An Open-label Extension Trial of Cannabidiol (GWP42003-P, CBD) for Seizures in Tuberous Sclerosis Complex (GWPCARE6)

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02544750
• Collaborator: GW Pharmaceuticals (Other)
• Enrollment: 199
• Location: 1
• Arm: 1
• Actual Duration (Months): 57.3
• Patients Per Site Per Month: 3.5

Study Details

Study Description

Brief Summary

This trial consists of 2 parts: a double-blinded phase and an open-label extension phase. The open-label extension phase only will be described in this record. All participants will receive the same dose of GWP42003-P. However, investigators may subsequently decrease or increase the participant's dose until the optimal dose is found.

Condition or Disease	Intervention/Treatment	Phase
Tuberous Sclerosis Complex; Seizures	Drug: GWP42003-P	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 199 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Randomized, Placebo-controlled Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P, CBD) as Add-on Therapy in Patients With Tuberous Sclerosis Complex Who Experience Inadequately-controlled Seizures
• Actual Study Start Date: Aug 31, 2016
• Actual Primary Completion Date: Jun 11, 2021
• Actual Study Completion Date: Jun 11, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GWP42003-P 100 mg/mL GWP42003-P oral solution taken twice daily (morning and evening). Participants will be dosed up to a maximum of 50 mg/kg/day. Dose may be lower if Investigator judges benefit and/or tolerability issues.	Drug: GWP42003-P; Yellow oily solution containing cannabidiol dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring.; Other Names: Cannabidiol CBD

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) [OLE Day 1 up to 4 years]

   An adverse event (AE) was defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which occurred following screening and at any point up to the post-treatment safety follow-up visit, which may or may not be related to the IMP. An AE that started, or worsened in severity or seriousness, following the first dose of IMP was considered a TEAE. A serious AE was defined as any AE that results in any of the following outcomes: death, life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or cancer, any other experience that suggests a significant hazard, contraindication, side effect or precaution that may require medical or surgical intervention to prevent one of the outcomes listed above, or an event that changes the risk/benefit ratio of the study.

2. Number of Participants With Any TEAE, by Severity [OLE Day 1 up to 4 years]

   An adverse event (AE) was defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which occurred following screening and at any point up to the post-treatment safety follow-up visit, which may or may not be related to the IMP. An AE that started, or worsened in severity or seriousness, following the first dose of IMP was considered a TEAE. Grade 1 (Mild) is defined as asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 (Moderate) is defined as minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living (ADL). Grade 3 (Severe) is defined as medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL.

Secondary Outcome Measures

1. Percent Change From Baseline in the Number of TSC-associated Seizures During the OLE Treatment Period [OLE Day 1 up to 4 years]

   TSC-associated seizures include: focal motor seizures without impairment of consciousness or awareness; focal seizures with impairment of consciousness or awareness; focal seizures evolving to bilateral generalized convulsive seizures and tonic-clonic, tonic, clonic or atonic seizures. A negative percent change from baseline indicates improvement.

2. Number of Participants Considered Treatment Responders During the OLE Treatment Period [OLE Day 1 up to 4 years]

   Treatment responders were defined as those participants with a ≥50% reduction from baseline in TSC-associated seizure frequency, during the treatment period, for participants who had not withdrawn from the trial during the treatment period. TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that were countable. Participants who withdrew from the trial during the treatment period were considered non-responders.

3. Caregiver Global Impression of Change (CGIC) and Subject Global Impression of Change (SGIC) Score During the OLE Treatment Period [OLE Day 1 and up to 4 years]

   The CGIC comprised the following question to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): "Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment)." The SGIC comprised the following question to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): "Since you started treatment, please assess the status of your overall condition (comparing your condition now to your condition before treatment)." The average CGIC and SGIC scores are being reported, with higher values indicating worse condition.

