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Clinical Trial Results:
A Phase 2, Double-blind, Randomized, Placebo-controlled, Pharmacokinetic Trial in Two Parallel Groups to Investigate Possible Drug-drug Interactions Between Stiripentol or Valproate and GWP42003-P in Patients with Epilepsy

Summary
EudraCT number	2015-002939-18
Trial protocol	ES SE NL PL
Global end of trial date	27 May 2019

Results information
Results version number	v1(current)
This version publication date	05 Apr 2020
First version publication date	05 Apr 2020
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GWEP1447

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GW Research Ltd

Sponsor organisation address

Sovereign House, Vision Park, Chivers Way, Histon, Cambridge, United Kingdom, CB24 9BZ

Public contact

Medical Enqiries, GW Research Ltd, medinfo@gwpharm.com

Scientific contact

Medical Enqiries, GW Research Ltd, medinfo@gwpharm.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

19 Sep 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 May 2019

Global end of trial reached?

Yes

Global end of trial date

27 May 2019

Was the trial ended prematurely?

Main objective of the trial

This study investigates possible drug-drug interactions between stiripentol or valproate and GWP42003-P in patients with epilepsy

Protection of trial subjects

This trial was conducted in accordance with the ethical principles that have their origin in the World Medical Association (WMA) Declaration of Helsinki, adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and subsequent amendments. This trial was also designed to comply with ICH E6 Guideline for good clinical practice (EMA/CHMP/ICH/135/1995) and the European Clinical Trial Directive 2001/20/EC. The International Council for Harmonisation adopted guidelines and other relevant international guidelines, recommendations and requirements were taken into account as comprehensively as possible, as long as they did not violate Spanish, Swedish or Dutch law.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Nov 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 4

Country: Number of subjects enrolled

Spain: 12

Country: Number of subjects enrolled

Sweden: 19

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Subjects were screened to assess their eligibility to enter the trial within 15 days prior to the first dose administration.

Number of subjects started

Number of subjects completed

Reason: Number of subjects

Did not meet inclusion/exclusion criteria;: 1

Period 1 title

Double Blind (DB)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Are arms mutually exclusive

Yes

STP + GWP42003-P

Arm description

On Day 2, subjects received an oral administration of GWP42003-P twice daily (morning and evening; immediately after the subject's stiripentol [STP] dose), commencing with up-titration of 100 milligrams per milliliter (mg/mL) GWP42003-P to a maintenance dose of 20 milligrams per kilogram per day (mg/kg/day) over 10 days (Days 2 to 11). After titration with GWP42003-P, subjects continued to take the maintenance dose of GWP42003-P for 14 days (Days 12 to 25). On Day 27, subjects either entered a tapering period (10% per day over 10 days) or, if the subject elected to participate in the open-label extension study, they entered a 10-day period of simultaneous tapering (of GWP42003-P) and titration (of GWP42003-P) in order to maintain blinding.

Arm type

Experimental

Investigational medicinal product name

GWP42003-P

Investigational medicinal product code

GWP42003-P

Other name

EPIDIOLEX, cannabidiol, CBD-OS

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Oral liquid formulation that is clear and colorless to yellow in appearance (100 milligrams per milliliter [mg/mL]), in sesame oil with anhydrous ethanol, added sweetener (sucralose) and strawberry flavoring. The oral liquid formulation was administered with a syringe.

STP + Placebo

Arm description

On Day 2, subjects received an oral administration of matching placebo twice daily (morning and evening; immediately after the subject's STP dose), commencing with up-titration of 100 mg/mL placebo to a maintenance dose of 20 mg/kg/day over 10 days (Days 2 to 11). After titration with placebo, subjects continued to take the maintenance dose of placebo for 14 days (Days 12 to 25). On Day 27, subjects either entered a tapering period (10% per day over 10 days) or, if the subject elected to participate in the open-label extension study, they entered a 10-day period of simultaneous tapering (of placebo) and titration (of placebo) in order to maintain blinding.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Volume of GW placebo solution equivalent to the planned GWP42003-P dose.

VPA + GWP42003-P

Arm description

On Day 2, subjects received an oral administration of GWP42003-P twice daily (morning and evening; immediately after the subject's Valproate [VPA] dose), commencing with up-titration of 100 mg/mL GWP42003-P to a maintenance dose of 20 mg/kg/day over 10 days (Days 2 to 11). After titration with GWP42003-P, subjects continued to take the maintenance dose of GWP42003-P for 14 days (Days 12 to 25). On Day 27, subjects either entered a tapering period (10% per day over 10 days) or, if the subject elected to participate in the open-label extension study, they entered a 10-day period of simultaneous tapering (of GWP42003-P) and titration (of GWP42003-P) in order to maintain blinding.

Arm type

Experimental

Investigational medicinal product name

GWP42003-P

Investigational medicinal product code

GWP42003-P

Other name

EPIDIOLEX, cannabidiol, CBD-OS

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

VPA + Placebo

Arm description

On Day 2, subjects received an oral administration of matching placebo twice daily (morning and evening; immediately after the subject's VPA dose), commencing with up-titration of 100 mg/mL placebo to a maintenance dose of 20 mg/kg/day over 10 days (Days 2 to 11). After titration with placebo, subjects continued to take the maintenance dose of placebo for 14 days (Days 12 to 25). On Day 27, subjects either entered a tapering period (10% per day over 10 days) or, if the subject elected to participate in the open-label extension study, they entered a 10-day period of simultaneous tapering (of placebo) and titration (of placebo) in order to maintain blinding.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Volume of GW placebo solution equivalent to the planned GWP42003-P dose.

Number of subjects in period 1 ^[1]	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Started	12	2	16	4
Completed	10	2	14	4
Not completed	2	0	2	0
Adverse event, non-fatal	1	-	-	-
Withdrawn Consent	-	-	2	-
Met Withdraw Criteria	1	-	-	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: One subject withdrew before receiving the first dose of investigational medicinal product. Baseline data are not reported for this subject.

Period 2 title

Open Label Extension (OLE)

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

STP/VPA + GWP42003-P

Arm description

Subjects completing the DB period were invited to participate in the OLE period. Subjects taking GWP42003-P during the DB period maintained their dose throughout the transition from the DB period into the OLE period. Subjects who received placebo during the DB period titrated 10% over 10 days to reach their maximum tolerable dose not to exceed 20 mg/kg/day in the OLE period. All subjects continued their STP or VPA as per physician's orders.

Arm type

Experimental

Investigational medicinal product name

GWP42003-P

Investigational medicinal product code

GWP42003-P

Other name

EPIDIOLEX, cannabidiol, CBD-OS

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 2	STP/VPA + GWP42003-P
Started	30
Completed	13
Not completed	17
Subject withdrew consent	5
Adverse event, non-fatal	9
Not specified	2
Subject withdrawn by Investigator	1

Baseline characteristics

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Reporting group title

STP + GWP42003-P

Reporting group description

Reporting group title

STP + Placebo

Reporting group description

Reporting group title

VPA + GWP42003-P

Reporting group description

Reporting group title

VPA + Placebo

Reporting group description

Reporting group values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo	Total
Number of subjects	12	2	16	4	34
Age categorical
Units: Subjects
<=18 years	0	0	1	0	1
Between 18 and 65 years	12	2	15	4	33
>=65 years	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	31.34 ( 11.09 )	20.95 ( 3.04 )	29.14 ( 11.40 )	29.80 ( 6.60 )	-
Gender categorical
Units: Subjects
Female	5	0	6	1	12
Male	7	2	10	3	22

End points

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Reporting group title

STP + GWP42003-P

Reporting group description

Reporting group title

STP + Placebo

Reporting group description

Reporting group title

VPA + GWP42003-P

Reporting group description

Reporting group title

VPA + Placebo

Reporting group description

Reporting group title

STP/VPA + GWP42003-P

Reporting group description

Primary: Double Blind: Dose Normalized (DN) Cmax of STP and VPA

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End point title

Double Blind: Dose Normalized (DN) Cmax of STP and VPA ^[1]

End point description

Cmax is the maximum measured plasma concentration. Blood samples were collected for pharmacokinetic (PK) analysis predose, 15 and 30 minutes, then 1, 1.5, 2, 4, 6, and 12 hours postdose. 999=No analysis was conducted for this treatment arm at this time point. n=number of subjects with evaluable data. The PK analysis set includes all subjects enrolled in the trial who received at least 1 dose of GWP42003-P or placebo and who provided some on-treatment data.

End point type

Primary

End point timeframe

Day 1 and Day 26

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for the PK endpoints. Descriptive statistics are included (geometric mean and % CV).

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[2]	2 ^[3]	12 ^[4]	3 ^[5]
Units: nanograms per milliliter per milligram
geometric mean (geometric coefficient of variation)
STP Day 1 n=11,2,0,0	7.6 ( 80.0 )	7.74 ( 16.3 )	999 ( 999 )	999 ( 999 )
STP Day 26 n=9,2,0,0	10.7 ( 59.4 )	7.65 ( 18.4 )	999 ( 999 )	999 ( 999 )
VPA Day 1 n=0,0,12,3	999 ( 999 )	999 ( 999 )	173 ( 54.7 )	161 ( 54.1 )
VPA Day 26 n=0,0,10,3	999 ( 999 )	999 ( 999 )	143 ( 60.6 )	168 ( 46.6 )

Notes
[2] - PK Analysis Set
[3] - PK Analysis Set
[4] - PK Analysis Set
[5] - PK Analysis Set

No statistical analyses for this end point

Primary: Double Blind: DN Cmax of CBD

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End point title

Double Blind: DN Cmax of CBD ^[6] ^[7]

End point description

Cmax is the maximum measured plasma concentration. Blood samples were collected for PK analysis predose, 15 and 30 minutes, then 1, 1.5, 2, 4, 6, and 12 hours postdose. The PK anaylsis set includes all subjects enrolled in the trial who received at least 1 dose of GWP42003-P or placebo and who provided some on-treatment data.

End point type

Primary

End point timeframe

Day 26

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for the PK endpoints. Descriptive statistics are included (geometric mean and % CV).
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for the PK endpoints. Descriptive statistics are included (geometric mean and % CV).

End point values	STP + GWP42003-P	VPA + GWP42003-P
Number of subjects analysed	10 ^[8]	10 ^[9]
Units: ng/mL/[mg/kg]
geometric mean (geometric coefficient of variation)	35.1 ( 64.4 )	25.4 ( 54.1 )

Notes
[8] - PK Analysis Set. Only subjects with available data were analyzed.
[9] - PK Analysis Set. Only subjects with available data were analyzed.

No statistical analyses for this end point

Primary: Double Blind: tmax of STP, VPA and CBD

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End point title

Double Blind: tmax of STP, VPA and CBD ^[10]

End point description

tmax is the time to the maximum measured plasma concentration. Blood samples were collected for PK analysis predose, 15 and 30 minutes, then 1, 1.5, 2, 4, 6, and 12 hours postdose. 999=No analysis was conducted for this treatment arm at this time point. n=number of subjects with evaluable data. The PK anaylsis set includes all subjects enrolled in the trial who received at least 1 dose of GWP42003-P or placebo and who provided some on-treatment data.

End point type

Primary

End point timeframe

Day 1 and Day 26

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for the PK endpoints. Descriptive statistics are included (geometric mean and full range).

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[11]	2 ^[12]	12 ^[13]	3 ^[14]
Units: hours (h)
geometric mean (full range (min-max))
STP Day 1 n=11,2,0,0	1.53 (0.25 to 6.08)	3.94 (2.00 to 5.88)	999 (999 to 999)	999 (999 to 999)
STP Day 26 n=9,2,0,0	2.07 (1.42 to 6.03)	1.70 (1.40 to 2.00)	999 (999 to 999)	999 (999 to 999)
VPA Day 1 n=0,0,12,3	999 (999 to 999)	999 (999 to 999)	3.03 (0.00 to 6.17)	3.92 (1.50 to 4.00)
VPA Day 26 n=0,0,10,3	999 (999 to 999)	999 (999 to 999)	1.76 (0.00 to 12.00)	4.00 (0.00 to 6.00)
CBD Day 26 n=10,0,10,0	4.05 (0.00 to 6.02)	999 (999 to 999)	2.33 (1.00 to 6.00)	999 (999 to 999)

Notes
[11] - PK Analysis Set
[12] - PK Analysis Set
[13] - PK Analysis Set
[14] - PK Analysis Set

No statistical analyses for this end point

Primary: Double Blind: DN AUCtau of STP and VPA

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End point title

Double Blind: DN AUCtau of STP and VPA ^[15]

End point description

AUCtau is the area under the concentration-time curve over the dosing interval. Blood samples were collected for PK analysis predose, 15 and 30 minutes, then 1, 1.5, 2, 4, 6, and 12 hours postdose. 999=No analysis was conducted for this treatment arm at this time point. n=number of subjects with evaluable data. The PK anaylsis set includes all subjects enrolled in the trial who received at least 1 dose of GWP42003-P or placebo and who provided some on-treatment data.

End point type

Primary

End point timeframe

Day 1 and Day 26

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for the PK endpoints. Descriptive statistics are included (geometric mean and % CV).

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[16]	2 ^[17]	12 ^[18]	3 ^[19]
Units: ngxh/mL/mg
geometric mean (geometric coefficient of variation)
STP Day 1 n=11,2,0,0	52.3 ( 108.5 )	49.7 ( 22.0 )	999 ( 999 )	999 ( 999 )
STP Day 26 n=9,2,0,0	80.7 ( 66.8 )	51.8 ( 41.3 )	999 ( 999 )	999 ( 999 )
VPA Day 1 n=0,0,12,3	999 ( 999 )	999 ( 999 )	1710 ( 64.3 )	1620 ( 63.2 )
VPA Day 26 n=0,0,10,3	999 ( 999 )	999 ( 999 )	1350 ( 62.2 )	1540 ( 51.4 )

Notes
[16] - PK Analysis Set
[17] - PK Analysis Set
[18] - PK Analysis Set
[19] - PK Analysis Set

No statistical analyses for this end point

Primary: Double Blind: DN AUCtau of CBD

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End point title

Double Blind: DN AUCtau of CBD ^[20] ^[21]

End point description

AUCtau is the area under the concentration-time curve over the dosing interval. Blood samples were collected for PK analysis predose, 15 and 30 minutes, then 1, 1.5, 2, 4, 6, and 12 hours postdose. The PK analysis set includes all subjects enrolled in the trial who received at least 1 dose of GWP42003-P or placebo and who provided some on-treatment data.

End point type

Primary

End point timeframe

Day 26

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for the PK endpoints. Descriptive statistics are included (geometric mean and % CV).
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for the PK endpoints. Descriptive statistics are included (geometric mean and % CV).

End point values	STP + GWP42003-P	VPA + GWP42003-P
Number of subjects analysed	10 ^[22]	10 ^[23]
Units: ngxh/mL/[mg/kg]
geometric mean (geometric coefficient of variation)	203 ( 48.1 )	145 ( 52.3 )

Notes
[22] - PK Analysis Set. Only subjects with available data were analyzed.
[23] - PK Analysis Set. Only subjects with available data were analyzed.

No statistical analyses for this end point

Primary: OLE: Number of subjects with adverse events (AE)

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End point title

OLE: Number of subjects with adverse events (AE) ^[24]

End point description

An AE is defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which was present following screening (Visit 1) and at any point up to the post treatment, safety follow-up visit (Visit 6 if patients did not enter the OLE or Visit 13 if they completed the OLE or 28 [± 3] days following the last dose of IMP), which may or may not have been considered to be related to the IMP. Results are categorized by system organ class and then by all-causality (any and all AEs, regardless of relation to IMP [investigational medicinal product]) and treatment-related (an AE marked as possibly attributed to IMP). The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Primary

End point timeframe

Day 40 to Day 418

Notes
[24] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for this endpoint.

End point values	STP/VPA + GWP42003-P
Number of subjects analysed	30 ^[25]
Units: subjects
Gastrointestinal Disorders, All-causality	19
Gastrointestinal Disorders, Treatment-related	16
Nervous System Disorders, All-causality	10
Nervous System Disorders, Treatment-related	5
Investigations, All-causality	9
Investigations, Treatment-related	8
Infections, All-causality	6
Infections, Treatment-related	1
Psychiatric Disorders, All-causality	6
Psychiatric Disorders, Treatment-related	5
General Disorders, All-causality	5
General Disorders, Treatment-related	4
Skin Disorders, All-causality	4
Skin DIsorders, Treatment-related	3
Musculoskeletal Disorders, All-causality	3
Musculoskeletal Disorders, Treatment-related	1

Notes
[25] - Safety Analysis Set

No statistical analyses for this end point

Primary: OLE: Number of subjects with shifts from normal in hematology laboratory values

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End point title

OLE: Number of subjects with shifts from normal in hematology laboratory values ^[26]

End point description

Results are categorized by the number of subjects with a shift from normal to low (N2L) or normal to high (N2H) at Visit 5 (V5, Day 40), Visit 6 (V6, Day 54), Visit 7 (V7, Day 82), Visit 8 (V8, Day 110), Visit 9 (V9, Day 194), Visit 10 (V10, Day 278), Visit 11 (V11, Day 362) and Visit 12 (V12, Day 372). The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Primary

End point timeframe

Day 40 to Day 372

Notes
[26] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for this endpoint.

End point values	STP/VPA + GWP42003-P
Number of subjects analysed	30 ^[27]
Units: subjects
V5, N2L, Hematocrit	6
V5, N2L, Lymphocytes	1
V5, N2L, Neutrophils	2
V5, N2L, Red Blood Cell Count (blood)	2
V5, N2H, Absolute Monocyte Count	3
V5, N2H, Lymphocytes	3
V5, N2H, Monocytes	2
V5, N2H, Neutrophils	1
V5, N2H, White Blood Cells Count with Differential	1
V6, N2L, Absolute Neutrophil Count	1
V6, N2L, Hematocrit	4
V6, N2L, Hemoglobin	1
V6, N2L, Lymphocytes	1
V6, N2L, Neutrophils	2
V6, N2L, Platelets	1
V6, N2L, Red Blood Cell Count (blood)	5
V6, N2L, White Blood Cell Count with Differential	1
V6, N2H, Absolute Eosinophil Count	1
V6, N2H, Absolute Monocyte Count	3
V6, N2H, Eosinophils	3
V6, N2H, Lymphocytes	4
V6, N2H, Mean Cell Volume	1
V6, N2H, Monocytes	2
V6, N2H, Neutrophils	1
V7, N2L, Hemtocrit	4
V7, N2L, Neutrophils	3
V7, N2L, Platelets	1
V7, N2L, Red Blood Cell Count (blood)	3
V7, N2L, White Blood Cell Count with Differential	3
V7, N2H, Eosinophils	3
V7, N2H, Lymphoblasts	1
V7, N2H, Lymphocytes	3
V7, N2H, Mean Cell Volume	1
V7, N2H, Monocytes	2
V7, N2H, Neutrophils	1
V8, N2L, Absolute Neutrophil Count	1
V8, N2L, Hematocrit	4
V8, N2L, Hemoglobin	2
V8, N2L, Lymphoblasts	1
V8, N2L, Lymphocytes	4
V8, N2L, Neutrophils	1
V8, N2L, Platelets	1
V8, N2L, Red Blood Cell Count (blood)	3
V8, N2L, White Blood Cell Count with Differential	1
V8, N2H, Absolute Monocyte Count	2
V8, N2H, Eosinophils	2
V8, N2H, Lymphocytes	3
V8, N2H, Monocytes	3
V8, N2H, Neutrophils	1
V9, N2L, Hematocrit	1
V9, N2L, Lymphocytes	5
V9, N2L, Red Blood Cell Count (blood)	4
V9, N2L, White Blood Cell Count with Differential	1
V9, N2H, Absolute Monocyte Count	2
V9, N2H, Absolute Neutrophil Count	1
V9, N2H, Lymphocytes	1
V9, N2H, Mean Cell Volume	1
V9, N2H, Monocytes	1
V9, N2H, Neutrophils	3
V9, N2H, White Blood Cell Count with Differential	1
V10, N2L, Absolute Neutrophil Count	1
V10, N2L, Lymphoblasts	1
V10, N2L, Lymphocytes	2
V10, N2L, Neutrophils	2
V10, N2L, Platelets	1
V10, N2L, Red Blood Cell Count (blood)	2
V10, N2L, White Blood Cell Count with Differential	1
V10, N2H, Lymphocytes	1
V10, N2H, Monocytes	1
V10, N2H, Neutrophils	1
V11, N2L, Absolute Neutrophil Count	2
V11, N2L, Hematocrit	5
V11, N2L, Hemoglobin	1
V11, N2L, Lymphocytes	1
V11, N2L, Neutrophils	3
V11, N2L, Platelets	1
V11, N2L, Red Blood Cell Count (blood)	4
V11, N2L, White Blood Cell Count with Differential	2
V11, N2H, Absolute Eosinophil Count	1
V11, N2H, Eosinophils	2
V11, N2H, Lymphoblasts	1
V11, N2H, Lymphocytes	2
V11, N2H, Mean Cell Volume	1
V11, N2H, Monocytes	1
V11, N2H, Neutrophils	1
V12, N2L, Absolute Neutrophil Count	1
V12, N2L, Hematocrit	4
V12, N2L, Lymphocytes	1
V12, N2L, Mean Cell Volume	1
V12, N2L, Neutrophils	1
V12, N2L, Red Blood Cell Count (blood)	1
V12, N2L, White Blood Cell Count with Differential	1
V12, N2H, Lymphocytes	3
V12, N2H, Mean Cell Volume	1
V12, N2H, Monocytes	2

Notes
[27] - Safety Analysis Set

No statistical analyses for this end point

Primary: OLE: Number of subjects with shifts from normal in biochemistry laboratory values

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End point title

OLE: Number of subjects with shifts from normal in biochemistry laboratory values ^[28]

End point description

Results are categorized by the number of subjects with a shift from normal to low (N2L) or normal to high (N2H) at Visit 5 (V5, Day 40), Visit 6 (V6, Day 54), Visit 7 (V7, Day 82), Visit 8 (V8, Day 110), Visit 9 (V9, Day 194), Visit 10 (V10, Day 278), Visit 11 (V11, Day 362) and Visit 12 (V12, Day 372). HDL=high-density lipoprotein. The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Primary

End point timeframe

Day 40 to Day 372

Notes
[28] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for this endpoint.

End point values	STP/VPA + GWP42003-P
Number of subjects analysed	30 ^[29]
Units: subjects
V5, N2L, Alkaline Phosphatase	1
V5, N2L, HDL-Cholesterol	1
V5, N2L, Sodium	2
V5, N2L, Total Bilirubin (blood)	1
V5, N2L, Urea Nitrogen	1
V5, N2H, Alanine Aminotransferase	8
V5, N2H, Alkaline Phosphatase	1
V5, N2H, Aspartate Aminotransferase	6
V5, N2H, Gamma-glutamyl transferase	4
V5, N2H, Glucose (blood)	1
V5, N2H, HDL-Cholesterol	2
V5, N2H, Prolactin	1
V5, N2H, Sodium	1
V5, N2H, Total Bilirubin (blood)	1
V5, N2H, Triglycerides	3
V6, N2L, Alkaline Phosphatase	3
V6, N2L, Apsartate Aminotransferase	1
V6, N2L, Clacium	2
V6, N2L, HDL-Cholesterol	1
V6, N2L, Sodium	1
V6, N2L, Total Bilirubin (blood)	4
V6, N2L, Total Protein (blood)	2
V6, N2H, Alanine Aminotransferase	9
V6, N2H, Alkaline Phosphatase	1
V6, N2H, Aspartate Aminotransferase	7
V6, N2H, Gamma-glutamyl Tansferase	4
V6, N2H, Glucose (blood)	1
V6, N2H, HDL-Cholesterol	1
V6, N2H, Sodium	1
V6, N2H, Triglycerides	3
V7, N2L, Alkaline Phosphatase	4
V7, N2L, Sodium	1
V7, N2L, Total Bilirubin (blood)	3
V7, N2L, Total Protein (blood)	4
V7, N2L, Urea Nitrogen	2
V7, N2H, Alanine Aminotransferase	5
V7, N2H, Aspartate Aminotransferase	1
V7, N2H, Gamma-glutamyl Transferase	2
V7, N2H, Glucose (blood)	1
V7, N2H, HDL-Cholesterol	2
V7, N2H, Sodium	1
V7, N2H, Triglycerides	1
V8, N2L, Alkaline Phosphatase	5
V8, N2L, Aspartate Aminotransferase	1
V8, N2L, Calcium	1
V8, N2L, Sodium	2
V8, N2L, Total Bilirubin (blood)	2
V8, N2L, Total Protein (blood)	2
V8, N2H, Alanine Aminotransferase	3
V8, N2H, Aspartate Aminotransferase	2
V8, N2H, Gamma-glutamyl Transferase	1
V8, N2H, Glucose (blood)	1
V8, N2H, HDL-Cholesterol	1
V8, N2H, Triglycerides	1
V8, N2H, Urea Nitrogen	2
V9, N2L, Alkaline Phospatase	1
V9, N2L, Calcium	1
V9, N2L, HDL-Cholesterol	1
V9, N2L, Total Bilirubin (blood)	3
V9, N2L, Total Protein (blood)	1
V9, N2H, Alanine Aminotransferase	3
V9, N2H, Aspartate Aminotransferase	1
V9, N2H, Gamma-glutamyl Transferase	1
V9, N2H, HDL-Cholesterol	1
V9, N2H, Prolactin	1
V9, N2H, Total Bilirubin (blood)	1
V9, N2H, Triglycerides	2
V10, N2L, Alkaline Phosphatase	1
V10, N2L, Sodium	1
V10, N2L, Total Bilirubin (blood)	1
V10, N2L, Total Protein (blood)	1
V10, N2H, Alanine Aminotransferase	1
V10, N2H, Aspartate Aminotransferase	1
V10, N2H, Gamma-glutamyl Transferase	1
V10, N2H, Total Bilirubin (blood)	1
V10, N2H, Triglycerides	3
V11, N2L, Alkaline Phosphatase	4
V11, N2L, Aspartate Phosphatase	1
V11, N2L, Calcium	3
V11, N2L, Creatine (Jaffe)	1
V11, N2L, HDL-Cholesterol	1
V11, N2L, Sodium	1
V11, N2L, Total Bilirubin (blood)	4
V11, N2L, Total Protein (blood)	3
V11, N2L, Urea Nitrogen	1
V11, N2H, Alanine Aminotransferase	5
V11, N2H, Aspartate Amintransferase	3
V11, N2H, Gamma-glutamyl Transferase	5
V11, N2H, HDL-Cholesterol	3
V11, N2H, Potassium	1
V11, N2H, Prolactin	2
V11, N2H, Triglycerides	2
V11, N2H, Urea Nitrogen	1
V12, N2L, Alkaline Phosphatase	1
V12, N2L, Aspartate Aminotransferase	1
V12, N2L, Calcium	2
V12, N2L, Total Bilirubin (blood)	3
V12, N2L, Total Protein (blood)	1
V12, N2L, Urea Nitrogen	1
V12, N2H, Alanine Aminotransferase	3
V12, N2H, Aspartate Aminotransferase	3
V12, N2H, Gamma-glutamyl Transferase	1

Notes
[29] - Safety Analysis Set

No statistical analyses for this end point

Primary: OLE: Number of subjects with shifts from normal in urinalysis laboratory values

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End point title

OLE: Number of subjects with shifts from normal in urinalysis laboratory values ^[30]

End point description

Results are categorized by the number of subjects with a shift from normal to low (N2L) or normal to high (N2H). The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Primary

End point timeframe

Day 40 to Day 372

Notes
[30] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for this endpoint.

End point values	STP/VPA + GWP42003-P
Number of subjects analysed	30 ^[31]
Units: subjects
N2L	0
N2H	0

Notes
[31] - Safety Analysis Set

No statistical analyses for this end point

Primary: OLE: Number of subjects with physical examination findings indicative of an adverse event

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End point title

OLE: Number of subjects with physical examination findings indicative of an adverse event ^[32]

End point description

Subjects were assessed for adverse events during physical examinations at every visit. The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Primary

End point timeframe

Day 40 to Day 372

Notes
[32] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for this endpoint.

End point values	STP/VPA + GWP42003-P
Number of subjects analysed	30 ^[33]
Units: subjects	0

Notes
[33] - Safety Analysis Set

No statistical analyses for this end point

Primary: OLE: Number of subjects with vital sign findings indicative of an adverse event

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End point title

OLE: Number of subjects with vital sign findings indicative of an adverse event ^[34]

End point description

Subjects were assessed for adverse events relating to vital signs at every visit. The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Primary

End point timeframe

Day 40 to Day 372

Notes
[34] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for this endpoint.

End point values	STP/VPA + GWP42003-P
Number of subjects analysed	30 ^[35]
Units: subjects	0

Notes
[35] - Safety Analysis Set

No statistical analyses for this end point

Primary: OLE: Number of subjects with 12-electrocardiogram (ECG) findings indicative of an adverse event

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End point title

OLE: Number of subjects with 12-electrocardiogram (ECG) findings indicative of an adverse event ^[36]

End point description

After 5 minutes in a supine position, subjects were assessed for adverse events related to their 12-ECG results. The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Primary

End point timeframe

Day 40 to Day 372

Notes
[36] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for this endpoint.

End point values	STP/VPA + GWP42003-P
Number of subjects analysed	30 ^[37]
Units: subjects	1

Notes
[37] - Safety Analysis Set

No statistical analyses for this end point

Primary: OLE: Number of subjects with a positive response to questions regarding suicidal behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS)

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End point title

OLE: Number of subjects with a positive response to questions regarding suicidal behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS) ^[38]

End point description

The C-SSRS questionnaire is a brief, standardized measure that uniquely assesses the essential information (behavior, ideation, lethality, and severity) and distinguishes between suicidal occurrences and non-suicidal self-injury. The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Primary

End point timeframe

Day 40 to Day 372

Notes
[38] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for this endpoint.

End point values	STP/VPA + GWP42003-P
Number of subjects analysed	30 ^[39]
Units: subjects	0

Notes
[39] - Safety Analysis Set

No statistical analyses for this end point

Primary: OLE: Change from Baseline in seizure frequency

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End point title

OLE: Change from Baseline in seizure frequency ^[40]

End point description

Subjects recorded seizures in a dairy throughout the trial. Seizure frequency was defined as the total number of seizures divided by the total number of reported days in the subject's diary. Any intermittent missing data for the number of seizures arising from unreported days in the diary were not imputed. Negative changes represent a decrease in frequency. Positive changes represent an increase in frequency. The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Primary

End point timeframe

Day 40 to Day 372

Notes
[40] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for this endpoint.

End point values	STP/VPA + GWP42003-P
Number of subjects analysed	22 ^[41]
Units: subjects
Change from Baseline, >25% increase	8
Change from Baseline, -25% to 25% (no change)	4
Change from Baseline, 25% to 50% decrease	6
Change from Baseline, 50% to 75% decrease	3
Change from Baseline, >75% decrease	1

Notes
[41] - Safety Analysis Set. Only participants with available data were analyzed.

No statistical analyses for this end point

Primary: OLE: Number of subjects abusing IMP

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End point title

OLE: Number of subjects abusing IMP ^[42]

End point description

Two types of events triggered the discussion of abuse potential with subjects - triggering AEs of special interest and/or drug accountability inconsistencies. A questionnaire was provided based on the triggering event and each case was reviewed by the Abuse Adjudication Committee. The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Primary

End point timeframe

Day 40 to Day 372

Notes
[42] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for this endpoint.

End point values	STP/VPA + GWP42003-P
Number of subjects analysed	30 ^[43]
Units: subjects	0

Notes
[43] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: DN Cmax of 4-ene-VPA, CLB, N-CLB, LEV and TPM

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End point title

Double Blind: DN Cmax of 4-ene-VPA, CLB, N-CLB, LEV and TPM

End point description

Cmax is the maximum measured plasma concentration. Blood samples were collected for PK analysis predose, 15 and 30 minutes, then 1, 1.5, 2, 4, 6, and 12 hours postdose. 998=a geometric coefficient of variation cannot be calculated for a single participant. 999=No analysis was conducted for this treatment arm at this time point. A subject may not have taken all anti-epileptic drugs. n=number of subjects with evaluable data. The PK anaylsis set includes all subjects enrolled in the trial who received at least 1 dose of GWP42003-P or placebo and who provided some on-treatment data.

