An Open-label Extension Study to Investigate Possible Drug-drug Interactions Between Clobazam and Cannabidiol

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02564952
• Collaborator: (none)
• Enrollment: 18
• Locations: 6
• Arm: 1
• Actual Duration (Months): 14.9
• Patients Per Site: 3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study consisted of 2 parts: a double-blind (DB) phase and an open-label extension (OLE) phase. Only the OLE phase is described in this record. The OLE phase was a safety study. All participants received GWP42003-P initially titrated to 20 milligrams (mg)/kilograms (kg)/day; however, investigators subsequently decreased or increased the participant's dose to a maximum of 30 mg/kg/day (no minimum).

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: GWP42003-P; Drug: Clobazam	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase 2, Double-blind, Randomized, Placebo-controlled Study to Investigate Possible Drug-drug Interactions Between Clobazam and Cannabidiol (GWP42003-P)
• Actual Study Start Date: Mar 11, 2016
• Actual Primary Completion Date: Jun 7, 2017
• Actual Study Completion Date: Jun 7, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: GWP42003-P Participants who transferred from the DB phase (NCT02565108) 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. Clobazam (CLB) was administered in line with the physician's preferred CLB dosing regimen for each participant.

Drug: GWP42003-P; 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). Participants received up to a maximum of 30 mg/kg/day.; Other Names: Cannabidiol (CBD) Epidiolex ; Drug: Clobazam; Participants were taking CLB upon entry into the OLE phase of the trial. CLB was not an investigational medicinal product (IMP) for the OLE phase and was not administered by the Sponsor, but was administered at the physician's discretion, as required for each participant. CLB could be stopped, if clinically indicated, without impact on analysis.; Other Names: CLB

Outcome Measures

Primary Outcome Measures

1. Number Of Participants Who Experienced Severe OLE-Emergent AEs [Postdose on Day 2 of Visit 4 up to Safety follow-up (28 [± 3] days following the last dose of IMP)]

   An OLE-emergent 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 Reported Adverse Events module.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Participant must have had epilepsy, as determined by the investigator, and must have been taking CLB.

• Participant must have had a documented magnetic resonance imaging/computerized tomography of the brain ruling out a progressive neurologic condition.

• Participant must have experienced at least 1 seizure of any type (that is, convulsive: tonic-clonic, tonic, clonic, atonic; focal: focal seizures with retained consciousness and a motor component, focal seizures with impaired consciousness, focal seizures evolving to bilateral secondary generalization) within the 2 months prior to randomization.

• Participant must have been taking CLB and no more than 2 other antiepileptic drugs (AEDs) during the course of the study. However, any participants who were taking these medications after screening were not withdrawn from the study unless there were safety concerns.

• AED(s), including CLB, must have been stable for 4 weeks prior to screening and regimen must have remained stable throughout the duration of the double-blind phase of the study.

• Intervention with vagus nerve stimulation and/or ketogenic diet must have been stable for 4 weeks prior to Baseline and participant/caregiver must have been willing to maintain a stable regimen throughout the double-blind phase of the study.

Key Exclusion Criteria:

• Participant had clinically significant unstable medical conditions other than epilepsy.

• Participants were on CLB at doses above 20 mg per day.

• Participants taking CLB intermittently as rescue medication.

• Participant had a history of symptoms related to a drop in blood pressure due to postural changes (for example, dizziness, light-headedness, blurred vision, palpitations, weakness, syncope).

• Participant had any history of suicidal behavior or any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale in the last month or at screening.

• Participant had clinically relevant symptoms or a clinically significant illness, other than epilepsy in the 4 weeks prior to screening or enrollment, other than epilepsy.

• Participant had consumed alcohol during the 7 days prior to enrollment and was unwilling to abstain during the double-blind phase of the study.

• Participant was currently using or has in the past used recreational or medicinal cannabis, or synthetic cannabinoid-based medications (including Sativex®) within the 3 months prior to study entry.

• Participant had any known or suspected history of any drug abuse or addiction.

• Participant was unwilling to abstain from recreational or medicinal cannabis, or synthetic cannabinoid-based medications (including Sativex) for the duration for the study.

• Participant consumed grapefruit or grapefruit juice 7 days prior to enrollment and was unwilling to abstain from drinking grapefruit juice within 7 days of pharmacokinetic visits.

• Participant had any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP, for example, sesame oil.

• Participant received an IMP within the 12 weeks prior to the screening visit.

• Participant had significantly impaired hepatic function at the screening or randomization visit, defined as any of the following: (A) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 × upper limit of normal (ULN). (B) ALT or AST > 3 × ULN and total bilirubin > 2 × ULN or international normalized ratio > 1.5. (C) ALT or AST > 3 × ULN with the presence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Barcelona		Spain	08035
2		Barcelona		Spain	08036
3		Birmingham		United Kingdom	B15 2FG
4		Brighton		United Kingdom	BN2 5BE
5		Leeds		United Kingdom	LS1 3EX
6		Salford		United Kingdom	M6 8HD

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jan 26, 2015
• Statistical Analysis Plan - Sep 23, 2016

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02564952
• Other Study ID Numbers: GWEP1428 Open-Label Extension; 2014-002942-33
• First Posted: Oct 1, 2015
• Last Update Posted: Sep 11, 2018
• Last Verified: Aug 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Jazz Pharmaceuticals: Cannabidiol (CBD); GWP42003-P; Clobazam; Epidiolex
• Additional relevant MeSH terms: Epilepsy; Cannabidiol; Clobazam

Study Results

Participant Flow

Recruitment Details	All participants were enrolled by invitation into the open-label extension (OLE) phase after completing the double-blind phase of the study.
Pre-assignment Detail	Two of the 18 participants withdrew during the OLE titration period: 1 met protocol-specified withdrawal criteria; 1 had GWP42003-P withdrawn due to adverse events (AEs) ongoing at entry to the OLE phase.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who transferred from the double blind (DB) phase (NCT02565108) 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. Clobazam (CLB) was administered in line with the physician's preferred CLB dosing regimen for each participant.
Period Title: Overall Study
STARTED	18
Received at Least 1 Dose of Study Drug	18
Completed OLE Titration Period	16
COMPLETED	7
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who transferred from the DB phase (NCT02565108) 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. CLB was administered in line with the physician's preferred CLB dosing regimen for each participant.
Overall Participants	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.35 (9.05)
Sex: Female, Male (Count of Participants)
Female	8 44.4%
Male	10 55.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	18 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Any History Of Current Seizures (Count of Participants)
Count of Participants [Participants]	18 100%

Outcome Measures

1. Primary Outcome

Title	Number Of Participants Who Experienced Severe OLE-Emergent AEs
Description	An OLE-emergent 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 Reported Adverse Events module.
Time Frame	Postdose on Day 2 of Visit 4 up to Safety follow-up (28 [± 3] days following the last dose of IMP)

Outcome Measure Data

Analysis Population Description

The OLE population included all participants who completed the double-blind phase and entered the OLE phase of the study. The OLE population was the primary analysis set for all safety endpoints reported.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who transferred from the DB phase (NCT02565108) 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. CLB was administered in line with the physician's preferred CLB dosing regimen for each participant.
Measure Participants	18
Count of Participants [Participants]	4 22.2%

Adverse Events

Time Frame	Postdose on Day 2 of Visit 4 up to Safety follow-up (28 [± 3] days following the last dose of IMP)
Adverse Event Reporting 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.
Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who transferred from the DB phase (NCT02565108) 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. CLB was administered in line with the physician's preferred CLB dosing regimen for each participant.
All Cause Mortality
	GWP42003-P
	Affected / at Risk (%)	# Events
Total	0/18 (0%)
Serious Adverse Events
	GWP42003-P
	Affected / at Risk (%)	# Events
Total	2/18 (11.1%)
Investigations
Alanine aminotransferase abnormal	1/18 (5.6%)
Aspartate aminotransferase abnormal	1/18 (5.6%)
Gamma-glutamyltransferase abnormal	1/18 (5.6%)
Nervous system disorders
Seizure	1/18 (5.6%)
Status epilepticus	1/18 (5.6%)
Other (Not Including Serious) Adverse Events
	GWP42003-P
	Affected / at Risk (%)	# Events
Total	17/18 (94.4%)
Gastrointestinal disorders
Diarrhoea	8/18 (44.4%)
Vomiting	3/18 (16.7%)
Abdominal pain	1/18 (5.6%)
Dyspepsia	1/18 (5.6%)
General disorders
Fatigue	2/18 (11.1%)
Gait disturbance	1/18 (5.6%)
Peripheral swelling	1/18 (5.6%)
Pyrexia	1/18 (5.6%)
Infections and infestations
Respiratory tract infection	2/18 (11.1%)
Cystitis	1/18 (5.6%)
Eczema infected	1/18 (5.6%)
Infected bite	1/18 (5.6%)
Tonsillitis	1/18 (5.6%)
Urinary tract infection	1/18 (5.6%)
Injury, poisoning and procedural complications
Ligament sprain	1/18 (5.6%)
Toxicity to various agents	1/18 (5.6%)
Investigations
Eosinophil count increased	1/18 (5.6%)
Gamma-glutamyltransferase increased	1/18 (5.6%)
Haemoglobin decreased	1/18 (5.6%)
Platelet count decreased	1/18 (5.6%)
Weight decreased	1/18 (5.6%)
White blood cell count decreased	1/18 (5.6%)
Metabolism and nutrition disorders
Hyponatraemia	2/18 (11.1%)
Musculoskeletal and connective tissue disorders
Back pain	1/18 (5.6%)
Musculoskeletal pain	1/18 (5.6%)
Nervous system disorders
Somnolence	7/18 (38.9%)
Dizziness	4/18 (22.2%)
Headache	4/18 (22.2%)
Seizure	2/18 (11.1%)
Dysarthria	1/18 (5.6%)
Sedation	1/18 (5.6%)
Psychiatric disorders
Irritability	2/18 (11.1%)
Abnormal behaviour	1/18 (5.6%)
Affect lability	1/18 (5.6%)
Hallucination, visual	1/18 (5.6%)
Panic attack	1/18 (5.6%)
Tearfulness	1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/18 (5.6%)
Dysphonia	1/18 (5.6%)
Skin and subcutaneous tissue disorders
Eczema	1/18 (5.6%)
Rash	1/18 (5.6%)
Skin lesion	1/18 (5.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.