4. Percent Change From Baseline in Total Seizure Frequency During the OLE Treatment Period [OLE Day 1 up to 4 years]

   Total seizures included all seizure types, eg. combination of TSC-associated and other seizures. TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that were countable. A negative percent change from baseline indicates improvement in total seizure frequency.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Completion of the GWEP1521 Blinded Phase

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Jazz Pharmaceuticals
• GW Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 23, 2019
• Statistical Analysis Plan - Apr 24, 2019

More Information

Publications

• Thiele EA, Bebin EM, Bhathal H, Jansen FE, Kotulska K, Lawson JA, O'Callaghan FJ, Wong M, Sahebkar F, Checketts D, Knappertz V; GWPCARE6 Study Group. Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial. JAMA Neurol. 2021 Mar 1;78(3):285-292. doi: 10.1001/jamaneurol.2020.4607.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02544750
• Other Study ID Numbers: GWEP1521 Open-Label Extension; 2015-002154-12
• First Posted: Sep 9, 2015
• Last Update Posted: Jul 14, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Tuberous Sclerosis; Seizures; Sclerosis; Cannabidiol

Study Results

Participant Flow

Recruitment Details	A total of 199 participants with tuberous sclerosis complex (TSC) who met all inclusion criteria and no exclusion criteria and completed the double-blind study GWEP1521 (NCT02544763) were enrolled into this Open-label Extension (OLE) study to receive GWP42003-P.
Pre-assignment Detail	OLE investigational medicinal product (IMP) was titrated up to 25 mg/kg/day while blinded IMP was simultaneously tapered down to zero to accommodate those participants who had been randomized to placebo during the double-blind phase (DBP) of the study. All participants were to complete the transition and enter the OLE taking 25 mg/kg/day GWP42003-P.

Arm/Group Title	GWP42003-P (Double-blind Phase)	Placebo (Double-blind Phase)
Arm/Group Description	Participants who had received GWP42003-P during the double-blind phase and then GWP42003-P in the OLE phase.	Participants who had received placebo during the double-blind phase and then GWP42003-P in the OLE phase.
Period Title: Overall Study
STARTED	124	75
COMPLETED	22	12
NOT COMPLETED	102	63

Baseline Characteristics

Arm/Group Title	GWP42003-P (Double-blind Phase)	Placebo (Double-blind Phase)	Total
Arm/Group Description	Participants who had received GWP42003-P during the double-blind phase and then GWP42003-P in the OLE phase.	Participants who had received placebo during the double-blind phase and then GWP42003-P in the OLE phase.	Total of all reporting groups
Overall Participants	124	75	199
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.69 (9.64)	13.92 (10.63)	13.15 (10.02)
Sex: Female, Male (Count of Participants)
Female	51 41.1%	30 40%	81 40.7%
Male	73 58.9%	45 60%	118 59.3%
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian	111 89.5%	66 88%	177 88.9%
Black/African American	4 3.2%	0 0%	4 2%
American Indian/Alaska Native	1 0.8%	0 0%	1 0.5%
Asian	1 0.8%	3 4%	4 2%
Other	7 5.6%	6 8%	13 6.5%
Baseline Tuberous Sclerosis Complex (TSC)-Associated Seizures (Seizures) [Median (Full Range) ]
Median (Full Range) [Seizures]	58.08	55.10	56.90
Baseline Total Seizures (Seizures) [Median (Full Range) ]
Median (Full Range) [Seizures]	59.95	56.97	58.90

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE)
Description	An adverse event (AE) was defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which occurred following screening and at any point up to the post-treatment safety follow-up visit, which may or may not be related to the IMP. An AE that started, or worsened in severity or seriousness, following the first dose of IMP was considered a TEAE. A serious AE was defined as any AE that results in any of the following outcomes: death, life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or cancer, any other experience that suggests a significant hazard, contraindication, side effect or precaution that may require medical or surgical intervention to prevent one of the outcomes listed above, or an event that changes the risk/benefit ratio of the study.
Time Frame	OLE Day 1 up to 4 years

Outcome Measure Data

Analysis Population Description

Adverse events were assessed in the OLE Safety Analysis Set.

