A Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effect on Seizures and Behavioral Symptoms of Multiple Individually Titrated Doses of Radiprodil in Children with GRIN-related Disorder
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 24
- 试验地点
- 15
- 主要终点
- Incidence of Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), TEAEs Leading to Discontinuation and Severity of TEAEs
研究概览
简要总结
Study RAD-GRIN-101 is a phase 1B trial to assess safety, tolerability, PK, and potential efficacy of radiprodil for the treatment of GRIN-related disorder in children with a Gain-of-Function (GoF) genetic variant. 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.
After the end of part A, all participants who are still eligible can choose to continue to receive radiprodil as part of an open-label long-term treatment period (Part B).
详细描述
The effect of radiprodil is assessed in two (2) cohorts of pediatric participants: one (1) cohort of participants with treatment-resistant seizures (with or without behavioral symptoms) (Cohort 1) and one (1) cohort of participants with behavioral symptoms but no qualifying seizures (Cohort 2) caused by Gain-of-Function (GoF) variants in the GRIN gene. As the daily doses of radiprodil will be individually titrated for every participant and all the participants will receive the study drug, this is in effect a "single group" study.
This study is divided into the following periods:
PART A:
- Screening/Observation Period (35 days): Investigators assess eligibility followed by a four(4)- week Observation Period to evaluate seizure frequency and/or behavioral symptoms.
- Titration Period (approx. 51 days): Overnight stay to administer radiprodil twice daily to assigned dose level, assessing plasma concentrations, safety, and tolerability during the titration period. Once a safe and potentially effective dose has been established, the participant will immediately enter the Maintenance Period.
- Maintenance Period (up to 53 days): During the Maintenance Period, the participant will continue to take the highest safe and potentially effective dose, as identified during the Titration Period. At the end of the Maintenance Period, there will be an additional overnight stay when the participant will either be invited to take part in Part B or enter the Tapering and Safety Follow-up Period.
- Tapering (15 days) and Safety Follow-up Period (14 days): the participant who doesn't take part in the long-term treatment period (Part B) will need to taper off (ie gradually decrease) the study medicine for 15 days and enter a safety Follow-up Period (14 days). In this case, the participant will make one (1) last visit to the study site 14 days after his/her last dose of radiprodil.
PART B:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: ≥6 months to ≤12 years, with GRIN gene variants known to result in GoF of the NMDA receptor.
- •Cohort 1 must have at least 1 observable motor seizure per week and ≥4 observable motor seizures (generalized or focal) during the prospective 4-week Observation Period and must have failed to obtain adequate seizure control with at least 2 antiseizure medications (ASMs) used at appropriate dose and duration.
- •Cohort 2 must have significant behavioral and/or motor symptoms based on caregiver report with a CGI-S score ≥
- •Stable antiseizure therapies and nonpharmacological treatments such as ketogenic diet throughout screening and study participation.
排除标准
- •Any other clinically relevant medical, neurologic, or psychiatric condition and/or behavioral disorder unrelated to GRIN-related disorder that would preclude or jeopardize participant's safe participation 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 for epilepsy or any other reason.
- •Receiving treatment with contraindicated concomitant drugs such as agonists or antagonists of the glutamate receptor, including but not limited to felbamate, memantine, and perampanel.
- •Receiving treatment with hormonal therapy such as adrenocorticotrophic hormone or prednisolone.
研究组 & 干预措施
Radiprodil
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, slowly up-titrated to the highest tolerated dose.
干预措施: Radiprodil (Drug)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), TEAEs Leading to Discontinuation and Severity of TEAEs
时间窗: through study completion (average of 2 years).
Frequency, type, severity and duration of adverse events, serious adverse events and adverse drug reactions.
Maximum Plasma concentration of radiprodil (Cmax)
时间窗: Titration Visit 1 (week 5): 0,1,2,4,6,8,10,12 hours post-dose. Titration Visits 2,3,4 (week 6 to 11) and Maintenance Visit 4 (week 20): 0,1,2,5 hours post-dose.
Pharmacokinetic plasma concentration of radiprodil: half-life (T1/2)
时间窗: Titration Visit 1 (week 5): 0,1,2,4,6,8,10,12 hours post-dose. Titration Visits 2,3,4 (week 6 to 11) and Maintenance Visit 4 (week 20): 0,1,2,5 hours post-dose.
Pharmacokinetic plasma concentration of radiprodil, Time corresponding to occurrence of Cmax (Tmax)
时间窗: Titration Visit 1 (week 5): 0,1,2,4,6,8,10,12 hours post-dose. Titration Visits 2,3,4 (week 6 to 11) and Maintenance Visit 4 (week 20): 0,1,2,5 hours post-dose.
Plasma concentration of radiprodil versus time, area under the curve (AUCt)
时间窗: Titration Visit 1 (week 5): 0,1,2,4,6,8,10,12 hours post-dose. Titration Visits 2,3,4 (week 6 to 11) and Maintenance Visit 4 (week 20): 0,1,2,5 hours post-dose.
Pharmacokinetic plasma concentration of radiprodil, clearance (Cl)
时间窗: Titration Visit 1 (week 5): 0,1,2,4,6,8,10,12 hours post-dose. Titration Visits 2,3,4 (week 6 to 11) and Maintenance Visit 4 (week 20): 0,1,2,5 hours post-dose.
次要结局
- Percent change from baseline in V-EEG seizure burden(Baseline (week 5) to study completion (average of 2 years).)
- Change from baseline in seizure frequency(Baseline (week 5) to study completion (average of 2 years).)
- Change from Baseline in Clinical Global Impression - Severity [CGI-S](Baseline (week 5) to study completion (average of 2 years).)
- Clinical Global Impression of Change [CGI-C](Baseline (week 5) to study completion (average of 2 years).)
- Caregiver Global Impression of Change (CaGI-C)(Baseline (week 5) to study completion (average of 2 years).)
- Gross Motor Function Measure (GMFM)(Baseline (week 5) to study completion (average of 2 years).)
- Caregiver Burden Inventory (CBI)(Baseline (week 5) to study completion (average of 2 years).)
- Aberrant Behavior Checklist-Community (ABC-C)(Baseline (week 5) to study completion (average of 2 years).)
- Sleep Disturbance Scale for Children (SDSC)(Baseline (week 5) to study completion (average of 2 years).)
- Pediatric Quality of Life Inventory [PedsQL](Baseline (week 5) to study completion (average of 2 years).)