Vucic Steve, Menon Parvathi, Huynh William, Mahoney Colin, Ho Karen S, Hartford Alan, Rynders Austin, Evan Jacob, Evan Jeremy, Ligozio Shelia, Glanzman Robert, Hotchkin Michael T, Kiernan Matthew C
Brain and Nerve Research Centre, Concord Clinical School and Department of Neurology, Concord Repatriation General Hospital, The University of Sydney, Sydney, Australia.
Brain and Mind Centre, University of Sydney, and Department of Neurology, Royal Prince Alfred Hospital, Sydney, Australia.
EClinicalMedicine. 2023 Jun 8;60:102036. doi: 10.1016/j.eclinm.2023.102036. eCollection 2023 Jun.
CNM-Au8® is a catalytically-active gold nanocrystal neuroprotective agent that enhances intracellular energy metabolism and reduces oxidative stress. The phase 2, randomised, double-blind, placebo-controlled trial and open label extension RESCUE-ALS trial evaluated the efficacy and safety of CNM-Au8 for treatment of amyotrophic lateral sclerosis (ALS).
RESCUE-ALS and its long-term open label extension (OLE) were conducted at two multidisciplinary ALS clinics located in Sydney, Australia: (i) the Brain and Mind Centre and (ii) Westmead Hospital. The double-blind portion of RESCUE-ALS was conducted from January 16, 2020 (baseline visit, first-patient first-visit (FPFV)) through July 13, 2021 (double-blind period, last-patient last-visit (LPLV)). Participants (N = 45) were randomised 1:1 to receive 30 mg of CNM-Au8 or matching placebo daily over 36 weeks in addition to background standard of care, riluzole. The primary outcome was mean percent change in summed motor unit number index (MUNIX), a sensitive neurophysiological biomarker of lower motor neuron function. Change in total (or summated) MUNIX score and change in forced vital capacity (FVC) were secondary outcome measures. ALS disease progression events, ALS Functional Rating Scale (ALSFRS-R) change, change in quality of life (ALSSQOL-SF) were assessed as exploratory outcome measures. Long-term survival evaluated vital status of original active versus placebo randomisation for all participants through at least 12 months following last-patient last-visit (LPLV) of the double-blind period. RESCUE-ALS and the open label study are registered in clinicaltrials.gov with registration numbers NCT04098406 and NCT05299658, respectively.
In the intention-to-treat (ITT) population, there was no significant difference in the summated MUNIX score percent change (LS mean difference: 7.7%, 95% CI: -11.9 to 27.3%, p = 0.43), total MUNIX score change (18.8, 95% CI: -56.4 to 94.0), or FVC change (LS mean difference: 3.6, 95% CI: -12.4 to 19.7) between the active and placebo treated groups at week 36. In contrast, survival analyses through 12-month LPLV demonstrated a 60% reduction in all-cause mortality with CNM-Au8 treatment [hazard ratio = 0.408 (95% Wald CI: 0.166 to 1.001, log-rank p = 0.0429). 36 participants entered the open label extension (OLE), and those initially randomised to CNM-Au8 exhibited a slower rate of disease progression, as measured by time to the occurrence of death, tracheostomy, initiation of non-invasive ventilatory support, or gastrostomy tube placement. CNM-Au8 was well-tolerated, and no safety signals were observed.
CNM-Au8, in combination with riluzole, was well-tolerated in ALS with no identified safety signals. While the primary and secondary outcomes of this trial were not significant, the clinically meaningful exploratory results support further investigation of CNM-Au8 in ALS.
The RESCUE-ALS was substantially funded by a grant from FightMND. Additional funding was provided by Clene Australia Pty Ltd.
CNM - Au8®是一种具有催化活性的金纳米晶体神经保护剂，可增强细胞内能量代谢并减少氧化应激。2期随机、双盲、安慰剂对照试验及开放标签扩展研究RESCUE - ALS试验评估了CNM - Au8治疗肌萎缩侧索硬化症（ALS）的疗效和安全性。
RESCUE - ALS试验及其长期开放标签扩展研究（OLE）在澳大利亚悉尼的两家多学科ALS诊所进行：（i）脑与心智中心和（ii）韦斯特米德医院。RESCUE - ALS试验的双盲阶段从2020年1月16日（基线访视，首例患者首次就诊（FPFV））至2021年7月13日（双盲期，末例患者末次就诊（LPLV））。参与者（N = 45）按1:1随机分组，除了接受背景标准治疗利鲁唑外，在36周内每天接受30 mg的CNM - Au8或匹配的安慰剂。主要结局是运动单位总数指数（MUNIX）总和的平均百分比变化，这是一种评估下运动神经元功能的敏感神经生理学生物标志物。总（或累计）MUNIX评分变化和用力肺活量（FVC）变化是次要结局指标。ALS疾病进展事件、ALS功能评定量表（ALSFRS - R）变化、生活质量变化（ALSSQOL - SF）被评估为探索性结局指标。长期生存情况通过双盲期末例患者末次就诊（LPLV）后至少12个月，评估所有参与者原始活性组与安慰剂随机分组的生命状态。RESCUE - ALS试验和开放标签研究分别在clinicaltrials.gov上注册，注册号为NCT04098406和NCT05299658。
在意向性分析（ITT）人群中，在第36周时，活性治疗组和安慰剂治疗组之间的累计MUNIX评分百分比变化（LS平均差异：7.7%，95%CI：-11.9至27.3%，p = 0.43）、总MUNIX评分变化（18.8，95%CI：-56.4至94.0）或FVC变化（LS平均差异：3.6，95%CI：-12.4至19.7）均无显著差异。相比之下，通过12个月LPLV的生存分析表明，CNM - Au8治疗使全因死亡率降低了60%[风险比 = 0.408（95% Wald CI：0.166至1.001，对数秩检验p = 0.0429）]。36名参与者进入开放标签扩展研究（OLE），那些最初随机分配到CNM - Au8组的患者疾病进展速度较慢，通过死亡、气管切开术、开始无创通气支持或胃造瘘管置入的时间来衡量。CNM - Au8耐受性良好，未观察到安全信号。
CNM - Au8与利鲁唑联合使用时，在ALS患者中耐受性良好，未发现安全信号。虽然该试验的主要和次要结局无显著差异，但具有临床意义的探索性结果支持对CNM - Au8在ALS中的进一步研究。
RESCUE - ALS试验主要由FightMND的一项赠款资助。额外资金由澳大利亚Clene私人有限公司提供。