Arm/Group Title	GWP42003-P (Double-blind Phase)	Placebo (Double-blind Phase)
Arm/Group Description	Participants who had received GWP42003-P during the double-blind phase and then GWP42003-P in the OLE phase.	Participants who had received placebo during double-blind phase and then GWP42003-P in the OLE phase.
Measure Participants	124	75
Any TEAE	117 94.4%	75 100%
Any treatment-related TEAE	80 64.5%	60 80%
Any TEAE leading to permanent discontinuation of IMP	11 8.9%	7 9.3%
Any treatment-related TEAE leading to permanent discontinuation of IMP	9 7.3%	7 9.3%
Any serious TEAE	38 30.6%	18 24%
Any treatment-related serious TEAE	7 5.6%	8 10.7%
Any fatal TEAEs	1 0.8%	0 0%

2. Primary Outcome

Title	Number of Participants With Any TEAE, by Severity
Description	An adverse event (AE) was defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which occurred following screening and at any point up to the post-treatment safety follow-up visit, which may or may not be related to the IMP. An AE that started, or worsened in severity or seriousness, following the first dose of IMP was considered a TEAE. Grade 1 (Mild) is defined as asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 (Moderate) is defined as minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living (ADL). Grade 3 (Severe) is defined as medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL.
Time Frame	OLE Day 1 up to 4 years

Outcome Measure Data

Analysis Population Description

Adverse events were assessed in the OLE Safety Analysis Set.

Arm/Group Title	GWP42003-P (Double-blind Phase)	Placebo (Double-blind Phase)
Arm/Group Description	Participants who had received GWP42003-P during the double-blind phase and then GWP42003-P in the OLE phase.	Participants who had received placebo during double-blind phase and then GWP42003-P in the OLE phase.
Measure Participants	124	75
Mild TEAE	35 28.2%	16 21.3%
Moderate TEAE	63 50.8%	48 64%
Severe TEAE	19 15.3%	11 14.7%

3. Secondary Outcome

Title	Percent Change From Baseline in the Number of TSC-associated Seizures During the OLE Treatment Period
Description	TSC-associated seizures include: focal motor seizures without impairment of consciousness or awareness; focal seizures with impairment of consciousness or awareness; focal seizures evolving to bilateral generalized convulsive seizures and tonic-clonic, tonic, clonic or atonic seizures. A negative percent change from baseline indicates improvement.
Time Frame	OLE Day 1 up to 4 years

Outcome Measure Data

Analysis Population Description

TSC-associated seizures were assessed in the OLE Safety Analysis Set.

Arm/Group Title	GWP42003-P (Double-blind Phase)	Placebo (Double-blind Phase)
Arm/Group Description	Participants who had received GWP42003-P during the double-blind phase and then GWP42003-P in the OLE phase.	Participants who had received placebo during double-blind phase and then GWP42003-P in the OLE phase.
Measure Participants	124	75
Median (Inter-Quartile Range) [percent change]	-55.66	-46.76

4. Secondary Outcome

Title	Number of Participants Considered Treatment Responders During the OLE Treatment Period
Description	Treatment responders were defined as those participants with a ≥50% reduction from baseline in TSC-associated seizure frequency, during the treatment period, for participants who had not withdrawn from the trial during the treatment period. TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that were countable. Participants who withdrew from the trial during the treatment period were considered non-responders.
Time Frame	OLE Day 1 up to 4 years

Outcome Measure Data

Analysis Population Description

Treatment responders were assessed in the OLE Safety Analysis Set.

