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 weakness in general, and respiratory decline in particular.
Objectives
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.
Search methods
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.
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 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).
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 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).
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 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.
Plain language summary
Antioxidants to prevent respiratory decline in people with Duchenne muscular dystrophy
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.
Summary of findings
Summary of findings 1. Idebenone compared to placebo in people with Duchenne muscular dystrophy and progressive respiratory decline.
| Idebenone compared to placebo in people with Duchenne muscular dystrophy and progressive respiratory decline | |||||
|
Patient or population: people with Duchenne muscular dystrophy and progressive respiratory decline Setting: outpatients Intervention: idebenone Comparison: placebo | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | No. of participants (studies) | Certainty of the evidence (GRADE) | |
| Risk with placebo | Risk with idebenone | ||||
|
Change in respiratory function from baseline to 12 months, assessed by forced vital capacity (FVC) Assessed by: change from baseline in per cent of predicted values. Follow‐up: 12 months |
The mean change from baseline in FVC was −8.95%. |
MD 3.28% higher (0.41 lower to 6.97 higher)a | ‐ | 64 (1 RCT) | ⨁⨁◯◯ LOWb,c |
| Hospitalisation due to respiratory infection | No studies measured this outcome. | ||||
|
Quality of life Assessed by: Pediatric Quality of Life Inventory, change from baseline (0 to 100; 0 = worst outcome, 100 = best outcome) Follow‐up: 12 months |
The mean change in quality of life was 2.46. | MD 3.8 lower (10.09 lower to 2.49 higher) | ‐ | 63 (1 RCT) | ⨁⨁⨁◯ MODERATEb |
|
Serious adverse events Follow‐up: 12 months |
147 per 1000 | 62 per 1000 (13 to 300) | RR 0.42 (0.09 to 2.04)a | 66 (1 RCT) | ⨁⨁◯◯ LOWc,d |
|
Non‐serious adverse events Follow‐up: 12 months |
941 per 1000 | 941 per 1000 (828 to 1000) | RR 1.00 (0.88 to 1.13)a | 66 (1 RCT) | ⨁⨁◯◯ LOWc,d |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio | |||||
| GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | |||||
aAnother study was stopped early due to lack of efficacy in the primary endpoint (FVC) with "no safety concerns". No numerical data were available; this information was reported in a press release (SIDEROS 2021). bDowngraded one level due to the small number of participants in the included study. cDowngraded one level due to publication bias; there were no available data on the SIDEROS 2021 study beyond the press release from the pharmaceutical company. dDowngraded one level due to the small number of participants and events in the included study.
Background
Description of the condition
Duchenne muscular dystrophy (DMD) is an X‐linked recessive disorder, caused by deletions, duplications, and mutations in the dystrophin gene leading to either absent or deficient production of the dystrophin protein. It is the most common muscular dystrophy of childhood, with a reported incidence of 1:5000 in male newborns (Mendell 2013). DMD is characterised by progressive muscle weakness beginning in early childhood, which, in the absence of steroid treatment, leads to loss of independent walking between seven and 13 years of age (Birnkrant 2018a; Birnkrant 2018b). Cardiac (heart) muscle is affected; progressive dilated cardiomyopathy is present in all patients by 18 years of age and accounts for up to 40% of premature death in the late teens and early 20s. Early aggressive treatment with angiotensin‐converting enzyme (ACE) inhibitors and beta‐blockers may benefit patients (Birnkrant 2018b; Stromberg 2012). Respiratory failure and weak cough develops in all patients as a consequence of muscle weakness in the late teens and early 20s leading to a risk of atelectasis (lung collapse), mucous plugging, and pneumonia. Proactive management using cough augmentation, vaccination against flu and pneumococcal infection, and nighttime non‐invasive ventilation (NIV) are vital components of care for individuals with DMD and can prolong life into the fourth and even fifth decades in some patients. Scoliosis occurs during the adolescent growth spurt and is common in patients not treated with corticosteroids. Most patients with scoliosis will undergo spinal fusion. Severe, untreated scoliosis may exacerbate respiratory complications (LoMauro 2018). Individuals with DMD therefore require periodic pulmonary function testing and sleep studies to monitor for nocturnal hypoventilation, as well as the use of lung volume recruitment and assisted coughing. NIV with bilevel positive airway pressure (BiPAP) at nighttime, progressing with advancing age to daytime NIV, is ultimately required for all patients (Birnkrant 2018b).
There is at present 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 (Matthews 2016). However, long‐term corticosteroid use leads to significant unacceptable side effects, in particular osteoporosis, growth and pubertal delay, obesity, and behavioural and mood issues, so that by 18 years of age more than 40% of patients will have stopped steroid treatment (Henricson 2013).
Description of the intervention
Dystrophin is a large cytoskeletal protein located on the cytoplasmic membrane of the sarcolemma (cell membrane of skeletal and cardiac muscle fibres). It plays a complex role in maintaining the integrity of the muscle fibre, providing structural reinforcement and stabilisation of the glycoprotein complex found within the sarcolemma, protecting it from degradation during muscle contraction. Dystrophin also plays a role in regulating neuronal nitric oxide synthase (nNOS) (Petrof 1993), which is involved in muscle blood flow to prevent early muscle fatigue during exercise (Sander 2000). Sarcolemmal fragility also leads to intracellular calcium dysregulation, a consequence of which is mitochondrial dysfunction leading to a reduction in resting adenosine triphosphate (ATP) levels, increased production of cell‐damaging reactive oxygen species (ROS), and ultimately mitochondrial damage (Brookes 2004; Cardoso 1999; Peng 2010). Thus, when dystrophin is deficient, muscle fibres necrose and degenerate through a complex pathway of apoptosis which ultimately causes muscle wasting and weakness (Aslesh 2018; Bellinger 2009; Mázala 2015; Petrof 1993; Turner 1988). Treatment with antioxidants has been proposed to try to reduce secondary mitochondrial damage and therefore reduce secondary apoptosis. The mdx mouse, a strain of mice arising from a spontaneous X chromosome‐linked mutation that produces lack of muscle dystrophin and possesses histological lesions similar to human muscular dystrophy, was used as an animal model for the following interventions.
N‐acetylcysteine 2% solution was added to drinking water of mdx mice for six weeks and demonstrated some improvements in muscle function (Head 2017).
A combination of alpha‐lipoic acid and L‐carnitine decreased plasma creatine kinase (CK) levels and decreased muscle fibre central nucleation and variations in fibre size, antioxidant activity, lipid peroxidation, and matrix metalloproteinase activity in a diaphragm preparation (Hnia 2007).
Similar findings occurred with ascorbic acid (vitamin C), coenzyme Q10 (CoQ10), vitamin E, cilostazol, diacerein, and melatonin, which decreased plasma CK levels and diaphragm myonecrosis and inflammation (Hermes 2016; Hibaoui 2011; Mâncio 2017a; Mâncio 2017b; Tonon 2012; Woodman 2016). Epigallocatechin‐3‐gallate, a green tea extract, is described as having a similar effect (Nakae 2008).
Pentoxifylline and sildenafil have been found to increase diaphragm force‐generating capacity (Burdi 2009; Percival 2012).
Idebenone and L‐arginine reduce muscle inflammation and fibrosis (Buyse 2015; Marques 2010).
However, considering the generally accepted limitations of animal models, any potential benefits need to be confirmed in people with DMD.
How the intervention might work
Free‐radical accumulation and oxidative stress have been proposed as contributing factors to the progression of DMD. Markers of oxidative stress including by‐products of lipid peroxidation and protein oxidation have been found to be elevated in people with DMD (Haycock 1996; Rodriguez 2003). Since oxidative stress results from an imbalance between the production and removal of ROS, there is a rationale to consider antioxidant therapy as a potential intervention in DMD for muscle dysfunction in general, and respiratory decline in particular. Antioxidant therapy might be capable of the inhibition of lipid peroxidation and consequent stimulation of mitochondrial electron flux and cellular energy production, thus improving respiratory muscle performance and respiratory function (Buyse 2015).
Why it is important to do this review
Given that there is no cure for DMD, and that corticosteroid use is limited by potential and real significant side effects and has a variable response, there is a need to look for other interventions that might reduce the effect of secondary muscle damage caused by dystrophin deficiency, such as antioxidants to protect mitochondrial function. Although the efficacy of antioxidant therapy has been reviewed for other neuromuscular diseases (e.g. amyotrophic lateral sclerosis) (Orrell 2007), to our knowledge there is no high‐quality systematic review evaluating the effectiveness of antioxidants to reduce respiratory decline in DMD.
Objectives
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.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs) and quasi‐RCTs that met our inclusion criteria. We did not include cluster‐ or cross‐over RCTs as they are not relevant to our review question. We included studies reported as full text, those published as abstract only, and unpublished data where it was possible to establish eligibility for inclusion based on limited data. There were no language restrictions.
We included studies that included both eligible and ineligible participants (e.g. a subset of participants in the respiratory decline phase of DMD) if the study authors presented separate data for eligible participants.
Types of participants
We included male participants with a diagnosis of Duchenne muscular dystrophy (DMD) with respiratory decline evidenced by a forced vital capacity (FVC%) < 80% and > 30% of predicted values.
FVC% > 80%, regardless of age, is considered normal (Miller 2005), and FVC < 30% represents a major decline in respiratory function probably requiring ventilatory support, where antioxidants are highly unlikely to be of value (Lyager 1995).
We included participants who were being treated with corticosteroids as well as those who were corticosteroid naïve or who stopped corticosteroid treatment for any reason (Matthews 2016).
Types of interventions
We included trials comparing antioxidant agents (given alone or in combination) with other therapies for the management of DMD (e.g. corticosteroids, physical therapy, respiratory muscle training, angiotensin‐converting enzyme (ACE) inhibitors) or with placebo. We included head‐to‐head comparisons between antioxidant agents.
Co‐interventions (e.g. corticosteroids) were allowed provided that they were provided to each group equally.
We included any of the antioxidant agents used in animal studies as above. Our inclusion criteria included, but were not limited to, the following.
Idebenone
Coenzyme Q10
Green tea extract
N‐acetylcysteine
Metformin
Citrulline
We also included any other intervention considered to have action as an antioxidant identified through our search strategy.
Types of outcome measures
The outcomes listed here were not inclusion criteria for the review. A minimal clinically important difference (MCID) was not available for all of the outcomes considered. We reported an MCID when it was available.
Primary outcomes
Change in respiratory function from baseline to 12 months or beyond, assessed as forced vital capacity (FVC): measured with standard spirometry at hospital visits with the aid of a qualified, trained, and certified operator and in accordance with the American Thoracic Society/European Respiratory Society guidelines (Miller 2005), converted to per cent of predicted values according to age, sex, race, and height. We considered an absolute change of 2% for improvement and 6% for worsening of the FVC predicted value as MCID (du Bois 2011).
Hospitalisation due to respiratory infections, measured in the number of admissions per year since the beginning of treatment.
Secondary outcomes
Quality of life: measured using the EuroQoL‐5D, Wille 2010, or the Pediatric Quality of Life Inventory (PedsQL), Varni 2001, or any other well‐known and validated scale. We considered a mean change of 0.074 in EuroQol‐5D (range 0 to 1; 0 = death, 1 = perfect health) (Walters 2005), and a mean change of 5 in PedsQL (range 0 to 100; 0 = worst outcome, 100 = best outcome) as MCID (Hilliard 2013).
Any adverse events: defined as any undesirable or harmful occurrence in a participant from the beginning of treatment. We reported non‐serious and serious adverse events (including death, disability, life‐threatening events, or those requiring hospitalisation) separately.
Change in muscle function: assessed by timed functional testing: walking a certain distance as fast as possible, climbing four standardised stairs or rising up from the floor to a standing position without assistance (Phillips 2008). We considered an absolute change of 2.3 seconds for the 10‐metre walk/run test, 2.1 seconds for the climbing stairs test, 3.7 seconds for the supine to stand test, and 31 m for the 6‐minute walk distance timed test as MCID (McDonald 2013). In non‐ambulant participants, we considered the change in pinch, grip and/or wrist flexion and extension strength (Servais 2013), or change in the Motor Function Measure (Bérard 2005), or similar. MCID for the given strength was identified where possible and used in the results (McDonald 2013).
Forced expiratory volume in the first second (FEV1): measured with standard spirometry at hospital visits with the aid of a qualified, trained, and certified operator and in accordance with the American Thoracic Society/European Respiratory Society guidelines (Graham 2019), converted to per cent of predicted values according to age, sex, race, and height or z‐scores.
Peak expiratory flow (PEF): measured with standard spirometry at hospital visits with the aid of a qualified, trained, and certified operator and in accordance with the American Thoracic Society/European Respiratory Society guidelines (Miller 2005), converted to per cent of predicted values according to age, sex, race, and height.
Timing of outcome measurement
We considered outcomes measured up to and including six months after randomisation as short term, from six to 12 months after randomisation as medium term, and more than 12 months as long term. When multiple results were reported for a given outcome, we included the longest follow‐up in each category.
Search methods for identification of studies
Electronic searches
The review authors prepared and ran the search strategies. We also identified trials from the Cochrane Neuromuscular Specialised Register, which is maintained by the Information Specialist for the Group. We searched the following databases (strategies provided in the appendices):
Cochrane Central Register of Controlled Trials (CENTRAL) searched 23 March 2021 (Appendix 1);
MEDLINE (PubMed; 1945 to present) searched 23 March 2021 (Appendix 2);
Embase (Elsevier; 1947 to present) searched 23 March 2021 (Appendix 3).
We also conducted a search of the following clinical trials registries (Appendix 4):
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) searched 23 March 2021;
World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch/) searched 23 March 2021.
We searched all databases from their inception to the date of search, and imposed no restrictions on language of publication or publication status. We did not use a filter for RCTs in these searches as we expected a low recall.
Searching other resources
We searched the reference lists of all primary studies and reviewed articles for additional references. We searched relevant manufacturers' websites for trial information. We searched for errata or retractions from the included studies. We contacted the authors of the included studies to identify other unpublished studies.
Data collection and analysis
Selection of studies
Two review authors (LG, PR) independently screened the titles and abstracts of all the studies identified as a result of the search, coding them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We retrieved the full‐text study reports or publications, and two review authors (LG, PR) independently screened these and identified studies for inclusion. We identified and recorded reasons for exclusion of the ineligible studies. Any disagreements were resolved through discussion or by consulting a third review author (JF or MH) if necessary. We identified and excluded duplicates and collated multiple reports of the same study so that each study, rather than each report, was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram, Liberati 2009, and 'Characteristics of excluded studies' table. We used Covidence software for study selection (Covidence).
Data extraction and management
We used a data extraction form for study characteristics and outcome data. Two review authors (LG, PR) independently extracted study characteristics from the included studies. We extracted the following study characteristics.
Methods: study design, total duration of study, details of any 'run‐in' period, number of study centres and location, study setting, withdrawals, and date of study.
Participants: number of participants, mean age, age range, gender, severity of condition, diagnostic criteria, baseline characteristics, inclusion criteria, and exclusion criteria.
Interventions: intervention, comparison, concomitant medications, and excluded medications.
Outcomes: primary and secondary outcomes specified and collected, and time points reported.
Notes: funding for trial and notable conflicts of interest of trial authors.
Two review authors (LG, PR) independently extracted outcome data from the included studies. We noted in the 'Characteristics of included studies' table if outcome data were not reported in a useable way. Any disagreements were resolved by consensus or by involving a third review author (JF). One review author (LG) transferred data into Review Manager 5 (Review Manager 2020), and a second review author (PR) checked the outcome data entries. A third review author (JF) spot‐checked study characteristics for accuracy against the trial report.
Had we found reports that required translation, the translator would have extracted data directly using a data extraction form, or the review authors would have extracted data from the provided translation. Where possible, a review author would have checked numerical data in the translation against the study report.
Assessment of risk of bias in included studies
Two review authors (LG, PR or MH) independently assessed the risk of bias for the results of the main outcomes (those included in the summary of findings table, see below) in each included study using the recently developed revision of the Cochrane risk of bias tool, RoB 2 (Higgins 2021b; Sterne 2019). Any disagreements were resolved by discussion or by involving another review author (JF). We assessed risk of bias according to the following domains, focusing on the effect of assignment to the intervention at baseline:
the randomisation process;
deviations from intended interventions;
missing outcome data;
measurement of the outcome;
selection of the reported results.
Answers to signalling questions and supporting information collectively lead to a domain‐level judgement of 'low risk', 'some concerns', or 'high risk' of bias. These domain‐level judgements informed an overall risk of bias judgement for the outcome. We provided a quote from the study report together with a justification for our judgement in the risk of bias table. We aimed to source published protocols in order to assess selective reporting. Where information on risk of bias related to unpublished data or correspondence with a trialist, we noted this in the risk of bias table.
When considering treatment effects, we took into account the risk of bias for the studies that contributed to that outcome. We made summary assessments of the risk of bias for each important outcome (across domains), within and across studies (Higgins 2021b).
We used the 22 August 2019 RoB 2 Excel tool to manage data supporting the answers to the signalling questions and risk of bias judgements (https://www.riskofbias.info/). All of these data are publicly available as supplementary material in the Open Science Framework platform (osf.io/).
Assessment of bias in conducting the systematic review
We conducted the review according to this published protocol and reported any deviations from it in the Differences between protocol and review section of the systematic review.
Measures of treatment effect
We analysed dichotomous data (adverse events) as risk ratios (RRs) and continuous data (all other outcomes) as mean differences (MDs). We reported corresponding 95% confidence intervals (CIs). We planned to analyse standardised mean differences for pooled results across studies for outcomes that were conceptually the same but measured in different ways. We entered data presented as a scale with a consistent direction of effect.
We planned to undertake meta‐analyses only where this was meaningful, that is if the treatments, participants, and the underlying clinical question were similar enough for pooling to make sense.
Unit of analysis issues
Where multiple trial arms were reported in a single trial, we would have included only the treatment arms relevant to the review topic. Had two comparisons from the same trial (e.g. drug A versus placebo and drug B versus placebo) been combined in the same meta‐analysis, we would have followed the guidance in Section 6.2 of the Cochrane Handbook for Systematic Reviews of Interventions to avoid double‐counting (Higgins 2021a). Our preferred approach was to combine groups to create a single pair‐wise comparison.
Dealing with missing data
We contacted investigators or study sponsors to verify key study characteristics and to obtain missing numerical outcome data where possible (e.g. when a study was available as an abstract only).
Where numerical outcome data were missing, such as standard deviations or correlation coefficients, and they could not be obtained from the authors, we calculated them from other available statistics such as 95% CI or P values, according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021a). If this was not possible, and the missing data could have introduced serious bias, we would explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.
Assessment of heterogeneity
We planned to use the I² statistic to measure heterogeneity amongst the trials in each analysis. Had we identified substantial unexplained heterogeneity, we would have reported it and explored possible causes by prespecified subgroup analysis. We would have used the rough guide to interpretation as outlined in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021a), as follows:
0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity;
75% to 100%: considerable heterogeneity.
We would have avoided the use of absolute cut‐off values, but interpreted I² in relation to the size and direction of effects and strength of evidence for heterogeneity (e.g. P value from the Chi²test, or CI for I²).
