Clinical trial NCT06392009: Astroscape: a Study of Radiprodil on Safety, Tolerability, Pharmacokinetics, and Effect on Seizures and Behavioral Symptoms in Patients with TSC or FCD Type II
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Tuberous Sclerosis Complex
Focal Cortical Dysplasia
Keywords: TSC
FCD
Tuberous Sclerosis Complex
Focal Cortical Dysplasia
Astroscape
Lead sponsor: GRIN Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2024-04-30
Enrollment: 30
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Study RAD-GRIN-201 is a phase 1B/2A trial to assess safety, tolerability, pharmacokinetics (PK), and potential efficacy of radiprodil in participants with Tuberous Sclerosis Complex (TSC) or Focal Cortical Dysplasia (FCD) type II. 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 and one year in Part B/long-term treatment period. The treatment period in Part B may be extended based on a favorable benefit/risk profile.

Detailed description: Approximately 20 participants with TSC and 10 participants with FCD type II will be enrolled.

The effects of radiprodil are assessed in participants with treatment-resistant seizures (with or without behavioral symptoms). The daily doses of radiprodil will be individually titrated for every participant and all the participants will receive study drug.

This study is divided into the following periods:

PART A:

* Screening/Observation Period (up to six(6) weeks): Investigators assess eligibility followed by an Observation Period (at least four(4) weeks) to evaluate seizure frequency.
* Titration Period (approx. four(4) weeks): Radiprodil twice daily will be administered in escalating doses and plasma concentrations, safety, and tolerability assessed. Once a safe and potentially effective dose has been established, the participant will immediately enter the Maintenance Period.
* Maintenance Period (approx. twelve(12) weeks): The participant will continue to take the safe and potentially effective dose identified during the Titration Period. At the end of the Maintenance Period the participant will either be invited to enter Part B or the Tapering and Safety Follow-up Period.
* Tapering (15 days) and Safety Follow-up Period (14 days): a participant who doesn't take part in the long-term treatment period (Part B) will taper (ie gradually decrease) the study medicine for 15 days and enter a safety Follow-up Period (14 days). In this case, the participant will have one (1) last visit at the end of the safety Follow-up Period.

PART B:

* Long-Term Treatment Period (one(1) year): During the Long-Term Treatment Period (Part B), participants will continue taking radiprodil at the usual dose level and making regular visits to the study site.
* Tapering (15 days) and Safety Follow-up Period (14 days): at the end of the long-term treatment period (Part B), the participant will taper (ie gradually decrease) the study medicine for 15 days and enter a safety Follow-up Period (14 days) after his/her last dose of radiprodil. The participant will have one (1) last visit at the end of the safety Follow-up Period.

Eligibility criteria: Inclusion Criteria:

* Failed to respond to at least 2 anti-seizure medications (ASMs) at appropriate dosages and duration.
* Disease specific criteria:

  1. diagnosis of FCD Type II based on clinical symptoms and confirmed by a positive magnetic resonance imaging (MRI)
  2. diagnosis of TSC by either clinical or genetic diagnostic criteria (Northrup, 2021) as documented in the participant's medical record.
* Participant on average has had at least 8 countable/witnessed primary seizures during a 4-week baseline period with at least 1 seizure occurring in at least 3 of the 4 weeks of baseline
* 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 must remain on a stable regimen throughout the treatment period.
* Participant has had an MRI scan within 12 months of the planned date of first dose of study drug.

Exclusion Criteria:

* 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.
* Clinically significant laboratory or ECG abnormalities.
* Severe hepatic dysfunction (Child-Pugh grade C).
* History of brain surgery within 6 months of screening for epilepsy or any other reason.
* Contraindications to radiprodil or with known hypersensitivity to the active substance or the excipients or other chemically closely related substances.
* Receiving treatment with contraindicated concomitant drugs such as agonists or antagonists of the glutamate receptor, including but not limited to felbamate, memantine, and perampanel.
* body weight \<10kg for whom a gastric tube is the only possibility for radiprodil dosing.

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), Adverse Drug Reactions (ADRs), TEAEs Leading to Discontinuation and Severity of TEAEs
timeFrame: from Baseline to End-of-study: 1 year 6 months
measure: Plasma concentration of radiprodil and maximum plasma concentration (Cmax)
timeFrame: Titration Visit 1 (week 7): Pre-dose to 12 hours post-dose. Titration Visits 2,3,4 (week 8 to 13) and Maintenance Visit 7 (week 25): pre-dose to 5 hours post-dose
measure: Plasma concentration of radiprodil versus time, area under the curve (AUCt)
timeFrame: Titration Visit 1 (week 7): Pre-dose to 12 hours post-dose. Titration Visits 2,3,4 (week 8 to 13) and Maintenance Visit 7 (week 25): pre-dose to 5 hours post-dose
measure: Pharmacokinetic plasma concentration of radiprodil: half-life (T1/2)
timeFrame: Titration Visit 1 (week 7): Pre-dose to 12 hours post-dose. Titration Visits 2,3,4 (week 8 to 13) and Maintenance Visit 7 (week 25): pre-dose to 5 hours post-dose
measure: Pharmacokinetic plasma concentration of radiprodil: time to Cmax (Tmax)
timeFrame: Titration Visit 1 (week 7): Pre-dose to 12 hours post-dose. Titration Visits 2,3,4 (week 8 to 13) and Maintenance Visit 7 (week 25): pre-dose to 5 hours post-dose
measure: Pharmacokinetic plasma concentration of radiprodil, clearance (Cl)
timeFrame: Titration Visit 1 (week 7): Pre-dose to 12 hours post-dose. Titration Visits 2,3,4 (week 8 to 13) and Maintenance Visit 7 (week 25): pre-dose to 5 hours post-dose
measure: Number of participants with abnormal laboratory tests results
timeFrame: from Baseline to End-of-study: 1 year 6 months
measure: Number of participants with abnormal physical and neurological examination findings
timeFrame: Baseline, MV7, and in Part B: Month 3, 6, 9, 12: week 6, week 28, week 40, week 52, week 64, week 76
measure: Clinically relevant changes in safety parameters: systolic blood pressure
timeFrame: from Baseline to End-of-study: 1 year 6 months
measure: Clinically relevant changes in safety parameters: diastolic blood pressure
timeFrame: from Baseline to End-of-study: 1 year 6 months
measure: Clinically relevant changes in safety parameters: pulse rate
timeFrame: from Baseline to End-of-study: 1 year 6 months
measure: 12-Lead ECG: Mean change from Baseline to End-of-Treatment in RR interval
timeFrame: from Baseline to End-of-study: 1 year 6 months
measure: 12-Lead ECG: Mean change from Baseline to End-of-Treatment in PR interval
timeFrame: from Baseline to End-of-study: 1 year 6 months
measure: 12-Lead ECG: Mean change from Baseline to End-of-Treatment in QRS interval
timeFrame: from Baseline to End-of-study: 1 year 6 months
measure: 12-Lead ECG: Mean change from Baseline to End-of-Treatment in QT interval
timeFrame: from Baseline to End-of-study: 1 year 6 months
measure: 12-Lead ECG: Mean change from Baseline to End-of-Treatment in QTcF interval
timeFrame: from Baseline to End-of-study: 1 year 6 months
Secondary outcomes:
measure: Percent change from baseline in Video-EEG seizure burden
timeFrame: Baseline to end-of-treatment: week 6 to week 76
measure: Change from baseline in seizure frequency
timeFrame: Baseline to Maintenance Visit 7: week 6 to week 25 and Baseline to end-of-treatment: week 6 to week 76
measure: Change from baseline in number of seizure-free days and longest period with no seizures
timeFrame: Baseline to end-of-treatment: week 6 to week 76
measure: Aberrant Behavior Checklist-Community (ABC-2C)
timeFrame: Baseline to end-of-treatment: week 6 to week 76
measure: Caregiver Global Impression of Change (CaGI-C)
timeFrame: Baseline to end-of-treatment: week 6 to week 76
measure: Clinical Global Impression of Change [CGI-C]
timeFrame: Baseline to end-of-treatment: week 6 to week 76
measure: Pediatric Quality of Life Inventory [PedsQL]
timeFrame: Baseline to end-of-treatment: week 6 to week 76
measure: Caregiver Burden Inventory (CBI)
timeFrame: Baseline to end-of-treatment: week 6 to week 76
measure: Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: Baseline to end-of-treatment: week 6 to week 76
Other outcomes:
Locations:
city: South Brisbane
country: Australia
facility: Queensland Children Hospital
city: Antwerp
country: Belgium
facility: Universitair Ziekenhuis Antwerpen (UZA)
city: Leuven
country: Belgium
facility: University Hospitals Leuven, Pediatric Neurology
city: Calgary
country: Canada
facility: Alberta Children's Hospital
city: Toronto
country: Canada
facility: The Hospital for Sick Children (Sick Kids)
city: Vancouver
country: Canada
facility: BC Children's Hospital
city: Genoa
country: Italy
facility: IRCCS Istituto Giannina Gaslini
state: Liguria
city: Florence
country: Italy
facility: AOU Meyer
state: Toscana
city: Roma
country: Italy
facility: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
city: Roma
country: Italy
facility: Universita Cattolica del Sacro Cuore - Policlinico Universitario "Agostino Gemelli"
city: Utrecht
country: Netherlands
facility: UMC Uthrecht - Wilhelmina Kinderziekenhuis
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Kraków
country: Poland
facility: Centrum Medyczne Plejady
city: Poznan
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Poznaniu
city: Warszawa
country: Poland
facility: Instytut Pomnik - Centrum Zdrowia Dziecka
city: Barcelona
country: Spain
facility: Hospital Universitario Vall D´Hebrón
city: Barcelona
country: Spain
facility: Hospital Materno Infantil Sant Joan de Deu de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario Vithas La Milagrosa
city: Madrid
country: Spain
facility: Hospital Ruber Internacional
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol and Weston NHS Foundation Trust Bristol Royal Hospital for Children
Study officials:
References: