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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 5
- 主要终点
- Maximum plasma concentration (Cmax) of STP, VPA, cannabidiol (CBD).
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 16 Years 至 55 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
- •ALT or AST > 3 × ULN with the presence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).
研究组 & 干预措施
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
干预措施: GWP42003-P (Drug)
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
干预措施: Placebo (Drug)
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
干预措施: GWP42003-P (Drug)
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
干预措施: Placebo (Drug)
结局指标
主要结局
Maximum plasma concentration (Cmax) of STP, VPA, cannabidiol (CBD).
时间窗: 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.
Area under the plasma concentration time curve over a dosing interval, where tau is the dosing interval [AUCtau].
时间窗: 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.
Area under the curve (AUC) from zero to final time of positive detection (0-t) of STP, VPA and CBD.
时间窗: 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.
Time to the maximum plasma concentration (Tmax) of STP, VPA and CBD.
时间窗: 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.
次要结局
- Number of participants with a clinically significant change in 12-lead electrocardiogram (ECG).(Up to 7 weeks.)
- Number of participants with a treatment-emergent suicidality flag.(Up to 7 weeks.)
- AUC(0-t) of 4-ene-VPA, CLB, N-CLB, LEV, and TOP.(0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose.)
- Number of participants with a clinically significant change in hematology.(Up to 7 weeks.)
- Seizure frequency by subtype.(Up to 6 weeks.)
- Cmax of 4-ene-VPA, clobazam (CLB), N-desmethylclobazam (N-CLB), levetiracetam (LEV), and topiramate (TOP).(0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose.)
- Tmax of 4-ene-VPA, CLB, N-CLB, LEV, and TOP.(0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose.)
- Number of participants with a clinically significant change in vital signs.(Up to 7 weeks.)
- Number of participants with a clinically significant change in serum biochemistry.(Up to 7 weeks.)
- Number of participants who experienced an adverse event.(Up to 11 weeks.)
- Number of participants with a clinically significant change in urinalysis.(Up to 7 weeks.)
- Number of participants with a clinically significant change in physical examination.(Up to 7 weeks.)
- Number of participants with a treatment-emergent finding indicative of drug abuse liability.(Up to 7 weeks.)
- AUC(tau) of 4-ene-VPA, CLB, N-CLB, LEV, and TOP.(0, 0.25, 0.5, 1, 1.5, 2, 4, 6, and 12 hours post-dose.)