A Multinational, Multicenter Study With an Open-Label Phase 1b and a Randomized, Double-Blind, Placebo-Controlled Phase 3 Followed by an Open-Label Extension to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Radiprodil in Participants With GRIN-Related Neurodevelopmental Disorder
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 100
- 试验地点
- 44
- 主要终点
- Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): Countable motor seizures (CMS)
研究概览
简要总结
The Phase 3 portion of Study RAD-GRIN-101 is a multinational, multicenter, randomized, double-blind, placebo-controlled trial followed by an open-label extension to evaluate the efficacy and safety of radiprodil in participants with GRIN-related neurodevelopmental disorder (GRIN-NDD) with a gain-of-function (GoF) genetic variant.
This study will enroll two cohorts: one cohort of participants with a minimal number of countable motor seizures (with or without behavioral symptoms) (Phase 3 Cohort 1: Qualifying Seizures Cohort); and a second cohort with disease symptoms but no seizures or fewer seizures than required for the Qualifying Seizures Cohort (Phase 3 Cohort 2: Without Qualifying Seizures Auxiliary Cohort).
Participants in each cohort will be randomized 1:1 to receive active drug (radiprodil) or matching placebo (Part A). Following completion of Part A, all eligible participants (including those previously on placebo) may continue into the open-label extension period (Part B) to receive radiprodil.
The placebo-controlled portion is expected to be approximately 16 weeks for participants in Phase 3 Cohort 1 and 28 weeks for participants in Phase 3 Cohort 2.
The study will evaluate the effect of radiprodil on seizures and non-seizure symptoms and assess safety.
详细描述
Participants are assigned in a 1:1 ratio to receive either radiprodil or placebo during Part A with the opportunity to receive radiprodil in the Open-Label Extension, Part B. The dosing regimen includes a fixed titration schedule over 4 weeks.
This study is divided into the following parts:
Part A: Randomized, double-blind, placebo-controlled
- Screening/Observation Period: To assess eligibility
- Titration Period (approximately 4 weeks): Titration of radiprodil or placebo to target dose
- Maintenance Period (Part A): Target dose of radiprodil or placebo maintained for 12 weeks (Phase 3 Cohort 1) or 24 weeks (Phase 3 Cohort 2)
- Tapering and Follow-up Period: Gradual decrease and Follow-up Period for participants not entering Part B
Part B: Open-label safety follow-up period
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
- Triple (Participant, Care Provider, Investigator)
盲法说明
study personnel, sponsor
入排标准
- 年龄范围
- 1 Month 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Part A, Participant:
- •Diagnosed with GRIN-NDD with GRIN1, GRIN2A, GRIN2B, or GRIN2D gene variants known to result in GoF of the NMDA receptor
- •Phase 3 Cohort 1 (Qualifying Seizures Cohort) ONLY: Experiencing at least 1 CMS per week and ≥4 CMS (generalized or focal) during screening
- •With history of inadequate response to at least 2 standard antiseizure medications (ASMs)
- •Phase 3 Cohort 2 (Without Qualifying Seizures Auxiliary Cohort) ONLY: With significant neurodevelopmental symptoms and a GRIN-CGI-S score ≥4
- •On a stable dose of standard ASMs for at least 4 weeks prior to screening and should remain on stable doses throughout study participation
- •On stable nonpharmacological treatments such as ketogenic diet and should remain stable throughout study participation
- •- Participant has completed Part A and is eligible to continue study participation according to the judgement of the investigator and sponsor.
排除标准
- •PART A, Participant:
- •Has clinically relevant medical, neurologic, or psychiatric condition and/or behavioral disorder (including those related to GRIN-NDD) that would preclude or jeopardize participant's safe participation or study drug administration or the conduct of the study according to the judgement of the investigator or sponsor.
- •Is receiving >4 standard ASMs at screening
- •Has a body weight of less than 5 kg at screening
- •- Participant has clinically relevant medical, neurologic, or psychiatric condition and/or behavioral disorder (including those related to GRIN-NDD) that would preclude or jeopardize participant's safe participation of study drug administration or the conduct of the study according to the judgement of the investigator or sponsor.
研究组 & 干预措施
Placebo
Liquid suspension of placebo matching radiprodil oral suspension and dose-escalation regimen.
干预措施: Placebo (Drug)
Radiprodil
Liquid suspension of radiprodil, at varying concentrations depending on participant's weight.
The following dose-escalation regimen (twice daily [BID]) will be used:
Titration Period Visit 1 (Visit T1): Dose 1, Visit T2: Dose 2, Visit T3: Dose 3, Visit T4: Maintenance Dose.
干预措施: Radiprodil (Drug)
结局指标
主要结局
Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): Countable motor seizures (CMS)
时间窗: 12 weeks
Part A - Phase 3 Cohort 2 (Without Qualifying Seizures Auxiliary Cohort): Adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs)
时间窗: 24 weeks
Part B - Open-Label Extension: Adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs)
时间窗: Average of 2 years
次要结局
- Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): Proportion of participants with ≥50% reduction in CMS(12 weeks)
- Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): CMS-free days(12 weeks)
- Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): GRIN-NDD-specific Clinical Global Impression - Change [CGI-C] scale(12 weeks)
- Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): Aberrant Behavior Checklist-Community (ABC-2C) irritability subscale(12 weeks)
- Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): Vineland Adaptive Behavior Scale 3rd edition (VABS-3) daily living personal subdomain(12 weeks)
- Part A - Phase 3 Cohort 2 (Without Qualifying Seizures Auxiliary Cohort): GRIN-CGI-C scale(24 weeks)
- Part A - Phase 3 Cohort 2 (Without Qualifying Seizures Auxiliary Cohort): ABC-2C irritability subscale(24 weeks)
- Part A - Phase 3 Cohort 2 (Without Qualifying Seizures Auxiliary Cohort): VABS-3 daily living personal subdomain(24 weeks)
- PART B - Open-Label Extension: CMS frequency(average of 2 years)
- PART B - Open-Label Extension: CMS-free days(average of 2 years)
- PART B - Open-Label Extension: ABC-2C irritability subscale(average of 2 years)
- PART B - Open-Label Extension: VABS-3 daily living personal subdomain score(average of 2 years)
- PART B - Open-Label Extension: GRIN-CGI-C scale(average of 2 years)