A Multicenter, Open-label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effect on Seizures and Behavioral Symptoms of Radiprodil in Patients With Tuberous Sclerosis Complex (TSC) or Focal Cortical Dysplasia (FCD) Type II
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 20
- 主要终点
- Pharmacokinetic plasma concentration of radiprodil: half-life (T1/2)
研究概览
简要总结
Study RAD-GRIN-201 is a phase 1B/2A trial to assess safety, tolerability, pharmacokinetics (PK), and potential efficacy of radiprodil in participants with Tuberous Sclerosis Complex (TSC) or Focal Cortical Dysplasia (FCD) type II. The study is open-label, so all participants will be treated with radiprodil. Subjects' participation in the study is expected to last up to six months in Part A and one year in Part B/long-term treatment period. The treatment period in Part B may be extended based on a favorable benefit/risk profile.
详细描述
Approximately 20 participants with TSC and 10 participants with FCD type II will be enrolled.
The effects of radiprodil are assessed in participants with treatment-resistant seizures (with or without behavioral symptoms). The daily doses of radiprodil will be individually titrated for every participant and all the participants will receive study drug.
This study is divided into the following periods:
PART A:
- Screening/Observation Period (up to six(6) weeks): Investigators assess eligibility followed by an Observation Period (at least four(4) weeks) to evaluate seizure frequency.
- Titration Period (approx. four(4) weeks): Radiprodil twice daily will be administered in escalating doses and plasma concentrations, safety, and tolerability assessed. Once a safe and potentially effective dose has been established, the participant will immediately enter the Maintenance Period.
- Maintenance Period (approx. twelve(12) weeks): The participant will continue to take the safe and potentially effective dose identified during the Titration Period. At the end of the Maintenance Period the participant will either be invited to enter Part B or the Tapering and Safety Follow-up Period.
- Tapering (15 days) and Safety Follow-up Period (14 days): a participant who doesn't take part in the long-term treatment period (Part B) will taper (ie gradually decrease) the study medicine for 15 days and enter a safety Follow-up Period (14 days). In this case, the participant will have one (1) last visit at the end of the safety Follow-up Period.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Failed to respond to at least 2 anti-seizure medications (ASMs) at appropriate dosages and duration.
- •Disease specific criteria:
- •diagnosis of FCD Type II based on clinical symptoms and confirmed by a positive magnetic resonance imaging (MRI)
- •diagnosis of TSC by either clinical or genetic diagnostic criteria (Northrup, 2021) as documented in the participant's medical record.
- •Participant on average has had at least 8 countable/witnessed primary seizures during a 4-week baseline period with at least 1 seizure occurring in at least 3 of the 4 weeks of baseline
- •All medical interventions for epilepsy / behavior (including ketogenic diet and any neurostimulation devices) should be stable for 28 days prior to screening with no more than 6 days per month use of rescue medication. Participants must remain on a stable regimen throughout the treatment period.
- •Participant has had an MRI scan within 12 months of the planned date of first dose of study drug.
排除标准
- •Any other clinically relevant medical, neurologic, or psychiatric condition and/or behavioral disorder unrelated to TSC or FCD Type II that would preclude or jeopardize participant's safe participation or administration of study drug or the conduct of the study according to the judgement of the investigator.
- •Clinically significant laboratory or ECG abnormalities.
- •Severe hepatic dysfunction (Child-Pugh grade C).
- •History of brain surgery within 6 months of screening for epilepsy or any other reason.
- •Contraindications to radiprodil or with known hypersensitivity to the active substance or the excipients or other chemically closely related substances.
- •Receiving treatment with contraindicated concomitant drugs such as agonists or antagonists of the glutamate receptor, including but not limited to felbamate, memantine, and perampanel.
- •body weight <10kg for whom a gastric tube is the only possibility for radiprodil dosing.
研究组 & 干预措施
TSC
Liquid suspension of radiprodil, at concentrations 0.25 mg/mL or 2.50 mg/mL for 1% and 10% formulation respectively. It will be administered twice a day (bid) either orally or via gastric or nasogastric tube.
干预措施: Radiprodil (Drug)
FCD Type II
Liquid suspension of radiprodil, at concentrations 0.25 mg/mL or 2.50 mg/mL for 1% and 10% formulation respectively. It will be administered twice a day (bid) either orally or via gastric or nasogastric tube.
干预措施: Radiprodil (Drug)
结局指标
主要结局
Pharmacokinetic plasma concentration of radiprodil: half-life (T1/2)
时间窗: Titration Visit 1 (week 7): Pre-dose to 12 hours post-dose. Titration Visits 2,3,4 (week 8 to 13) and Maintenance Visit 7 (week 25): pre-dose to 5 hours post-dose
Number of participants with abnormal physical and neurological examination findings
时间窗: Baseline, MV7, and in Part B: Month 3, 6, 9, 12: week 6, week 28, week 40, week 52, week 64, week 76
A complete physical and neurological examination according to standard of care excluding the genitourinary examination will be performed
12-Lead ECG: Mean change from Baseline to End-of-Treatment in QRS interval
时间窗: from Baseline to End-of-study: 1 year 6 months
Pharmacokinetic plasma concentration of radiprodil, clearance (Cl)
时间窗: Titration Visit 1 (week 7): Pre-dose to 12 hours post-dose. Titration Visits 2,3,4 (week 8 to 13) and Maintenance Visit 7 (week 25): pre-dose to 5 hours post-dose
Clinically relevant changes in safety parameters: systolic blood pressure
时间窗: from Baseline to End-of-study: 1 year 6 months
changes from Baseline to End of study for systolic blood pressure
12-Lead ECG: Mean change from Baseline to End-of-Treatment in QTcF interval
时间窗: from Baseline to End-of-study: 1 year 6 months
Incidence of Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), Adverse Drug Reactions (ADRs), TEAEs Leading to Discontinuation and Severity of TEAEs
时间窗: from Baseline to End-of-study: 1 year 6 months
Frequency, type, severity and duration of adverse events, serious adverse events and adverse drug reactions.
Plasma concentration of radiprodil and maximum plasma concentration (Cmax)
时间窗: Titration Visit 1 (week 7): Pre-dose to 12 hours post-dose. Titration Visits 2,3,4 (week 8 to 13) and Maintenance Visit 7 (week 25): pre-dose to 5 hours post-dose
Pharmacokinetic plasma concentration of radiprodil: time to Cmax (Tmax)
时间窗: Titration Visit 1 (week 7): Pre-dose to 12 hours post-dose. Titration Visits 2,3,4 (week 8 to 13) and Maintenance Visit 7 (week 25): pre-dose to 5 hours post-dose
Number of participants with abnormal laboratory tests results
时间窗: from Baseline to End-of-study: 1 year 6 months
The clinical laboratory tests include Hematology, Serum Chemistry and Coagulation
Clinically relevant changes in safety parameters: pulse rate
时间窗: from Baseline to End-of-study: 1 year 6 months
changes from Baseline to End of Treatment for pulse rate
12-Lead ECG: Mean change from Baseline to End-of-Treatment in RR interval
时间窗: from Baseline to End-of-study: 1 year 6 months
12-Lead ECG: Mean change from Baseline to End-of-Treatment in QT interval
时间窗: from Baseline to End-of-study: 1 year 6 months
Plasma concentration of radiprodil versus time, area under the curve (AUCt)
时间窗: Titration Visit 1 (week 7): Pre-dose to 12 hours post-dose. Titration Visits 2,3,4 (week 8 to 13) and Maintenance Visit 7 (week 25): pre-dose to 5 hours post-dose
12-Lead ECG: Mean change from Baseline to End-of-Treatment in PR interval
时间窗: from Baseline to End-of-study: 1 year 6 months
Clinically relevant changes in safety parameters: diastolic blood pressure
时间窗: from Baseline to End-of-study: 1 year 6 months
changes from Baseline to End of study for diastolic blood pressure
次要结局
- Change from baseline in number of seizure-free days and longest period with no seizures(Baseline to end-of-treatment: week 6 to week 76)
- Pediatric Quality of Life Inventory [PedsQL](Baseline to end-of-treatment: week 6 to week 76)
- Percent change from baseline in Video-EEG seizure burden(Baseline to end-of-treatment: week 6 to week 76)
- Change from baseline in seizure frequency(Baseline to Maintenance Visit 7: week 6 to week 25 and Baseline to end-of-treatment: week 6 to week 76)
- Aberrant Behavior Checklist-Community (ABC-2C)(Baseline to end-of-treatment: week 6 to week 76)
- Columbia-Suicide Severity Rating Scale (C-SSRS)(Baseline to end-of-treatment: week 6 to week 76)
- Caregiver Global Impression of Change (CaGI-C)(Baseline to end-of-treatment: week 6 to week 76)
- Caregiver Burden Inventory (CBI)(Baseline to end-of-treatment: week 6 to week 76)
- Clinical Global Impression of Change [CGI-C](Baseline to end-of-treatment: week 6 to week 76)