Trial of Safety, Tolerability and Efficacy of Trametinib (SNR1611) in Patients With Amyotrophic Lateral Sclerosis (ALS)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability and efficacy of trametinib (SNR1611) in the treatment of amyotrophic lateral sclerosis.

Detailed Description
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Trametinib (SNR1611) is a MEK inhibitor that downregulates the MAPK/ERK pathway. In this study, the potential of MAPK/ERK pathway downregulation through trametinib (SNR1611) as a therapeutic treatment for amyotrophic lateral sclerosis (ALS) will be evaluated.

Official Title
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A Sequential Dose-Escalation, Randomized, Active-Controlled, Multi-Center, Phase 1/2a Clinical Trial to Evaluate the Safety, Tolerability and Efficacy of SNR1611 in Patients With Amyotrophic Lateral Sclerosis

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Trametinib (0.5 mg)
* Drug: Trametinib (1 mg)
* Drug: Riluzole (100 mg)


Participation Criteria
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Eligibility Criteria
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Main inclusion criteria: Patients diagnosed as definite, probable or probable-laboratory-supported ALS according to El Escorial Criteria. Patients of less than 2 years after the onset of ALS. Patients who meet the criteria of K-ALSFRS-R score and forced vital capacity. Main exclusion criteria: Patients with primary lateral sclerosis, progressive muscular atrophy or lower motor neuron disease. Patients who have history of ALS treatment of edaravone or stem cell therapy within 16 weeks before screening. Patients who have permanently ceased the administration of riluzole due to lack of tolerability and/or efficacy. Patients in Class II to IV according to the New York Heart Association functional classification. Patients with myocardial infarction, unstable arrhythmia, and/or significant cardiovascular disease such as unstable angina within 12 weeks before screening. Patients who do not meet the criteria of laboratory tests and medical/operation history.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomly assigned 4:1 to receive SNR1611 (0.5, 1 mg) or riluzole as an active comparator. The study will initiate with the first group of patients who will receive SNR1611 (0.5 mg, 8 patients) or riluzole (100 mg, 2 patients), while the initiation of the next dose groups will be decided by the IDMC (Independent Data Monitoring Committee) through safety assessment of the first 4-week periods of prior dose groups.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trametinib (0.5 mg)<br>One tablet of trametinib 0.5 mg per day | Drug: Trametinib (0.5 mg)<br>* 0.5 mg/day<br>* Other names: SNR1611;|
| Experimental: Trametinib (1 mg)<br>Two tablets of trametinib 0.5 mg per day | Drug: Trametinib (1 mg)<br>* 1 mg/day<br>* Other names: SNR1611;|
| Active Comparator: Riluzole (100 mg)<br>One tablet of riluzole 50 mg taken twice per day | Drug: Riluzole (100 mg)<br>* 100 mg/day (50 mg twice)<br>* Other names: Yooritek;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of SNR1611: adverse events | Observation of adverse events | 24-week (24-week extension and additional 48-week are optional) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| K-ALSFRS-R score | Change in Korean Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (K-ALSFRS-R) score from baseline | 24-week (24-week extension and additional 48-week are optional) | 
| FVC | Change in Forced Vital Capacity (FVC) from baseline | 24-week (24-week extension and additional 48-week are optional) | 
| CSF trough concentrations of SNR1611 | Trough concentrations of SNR1611 in cerebrospinal fluid (CSF) | 24-week (24-week extension and additional 48-week are optional) | 
| Plasma trough concentrations of SNR1611 | Trough concentrations of SNR1611 in plasma | 24-week (24-week extension and additional 48-week are optional) | 
| Milestone | Time to event milestones | Additional 48-week (optional) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALS, Lou Gehrig's disease