A Multinational, Multicenter Study With an Open-Label Phase 1b and a Randomized, Double-Blind, Placebo-Controlled Phase 3 Followed by an Open-Label Extension to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Radiprodil in Participants With GRIN-Related Neurodevelopmental Disorder

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grin Therapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

2 Feb 2023 → ongoing

Decision date (initial)

2024-11-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

GRIN Therapeutics, Inc.

External identifiers

EU CT number

2023-509672-42-00

EudraCT number

2022-000317-14

ClinicalTrials.gov

NCT07224581

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy, Pharmacokinetic

PART A - PHASE 1b
• To determine the long-term 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 in Part A
• To determine the pharmacokinetics (PK) and plasma exposure of radiprodil

PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT
• To evaluate the change in seizure frequency following treatment with radiprodil compared with placebo

PART A – PHASE 3 RANDOMIZED WITHOUT QUALIFYING SEIZURES AUXILIARY COHORT
• To evaluate the efficacy of radiprodil compared with placebo on non-seizure behavior features

PART B – OLE STUDY
• To determine the long-term safety and tolerability of radiprodil

Secondary objectives 8

1. PART A – PHASE 1b: To evaluate initial signs of efficacy on frequency and severity of epileptic seizures in those participants with seizures
2. PART A – PHASE 1b: To evaluate initial signs of efficacy of radiprodil on additional central nervous system (CNS) features including behavior, motor symptoms, sleep, and quality of life and the maintenance of the treatment effect
3. PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: To evaluate the change in seizure frequency following treatment with radiprodil compared with placebo
4. PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: To evaluate the efficacy of radiprodil compared with placebo on non-seizure features (including behavior, motor symptoms, quality of life)
5. PART A – PHASE 3 RANDOMIZED WITHOUT QUALIFYING SEIZURES AUXILIARY COHORT: To evaluate the efficacy of radiprodil compared with placebo on non-seizure features (including behavior, motor symptoms, quality of life)
6. PART A – PHASE 3 RANDOMIZED WITHOUT QUALIFYING SEIZURES AUXILIARY COHORT: To evaluate the safety and tolerability of radiprodil compared with placebo
7. PART B – OLE STUDY: To evaluate the efficacy of radiprodil on frequency of seizures in those participants with seizures
8. PART B – OLE STUDY: To evaluate the efficacy of radiprodil on non-seizure features (including behavior, motor symptoms, and quality of life)

Conditions and MedDRA coding

GRIN-related neurodevelopmental disorder

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Medicines Evaluation Board, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003462-PIP01-23

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. 1. 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.
2. 2. 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).
3. 3. 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.
4. 4. 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.
5. 5. PART A AND PART B - PHASE 1b: 5. Participant’s caregivers have signed informed consent and participant has signed assent (if applicable).
6. 6. 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.
7. 7. 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.
8. 8. 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.
9. 9. 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.
10. 10. 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.
11. 11. 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.
12. 12. 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).
13. 13. 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.
14. 14. 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.
15. 15. 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.
16. 16. 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).
17. 17. 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.
18. 18. 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.
19. 19. 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.
20. 20. 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 31

1. 1. 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.
2. 2. 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).
3. 3. PART A AND B – PHASE 1b: 3. Participant with any clinically significant laboratory or ECG abnormalities.
4. 4. PART A AND B – PHASE 1b: 4. Participant has severe hepatic dysfunction (Child-Pugh grade C).
5. 5. PART A AND B – PHASE 1b: 5. Participant has a history of brain surgery for epilepsy or any other reason.
6. 6. 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..
7. 7. 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.
8. 8. PART A AND B – PHASE 1b: 8. Participant is on treatment with hormonal therapy such as adrenocorticotrophic hormone or prednisolone (Part A only).
9. 9. PART A AND B – PHASE 1b: 9. Participant has participated in any other investigational clinical study within 3 months of Screening (Part A only).
10. 10. 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.
11. 11. PART A – PHASE 3 RANDOMIZED COHORTS: 2. Participant or caregiver is unwilling or unable to comply with all procedures for the duration of study.
12. 12. PART A – PHASE 3 RANDOMIZED COHORTS: 3. Participant receiving >4 standard ASMs at the time of Screening.
13. 13. PART A – PHASE 3 RANDOMIZED COHORTS: 4. Participant with a body weight <5 kg at Screening.
14. 14. 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.
15. 15. PART A – PHASE 3 RANDOMIZED COHORTS: 6. Participant has severe hepatic dysfunction (Child-Pugh grade C).
16. 16. 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.
17. 17. 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.
18. 18. 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.
19. 19. PART A – PHASE 3 RANDOMIZED COHORTS: 11. Participant has received any prior gene therapy.
20. 20. PART A – PHASE 3 RANDOMIZED COHORTS: 12. Participant is on treatment with hormonal therapy such as adrenocorticotrophic hormone or prednisolone.
21. 21. 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.
22. 22. PART A – PHASE 3 RANDOMIZED COHORTS: 14. Participant has previously received radiprodil.
23. 23. 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.
24. 24. 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.
25. 25. PART B OLE – PHASE 3 RANDOMIZED COHORTS: 3. Participant receiving >4 standard ASMs.
26. 26. PART B OLE – PHASE 3 RANDOMIZED COHORTS: 4. Participant with a body weight <5 kg.
27. 27. 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.
28. 28. PART B OLE – PHASE 3 RANDOMIZED COHORTS: 6. Participant has severe hepatic dysfunction (Child-Pugh grade C).
29. 29. 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.
30. 30. 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.
31. 31. PART B OLE – PHASE 3 RANDOMIZED COHORTS: 9. Participant is on treatment with hormonal therapy such as adrenocorticotrophic hormone or prednisolone.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. PART A – PHASE 1b: • 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
2. PART A – PHASE 1b: Plasma concentrations of radiprodil at predefined timepoints
3. PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: Countable motor seizure frequency (per 28 days) during the Maintenance Period (Weeks 1 through 12), as captured in the daily seizure eDiary
4. PART A – PHASE 3 RANDOMIZED WITHOUT QUALIFYING SEIZURES AUXILIARY COHORT: Change from baseline to end of Maintenance Period (Week 24) in the ABC-2C irritability subscale score
5. PART B – OLE STUDY: AEs, SAEs, and ADRs (frequency, type, severity, and duration)