Arm/Group Title	GWP42003-P (Double-blind Phase)	Placebo (Double-blind Phase)
Arm/Group Description	Participants who had received GWP42003-P during the double-blind phase and then GWP42003-P in the OLE phase.	Participants who had received placebo during double-blind phase and then GWP42003-P in the OLE phase.
Measure Participants	124	75
≥ 50% reduction: Yes	70 56.5%	36 48%
≥ 50% reduction: No	54 43.5%	39 52%

5. Secondary Outcome

Title	Caregiver Global Impression of Change (CGIC) and Subject Global Impression of Change (SGIC) Score During the OLE Treatment Period
Description	The CGIC comprised the following question to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): "Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment)." The SGIC comprised the following question to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): "Since you started treatment, please assess the status of your overall condition (comparing your condition now to your condition before treatment)." The average CGIC and SGIC scores are being reported, with higher values indicating worse condition.
Time Frame	OLE Day 1 and up to 4 years

Outcome Measure Data

Analysis Population Description

Caregiver Global Impression of Change and Subject Global Impression of Change were assessed in the OLE Safety Analysis Set in participants with available data.

Arm/Group Title	GWP42003-P (Double-blind Phase)	Placebo (Double-blind Phase)
Arm/Group Description	Participants who had received GWP42003-P during the double-blind phase and then GWP42003-P in the OLE phase.	Participants who had received placebo during double-blind phase and then GWP42003-P in the OLE phase.
Measure Participants	40	28
Caregiver	3.2 (1.58)	3.4 (1.12)
Subjects	4.0 (0.0)	2.7 (1.53)
Combined Caregiver and Subjects	3.2 (1.56)	3.3 (1.16)

6. Secondary Outcome

Title	Percent Change From Baseline in Total Seizure Frequency During the OLE Treatment Period
Description	Total seizures included all seizure types, eg. combination of TSC-associated and other seizures. TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that were countable. A negative percent change from baseline indicates improvement in total seizure frequency.
Time Frame	OLE Day 1 up to 4 years

Outcome Measure Data

Analysis Population Description

Total seizure frequency was assessed in the OLE Safety Analysis Set.

Arm/Group Title	GWP42003-P (Double-blind Phase)	Placebo (Double-blind Phase)
Arm/Group Description	Participants who had received GWP42003-P during the double-blind phase and then GWP42003-P in the OLE phase.	Participants who had received placebo during double-blind phase and then GWP42003-P in the OLE phase.
Measure Participants	124	75
Median (Inter-Quartile Range) [percent change]	-55.18	-46.76