End point type

Secondary

End point timeframe

Day 1 and Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[44]	2 ^[45]	12 ^[46]	3 ^[47]
Units: ng/mL/mg
geometric mean (geometric coefficient of variation)
4-ene-VPA Day 1 n=3,0,12,3	0.144 ( 27.0 )	999 ( 999 )	0.253 ( 102.7 )	0.226 ( 39.0 )
4-ene-VPA Day 26 n=2,0,10,3	0.129 ( 36.4 )	999 ( 999 )	0.182 ( 89.5 )	0.19 ( 45.0 )
CLB Day 1 n=4,0,3,0	61.5 ( 33.3 )	999 ( 999 )	25.9 ( 53.5 )	999 ( 999 )
CLB Day 26 n=3,0,3,0	73.4 ( 42.6 )	999 ( 999 )	28.2 ( 44.3 )	999 ( 999 )
N-CLB Day 1 n=4,0,3,0	508 ( 66.1 )	999 ( 999 )	71.6 ( 76.4 )	999 ( 999 )
N-CLB Day 26 n=3,0,3,0	790 ( 36.7 )	999 ( 999 )	292 ( 57.0 )	999 ( 999 )
LEV Day 1 n=0,1,0,0	999 ( 999 )	31.6 ( 998 )	999 ( 999 )	999 ( 999 )
LEV Day 26 n=0,1,0,0	999 ( 999 )	38.9 ( 998 )	999 ( 999 )	999 ( 999 )
TPM Day 1 n=2,0,1,0	65.1 ( 34.0 )	999 ( 999 )	87.7 ( 998 )	999 ( 999 )
TPM Day 26 n=2,0,1,0	60.7 ( 35.2 )	999 ( 999 )	738 ( 998 )	999 ( 999 )

Notes
[44] - PK Analysis Set
[45] - PK Analysis Set
[46] - PK Analysis Set
[47] - PK Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: tmax of 4-ene-VPA, CLB, N-CLB, LEV and TPM

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End point title

Double Blind: tmax of 4-ene-VPA, CLB, N-CLB, LEV and TPM

End point description

tmax is the time to the maximum measured plasma concentration. Blood samples were collected for PK analysis predose, 15 and 30 minutes, then 1, 1.5, 2, 4, 6, and 12 hours postdose. 998=a geometric coefficient of variation cannot be calculated for a single participant. 999=No analysis was conducted for this treatment arm at this time point. A subject may not have taken all anti-epileptic drugs. n=number of subjects with evaluable data. The PK anaylsis set includes all subjects enrolled in the trial who received at least 1 dose of GWP42003-P or placebo and who provided some on-treatment data.

End point type

Secondary

End point timeframe

Day 1 and Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[48]	2 ^[49]	12 ^[50]	3 ^[51]
Units: hours
median (full range (min-max))
4-ene-VPA Day 1 n=3,0,12,3	0.50 (0.25 to 4.03)	999 (999 to 999)	6.00 (0.25 to 12.48)	5.92 (4.00 to 6.00)
4-ene-VPA Day 26 n=2,0,10,3	3.67 (1.50 to 5.83)	999 (999 to 999)	1.73 (0.00 to 11.50)	3.85 (0.00 to 6.00)
CLB Day 1 n=4,0,3,0	5.06 (1.52 to 11.02)	999 (999 to 999)	2.33 (1.00 to 4.00)	999 (999 to 999)
CLB Day 26 n=3,0,3,0	6.03 (2.07 to 10.97)	999 (999 to 999)	1.00 (0.92 to 4.00)	999 (999 to 999)
N-CLB Day 1 n=4,0,3,0	5.03 (0.00 to 6.08)	999 (999 to 999)	1.50 (0.00 to 4.00)	999 (999 to 999)
N-CLB Day 26 n=3,0,3,0	2.00 (0.53 to 10.90)	999 (999 to 999)	4.00 (0.00 to 6.00)	999 (999 to 999)
LEV Day 1 n=0,1,0,0	999 (999 to 999)	1.00 (1.00 to 1.00)	999 (999 to 999)	999 (999 to 999)
LEV Day 26 n=0,1,0,0	999 (999 to 999)	1.00 (1.00 to 1.00)	999 (999 to 999)	999 (999 to 999)
TPM Day 1 n=2,0,1,0	3.04 (2.08 to 4.00)	999 (999 to 999)	1.50 (1.50 to 1.50)	999 (999 to 999)
TPM Day 26 n=2,0,0,0	2.03 (2.00 to 2.07)	999 (999 to 999)	999 (999 to 999)	999 (999 to 999)

Notes
[48] - Safety Analysis Set
[49] - Safety Analysis Set
[50] - Safety Analysis Set
[51] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: DN AUCtau of 4-ene-VPA, CLB, N-CLB, LEV and TPM

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End point title

Double Blind: DN AUCtau of 4-ene-VPA, CLB, N-CLB, LEV and TPM

End point description

End point type

Secondary

End point timeframe

Day 1 and Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[52]	2 ^[53]	12 ^[54]	3 ^[55]
Units: ngxh/mL/mg
geometric mean (geometric coefficient of variation)
4-ene-VPA Day 1 n=3,0,12,3	1.34 ( 21.0 )	999 ( 999 )	2.54 ( 104.8 )	2.35 ( 42.3 )
4-ene-VPA Day 26 n=2,0,10,3	1.23 ( 40.4 )	999 ( 999 )	1.7 ( 103.3 )	1.86 ( 42.2 )
CLB Day 1 n=4,0,3,0	567 ( 38.1 )	999 ( 999 )	219 ( 61.3 )	999 ( 999 )
CLB Day 26 n=3,0,3,0	692 ( 42.4 )	999 ( 999 )	277 ( 47.7 )	999 ( 999 )
N-CLB Day 1 n=4,0,3,0	5100 ( 63.5 )	999 ( 999 )	744 ( 65.0 )	999 ( 999 )
N-CLB Day 26 n=3,0,3,0	7710 ( 35.5 )	999 ( 999 )	3200 ( 49.9 )	999 ( 999 )
LEV Day 1 n=0,1,0,0	999 ( 999 )	222 ( 999 )	999 ( 999 )	999 ( 999 )
LEV Day 26 n=0,0,0,0	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )
TPM Day 1 n=2,0,1,0	658 ( 29.9 )	999 ( 999 )	738 ( 999 )	999 ( 999 )
TPM Day 26 n=2,0,0,0	597 ( 27.6 )	999 ( 999 )	999 ( 999 )	999 ( 999 )

Notes
[52] - PK Analysis Set
[53] - PK Analysis Set
[54] - PK Analysis Set
[55] - PK Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: Number of subjects with Cytochrome P450 (CYP450) isoforms

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End point title

Double Blind: Number of subjects with Cytochrome P450 (CYP450) isoforms ^[56]

End point description

Genetic testing was only conducted if specific consent was obtained from the patient or their legal representative. There was a separate ICF for this testing. Genetic testing was conducted to look at sequencing CYP450 isoforms, with particular focus on CYP2C19 and CYP3A4, involved in the metabolism of AEDs and CBD. The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Secondary

End point timeframe

Day 1

Notes
[56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Quantitative statistical analysis (for example, a p-value) was not performed for this endpoint.

End point values	STP + GWP42003-P	VPA + GWP42003-P
Number of subjects analysed	12 ^[57]	16 ^[58]
Units: subjects
CYP3A4, Poor Metabolizer	0	0
CYP3A4, Intermediate Metabolizer	1	0
CYP3A4, Extensive Metabolizer	13	16
CYP3A4, Ultraraoid Metabolizer	0	0
CYP3A4, Undetermined	0	0
CYP3A4, Missing	0	3
CYP2C19, Poor Metabolizer	0	2
CYP2C19, Intermediate Metabolizer	4	4
CYP2C19, Extensive Metabolizer	6	5
CYP2C19, Ultrarapid Metabolizer	4	4
CYP2C19, Undetermined	0	1
CYP2C19, Missing	0	3

Notes
[57] - Safety Analysis Set
[58] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: Number of subjects with adverse events

Top of page

End point title

Double Blind: Number of subjects with adverse events

End point description

End point type

Secondary

End point timeframe

Day 1 to Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[59]	2 ^[60]	16 ^[61]	4 ^[62]
Units: subjects
Gastrointestinal Disorders, All-causality	6	0	11	0
Gastrointestinal Disorders, Treatment-related	6	0	11	0
General Disorders, All-causality	3	0	1	0
General Disorders, Treatment-related	3	0	0	0
Investigations, All-causality	2	0	2	0
Investigations, Treatment-related	2	0	2	0
Metabolic Disorders, All-causality	2	0	1	0
Metabolic Disorders, Treatment-related	2	0	1	0
Psychiatric Disorders, All-causality	2	0	1	0
Psychiatric, Treatment-related	2	0	1	0
Infections, All-causality	1	0	3	1
Infections, Treatment-related	0	0	0	0
Injury/Procedural Complications, All-causality	1	0	1	0
Injury/Procedural Complications, Treatment-related	0	0	0	0
Skin Disorders, All-causality	1	0	1	0
Skin Disorders, Treatment-related	1	0	0	0
Nervous System Disorders, All-causality	0	0	2	0
Nervous System Disorders, Treatment-related	0	0	2	0
Hepatobiliary Disorders, All-causality	0	0	1	0
Hepatobiliary Disorders, Treatment-related	0	0	1	0
Vascular Disorders, All-causality	0	0	1	0
Vascular Disorders, Treatment-related	0	0	1	0

