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Ropinirole hydrochloride (ropinirole) is safe and tolerable for patients with amyotrophic lateral sclerosis (ALS).
The results encourage a subsequent large-scale trial using ropinirole in ALS worldwide.
Why This Matters
ALS is a neurodegenerative disease with a median survival time of approximately 2 years. Muscle weakness eventually leads to respiratory failure and death.
Only two drugs have been approved by the US Food and Drug Administration for the treatment of ALS: riluzole (Rilutek) and edaravone (Radicava). Riluzole extends survival by 2-3 months with no reported benefits to muscle strength, whereas edaravone improves short-term functional outcomes but has no statistically significant effect on survival. As a result, dj renovations montreal the need for effective ALS therapies remains unmet.
Compared with other therapeutic areas, drug development for diseases of the nervous system has the second-lowest success rate at the pivotal phase. In particular, neurodegenerative diseases are heterogeneous and the majority of them are sporadic, limiting the translational potential of preclinical animal models.
By exploiting induced pluripotent stem cell-derived motor neurons generated from ALS patients, the investigators aimed to enable large-scale drug screening and overcome the limitations of preclinical animal models for the development of drugs to treat highly heterogeneous neurodegenerative diseases.
Investigators previously used an induced pluripotent stem cell-based drug repurposing approach to demonstrate that ropinirole attenuated ALS-specific pathological phenotypes.
In this single-center, randomized feasibility, double-blind, placebo-controlled trial, they assessed the safety and feasibility of ropinirole in ALS patients to verify its efficacy.
The trial enrolled 20 participants with ALS Functional Rating Scale-Revised (ALSFRS-R) scores greater than 2 points and randomly assigned them using dynamic allocation to receive ropinirole or placebo for 24 weeks in the double-blind period.
Upon completion, participants could opt to participate in the following 24-week open-label active extension period.
The primary outcomes were safety and tolerability.
The secondary outcomes for the feasibility trial objective were the change in the ALSFRS-R score, composite functional endpoint, combined assessment of function and survival, event-free survival, and time to ≤ 50% forced vital capacity (blinded outcome assessment).
This study is registered with the UMIN Clinical Trials Registry, UMIN000034954.
The primary outcomes of safety and tolerability were demonstrated.
Participants in the ropinirole group had lived an additional 27.9 weeks without disease progression events compared with the placebo group (log-rank test, 95% CI, 4.3 – 37.4) at 12 months (secondary outcome).
Regarding the feasibility of verifying efficacy, there were no significant differences in the ALSFRS-R score and combined assessment of function and survival scores during the double-blind period for 6 months.
Overall, the incidences of adverse events, most of which had been reported previously, were similar within both groups.
The incidence of gastrointestinal disorders (mainly, temporary mild nausea and diarrhea) was high at 76.9% in the ropinirole group (14.3% in the placebo group).
Interpretations of efficacy analyses in this feasibility study were limited by the small sample size of 20 participants.
There was an unexpectedly higher rate of discontinuation in this study than the historical rate in clinical trials of ALS. These discontinuation rates, particularly during the open-label extension phase, were attributable, at least in part, to the COVID-19 outbreak, which accounted for 23% and 29% of the participants in the ropinirole and placebo groups, respectively. The number of participants in the placebo group who discontinued the trial because of a worsening condition (47%) was higher than that in the ropinirole group (23%).
The placebo group had more bulbar onset, more female patients, and a lower BMI at baseline, which could be the relevant prognostic factors for ALS.
The onset of disease is self-reported and can be influenced by the sensitivity and character of an individual patient, rendering it difficult to confirm the accuracy of the period of disease duration.
This clinical trial was sponsored by K Pharma, Inc. The study drug, active drugs, and placebo were supplied free of charge by GlaxoSmithKline K.K.
Lead author Satoru Morimoto, MD, PhD, reports grants from Keio University School of Medicine during this study.
This is a summary of a preprint research study by Satoru Morimoto, MD, PhD, and colleagues from Keio University School of Medicine, Tokyo, Japan provided to you by Medscape. This study has not yet been peer-reviewed. The full text of the study can be found on medRxiv.org.
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