A Study of Possible Drug-drug Interactions Between Stiripentol or Valproate and Cannabidiol in Patients With Epilepsy

• ClinicalTrials.gov Identifier: NCT02607891
• Recruitment Status: Completed
• First Posted: November 18, 2015
• Last Update Posted: September 25, 2019
• Sponsor: GW Research Ltd
• Information provided by (Responsible Party): GW Research Ltd

Study Description

Brief Summary:

This trial consists of 2 parts: a double-blinded phase and an open-label extension phase. The blinded phase only will be described in this record. Participants will be randomized in a 4:1 ratio to receive GWP42003-P or matching placebo. The hypothesis is that levels of stiripentol (STP) or valproate (VPA) may be altered (increased or decreased) as a result of using GWP42003-P.

Condition or disease	Intervention/treatment	Phase
Epilepsy	Drug: GWP42003-P; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Double-blind, Randomized, Placebo-controlled Pharmacokinetic Trial in 2 Parallel Groups to Investigate Possible Drug-drug Interactions Between Stiripentol or Valproate and GWP42003-P in Patients With Epilepsy
• Actual Study Start Date: November 9, 2016
• Actual Primary Completion Date: September 11, 2018
• Actual Study Completion Date: October 2, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: STP + GWP42003-P; Administered orally, twice daily (morning and evening; immediately after the participant's STP dose), commencing with up-titration of 100 mg/mL GWP42003-P to a maintenance dose of 20 mg/kg/day over 11 days. Participants remain on the maintenance dose for a further 14 days. Dosing is tapered (10% each day) for participants who do not enter the open-label-extension (OLE) phase or who withdraw early. STP Arm: Last patient completion October 2018	Drug: GWP42003-P; Clear, colorless to yellow solution containing cannabidiol dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring.; Other Names: Cannabidiol; CBD; Epidiolex
Placebo Comparator: STP + Placebo; Administered orally, twice daily (morning and evening; immediately after the participant's STP dose), commencing with up-titration of placebo to an equivalent maintenance dose of 20 mg/kg/day over 11 days. Participants remain on the maintenance dose for a further 14 days. Dosing is tapered (10% each day) for participants who do not enter the OLE phase or who withdraw early. STP Arm: Last patient completion February 2018	Drug: Placebo; Clear, colorless to yellow solution containing the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring.
Experimental: VPA + GWP42003-P; Administered orally, twice daily (morning and evening; immediately after the participant's VPA dose), commencing with up-titration of 100 mg/mL GWP42003-P to a maintenance dose of 20 mg/kg/day over 11 days. Participants remain on the maintenance dose for a further 14 days. Dosing is tapered (10% each day) for participants who do not enter the OLE phase or who withdraw early. VPA Arm: Last patient completion February 2018	Drug: GWP42003-P; Clear, colorless to yellow solution containing cannabidiol dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring.; Other Names: Cannabidiol; CBD; Epidiolex
Placebo Comparator: VPA + Placebo; Administered orally, twice daily (morning and evening; immediately after the participant's VPA dose), commencing with up-titration of placebo to an equivalent maintenance dose of 20 mg/kg/day over 11 days. Participants remain on the maintenance dose for a further 14 days. Dosing is tapered (10% each day) for participants who do not enter the OLE phase or who withdraw early. VPA Arm: Last patient completion January 2018	Drug: Placebo; Clear, colorless to yellow solution containing the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring.

Outcome Measures

Primary Outcome Measures :

1. Maximum plasma concentration (Cmax) of STP, VPA, cannabidiol (CBD). [ Time Frame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose. ]
   The Cmax of STP, VPA and CBD is presented.
2. Time to the maximum plasma concentration (Tmax) of STP, VPA and CBD. [ Time Frame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose. ]
   The Tmax of STP, VPA and CBD is presented.
3. Area under the curve (AUC) from zero to final time of positive detection (0-t) of STP, VPA and CBD. [ Time Frame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose. ]
   The AUC(0-t) of STP, VPA and CBD is presented.
4. Area under the plasma concentration time curve over a dosing interval, where tau is the dosing interval [AUCtau]. [ Time Frame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose. ]
   The AUC(tau) of STP, VPA, and CBD is presented.

Secondary Outcome Measures :

1. Number of participants who experienced an adverse event. [ Time Frame: Up to 11 weeks. ]
   The number of participants who experienced an adverse event during the trial is presented.
2. Number of participants with a clinically significant change in 12-lead electrocardiogram (ECG). [ Time Frame: Up to 7 weeks. ]
   The number of participants with a clinically significant change in ECG is presented.
3. Number of participants with a clinically significant change in serum biochemistry. [ Time Frame: Up to 7 weeks. ]
   The number of participants with a clinically significant change in serum biochemistry is presented.
4. Number of participants with a clinically significant change in hematology. [ Time Frame: Up to 7 weeks. ]
   The number of participants with a clinically significant change in hematology is presented.
5. Number of participants with a clinically significant change in urinalysis. [ Time Frame: Up to 7 weeks. ]
   The number of participants with a clinically significant change in urinalysis is presented.
6. Number of participants with a clinically significant change in vital signs. [ Time Frame: Up to 7 weeks. ]
   The number of participants with a clinically significant change in vital signs (systolic blood pressure, diastolic blood pressure, pulse rate) is presented.
7. Number of participants with a clinically significant change in physical examination. [ Time Frame: Up to 7 weeks. ]
   The number of participants with a clinically significant change in physical examination is presented.
8. Number of participants with a treatment-emergent suicidality flag. [ Time Frame: Up to 7 weeks. ]
   Suicidality was assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS). The number of participants with a treatment-emergent flag is presented.
9. Seizure frequency by subtype. [ Time Frame: Up to 6 weeks. ]
   The frequency of each subtype of seizure at baseline and end of treatment is presented.
10. Number of participants with a treatment-emergent finding indicative of drug abuse liability. [ Time Frame: Up to 7 weeks. ]
    Abuse liability was assessed through monitoring of triggering adverse events of interest and study medication accountability discrepancies. Any findings were assigned to an appropriate classification by the investigator. The number of participants with a treatment-emergent finding indicative of drug abuse liability is presented.
11. Cmax of 4-ene-VPA, clobazam (CLB), N-desmethylclobazam (N-CLB), levetiracetam (LEV), and topiramate (TOP). [ Time Frame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose. ]
    The Cmax of 4-ene-VPA, CLB, N-CLB, LEV, and TOP is presented.
12. Tmax of 4-ene-VPA, CLB, N-CLB, LEV, and TOP. [ Time Frame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose. ]
    The Tmax of 4-ene-VPA, CLB, N-CLB, LEV, and TOP is presented.
13. AUC(0-t) of 4-ene-VPA, CLB, N-CLB, LEV, and TOP. [ Time Frame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose. ]
    The AUC(0-t) of 4-ene-VPA, CLB, N-CLB, LEV, and TOP is presented.
14. AUC(tau) of 4-ene-VPA, CLB, N-CLB, LEV, and TOP. [ Time Frame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose. ]
    The AUC(tau) of 4-ene-VPA, CLB, N-CLB, LEV, and TOP is presented.

Eligibility Criteria

• Ages Eligible for Study: 16 Years to 55 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Note: Participants who enroll in Sweden must be aged 18-55 years.

Key Inclusion Criteria:

• Participant must be taking STP (for the STP arm) or VPA (for the VPA arm) and no more than 2 other antiepileptic drugs (AEDs) during the blinded period of the trial.

  • In the VPA arm only, the participant must not be receiving STP (VPA allowed in STP arm).
• AED doses, including STP or VPA, must be stable for 4 weeks prior to screening and regimen must remain stable throughout the duration of the blinded period of the trial.
• Participant must have a documented magnetic resonance imaging/computerized tomography of the brain that ruled out a progressive neurologic condition.
• Participant must have experienced at least 1 countable uncontrolled seizure of any type (i.e., tonic-clonic, tonic, clonic, atonic, partial onset or focal: focal seizures with retained consciousness and a motor component, focal seizures with impaired consciousness, focal seizures evolving to bilateral secondary generalization) within 2 months prior to randomization.
• Intervention with vagus nerve stimulation and/or ketogenic diet must be stable for 4 weeks prior to baseline and the participant must be willing to maintain a stable regimen during the blinded period of the trial.
• Participant must abstain from alcohol during the blinded period of the trial.

Key Exclusion Criteria:

• Participant has clinically significant unstable medical conditions other than epilepsy.
• Participant has a history of symptoms related to a drop in blood pressure due to postural changes (e.g., dizziness, light-headedness, blurred vision, palpitations, weakness, syncope).

• Participant has a QT interval, corrected for heart rate with Bazett's formula (QTcB), greater than:

  • 450 msec for males.
  • 470 msec for females.
  • 480 msec if right bundle branch block is present.
• Participant has any history of suicidal behavior or any suicidal ideation of type 4 or 5 on the C-SSRS in the last month or at screening.
• Participant has had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to screening or enrollment, other than epilepsy.
• Participant is currently using felbamate and has been taking it for less than 12 months prior to screening.
• Participant has consumed alcohol during the 7 days prior to enrollment and is unwilling to abstain during the blinded phase of the trail.
• Participant is 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 trial entry.
• Participant has any known or suspected history of any drug abuse or addiction.
• Participant is unwilling to abstain from recreational or medicinal cannabis, or synthetic cannabinoid based medications (including Sativex) for the duration for the study.
• Participant has consumed grapefruit or grapefruit juice 7 days prior to enrollment and is unwilling to abstain from drinking grapefruit juice within 7 days of pharmacokinetic visits.
• Participant has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the Investigational Medicinal Product (IMP), e.g., sesame oil.
• Participant has received an IMP within the 12 weeks prior to the screening visit.

• Participant has significantly impaired hepatic function at the screening or randomization visit, defined as any of the following:

  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 × upper limit of normal (ULN).
  • ALT or AST > 3 × ULN and total bilirubin (TBL) > 2 × ULN or international normalized ratio (INR) > 1.5.
  • 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

Netherlands

SEIN - Epilepsy Institute in the Netherlands Foundation

Zwolle, Netherlands

Spain

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Hospital Ruber Internacional

Madrid, Spain

Hospital Universitario Virgen del Rocio

Sevilla, Spain

Sweden

Sahlgrenska University Hospital

Göteborg, Sweden

Sponsors and Collaborators

GW Research Ltd

More Information

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

Ben-Menachem E, Gunning B, Arenas Cabrera CM, VanLandingham K, Crockett J, Critchley D, Wray L, Tayo B, Morrison G, Toledo M. A Phase II Randomized Trial to Explore the Potential for Pharmacokinetic Drug-Drug Interactions with Stiripentol or Valproate when Combined with Cannabidiol in Patients with Epilepsy. CNS Drugs. 2020 Jun;34(6):661-672. doi: 10.1007/s40263-020-00726-4.

• Responsible Party: GW Research Ltd
• ClinicalTrials.gov Identifier: NCT02607891
• Other Study ID Numbers: GWEP1447 Blinded Phase; 2015-002939-18 ( EudraCT Number )
• First Posted: November 18, 2015
• Last Update Posted: September 25, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by GW Research Ltd:

Cannabidiol; GWP42003-P; Epidiolex; Stiripentol; Valproate

Additional relevant MeSH terms:

Epilepsy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epidiolex; Anticonvulsants