gain of function (GoF) variants in the GRIN 1, 2A, 2B or 2D genes MedDRA version: 26.0 Level: PT Classification code 10064062 Term: Neurodevelopmental disorder System Organ Class: 10029205 - Nervous system disorders
Conditions
Sponsors
GRIN Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: For Part A and Part B (unless stated otherwise): 1. For Part A, pediatric participants aged =6 months to =12 years with GRIN 1, 2A, 2B, or 2D gene variants known to result in GoF of the NMDA receptor. For Part B, pediatric participants aged =6 months with GRIN 1, 2A, 2B, or 2D gene variants known to result in GoF of the NMDA receptor. 2. Participant to be enrolled in the first cohort experiences the following (Part A only): a) At least 1 observable motor seizure per week and =4 observable motor seizures (generalized or focal) during the prospective 4-week Observation Period. b) Has failed to obtain adequate seizure control with at least 2 ASMs used at appropriate dose and duration with assured medication adherence (if applicable). 3. Participant to be enrolled in the second cohort experiences the following (Part A only): a) Significant behavioral and/or motor symptoms based on caregiver report with a CGI-S score =4 at the Screening Visit and Day -1 of Visit T1. 4. For Part A, current therapies need to be on a stable dose for at least 4 weeks prior to Screening and should be maintained stable throughout the whole study duration. Nonpharmacological treatments such as ketogenic diet should be kept as stable as possible during screening and participation in the study. Changes in antiseizure medication should be discussed with the sponsor in consultation with the investigator. 5. Participant’s caregivers have signed informed consent and participant has signed assent (if applicable). 6. Participant’s caregivers are willing and able to complete entries in the eDiary on a daily basis. 7. Participant is 1 of the following: a. Not of childbearing potential (premenarchal or male/not in possession of a uterus). b. If of childbearing potential, is nonpregnant (negative serum pregnancy test results at Screening), nonlactating, and practicing 1 of the following medically acceptable methods of birth control: • Abstinence from heterosexual intercourse as a lifestyle choice. • Hormonal methods such as oral, implantable, injectable, or transdermal contraceptives for a minimum of 1 full cycle (based on the participant’s usual menstrual cycle period) before IP administration. • Intrauterine device. c. If male, is willing to use a highly effective method of contraception throughout the study period. Rescreening criteria for Part B only: 1. Participant has received at least 8 weeks of treatment (combined Titration and Maintenance Period) with radiprodil during Part A. 2. The benefit-risk of continuing radiprodil treatment remains favorable as determined by the investigator’s clinical assessment and is eligible to continue treatment according to the judgement of the investigator. Are the trial subjects under 18? yes Number of subjects for this age range: 24 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Exclusion criteria (at initial Screening and following completion of the Maintenance Period of Part A, unless stated otherwise): 1. Participant with any other clinically relevant medical, neurologic, or psychiatric condition and/or behavioral disorder unrelated to GRIN-related disorders that would preclude or jeopardize participant’s safe participation or administration of study drug or the conduct of the study according to the judgement of the investigator. 2. Participant with a body weight <10 kg on Day -1 of Visit T1 for whom a gastric tube is the only possibility for radiprodil dosing (during treatment with the first dose in Part A only). 3. Participant with any clinically significant laboratory or ECG abnormalities. 4. Participant has severe hepatic dysfunction (Child-Pugh grade C). 5. Participant has a history of brain surgery for epilepsy or any other reason. 6. Participant with any contraindications to radiprodil or with known hypersensitivity to the active substance or the excipients or other chemically closely related substances. 7. Participant receiving treatment with contraindicated concomitant drugs such as agonists or antagonists of the glutamate receptor, including but not limited to lamotrigine, felbamate, memantine, and perampanel. 8. Participant is on treatment with hormonal therapy such as adrenocorticotrophic hormone or prednisolone (Part A only). 9. Participant has participated in any other investigational clinical study within 3 months of Screening (Part A only).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: •To determine the safety and tolerability of multiple individually titrated doses of radiprodil as an add-on therapy to standard of care (SOC) in pediatric participants •To establish a safe and well tolerated dose after 8 weeks of continuous treatment •To determine the pharmacokinetics (PK) and plasma exposure of radiprodil;Secondary Objective: •To evaluate initial signs of efficacy on frequency and severity of epileptic seizures in those participants with seizures •To evaluate initial signs of efficacy of radiprodil on additional central nervous system (CNS) features including, behavior, motor symptoms, sleep, quality of life, and the maintenance of the treatment effect ;Primary end point(s): •Adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs) (frequency, type, severity, and duration) •Changes in vital signs •Physical examination findings •12-lead electrocardiogram (ECG) findings •Clinically significant changes in laboratory parameters •Emergence of new seizure types •Occurrence of suicidal ideation or behavior •Plasma concentrations of radiprodil at predefined timepoints ;Timepoint(s) of evaluation of this end point: Please refer to the Schedule of Events presented in the study protocol (Table 2-1 (Part A), page 17-18 and to Table 2-2 (Part B), page 21-22) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •Change from Baseline to end of treatment in seizure frequency from daily seizure electronic diary (eDiary) •Percent change from Baseline to end of treatment in video electroencephalogram (V EEG) seizure burden (e.g., seizure type, severity, and frequency recorded during V EEGs) •Seizure free days and longest period with no seizures •Change from Baseline to end of treatment in behavioral features as measured by the aberrant behavior checklist-community (ABC-C), as well as other disorder features as measured by gross motor function measure (GMFM), sleep disturbance scale for children (SDSC), quality of life (Pediatric Quality of Life Inventory [PedsQL]), Caregiver Burden Inventory (CBI),and global impression (Caregiver Global Impression of Change [CaGI-C]), and Clinical Global Impression of Change [CGI-C] scales) ;Timepoint(s) of evaluation of this end point: Please refer to the Schedule of Events presented in the study protocol (Table 2-1 (Part A), page 17-18 and to Table 2-2 (Part B), page 21-22) | — |
Countries
Canada, Germany, Italy, Netherlands, Spain, United States
Contacts
Public ContactClinical Operations
GRIN Therapeutics, Inc.
Outcome results
None listed