Efficacy and Safety of GWP42003-P for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults (GWPCARE3)

• ClinicalTrials.gov Identifier: NCT02224560
• Recruitment Status: Completed
• First Posted: August 25, 2014
• Results First Posted: July 27, 2018
• Last Update Posted: July 27, 2018
• Sponsor: GW Research Ltd
• 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; Drug: Placebo control
• Enrollment: 225

Participant Flow

Recruitment Details
Pre-assignment Details	The dose levels of 10 and 20 milligram (mg) per kilogram (kg) per day (mg/kg/day) were recommended by the Data Safety Monitoring Committee (DSMC) of study GWEP1332 Part A (NCT02091206) after assessment of safety and pharmacokinetic data. Participants of GWEP1414 were not enrolled until the DSMC had reviewed the safety data of GWEP1332 Part A.

Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose	GWP42003-P 10 mg/kg/Day Dose	Placebo
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 GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 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/milliliter [mL] cannabidiol [CBD]), volume matched to 1 of the 2 dose levels (10 or 20 mg/kg/day), 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 7 to 11 days according to the matched investigational medicinal product (IMP) group (7 or 11 days for the 10 or 20 mg/kg/day GWP42003-P groups, respectively) 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 of the matched dose) period.
Period Title: Overall Study
Started	76	73	76
Safety Analysis Set [1]	82 [2]	67 [2]	76
Intent to Treat (ITT) Analysis Set [3]	76	73	76
Completed	67	71	74
Not Completed	9	2	2
Reason Not Completed
Protocol Deviation	1	0	0
Withdrawal by Subject	2	0	1
Met Withdrawal Criteria	1	0	0
Adverse Event	4	1	1
Withdrawn by Investigator	1	1	0
[1] Received at least 1 dose of IMP; analyzed as per actual treatment received.; [2] Six participants assigned to the 10 mg/kg/day dose were included in the 20 mg/kg/day group.; [3] 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-ITT Analysis Set	GWP42003-P 10 mg/kg/Day Dose-ITT Analysis Set	Placebo-ITT Analysis Set	Total
Arm/Group Description		Participants received at least 1 dose of IMP with at least 1 post-baseline efficacy endpoint measurement; analyzed according to the treatment group to which they were randomized (GWP42003-P 20 mg/kg/day).	Participants received at least 1 dose of IMP with at least 1 post-baseline efficacy endpoint measurement; analyzed according to the treatment group to which they were randomized (GWP42003-P 10 mg/kg/day).	Participants received at least 1 dose of IMP with at least 1 post-baseline efficacy endpoint measurement; analyzed according to the treatment group to which they were randomized (Placebo).	Total of all reporting groups
Overall Number of Baseline Participants		76	73	76	225
Baseline Analysis Population Description		ITT Analysis Set: Received at least 1 dose of IMP with at least 1 post-baseline efficacy endpoint measurement. Participants were analyzed according to the treatment group to which they were randomized.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	76 participants	73 participants	76 participants	225 participants
		16.0 (10.8)	15.4 (9.5)	15.3 (9.3)	15.6 (9.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	76 participants	73 participants	76 participants	225 participants
	Female	31 40.8%	33 45.2%	32 42.1%	96 42.7%
	Male	45 59.2%	40 54.8%	44 57.9%	129 57.3%

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 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) 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). 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: Received at least 1 dose of IMP with 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	GWP42003-P 10 mg/kg/Day Dose	Placebo
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 GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 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 1 of the 2 dose levels (10 or 20 mg/kg/day), 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 7 to 11 days according to the matched IMP group (7 or 11 days for the 10 or 20 mg/kg/day GWP42003-P groups, respectively) 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 of the matched dose) period.
Overall Number of Participants Analyzed	76	73	76
Median (Inter-Quartile Range); Unit of Measure: percentage change
	-41.86; (-72.4 to -1.3)	-37.16; (-63.8 to -5.6)	-17.17; (-37.1 to 0.9)