Secondary endpoints 16

1. PART A – PHASE 1b: • Change from baseline to End of Treatment (EOT) in seizure frequency from daily seizure electronic diary (eDiary); • Percent change from baseline to EOT in video electroencephalogram (V EEG) seizure burden (eg, seizure type, severity, and frequency recorded during V EEGs); • Seizure-free days and longest period with no seizures
2. PART A – PHASE 1b: Change from baseline to EOT in behavioral features as measured by the aberrant behavior checklist-community (ABC 2C), 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)
3. PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: Proportion of participants with ≥50% reduction in CMS frequency (per 28 days) from baseline (the last 4 weeks prior to randomization) to the entire Maintenance Period (Weeks 1 through 12), as captured in the daily seizure eDiary
4. PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: Change in the number of CMS-free days (per 28 days) from baseline (the last 4 weeks prior to randomization) to the entire Maintenance Period (Weeks 1 through 12), as captured in the daily seizure eDiary
5. PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: Cumulative distribution of percent reduction in seizure frequency from Baseline to the entire Maintenance Period (Weeks 1 through 12)
6. PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: GRIN-NDD-specific CGI-C (GRIN-CGI-C) evaluated at the end of the Maintenance Period (Week 12) relative to baseline for relevant domains, including expressive communication, receptive communication, fine motor, gross motor, and dysregulated behavior
7. PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: Change from baseline to the end of the Maintenance Period (Week 12) in the ABC 2C irritability subscale score
8. PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: Change from baseline to the end of the Maintenance Period (Week 12) in the Vineland Adaptive Behavior Scale, Third Edition (VABS-3) Daily Living personal subdomain score
9. PART A – PHASE 3 RANDOMIZED QUALIFYING SEIZURES COHORT: Change from baseline to the end of the Maintenance Period (Week 12) in quality of life as measured by the PedsQL
10. PART A – PHASE 3 RANDOMIZED WITHOUT QUALIFYING SEIZURES AUXILIARY COHORT: GRIN-CGI-C evaluated at the end of the Maintenance Period (Week 24) relative to baseline for relevant domains, including expressive communication, receptive communication, fine motor, gross motor, and dysregulated behavior
11. PART A – PHASE 3 RANDOMIZED WITHOUT QUALIFYING SEIZURES AUXILIARY COHORT: Change from baseline to the end of the Maintenance Period (Week 24) in the VABS-3 Daily Living personal subdomain score
12. PART A – PHASE 3 RANDOMIZED WITHOUT QUALIFYING SEIZURES AUXILIARY COHORT: Change from baseline to the end of the Maintenance Period (Week 24) in quality of life as measured by the PedsQL
13. PART A – PHASE 3 RANDOMIZED WITHOUT QUALIFYING SEIZURES AUXILIARY COHORT: AEs, SAEs, and ADRs (frequency, type, severity, and duration)
14. PART B – OLE STUDY: Percent change in the CMS frequency per 28 days from baseline to each 12-week interval in the open-label extension (OLE) through the end of the OLE, as captured in the daily seizure eDiary
15. PART B – OLE STUDY: Change in the number of CMS-free days per 28 days from baseline to each 12-week interval in the OLE through the end of the OLE, as captured in the daily seizure eDiary
16. PART B – OLE STUDY: Change from baseline to each open-label treatment visit through the end of open-label treatment in the ABC-2C irritability subscale score, the VABS-3 Daily Living personal subdomain score, the PedsQL, and the GRIN-CGI-C scale for relevant domains (including expressive communication, receptive communication, fine motor, gross motor, and dysregulated behavior) Note: VABS-3 and GRIN-CGI-C scales to be assessed for Phase 3 participants only

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grin Therapeutics Inc.

Sponsor organisation

Grin Therapeutics Inc.

Address

101 Main Street Suite 1210

City

Cambridge

Postcode

02142-1519

Country

United States

Scientific contact point

Organisation

Grin Therapeutics Inc.

Contact name

Clinical Operations Department

Public contact point

Organisation

Grin Therapeutics Inc.

Contact name

Clinical Operations Department

Third parties 19

Locations

8 EU/EEA countries · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

12 submissions — initial application plus substantial / non-substantial modifications