Assessment of reporting biases
Had we included more than 10 trials, we would have created and examined a funnel plot to explore possible small‐study biases. Had our searches identified trial protocols, clinical trial registrations, or abstracts indicating the existence of unpublished studies, we would have attempted to determine the status of any unpublished studies through contact with the investigators.
We considered outcome reporting bias in our risk of bias assessment.
Data synthesis
As a general rule, we planned to use a random‐effects model in Review Manager 5, as this is usually a more conservative approach. Had the analyses included both small and large studies, we would have performed a sensitivity analysis to determine whether their results were systematically different, since, in such circumstances, the use of a random‐effects meta‐analysis would exacerbate the effects of the bias. Had they been systematically different, we would have performed a sensitivity analysis in which small studies would have been excluded.
Subgroup analysis and investigation of heterogeneity
We planned to carry out the following subgroup analyses for our primary outcome.
Participants with and without corticosteroids as co‐intervention.
Participants with differing degrees of severity of spinal scoliosis: null or mild (Cobb angle < 20°), moderate (20º to 40º), and severe (> 40º).
We would use the formal test for subgroup interactions in Review Manager 5 (Review Manager 2020).
Sensitivity analysis
We planned the following sensitivity analyses for our primary outcome.
Repeat the analysis excluding unpublished studies (if there were any).
Repeat the analysis excluding studies at an overall high risk of bias for the selected outcome.
Reaching conclusions
We based our conclusions only on the findings from the quantitative or narrative synthesis of the included studies for this review. We avoided making recommendations for practice, and our implications for research suggest priorities for future research and outline the remaining uncertainties in the area.
Summary of findings and assessment of the certainty of the evidence
We created a summary of findings table using GRADEpro GDT software (GRADEpro GDT), presenting the following outcomes.
Change in respiratory function from baseline to 12 months or beyond, assessed by forced vital capacity (FVC): measured with standard spirometry at hospital visits with the aid of a qualified, trained, and certified operator and in accordance with the American Thoracic Society/European Respiratory Society guidelines (Miller 2005), converted to per cent of predicted values according to age, sex, race, and height. We considered an absolute change of 2% for improvement and 6% for worsening of the FVC predicted value as MCID (du Bois 2011).
Hospitalisation due to respiratory infections, measured in the number of admissions per year since the beginning of treatment.
Quality of life from baseline to 12 months or beyond, measured using the EuroQoL‐5D, Wille 2010, or the Pediatric Quality of Life Inventory (PedsQL), Varni 2001, or other well‐known scales. We considered a mean change of 0.074 in EuroQol‐5D (range 0 to 1; 0 = death, 1 = perfect health) (Walters 2005), and a mean change of 5 in PedsQL (range 0 to 100, 0 = worst outcome, 100 = best outcome) as MCID (Hilliard 2013).
Serious adverse events, including death, disability, life‐threatening events, or those requiring hospitalisation.
Non‐serious adverse events.
Two review authors (LG, PR, MH) used the five GRADE considerations (overall risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to independently assess the certainty of the body of evidence (studies that contribute data for the prespecified outcomes). We used the methods and recommendations in Chapters 14 and 15 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2021a; Schünemann 2021b). Any disagreements were resolved by discussion or by involving another review author (JF). We considered RCTs as high‐certainty evidence if the five factors above were not present to any serious degree, but downgraded the certainty of evidence once if a GRADE consideration was present to a serious extent and twice if it was very serious. We justified all decisions to downgrade the certainty of evidence using footnotes and made comments to aid readers' understanding of the review where necessary.
Results
Description of studies
For details of the included studies, see Characteristics of included studies.
Results of the search
We identified 1267 records through database searching and one additional record through other sources, of which 189 records were removed as duplicates. We excluded 1008 records after title and abstract screening and obtained the full texts for 71 studies. Screening the reference lists of the included publications did not reveal any additional RCTs. We excluded 25 studies with 35 records after full‐text assessment (see Characteristics of excluded studies). We identified one ongoing study with four records (see Characteristics of ongoing studies). We finally included two studies reported in 32 records. A study flow diagram illustrating the study selection process is presented in Figure 1.
1.
Study flow diagram.
Included studies
We included one study with 66 participants that contributed to our main analysis (DELOS 2015). We also included the results of a study with 255 participants that was only available as a press release (SIDEROS 2021). See Characteristics of included studies.
Design
The included studies were parallel RCTs.
Sample size
One study included 66 participants (DELOS 2015). The press release of the other study did not state the number of participants; however, the clinical trial registry reported an enrolment of 255 participants (SIDEROS 2021).
Setting
One study was conducted in an outpatient setting (DELOS 2015), with international participating centres in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA. All the study's reports were written in English. The press release of SIDEROS 2021 did not provide any information related to the setting; however, the clinical trial registry reported 63 centres across the USA, Europe, and Israel.
Participants
One study involved patients not receiving corticosteroid, who were 10 to 18 years of age at inclusion, with a mean (standard deviation (SD)) age of 14.3 (2.7) years and mean (SD) FVC of 52.85 (17.9) of predicted at baseline (DELOS 2015). Participants needed to have a documented diagnosis of DMD or severe dystrophinopathy with clinical features consistent with typical DMD at diagnosis, confirmed by mutation analysis in the dystrophin gene or by substantially reduced levels of dystrophin protein. The trial registry of the other included study stated that they included patients with respiratory decline who were receiving concomitant corticosteroid treatment and excluded those who needed daytime ventilator assistance; however, there was no information on age or respiratory status (SIDEROS 2021).
Interventions
One study delivered 900 mg/day of idebenone or placebo in two tablets of 150 mg each, taken orally three times daily with meals for 52 weeks. No corticosteroid co‐treatment was given (DELOS 2015). The press release of SIDEROS 2021 did not provide any information related to the interventions, but the clinical trial register indicated that the planned interventions were 900 mg/day of idebenone or placebo in two tablets of 150 mg each three times daily.
Outcomes
One study reported the effect of idebenone on change in respiratory function from baseline to 12 months, assessed as FVC (DELOS 2015). It also reported the effects of idebenone on quality of life, adverse events, change in muscle function, FEV1, and PEF. DELOS 2015 did not report on hospitalisation due to respiratory infections. Information on adverse events was reported in different ways across reports. The press release of the other study (without numerical data) stated that the trial was discontinued after an efficacy interim analysis based on FVC due to futility and that there were no safety concerns (SIDEROS 2021).
Funding sources
The included studies were sponsored by Santhera Pharmaceuticals.
Excluded studies
We excluded 25 studies after full‐text assessment.
Three studies were synopses of studies using idebenone (Buyse 2015a; Buyse 2015b; Buyse 2019).
Thirteen studies did not report respiratory function of participants at baseline (Bäckman 1988; Bertorini 1985; Bonati 2014; Buyse 2008; Buyse 2013; DELPHI 2011; Escolar 2012; Fenichel 1988; Mendell 1979; Nagy 2019; Stern 1981; Stern 1982; Tamari 1982).
Two studies were observational (Barcellona 2014; SYROS 2019).
Two reports were registry entries for an observational extension study of the active arm of one of the included studies (EUCTR2017‐004279‐30‐GB; NCT03603288).
Two reports were registry entries for RCTs of interventions with no antioxidant effect (EUCTR2017‐002213‐60‐GB; EUCTR2019‐004602‐94‐BE).
One study was a cross‐over RCT (Hunter 1983).
Two reports were registry entries for RCTs that did not include participants with diagnosed respiratory decline as considered for this review (EUCTR2005‐002520‐33‐BE; NCT00308113).
Risk of bias in included studies
The risk of bias assessments for each outcome, including all domain judgements and support for judgement, are provided in the risk of bias sections of the Characteristics of included studies tables. To access the detailed risk of bias assessment data, visit https://osf.io/w5dgu/ (DOI 10.17605/OSF.IO/W5DGU).
The overall risk of bias across most outcomes in DELOS 2015 was 'low'. Some issues arose because allocation concealment might have been overridden in a pair of siblings who were already randomly allocated and who were assigned to the same group as their siblings to avoid mix‐up of study medication, but we did not consider this to be a serious concern regarding bias; our final judgement was therefore 'low'. There was no bias related to deviations from intended interventions. Missing outcome data was not an issue for outcomes included in the summary of findings table, as data were available for more than 95% of participants, although for the outcomes change in muscle function and FEV1 there were missing data as high as 21.21% and 19.70% of participants, respectively. The methods for outcome measurement were appropriate and equally applied between groups, using standard spirometry for FVC and PedsQL for quality of life. There were no concerns regarding the selection of reported results.
We were unable to assess the risk of bias of the results from the SIDEROS 2021 study as data were only available as a press release.
Effects of interventions
See: Table 1
Idebenone versus placebo
We included the results of one study with 66 participants in this comparison (DELOS 2015). Where possible, we included a narrative statement extracted from the press release of the other study (SIDEROS 2021). See Table 1.
Primary outcomes
Change in respiratory function from baseline to 12 months, assessed by forced vital capacity (FVC)
One study reported this outcome (DELOS 2015). Idebenone may result in slightly less of a decline from baseline in FVC compared to placebo at 12 months follow‐up (mean difference (MD) 3.28%, 95% confidence interval (CI) −0.41 to 6.97; 64 participants) (Analysis 1.1). We assessed the evidence for this outcome as of low certainty due to imprecision. The other study stated that the trial was discontinued after an efficacy interim analysis based on FVC due to futility (SIDEROS 2021).
1.1. Analysis.
Comparison 1: Idebenone versus placebo, Outcome 1: Forced vital capacity (FVC)
Hospitalisation due to respiratory infections
DELOS 2015 did not report the specific outcome ‘hospitalisation due to respiratory infections’. However, the study did state that one participant in the idebenone group and four participants in the placebo group were hospitalised as a result of "respiratory complications".
Secondary outcomes
Quality of life
One study reported this outcome (DELOS 2015), measuring the change from baseline in PedsQL (range 0 to 100; 0 = worst outcome, 100 = best outcome). Idebenone probably results in little to no difference in change from baseline in quality of life compared to placebo at 12 months follow‐up (MD −3.80, 95% CI −10.09 to 2.49; 63 participants) (Analysis 1.2). We assessed the evidence for this outcome as of moderate certainty due to imprecision.
1.2. Analysis.
Comparison 1: Idebenone versus placebo, Outcome 2: Quality of life
Serious adverse events
DELOS 2015 reported this outcome. Idebenone was associated with a decrease in serious adverse events compared to placebo at 12 months follow‐up (risk ratio (RR) 0.42, 95% CI 0.09 to 2.04; 66 participants) (Analysis 1.3). We assessed the evidence for this outcome as of low certainty due to imprecision and publication bias. The other study stated that there were no safety concerns (no numerical data available) (SIDEROS 2021).
1.3. Analysis.
Comparison 1: Idebenone versus placebo, Outcome 3: Any adverse events
Non‐serious adverse events
DELOS 2015 reported this outcome. Idebenone was associated with little to no difference in non‐serious adverse events compared to placebo at 12 months follow‐up (RR 1.00, 95% CI 0.88 to 1.13; 66 participants) (Analysis 1.3). We assessed the evidence for this outcome as of low certainty due to imprecision and publication bias. The other study stated that there were no safety concerns (no numerical data available) (SIDEROS 2021)
Change in muscle function (elbow flexors)
One study reported this outcome (DELOS 2015). Idebenone may result in little to no difference in change in muscle strength function (elbow flexors) compared to placebo at 12 months follow‐up (MD −2.45 N, 95% CI −8.60 to 3.70; 52 participants) (Analysis 1.4).
1.4. Analysis.
Comparison 1: Idebenone versus placebo, Outcome 4: Change in muscle function (elbow flexors)
Change in muscle function (elbow extensors)
One study reported this outcome (DELOS 2015). Idebenone may result in little to no difference in change in muscle strength function (elbow extensors) compared to placebo at 12 months follow‐up (MD −1.06 N, 95% CI −6.77 to 4.65; 52 participants) (Analysis 1.5).
1.5. Analysis.
Comparison 1: Idebenone versus placebo, Outcome 5: Change in muscle function (elbow extensors)
Forced expiratory volume in the first second (FEV1)
One study reported this outcome (DELOS 2015). Idebenone may result in less of a decline in FEV1 compared to placebo at 12 months follow‐up (MD 8.28%, 95% CI 0.89 to 15.67; 53 participants) (Analysis 1.6).
1.6. Analysis.
Comparison 1: Idebenone versus placebo, Outcome 6: Forced expiratory volume in the first second (FEV1)
Peak expiratory flow (PEF)
One study reported this outcome (DELOS 2015). Idebenone may result in less of a decline in PEF compared to placebo at a 12 months follow‐up (MD 6.27%, 95% CI 0.61 to 11.93; 64 participants) (Analysis 1.7).