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	0.0047
	Comments	[Not Specified]
	Method	Wilcoxon rank-sum test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-21.57
	Confidence Interval	(2-Sided) 95%; -34.79 to -6.67
	Estimation Comments	Calculated using the Hodges–Lehmann approach

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 10 mg/kg/Day Dose, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0016
	Comments	[Not Specified]
	Method	Wilcoxon rank-sum test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-19.19
	Confidence Interval	(2-Sided) 95%; -31.24 to -7.69
	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 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

ITT Analysis Set: Received at least 1 dose of IMP with 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	GWP42003-P 10 mg/kg/Day Dose	Placebo
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 GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 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 1 of the 2 dose levels (10 or 20 mg/kg/day), 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 7 to 11 days according to the matched IMP group (7 or 11 days for the 10 or 20 mg/kg/day GWP42003-P groups, respectively) 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 of the matched dose) period.
Overall Number of Participants Analyzed	76	73	76
Measure Type: Count of Participants; Unit of Measure: Participants
	30 39.5%	26 35.6%	11 14.5%

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	0.0006
	Comments	Calculated using a Cochran–Mantel–Haenszel (CMH) test stratified by age group (2-5, 6-11, 12-17 and 18-55 years)
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.85
	Confidence Interval	(2-Sided) 95%; 1.75 to 8.47
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 10 mg/kg/Day Dose, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0030
	Comments	Calculated using a CMH test stratified by age group (2-5, 6-11, 12-17 and 18-55 years)
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.27
	Confidence Interval	(2-Sided) 95%; 1.47 to 7.26
	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, 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

ITT Analysis Set: Received at least 1 dose of IMP with 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	GWP42003-P 10 mg/kg/Day Dose	Placebo
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 GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 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 1 of the 2 dose levels (10 or 20 mg/kg/day), 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 7 to 11 days according to the matched IMP group (7 or 11 days for the 10 or 20 mg/kg/day GWP42003-P groups, respectively) 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 of the matched dose) period.
Overall Number of Participants Analyzed	76	73	76
Median (Inter-Quartile Range); Unit of Measure: percentage change
	-38.40; (-64.6 to -0.7)	-36.44; (-64.5 to -10.8)	-18.47; (-39.0 to 0.5)

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	0.0091
	Comments	[Not Specified]
	Method	Wilcoxon rank-sum test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-18.76
	Confidence Interval	(2-Sided) 95%; -31.80 to -4.43
	Estimation Comments	Calculated using the Hodges–Lehmann approach

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 10 mg/kg/Day Dose, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0015
	Comments	[Not Specified]
	Method	Wilcoxon rank-sum test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-19.47
	Confidence Interval	(2-Sided) 95%; -30.37 to -7.47
	Estimation Comments	Calculated using the Hodges–Lehmann approach

4. Secondary Outcome

Title	Subject/Caregiver Global Impression Of Change (S/CGIC) Assessment
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

ITT Analysis Set: Received at least 1 dose of IMP with 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	GWP42003-P 10 mg/kg/Day Dose	Placebo
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 GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 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 1 of the 2 dose levels (10 or 20 mg/kg/day), 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 7 to 11 days according to the matched IMP group (7 or 11 days for the 10 or 20 mg/kg/day GWP42003-P groups, respectively) 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 of the matched dose) period.
Overall Number of Participants Analyzed	75	73	75
Measure Type: Count of Participants; Unit of Measure: Participants
Very Much Improved	6 8.0%	9 12.3%	1 1.3%
Much Improved	15 20.0%	14 19.2%	8 10.7%
Slightly Improved	22 29.3%	25 34.2%	24 32.0%
No Change	25 33.3%	21 28.8%	35 46.7%
Slightly Worse	6 8.0%	3 4.1%	4 5.3%
Much Worse	1 1.3%	1 1.4%	3 4.0%
Very Much Worse	0 0.0%	0 0.0%	0 0.0%