Adverse Events

Time Frame	Treatment-emergent adverse events (TEAEs) were collected from OLE Day 1 up to 4 years.
Adverse Event Reporting Description	An adverse event (AE) was defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which occurred following screening and at any point up to the post-treatment safety follow-up visit, which may or may not be related to the IMP. TEAEs were defined as AEs with a start date on or after the first dose of IMP in the OLE Day 1.
Arm/Group Title	Placebo (Double-blind Phase)		GWP42003-P (Double-blind Phase)
Arm/Group Description	Participants who had received placebo during double-blind phase and then GWP42003-P in the OLE phase.		Participants who had received GWP42003-P during the double-blind phase and then GWP42003-P in the OLE phase.
All Cause Mortality
	Placebo (Double-blind Phase)		GWP42003-P (Double-blind Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/124 (0.8%)		0/75 (0%)
Serious Adverse Events
	Placebo (Double-blind Phase)		GWP42003-P (Double-blind Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/124 (30.6%)		18/75 (24%)
Blood and lymphatic system disorders
Leukocytosis	1/124 (0.8%)		0/75 (0%)
Neutropenia	0/124 (0%)		1/75 (1.3%)
Thrombocytopenia	0/124 (0%)		1/75 (1.3%)
Cardiac disorders
Cardiopulmonary failure	1/124 (0.8%)		0/75 (0%)
Gastrointestinal disorders
Dental caries	0/124 (0%)		1/75 (1.3%)
Diarrhoea	1/124 (0.8%)		0/75 (0%)
Pancreatitis	1/124 (0.8%)		0/75 (0%)
Vomiting	1/124 (0.8%)		0/75 (0%)
General disorders
Pyrexia	1/124 (0.8%)		0/75 (0%)
Soft tissue inflammation	1/124 (0.8%)		0/75 (0%)
Infections and infestations
Adenoiditis	1/124 (0.8%)		0/75 (0%)
Adenovirus infection	2/124 (1.6%)		0/75 (0%)
Bronchitis	0/124 (0%)		1/75 (1.3%)
Enterovirus infection	1/124 (0.8%)		0/75 (0%)
Gastroenteritis	1/124 (0.8%)		0/75 (0%)
Gastroenteritis astroviral	0/124 (0%)		1/75 (1.3%)
Gastroenteritis viral	1/124 (0.8%)		0/75 (0%)
Implant site infection	1/124 (0.8%)		0/75 (0%)
Infective myositis	1/124 (0.8%)		0/75 (0%)
Influenza	5/124 (4%)		0/75 (0%)
Laryngitis	0/124 (0%)		1/75 (1.3%)
Lower respiratory tract infection	0/124 (0%)		1/75 (1.3%)
Parainfluenzae virus infection	1/124 (0.8%)		0/75 (0%)
Pharyngitis	1/124 (0.8%)		0/75 (0%)
Pharyngitis streptococcal	1/124 (0.8%)		0/75 (0%)
Pneumonia	4/124 (3.2%)		1/75 (1.3%)
Pneumonia bacterial	1/124 (0.8%)		0/75 (0%)
Pneumonia viral	0/124 (0%)		1/75 (1.3%)
Respiratory tract infection	1/124 (0.8%)		0/75 (0%)
Rhinovirus infection	1/124 (0.8%)		0/75 (0%)
Septic shock	1/124 (0.8%)		0/75 (0%)
Urinary tract infection	0/124 (0%)		1/75 (1.3%)
Injury, poisoning and procedural complications
Fall	1/124 (0.8%)		0/75 (0%)
Head injury	1/124 (0.8%)		0/75 (0%)
Joint dislocation	1/124 (0.8%)		0/75 (0%)
Toxicity to various agents	1/124 (0.8%)		1/75 (1.3%)
Investigations
Alanine aminotransferase increased	1/124 (0.8%)		1/75 (1.3%)
Anticonvulsant drug level increased	0/124 (0%)		1/75 (1.3%)
