Clinical trial NCT05818943: Honeycomb: Evaluation of Radiprodil in Children with GRIN-related Disorder
Official title: A Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effect on Seizures and Behavioral Symptoms of Multiple Individually Titrated Doses of Radiprodil in Children with GRIN-related Disorder
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: GRIN-related Disorders
Keywords: GRIN1
GRIN2A
GRIN2B
GRIN2D
Lead sponsor: GRIN Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2023-04-19
Enrollment: 24
Sex: ALL
Minimum age (years): 6
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Study RAD-GRIN-101 is a phase 1B trial to assess safety, tolerability, PK, and potential efficacy of radiprodil for the treatment of GRIN-related disorder in children with a Gain-of-Function (GoF) genetic variant. The study is open-label, so all participants will be treated with radiprodil.

Subjects' participation in the study is expected to last up to six months in Part A.

After the end of part A, all participants who are still eligible can choose to continue to receive radiprodil as part of an open-label long-term treatment period (Part B).

Detailed description: The effect of radiprodil is assessed in two (2) cohorts of pediatric participants: one (1) cohort of participants with treatment-resistant seizures (with or without behavioral symptoms) (Cohort 1) and one (1) cohort of participants with behavioral symptoms but no qualifying seizures (Cohort 2) caused by Gain-of-Function (GoF) variants in the GRIN gene. As the daily doses of radiprodil will be individually titrated for every participant and all the participants will receive the study drug, this is in effect a "single group" study.

This study is divided into the following periods:

PART A:

* Screening/Observation Period (35 days): Investigators assess eligibility followed by a four(4)- week Observation Period to evaluate seizure frequency and/or behavioral symptoms.
* Titration Period (approx. 51 days): Overnight stay to administer radiprodil twice daily to assigned dose level, assessing plasma concentrations, safety, and tolerability during the titration period. Once a safe and potentially effective dose has been established, the participant will immediately enter the Maintenance Period.
* Maintenance Period (up to 53 days): During the Maintenance Period, the participant will continue to take the highest safe and potentially effective dose, as identified during the Titration Period. At the end of the Maintenance Period, there will be an additional overnight stay when the participant will either be invited to take part in Part B or enter the Tapering and Safety Follow-up Period.
* Tapering (15 days) and Safety Follow-up Period (14 days): the participant who doesn't take part in the long-term treatment period (Part B) will need to taper off (ie gradually decrease) the study medicine for 15 days and enter a safety Follow-up Period (14 days). In this case, the participant will make one (1) last visit to the study site 14 days after his/her last dose of radiprodil.

PART B:

* Long-Term Treatment Period (not specified): Participation in Part B of the study, at the dose established during part A, will be continued until such time as either the participant withdraws/is withdrawn from the study or sponsor terminates the study. During this period there will be four (4) visits per year, two(2) of which will require overnight stays. At the end of the Long-Term Treatment Period, the participant will enter the Tapering and Safety Follow-up Period.
* Tapering (15 days) and Safety Follow-up Period (14 days): the participant will need to taper off the study medicine for 15 days and enter a safety Follow-up Period of 14 days. In this case, the participant will make one (1) last visit to the study site 14 days after his/her last dose of radiprodil.

Eligibility criteria: Inclusion Criteria:

* Age: ≥6 months to ≤12 years, with GRIN gene variants known to result in GoF of the NMDA receptor.
* Cohort 1 must have at least 1 observable motor seizure per week and ≥4 observable motor seizures (generalized or focal) during the prospective 4-week Observation Period and must have failed to obtain adequate seizure control with at least 2 antiseizure medications (ASMs) used at appropriate dose and duration.
* Cohort 2 must have significant behavioral and/or motor symptoms based on caregiver report with a CGI-S score ≥4.
* Stable antiseizure therapies and nonpharmacological treatments such as ketogenic diet throughout screening and study participation.

Exclusion Criteria:

* Any other clinically relevant medical, neurologic, or psychiatric condition and/or behavioral disorder unrelated to GRIN-related disorder that would preclude or jeopardize participant's safe participation or the conduct of the study according to the judgement of the investigator.
* Clinically significant laboratory or ECG abnormalities.
* Severe hepatic dysfunction (Child-Pugh grade C).
* History of brain surgery for epilepsy or any other reason.
* Receiving treatment with contraindicated concomitant drugs such as agonists or antagonists of the glutamate receptor, including but not limited to felbamate, memantine, and perampanel.
* Receiving treatment with hormonal therapy such as adrenocorticotrophic hormone or prednisolone.

