Clinical trial NCT02607891: A Study of Possible Drug-drug Interactions Between Stiripentol or Valproate and Cannabidiol in Patients With Epilepsy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Epilepsy
Keywords: Cannabidiol
GWP42003-P
Epidiolex
Stiripentol
Valproate
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2015-11-18
Enrollment: 35
Sex: ALL
Minimum age (years): 16
Maximum age (years): 55
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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%).

Primary outcomes:
measure: Maximum plasma concentration (Cmax) of STP, VPA, cannabidiol (CBD).
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose.
measure: Time to the maximum plasma concentration (Tmax) of STP, VPA and CBD.
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose.
measure: Area under the curve (AUC) from zero to final time of positive detection (0-t) of STP, VPA and CBD.
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose.
measure: Area under the plasma concentration time curve over a dosing interval, where tau is the dosing interval [AUCtau].
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose.
Secondary outcomes:
measure: Number of participants who experienced an adverse event.
timeFrame: Up to 11 weeks.
measure: Number of participants with a clinically significant change in 12-lead electrocardiogram (ECG).
timeFrame: Up to 7 weeks.
measure: Number of participants with a clinically significant change in serum biochemistry.
timeFrame: Up to 7 weeks.
measure: Number of participants with a clinically significant change in hematology.
timeFrame: Up to 7 weeks.
measure: Number of participants with a clinically significant change in urinalysis.
timeFrame: Up to 7 weeks.
measure: Number of participants with a clinically significant change in vital signs.
timeFrame: Up to 7 weeks.
measure: Number of participants with a clinically significant change in physical examination.
timeFrame: Up to 7 weeks.
measure: Number of participants with a treatment-emergent suicidality flag.
timeFrame: Up to 7 weeks.
measure: Seizure frequency by subtype.
timeFrame: Up to 6 weeks.
measure: Number of participants with a treatment-emergent finding indicative of drug abuse liability.
timeFrame: Up to 7 weeks.
measure: Cmax of 4-ene-VPA, clobazam (CLB), N-desmethylclobazam (N-CLB), levetiracetam (LEV), and topiramate (TOP).
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose.
measure: Tmax of 4-ene-VPA, CLB, N-CLB, LEV, and TOP.
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose.
measure: AUC(0-t) of 4-ene-VPA, CLB, N-CLB, LEV, and TOP.
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose.
measure: AUC(tau) of 4-ene-VPA, CLB, N-CLB, LEV, and TOP.
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose.
Other outcomes:
Locations:
city: Zwolle
country: Netherlands
facility: SEIN - Epilepsy Institute in the Netherlands Foundation
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Ruber Internacional
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital
Study officials:
References:
citation: 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.