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

• ClinicalTrials.gov Identifier: NCT02224703
• Recruitment Status: Completed
• First Posted: August 25, 2014
• Results First Posted: August 1, 2019
• Last Update Posted: September 28, 2022
• Sponsor: Jazz Pharmaceuticals
• Information provided by (Responsible Party): Jazz Pharmaceuticals

Study Description

Brief Summary:

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

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

Detailed Description:

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

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

Study Design

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

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Change In Total Seizures During The Treatment Period Compared To Baseline [ Time Frame: Baseline to Day 99 or ET ]
   Total seizures were defined as the combination of convulsive and non-convulsive seizures. Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic seizures. Non-convulsive seizures were defined as myoclonic, countable partial, other partial, or absence seizures. Participants or their caregivers recorded the number and type of convulsive seizures and non-convulsive seizures each day from screening until completion of dosing using an IVRS diary. Change compared to baseline was calculated as per the primary outcome measure. Data reported as the ratio of geometric least squares mean in total seizures and expressed as a percentage reduction.
2. Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period [ Time Frame: Baseline to Day 99 or ET ]
   Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic. Participants or their caregivers recorded the number and type of convulsive seizures each day from screening until completion of dosing using an IVRS diary. Baseline included all available data prior to Day 1 (28-day average). Percentage change from baseline was calculated as: ([frequency during the treatment period - frequency during baseline]/frequency during baseline) x 100. The frequency during each period was based on 28-day averages and calculated as: (number of seizures in the period/number of reported days in the IVRS period) x 28. Baseline included all available data prior to Day 1 (28-day average).
3. Caregiver Global Impression Of Change (CGIC) At The Last Visit [ Time Frame: Baseline to Last Visit ]
   On Day 1 (prior to receiving study drug), the caregiver was asked to write a brief description of the participant's overall condition as a memory aid for the CGIC questionnaire at subsequent visits. The CGIC questionnaire comprised the following question, to be rated on a 7-point scale: Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment) using the scale below. The markers were: "Very Much Improved"; "Much Improved"; "Slightly Improved"; "No Change"; "Slightly Worse"; "Much Worse"; "Very Much Worse". The CGIC response/score, recorded at each visit, was summarized, on both a categorical and continuous scale, by treatment group. The scores at the last scheduled visit (not including the end of taper or safety follow-up visits) at which participant's last evaluation was performed were analyzed using ordinal logistic regression.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

• Participant must have been male or female, aged between 2 and 18 years (inclusive).
• Participant must have had a documented history of Dravet syndrome that was not completely controlled by current antiepileptic drugs.
• Participant must have been taking 1 or more antiepileptic drugs at a dose that had been stable for at least 4 weeks.
• All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation) must have been stable for 4 weeks prior to screening and participant was willing to maintain a stable regimen throughout the study.

Key Exclusion Criteria:

• Participant had clinically significant unstable medical conditions other than epilepsy.
• Participant had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to screening or randomization, other than epilepsy.
• Participant was currently using or had in the past used recreational cannabis, medicinal cannabis, or synthetic cannabinoid-based medications (including Sativex®) within the 3 months prior to study entry and was unwilling to abstain for the duration for the study.
• Participant had any known or suspected hypersensitivity to cannabinoids or any of the excipients of the investigational medicinal products.
• There were plans for the participant to travel outside their country of residence during the study.
• Any history of suicidal behavior or any suicidal ideation of type four or five on the Columbia-Suicide Severity Rating Scale (Children's) at screening.

Contacts and Locations

Locations

United States, Alabama

Birmingham, Alabama, United States, 35233

United States, Arkansas

Little Rock, Arkansas, United States, 72202

United States, California

Los Angeles, California, United States, 90027

Sacramento, California, United States, 95816

United States, Connecticut

Hartford, Connecticut, United States, 06106

United States, Florida

Miami, Florida, United States, 33155

United States, Georgia

Savannah, Georgia, United States, 31404

United States, Illinois

Chicago, Illinois, United States, 60611

United States, Kentucky

Lexington, Kentucky, United States, 40536-0284

Louisville, Kentucky, United States, 40202

United States, Minnesota

Saint Paul, Minnesota, United States, 55102

United States, Missouri

Saint Louis, Missouri, United States, 63141

United States, Nebraska

Omaha, Nebraska, United States, 68106

United States, New Hampshire

Lebanon, New Hampshire, United States, 03756

United States, New York

Buffalo, New York, United States, 14203

United States, North Carolina

Chapel Hill, North Carolina, United States, 27599

United States, Oregon

Portland, Oregon, United States, 97239

United States, Pennsylvania

Philadelphia, Pennsylvania, United States, 19104-4399

United States, South Carolina

Charleston, South Carolina, United States, 29425

United States, Texas

Austin, Texas, United States, 78723

Fort Worth, Texas, United States, 76104

United States, Virginia

Richmond, Virginia, United States, 23298-0211

United States, Washington

Seattle, Washington, United States, 98105

Australia

Heidelberg, Australia, 3084

Randwick, Australia, NSW 2031

Israel

Ramat Gan, Israel, 52621

Netherlands

Heeze, Netherlands, 5591 VE

Zwolle, Netherlands, 8025 BV

Poland

Kraków, Poland, 30-363

Warszawa, Poland, 04-730

Łódź, Poland, 93-271

Spain

Barcelona, Spain, 08022

Madrid, Spain, 28009

Madrid, Spain, 28034

Madrid, Spain, 28222

Pamplona, Spain, 31008

Sevilla, Spain, 41013

Valencia, Spain, 46026

Sponsors and Collaborators

Jazz Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Jazz Pharmaceuticals:

Study Protocol  [PDF] September 6, 2018

Statistical Analysis Plan  [PDF] October 5, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Madan Cohen J, Checketts D, Dunayevich E, Gunning B, Hyslop A, Madhavan D, Villanueva V, Zolnowska M, Zuberi SM. Time to onset of cannabidiol treatment effects in Dravet syndrome: Analysis from two randomized controlled trials. Epilepsia. 2021 Sep;62(9):2218-2227. doi: 10.1111/epi.16974. Epub 2021 Jul 15.

Miller I, Scheffer IE, Gunning B, Sanchez-Carpintero R, Gil-Nagel A, Perry MS, Saneto RP, Checketts D, Dunayevich E, Knappertz V; GWPCARE2 Study Group. Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome: A Randomized Clinical Trial. JAMA Neurol. 2020 May 1;77(5):613-621. doi: 10.1001/jamaneurol.2020.0073. Erratum In: JAMA Neurol. 2020 May 1;77(5):655.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02224703
• Other Study ID Numbers: GWEP1424; 2014-002939-34 ( EudraCT Number )
• First Posted: August 25, 2014
• Results First Posted: August 1, 2019
• Last Update Posted: September 28, 2022
• Last Verified: September 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jazz Pharmaceuticals:

Cannabidiol; CBD; GWP42003-P; Epidiolex

Additional relevant MeSH terms:

Cannabidiol; Epilepsies, Myoclonic; Syndrome; Disease; Pathologic Processes; Epilepsy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy, Generalized; Epileptic Syndromes; Anticonvulsants