Evaluation of Radiprodil's Safety, Tolerability, and Pharmacokinetics in Pediatric GRIN-Related Disorder: A Multicenter Study
- Trial ID
- 2023-509672-42-00
- Protocol
- RAD-GRIN-101
- Sponsor
- Grin Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objectives of this multicenter study are to determine the long-term **safety** and tolerability of multiple individually titrated doses of **radiprodil** as an add-on therapy to standard of care in pediatric participants with GRIN-related disorder. Additionally, the study aims to establish a safe and well-tolerated dose after 8 weeks of continuous treatment in Part A, and to determine the pharmacokinetics and plasma exposure of radiprodil. These objectives are clinically relevant as they address the need for effective and safe treatment options for children with GRIN-related disorder, a condition characterized by severe neurological symptoms.
Secondary objectives include evaluating initial signs of efficacy on the frequency and severity of epileptic seizures in participants with seizures, and assessing the initial signs of efficacy of radiprodil on additional central nervous system features such as behavior, motor symptoms, sleep, quality of life, and the maintenance of the treatment effect. These evaluations are crucial for understanding the broader impact of radiprodil on the quality of life and neurological function in affected children.
Participants
The clinical trial involves a total of **7 pediatric participants** diagnosed with **GRIN-related disorder**, specifically those with GRIN 1, 2A, 2B, or 2D gene variants known to result in gain-of-function (GoF) of the NMDA receptor. The study population includes both **male and female subjects** aged between **6 months to 12 years**. Participants were selected based on their medical condition and the presence of observable motor seizures or significant behavioral and/or motor symptoms. The trial population is considered vulnerable due to the pediatric nature of the participants. All participants are required to have stable current therapies, including any nonpharmacological treatments such as a ketogenic diet, for at least 4 weeks prior to screening and throughout the study. The caregivers of the participants have provided informed consent, and the participants themselves have given assent where applicable. The trial aims to assess the long-term safety and tolerability of radiprodil as an add-on therapy to standard care, with a focus on establishing a safe and well-tolerated dose after 8 weeks of continuous treatment.
Plans and Procedures
The clinical trial is designed to evaluate the **safety**, tolerability, and pharmacokinetics of **radiprodil** in pediatric participants with GRIN-related disorder. This is a Phase 3, multicenter, randomized, double-blind, controlled study. The trial aims to establish a safe and well-tolerated dose of radiprodil after 8 weeks of continuous treatment. The study is expected to conclude by November 30, 2025, with recruitment having commenced on February 2, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age and genetic variants. The trial includes two parts: Part A and Part B. In Part A, participants aged 6 months to 12 years with specific GRIN gene variants will be enrolled. Part B will include participants who have completed Part A and meet rescreening criteria. The study visits will include follow-up assessments to monitor adverse events, changes in vital signs, and other clinical parameters. The end-of-study visit will evaluate the overall outcomes and safety of the treatment.
The expected length of participant involvement varies, with Part A requiring at least 8 weeks of treatment. Participants may be terminated early from the study if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator determines that continued participation is not in the participant's best interest. The primary endpoints include the frequency and severity of adverse events, changes in vital signs, and plasma concentrations of radiprodil. Secondary endpoints focus on changes in seizure frequency and behavioral features, as well as quality of life assessments.
Treatment
The clinical trial involves the administration of **Radiprodil**, an experimental medication formulated as an **oral suspension**. This pharmaceutical form is specifically designed for pediatric use and is administered orally. The active substance, **Radiprodil**, is of chemical origin and is also known by the synonym UCB3491. The medication is provided by GRIN THERAPEUTICS, INC. The trial aims to assess the safety, tolerability, pharmacokinetics, and effects on seizures and behavioral symptoms in children with GRIN-related disorder. The dosing regimen involves multiple individually titrated doses, allowing for adjustments based on the participant's response and tolerance. The frequency of administration is determined by the study protocol, ensuring optimal therapeutic exposure while monitoring for any adverse effects.
In addition to the experimental treatment, participants will continue to receive standard-of-care therapy as part of their ongoing management for GRIN-related disorder. This approach ensures that all participants receive the necessary medical care while evaluating the added benefits of Radiprodil as an adjunct therapy. The study does not include a placebo or comparator treatment, focusing solely on the effects of Radiprodil in conjunction with standard care. Participant compliance with the dosing schedule is closely monitored throughout the trial to ensure accurate assessment of the medication's efficacy and safety profile.
Efficacy
Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the evaluation of adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs) in terms of frequency, type, severity, and duration. Additionally, 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, and plasma concentrations of **radiprodil** at predefined timepoints will be monitored.
