1. 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)
- Author
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Hideyuki Okano, Jin Nakahara, Norihiro Suzuki, Shinichi Takahashi, Komei Fukushima, Masashi Aoki, Satoru Morimoto, and Hideyuki Saya
- Subjects
0301 basic medicine ,Ropinirole hydrochloride ,ALP, Alkaline phosphatase ,SOD, Superoxide dismutase ,ALS, Amyotrophic lateral sclerosis ,0302 clinical medicine ,HDL, High-density lipoprotein ,Amyotrophic lateral sclerosis ,APTT, Activated partial thromboplastin time ,ADR, Adverse reaction ,lcsh:R5-920 ,6-OHDA, 6-hydroxydopamine ,lcsh:Cytology ,HBs, Hepatitis B surface ,HTLV-1, Human T-cell leukemia virus type 1 ,MMT, Manual muscle testing ,CPK, Creatine phosphokinase ,GCP, Good clinical practice ,Riluzole ,%FVC, Forced vital capacity ,HIV, Human immunodeficiency virus ,Tolerability ,CRP, C-reactive protein ,Original Article ,CTCAE, Common terminology Criteria for Adverse Events ,AST, Aspartate aminotransferase ,lcsh:Medicine (General) ,Requip CR ,BUN, Blood urea nitrogen ,medicine.drug ,SALS, sporadic ALS ,medicine.medical_specialty ,FAS, Full analysis set ,Randomization ,EDC, Electronic data capture ,TDP-43, Transactive response DNA-binding protein 43 ,TPHA, Treponema pallidum hemagglutination ,Biomedical Engineering ,IRB, Institutional review board ,Placebo ,HCV, Hepatitis C virus ,Biomaterials ,SAE, Severe adverse effect ,03 medical and health sciences ,HCG, Human chorionic gonadotropin ,8-OHdG, 8-Hydroxydeoxyguanosine ,NfL, Neurofilament light chain ,Internal medicine ,medicine ,ALSFRS-R, ALS Functional Rating Scale-Revised ,Ropinirole Hydrochloride ,lcsh:QH573-671 ,ALSAQ-40, Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 ,AE, Adverse effect ,LDH, Lactate dehydrogenase ,business.industry ,PPS, Per protocol set ,QOL, Quality of life ,ALT, Alanine aminotransferase ,CK, Creatine kinase ,medicine.disease ,Clinical trial ,FALS, Familial ALS ,PT, Prothrombin time ,iPSC-drug discovery ,CAFS, Combined Assessment of Function and Survival ,030104 developmental biology ,LDL, Low-density lipoprotein ,business ,030217 neurology & neurosurgery ,Progressive disease ,Developmental Biology - Abstract
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)., Highlights • ALS is a progressive neurodegenerative disease caused by selective vulnerability of upper and lower motor neurons. • ALS patients have no radical treatment. • The ROPALS trial reveals the safety, tolerability, and efficacy of the ropinirole hydrochloride in patients with ALS. • This trial is the pioneering clinical trial for ALS based on iPSCs-drug discovery in Japan.
- Published
- 2019
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