Abstract

--- - Background Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterised by progressive muscle weakness beginning in early childhood. Respiratory failure and weak cough develop in all patients as a consequence of muscle weakness leading to a risk of atelectasis, pneumonia, or the need for ventilatory support. There is no curative treatment for DMD. Corticosteroids are the only pharmacological intervention proven to delay the onset and progression of muscle weakness and thus respiratory decline in DMD. Antioxidant treatment has been proposed to try to reduce muscle weaknessin general, and respiratory decline in particular. Objectives To assess the eJects of antioxidant agents on preventing respiratory decline in people with Duchenne muscular dystrophy during the respiratory decline phase of the condition. Search methods We searched CENTRAL, MEDLINE, Embase,and two trialsregistersto 23 March2021,together with reference checking, citation searching, and contact with study authors to identify additional studies. Selection criteria We included randomised controlled trials (RCTs) and quasi-RCTs that met our inclusion criteria.We included male patients with a diagnosis of DMD who had respiratory decline evidenced by a forced vital capacity (FVC%) less than 80% but greater than 30% of predicted values, receiving any antioxidant agent compared with other therapies for the management of DMD or placebo. Data collection and analysis Two review authors screened studies for eligibility, assessed risk of bias of studies, and extracted data. We used standard methods expected by Cochrane.We assessed the certainty of the evidence using the GRADE approach. The primary outcomes were FVC andhospitalisation due to respiratory infections. Secondary outcomes were quality of life, adverse events, change in muscle function,forced expiratory volume in the first second (FEV1), and peak expiratory flow (PEF). Main results We included one study with 66 participants who were not co-treated with corticosteroids, which was the only study to contribute data to our main analysis. We also included a study that enrolled 255 participants treated with corticosteroids, which was only available as a press release without numerical results. The studies were parallel-group RCTs that assessed the eJect of idebenoneon respiratory function compared to placebo. The trial that contributed numerical data includedpatientswith a mean (standard deviation) age of 14.3 (2.7) years at the time of inclusion,with a documented diagnosis of DMD or severe dystrophinopathy with clinical features consistent with typical DMD. The overall risk of bias across most outcomes was similar and judged as 'low'. Idebenone may result in a slightly less of a decline in FVC from baseline to one year compared to placebo (mean diJerence (MD) 3.28%, 95% confidence interval (CI) -0.41 to 6.97; 64 participants; low-certainty evidence), and probably has little or no eJect on change in quality of life (MD -3.80, 95% CI -10.09 to 2.49; 63 participants; moderate-certainty evidence) (Pediatric Quality of Life Inventory (PedsQL), range 0 to 100, 0 = worst, 100 = best quality of life). As a related but secondary outcome,idebenonemay resultin less of a decline from baseline inFEV1 (MD 8.28%, 95% CI 0.89 to 15.67; 53 participants) andPEF(MD 6.27%, 95% CI 0.61 to 11.93; 1 trial, 64 participants) compared to placebo. Idebenone was associated with fewer serious adverse events (RR 0.42, 95% CI 0.09 to 2. - 04; 66 participants; low-certainty evidence) andlittle to no diJerence in non-serious adverse events (RR 1.00, 95% CI 0.88 to 1.13; 66 participants; low-certainty evidence) compared to placebo. Idebenonemay result in little to no diJerence in change in arm muscle function (MD -2.45 N, 95% CI -8.60 to 3.70 for elbow flexorsand MD -1.06 N, 95% CI -6.77 to 4.65 for elbow extensors; both 52 participants) compared to placebo. We found no studies evaluating the outcome hospitalisation due to respiratory infection. The second trial, involving 255 participants, for which data were available only as a press release without numerical data, was prematurely discontinued due to futility aQer an interim eJicacyanalysis based on FVC. There were no safety concerns. The certainty of the evidence was low for most outcomes due to imprecision and publication bias (the lack of a full report of the larger trial, which was prematurely terminated). Authors' conclusions Idebenone is the only antioxidant agent tested in RCTs for preventing respiratory decline in people with DMD for which evidence was available for assessment. Idebenone may result in slightly less of a decline in FVC and less of a decline inFEV1 and PEF, but probably has little to no measurable eJect on change in quality of life. Idebenone is associated with fewer serious adverse events than placebo. Idebenonemay result in little to no diJerence in change in muscle function. Discontinuation due to the futility of the SIDEROS trial and its expanded access programmes may indicate that idebenone research in this condition is no longer needed, but we await the trial data.Further research is needed to establish the eJect of diJerent antioxidant agents on preventing respiratory decline in people with DMD during the respiratory decline phase of the condition.