Secondary endpoints focus on changes from baseline to the end of treatment in seizure frequency, as recorded in a daily seizure electronic diary (eDiary). The percent change in seizure burden, including seizure type, severity, and frequency, will be assessed using video electroencephalogram (V EEG). Other secondary measures include seizure-free days, the longest period with no seizures, and changes in behavioral features as measured by the Aberrant Behavior Checklist-Community (ABC-C). Additional assessments will be conducted using the Gross Motor Function Measure (GMFM), Sleep Disturbance Scale for Children (SDSC), Pediatric Quality of Life Inventory (PedsQL), Caregiver Burden Inventory (CBI), and global impression scales such as the Caregiver Global Impression of Change (CaGI-C) and Clinical Global Impression of Change (CGI-C).
Inclusion and Exclusion Criteria
Inclusion Criteria
- PART A AND PART B - PHASE 1b : 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.
- PART A AND PART B - PHASE 1b: 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).
- PART A AND PART B - PHASE 1b: 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.
- PART A AND PART B - PHASE 1b: 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.
- PART A AND PART B - PHASE 1b: 5. Participant’s caregivers have signed informed consent and participant has signed assent (if applicable).
- PART A AND PART B - PHASE 1b: 6. Participant’s caregivers are willing and able to complete entries in the eDiary on a daily basis.
- PART A AND PART B - PHASE 1b: 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 (ie, condom) throughout the study period.
- PART A AND PART B - PHASE 1b: 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.
- PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: 1. Participants aged ≥1 month to ≤18 years with GRIN-NDD with GRIN1, GRIN2A, GRIN2B, or GRIN2D gene variants known to result in GoF of the NMDA receptor as determined using a functional characterization method consistent with Myers et al., 2023.
- PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: 2. Participant experiences the following: a. At least 1 CMS (defined here) per week and ≥4 CMS (generalized or focal) during the prospective 4-week Observation Period immediately preceding randomization. b. Has not obtained adequate response to at least 2 standard ASMs used at appropriate dose and duration with assured medication adherence (if applicable). Participant will continue to receive SOC ASMs while receiving study drug.
- PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: 3. Participants must be on a stable dose of standard ASMs regardless of indication for at least 4 weeks prior to and during the Screening Period and should remain on stable doses throughout the study. Nonpharmacological treatments such as ketogenic diet should also be kept stable during screening and participation in the study.
- PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: 4. Participant has signed informed consent or participant’s caregivers have signed informed consent and participant has signed assent (if applicable).
- PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: 5. Participant’s caregivers are willing and able to complete entries in the eDiary on a daily basis and have demonstrated compliance (based on investigator and sponsor review) with eDiary entries during the Screening Period.
- PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: 6. Participant is one 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 one of the following medically acceptable methods of birth control from Screening through 90 days after the last dose of study drug: • 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 study drug administration. • Intrauterine device. c. If male, is willing to use a condom from Screening through 90 days after the last dose of study drug.
- PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: 7. Participant is willing to abstain from sperm or egg donation from Screening through 90 days after the last dose of study drug.
- PART A – PHASE 3 RANDOMIZED WITHOUT QUALIFYING SEIZURES AUXILIARY COHORT: For all other inclusion criteria, see Inclusion Criteria for Part A – Phase 3 Randomized Qualifying Seizures Cohort with the exception of inclusion criterion 2 (eg, participants with seizures that are not CMS or those with <1 CMS per week would be eligible for the Randomized Without Qualifying Seizures Auxiliary Cohort).
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 1. Participant’s caregivers are willing and able to complete entries in the eDiary on a daily basis and have demonstrated compliance (based on investigator and sponsor review) with eDiary entries during Part A.
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 2. Participant is one 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 pregnancy test results at the TT1 Visit), nonlactating, and practicing one of the following medically acceptable methods of birth control throughout Part B through 90 days after the last dose of study drug: • 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 study drug administration. • Intrauterine device. c. If male, is willing to use a condom throughout Part B and for 90 days after the last dose of study drug.
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 3. Participant is willing to abstain from sperm or egg donation throughout Part B and for 90 days after the last dose of study drug.
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 4. Participant has completed Part A (remained on study and were compliant with dosing and study procedures [based on investigator and sponsor assessment] through the last visit of Part A) of the Phase 3 portion of the study. The participant is eligible to continue study participation according to the judgment of the investigator.
Exclusion Criteria
- PART A AND B – PHASE 1b: 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.
- PART A AND B – PHASE 1b: 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).
- PART A AND B – PHASE 1b: 3. Participant with any clinically significant laboratory or ECG abnormalities.
- PART A AND B – PHASE 1b: 4. Participant has severe hepatic dysfunction (Child-Pugh grade C).
- PART A AND B – PHASE 1b: 5. Participant has a history of brain surgery for epilepsy or any other reason.
- PART A AND B – PHASE 1b: 6. Participant with any contraindications to radiprodil or with known hypersensitivity to the active substance or the excipients or other chemically closely related substances..
- PART A AND B – PHASE 1b: 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.
- PART A AND B – PHASE 1b: 8. Participant is on treatment with hormonal therapy such as adrenocorticotrophic hormone or prednisolone (Part A only).