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	0.0439
	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	1.83
	Confidence Interval	(2-Sided) 95%; 1.02 to 3.30
	Estimation Comments	Odds of participant recording a lower score (improvement) on a continuous scale

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GWP42003-P 10 mg/kg/Day Dose, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0020
	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	2.57
	Confidence Interval	(2-Sided) 95%; 1.41 to 4.66
	Estimation Comments	Odds of participant 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: Received at least 1 dose of IMP; analyzed as per actual treatment received. Six participants who were assigned to the GWP42003-P 10 mg/kg/day dose received dosing schedules for GWP42003-P 20 mg/kg/day. For safety analyses, these participants were assigned to the GWP42003-P 20 mg/kg/day group.
Arm/Group Title	GWP42003-P 20 mg/kg/Day Dose-Safety Analysis Set	GWP42003-P 10 mg/kg/Day Dose-Safety Analysis Set	Placebo-Safety Analysis Set
Arm/Group Description	Participants received at least 1 dose of IMP; analyzed as per actual treatment received. Six participants who were assigned to the GWP42003-P 10 mg/kg/day dose received dosing schedules for GWP42003-P 20 mg/kg/day. For safety analyses, these participants were assigned to the GWP42003-P 20 mg/kg/day group.	Participants received at least 1 dose of IMP; analyzed as per actual treatment received. Six participants who were assigned to the GWP42003-P 10 mg/kg/day dose received dosing schedules for GWP42003-P 20 mg/kg/day. For safety analyses, these participants were assigned to the GWP42003-P 20 mg/kg/day group.	Participants received at least 1 dose of IMP; analyzed as per actual treatment received.
All-Cause Mortality
	GWP42003-P 20 mg/kg/Day Dose-Safety Analysis Set	GWP42003-P 10 mg/kg/Day Dose-Safety Analysis Set	Placebo-Safety Analysis Set
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	GWP42003-P 20 mg/kg/Day Dose-Safety Analysis Set	GWP42003-P 10 mg/kg/Day Dose-Safety Analysis Set	Placebo-Safety Analysis Set
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	13/82 (15.85%)	13/67 (19.40%)	8/76 (10.53%)
Blood and lymphatic system disorders
Lymphopenia † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Gastrointestinal disorders
Constipation † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Pneumatosis intestinalis † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Pancreatitis † 1	0/82 (0.00%)	1/67 (1.49%)	0/76 (0.00%)
Faecaloma † 1	0/82 (0.00%)	0/67 (0.00%)	1/76 (1.32%)
General disorders
Device malfunction † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Pyrexia † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Hepatobiliary disorders
Cholecystitis chronic † 1	0/82 (0.00%)	1/67 (1.49%)	0/76 (0.00%)
Infections and infestations
Pneumonia † 1	2/82 (2.44%)	3/67 (4.48%)	0/76 (0.00%)
Adenovirus infection † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Pneumonia mycoplasmal † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Respiratory syncytial virus infection † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Upper respiratory tract infection † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Pneumonia bacterial † 1	0/82 (0.00%)	1/67 (1.49%)	0/76 (0.00%)
Pneumonia respiratory syncytial viral † 1	0/82 (0.00%)	1/67 (1.49%)	0/76 (0.00%)
Tracheobronchitis † 1	0/82 (0.00%)	0/67 (0.00%)	1/76 (1.32%)
