Radiprodil for Seizures

Recruiting at 20 trial locations

Overseen By Clinical Operations

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: GRIN Therapeutics, Inc.

Must be taking: Anti-seizure medications

Must not be taking: Glutamate receptor drugs

Disqualifiers: Severe hepatic dysfunction, Brain surgery, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that participants stay on their current stable medication regimen for epilepsy and behavior throughout the treatment period.

How is the drug Radiprodil unique in treating seizures?

Radiprodil is unique because it targets specific dopamine receptors in the brain, which may help reduce seizure activity by influencing dopamine pathways, unlike many traditional seizure medications that focus on other mechanisms. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for individuals with Tuberous Sclerosis Complex (TSC) or Focal Cortical Dysplasia type II who experience seizures and behavioral symptoms. Participants will be involved in the study for up to six months initially, with a possible extension to one year if benefits outweigh risks.

Inclusion Criteria

My epilepsy treatment has been stable for the last 28 days with limited emergency medication use.

I have been diagnosed with FCD Type II confirmed by an MRI.

I have been diagnosed with TSC either through symptoms or genetic testing.

Exclusion Criteria

I had brain surgery within the last 6 months.

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

Timeline

Screening/Observation

Participants are screened for eligibility to participate in the trial followed by an Observation Period to evaluate seizure frequency

6 weeks

Titration

Radiprodil is administered in escalating doses to assess plasma concentrations, safety, and tolerability

4 weeks

Maintenance

Participants continue taking the safe and potentially effective dose identified during the Titration Period

12 weeks

Tapering and Safety Follow-up

Participants taper off the study medication and enter a safety follow-up period

4 weeks

Long-Term Treatment

Participants continue taking radiprodil at the usual dose level with regular visits to the study site

1 year

Tapering and Safety Follow-up

Participants taper off the study medication and enter a safety follow-up period after the long-term treatment

4 weeks

Treatment Details

Interventions

• Radiprodil

Trial Overview The trial is testing Radiprodil's safety, how well it's tolerated by patients, its behavior in the body (pharmacokinetics), and its effectiveness on reducing seizures and improving behavioral symptoms in participants.

Participant Groups

Group I: TSC Experimental Treatment 1 Intervention

Liquid suspension of radiprodil, at concentrations 0.25 mg/mL or 2.50 mg/mL for 1% and 10% formulation respectively. It will be administered twice a day (bid) either orally or via gastric or nasogastric tube.

Group II: FCD Type II Experimental Treatment 1 Intervention

Liquid suspension of radiprodil, at concentrations 0.25 mg/mL or 2.50 mg/mL for 1% and 10% formulation respectively. It will be administered twice a day (bid) either orally or via gastric or nasogastric tube.

Who Is Running the Clinical Trial?

GRIN Therapeutics, Inc.

Lead Sponsor

Trials

2

Recruited

50+

Findings from Research

Dopamine D1 receptor agonists, particularly SKF 38393, showed a dose-dependent ability to block seizures induced by pentylenetetrazole, indicating their potential as anticonvulsants.

The D1/D2 agonist apomorphine also effectively blocked seizures, suggesting that its anticonvulsant effects are linked to the activation of both D1 and D2 receptors, potentially enhancing GABA transmission in specific brain regions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of dopamine D1 and D2 receptor agonists and antagonists on seizures induced by chemoconvulsants in mice. Ogren, SO., Pakh, B.[2019]

D3 receptor agonists, particularly RU 24213, can significantly delay the onset of limbic motor seizures induced by pilocarpine in rats, indicating a potential anticonvulsant effect, especially at low doses.

The study suggests that the protective effects against seizures are more likely mediated by D2 receptors rather than D3 receptors, as other selective D3 agonists did not provide the same level of protection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of dopamine D3 receptor agonists on pilocarpine-induced limbic seizures in the rat. Alam, AM., Starr, MS.[2019]

Bromocryptine significantly reduces both total and lethal audiogenic seizures in 21-day-old DBA/2H mice, with the protective effect increasing within the first hour after administration.

The protective effect of bromocryptine is blocked by spiroperidol, indicating that dopaminergic pathways play a crucial role in inhibiting audiogenic seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blockade of audiogenic seizures by bromocryptine. González Pérez, JN., González-Quevedo, A.[2019]

Dopamine D1 receptor agonists, like SKF 38393, can induce seizures in mice previously treated with reserpine, but this effect can be blocked by D2 receptor agonists or D1 receptor antagonists, indicating a complex interaction between these receptors in seizure modulation.

In rats, the D2 agonist LY 171555 showed anticonvulsant properties against pilocarpine-induced seizures, suggesting that targeting D2 receptors may provide a therapeutic approach to manage seizures, while D1 receptor activation appears to increase seizure susceptibility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Opposite effects of stimulation of D1 and D2 dopamine receptors on the expression of motor seizures in mouse and rat. al-Tajir, G., Chandler, CJ., Starr, BS., et al.[2019]

In a study using rabbits, the D-1 antagonist SCH 23390 significantly decreased the susceptibility to seizures, while the D-2 antagonist haloperidol increased seizure susceptibility, indicating a marked difference in their effects on epilepsy.

The findings suggest that D-1 and D-2 dopamine receptor subtypes play distinct roles in the mechanisms of seizures, which could inform future treatments for epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Role of the dopaminergic system in experimental models of epilepsy]. Bo, P., Soragna, D., Murelli, R., et al.[2013]

References

1. Denmark pubmed.ncbi.nlm.nih.gov

Effects of dopamine D1 and D2 receptor agonists and antagonists on seizures induced by chemoconvulsants in mice. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Effects of dopamine D3 receptor agonists on pilocarpine-induced limbic seizures in the rat. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Blockade of audiogenic seizures by bromocryptine. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Opposite effects of stimulation of D1 and D2 dopamine receptors on the expression of motor seizures in mouse and rat. [2019]

5. Italy pubmed.ncbi.nlm.nih.gov

[Role of the dopaminergic system in experimental models of epilepsy]. [2013]