1.7. Analysis.
Comparison 1: Idebenone versus placebo, Outcome 7: Peak expiratory flow (PEF)
Discussion
Summary of main results
We included two studies with a total of 321 participants. One unpublished study including 255 participants with DMD was terminated early for futility, and full results are not yet available. A study with 66 participants assessed the effects of idebenone compared to placebo in participants with DMD and signs of respiratory decline. The certainty of the evidence for all outcomes was low.
Idebenone may result in slightly less of a decline from baseline in FVC at 12 months follow‐up, and probably results in little to no difference in change in quality of life at 12 months follow‐up. Idebenone was associated with a decrease in serious adverse events and little to no difference in non‐serious adverse events compared to placebo at 12 months follow‐up. Idebenone may result in little to no difference in change in muscle function at 12 months follow‐up. Idebenone may result in less of a decline in FEV1 and PEF at 12 months follow‐up. We found no studies evaluating the outcome hospitalisation due to respiratory infection.
Overall completeness and applicability of evidence
One study included participants 10 to 18 years old with a DMD diagnosis and signs of respiratory decline evidenced by an FVC of less than 60% of predicted with no concomitant corticosteroid treatment (DELOS 2015). The study did not include patients with symptomatic heart failure, symptomatic ventricular arrhythmias, or those using other therapeutic drugs (like carnitine, coenzyme Q10, vitamin E, or herbal medicines) within 90 days prior to inclusion. Participants were also not co‐treated with corticosteroids. The study delivered idebenone orally in two film‐coated tablets of 150 mg each, three times a day with meals for 52 weeks, for a total dose of idebenone of 900 mg/day, which is the same dose used for the drug's approved use in Leber’s hereditary optic neuropathy (EPAR 2015). The included study reported most outcomes of interest in the review, except for hospitalisation due to respiratory infections. We found heterogeneity in adverse events reporting across all study reports, but we were able to extract the adverse events data from the results uploaded in the clinical trial register (ClinicalTrials.gov ID NCT01027884).
People with DMD often have comorbidities, such as asthma, heart disease, or severe scoliosis that requires spinal surgery or spinal fusion (LoMauro 2018). We did not find studies including participants with these comorbidities, resulting in uncertainty about the applicability of our findings in these populations. Furthermore, corticosteroid therapy in DMD has led to improvements in function, quality of life, health, and longevity (Matthews 2016), but DELOS 2015 did not include patients taking corticosteroids. Participants in the recently stopped trial were receiving corticosteroids (SIDEROS 2021).
There is currently no cure for DMD, making multidisciplinary approaches necessary to provide symptomatic treatment whilst the disease progresses. A 2018 clinical practice guideline proposed that co‐ordination of clinical care is a crucial component of DMD management, and recommended that it should include a wide range of healthcare professionals and interventions considering rehabilitation, orthopaedic, psychosocial, cardiac, gastrointestinal, speech, and corticosteroid and respiratory management (Birnkrant 2018a; Birnkrant 2018b). With regard to respiratory management, no pharmacological intervention is recommended in the guidelines other than corticosteroid use. Nevertheless, compliance with guidelines has been shown to be poor in Italy, the UK, the USA, and Germany, with fewer than 30% of patients meeting all absolute recommendations (Landfeldt 2015). This highlights the low number of therapeutic options available for DMD and the need to develop and evaluate new approaches and therapies with an adequate body of evidence to support their use.
Current access to newer DMD drugs is limited and generally restricted to participation in clinical trials. All the available evidence for idebenone in the treatment of decline in respiratory function in DMD comes from small trials and studies with multiple reports. When considering new therapies such as idebenone, a major barrier to uptake following regulatory approval is likely to be the associated cost. Furthermore, it is possible that some of the available medications could be used in combination, thereby increasing the cost much further (Shawi 2017). Idebenone is orally administered and requires multiple daily doses. This may present additional challenges for people with DMD who have swallowing disorders (Shawi 2017).
Quality of the evidence
The overall certainty of the evidence was low, but all the evidence comes from one relatively small study with few events, which leads to serious imprecision. Another, larger study was discontinued due to futility with only a press release available and no numerical data. We judged all outcomes reported in the study as at low risk of bias. We also downgraded the certainty of the evidence for the outcomes of the SIDEROS 2021 trial for publication bias, as there were no results beyond statements from the pharmaceutical company in a press release.
Potential biases in the review process
We modified the outcome 'any adverse events' to maximise the use of the available data, reporting it as serious and non‐serious adverse events. We extracted and analysed data regarding 'change in muscle function' as two separate muscle groups (elbow flexors and elbow extensors). We took precautions to avoid bias in this process by documenting all changes in the Differences between protocol and review section of the review.
We encountered difficulties in determining the 'antioxidant effect' of several interventions reported in trials retrieved by our search strategy, as some interventions being studied in this population are hypothesised to have concomitant antioxidant properties. Nevertheless, when considering all of our predefined possible antioxidant agent interventions, we were able to screen studies with no major problems.
We found studies reporting quality of life, adverse events, or muscle function in people with DMD; unfortunately, however, several of these studies did not consider or did not report respiratory function of participants at baseline (Bäckman 1988; Bertorini 1985; Bonati 2014; Fenichel 1988; Mendell 1979; Nagy 2019; NCT00308113; Stern 1982; Tamari 1982). Consequently, we were not able to identify whether the participants in these studies actually had respiratory decline as defined in our protocol, therefore we finally excluded all of them.
Agreements and disagreements with other studies or reviews
Narrative reviews have addressed respiratory function in DMD, considering the impact of pharmacological interventions to delay its decline (Gogou 2020; Werneck 2019). Although these reviews stated that every treatment strategy should prioritise the preservation of lung function, they concluded that corticosteroid therapy remains the best‐studied pharmacologic therapy for DMD and very likely delays the expected decline in lung function. A Cochrane Review of corticosteroids for DMD concluded that corticosteroid therapy in DMD improves muscle strength and function in the short term as well as up to two years, but did not consider respiratory function outcomes (Matthews 2016).
The American Thoracic Society (ATS) Consensus Statement for respiratory care of DMD patients is based mostly on airway clearance, respiratory muscle training, or mechanical ventilation support (Finder 2004). The last update of this statement was published before the trial included in this review was published (Finder 2009). Regarding mechanical ventilation, a Cochrane Review concluded that there is a survival benefit of mechanical ventilation against no ventilation in DMD, but did not consider respiratory function outcomes in this population (Annane 2014).
Along with respiratory decline, cardiomyopathy is a significant limiting factor for long‐term survival in DMD. As physical disability progresses, it is rarely possible to differentiate complications in the context of a chest infection with associated respiratory failure from complications of a primary cardiac cause. Regarding the latter, a Cochrane Review concluded that early treatment with angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers may be comparably beneficial for people with dystrophinopathy for the prevention and treatment of cardiac complications in people with DMD or Becker muscular dystrophy (Bourke 2018).
Although the effects of idebenone on PEF in DMD patients with cardiac dysfunction appeared promising (DELPHI 2011), they have not been replicated in a different population of DMD participants with signs of respiratory decline, with or without concomitant corticosteroid treatment (DELOS 2015; SIDEROS 2021). Furthermore, the effect of any antioxidant in patients with spinal scoliosis, a common complication in DMD that affects respiratory function, remains unknown. Nor have the positive effects of idebenone on PEF been translated into benefit in different major outcomes like FVC, despite the fact that the effects of idebenone have been studied in former participants of the study included in this review (DELOS 2015), showing a consistent and sustained reduction in the rate of respiratory function decline for up to six years, although no procedure ensured the consistency of assessment methods across the research sites or the systematic collection of all concomitant medication use, which could also have influenced the observed effects (Buyse 2019; SYROS 2019). The discontinuation of SIDEROS 2021 and its expanded access programmes, EUCTR2019‐004602‐94‐BE; NCT03603288, due to futility may indicate that research on this drug in DMD is no longer needed.
Antioxidant agents other than idebenone have been tested in people with DMD with regard to their effect on motor function of different muscle groups or serum levels of several biomarkers, with promising results (Bonati 2014; Kawamura 2020), but respiratory function was neither considered as an inclusion criterion nor an outcome of interest in these studies.
Authors' conclusions
Implications for practice.
Idebenone is the only antioxidant agent tested in randomised controlled trials for the prevention of respiratory decline in individuals with Duchenne muscular dystrophy (DMD). The limited available evidence is from a single published study. A larger study was stopped in October 2020 for futility, and at the time of writing is unpublished. Idebenone may result in slightly less of a decline from baseline in forced vital capacity (FVC) and probably results in little to no difference in change in quality of life. Idebenone may result in little to no difference in change in muscle function and less of a decline from baseline in forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF).
Implications for research.
The discontinuation of the SIDEROS trial and its expanded access programmes due to futility may indicate that research for this drug in this condition is no longer needed. Further research is needed to establish the effect of different antioxidant agents on preventing respiratory decline in DMD patients during the respiratory decline phase of the condition. Other antioxidant agents different from idebenone need to be considered and tested. Randomised controlled trials designed for this purpose need to include a greater number of participants and be powered to detect the effects of the intervention on relevant respiratory outcomes like FVC, total lung capacity, or the need for ventilatory support, both in the short and long term. These outcomes must be included as primary outcomes, alongside other outcomes relevant to patients, families, and relevant stakeholders, such as hospitalisations, quality of life, functional independence, or cost associated with treatment. Furthermore, comorbidities in patients with DMD, such as spinal scoliosis, amongst others, need to be considered as potential influencing factors in the treatment effects.
History
Protocol first published: Issue 9, 2020
Risk of bias
Risk of bias for analysis 1.1 Forced vital capacity (FVC).
| Study | Bias | |||||||||||
| Randomisation process | Deviations from intended interventions | Missing outcome data | Measurement of the outcome | Selection of the reported results | Overall | |||||||
| Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | |
| DELOS 2015 | Low risk of bias | A random component was used in the sequence generation process and a central interactive web system for allocation. No serious imbalance in baseline characteristics was found. While allocation concealment might have been overridden in a pair of siblings we don't consider it to be a serious concern regarding bias. | Low risk of bias | Participants and those involved in caring for participants were not aware of the assigned intervention. There are no concerns regarding the analysis used to estimate the effect of assignment to intervention. | Low risk of bias | Data were available for nearly all randomized participants. | Low risk of bias | Method for outcome measurement was appropriate and equally applied between groups. Outcome assessors were blinded to intervention status. | Low risk of bias | Data were analysed in accordance with the pre‐specified plan and assessed based on pre‐specified domains and time‐points. | Low risk of bias | The study is judged to be at low risk of bias for all domains for this result. |
Risk of bias for analysis 1.2 Quality of life.
| Study | Bias | |||||||||||
| Randomisation process | Deviations from intended interventions | Missing outcome data | Measurement of the outcome | Selection of the reported results | Overall | |||||||
| Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | |
| DELOS 2015 | Low risk of bias | A random component was used in the sequence generation process and a central interactive web system for allocation. No serious imbalance in baseline characteristics was found. While allocation concealment might have been overridden in a pair of siblings we don't consider it to be a serious concern regarding bias. | Low risk of bias | Participants and those involved in caring for participants were not aware of the assigned intervention. There are no concerns regarding the analysis used to estimate the effect of assignment to intervention. | Low risk of bias | Data were available for nearly all randomized participants. | Low risk of bias | Method for outcome measurement was appropriate and equally applied between groups. Outcome assessors were blinded to intervention status. | Low risk of bias | Data were analysed in accordance with the pre‐specified plan and assessed based on pre‐specified domains and time‐points. | Low risk of bias | The study is judged to be at low risk of bias for all domains for this result. |
Risk of bias for analysis 1.3 Any adverse events.
| Study | Bias | |||||||||||
| Randomisation process | Deviations from intended interventions | Missing outcome data | Measurement of the outcome | Selection of the reported results | Overall | |||||||
| Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | |
| Subgroup 1.3.1 Serious adverse events | ||||||||||||
| DELOS 2015 | Low risk of bias | A random component was used in the sequence generation process and a central interactive web system for allocation. No serious imbalance in baseline characteristics was found. While allocation concealment might have been overridden in a pair of siblings we don't consider it to be a serious concern regarding bias. | Low risk of bias | Participants and those involved in caring for participants were not aware of the assigned intervention. There are no concerns regarding the analysis used to estimate the effect of assignment to intervention. | Low risk of bias | Data were available for nearly all randomized participants. | Low risk of bias | Method for outcome measurement was appropriate and equally applied between groups. Outcome assessors were blinded to intervention status. | Low risk of bias | Data were analysed in accordance with the pre‐specified plan and assessed based on pre‐specified domains and time‐points | Low risk of bias | The study is judged to be at low risk of bias for all domains for this result. |
| Subgroup 1.3.2 Nonserious adverse events | ||||||||||||
| DELOS 2015 | Low risk of bias | A random component was used in the sequence generation process and a central interactive web system for allocation. No serious imbalance in baseline characteristics was found. While allocation concealment might have been overridden in a pair of siblings we don't consider it to be a serious concern regarding bias. | Low risk of bias | Participants and those involved in caring for participants were not aware of the assigned intervention. There are no concerns regarding the analysis used to estimate the effect of assignment to intervention. | Low risk of bias | Data were available for nearly all randomized participants. | Low risk of bias | Method for outcome measurement was appropriate and equally applied between groups. Outcome assessors were blinded to intervention status. | Low risk of bias | Data were analysed in accordance with the pre‐specified plan and assessed based on pre‐specified domains and time‐points | Low risk of bias | The study is judged to be at low risk of bias for all domains for this result. |
Acknowledgements
The Information Specialist of Cochrane Neuromuscular, Angela Gunn, reviewed the search strategy in consultation with the review authors.
