A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P; CBD) as Adjunctive Treatment for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 225
- 主要终点
- Percentage Change From Baseline In Drop Seizure Frequency During The Treatment Period
研究概览
简要总结
The primary objective of this study was to evaluate the efficacy of GWP42003-P as adjunctive treatment in reducing the number of drop seizures when compared with placebo in participants with Lennox-Gastaut syndrome (LGS).
详细描述
This study was a 1:1:1 randomized, double-blind, 14-week comparison of 2 dose levels (10 milligram [mg] per kilogram [kg] per day [mg/kg/day] and 20 mg/kg/day) of GWP42003-P versus placebo. Participants who satisfied all inclusion and none of the exclusion criteria began a 28-day baseline observation period. The treatment period consisted of a 2-week titration period followed by a 12-week maintenance period. The 20 mg/kg/day dose was recommended by the Data Safety Monitoring Committee (DSMC) after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (NCT02091206). The 10 mg/kg/day dose was defined as 50% of the 20 mg/kg/day dose. The first participant was not enrolled into this study until the DSMC had reviewed the safety data from Part A of study GWEP1332.
Participants who satisfied all eligibility criteria were randomized at Day 1 to receive 10 mg/kg/day GWP42003-P, 20 mg/kg/day GWP42003-P, or placebo at a 1:1:1 ratio. Participants in the placebo group were split into 2 equivalent cohorts; one half received 10 mg/kg/day dosing volumes and one half received 20 mg/kg/day dosing volumes. The 2 placebo cohorts were pooled for the analyses of efficacy. Participants titrated GWP42003-P to the 10 mg/kg/day or 20 mg/kg/day (or equivalent volume of placebo) dose over 7 and 11 days, respectively, and remained at this dose for the 12-week maintenance period. Following the end of treatment (Day 99), participants were invited to continue to receive GWP42003-P in an open-label extension (OLE) study under a separate protocol (GWEP1415; NCT02224573). All participants who did not immediately enter the OLE study tapered investigational medicinal product (IMP) (10% per day over 10 days). However, the taper period could be interrupted if the participant wished to enter the OLE study within a 7-day timeframe. Participants who down-titrated IMP returned for an end of taper period visit (Day 109). Participants who did not enter the OLE study or who withdrew prematurely had a safety follow-up visit 28 days later (Day 137).
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
- 2 Years 至 55 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant and/or parent(s)/legal representatives were willing and able to give informed assent/consent for participation in the study.
- •Participant and his or her caregivers were willing and able (in the investigator's opinion) to comply with all study requirements.
- •Participant was male or female aged between 2 and 55 years (inclusive).
- •Participant had a documented history of LGS. This included written documentation of having met electroencephalogram (EEG) diagnostic criteria during the participant's history and evidence of at least 1 type of generalized seizure, including drop seizures (atonic, tonic, tonic-clonic or myoclonic) for at least 6 months.
- •Participant had a history of slow (<3.0 hertz [Hz]) spike-and-wave pattern in an EEG prior to the enrollment into the baseline period.
- •Participant had at least 2 drop seizures each week during the first 28 days of the baseline period.
- •Participant was refractory; that is having documented failures on more than 1 antiepileptic drug (AED).
- •Participant was taking 1 or more AEDs at a dose which had been stable for at least 4 weeks prior to screening.
- •All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation [VNS]) were stable for 4 weeks prior to screening and the participant was willing to maintain a stable regimen throughout the study. The ketogenic diet and VNS treatments were not counted as an AED.
- •Participant and/or parent(s)/legal representatives were willing to allow his or her primary care practitioner and consultant to be notified of participation in the study.
- •Participant completed his or her interactive voice response (IVRS) telephone diary on at least 25 days of the baseline period.
排除标准
- •Etiology of participant's seizures was a progressive neurologic disease. Participants with tuberous sclerosis were not excluded from study participation, unless there was a progressive tumor.
