A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 262
- 试验地点
- 55
- 主要终点
- Change From Baseline in the Mean Convulsive Seizures Frequency (MCSF) to the Combined Titration and Maintenance Periods (T+M) in Participants Receiving ZX008 0.8 mg/kg/Day Compared to Placebo
研究概览
简要总结
Study 1 and Study 3 are the prospective, merged analyses of 2 identical double-blind, placebo-controlled studies, ZX008-1501 and ZX008-1502, to assess the efficacy, safety, and pharmacokinetics of ZX008 when used as adjunctive therapy in pediatric and young adult subjects with Dravet syndrome. Study 1501 and Study 1502 were conducted in parallel; Study 1501 was conducted at approximately 30 study sites in North America; Study 1502 was conducted at approximately 30 study sites in Europe, Asia and Australia. Upon completion of the Baseline Period after initial Screening and Baseline charting of seizure frequency, subjects who qualified for the studies were randomized (1:1:1) in a double-blind manner to receive either 1 of 2 doses of ZX008 (0.2 mg/kg/day or 0.8 mg/kg/day; maximum dose: 30 mg/day) or placebo. Randomization was stratified by age group (< 6 years, ≥6 to 18 years) to achieve balance across treatment arms, with the target of 25% of subjects in each age group. All subjects were titrated to their randomized dose over a 14-day Titration Period. Following titration, subjects continued treatment at their randomly assigned dose over a 12-week Maintenance Period. Subjects exiting the study underwent a 2-week taper, unless they enrolled in a follow-on study. Subjects were followed for post-study safety monitoring.
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 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of the day of the Screening Visit.
- •Clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.
- •Must have a minimum # of convulsive seizures per 4-week period for past 12 weeks prior to screening.
- •All medications or interventions for epilepsy must be stable for at least 4 weeks prior to screening and expected to remain stable throughout the study.
- •No cardiovascular or cardiopulmonary abnormality based on ECHO, ECG or physical examination.
- •Parent/caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability.
排除标准
- •Pulmonary arterial hypertension.
- •Current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction or stroke.
- •Current or past history of glaucoma.
- •Moderate or severe hepatic impairment.
- •Receiving concomitant therapy with: anorectic agents; monoamine-oxidase inhibitors; medications that act via serotonin including serotonin reuptake inhibitors; atomoxetine, or other centrally-acting noradrenergic agonist; or cyproheptadine.
- •Currently receiving or has received stiripentol in the past 21 days prior to Screening.
- •Currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days.
- •Positive result on tetrahydrocannabinol (THC) or cannabidiol (CBD) test at the Screening Visit.
- •A clinically significant medical condition,that would interfere with study participation, collection of study data, or pose a risk to the subject.
研究组 & 干预措施
ZX008 - 0.2 mg/kg/day
ZX008 (fenfluramine HCl) is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. ZX008 will be administered twice a day (BID) in equally divided doses with food.
干预措施: ZX008 (Fenfluramine Hydrochloride) (Drug)
Matching Placebo
Placebo will be administered twice a day (BID) in equally divided doses with food.
干预措施: Matching Placebo (Drug)
ZX008 - 0.8 mg/kg/day
ZX008 (fenfluramine HCl) is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. ZX008 will be administered twice a day (BID) in equally divided doses with food.
干预措施: ZX008 (Fenfluramine Hydrochloride) (Drug)
结局指标
主要结局
Change From Baseline in the Mean Convulsive Seizures Frequency (MCSF) to the Combined Titration and Maintenance Periods (T+M) in Participants Receiving ZX008 0.8 mg/kg/Day Compared to Placebo
时间窗: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF.
次要结局
- Number of Convulsive Seizure-free Days in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period(During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days))
- Quality of Life (QoL) of the Parent/Caregiver Using the EQ- 5D-5L Scale in Each ZX008 Treatment Arm Compared to Placebo at Baseline and Day 99(At Baseline and Day 99)
- Change From Baseline in Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo(From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)])
- Percentage of Participants Who Achieved a ≥50% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period(From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)])
- Percentage of Participants With Status Epilepticus (SE) in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period(During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days))
- Distribution of Duration of Convulsive Seizures (in Percentage) in Each ZX008 Treatment Arm Compared to Placebo at Baseline and During the Titration and Maintenance Period(At Baseline and 14 weeks of Titration (2 weeks) and Maintenance Period (12 weeks))
- Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Rating Score, as Assessed by the Principal Investigator in Each ZX008 Treatment Arm Compared to Placebo(At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99))
- Change From Baseline in the Mean Convulsive Seizures Frequency to the Combined Titration and Maintenance Period (T+M) in Participants Receiving ZX008 0.2 mg/kg/Day Compared to Placebo(From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)])
- Percentage of Participants Who Achieved Greater Than or Equal to 25% (≥25%) Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period(From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)])
- Percentage of Participants Who Achieved a ≥75% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period(From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)])
- Longest Convulsive Seizure-free Interval in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period(During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days))
- Percentage of Participants Who Achieved a 100% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period(From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)])
- Change From Baseline in Convulsive + Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo(From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)])
- Percentage of Participants With Rescue Medication Usage in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period(From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)])
- Percentage of Participants With Hospitalization and Healthcare Resource Utilization to Treat Seizures in Each ZX008 Treatment Arm Compared to Placebo During Study(During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days))
- Change From Baseline to Day 99 in the Total Score From PedsQL Family Impact Module Score in Each ZX008 Treatment Arm Compared to Placebo(From Baseline to Day 99)
- Percentage of Participants With Clinical Global Impression - Improvement Rating Score, as Assessed by the Parent/Caregiver in Each ZX008 Treatment Arm Compared to Placebo(At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99))
- Change From Baseline to Day 99 in the Quality of Life in Childhood Epilepsy (QOLCE) Score to Measure Quality of Life in Each ZX008 Treatment Arm Compared to Placebo(From Baseline to Day 99)
- Change From Baseline to Day 99 in the Overall Quality of Life Score From the Pediatric Quality of Life Inventory™ (PedsQL) Score in Each ZX008 Treatment Arm Compared to Placebo(From Baseline to Day 99)
- Change From Baseline to Day 99 in Affective Symptoms of the Parent/Caregiver Using the Hospital Anxiety and Depression Scale (HADS) in Each ZX008 Treatment Arm Compared to Placebo(From Baseline to Day 99)
- Time to Maximum Concentration [Tmax] of ZX008 at Steady State(At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose)
- Maximum Observed Concentration of ZX008 Determined Directly From the Concentration Time Profile [Cmax] at Steady State(At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose)
- Area Under the Concentration Time Curve of ZX008 From Time Zero to Time 24 Hours [AUC0-24hours] at Steady State(At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose)
- Elimination Half-life [t1/2 Beta] of ZX008 at Steady State(At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose)