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A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P; CBD) as Adjunctive Treatment for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults (GWPCARE4)

Primary Purpose

Epilepsy, Lennox-Gastaut Syndrome

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
GWP42003-P 20 mg/kg/day Dose
Placebo
Sponsored by
Jazz Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Epilepsy focused on measuring Cannabidiol, CBD, Epidiolex, GWP42003-P

Eligibility Criteria

2 Years - 55 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria:

  • Participant must have been male or female aged between 2 and 55 years (inclusive).
  • Participant must have had a documented history of Lennox-Gastaut syndrome. This included written documentation of having met electroencephalogram (EEG) diagnostic criteria during the participant's history and evidence of at least 1 type of generalized seizure, including drop seizures (atonic, tonic, tonic-clonic or myoclonic) for at least 6 months.
  • Participants had a history of slow (<3.0 Hertz) spike-and-wave pattern in an EEG prior to the enrollment into the baseline period.
  • Participants were refractory; that is having documented failures on more than one antiepileptic drug (AED).
  • Participant must have been taking 1 or more AEDs at a dose which has been stable for at least 4 weeks prior to screening.
  • All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation [VNS]) must have been stable for 4 weeks prior to screening and participant is willing to maintain a stable regimen throughout the study. The ketogenic diet and VNS treatments are not accounted as an AED.

Key Exclusion Criteria:

  • Etiology of participant's seizures was a progressive neurologic disease. Participants with tuberous sclerosis were not excluded from study participation, unless there was a progressive tumor.
  • Participant had an anoxic episode requiring resuscitation within 6 months of screening.
  • 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 has in the past used recreational or 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 of the study.
  • Participant had any known or suspected hypersensitivity to cannabinoids or any of the excipients of the Investigational Medicinal Product (IMP), such as sesame oil.
  • Participant had been part of a clinical trial involving another IMP in the previous 6 months.
  • Participant had significantly impaired hepatic function at screening or randomization (Alanine aminotransferase [ALT] >5 x upper limit of normal [ULN] or total bilirubin [TBL] >2 x ULN) OR the ALT or Aspartate aminotransferase (AST) >3 x ULN and (TBL >2 x ULN or international normalized ratio >1.5). This criterion can only be confirmed once the laboratory results are available; Participants randomized into the study who are later found not to meet this criterion should be withdrawn from the study.
  • Any history of suicidal behavior or any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale in the last month or at screening.
  • Participant was taking more than 4 concurrent AEDs.
  • Participant was taking corticotropins in the 6 months prior to screening.
  • Participant was taking long-term systemic steroids (excluding inhaled medication for asthma treatment) or any other daily medication known to exacerbate epilepsy. An exception was made of prophylactic medication, for example, idiopathic nephrotic syndrome or asthma.
  • Participant was taking felbamate, and they had been taking it for less than 1 year prior to screening.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

GWP42003-P 20 mg/kg/day Dose

Placebo

Arm Description

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 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, 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) period.

Outcomes

Primary Outcome Measures

Percentage Change From Baseline In Drop Seizure Frequency During The Treatment Period
Drop seizures were recorded by the participant or caregiver using an interactive voice response system (IVRS) diary. Drop seizures were defined as the subset of tonic-clonic, tonic or atonic seizures that were reported as drop seizures in the IVRS. 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

Number Of Participants With a ≥50% Reduction From Baseline in Drop Seizure Frequency During The Treatment Period
Drop seizures were recorded by the participant or caregiver using an IVRS diary. Drop seizures included the subset of tonic-clonic, tonic or atonic seizures that were reported as drop seizures in IVRS. Percentage change from baseline was calculated as per the primary outcome measure.
Percentage Change From Baseline In Total Seizure Frequency During The Treatment Period
Total seizures included the sum of all seizures (tonic-clonic, tonic, atonic, clonic, myoclonic, countable partial, other partial and absence seizures) recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure. Negative percentages show an improvement from baseline.
Subject/Caregiver Global Impression Of Change Assessment (S/CGIC)
The S/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 S/CGIC questionnaire at subsequent visits. If both a CGIC and SGIC were completed then the CGIC was used; if only a CGIC was completed then the CGIC was used; if only a SGIC was completed then the SGIC was used. 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.

Full Information

First Posted
August 21, 2014
Last Updated
September 22, 2022
Sponsor
Jazz Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT02224690
Brief Title
A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P; CBD) as Adjunctive Treatment for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults
Acronym
GWPCARE4
Official Title
A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P; CBD) as Adjunctive Treatment for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults.
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Completed
Study Start Date
April 28, 2015 (Actual)
Primary Completion Date
March 18, 2016 (Actual)
Study Completion Date
March 18, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Jazz Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
To evaluate the efficacy of GWP42003-P as adjunctive treatment in reducing the number of drop seizures when compared with placebo, in participants with Lennox-Gastaut Syndrome (LGS).
Detailed Description
This study was a 1:1 randomized, double-blind, 14-week comparison of 20 milligram [mg] per kilogram [kg] per day [mg/kg/day] of GWP42003-P versus placebo. The treatment period consisted of a 2-week titration period followed by a 12-week maintenance period. The study determined the efficacy, safety and tolerability of GWP42003-P compared with placebo. The dose was recommended by the Data Safety Monitoring Committee (DSMC) after assessment of safety and pharmacokinetic data from Part A of study GWEP1332. The first participants enrolled into this study after the DSMC reviewed the safety data from Part A of study GWEP1332. Following study completion, all participants were invited to continue to receive GWP42003-P in an open label extension (OLE) study (under a separate protocol).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Epilepsy, Lennox-Gastaut Syndrome
Keywords
Cannabidiol, CBD, Epidiolex, GWP42003-P

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
171 (Actual)

