gain of function (GoF) variants in the GRIN2B gene MedDRA version: 21.1 Level: PT Classification code 10064062 Term: Neurodevelopmental disorder System Organ Class: 10037175 - Psychiatric disorders
Conditions
Sponsors
GRIN Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Pediatric participants aged =6 months to =12 years with GRIN2B gene variants known to result in GoF of the NMDA receptor. 2.Participant to be enrolled in the first cohort experiences the following: 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: 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.Current antiseizure therapies should be maintained stable throughout the whole study duration, and nonpharmacological treatments such as ketogenic diet should be kept as stable as possible during the participation in the study. 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 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. Are the trial subjects under 18? yes Number of subjects for this age range: 12 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: 1.Participant with any other clinically relevant medical, neurologic, or psychiatric condition and/or behavioral disorder unrelated to GRIN2B that would preclude or jeopardize participant’s safe participation or the conduct of the study according to the judgement of the investigator. 2.Participant with any clinically significant laboratory or ECG abnormalities. 3. Participant has severe hepatic dysfunction (Child-Pugh grade C). 4.Participant has a history of brain surgery for epilepsy or any other reason. 5.Participant with any contraindications to radiprodil or with known hypersensitivity to the active substance or the excipients or other chemically closely related substances. 6.Participant receiving treatment with contraindicated concomitant drugs such as agonists or antagonists of the glutamate receptor, including but not limited to felbamate, memantine, and perampanel. 7.Participant is on treatment with hormonal therapy such as adrenocorticotrophic hormone or prednisolone. 8.Participant receiving treatment with marijuana or tetrahydrocannabinol or derivatives (the use of Epidiolex® is permitted). 9.Participant has participated in any other investigational clinical study within 3 months of Screening. 10.Participant has previously been enrolled in the current study
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, and quality of life •To determine the PK and the plasma exposure of radiprodil major metabolites obtained at different doses ;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 •Tolerable dose that delivers the highest expected estimated receptor occupancy (RO) of approximately 80% •Plasma concentrations of radiprodil ;Timepoint(s) of evaluation of this end point: Please refer to the Schedule of Events presented in the study protocol (table 2-1, page 15-16) | — |
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 (ABCC), 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) •Plasma concentrations of the 2 major metabolites of radiprodil ;Timepoint(s) of evaluation of this end point: Please refer to the Schedule of Events presented in the study protocol (table 2-1, page 15-16) | — |
Countries
Germany, Italy, Netherlands, Spain, United States
Contacts
Public ContactClinical Operations
GRIN Therapeutics, Inc.
Outcome results
None listed