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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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Epilepsy
Lennox-Gastaut Syndrome
Interventions Drug: GWP42003-P 20 mg/kg/day Dose
Drug: Placebo
Enrollment 171
Recruitment Details  
Pre-assignment Details The dose level of 20 milligram (mg) per kilogram (kg) per day (mg/kg/day) was recommended by the GWEP1332 Part A (NCT02091206) Data Safety Monitoring Committee after assessment of safety and pharmacokinetic data. The investigational medicinal product (IMP) was given daily in 2 divided doses (the preferred dosing regimen for antiepileptic drugs).
Arm/Group Title GWP42003-P 20 mg/kg/Day Dose Placebo
Hide Arm/Group 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 open-label extension (OLE) study, the maintenance period was followed by a 10-day taper (10% per day) period. Participants received placebo (0 mg/milliliter [mL] cannabidiol [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.
Period Title: Overall Study
Started 86 85
Safety Analysis Set [1] 86 85
Intent to Treat (ITT) Analysis Set [2] 86 85
Completed 72 84
Not Completed 14 1
Reason Not Completed
Adverse Event             8             1
Met Withdrawal Criteria             4             0
Use of G-tube             1             0
Did not meet eligibility criteria             1             0
[1]
Received at least 1 dose of IMP; analyzed as per actual treatment received.
[2]
Received at least 1 dose of IMP with at least 1 post-baseline efficacy endpoint measurement.
Arm/Group Title GWP42003-P 20 mg/kg/Day Dose Placebo Total
Hide Arm/Group 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. Total of all reporting groups
Overall Number of Baseline Participants 86 85 171
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 86 participants 85 participants 171 participants
15.478  (8.685) 15.284  (9.7945) 15.381  (9.2264)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 86 participants 85 participants 171 participants
Female
41
  47.7%
42
  49.4%
83
  48.5%
Male
45
  52.3%
43
  50.6%
88
  51.5%
1.Primary Outcome
Title Percentage Change From Baseline In Drop Seizure Frequency During The Treatment Period
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Analysis Set: All randomized participants who received at least 1 dose of IMP and had at least 1 post-baseline efficacy endpoint measurement. Participants were analyzed according to the treatment group to which they were randomized.
Arm/Group Title GWP42003-P 20 mg/kg/Day Dose Placebo
Hide Arm/Group 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.
Overall Number of Participants Analyzed 86 85
Median (Inter-Quartile Range)
Unit of Measure: percentage change
-43.90
(-69.62 to 1.93)
-21.80
(-45.72 to 1.74)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GWP42003-P 20 mg/kg/Day Dose, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0135
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value -17.21
Confidence Interval (2-Sided) 95%
-30.32 to -4.09
Estimation Comments Calculated using the Hodges–Lehmann approach
2.Secondary Outcome
Title Number Of Participants With a ≥50% Reduction From Baseline in Drop Seizure Frequency During The Treatment Period
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Analysis Set: All randomized participants who received at least 1 dose of IMP and had at least 1 post-baseline efficacy endpoint measurement. Participants were analyzed according to the treatment group to which they were randomized.
Arm/Group Title GWP42003-P 20 mg/kg/Day Dose Placebo
Hide Arm/Group 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.
Overall Number of Participants Analyzed 86 85
Measure Type: Count of Participants
Unit of Measure: Participants
38
  44.2%
20
  23.5%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GWP42003-P 20 mg/kg/Day Dose, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0043
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Calculated using a Cochran-Mantel-Haenszel test stratified by age group (2-5, 6-11, 12-17 and 18-55 years)
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.57
Confidence Interval (2-Sided) 95%
1.33 to 4.97
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage Change From Baseline In Total Seizure Frequency During The Treatment Period
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Analysis Set: All randomized participants who received at least 1 dose of IMP and had at least 1 post-baseline efficacy endpoint measurement. Participants were analyzed according to the treatment group to which they were randomized.
Arm/Group Title GWP42003-P 20 mg/kg/Day Dose Placebo
Hide Arm/Group 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.
Overall Number of Participants Analyzed 86 85
Median (Inter-Quartile Range)
Unit of Measure: percentage change
-41.24
(-62.85 to -13.00)
-13.70
(-45.00 to 7.27)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GWP42003-P 20 mg/kg/Day Dose, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -21.13
Confidence Interval (2-Sided) 95%
-33.26 to -9.37
Estimation Comments Calculated using the Hodges–Lehmann approach
4.Secondary Outcome
Title Subject/Caregiver Global Impression Of Change Assessment (S/CGIC)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Analysis Set: All randomized participants who received at least 1 dose of IMP and had at least 1 post-baseline efficacy endpoint measurement. Participants were analyzed according to the treatment group to which they were randomized.
Arm/Group Title GWP42003-P 20 mg/kg/Day Dose Placebo
Hide Arm/Group 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.
Overall Number of Participants Analyzed 84 85
Measure Type: Count of Participants
Unit of Measure: Participants
Very Much Improved
15
  17.9%
5
   5.9%
Much Improved
14
  16.7%
9
  10.6%
Slightly Improved
20
  23.8%
15
  17.6%
No Change
27
  32.1%
43
  50.6%
Slightly Worse
7
   8.3%
9
  10.6%
Much Worse
1
   1.2%
2
   2.4%
Very Much Worse
0
   0.0%
2
   2.4%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GWP42003-P 20 mg/kg/Day Dose, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0012
Comments [Not Specified]
Method Regression, Logistic
Comments Ordinal logistic regression model with treatment group as a fixed factor.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.54
Confidence Interval (2-Sided) 95%
1.45 to 4.47
Estimation Comments Odds of participants recording a lower score (improvement) on a continuous scale
Time Frame Day 1 through Day 137 (Safety Follow-up)
Adverse Event Reporting Description Safety Analysis Set: All participants randomized to treatment who received at least 1 dose of IMP. Participants were analyzed according to the treatment they received.
 
Arm/Group Title GWP42003-P 20 mg/kg/Day Dose Placebo
Hide Arm/Group 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.
All-Cause Mortality
GWP42003-P 20 mg/kg/Day Dose Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
GWP42003-P 20 mg/kg/Day Dose Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   20/86 (23.26%)   4/85 (4.71%) 
Gastrointestinal disorders     
Constipation  1  1/86 (1.16%)  0/85 (0.00%) 
Vomiting  1  1/86 (1.16%)  0/85 (0.00%) 
General disorders     
Pyrexia  1  0/86 (0.00%)  1/85 (1.18%) 
Hepatobiliary disorders     
Acute hepatic failure  1  1/86 (1.16%)  0/85 (0.00%) 
Infections and infestations     
Perirectal abscess  1  1/86 (1.16%)  0/85 (0.00%) 
Pilonidal cyst  1  0/86 (0.00%)  1/85 (1.18%) 
Pneumonia  1  3/86 (3.49%)  0/85 (0.00%) 
Pneumonia adenoviral  1  1/86 (1.16%)  0/85 (0.00%) 
Sepsis  1  1/86 (1.16%)  0/85 (0.00%) 
Urinary tract infection  1  0/86 (0.00%)  1/85 (1.18%) 
Viral infection  1  2/86 (2.33%)  0/85 (0.00%) 
Investigations     
Alanine aminotransferase increased  1  4/86 (4.65%)  0/85 (0.00%) 