Aspartate aminotransferase increased	1/124 (0.8%)		1/75 (1.3%)
Astrovirus test positive	1/124 (0.8%)		0/75 (0%)
Blood bilirubin increased	1/124 (0.8%)		0/75 (0%)
Eosinophil count increased	0/124 (0%)		1/75 (1.3%)
Influenza A virus test positive	1/124 (0.8%)		0/75 (0%)
Investigation	1/124 (0.8%)		0/75 (0%)
Liver function test abnormal	0/124 (0%)		1/75 (1.3%)
Liver function test increased	1/124 (0.8%)		1/75 (1.3%)
Platelet count decreased	1/124 (0.8%)		1/75 (1.3%)
Respiratory syncytial virus test positive	1/124 (0.8%)		0/75 (0%)
Sapovirus test positive	1/124 (0.8%)		0/75 (0%)
Transaminases increased	0/124 (0%)		2/75 (2.7%)
Weight decreased	1/124 (0.8%)		0/75 (0%)
Metabolism and nutrition disorders
Acidosis	0/124 (0%)		1/75 (1.3%)
Decreased appetite	1/124 (0.8%)		1/75 (1.3%)
Dehydration	4/124 (3.2%)		2/75 (2.7%)
Fluid intake reduced	0/124 (0%)		1/75 (1.3%)
Hypokalaemia	1/124 (0.8%)		0/75 (0%)
Hyponatraemia	1/124 (0.8%)		0/75 (0%)
Musculoskeletal and connective tissue disorders
Flank pain	0/124 (0%)		1/75 (1.3%)
Myositis	1/124 (0.8%)		0/75 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Kidney angiomyolipoma	1/124 (0.8%)		0/75 (0%)
Nervous system disorders
Ataxia	0/124 (0%)		1/75 (1.3%)
Change in seizure presentation	1/124 (0.8%)		0/75 (0%)
Dizziness	1/124 (0.8%)		0/75 (0%)
Encephalopathy	1/124 (0.8%)		0/75 (0%)
Epileptic encephalopathy	0/124 (0%)		1/75 (1.3%)
Generalised tonic-clonic seizure	1/124 (0.8%)		0/75 (0%)
Lethargy	1/124 (0.8%)		1/75 (1.3%)
Memory impairment	1/124 (0.8%)		0/75 (0%)
Postictal state	1/124 (0.8%)		0/75 (0%)
Sedation	0/124 (0%)		1/75 (1.3%)
Seizure	12/124 (9.7%)		4/75 (5.3%)
Seizure cluster	1/124 (0.8%)		0/75 (0%)
Status epilepticus	9/124 (7.3%)		1/75 (1.3%)
Syncope	1/124 (0.8%)		0/75 (0%)
Psychiatric disorders
Mental status changes	2/124 (1.6%)		0/75 (0%)
Renal and urinary disorders
Acute kidney injury	1/124 (0.8%)		0/75 (0%)
Nephrolithiasis	0/124 (0%)		1/75 (1.3%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/124 (0.8%)		0/75 (0%)
Cough	1/124 (0.8%)		0/75 (0%)
Lung infiltration	1/124 (0.8%)		0/75 (0%)
Pneumonitis	1/124 (0.8%)		1/75 (1.3%)
Respiratory distress	0/124 (0%)		1/75 (1.3%)
Respiratory failure	1/124 (0.8%)		0/75 (0%)
Wheezing	1/124 (0.8%)		0/75 (0%)
Social circumstances
Alcohol use	1/124 (0.8%)		0/75 (0%)
Other (Not Including Serious) Adverse Events
	Placebo (Double-blind Phase)		GWP42003-P (Double-blind Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	117/124 (94.4%)		75/75 (100%)
Blood and lymphatic system disorders
Anaemia	4/124 (3.2%)		2/75 (2.7%)
Gastrointestinal disorders
Abdominal pain	4/124 (3.2%)		3/75 (4%)
Constipation	12/124 (9.7%)		9/75 (12%)
Diarrhoea	50/124 (40.3%)		43/75 (57.3%)
Nausea	3/124 (2.4%)		4/75 (5.3%)
Retching	3/124 (2.4%)		3/75 (4%)
Vomiting	27/124 (21.8%)		13/75 (17.3%)
Gastrooesophageal reflux disease	4/124 (3.2%)		1/75 (1.3%)
Toothache	4/124 (3.2%)		0/75 (0%)
General disorders
Fatigue	7/124 (5.6%)		10/75 (13.3%)
Pyrexia	33/124 (26.6%)		15/75 (20%)
Gait disturbance	4/124 (3.2%)		1/75 (1.3%)
Infections and infestations
Bronchitis	2/124 (1.6%)		5/75 (6.7%)
Conjunctivitis	8/124 (6.5%)		3/75 (4%)
Ear infection	6/124 (4.8%)		3/75 (4%)
Gastroenteritis	5/124 (4%)		2/75 (2.7%)
Gastroenteritis viral	7/124 (5.6%)		3/75 (4%)
Influenza	16/124 (12.9%)		4/75 (5.3%)
Nasopharyngitis	19/124 (15.3%)		16/75 (21.3%)
Otitis media	8/124 (6.5%)		4/75 (5.3%)
Pharyngitis	8/124 (6.5%)		2/75 (2.7%)
Pharyngitis streptococcal	13/124 (10.5%)		4/75 (5.3%)
Pneumonia	5/124 (4%)		3/75 (4%)
Rhinitis	4/124 (3.2%)		1/75 (1.3%)
Sinusitis	7/124 (5.6%)		2/75 (2.7%)
Upper respiratory tract infection	22/124 (17.7%)		10/75 (13.3%)
Urinary tract infection	7/124 (5.6%)		3/75 (4%)
Viral infection	4/124 (3.2%)		5/75 (6.7%)
Viral upper respiratory tract infection	4/124 (3.2%)		3/75 (4%)
Injury, poisoning and procedural complications
Accident	4/124 (3.2%)		0/75 (0%)
Contusion	6/124 (4.8%)		4/75 (5.3%)
Fall	13/124 (10.5%)		8/75 (10.7%)
Head injury	4/124 (3.2%)		0/75 (0%)
Laceration	9/124 (7.3%)		4/75 (5.3%)
Ligament sprain	1/124 (0.8%)		3/75 (4%)
Skin abrasion	2/124 (1.6%)		3/75 (4%)
Tooth fracture	5/124 (4%)		1/75 (1.3%)
Investigations
Alanine aminotransferase increased	8/124 (6.5%)		6/75 (8%)
Aspartate aminotransferase increased	6/124 (4.8%)		4/75 (5.3%)
Blood prolactin increased	2/124 (1.6%)		3/75 (4%)
Gamma-glutamyltransferase increased	4/124 (3.2%)		9/75 (12%)
Liver function test increased	2/124 (1.6%)		6/75 (8%)
Weight decreased	7/124 (5.6%)		9/75 (12%)
Weight increased	3/124 (2.4%)		3/75 (4%)
Metabolism and nutrition disorders
Decreased appetite	23/124 (18.5%)		24/75 (32%)
Dehydration	6/124 (4.8%)		4/75 (5.3%)
Nervous system disorders
Ataxia	4/124 (3.2%)		5/75 (6.7%)
Dizziness	5/124 (4%)		4/75 (5.3%)
Generalised tonic-clonic seizure	4/124 (3.2%)		2/75 (2.7%)
Headache	9/124 (7.3%)		5/75 (6.7%)
Lethargy	3/124 (2.4%)		5/75 (6.7%)
Sedation	2/124 (1.6%)		4/75 (5.3%)
Seizure	40/124 (32.3%)		19/75 (25.3%)
Somnolence	15/124 (12.1%)		24/75 (32%)
Status epilepticus	9/124 (7.3%)		1/75 (1.3%)
Psychiatric disorders
Abnormal behaviour	6/124 (4.8%)		5/75 (6.7%)
Aggression	5/124 (4%)		9/75 (12%)
Agitation	7/124 (5.6%)		2/75 (2.7%)
Anxiety	4/124 (3.2%)		3/75 (4%)
Insomnia	5/124 (4%)		6/75 (8%)
Intentional self-injury	4/124 (3.2%)		0/75 (0%)
Irritability	9/124 (7.3%)		5/75 (6.7%)
Sleep disorder	6/124 (4.8%)		4/75 (5.3%)
Mental status changes	4/124 (3.2%)		0/75 (0%)
Renal and urinary disorders
Urinary retention	2/124 (1.6%)		3/75 (4%)
Respiratory, thoracic and mediastinal disorders
Cough	13/124 (10.5%)		13/75 (17.3%)
Nasal congestion	7/124 (5.6%)		5/75 (6.7%)
Oropharyngeal pain	6/124 (4.8%)		5/75 (6.7%)
Respiration abnormal	4/124 (3.2%)		0/75 (0%)
Rhinorrhoea	6/124 (4.8%)		4/75 (5.3%)
Skin and subcutaneous tissue disorders
Rash	8/124 (6.5%)		4/75 (5.3%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.