Review question
What are the effects (benefits and harms) of antioxidants for preventing breathing problems becoming worse in people with Duchenne muscular dystrophy (DMD)?
Background
Duchenne muscular dystrophy is an inherited condition where boys show signs of muscle weakness in early childhood that become worse over time. The muscles used in breathing become involved, which leads to shortness of breath and the need for artificial ventilation (a machine to support breathing). Treatment with antioxidants has been proposed to slow down the loss of muscle strength and the decline in breathing.
Study characteristics
We searched the evidence up to 23 March 2021. We included two studies in boys with DMD whose breathing was affected. Both studies compared the antioxidant medicine idebenone with a dummy medicine. One study included 66 participants between 10 and 18 years of age. The participants in this study were not receiving corticosteroids (medicines shown to be beneficial in DMD). The other study involved 255 children with DMD who were also taking corticosteroids. This study was stopped early for lack of benefit. The full results of the study are not yet available.
Study funding sources
The studies were sponsored by Santhera Pharmaceuticals, the maker of idebenone.
Key results
Idebenone may result in slightly less of a decline in forced vital capacity (a measure of lung capacity), but probably has little or no effect on quality of life in patients with worsening breathing. Idebenone may result in less of a decline in the ability to force air out of the lungs and airways (based on tests of forced expiratory volume in the first second and peak expiratory flow). Idebenone was associated with fewer serious side effects than the dummy drug and has little or no effect on non-serious side effects. Idebenone may have little or no effect on muscle function (arm strength). We found no studies that looked at hospitalisation due to respiratory infection.
Quality of the evidence
The overall certainty of the evidence was low.
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 in FEV1 and PEF, but probably has little to no measurable effect on change in quality of life. Idebenone is associated with fewer serious adverse events than placebo. Idebenone may result in little to no difference 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 effect of different antioxidant agents on preventing respiratory decline in people with DMD during the respiratory decline phase of the condition.
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 weakness in general, and respiratory decline in particular.
To assess the effects of antioxidant agents on preventing respiratory decline in people with Duchenne muscular dystrophy during the respiratory decline phase of the condition.
We searched CENTRAL, MEDLINE, Embase, and two trials registers to 23 March 2021, together with reference checking, citation searching, and contact with study authors to identify additional studies.
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.
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 and hospitalisation 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).
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 effect of idebenone on respiratory function compared to placebo. The trial that contributed numerical data included patients with 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 difference (MD) 3.28%, 95% confidence interval (CI) −0.41 to 6.97; 64 participants; low-certainty evidence), and probably has little or no effect 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, idebenone may result in less of a decline from baseline in FEV1 (MD 8.28%, 95% CI 0.89 to 15.67; 53 participants) and PEF (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) and little to no difference in non-serious adverse events (RR 1.00, 95% CI 0.88 to 1.13; 66 participants; low-certainty evidence) compared to placebo. Idebenone may result in little to no difference in change in arm muscle function (MD −2.45 N, 95% CI −8.60 to 3.70 for elbow flexors and 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 after an interim efficacy analysis 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).