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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02091206
Recruitment Status : Completed
First Posted : March 19, 2014
Results First Posted : July 19, 2018
Last Update Posted : August 24, 2018
Sponsor:
Information provided by (Responsible Party):
GW Research Ltd

Tracking Information
First Submitted Date  ICMJE March 17, 2014
First Posted Date  ICMJE March 19, 2014
Results First Submitted Date  ICMJE June 25, 2018
Results First Posted Date  ICMJE July 19, 2018
Last Update Posted Date August 24, 2018
Actual Study Start Date  ICMJE October 22, 2014
Actual Primary Completion Date March 9, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 25, 2018)
Number Of Participants Who Experienced Severe Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 18, 2014)
The incidence of adverse events as measure of subject safety [ Time Frame: Day 0 - Day 49 ]
The number of subjects who experienced an adverse event during the study is presented. The time frame for adverse event reporting was from screening to the Part A follow-up visit.
Change History Complete list of historical versions of study NCT02091206 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 25, 2018)
  • 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 [ Time Frame: 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.
  • Mean Percentage Change From Baseline To End Of Treatment In Plasma Clobazam (CLB) And N-Desmethylclobazam (N-CLB) Concentrations [ Time Frame: 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2014)
  • To determine the plasma concentration time curves for cannabidiol and 7-hydroxy-cannabidiol following a single dose of GWP42003-P [ Time Frame: Pre-dose then 2-3 and 4-6 h post-dose ]
    • The pre-dose blood sample was taken prior to the administration of the first dose of study medication.
    • Further samples were taken between 2 and 3 hours post-dose and 4 and 6 hours post-dose, with a minimum of at least 2 hours between each of the three blood sampling time-points
    The following pharmacokinetic parameters were investigated:
    • Cmax
    • tmax
    • Area Under the plasma concentration Curve (AUC)(0-∞), AUC(0-t)
  • To determine the plasma concentration time curves for cannabidiol and 7-hydroxy-cannabidiol following 14 days of consecutive dosing with GWP42003-P [ Time Frame: Pre-dose then 2-3 and 4-6 h post-dose ]
    • The pre-dose blood sample was taken prior to the administration of the first dose of study medication.
    • Further samples were taken between 2 and 3 hours post-dose and 4 and 6 hours post-dose, with a minimum of at least 2 hours between each of the three blood sampling time-points
    The following pharmacokinetic parameters were investigated:
    • Cmax
    • tmax
    • Area Under the plasma concentration Curve (AUC)(0-∞), AUC(0-t)
  • Pre-treatment plasma concentrations of clobazam and N-desmethylclobazam if taken concomitantly with GWP42003-P prior to a single dose of GWP42003-P [ Time Frame: Pre-dose ]
    If taken as a concomitant medication, the plasma concentrations of clobazam and its major metabolite N-desmethylclobazam were described pre-treatment and then after 14 days of treatment with GWP42003-P. Any subjects taking clobazam were instructed to take their daily dose of clobazam two hours prior to attending the clinic for pharmacokinetic blood sampling. The following pharmacokinetic parameters were investigated:
    • Cmax
    • tmax
    • Area Under the plasma concentration Curve (AUC)(0-∞), AUC(0-t)
  • Pre-treatment plasma concentrations of clobazam and N-desmethylclobazam if taken concomitantly with GWP42003-P after 14 consecutive days of dosing with GWP42003-P [ Time Frame: Pre-dose ]
    If taken as a concomitant medication, the plasma concentrations of clobazam and its major metabolite N-desmethylclobazam were described pre-treatment and then after 14 days of treatment with GWP42003-P. Any subjects taking clobazam were instructed to take their daily dose of clobazam two hours prior to attending the clinic for pharmacokinetic blood sampling. The following pharmacokinetic parameters were investigated:
    • Cmax
    • tmax
    • Area Under the plasma concentration Curve (AUC)(0-∞), AUC(0-t)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Dose-ranging Pharmacokinetics and Safety Study of GWP42003-P in Children With Dravet Syndrome (GWPCARE1)
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Epilepsy
  • Dravet Syndrome
Intervention  ICMJE
  • 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
  • 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 Name: Placebo
  • 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
  • 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
Study Arms  ICMJE
  • 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.
    Intervention: Drug: GWP42003-P 5 mg/kg/day Dose
  • 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.
    Intervention: Drug: GWP42003-P 10 mg/kg/day Dose
  • 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.
    Intervention: Drug: GWP42003-P 20 mg/kg/day Dose
  • 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.
    Intervention: Drug: Placebo control
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 15, 2016)
34
Original Estimated Enrollment  ICMJE
 (submitted: March 18, 2014)
30
Actual Study Completion Date  ICMJE March 9, 2015
Actual Primary Completion Date March 9, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 4 Years to 10 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02091206
Other Study ID Numbers  ICMJE GWEP1332 Part A
2014-002941-23 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party GW Research Ltd
Study Sponsor  ICMJE GW Research Ltd
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account GW Research Ltd
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP