Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis.

Autor: Pupillo E; Research Center for ALS, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy. Electronic address: elisabetta.pupillo@marionegri.it., Bianchi E; Research Center for ALS, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy., Bonetto V; Research Center for ALS, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy., Pasetto L; Research Center for ALS, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy., Bendotti C; Research Center for ALS, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy., Paganoni S; Sean M. Healey & AMG Center for ALS at Mass General Hospital, Department of Neurology, Boston, USA; Spaulding Rehabilitation Hospital, Department of PM&R, Harvard Medical School, Boston, USA., Mandrioli J; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Department of Neurosciences, Azienda Ospedaliero-Universitaria Di Modena, Modena, Italy., Mazzini L; ALS Expert Center 'Maggiore della Carità' Hospital and University of Piemonte Orientale, Novara, Italy.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2024 Nov; Vol. 122, pp. 456-462. Date of Electronic Publication: 2024 Aug 28.
DOI: 10.1016/j.bbi.2024.08.044
Abstrakt: Background: Positive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS).
Objective: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation.
Study Design and Settings: A randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial's last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated.
Results: Mean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL - RNS60 group; 3.3 years in low NfL - placebo group; 1.9 years in high NfL - RNS60 group; 1.8 years in high NfL - placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 - RNS60 group; 2.3 years in low MCP-1 - placebo group; 2.8 years in high MCP-1 - RNS60 group; 2.6 years in high MCP-1 - placebo group) levels at baseline.
Conclusions and Relevance: In this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug's effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival.
Trial Registration: Study preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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