Beeline: A Phase 3 Study in GRIN-related Neurodevelopmental Disorder

Официальное название

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

Обзор

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.

Подробное описание

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

* Open-Label Treatment Period: Participants will continue to receive radiprodil until such time as either the participant withdraws/is withdrawn from the study, sponsor terminates the study, or market access is available * Tapering and Follow-up Period: Gradual decrease and follow-up observation period for participants upon leaving the study

Вмешательства

• Препарат Radiprodil
  Radiprodil oral suspension
• Препарат Placebo
  Placebo-to-match radiprodil oral suspension

Первичные конечные точки

• Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): Countable motor seizures (CMS) [Срок оценки: 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) [Срок оценки: 24 weeks]
• Part B - Open-Label Extension: Adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs) [Срок оценки: Average of 2 years]

Вторичные конечные точки (12)

• Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): Proportion of participants with ≥50% reduction in CMS [Срок оценки: 12 weeks]
• Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): CMS-free days [Срок оценки: 12 weeks]
• Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): GRIN-NDD-specific Clinical Global Impression - Change [CGI-C] scale [Срок оценки: 12 weeks]
• Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): Aberrant Behavior Checklist-Community (ABC-2C) irritability subscale [Срок оценки: 12 weeks]
• Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): Vineland Adaptive Behavior Scale 3rd edition (VABS-3) daily living personal subdomain [Срок оценки: 12 weeks]
• Part A - Phase 3 Cohort 2 (Without Qualifying Seizures Auxiliary Cohort): GRIN-CGI-C scale [Срок оценки: 24 weeks]
• Part A - Phase 3 Cohort 2 (Without Qualifying Seizures Auxiliary Cohort): ABC-2C irritability subscale [Срок оценки: 24 weeks]
• Part A - Phase 3 Cohort 2 (Without Qualifying Seizures Auxiliary Cohort): VABS-3 daily living personal subdomain [Срок оценки: 24 weeks]
• PART B - Open-Label Extension: CMS frequency [Срок оценки: average of 2 years]
• PART B - Open-Label Extension: CMS-free days [Срок оценки: average of 2 years]
• PART B - Open-Label Extension: ABC-2C irritability subscale [Срок оценки: average of 2 years]
• PART B - Open-Label Extension: VABS-3 daily living personal subdomain score [Срок оценки: average of 2 years]

Критерии участия

Критерии включения

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

Part B:

\- Participant has completed Part A and is eligible to continue study participation according to the judgement of the investigator and sponsor.

Критерии исключения

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

Part B:

\- 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

США · 17 центров

• UCLA Health - Ronald Reagan UCLA Medical Center — Los Angeles
• Lucile Packard Children's Hospital — Palo Alto
• Children's Hospital Colorado - Anschutz Medical Campus — Aurora
• Children's National Hospital — Washington D.C.
• Nicklaus Children's Hospital — Miami
• Pediatric Neurology and Epilepsy — Winter Park
• Iowa Health Care - Pediatric Neurology & Specialty Clinic — Iowa City
• Boston Children's Hospital — Boston
• … и ещё 9 центров

Франция · 4 центра

• Centre Hospitalier Universitaire d'Angers (CHU Angers) — Angers
• Hospices Civils De Lyon — Bron
• Hôpital Necker Enfants Malades — Paris
• CHU Toulouse - Hôpital Purpan — Toulouse

Италия · 3 центра

• Azienda Ospedaliera Universitaria Meyer IRCCS — Florence
• IRCCS Fondazione Istituto Neurologico Nazionale Casimiro Mondino — Pavia
• Ospedale Pediatrico Bambino Gesu — Roma

Великобритания · 3 центра

• Sheffield Children's Hospital NHS Foundation Trust — Sheffield
• Royal Hospital for Children Glasgow — Glasgow
• Great Ormond Street Hospital For Children NHS Foundation Trust — London

Германия · 2 центра

• Universitatsmedizin Greifswald Klinik und Poliklinik fur Frauenheilkunde und Geburtshilfe — Greifswald
• Klinik und Policlinik fur Kinder - und Jugendmedizin — Leipzig

Бельгия · 1 центр

• UZ Brussel — Brussels

Нидерланды · 1 центр

• Erasmus MC (Erasmus Universitair Medisch Centrum Rotterdam) — Rotterdam

Польша · 1 центр

• Institute of Polish Mother's Health Center (Instytut Centrum Zdrowia Matki Polki) — Lodz

Словения · 1 центр

• University Children's Hospital — Ljubljana

Испания · 1 центр

• Hospital Sant Joan de Deus — Esplugues de Llobregat

Идентификаторы

NCT: NCT07224581 · Beeline RAD-GRIN-101

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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