A Multicenter, Open-label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effect on Seizures and Behavioral Symptoms of Radiprodil in Patients with Tuberous Sclerosis Complex (TSC) or Focal Cortical Dysplasia (FCD) Type II

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grin Therapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

15 Apr 2024 → ongoing

Decision date (initial)

2024-07-30

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

GRIN Therapeutics, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy, Safety, Others, Pharmacokinetic

-To determine the safety and tolerability of multiple individually titrated doses of radiprodil in TSC and FCD Type II patients
-To determine the pharmacokinetics (PK) and plasma exposure of radiprodil

Secondary objectives 2

1. To evaluate initial signs of efficacy on frequency and severity of epileptic seizures (both non-countable seizures and countable motor seizures) in those participants with seizures
2. To evaluate initial signs of efficacy of radiprodil on additional central nervous system (CNS) features including behavior and quality of life

Conditions and MedDRA coding

Tuberous Sclerosis Complex (TSC)

Regulatory references

Scientific advice from competent authorities

Medicines Evaluation Board

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Age range: ≥ 6 months up to 18 years at Part A Baseline
2. Failed to respond to at least 2 anti-seizure medications (ASMs) at appropriate dosages and durations
3. Disease specific criteria: a. diagnosis of FCD Type II based on clinical symptoms and confirmed by a positive magnetic resonance imaging (MRI) b. diagnosis of TSC by either clinical or genetic diagnostic criteria (Northrup, 2021) as documented in the participant’s medical record.
4. Participant on average has had at least 8 countable motor seizures during a 4 week baseline period with at least 1 seizure occurring in at least 3 of the 4 weeks of Baseline
5. All medical interventions for epilepsy / behavior (including ketogenic diet and any neurostimulation devices) should be stable for 28 days prior to Screening with no more than 6 days per month use of rescue medication. Participants should remain on a stable regimen throughout the treatment period.
6. Participant’s or their caregivers have signed informed consent and participant has signed assent (if applicable).
7. Participant’s or their caregivers are willing and able to complete entries in the eDiary on a daily basis.
8. Participant has had an MRI scan within 12 months of the planned date of first dose of study drug.
9. 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 (see Section 11.3.4), is nonpregnant (negative serum pregnancy test results at Screening and negative urine pregnancy test results at Baseline), nonlactating, and practicing 1 of the following medically acceptable methods of birth control from Screening through 90 days after the last dose of study drug: • 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 condom from Screening through 90 days after the last dose of study drug.

Exclusion criteria 7

1. Participant with any other clinically relevant medical, neurologic, or psychiatric condition and/or behavioral disorder unrelated to TSC or FCD Type II 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 any clinically significant laboratory or ECG abnormalities that according to the Investigator in consultation with the Sponsor would jeopardize the safety of the participant, limit participation, or compromise the interpretation of the safety data from the participant.
3. Participant has severe hepatic dysfunction (Child-Pugh grade C).
4. Participant has a history of brain surgery within 6 months of Screening 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 has received an investigational treatment within 3 months or 5 half-lives of Screening, whichever is longer.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs) (frequency, type, severity, and duration) over the course of treatment (Part A and Part B)  Changes in vital signs  Physical examination findings  12-lead electrocardiogram (ECG) findings  Clinically significant changes in laboratory parameters  Occurrence of suicidal ideation or behavior Plasma concentrations of radiprodil at predefined timepoints

Secondary endpoints 5

1. Change from baseline to end of the Maintenance Period (Day 84) in seizure frequency from daily seizure electronic diary (eDiary)
2. Change from baseline to end of Part B in seizure frequency from daily seizure eDiary
3. Percent change from baseline to end of treatment (Part A and Part B) in video electroencephalogram (V-EEG) seizure burden (e.g., seizure type, severity, and frequency recorded during V-EEGs)
4. Number of seizure free days and longest period with no seizures from baseline to end of treatment
5. Change from baseline to end of treatment (Part A and Part B) in behavioral features as measured by the aberrant behavior checklist-community (ABC-2C), as well as other disorder features as measured by 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)

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grin Therapeutics Inc.

Sponsor organisation

Grin Therapeutics Inc.

Address

230 Park Avenue Suite 2830

City

New York

Postcode

10169-2804

Country

United States

Scientific contact point

Organisation

Grin Therapeutics Inc.

Contact name

Clinical Operation Department

Public contact point

Organisation

Grin Therapeutics Inc.

Contact name

Clinical Operation Department

Third parties 11

Locations

5 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Corrective measures 1 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 213 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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