Aspartate aminotransferase increased  1  4/86 (4.65%)  0/85 (0.00%) 
Drug level increased  1  1/86 (1.16%)  0/85 (0.00%) 
Gamma-glutamyltransferase increased  1  3/86 (3.49%)  0/85 (0.00%) 
Liver function test abnormal  1  1/86 (1.16%)  0/85 (0.00%) 
Oxygen saturation decreased  1  0/86 (0.00%)  1/85 (1.18%) 
Transaminases increased  1  1/86 (1.16%)  0/85 (0.00%) 
Metabolism and nutrition disorders     
Dehydration  1  0/86 (0.00%)  2/85 (2.35%) 
Nervous system disorders     
Convulsion  1  2/86 (2.33%)  0/85 (0.00%) 
Generalised tonic-clonic seizure  1  0/86 (0.00%)  1/85 (1.18%) 
Lethargy  1  1/86 (1.16%)  0/85 (0.00%) 
Seizure cluster  1  1/86 (1.16%)  1/85 (1.18%) 
Somnolence  1  1/86 (1.16%)  0/85 (0.00%) 
Status epilepticus  1  1/86 (1.16%)  1/85 (1.18%) 
Renal and urinary disorders     
Nephrolithiasis  1  1/86 (1.16%)  0/85 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress  1  1/86 (1.16%)  0/85 (0.00%) 
Acute respiratory failure  1  3/86 (3.49%)  0/85 (0.00%) 
Bronchial secretion retention  1  1/86 (1.16%)  0/85 (0.00%) 
Hypercapnia  1  1/86 (1.16%)  0/85 (0.00%) 
Hypoxia  1  2/86 (2.33%)  0/85 (0.00%) 
Pneumonia aspiration  1  1/86 (1.16%)  1/85 (1.18%) 
Pneumothorax  1  1/86 (1.16%)  0/85 (0.00%) 
Respiratory distress  1  1/86 (1.16%)  0/85 (0.00%) 
Sleep apnoea syndrome  1  1/86 (1.16%)  0/85 (0.00%) 
Vascular disorders     
Deep vein thrombosis  1  1/86 (1.16%)  0/85 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (17.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
GWP42003-P 20 mg/kg/Day Dose Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   53/86 (61.63%)   43/85 (50.59%) 
Gastrointestinal disorders     
Diarrhoea  1  16/86 (18.60%)  7/85 (8.24%) 
Vomiting  1  8/86 (9.30%)  14/85 (16.47%) 
Constipation  1  5/86 (5.81%)  4/85 (4.71%) 
General disorders     
Pyrexia  1  11/86 (12.79%)  7/85 (8.24%) 
Fatigue  1  5/86 (5.81%)  2/85 (2.35%) 
Infections and infestations     
Sinusitis  1  5/86 (5.81%)  2/85 (2.35%) 
Upper respiratory tract infection  1  2/86 (2.33%)  6/85 (7.06%) 
Metabolism and nutrition disorders     
Decreased appetite  1  11/86 (12.79%)  2/85 (2.35%) 
Nervous system disorders     
Somnolence  1  12/86 (13.95%)  8/85 (9.41%) 
Sedation  1  7/86 (8.14%)  1/85 (1.18%) 
Convulsion  1  3/86 (3.49%)  5/85 (5.88%) 
Headache  1  2/86 (2.33%)  5/85 (5.88%) 
Respiratory, thoracic and mediastinal disorders     
Nasal congestion  1  7/86 (8.14%)  2/85 (2.35%) 
Cough  1  5/86 (5.81%)  2/85 (2.35%) 
Skin and subcutaneous tissue disorders     
Rash  1  6/86 (6.98%)  1/85 (1.18%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (17.1)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Enquires
Organization: GW Research Ltd.
EMail: medinfo.USA@gwpharm.com, medinfo@greenwichbiosciences.com
Layout table for additonal information
Responsible Party: GW Research Ltd
ClinicalTrials.gov Identifier: NCT02224690     History of Changes
Other Study ID Numbers: GWEP1423
2014-002941-23 ( EudraCT Number )
First Submitted: August 21, 2014
First Posted: August 25, 2014
Results First Submitted: June 25, 2018
Results First Posted: July 27, 2018
Last Update Posted: July 27, 2018