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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)

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ClinicalTrials.gov Identifier: NCT02224690
Recruitment Status : Completed
First Posted : August 25, 2014
Results First Posted : July 27, 2018
Last Update Posted : July 27, 2018
Sponsor:
Information provided by (Responsible Party):
GW Research Ltd

Tracking Information
First Submitted Date  ICMJE August 21, 2014
First Posted Date  ICMJE August 25, 2014
Results First Submitted Date  ICMJE June 25, 2018
Results First Posted Date  ICMJE July 27, 2018
Last Update Posted Date July 27, 2018
Actual Study Start Date  ICMJE April 28, 2015
Actual Primary Completion Date March 18, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 26, 2018)
Percentage Change From Baseline In Drop Seizure Frequency During The Treatment Period [ Time Frame: Baseline to End of Treatment (EOT) (Day 99) or Early Termination (ET) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 22, 2014)
Mean percentage change from baseline in number of drop seizures (average per week) during the maintenance period. [ Time Frame: 2-14 weeks ]
The primary endpoint is the mean percentage change from baseline in number of drop seizures (average per week) during the maintenance period (Day 15 to the end of the evaluable period) in subjects taking GWP42003-P compared with placebo.
Change History Complete list of historical versions of study NCT02224690 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 26, 2018)
  • Number Of Participants With a ≥50% Reduction From Baseline in Drop Seizure Frequency During The Treatment Period [ Time Frame: Baseline to EOT (Day 99) or ET ]
    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 [ Time Frame: Baseline to EOT (Day 99) or ET ]
    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) [ Time Frame: Baseline to Last Visit (Day 99) or ET ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 22, 2014)
  • Mean percentage change from baseline in number of drop seizures (average per week) during the Weeks 1-4, 5-8 and 9-12 of the maintenance period. [ Time Frame: 2-14 weeks ]
  • Number of subjects considered treatment responders, defined as those with a ≥25%, ≥50%, ≥75%, or 100% reduction in drop seizures from baseline. [ Time Frame: 2-14 weeks ]
  • Number of subjects experiencing a >25% worsening, −25 to +25% no change, 25-50% improvement, 50-75% improvement or >75% improvement in drop seizures from baseline. [ Time Frame: 2-14 weeks ]
  • Mean percentage change from baseline in number of non-drop seizures (average per week). [ Time Frame: 2-14 weeks ]
  • Mean percentage change from baseline in the frequencies of sub-types of seizures (average per week). [ Time Frame: 2-14 weeks ]
  • Mean change from baseline in quality of life. [ Time Frame: 2-14 weeks ]
  • Changes from baseline in the Caregiver Global Impression of Change (CGIC) score. [ Time Frame: End of week 14 of treatment ]
  • The incidence of adverse events as measure of subject safety. [ Time Frame: Day -28 to Day 137 ]
  • The number of age-appropriate subjects with a treatment-emergent flag using the Columbia-Suicide Severity Rating Scale (C-SSRS or C-SSRS Children's depending on age) during the course of the study. [ Time Frame: Day -28 to Day 137 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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.
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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Epilepsy
  • Lennox-Gastaut Syndrome
Intervention  ICMJE
  • Drug: GWP42003-P 20 mg/kg/day Dose
    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).
    Other Names:
    • Cannabidiol
    • Epidiolex
  • Drug: Placebo
    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).
Study Arms  ICMJE
  • 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 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: Drug: GWP42003-P 20 mg/kg/day Dose
  • Placebo Comparator: Placebo
    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: Drug: Placebo
Publications * 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.

*   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: December 21, 2015)
171
Original Estimated Enrollment  ICMJE
 (submitted: August 22, 2014)
80
Actual Study Completion Date  ICMJE March 18, 2016
Actual Primary Completion Date March 18, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 55 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands,   Poland,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02224690
Other Study ID Numbers  ICMJE GWEP1423
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