- •Participant had an anoxic episode requiring resuscitation within 6 months of screening.
- •Participant had clinically significant unstable medical conditions other than epilepsy.
- •Participant had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to screening or randomization, other than epilepsy.
- •Participant had a history or presence of alcohol or substance abuse within the last 2 years prior to the study or daily consumption of 5 or more alcohol-containing beverages.
- •Participant was currently using or had in the past used recreational or medicinal cannabis, or synthetic cannabinoid-based medications (including Sativex®) within the 3 months prior to study entry and was unwilling to abstain for the duration of the study.
- •Participant had a history of symptoms (for example, dizziness, light-headedness, blurred vision, palpitations, weakness, syncope) related to a drop in blood pressure due to postural changes.
- •Participant had any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP, such as sesame oil.
- •Female participant was of child bearing potential or male participant's partner was of child bearing potential; unless willing to ensure that they or their partner used a highly effective method of contraception for the duration of the study and for 3 months thereafter.
- •Female participant was pregnant (positive pregnancy test), lactating or planning pregnancy during the course of the study and for 3 months thereafter.
- •Participant had been part of a clinical study involving another IMP in the previous 6 months.
- •Patient had significantly impaired hepatic function at screening (Day -28) or randomization (Day 1), 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 > 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%). This criterion could only be confirmed once the laboratory results were available; participants randomized into the study who were later found not to meet this criterion were withdrawn from the study.
- •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 was unwilling to abstain from donation of blood during the study.
- •Participant planned to travel outside his or her country of residence during the study.
- •Participant had previously randomized into the study.
- •Participant was taking more than 4 concurrent AEDs.
- •Participant had taken corticotropins in the 6 months prior to screening.
- •Participant was currently taking long-term systemic steroids (excluding inhaled medication for asthma treatment) or any other daily medication known to exacerbate epilepsy. An exception was made of prophylactic medication, for example, idiopathic nephrotic syndrome or asthma.
- •Participant was taking felbamate, and he or she had been taking it for less than 1 year prior to screening.
研究组 & 干预措施
GWP42003-P 20 mg/kg/day Dose
Participants received GWP42003-P 20 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.
干预措施: GWP42003-P (Drug)
GWP42003-P 10 mg/kg/day Dose
Participants received GWP42003-P 10 mg/kg/day administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 10 mg/kg/day over 7 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.
干预措施: GWP42003-P (Drug)
Placebo
Participants received placebo (0 mg/mL CBD) volume matched to 1 of the 2 dose levels (10 or 20 mg/kg/day) administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 7 to 11 days according to the matched IMP group (7 or 11 days for the 10 or 20 mg/kg/day GWP42003-P groups, respectively) and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
干预措施: Placebo control (Drug)
结局指标
主要结局
Percentage Change From Baseline In Drop Seizure Frequency During The Treatment Period
时间窗: Baseline to End of Treatment (EOT) (Day 99) or Early Termination (ET)
Drop seizures were recorded by the participant or caregiver using an interactive voice response system (IVRS) diary. Drop seizures were defined as the subset of tonic-clonic, tonic or atonic seizures that were reported as drop seizures in the IVRS. Percentage change from baseline was calculated as: (\[frequency during the treatment period - frequency during baseline\]/frequency during baseline) x 100. The frequency during each period was based on 28-day averages and calculated as: (number of seizures in the period/number of reported days in the IVRS period) x 28. Baseline included all available data prior to Day 1 (28-day average). Negative percentages show an improvement from baseline.
次要结局
- Percentage Change From Baseline In Total Seizure Frequency During The Treatment Period(Baseline to EOT (Day 99) or ET)
- Number Of Participants With A ≥50% Reduction From Baseline In Drop Seizure Frequency During The Treatment Period(Baseline to EOT (Day 99) or ET)
- Subject/Caregiver Global Impression Of Change (S/CGIC) Assessment(Baseline to Last Visit (Day 99) or ET)