Injury, poisoning and procedural complications
Delayed recovery from anaesthesia † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Investigations
Aspartate aminotransferase increased † 1	1/82 (1.22%)	1/67 (1.49%)	0/76 (0.00%)
Alanine aminotransferase increased † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Gamma-glutamyltransferase increased † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Transaminases increased † 1	0/82 (0.00%)	1/67 (1.49%)	0/76 (0.00%)
Investigation † 1	0/82 (0.00%)	0/67 (0.00%)	1/76 (1.32%)
Metabolism and nutrition disorders
Dehydration † 1	0/82 (0.00%)	1/67 (1.49%)	0/76 (0.00%)
Nervous system disorders
Status epilepticus † 1	4/82 (4.88%)	7/67 (10.45%)	3/76 (3.95%)
Convulsion † 1	2/82 (2.44%)	0/67 (0.00%)	0/76 (0.00%)
Lethargy † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Somnolence † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Sedation † 1	0/82 (0.00%)	1/67 (1.49%)	0/76 (0.00%)
Renal and urinary disorders
Nephrolithiasis † 1	0/82 (0.00%)	0/67 (0.00%)	1/76 (1.32%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (0.00%)
Hypoxia † 1	0/82 (0.00%)	1/67 (1.49%)	1/76 (1.32%)
Hypoventilation † 1	0/82 (0.00%)	1/67 (1.49%)	0/76 (0.00%)
Sleep apnoea syndrome † 1	0/82 (0.00%)	1/67 (1.49%)	0/76 (0.00%)
Vascular disorders
Hypotension † 1	1/82 (1.22%)	0/67 (0.00%)	0/76 (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-Safety Analysis Set	GWP42003-P 10 mg/kg/Day Dose-Safety Analysis Set	Placebo-Safety Analysis Set
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	63/82 (76.83%)	36/67 (53.73%)	40/76 (52.63%)
Gastrointestinal disorders
Diarrhoea † 1	12/82 (14.63%)	7/67 (10.45%)	6/76 (7.89%)
Vomiting † 1	10/82 (12.20%)	4/67 (5.97%)	9/76 (11.84%)
General disorders
Pyrexia † 1	9/82 (10.98%)	6/67 (8.96%)	12/76 (15.79%)
Fatigue † 1	8/82 (9.76%)	5/67 (7.46%)	2/76 (2.63%)
Infections and infestations
Upper respiratory tract infection † 1	10/82 (12.20%)	11/67 (16.42%)	11/76 (14.47%)
Nasopharyngitis † 1	9/82 (10.98%)	3/67 (4.48%)	5/76 (6.58%)
Metabolism and nutrition disorders
Decreased appetite † 1	21/82 (25.61%)	11/67 (16.42%)	6/76 (7.89%)
Nervous system disorders
Somnolence † 1	25/82 (30.49%)	14/67 (20.90%)	4/76 (5.26%)
Lethargy † 1	5/82 (6.10%)	3/67 (4.48%)	2/76 (2.63%)
Convulsion † 1	5/82 (6.10%)	2/67 (2.99%)	7/76 (9.21%)
Headache † 1	5/82 (6.10%)	2/67 (2.99%)	3/76 (3.95%)
Psychiatric disorders
Irritability † 1	4/82 (4.88%)	6/67 (8.96%)	2/76 (2.63%)
Insomnia † 1	4/82 (4.88%)	4/67 (5.97%)	2/76 (2.63%)
† 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

• Name/Title: Medical Enquiries
• Organization: GW Research Ltd
• EMail: medinfo@gwpharm.com, medinfo@greenwichbiosciences.com

Publications of Results:

Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, Greenwood SM, Roberts C, Checketts D, VanLandingham KE, Zuberi SM; GWPCARE3 Study Group. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N Engl J Med. 2018 May 17;378(20):1888-1897. doi: 10.1056/NEJMoa1714631.

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

Perry MS. Don't Fear the Reefer-Evidence Mounts for Plant-Based Cannabidiol as Treatment for Epilepsy. Epilepsy Curr. 2019 Mar-Apr;19(2):93-95. doi: 10.1177/1535759719835671.

• Responsible Party: GW Research Ltd
• ClinicalTrials.gov Identifier: NCT02224560
• Other Study ID Numbers: GWEP1414; 2014-002940-42 ( 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