- PART A AND B – PHASE 1b: 9. Participant has participated in any other investigational clinical study within 3 months of Screening (Part A only).
- PART A – PHASE 3 RANDOMIZED COHORTS: 1. Participant with any other clinically relevant medical, neurologic, or psychiatric condition and/or behavioral disorder (including those related to GRIN NDD) that would preclude or jeopardize the participant’s safe participation or administration of study drug or the conduct of the study according to the judgment of the investigator or the sponsor.
- PART A – PHASE 3 RANDOMIZED COHORTS: 2. Participant or caregiver is unwilling or unable to comply with all procedures for the duration of study.
- PART A – PHASE 3 RANDOMIZED COHORTS: 3. Participant receiving >4 standard ASMs at the time of Screening.
- PART A – PHASE 3 RANDOMIZED COHORTS: 4. Participant with a body weight <5 kg at Screening.
- PART A – PHASE 3 RANDOMIZED COHORTS: 5. Participant with any clinically significant laboratory or ECG abnormalities according to the judgment of the investigator or the sponsor.
- PART A – PHASE 3 RANDOMIZED COHORTS: 6. Participant has severe hepatic dysfunction (Child-Pugh grade C).
- PART A – PHASE 3 RANDOMIZED COHORTS: 7. Participant has a history of brain surgery within 6 months of randomization for epilepsy or any other reason.
- PART A – PHASE 3 RANDOMIZED COHORTS: 8. Participant with any known hypersensitivity to radiprodil drug product (DP) active substance or the excipients or other chemically closely related substances.
- PART A – PHASE 3 RANDOMIZED COHORTS: 9. Participant receiving treatment with prohibited concomitant drugs such as agonists or antagonists of the glutamate receptor, including but not limited to felbamate, memantine, and perampanel. If the participant has been on any of these listed drugs, they must have discontinued the drug at least 5 half-lives or 28 days prior to the planned first dose of study drug, whichever is longer.
- PART A – PHASE 3 RANDOMIZED COHORTS: 11. Participant has received any prior gene therapy.
- PART A – PHASE 3 RANDOMIZED COHORTS: 12. Participant is on treatment with hormonal therapy such as adrenocorticotrophic hormone or prednisolone.
- PART A – PHASE 3 RANDOMIZED COHORTS: 13. Participant has participated in any other investigational clinical study using an IP or device within 3 months or 5 half-lives of the IP, whichever is longer, of Screening.
- PART A – PHASE 3 RANDOMIZED COHORTS: 14. Participant has previously received radiprodil.
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 1. Participant with any other clinically relevant medical, neurologic, or psychiatric condition and/or behavioral disorder (including those related to GRIN-NDD) that would preclude or jeopardize the participant’s safe participation or administration of study drug or the conduct of the study according to the judgment of the investigator or the sponsor.
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 2. Participant or caregiver is unwilling or unable to comply with all study procedures for the duration of the study.
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 3. Participant receiving >4 standard ASMs.
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 4. Participant with a body weight <5 kg.
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 5. Participant with any clinically significant laboratory or ECG abnormalities according to the judgment of the investigator or the sponsor.
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 6. Participant has severe hepatic dysfunction (Child-Pugh grade C).
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 7. Participant with any known hypersensitivity to radiprodil DP active substance or the excipients or other chemically closely related substances.
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 8. Participant receiving treatment with prohibited concomitant drugs such as agonists or antagonists of the glutamate receptor, including but not limited to felbamate, memantine, and perampanel.
- PART B OLE – PHASE 3 RANDOMIZED COHORTS: 9. Participant is on treatment with hormonal therapy such as adrenocorticotrophic hormone or prednisolone.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 02 Feb 2023 | 4 |
 France | Recruiting | 02 Feb 2023 | 8 |
 Germany | Recruiting | 02 Feb 2023 | 10 |
 Italy | Recruiting | 02 Feb 2023 | 14 |
 The Netherlands | Recruiting | 02 Feb 2023 | — |
 Poland | Recruiting | 02 Feb 2023 | 7 |
 Slovenia | Recruiting | 02 Feb 2023 | 2 |
 Spain | Recruiting | 02 Feb 2023 | 2 |
| Netherlands | — | — | 9 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Radiprodil | Test | ORAL SUSPENSION | ORAL, NASOGASTRIC TUBE OR PERCUTANEOUS ENDOSCOPIC GASTROSTOMY TUBE USE | — | — | PRD10768704 |
Radiprodil | Test | ORAL SUSPENSION | ORAL, NASOGASTRIC TUBE OR PERCUTANEOUS ENDOSCOPIC GASTROSTOMY TUBE USE | — | — | PRD10762775 |
matching Radiprodil oral suspension | Placebo | N/A | — | — | — | N/A |
Radiprodil | Test | ORAL SUSPENSION | ORAL, NASOGASTRIC TUBE OR PERCUTANEOUS ENDOSCOPIC GASTROSTOMY TUBE USE | — | — | PRD11987187 |