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 : September 28, 2022

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Sponsor:

Information provided by (Responsible Party):

Jazz Pharmaceuticals

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

Participant Flow

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
Arm/Group Description	Participants received GWP42003-P 20...	Participants received placebo (0 mg...
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.

Baseline Characteristics

Arm/Group Title		GWP42003-P 20 mg/kg/Day Dose	Placebo	Total
Arm/Group Description		Participants received GWP42003-P 20...	Participants received placebo (0 mg...	Total of all reporting groups
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
Baseline Analysis Population Description		[Not Specified]
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%

Outcome Measures

1.Primary Outcome


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 i...
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)

Outcome Measure Data

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
Arm/Group Description:	Participants received GWP42003-P 20...	Participants received placebo (0 mg...
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)

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
Description	Drop seizures were recorded by the participant or caregiver using an I...
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

Outcome Measure Data

Analysis Population Description


Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description:	Participants received GWP42003-P 20...	Participants received placebo (0 mg...
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%

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
Description	Total seizures included the sum of all seizures (tonic-clonic, tonic, ...
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

Outcome Measure Data

Analysis Population Description


Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description:	Participants received GWP42003-P 20...	Participants received placebo (0 mg...
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)

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)
Description	The S/CGIC was used to assess the participant's overall condition on a...
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

Outcome Measure Data

Analysis Population Description


Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	Placebo
Arm/Group Description:	Participants received GWP42003-P 20...	Participants received placebo (0 mg...
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%

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

Adverse Events

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
Arm/Group Description	Participants received GWP42003-P 20...	Participants received placebo (0 mg...
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	--/--	--/--
Serious Adverse Events 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)
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)

Limitations and Caveats

[Not Specified]

More Information

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

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.

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

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.

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.

Layout table for additonal information

Responsible Party:	Jazz Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT02224690
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:	September 28, 2022

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