8. Arms, Groups, and Interventions

Arm Title
GWP42003-P 20 mg/kg/day Dose
Arm Type
Experimental
Arm Description
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 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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants received placebo (0 mg/mL CBD), volume matched to the 20 mg/kg/day dose, 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) period.
Intervention Type
Drug
Intervention Name(s)
GWP42003-P 20 mg/kg/day Dose
Other Intervention Name(s)
Cannabidiol, Epidiolex
Intervention Description
GWP42003-P was presented as an oral solution containing 100 mg/milliliter (mL) cannabidiol (CBD) 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).
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo was presented as an oral solution containing 0 mg/mL CBD 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).
Primary Outcome Measure Information:
Title
Percentage Change From Baseline In Drop Seizure Frequency During The Treatment Period
Description
Drop seizures were recorded by the participant or caregiver using an interactive voice response system (IVRS) diary. Drop seizures were defined as the subset of tonic-clonic, tonic or atonic seizures that were reported as drop seizures in the IVRS. 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)
Secondary Outcome Measure Information:
Title
Number Of Participants With a ≥50% Reduction From Baseline in Drop Seizure Frequency During The Treatment Period
Description
Drop seizures were recorded by the participant or caregiver using an IVRS diary. Drop seizures included the subset of tonic-clonic, tonic or atonic seizures that were reported as drop seizures in IVRS. Percentage change from baseline was calculated as per the primary outcome measure.
Time Frame
Baseline to EOT (Day 99) or ET
Title
Percentage Change From Baseline In Total Seizure Frequency During The Treatment Period
Description
Total seizures included the sum of all seizures (tonic-clonic, tonic, atonic, clonic, myoclonic, countable partial, other partial and absence seizures) recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure. Negative percentages show an improvement from baseline.
Time Frame
Baseline to EOT (Day 99) or ET
Title
Subject/Caregiver Global Impression Of Change Assessment (S/CGIC)
Description
The S/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 S/CGIC questionnaire at subsequent visits. If both a CGIC and SGIC were completed then the CGIC was used; if only a CGIC was completed then the CGIC was used; if only a SGIC was completed then the SGIC was used. 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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria: Participant must have been male or female aged between 2 and 55 years (inclusive). Participant must have had a documented history of Lennox-Gastaut syndrome. This included written documentation of having met electroencephalogram (EEG) diagnostic criteria during the participant's history and evidence of at least 1 type of generalized seizure, including drop seizures (atonic, tonic, tonic-clonic or myoclonic) for at least 6 months. Participants had a history of slow (<3.0 Hertz) spike-and-wave pattern in an EEG prior to the enrollment into the baseline period. Participants were refractory; that is having documented failures on more than one antiepileptic drug (AED). Participant must have been taking 1 or more AEDs at a dose which has been stable for at least 4 weeks prior to screening. All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation [VNS]) must have been stable for 4 weeks prior to screening and participant is willing to maintain a stable regimen throughout the study. The ketogenic diet and VNS treatments are not accounted as an AED. Key Exclusion Criteria: Etiology of participant's seizures was a progressive neurologic disease. Participants with tuberous sclerosis were not excluded from study participation, unless there was a progressive tumor. Participant had an anoxic episode requiring resuscitation within 6 months of screening. 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 has in the past used recreational or 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 of the study. Participant had any known or suspected hypersensitivity to cannabinoids or any of the excipients of the Investigational Medicinal Product (IMP), such as sesame oil. Participant had been part of a clinical trial involving another IMP in the previous 6 months. Participant had significantly impaired hepatic function at screening or randomization (Alanine aminotransferase [ALT] >5 x upper limit of normal [ULN] or total bilirubin [TBL] >2 x ULN) OR the ALT or Aspartate aminotransferase (AST) >3 x ULN and (TBL >2 x ULN or international normalized ratio >1.5). This criterion can only be confirmed once the laboratory results are available; Participants randomized into the study who are later found not to meet this criterion should be withdrawn from the study. Any history of suicidal behavior or any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale in the last month or at screening. Participant was taking more than 4 concurrent AEDs. Participant was taking corticotropins in the 6 months prior to screening. Participant was taking long-term systemic steroids (excluding inhaled medication for asthma treatment) or any other daily medication known to exacerbate epilepsy. An exception was made of prophylactic medication, for example, idiopathic nephrotic syndrome or asthma. Participant was taking felbamate, and they had been taking it for less than 1 year prior to screening.
Facility Information:
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30328
Country
United States
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
City
Ames
State/Province
Iowa
ZIP/Postal Code
50010
Country
United States
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55102
Country
United States
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63131
Country
United States
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104-4399
Country
United States
City
Dallas
State/Province
Texas
ZIP/Postal Code
75251
Country
United States
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
81143
Country
United States
City
Winchester
State/Province
Virginia
ZIP/Postal Code
22601
Country
United States
City
Denekamp
State/Province
BV Zwolle
ZIP/Postal Code
8025
Country
Netherlands
City
Bydgoszcz
ZIP/Postal Code
85-080
Country
Poland
City
Gdańsk
ZIP/Postal Code
80-952
Country
Poland
City
Kraków
ZIP/Postal Code
30-349
Country
Poland
City
Lublin
ZIP/Postal Code
20-093
Country
Poland
City
Lublin
ZIP/Postal Code
20-718
Country
Poland
City
Poznań
ZIP/Postal Code
60-355
Country
Poland

12. IPD Sharing Statement

Citations:
PubMed Identifier
29395273
Citation
Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K; GWPCARE4 Study Group. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018 Mar 17;391(10125):1085-1096. doi: 10.1016/S0140-6736(18)30136-3. Epub 2018 Jan 26.
Results Reference
background
PubMed Identifier
33825230
Citation
Brigo F, Jones K, Eltze C, Matricardi S. Anti-seizure medications for Lennox-Gastaut syndrome. Cochrane Database Syst Rev. 2021 Apr 7;4(4):CD003277. doi: 10.1002/14651858.CD003277.pub4.
Results Reference
derived
PubMed Identifier
33797076
Citation
Privitera M, Bhathal H, Wong M, Cross JH, Wirrell E, Marsh ED, Mazurkiewicz-Beldzinska M, Villanueva V, Checketts D, Knappertz V, VanLandingham K. Time to onset of cannabidiol (CBD) treatment effect in Lennox-Gastaut syndrome: Analysis from two randomized controlled trials. Epilepsia. 2021 May;62(5):1130-1140. doi: 10.1111/epi.16878. Epub 2021 Apr 2.
Results Reference
derived

Learn more about this trial

A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P; CBD) as Adjunctive Treatment for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults

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