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Clinical Trial Results:
A phase 2, double-blind, randomized, placebo-controlled study to investigate possible drug-drug interactions between clobazam and cannabidiol (GWP42003-P).

Summary
EudraCT number	2014-002942-33
Trial protocol	GB ES
Global end of trial date	07 Jun 2017

Results information
Results version number	v1(current)
This version publication date	06 Oct 2018
First version publication date	06 Oct 2018
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

GWEP1428

ISRCTN number

US NCT number

NCT02565108

WHO universal trial number (UTN)

Other trial identifiers

NCT02565108: NCT number for GWEP1428 Blinded Phase, NCT02564952: NCT Number for GWEP1428 Open-Label Extension

Sponsor organisation name

GW Research Ltd

Sponsor organisation address

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

Public contact

Alternate contact: medinfo@greenwichbiosciences.com, GW Research Ltd, medinfo@gwpharm.com

Scientific contact

Alternate contact: medinfo@greenwichbiosciences.com, 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?

Analysis stage

Final

Date of interim/final analysis

07 Jun 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

07 Jun 2017

Global end of trial reached?

Yes

Global end of trial date

07 Jun 2017

Was the trial ended prematurely?

Main objective of the trial

Period 1 (Double-Blind [DB] Phase): To determine whether GWP42003-P affects the pharmacokinetic (PK) profile of clobazam (CLB) and its primary metabolite N-desmethylclobazam (N-CLB). The primary completion date for the DB phase was 21-July-2016. Period 2 (Open-Label [OLE] Phase): To assess the long-term safety and tolerability of GWP42003-P in participants with epilepsy.

Protection of trial subjects

This study was conducted in accordance with International Council for Harmonisation Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which the study was conducted. No study procedures were performed on study candidates until written consent had been obtained from the participant. The informed consent form, protocol, and amendments for this study were submitted to and approved by the institutional review board or independent ethics committee at each participating study.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Jan 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

United Kingdom: 10

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

Participants had been clinically diagnosed with epilepsy and had been taking CLB and no more than 2 other antiepileptic drugs (AEDs) during the course of the study. Participant must have experienced at least 1 seizure of any type within the 2 months prior to randomization.

Period 1 title

Double-Blind (BL, trtmt, follow-up)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Period 1: GWP42003-P

Arm description

Participants received GWP42003-P 20 milligram (mg)/kilogram (kg)/day orally, twice daily immediately after their CLB dose. Participants titrated GWP42003-P to 20 mg/kg/day over 10 days and remained at this dose for the 21-day treatment period. Participants who then did not enter the OLE or withdrew early had a 10-day taper (10% per day) period. Participants who transferred to the OLE (still blinded at that stage) tapered off their GWP42003-P treatment by reducing their maintenance dose by 10% per day and concomitantly titrating GWP42003-P for the OLE. All participants (in the GWP42003-P and Placebo treatment groups) were on a stable dose of CLB at Baseline, administered either once or twice daily as per the physician’s preferred CLB dosing regimen for each participant, and continued taking CLB, as an Investigational Medicinal Product (IMP), for the duration of this study.

Arm type

Experimental

Investigational medicinal product name

GWP42003-P

Investigational medicinal product code

GWP42003-P

Other name

Epidiolex, Cannabidiol, CBD

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

GWP42003-P was presented as an oral solution containing 100 mg/milliliter (mL) cannabidiol (CBD) in the excipients sesame oil and anhydrous ethanol (79 mg/mL) with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).

Period 1: Placebo

Arm description

Participants received placebo (0 mg/mL GWP42003-P) orally, twice daily immediately after the participant’s CLB dose. Participants titrated the placebo dose over 10 days, followed by a 21-day treatment period. Participants who then did not enter the OLE or withdrew early had a 10-day taper (10% per day) period. Participants who transferred to the OLE (still blinded at that stage) tapered off their placebo treatment by reducing their maintenance dose by 10% per day and concomitantly titrating GWP42003-P for the OLE. All participants (in the GWP42003-P and Placebo treatment groups) were on a stable dose of CLB at Baseline, administered either once or twice daily as per the physician’s preferred CLB dosing regimen for each participant, and continued taking CLB, as an IMP, for the duration of this study.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Placebo control

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Placebo was presented as an oral solution containing 0 mg/mL CBD in the excipients sesame oil and anhydrous ethanol (79 mg/mL) with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).

Number of subjects in period 1	Period 1: GWP42003-P	Period 1: Placebo
Started	16	4
PK Set	10 ^[1]	3 ^[2]
Safety Set	16	4
Completed	14	4
Not completed	2	0
Withdrew Consent	1	-
Adverse event, non-fatal	1	-

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The GWP42003-P group had 16 participants start and 14 participants who completed the study. Of the 2 who did not complete the study, 1 withdrew consent and 1 was withdrawn from the study by the investigator due to a serious AE. The Safety Set included all 16 participants. The PK set included 10 participants (6 were excluded due to GWP42003-P and/or CLB dose modification, GWP42003-P or placebo discontinuation, discontinuation from the study, or incorrect dose administration).
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: There were 4 participants who started in the Placebo group, and 4 who completed the study. The Safety Set included all 4 participants. The PK set included 3 participants; 1 participant was excluded from the PK set because placebo was administered on Day 1, after predose sampling.

Period 2 title

Open-Label Extension

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Period 2: GWP42003-P

Arm description

Participants who transferred from the DB phase to the OLE (still blinded at that stage) tapered off their GWP42003-P or placebo treatment by reducing their maintenance dose by 10% per day and concomitantly titrating GWP42003-P to 20 mg/kg/day initially for the OLE; doses could then be adjusted up or down, dependent on investigator opinion, to a maximum of 30 mg/kg/day GWP42003-P. Participants were taking CLB upon entry into the OLE phase of the trial. CLB was not an IMP for the OLE phase and was not administered by the Sponsor. CLB was administered in line with the physician’s preferred CLB dosing regimen for each participant. CLB could be stopped, if clinically indicated, without impact on analysis.

Arm type

Experimental

Investigational medicinal product name

GWP42003-P up to a maximum of 30 mg/kg/day dose

Investigational medicinal product code

GWP42003-P

Other name

Epidiolex, Cannabidiol, CBD

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

GWP42003-P was presented as an oral solution containing 100 mg/mL CBD in the excipients sesame oil and anhydrous ethanol (79 mg/mL) with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).

Number of subjects in period 2	Period 2: GWP42003-P
Started	18
Received at Least 1 Dose of Study Drug	18
Completed OLE Titration Period	16
Completed	7
Not completed	11
Withdrawal by Participant	1
Adverse Event	6
Participant Withdrawn by Investigator	1
Participant Met Withdrawal Criteria	1
Low efficacy	1
Lost to follow-up	1

Baseline characteristics

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Reporting group title

Period 1: GWP42003-P

Reporting group description

Reporting group title

Period 1: Placebo

Reporting group description

Reporting group values	Period 1: GWP42003-P	Period 1: Placebo	Total
Number of subjects	16	4	20
Age categorical
Units: Subjects
Adults (18-64 years)	16	4	20
Age continuous
Units: years
arithmetic mean (standard deviation)	36.60 ( 8.51 )	37.57 ( 10.67 )	-
Gender categorical
Units: Subjects
Female	8	2	10
Male	8	2	10

Subject analysis set title

Safety Set

Subject analysis set type

Full analysis

Subject analysis set description

The safety set included all participants who received a dose of GWP42003-P or placebo.

Subject analysis sets values	Safety Set
Number of subjects	20
Age categorical
Units: Subjects
Adults (18-64 years)	20
Age continuous
Units: years
arithmetic mean (standard deviation)	36.79 ( 8.68 )
Gender categorical
Units: Subjects
Female	10
Male	10

End points

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Reporting group title

Period 1: GWP42003-P

Reporting group description

Reporting group title

Period 1: Placebo

Reporting group description

Reporting group title

Period 2: GWP42003-P

Reporting group description

Subject analysis set title

Safety Set

Subject analysis set type

Full analysis

Subject analysis set description

The safety set included all participants who received a dose of GWP42003-P or placebo.

Primary: Period 1: PK: Maximum Measured Plasma Concentration (Cmax) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

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End point title

Period 1: PK: Maximum Measured Plasma Concentration (Cmax) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33 ^[1]

End point description

The Cmax of CLB and its primary metabolite, N-CLB, was measured on Day 1 (before first GWP42003-P dose; participants were taking CLB only) and Day 33 (following 21 days of GWP42003-P or placebo maintenance treatment; participants were taking CLB and GWP42003-P or CLB and placebo). PK samples were taken at time points relative to the morning dose of CLB: Predose, 15 minutes (min), 30 min, 1 hour (h), 1.5 h, 2 h, 4 h, 6 h, 12 h, and 24 h. PK Set: All participants who received at least 1 dose of GWP42003-P or placebo, who had not reduced their CLB dose between Day 1 and Day 33, and who provided some on-treatment data. One participant in the placebo group was excluded from the PK set because placebo was administered on Day 1, after predose sampling. Six participants in the GWP42003-P group were excluded from the PK set due to GWP42003-P and/or CLB dose modification, GWP42003-P or placebo discontinuation, discontinuation from study, or incorrect dose administration.

End point type

Primary

End point timeframe

Predose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 12, and 24 h postdose on Days 1 and 33

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	Period 1: GWP42003-P	Period 1: Placebo
Number of subjects analysed	10	3
Units: nanograms (ng)/mL
geometric mean (geometric coefficient of variation)
Day 1 CLB	330 ( 40.4 )	440 ( 29.9 )
Day 33 CLB	329 ( 54.8 )	461 ( 102.3 )
Day 1 N-CLB	2060 ( 138.4 )	1130 ( 82.1 )
Day 33 N-CLB	4570 ( 54.0 )	1320 ( 134.1 )
Day 1 CLB Dose-normalized	19.3 ( 31.4 )	22.0 ( 29.9 )
Day 33 CLB Dose-normalized	19.2 ( 44.7 )	23.1 ( 102.3 )
Day 1 N-CLB Dose-normalized	121 ( 125.1 )	56.6 ( 82.1 )
Day 33 N-CLB Dose-normalized	267 ( 38.6 )	66.1 ( 134.1 )

No statistical analyses for this end point

Primary: Period 1: PK: Time To The Maximum Plasma Concentration (tmax) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

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End point title

Period 1: PK: Time To The Maximum Plasma Concentration (tmax) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33 ^[2]

End point description

The tmax of CLB and its primary metabolite, N-CLB, was measured on Day 1 (before first GWP42003-P dose; participants were taking CLB only) and Day 33 (following 21 days of GWP42003-P or placebo maintenance treatment; participants were taking CLB and GWP42003-P or CLB and placebo). PK samples were taken at time points relative to the morning dose of CLB: Predose, 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 12 h, and 24 h. PK Set: All participants who received at least 1 dose of GWP42003-P or placebo, who had not reduced their CLB dose between Day 1 and Day 33, and who provided some on-treatment data. One participant in the placebo group was excluded from the PK set because placebo was administered on Day 1, after predose sampling. Six participants in the GWP42003-P group were excluded from the PK set due to GWP42003-P and/or CLB dose modification, GWP42003-P or placebo discontinuation, discontinuation from study, or incorrect dose administration.

End point type

Primary

End point timeframe

Predose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 12, and 24 h postdose on Days 1 and 33

Notes
[2] - 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 (median and range).

End point values	Period 1: GWP42003-P	Period 1: Placebo
Number of subjects analysed	10	3
Units: hours
median (full range (min-max))
Day 1 CLB	1.00 (0.8 to 4.0)	1.17 (1.0 to 1.5)
Day 33 CLB	1.86 (0.5 to 4.0)	1.58 (1.5 to 2.0)
Day 1 N-CLB	1.50 (0.3 to 6.0)	2.00 (0.0 to 12.0)
Day 33 N-CLB	3.03 (0.0 to 11.1)	1.00 (0.3 to 2.0)

No statistical analyses for this end point

Primary: Period 1: PK: Area Under The Plasma Concentration Time Curve Over A Dosing Interval, Where Tau Is The Dosing Interval (AUCtau) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

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End point title

Period 1: PK: Area Under The Plasma Concentration Time Curve Over A Dosing Interval, Where Tau Is The Dosing Interval (AUCtau) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33 ^[3]

End point description

The AUCtau of CLB and its primary metabolite, N-CLB, was measured on Day 1 (before first GWP42003-P dose; participants were taking CLB only) and Day 33 (following 21 days of GWP42003-P or placebo maintenance treatment; participants were taking CLB and GWP42003-P or CLB and placebo). PK samples were taken at time points relative to the morning dose of CLB: Predose, 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 12 h, and 24 h. PK Set: All participants who received at least 1 dose of GWP42003-P or placebo, who had not reduced their CLB dose between Day 1 and Day 33, and who provided some on-treatment data. One participant in the placebo group was excluded from the PK set because placebo was administered on Day 1, after predose sampling. Six participants in the GWP42003-P group were excluded from the PK set due to GWP42003-P and/or CLB dose modification, GWP42003-P or placebo discontinuation, discontinuation from study, or incorrect dose administration.

End point type

Primary

End point timeframe

Predose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 12, and 24 h postdose on Days 1 and 33

Notes
[3] - 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	Period 1: GWP42003-P	Period 1: Placebo
Number of subjects analysed	10	3
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
Day 1 CLB	2690 ( 52.9 )	3320 ( 67.5 )
Day 33 CLB	2840 ( 46.2 )	3310 ( 102.5 )
Day 1 N-CLB	18300 ( 124.2 )	11400 ( 63.7 )
Day 33 N-CLB	48400 ( 53.9 )	11500 ( 79.1 )
Day 1 CLB Dose-normalized	157 ( 47.1 )	166 ( 67.5 )
Day 33 CLB Dose-normalized	166 ( 34.7 )	165 ( 102.5 )
Day 1 N-CLB Dose-normalized	1070 ( 105.1 )	571 ( 63.7 )
Day 33 N-CLB Dose-normalized	2830 ( 38.3 )	573 ( 79.1 )

No statistical analyses for this end point

Primary: Period 1: PK: Geometric Mean Ratios Of CLB And N-CLB For Cmax On Day 33 Compared With Day 1

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End point title

Period 1: PK: Geometric Mean Ratios Of CLB And N-CLB For Cmax On Day 33 Compared With Day 1 ^[4]

End point description

The Day 33 compared to Day 1 geometric mean ratios of CLB and N-CLB were calculated for Cmax to look for evidence of drug-drug interactions between GWP42003-P/Placebo and CLB and between GWP42003 P/Placebo and N-CLB. A standard 90% confidence interval (CI) approach for the between time point ratios of geometric means of Cmax was carried out on a logarithmic scale using a linear mixed effect model. The no-effect boundary was set between 0.5 and 2.0, and if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0], a lack of meaningful effect was declared. Estimates were back transformed to provide summaries on the original scale. The model included a fixed effect term for PK assessment period. An unstructured covariance matrix was used. Kenward and Roger's method was used to calculate the denominator degrees of freedom for the fixed effects.

End point type

Primary

End point timeframe

Predose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 12, and 24 h postdose on Days 1 and 33

Notes
[4] - 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: The Day 33 compared to Day 1 geometric mean ratios of CLB and N-CLB were calculated for Cmax, with a standard 90% CI.

End point values	Period 1: GWP42003-P	Period 1: Placebo
Number of subjects analysed	10	3
Units: Ratio
number (confidence interval 90%)
Geometric Mean Ratio of CLB, Cmax	0.997 (0.834 to 1.19)	1.05 (0.401 to 2.74)
Geometric Mean Ratio of N-CLB, Cmax	2.22 (1.42 to 3.46)	1.17 (0.628 to 2.17)

No statistical analyses for this end point

Primary: Period 1: PK: Geometric Mean Ratios Of CLB And N-CLB For AUCtau On Day 33 Compared With Day 1

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End point title

Period 1: PK: Geometric Mean Ratios Of CLB And N-CLB For AUCtau On Day 33 Compared With Day 1 ^[5]

End point description

The Day 33 compared to Day 1 geometric mean ratios of CLB and N-CLB were calculated for AUCtau to look for evidence of drug-drug interactions between GWP42003-P/Placebo and CLB and between GWP42003 P/Placebo and N-CLB. A standard 90% confidence interval (CI) approach for the between time point ratios of geometric means of AUCtau was carried out on a logarithmic scale using a linear mixed effect model. The no-effect boundary was set between 0.5 and 2.0, and if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0], a lack of meaningful effect was declared. Estimates were back transformed to provide summaries on the original scale. The model included a fixed effect term for PK assessment period. An unstructured covariance matrix was used. Kenward and Roger's method was used to calculate the denominator degrees of freedom for the fixed effects.

End point type

Primary

End point timeframe

Predose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 12, and 24 h postdose on Days 1 and 33

Notes
[5] - 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: The Day 33 compared to Day 1 geometric mean ratios of CLB and N-CLB were calculated for AUCtau, with a standard 90% CI.

End point values	Period 1: GWP42003-P	Period 1: Placebo
Number of subjects analysed	10	3
Units: Ratio
number (confidence interval 90%)
Geometric Mean Ratio of CLB, AUCtau	1.06 (0.898 to 1.24)	0.996 (0.652 to 1.52)
Geometric Mean Ratio of N-CLB, AUCtau	2.64 (1.95 to 3.58)	1.00 (0.795 to 1.27)

No statistical analyses for this end point

Primary: Period 2: Number Of Participants Who Experienced Severe OLE-Emergent Adverse Events

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End point title

Period 2: Number Of Participants Who Experienced Severe OLE-Emergent Adverse Events ^[6]

End point description

An OLE-emergent adverse event (AE) was defined as an AE with an onset date after the first dose of IMP in the OLE phase of the study. The number of participants who experienced 1 or more severe OLE-emergent AEs after the first dose of IMP in the OLE phase of the study up to the Safety follow-up visit (28 [± 3] days following the last dose of IMP) is presented. A summary of serious and all other non-serious AEs regardless of causality is located in the Adverse Events section.

End point type

Primary

End point timeframe

Postdose on Day 2 of Visit 4 up to Safety follow-up (28 [± 3] days following the last dose of IMP)

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: Safety data in the OLE phase were analysed descriptively.

End point values	Period 2: GWP42003-P
Number of subjects analysed	18
Units: Number of Participants
Overall Number of Participants Analyzed	18
Number Of Participants With Severe OLE-Emergent AE	4

No statistical analyses for this end point

Secondary: Period 1: Number Of Participants Who Experienced Severe Treatment Emergent Adverse Events (TEAEs)

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End point title

Period 1: Number Of Participants Who Experienced Severe Treatment Emergent Adverse Events (TEAEs)

End point description

A TEAE was defined as an AE with an onset date on or after the first dose of IMP. If an AE had a partial onset date and it was unclear from the partial date (or the stop date) whether the AE started prior to or following the first dose of IMP then the AE was considered a TEAE. The number of participants who experienced 1 or more severe TEAEs after screening up to Day 71 is presented here. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

End point type

Secondary

End point timeframe

Postdose on Day 2 up to Safety follow-up (Day 71)

End point values	Period 1: GWP42003-P	Period 1: Placebo
Number of subjects analysed	16	4
Units: participants	1	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Period 1: Postdose on Baseline (Day 1) up to Day 71 Period 2: Postdose on Day 2 of Visit 4 up to Safety follow-up (28 [± 3] days following the last dose of IMP)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Period 1: GWP42003-P 20 mg/kg/Day Dose

Reporting group description

Participants received GWP42003-P 20 mg/kg/day orally, twice daily immediately after their CLB dose. Participants titrated GWP42003-P to 20 mg/kg/day over 10 days and remained at this dose for the 21-day treatment period. Participants who then did not enter the OLE or withdrew early had a 10-day taper (10% per day) period. Participants who transferred to the OLE (still blinded at that stage) tapered off their GWP42003-P treatment by reducing their maintenance dose by 10% per day and concomitantly titrating GWP42003-P for the OLE. All participants (in the GWP42003-P and Placebo treatment groups) were on a stable dose of CLB at Baseline, administered either once or twice daily as per the physician’s preferred CLB dosing regimen for each participant, and continued taking CLB, as an IMP, for the duration of this study.

Reporting group title

Period 1: Placebo

Reporting group description

Reporting group title

Period 2: GWP42003-P 20 mg/kg/Day Dose

Reporting group description

The number of participants who experienced OLE-emergent AEs after the first dose of IMP in the OLE phase of the study up to the Safety follow-up visit (28 [± 3] days following the last dose of IMP) is presented. The OLE population was the primary analysis set for all safety endpoints reported. Participants' expected seizure types were not routinely documented as AEs. However, any worsening, including change in the pattern or severity of seizures, was documented as an AE.

Serious adverse events	Period 1: GWP42003-P 20 mg/kg/Day Dose	Period 1: Placebo	Period 2: GWP42003-P 20 mg/kg/Day Dose
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	2 / 18 (11.11%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0
Investigations
Alanine aminotransferase abnormal
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase abnormal
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase abnormal
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Seizure cluster
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Period 1: GWP42003-P 20 mg/kg/Day Dose	Period 1: Placebo	Period 2: GWP42003-P 20 mg/kg/Day Dose
Total subjects affected by non serious adverse events
subjects affected / exposed	12 / 16 (75.00%)	2 / 4 (50.00%)	17 / 18 (94.44%)
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	2 / 18 (11.11%)
occurrences all number	1	0	3
Feeling cold
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Gait disturbance
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Peripheral swelling
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Pyrexia
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	2
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 16 (0.00%)	1 / 4 (25.00%)	0 / 18 (0.00%)
occurrences all number	0	1	0
Reproductive system and breast disorders
Menstruation irregular
subjects affected / exposed ^[1]	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Dysphonia
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	2
Psychiatric disorders
Abnormal dreams
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Nervousness
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Tearfulness
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	1	0	1
Irritability
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	3
Abnormal behaviour
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Affect lability
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Hallucination, visual
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	3
Panic attack
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Investigations
Liver function test abnormal
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Weight decreased
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	1	0	1
Eosinophil count increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Haemoglobin decreased
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Platelet count decreased
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
White blood cell count decreased
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Injury, poisoning and procedural complications
Thermal burn
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Ligament sprain
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Toxicity to various agents
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Nervous system disorders
Aphasia
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Dizziness
subjects affected / exposed	2 / 16 (12.50%)	0 / 4 (0.00%)	4 / 18 (22.22%)
occurrences all number	3	0	6
Dysarthria
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	1	0	1
Headache
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	4 / 18 (22.22%)
occurrences all number	1	0	13
Hypersomnia
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	2	0	0
Lethargy
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Memory impairment
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Sedation
subjects affected / exposed	2 / 16 (12.50%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	2	0	1
Somnolence
subjects affected / exposed	2 / 16 (12.50%)	0 / 4 (0.00%)	7 / 18 (38.89%)
occurrences all number	2	0	9
Speech disorder
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Dizziness postural
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Seizure
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	3
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	1	0	1
Diarrhoea
subjects affected / exposed	6 / 16 (37.50%)	1 / 4 (25.00%)	8 / 18 (44.44%)
occurrences all number	11	1	25
Dyspepsia
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	1	0	1
Nausea
subjects affected / exposed	3 / 16 (18.75%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	3	0	0
Vomiting
subjects affected / exposed	3 / 16 (18.75%)	0 / 4 (0.00%)	3 / 18 (16.67%)
occurrences all number	5	0	4
Hepatobiliary disorders
Hypertransaminasaemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	2 / 16 (12.50%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	2	0	0
Petechiae
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Rash maculo-papular
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Rash pruritic
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Urticaria
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Rash
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	1	0	2
Pruritus
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Eczema
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Skin lesion
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Back pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Musculoskeletal pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Infections and infestations
Respiratory tract infection
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	3
Cystitis
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	3
Eczema infected
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Infected bite
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Tonsillitis
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1
Urinary tract infection
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Hypovolaemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 4 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0
Hyponatraemia
subjects affected / exposed	0 / 16 (0.00%)	0 / 4 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	2

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The reporting group includes males. The AE of irregular menstruation can only affect females, and there are 8 total females exposed in the GWP42003-P group and 2 females exposed in the Placebo group in Period 1, and 8 females exposed in Period 2.

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Were there any global substantial amendments to the protocol? Yes

09 Jul 2015

Study Design • The study design was changed from single-blind to double-blind and applicable visit days were revised. • The screening and maintenance periods were increased. Procedures • Procedures were revised to include serum alcohol tests and blood draws for CYP2C19 and 3A4 genetic testing and a Study Medication Use and Behavior Survey. Participant height measurement was removed. IMP • Information pertaining to the IMP, including color of IMP and guidance for IMP reduction, and IMP nomenclature, was added. CLB was designated as the IMP for the blinded phase of the study. • Secondary Endpoints • PK Parameters or THC and major metabolites as well as a safety assessment for drug abuse liability were added. Inclusion/Exclusion/Withdrawal Criteria • Revisions to inclusion criteria describing to seizure type, intervention with VNS, ketogenic diet, and alcohol consumption, contraception, pregnancy, and withdrawal if another IMP is taken were added. • Clarification of liver function testing related to drug-induced liver injury and eligibility criterion related to hepatic impairment were added.

08 Oct 2015

Secondary Endpoints • Analysis of the secondary blood draw samples for CYP2C19 and 3A4 genotype analysis added. Procedures • Clarification text added stating that participants must remain at the clinic for at least 30 minutes on Visit 2, Day 2 to monitor for adverse reactions. • Clarification text added stating that the evening dose of GWP42003-P/placebo and any AEDs must be taken 12 hours after the PK blood draw. • Clarification text added stating that the dose of GWP42003-P can only be adjusted to 30 mg/kg/day from Visit 5 onwards to allow participants to titrate up to 20 mg/kg/day prior to any further dose increases. Exclusion/Withdrawal Criteria • Exclusion criterion of participants taking felbamate for less than 1 year prior to screening added, to mitigate the risks associated with felbamate treatment, which are greatest within the first year of treatment. • Travel outside of the country of residence exclusion criterion amended to be allowed if the IMP was permitted in that country. • Exclusion criterion of participants with prolonged QTcB (> 450 msec for males and > 470 msec for females) added as safety precaution as the formal QT interval corrected for heart rate (QTc) study had not been completed. • Addition of the withdrawal criterion of participants with a significant change in QTcB (> 60 msec) from the previous ECG or absolute QTcB of > 500 msec as the formal QTc study had not been completed. Laboratory Tests • PK analysis for CBD, THC, and their major metabolites not to be conducted at Visit 2 as the participants would not be exposed at that time. • STP, VPA, LEV, and TPM PK analysis to be conducted at Visit 2 if the participants were taking them. • Addition of gamma-glutamyltransferase added to the list of liver enzymes to be analyzed at the request of the Food and Drug Administration. • Participants with elevated liver enzymes had to go back to the site for repeat testing.

04 Feb 2016

Inclusion Criteria • Upper age limit of the inclusion criteria was amended to 65 years to expand the trial to more participants. Procedures • Clarification text was added stating that participants had to remain at the clinic for at least 30 minutes if they were changing from placebo to GWP42003-P during the OLE period. • Clarification that during the OLE period, 1 month was equal to 28 days or 4 weeks.

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 study to investigate possible drug-drug interactions between clobazam and cannabidiol (GWP42003-P).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Period 1: PK: Maximum Measured Plasma Concentration (Cmax) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

Primary: Period 1: PK: Maximum Measured Plasma Concentration (Cmax) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

Primary: Period 1: PK: Time To The Maximum Plasma Concentration (tmax) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

Primary: Period 1: PK: Time To The Maximum Plasma Concentration (tmax) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

Primary: Period 1: PK: Area Under The Plasma Concentration Time Curve Over A Dosing Interval, Where Tau Is The Dosing Interval (AUCtau) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

Primary: Period 1: PK: Area Under The Plasma Concentration Time Curve Over A Dosing Interval, Where Tau Is The Dosing Interval (AUCtau) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

Primary: Period 1: PK: Geometric Mean Ratios Of CLB And N-CLB For Cmax On Day 33 Compared With Day 1

Primary: Period 1: PK: Geometric Mean Ratios Of CLB And N-CLB For Cmax On Day 33 Compared With Day 1

Primary: Period 1: PK: Geometric Mean Ratios Of CLB And N-CLB For AUCtau On Day 33 Compared With Day 1

Primary: Period 1: PK: Geometric Mean Ratios Of CLB And N-CLB For AUCtau On Day 33 Compared With Day 1

Primary: Period 2: Number Of Participants Who Experienced Severe OLE-Emergent Adverse Events

Primary: Period 2: Number Of Participants Who Experienced Severe OLE-Emergent Adverse Events

Secondary: Period 1: Number Of Participants Who Experienced Severe Treatment Emergent Adverse Events (TEAEs)

Secondary: Period 1: Number Of Participants Who Experienced Severe Treatment Emergent Adverse Events (TEAEs)

Adverse events

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Substantial protocol amendments (globally)

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Limitations and caveats

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Clinical trials

Clinical Trial Results: A phase 2, double-blind, randomized, placebo-controlled study to investigate possible drug-drug interactions between clobazam and cannabidiol (GWP42003-P).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Period 1: PK: Maximum Measured Plasma Concentration (Cmax) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

Primary: Period 1: PK: Maximum Measured Plasma Concentration (Cmax) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

Primary: Period 1: PK: Time To The Maximum Plasma Concentration (tmax) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

Primary: Period 1: PK: Time To The Maximum Plasma Concentration (tmax) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

Primary: Period 1: PK: Area Under The Plasma Concentration Time Curve Over A Dosing Interval, Where Tau Is The Dosing Interval (AUCtau) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

Primary: Period 1: PK: Area Under The Plasma Concentration Time Curve Over A Dosing Interval, Where Tau Is The Dosing Interval (AUCtau) Of CLB And N-CLB With GWP42003-P Treatment, Days 1 And 33

Primary: Period 1: PK: Geometric Mean Ratios Of CLB And N-CLB For Cmax On Day 33 Compared With Day 1

Primary: Period 1: PK: Geometric Mean Ratios Of CLB And N-CLB For Cmax On Day 33 Compared With Day 1

Primary: Period 1: PK: Geometric Mean Ratios Of CLB And N-CLB For AUCtau On Day 33 Compared With Day 1

Primary: Period 1: PK: Geometric Mean Ratios Of CLB And N-CLB For AUCtau On Day 33 Compared With Day 1

Primary: Period 2: Number Of Participants Who Experienced Severe OLE-Emergent Adverse Events

Primary: Period 2: Number Of Participants Who Experienced Severe OLE-Emergent Adverse Events

Secondary: Period 1: Number Of Participants Who Experienced Severe Treatment Emergent Adverse Events (TEAEs)

Secondary: Period 1: Number Of Participants Who Experienced Severe Treatment Emergent Adverse Events (TEAEs)

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 study to investigate possible drug-drug interactions between clobazam and cannabidiol (GWP42003-P).