Notes
[59] - Safety Analysis Set
[60] - Safety Analysis Set
[61] - Safety Analysis Set
[62] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: Number of subjects with shifts from normal in hematology laboratory values

Top of page

End point title

Double Blind: Number of subjects with shifts from normal in hematology laboratory values

End point description

End point type

Secondary

End point timeframe

Day 1 to Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[63]	2 ^[64]	16 ^[65]	4 ^[66]
Units: subjects
V3, N2L, Neutrophils (%)	0	0	1	0
V3, N2L, Red Blood Cell Count	2	0	0	1
V3, N2L, Hematocrit	2	1	0	0
V3, N2L, Lymphocytes (%)	2	0	0	0
V3, N2H, Absolute Monocyte Count	1	0	1	2
V3, N2H, Lymphocytes (%)	0	0	2	0
V3, N2H, Absolute Neutrophil Count	1	0	0	0
V3, N2H, Eosinophils (%)	0	1	0	0
V3, N2H, Neutrophils (%)	2	0	0	0
V3, N2H, White Blood Cell Count with Differential	1	0	0	0
V4, N2L, Absolute Neutrophil Count	1	0	1	0
V4, N2L, Hematocrit	1	0	1	0
V4, N2L, Hemoglobin	1	0	0	0
V4, N2L, Lymphoblasts	1	0	1	0
V4, N2L, Lymphocytes (%)	3	0	0	0
V4, N2L, Neutrophils (%)	3	0	2	1
V4, N2L, Platelets	1	0	0	0
V4, N2L, Red Blood Cell Count	1	0	0	1
V4, N2L, White Blood Cell Count with Differential	1	0	0	0
V4, N2H, Absolute Eosinophil Count	1	0	1	0
V4, N2H, Absolute Monocyte Count	2	0	0	1
V4, N2H, Eosinophils (%)	3	0	2	0
V4, N2H, Lymphoblasts	1	0	0	0
V4, N2H, Lymphocytes (%)	2	0	3	0
V4, N2H, Neutrophils (%)	1	0	0	1
V4, N2H, Monocytes (%)	0	0	1	0
V5, N2H, Eosinophils (%)	1	0	0	0

Notes
[63] - Safety Analysis Set
[64] - Safety Analysis Set
[65] - Safety Analysis Set
[66] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: Number of subjects with shifts from normal in biochemistry laboratory values

Top of page

End point title

Double Blind: Number of subjects with shifts from normal in biochemistry laboratory values

End point description

End point type

Secondary

End point timeframe

Day 1 to Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[67]	2 ^[68]	16 ^[69]	4 ^[70]
Units: subjects
V3, N2L, Total Bilirubin (blood)	2	1	1	1
V3, N2L, Total Protein (blood)	1	0	0	0
V3, N2L, Calcium	0	0	1	0
V3, N2L, Creatinine (Jaffe)	0	0	2	0
V3, N2L, HDL-Cholesterol	0	0	1	0
V3, N2L, Sodium	0	0	2	0
V3, N2H, ALT	1	0	1	0
V3, N2H, GGT	0	0	1	0
V3, N2H, Prolactin	0	0	0	1
V3, N2H, Total Bilirubin (blood)	0	0	1	0
V3, N2H, Triglycerides	0	0	1	0
V3, N2H, AST	1	0	0	0
V4, N2L, Alkaline Phosphatase	2	0	0	1
V4, N2L, Calcium	0	0	3	0
V4, N2L, Creatinine (Jaffe)	0	0	1	0
V4, N2L, Sodium	1	0	1	0
V4, N2L, Total Bilirubin (blood)	2	0	2	1
V4, N2L, Total Protein (blood)	0	0	1	0
V4, N2L, HDL-Cholesterol	1	0	0	0
V4, N2L, Urea Nitrogen	1	0	0	0
V4, N2H, ALT	2	0	5	0
V4, N2H, AST	2	0	3	1
V4, N2H, GGT	1	0	2	0
V4, N2H, HDL-Cholesterol	0	0	1	1
V4, N2H, Potassium	0	0	1	0
V4, N2H, Prolactin	1	0	0	1
V4, N2H, Sodium	0	0	0	1
V4, N2H, Total Bilirubin (blood)	0	0	1	0
V4, N2H, Alkaline Phosphatase	1	0	0	0
V4, N2H, Triglycerides	1	0	0	0
V5, N2H, ALT	1	0	0	0

Notes
[67] - Safety Analysis Set
[68] - Safety Analysis Set
[69] - Safety Analysis Set
[70] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: Number of subjects with shifts from normal in urinalysis laboratory values

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End point title

Double Blind: Number of subjects with shifts from normal in urinalysis laboratory values

End point description

End point type

Secondary

End point timeframe

Day 1 to Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[71]	2 ^[72]	16 ^[73]	4 ^[74]
Units: subjects
N2L	0	0	0	0
N2H	0	0	0	0

Notes
[71] - Safety Analysis Set
[72] - Safety Analysis Set
[73] - Safety Analysis Set
[74] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: Number of subjects with physical examination findings indicative of an adverse event

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End point title

Double Blind: Number of subjects with physical examination findings indicative of an adverse event

End point description

Subjects were assessed for adverse events during physical examinations at every visit. The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Secondary

End point timeframe

Day 1 to Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[75]	2 ^[76]	16 ^[77]	4 ^[78]
Units: subjects	0	0	0	0

Notes
[75] - Safety Analysis Set
[76] - Safety Analysis Set
[77] - Safety Analysis Set
[78] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: Number of subjects with vital sign findings indicative of an adverse event

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End point title

Double Blind: Number of subjects with vital sign findings indicative of an adverse event

End point description

Subjects were assessed for adverse events relating to vital signs at every visit. The safety analysis set includes all subjects who received at least 1 dose of GWP42003-P or placebo.

End point type

Secondary

End point timeframe

Day 1 to Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[79]	2 ^[80]	16 ^[81]	4 ^[82]
Units: subjects	0	0	0	0

Notes
[79] - Safety Analysis Set
[80] - Safety Analysis Set
[81] - Safety Analysis Set
[82] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: Number of subjects with 12-ECG findings indicative of an adverse event

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End point title

Double Blind: Number of subjects with 12-ECG findings indicative of an adverse event

End point description

End point type

Secondary

End point timeframe

Day 1 to Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[83]	2 ^[84]	16 ^[85]	4 ^[86]
Units: subjects	0	0	0	0

Notes
[83] - Safety Analysis Set
[84] - Safety Analysis Set
[85] - Safety Analysis Set
[86] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: Number of subjects with a positive response to questions regarding suicidal behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS)

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End point title

Double Blind: Number of subjects with a positive response to questions regarding suicidal behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS)

End point description

End point type

Secondary

End point timeframe

Day 1 to Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[87]	2 ^[88]	16 ^[89]	4 ^[90]
Units: subjects	0	0	0	0

Notes
[87] - Safety Analysis Set
[88] - Safety Analysis Set
[89] - Safety Analysis Set
[90] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: Change from Baseline in seizure frequency

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End point title

Double Blind: Change from Baseline in seizure frequency

End point description

End point type

Secondary

End point timeframe

Day 1 to Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[91]	2 ^[92]	16 ^[93]	4 ^[94]
Units: subjects
Change from Baseline, >25% increase	2	0	4	1
Change from Baseline, -25% to 25% (no change)	3	0	3	1
Change from Baseline, 25% to 50% decrease	3	0	0	1
Change from Baseline, 50% to 75% decrease	2	0	3	0
Change from Baseline, >75% decrease	0	0	2	1

Notes
[91] - Safety Analysis Set
[92] - Safety Analysis Set
[93] - Safety Analysis Set
[94] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: Number of subjects abusing IMP

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End point title

Double Blind: Number of subjects abusing IMP

End point description

End point type

Secondary

End point timeframe

Day 1 to Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	12 ^[95]	2 ^[96]	16 ^[97]	4 ^[98]
Units: subjects	0	0	0	0

Notes
[95] - Safety Analysis Set
[96] - Safety Analysis Set
[97] - Safety Analysis Set
[98] - Safety Analysis Set

No statistical analyses for this end point

Secondary: Double Blind: AUC(0-t) of 4-ene-VPA, CLB, N-CLB, LEV and TPM

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End point title

Double Blind: AUC(0-t) of 4-ene-VPA, CLB, N-CLB, LEV and TPM

End point description

All the calculations were to be based on the first dosing period (tau); thus, analysis of AUC(0-t) was no longer planned.

End point type

Secondary

End point timeframe

Day 1 and Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	0 ^[99]	0 ^[100]	0 ^[101]	0 ^[102]
Units: ngxh/mL/mg
geometric mean (geometric coefficient of variation)	( )	( )	( )	( )

Notes
[99] - Analysis of this endpoint was not conducted.
[100] - Analysis of this endpoint was not conducted.
[101] - Analysis of this endpoint was not conducted.
[102] - Analysis of this endpoint was not conducted.

No statistical analyses for this end point

Secondary: Double Blind: AUC(0-t) for STP, VPA and CBD

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End point title

Double Blind: AUC(0-t) for STP, VPA and CBD

End point description

All the calculations were to be based on the first dosing period (tau); thus, analysis of AUC(0-t) was no longer planned.

End point type

Secondary

End point timeframe

Day 1 and Day 26

End point values	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo
Number of subjects analysed	0 ^[103]	0 ^[104]	0 ^[105]	0 ^[106]
Units: ngxh/mL/mg
geometric mean (geometric coefficient of variation)	( )	( )	( )	( )

Notes
[103] - Analysis of this endpoint was not conducted.
[104] - Analysis of this endpoint was not conducted.
[105] - Analysis of this endpoint was not conducted.
[106] - Analysis of this endpoint was not conducted.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

up to Day 418

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

STP + GWP42003-P

Reporting group description

Reporting group title

STP + Placebo

Reporting group description

Reporting group title

VPA + GWP42003-P

Reporting group description

Reporting group title

VPA + Placebo

Reporting group description

Reporting group title

STP/VPA + GWP42003-P

Reporting group description

Serious adverse events	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo	STP/VPA + GWP42003-P
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 12 (8.33%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	5 / 30 (16.67%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	3 / 30 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	3 / 30 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eosinophil count increased
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Status epilepticus
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	2 / 30 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	2 / 30 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hypertransaminasaemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 12 (8.33%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypophagia
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	STP + GWP42003-P	STP + Placebo	VPA + GWP42003-P	VPA + Placebo	STP/VPA + GWP42003-P
Total subjects affected by non serious adverse events
subjects affected / exposed	8 / 12 (66.67%)	0 / 2 (0.00%)	14 / 16 (87.50%)	1 / 4 (25.00%)	25 / 30 (83.33%)
Vascular disorders
Peripheral coldness
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Reproductive system and breast disorders
Gynaecomastia
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Psychiatric disorders
Aggression
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Apathy
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	2
Binge eating
subjects affected / exposed	1 / 12 (8.33%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	2	0	0	0	0
Bradyphrenia
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	1	0	1
Irritability
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	3 / 30 (10.00%)
occurrences all number	0	0	0	0	6
Listless
subjects affected / exposed	1 / 12 (8.33%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
Personality disorder
subjects affected / exposed	1 / 12 (8.33%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
Stubbornness
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 12 (16.67%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	2	0	1	0	1
Ammonia increased
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Aspartate aminotransferase increased
subjects affected / exposed	2 / 12 (16.67%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	2	0	0	0	0
Bacterial test positive
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	2
Weight decreased
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	1	0	2
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Eyelid contusion
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Face injury
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0
Stoma site reaction
subjects affected / exposed	1 / 12 (8.33%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	1	0	2
Drooling
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Dysarthria
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	3
Head titubation
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0
Seizure
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	5 / 30 (16.67%)
occurrences all number	0	0	1	0	5
Somnolence
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	1	0	3
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Eye disorders
Eczema eyelids
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Eyelid haematoma
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Gastrointestinal disorders
Abnormal faeces
subjects affected / exposed	1 / 12 (8.33%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
Constipation
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Diarrhoea
subjects affected / exposed	5 / 12 (41.67%)	0 / 2 (0.00%)	11 / 16 (68.75%)	0 / 4 (0.00%)	17 / 30 (56.67%)
occurrences all number	6	0	22	0	60
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	2
Nausea
subjects affected / exposed	2 / 12 (16.67%)	0 / 2 (0.00%)	2 / 16 (12.50%)	0 / 4 (0.00%)	2 / 30 (6.67%)
occurrences all number	3	0	2	0	2
Salivary hypersecretion
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Vomiting
subjects affected / exposed	1 / 12 (8.33%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0
Fatigue
subjects affected / exposed	3 / 12 (25.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	4 / 30 (13.33%)
occurrences all number	3	0	0	0	4
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	2
Eczema
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Erythema
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Rash
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0
Skin lesion
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Pain in extremity
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	2
Infections and infestations
Nasopharyngitis
subjects affected / exposed	1 / 12 (8.33%)	0 / 2 (0.00%)	2 / 16 (12.50%)	0 / 4 (0.00%)	2 / 30 (6.67%)
occurrences all number	1	0	2	0	4
Pharyngitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	1 / 4 (25.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	1	0
Pneumonia
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Respiratory tract infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	2
Upper respiratory tract infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1
Viral infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 12 (16.67%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	2	0	1	0	1
Fluid intake reduced
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0
Increased appetite
subjects affected / exposed	0 / 12 (0.00%)	0 / 2 (0.00%)	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1

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Were there any global substantial amendments to the protocol? Yes

20 Jul 2016

• All subjects were required to remain in the clinic for at least 30 minutes following administration of GWP42003-P at Visit 2 (Day 2) and Visit 4 (Day 27) to monitor for any adverse reactions, as this may have been the first exposure to the trial drug; • PK analysis of plasma levels of 4-ene-VPA was carried out along with AED (antiepileptic drugs) tests. No further blood sampling would be required in order to perform this analysis; • Clarification on the order of PK samples with respect to dosing of AEDs or IMP; • Sites (or caregiver, where appropriate) were required to record the times at which patients were fed at Visit 2 (Day 2) and Visit 4 (Day 27) for PK purposes; • Visits were provided in weeks rather than months for clarity; • Addition of exclusion criterion: Patient has a prolonged QTcB (the QT interval corrected for heart rate with Bazett correction) (> 450 msec for males and > 470 msec for females) [if right bundle branch block is present, QTcB limit is > 480 msec]. Exclusion criterion was added as a safety precaution as a formal QTc (QT interval corrected for heart rate) trial had not yet been completed with GWP42003-P; • Addition of withdrawal criterion: Significant change from baseline 12-lead electrocardiogram (ECG) in QTcB (> 60 msec) or absolute QTcB of > 500 msec. If right bundle branch block is present, absolute QTcB is 520 msec. Withdrawal criterion was added as a safety precaution as a formal QTc trial has not yet been completed with GWP42003-P; • The clinical trial GWEP1332 Part A Data Safety Monitoring Committee recommended dose has been amended from 25 mg/kg to 20 mg/kg due to an error in the original protocol.

20 Jul 2016

• The titration of dose increases above 20 mg/kg/day was changed. Dose increases were recommended to be done slowly, with maximum increments of 2.5 mg/kg every 5 to 7 days. The investigator could schedule additional clinic visits during the OLE period to facilitate dose adjustments. This change in requirement was added as a safety precaution; • A benefit/risk section was added to the protocol, as per regulatory guidelines, and additional references included as applicable; • The physical description of the IMP was updated to “clear, colorless to yellow”. • Additional text was added to clarify the process for confirming laboratory results for potential cases of drug-induced liver injury; • Additional text was added to clarify that instructions regarding IMP home storage requirements and dosing instructions would be provided to patients or their caregivers; • List of abbreviations was updated to include all abbreviations in the protocol; • References were updated to reflect the latest safety information; • Typographical, formatting, and consistency issues errors amended where applicable.

26 Jul 2016

• Due to an error in the previous protocol version, the exclusion and withdrawal criteria relating to prolonged QTcB (the QT interval corrected for heart rate with Bazett correction) and significant change from baseline 12-lead ECG in QTcB or absolute QTcB were updated for clarity.

11 May 2017

• The amount of Δ9-tetrahydrocannabinol in the IMP was more accurately described in the latest investigator’s brochure. It was previously stated to be 0.5%; however, in the oral solution, it is actually ≤ 0.15%; • Two pivotal phase 3 clinical trials had completed since the GWEP1447 protocol was written, so the rationale was updated to reflect this; • Protocol was updated with information from the latest Development Core Safety Information dated 17-FEB-17; • The blood sample for the 24-hour PK time point was removed as it does not provide any additional information that cannot be obtained from the 12-hour sample. Removing this PK sample eliminated the need for an overnight stay for the patients in the clinic or a return visit the next day. It also removed the additional blood draw burden on the patients and was anticipated to aid recruitment. This change affected various sections of the protocol, which were updated accordingly; • The 30-minute observation period after the first dose of GWP42003-P was removed. Based on experience from randomized clinical trials, there was no evidence for this requirement of additional monitoring of patients after the first dose of GWP42003-P; • The primary PK parameter AUC0-∞ was replaced with AUCtau. This is because the dosing was twice daily, and therefore, only AUCtau was required; no further information would be gained from the 24-hour time point; • As the 24-hour PK time point was removed, it would no longer be possible to accurately determine the t½ of the drug, so the t½ PK parameter was also removed; • Reference to CBD metabolites and THC and THC metabolites was removed as these have been fully characterized in other trials. CBD is the perpetrator drug in this trial, and therefore, only the parent drug needed to be reported and analyzed to check for compliance.

11 May 2017

• An update was added to allow database lock and analysis of either the VPA or STP arm first, if 1 arm completed recruitment before the other; • There were various sections throughout the GWEP1447 protocol and in the abbreviations that pertained only to clinical trials conducted in France. Since there was a France-specific protocol (GWEP1447 Version 5 28Jul16) for this trial, the text was removed; • The medical monitor that was listed had left GW, so the contact information for the new medical monitor was added. Also, to ensure that all relevant GW medical personnel were notified of any issues, the common medical monitor e-mail address was added.

04 Jun 2018

• The protocol provided for pregnancy testing at Visit 1 for females of childbearing potential. The amendment implemented additional monthly (4 weekly) pregnancy tests at clinic visits or at home throughout the blinded and open-label phases of the trial; • The sample size of the STP arm was reduced from 20 to 14 patients; • There was an error in the protocol because there was no objective linked to the secondary endpoint mentioned in the protocol. To correct this error, Section 1 (Protocol Synopsis) and Section 2.2 (Secondary Objectives) of the protocol were updated to include the following secondary objective: • To assess whether GWP42003-P affects the PK profile of 4-ene-VPA, CLB, N-CLB, LEV, TPM in patients also being treated with STP or VPA and other AEDs; • The classification of increased appetite was changed from “the most common adverse events (> 10% all-causality)” to “common (1-10%).”; • To accommodate the amended text, minor updates were made to the original text in other locations in the document to maintain internal consistency/style, and other typographical errors were amended where applicable.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 2, Double-blind, Randomized, Placebo-controlled, Pharmacokinetic Trial in Two Parallel Groups to Investigate Possible Drug-drug Interactions Between Stiripentol or Valproate and GWP42003-P in Patients with Epilepsy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Double Blind: Dose Normalized (DN) Cmax of STP and VPA

Primary: Double Blind: Dose Normalized (DN) Cmax of STP and VPA

Primary: Double Blind: DN Cmax of CBD

Primary: Double Blind: DN Cmax of CBD

Primary: Double Blind: tmax of STP, VPA and CBD

Primary: Double Blind: tmax of STP, VPA and CBD

Primary: Double Blind: DN AUCtau of STP and VPA

Primary: Double Blind: DN AUCtau of STP and VPA

Primary: Double Blind: DN AUCtau of CBD

Primary: Double Blind: DN AUCtau of CBD

Primary: OLE: Number of subjects with adverse events (AE)

Primary: OLE: Number of subjects with adverse events (AE)

Primary: OLE: Number of subjects with shifts from normal in hematology laboratory values

Primary: OLE: Number of subjects with shifts from normal in hematology laboratory values

Primary: OLE: Number of subjects with shifts from normal in biochemistry laboratory values

Primary: OLE: Number of subjects with shifts from normal in biochemistry laboratory values

Primary: OLE: Number of subjects with shifts from normal in urinalysis laboratory values

Primary: OLE: Number of subjects with shifts from normal in urinalysis laboratory values

Primary: OLE: Number of subjects with physical examination findings indicative of an adverse event

Primary: OLE: Number of subjects with physical examination findings indicative of an adverse event

Primary: OLE: Number of subjects with vital sign findings indicative of an adverse event

Primary: OLE: Number of subjects with vital sign findings indicative of an adverse event

Primary: OLE: Number of subjects with 12-electrocardiogram (ECG) findings indicative of an adverse event

Primary: OLE: Number of subjects with 12-electrocardiogram (ECG) findings indicative of an adverse event

Primary: OLE: Number of subjects with a positive response to questions regarding suicidal behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS)

Primary: OLE: Number of subjects with a positive response to questions regarding suicidal behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS)

Primary: OLE: Change from Baseline in seizure frequency

Primary: OLE: Change from Baseline in seizure frequency

Primary: OLE: Number of subjects abusing IMP

Primary: OLE: Number of subjects abusing IMP

Secondary: Double Blind: DN Cmax of 4-ene-VPA, CLB, N-CLB, LEV and TPM

Secondary: Double Blind: DN Cmax of 4-ene-VPA, CLB, N-CLB, LEV and TPM

Secondary: Double Blind: tmax of 4-ene-VPA, CLB, N-CLB, LEV and TPM

Secondary: Double Blind: tmax of 4-ene-VPA, CLB, N-CLB, LEV and TPM

Secondary: Double Blind: DN AUCtau of 4-ene-VPA, CLB, N-CLB, LEV and TPM

Secondary: Double Blind: DN AUCtau of 4-ene-VPA, CLB, N-CLB, LEV and TPM

Secondary: Double Blind: Number of subjects with Cytochrome P450 (CYP450) isoforms

Secondary: Double Blind: Number of subjects with Cytochrome P450 (CYP450) isoforms

Secondary: Double Blind: Number of subjects with adverse events

Secondary: Double Blind: Number of subjects with adverse events

Secondary: Double Blind: Number of subjects with shifts from normal in hematology laboratory values

Secondary: Double Blind: Number of subjects with shifts from normal in hematology laboratory values

Secondary: Double Blind: Number of subjects with shifts from normal in biochemistry laboratory values

Secondary: Double Blind: Number of subjects with shifts from normal in biochemistry laboratory values

Secondary: Double Blind: Number of subjects with shifts from normal in urinalysis laboratory values

Secondary: Double Blind: Number of subjects with shifts from normal in urinalysis laboratory values

Secondary: Double Blind: Number of subjects with physical examination findings indicative of an adverse event

Secondary: Double Blind: Number of subjects with physical examination findings indicative of an adverse event

Secondary: Double Blind: Number of subjects with vital sign findings indicative of an adverse event

Secondary: Double Blind: Number of subjects with vital sign findings indicative of an adverse event

Secondary: Double Blind: Number of subjects with 12-ECG findings indicative of an adverse event

Secondary: Double Blind: Number of subjects with 12-ECG findings indicative of an adverse event

Secondary: Double Blind: Number of subjects with a positive response to questions regarding suicidal behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS)

Secondary: Double Blind: Number of subjects with a positive response to questions regarding suicidal behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS)

Secondary: Double Blind: Change from Baseline in seizure frequency

Secondary: Double Blind: Change from Baseline in seizure frequency

Secondary: Double Blind: Number of subjects abusing IMP

Secondary: Double Blind: Number of subjects abusing IMP

Secondary: Double Blind: AUC(0-t) of 4-ene-VPA, CLB, N-CLB, LEV and TPM

Secondary: Double Blind: AUC(0-t) of 4-ene-VPA, CLB, N-CLB, LEV and TPM

Secondary: Double Blind: AUC(0-t) for STP, VPA and CBD

Secondary: Double Blind: AUC(0-t) for STP, VPA and CBD

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2, Double-blind, Randomized, Placebo-controlled, Pharmacokinetic Trial in Two Parallel Groups to Investigate Possible Drug-drug Interactions Between Stiripentol or Valproate and GWP42003-P in Patients with Epilepsy