Evaluation of Radiprodil in Children With GRIN-related Disorder

Study Overview
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Brief Summary
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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. Subjects' participation in the study is expected to last up to six months. The study is open-label, so all participants will be treated with radiprodil. After the end of this study, all participants who are still eligible can choose to continue to receive radiprodil as part of an open-label extension period.

Detailed Description
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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: Screening/Observation Period (five (5) weeks): Investigators assess eligibility followed by a four(4)- week Observation Period to evaluate seizure frequency and/or behavioral symptoms. Titration Period (up to 43 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. A Maintenance Period (approx. 50 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 the extension study, during which the participant will continue taking radiprodil at the usual dose level and making regular visits to the study site or taper off 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.

Official Title
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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

Conditions
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GRIN-related Disorders

Intervention / Treatment
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* Drug: Radiprodil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 ≥4. Stable antiseizure therapies and nonpharmacological treatments such as ketogenic diet throughout screening and study participation. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiprodil<br>Liquid suspension of Radiprodil, administered twice a day (bid) either orally or via gastric or nasogastric tube, slowly up-titrated to the highest tolerated dose. | Drug: Radiprodil<br>* Radiprodil is an orally active, negative allosteric modulator of the NR2B subunit of the NMDA receptor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), TEAEs Leading to Discontinuation and Severity of TEAEs | Frequency, type, severity and duration of adverse events, serious adverse events and adverse drug reactions. | from Baseline to End-of-study: up to 20 weeks | 
| Maximum Plasma concentration of radiprodil (Cmax) |  | 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) |  | 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) |  | 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) |  | 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) |  | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline in V-EEG seizure burden | Assessed by 8- to 24- hour video electroencephalogram | Baseline to end-of-treatment: week 5 to week 20 | 
| Change from baseline in seizure frequency | Assessed by seizure diaries | Baseline to end-of-treatment: week 5 to week 20 | 
| Aberrant Behavior Checklist-Community (ABC-C) | The ABCC is a standardized 58-item caregiver-reported problem-behavior rating scale, originally designed to assess treatment effects in people with intellectual disabilities. Each item is scored from 0 (never a problem) to 3 (severe problem). Items load onto one of five empirically derived subscales: Irritability, Agitation, & Crying (15 items); Lethargy/Social Withdrawal (16 items); Stereotypic Behavior (7 items); Hyperactivity/Noncompliance (16 items); and Inappropriate Speech (4 items). A total score would range from 0 to 174. | Baseline to End-of-Treatment: week 5 to week 20 | 
| Caregiver Global Impression of Change (CaGI-C) | The CaGI-C is a 7-point caregiver-rated scale ranging from 1 (very much improved) to 7 (very much worse). | Baseline to End-of-Treatment: week 5 to week 20 | 
| Change from Baseline in Clinical Global Impression - Severity [CGI-S] | The CGI-S scale is a clinician-rated measures of severity of a symptom or condition, using a single item, 6- or 7-point scale. The CGI-S scale ranges from 1 (None) to 6 (Very Severe). | Baseline to End-of-Treatment: week 5 to week 20 | 
| Clinical Global Impression of Change [CGI-C] | The CGI scale is a clinician-rated measures of change of a symptom or condition, using a single item, 6- or 7-point scale. The CGI-C scale ranges from 1 (Very much worse) to 7 (Very much improved). | Baseline to End-of-Treatment: week 5 to week 20 | 
| Gross Motor Function Measure (GMFM) | The GMFM is a standardized observational instrument designed and validated to measure change in gross motor function over time in children with cerebral palsy. There is a 4-point (0 to 3) scoring system for each of the 5 dimensions of gross motor function, with higher scores denoting better performance. | Baseline to End-of-Treatment: week 5 to week 20 | 
| Sleep Disturbance Scale for Children (SDSC) | The SDSC is a parent-report measure to screen for sleep disturbances within the preceding period. It is a 27-item questionnaire rated on a 5-point Likert scale, with higher scores being indicative of more acute sleep disturbances. | Baseline to End-of-Treatment: week 5 to week 20 | 
| Pediatric Quality of Life Inventory [PedsQL] | The PedsQL is a 23-item generic health status instrument assessing 5 domains of health in children. It's a 0-100 scale, and higher scores are indicative of better health-related quality of life. | Baseline to End-of-Treatment: week 5 to week 20 | 
| Caregiver Burden Inventory (CBI) | The CBI is a validated scale providing information regarding the impact of caregiving on the lives of caregivers. It comprises 24 closed questions divided into 5 dimensions. Each dimension includes 4 or 5 items. Each item is given a score between 0 and 4, where higher scores indicate greater caregiver burden. | Baseline to End-of-Treatment: week 5 to week 20 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GRIN1, GRIN2A, GRIN2B, GRIN2D