Texas
city: Edinburgh
country: United Kingdom
city: Liverpool
country: United Kingdom
city: London
country: United Kingdom
Study officials:
References:
citation: 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.