GRIN-related Neurodevelopmental Disorder
Conditions
Keywords
Beeline, GRIN1, GRIN2A, GRIN2B, GRIN2D, GRIN-NDD
Brief summary
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.
Detailed description
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Period: Participants will continue to receive radiprodil until such time as either the participant withdraws/is withdrawn from the study, sponsor terminates the study, or market access is available * Tapering and Follow-up Period: Gradual decrease and follow-up observation period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
Interventions
DRUGRadiprodil
Radiprodil oral suspension
DRUGPlacebo
Placebo-to-match radiprodil oral suspension
Sponsors
GRIN Therapeutics, Inc.
Aziende Chimiche Riunite Angelini Francesco S.p.A
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
study personnel, sponsor
Eligibility
Sex/Gender
ALL
Age
1 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
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.
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part A - Phase 3 Cohort 1 (Qualifying Seizures Cohort): Countable motor seizures (CMS) | 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) | 24 weeks |
| Part B - Open-Label Extension: Adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs) | Average of 2 years |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
Countries
Belgium, France, Germany, Italy, Netherlands, Poland, Slovenia, Spain, United Kingdom, United States
Contacts
CONTACTClinical Operations
STUDY_DIRECTORStephen Tisi
GRIN Therapeutics, Inc.
STUDY_DIRECTORRussell Chin
GRIN Therapeutics, Inc.
Outcome results
None listed