Ropinirole hydrochloride remedy for amyotrophic lateral sclerosis - Protocol for a randomized, double-blind, placebo-controlled, single-center, and open-label continuation phase I/IIa clinical trial (ROPALS trial)

Abstract Background: Amyotrophic lateral sclerosis (ALS) is one of intractable neurological diseases, which is an incurable disease. ALS is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In the disease research ever conducted, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering preferable transitivity in the brain, tolerability including adverse reactions, and others. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride to ALS in this clinical trial. Methods/Design: ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of ropinirole hydrochloride extended-release tablet (Requip CR) at 2mg - 16mg doses in patients with ALS. 20 patients will be recruited as active drug and placebo group. All patients will be able to be on the standard treatment for ALS of riluzole if not changed the dosage. The primary outcome will be safety and tolerability at 24 weeks defined from the date of randomization. Secondary outcome will be the efficacy including the change of ALS Functional Rating Scale-Revised (ALSFRS-R), the change in Combined Assessment of Function and Survival (CAFS), and composite endpoint as a sum of Z-transformed scores on the various clinical items. Noteworthy, we will perform explorative search for drug effect evaluation by using the patients-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), ALSFRS-R score ≥2 points on all items and age from 20 to 80 years. Discussion: Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020. Trial registration: Current controlled trials UMIN000034954 Protocol version: version 1.1 (Date; 7/Nov/2018) Keywords: Amyotrophic Lateral Sclerosis, Ropinirole hydrochloride, Requip CR, iPSC-drug discovery