Introduction: Amyotrophic lateral sclerosis (ALS) is an intractable and incurable neurological disease. It is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In disease research, 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 such results as its preferable transitivity in the brain and tolerability, including possible adverse reactions. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial.
Methods: The ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of the ropinirole hydrochloride extended-release tablet (Requip CR) at 2- to 16-mg doses in patients with ALS. Twenty patients will be recruited for the active drug group (fifteen patients) and placebo group (five patients). All patients will be able to receive the standard ALS treatment of riluzole if not changed the dosage during this trial. The primary outcome will be safety and tolerability at 24 weeks, defined from the date of randomization. Secondary outcome will be the efficacy, including any change in the ALS Functional Rating Scale-Revised (ALSFRS-R), change in the Combined Assessment of Function and Survival (CAFS), and the composite endpoint as a sum of Z-transformed scores on various clinical items. Notably, we will perform an explorative search for a drug effect evaluation using the patient-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), an ALSFRS-R score ≥2 points on all items and age from 20 to 80 years.
Conclusion: 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 and JMA-IIA00397.
Protocol version: version 1.6 (Date; 5/Apr/2019).
Keywords: %FVC, Forced vital capacity; 6-OHDA, 6-hydroxydopamine; 8-OHdG, 8-Hydroxydeoxyguanosine; ADR, Adverse reaction; AE, Adverse effect; ALP, Alkaline phosphatase; ALS, Amyotrophic lateral sclerosis; ALSAQ-40, Amyotrophic Lateral Sclerosis Assessment Questionnaire-40; ALSFRS-R, ALS Functional Rating Scale-Revised; ALT, Alanine aminotransferase; APTT, Activated partial thromboplastin time; AST, Aspartate aminotransferase; Amyotrophic lateral sclerosis; BUN, Blood urea nitrogen; CAFS, Combined Assessment of Function and Survival; CK, Creatine kinase; CPK, Creatine phosphokinase; CRP, C-reactive protein; CTCAE, Common terminology Criteria for Adverse Events; EDC, Electronic data capture; FALS, Familial ALS; FAS, Full analysis set; GCP, Good clinical practice; HBs, Hepatitis B surface; HCG, Human chorionic gonadotropin; HCV, Hepatitis C virus; HDL, High-density lipoprotein; HIV, Human immunodeficiency virus; HTLV-1, Human T-cell leukemia virus type 1; IRB, Institutional review board; LDH, Lactate dehydrogenase; LDL, Low-density lipoprotein; MMT, Manual muscle testing; NfL, Neurofilament light chain; PPS, Per protocol set; PT, Prothrombin time; QOL, Quality of life; Requip CR; Ropinirole hydrochloride; SAE, Severe adverse effect; SALS, sporadic ALS; SOD, Superoxide dismutase; TDP-43, Transactive response DNA-binding protein 43; TPHA, Treponema pallidum hemagglutination; iPSC-drug discovery.