Finnigan Lucy E M, Cassar Mark Philip, Koziel Margaret James, Pradines Joel, Lamlum Hanan, Azer Karim, Kirby Dan, Montgomery Hugh, Neubauer Stefan, Valkovič Ladislav, Raman Betty
Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Axcella Therapeutics, Cambridge, MA, USA.
EClinicalMedicine. 2023 May;59:101946. doi: 10.1016/j.eclinm.2023.101946. Epub 2023 Apr 14.
'Long COVID' describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID.
Patients with fatigue-dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical-based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two-week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849.
Between December 15th 2021, and May 23th 2022, 60 participants were screened, and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τ) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] -4.30, 95% confidence interval (95% CI) -7.14, -1.47; = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious or led to treatment discontinuation.
Although treatment with AXA1125 did not improve the primary endpoint (τ-measure of mitochondrial respiration), when compared to placebo, there were significant improvements in fatigue-based symptoms among patients living with Long COVID following a four-week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID.
Axcella Therapeutics.
“长新冠”指的是严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染12周后仍持续存在的症状，常见症状为疲劳。潜在原因包括线粒体功能降低和细胞生物能学改变。AXA1125此前在临床前模型以及某些临床病症中可增加β-氧化并改善生物能学，因此可能减轻与“长新冠”相关的疲劳。我们旨在评估AXA1125治疗“长新冠”的疗效、安全性和耐受性。
在英国完成的这项单中心、双盲、随机对照2a期试验性研究中，招募了以疲劳为主的“长新冠”患者。使用交互式应答技术将患者按1:1随机分配，在临床环境中接受AXA1125或匹配的安慰剂。AXA1125或安慰剂的每剂（33.9 g）以液体混悬液形式口服给药，每日两次，共四周，随后有两周的随访期。主要终点是通过磷磁共振波谱（P-MRS）评估的中度运动后磷酸肌酸（PCr）恢复率从基线到第28天的平均变化。所有患者均纳入意向性分析。该试验已在ClinicalTrials.gov注册，注册号为NCT05152849。
在2021年12月15日至2022年5月23日期间，筛查了60名参与者，41名参与者被随机分组并纳入最终分析。治疗组（n = 21）和安慰剂组（n = 20）之间骨骼肌磷酸肌酸恢复时间常数（τ）和6分钟步行试验（6MWT）的变化无显著差异。然而，与安慰剂相比，AXA1125治疗使第28天的查尔德疲劳问卷[CFQ-11]疲劳评分显著降低（最小二乘均值差[LSMD] -4.30，95%置信区间（95%CI）-7.14，-1.47；P = 0.0039）。11名（52.4%，AXA1125组）和4名（20.0%，安慰剂组）患者报告了治疗中出现的不良事件；均不严重，也未导致治疗中断。
虽然AXA1125治疗未改善主要终点（线粒体呼吸的τ测量值），但与安慰剂相比，在为期四周的治疗期后，“长新冠”患者中以疲劳为基础的症状有显著改善。需要进一步开展多中心研究，以在更大的以疲劳为主的“长新冠”患者队列中验证我们的研究结果。
Axcella Therapeutics公司。
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