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), TEAEs Leading to Discontinuation and Severity of TEAEs
timeFrame: through study completion (average of 2 years).
measure: Maximum Plasma concentration of radiprodil (Cmax)
timeFrame: Titration Visit 1 (week 5): 0,1,2,4,6,8,10,12 hours post-dose. Titration Visits 2,3,4 (week 6 to 11) and Maintenance Visit 4 (week 20): 0,1,2,5 hours post-dose.
measure: Pharmacokinetic plasma concentration of radiprodil: half-life (T1/2)
timeFrame: Titration Visit 1 (week 5): 0,1,2,4,6,8,10,12 hours post-dose. Titration Visits 2,3,4 (week 6 to 11) and Maintenance Visit 4 (week 20): 0,1,2,5 hours post-dose.
measure: Plasma concentration of radiprodil versus time, area under the curve (AUCt)
timeFrame: Titration Visit 1 (week 5): 0,1,2,4,6,8,10,12 hours post-dose. Titration Visits 2,3,4 (week 6 to 11) and Maintenance Visit 4 (week 20): 0,1,2,5 hours post-dose.
measure: Pharmacokinetic plasma concentration of radiprodil, clearance (Cl)
timeFrame: Titration Visit 1 (week 5): 0,1,2,4,6,8,10,12 hours post-dose. Titration Visits 2,3,4 (week 6 to 11) and Maintenance Visit 4 (week 20): 0,1,2,5 hours post-dose.
measure: Pharmacokinetic plasma concentration of radiprodil, Time corresponding to occurrence of Cmax (Tmax)
timeFrame: Titration Visit 1 (week 5): 0,1,2,4,6,8,10,12 hours post-dose. Titration Visits 2,3,4 (week 6 to 11) and Maintenance Visit 4 (week 20): 0,1,2,5 hours post-dose.
Secondary outcomes:
measure: Percent change from baseline in V-EEG seizure burden
timeFrame: Baseline (week 5) to study completion (average of 2 years).
measure: Change from baseline in seizure frequency
timeFrame: Baseline (week 5) to study completion (average of 2 years).
measure: Aberrant Behavior Checklist-Community (ABC-C)
timeFrame: Baseline (week 5) to study completion (average of 2 years).
measure: Caregiver Global Impression of Change (CaGI-C)
timeFrame: Baseline (week 5) to study completion (average of 2 years).
measure: Change from Baseline in Clinical Global Impression - Severity [CGI-S]
timeFrame: Baseline (week 5) to study completion (average of 2 years).
measure: Clinical Global Impression of Change [CGI-C]
timeFrame: Baseline (week 5) to study completion (average of 2 years).
measure: Gross Motor Function Measure (GMFM)
timeFrame: Baseline (week 5) to study completion (average of 2 years).
measure: Sleep Disturbance Scale for Children (SDSC)
timeFrame: Baseline (week 5) to study completion (average of 2 years).
measure: Pediatric Quality of Life Inventory [PedsQL]
timeFrame: Baseline (week 5) to study completion (average of 2 years).
measure: Caregiver Burden Inventory (CBI)
timeFrame: Baseline (week 5) to study completion (average of 2 years).
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Mid-Atlantic Epilepsy and Sleep Center
state: Maryland
city: New York
country: United States
facility: Columbia University Irving Medical Center, Dept of Neurology
state: New York
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Toronto
country: Canada
facility: The Hospital for Sick Children (Sick Kids)
state: Ontario
city: Vancouver
country: Canada
facility: BC Children's Hospital
city: Leipzig
country: Germany
facility: Abteilung für Neuropädiatrie, Klinik und Poliklinik für Kinder - und Jugendmedizin, Universitätsklinikum Leipzig
city: München
country: Germany
facility: KBO-Kinderzentrum München gemeinnützige GmbH
city: Roma
country: Italy
facility: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale Pediatrico Bambino Gesu
state: Lazio
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi (AOUC) Firenze - Azienda Ospedaliera Universitaria Meyer
state: Toscana
city: Rotterdam
country: Netherlands
facility: ERASMUS Medisch Centrum, Developmental & Genetic pediatrics
city: Utrecht
country: Netherlands
facility: UMC Utrecht - Wilhelmina Kinderziekenhuis, Polikliniek Kinderneurologie
city: Barcelona
country: Spain
facility: Universitat de Barcelona - Hospital Sant Joan de Deu Barcelona (HSJDB)
city: Madrid
country: Spain
facility: Hospital Ruber Internacional
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Children Glasgow
city: London
country: United Kingdom
facility: Great Ormond Street Hospital For Children NHS Foundation Trust
Study officials:
affiliation: Associate Director of Clinical Operations
name: Vijay Rai, PhD
role: STUDY_DIRECTOR
affiliation: Chief Medical Officer
name: Michael Panzara, MD, MPH
role: STUDY_CHAIR
References: