Research Center for ALS, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
Research Center for ALS, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
Brain Behav Immun. 2024 Nov;122:456-462. doi: 10.1016/j.bbi.2024.08.044. Epub 2024 Aug 28.
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).
to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation.
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.
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.
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.
Study preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.
在一项针对肌萎缩侧索硬化症（ALS）患者的 2 期随机、安慰剂对照试验中，观察到 RNS60 对呼吸和延髓功能有积极影响。
研究试验参与者的长期生存率及其与呼吸状况以及神经退行性和炎症生物标志物的关系。
进行了一项随机、双盲、2 期临床试验。试验参与者于 2017 年 5 月至 2020 年 1 月在 22 家意大利专家 ALS 中心招募。在试验最后一名患者最后一次就诊后 33 个月确定所有参与者的生存状态（LPLV）。参与者为肌萎缩侧索硬化症患者，根据试验治疗期间用力肺活量（FVC）斜率分为慢进展者或快进展者。还评估了人口统计学、临床和生物标志物水平及其与生存的关系。
平均随访时间为 2.8 年。RNS60 组的长期中位生存率延长了 6 个月（p=0.0519）。基线 FVC 和试验参与的前 4 周内 FVC 下降率在活性治疗组和安慰剂治疗组之间平衡。在随机、安慰剂对照治疗 6 个月后，与安慰剂组相比，RNS60 组的 FVC 下降速度明显较慢。治疗期间 FVC 进展率与长期生存率密切相关（中位生存率：慢 FVC 进展者为 3.7 年；快 FVC 进展者为 1.6 年）。在基线时神经丝轻链（NfL）水平较低（中位生存率：RNS60 组>4 年；低 NfL-安慰剂组为 3.3 年；高 NfL-RNS60 组为 1.9 年；高 NfL-安慰剂组为 1.8 年）和单核细胞趋化蛋白-1（MCP-1）水平较低（中位生存率：低 MCP-1-RNS60 组为 3.7 年；低 MCP-1-安慰剂组为 2.3 年；高 MCP-1-RNS60 组为 2.8 年；高 MCP-1-安慰剂组为 2.6 年）的参与者中，RNS60 组的长期生存率较长。
在这项事后分析中，与随机分配到安慰剂的参与者相比，随机分配到 RNS60 的参与者的长期生存率更长，并且与较慢的 FVC 进展率相关，表明较长的生存率可能是由药物对呼吸功能的影响介导的。在这些事后分析中，RNS60 对生存的有益影响在研究入组时 NfL 和 MCP-1 水平较低的参与者中最为明显，这表明这可能是未来研究 RNS60 对生存影响的目标亚组。
研究于 2017 年 1 月 13 日在 EUDRA-CT（2016-002382-62）进行预注册。该研究也在 ClinicalTrials.gov 注册，编号为 NCT03456882。