The Methods section of this review is based on a template developed by Cochrane Neuromuscular from an original created by Cochrane Airways.
This project was supported by the National Institute for Health Research (NIHR) via Cochrane Infrastructure funding to Cochrane Neuromuscular. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS, or the Department of Health. Cochrane Neuromuscular is also supported by the MRC Centre for Neuromuscular Disease.
We thank Dr Rosaline Quinlivan for her contribution to the Background section of the protocol and full review.
We thank the members of the Editorial Base (Ruth Brassington, Michael Lunn, Sarah Nevitt, and Farhad Shokraneh) and peer‐reviewer (Tracey Willis, Muscle team, Robert Jones and Agnes Hunt Hospital, Oswestry UK and Chester University Medical School) for their comments and feedback during the review process.
Appendices
Appendix 1. Appendix 1. Cochrane Central Register of Controlled Trials (CENTRAL) search strategy
#1 MeSH descriptor: [Muscular Dystrophy, Duchenne] explode all trees
#2 (duchenne*):ti,ab,kw
#3 (DMD):ti,ab,kw
#4 #1 OR #2 OR #3
#5 MeSH descriptor: [Antioxidants] explode all trees
#6 MeSH descriptor: [Acetylcysteine] explode all trees
#7 MeSH descriptor: [Metformin] explode all trees
#8 MeSH descriptor: [Citrulline] explode all trees
#9 MeSH descriptor: [Tea] explode all trees
#10 (N‐acetylcysteine lysinate):ti,ab,kw
#11 (raxone):ti,ab,kw
#12 (Antioxidant*):ti,ab,kw OR (Anti‐oxidant*):ti,ab,kw
#13 (Tea):ti,ab,kw
#14 ("Coenzyme Q10"):ti,ab,kw
#15 (idebenone):ti,ab,kw
#16 ("CoQ 10"):ti,ab,kw
#17 (metformin*):ti,ab,kw
#18 (citrulline):ti,ab,kw
#19 #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18
#20 #4 AND #19
Appendix 2. Appendix 2. MEDLINE (PubMed) search strategy
#1 "Muscular Dystrophy, Duchenne"[Mesh]
#2 duchenne*[Tiab]
#3 DMD[Tiab]
#4 #1 OR #2 OR #3
#5 "Antioxidants"[Mesh]
#6 "Acetylcysteine"[Mesh]
#7 "Metformin"[Mesh]
#8 "Citrulline"[Mesh]
#9 "Tea"[Mesh]
#10 "Antioxidants"[Pharmacological Action]
#11"N‐acetylcysteine lysinate"[Supplementary Concept]
#12 raxone[Tiab]
#13 Antioxidant*[Tiab] OR Anti‐oxidant*[Tiab]
#14 Tea[Tiab]
#15 "Coenzyme Q10"[Tiab]
#16 idebenone[Tiab]
#17 "CoQ 10"[Tiab]
#18 metformin*[Tiab]
#19 Citrulline[Tiab]
#20 #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19
#21 #4 AND #20
Appendix 3. Appendix 3. Embase (Elsevier) search strategy
#1. 'duchenne muscular dystrophy'/exp
#2. duchenne*:ti,ab
#3. dmd:ti,ab
#4. #1 OR #2 OR #3
#5. 'antioxidant'/exp
#6. 'acetylcysteine'/exp
#7. 'metformin'/exp
#8. 'citrulline'/exp
#9. 'herbal tea'/exp
#10. 'antioxidants pharmacology'/exp
#11. 'lysine acetylsalicylate'/exp
#12. 'idebenone'/exp
#13. raxone:ti,ab
#14. antioxidant*:ti,ab OR anti‐oxidant*:ti,ab
#15. tea:ti,ab
#16. 'ubidecarenone'/exp
#17. 'coenzyme q10':ti,ab
#18. idebenone:ti,ab
#19. 'coq 10':ti,ab
#20. metformin*:ti,ab
#21. citrulline:ti,ab
#22. #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21
#23. #4 AND #22
Appendix 4. Appendix 4. Clinical trials registries search strategies
US National Institutes for Health Clinical Trials Registry, ClinicalTrials.gov search strategy (Expert Search)
(Muscular Dystrophy, Duchenne OR Duchenne OR DMD) [DISEASE] AND (Antioxidants OR Antioxidant OR Anti‐oxidant OR Anti‐oxidants OR Acetylcysteine OR Metformin OR Citrulline OR Tea OR "N‐acetylcysteine lysinate" OR raxone OR "Coenzyme Q10" OR idebenone OR "CoQ 10") [TREATMENT]
WHO International Clinical Trials Registry Portal (ICTRP) search strategy
Advanced search
Condition: Muscular Dystrophy, Duchenne OR Duchenne OR DMD
Intervention: Antioxidants OR Antioxidant OR Anti‐oxidant OR Anti‐oxidants OR Acetylcysteine OR Metformin OR Citrulline OR Tea OR "N‐acetylcysteine lysinate" OR raxone OR "Coenzyme Q10" OR idebenone OR "CoQ 10"
Recruitment status is ALL
Data and analyses
Comparison 1. Idebenone versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Forced vital capacity (FVC) | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.2 Quality of life | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.3 Any adverse events | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.3.1 Serious adverse events | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.3.2 Nonserious adverse events | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.4 Change in muscle function (elbow flexors) | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.5 Change in muscle function (elbow extensors) | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.6 Forced expiratory volume in the first second (FEV1) | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.7 Peak expiratory flow (PEF) | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
DELOS 2015.
| Study characteristics | ||
| Methods |
Study design: prospective, randomised study. Study dates: 27July 2009 to 14 January 2014. Setting: outpatient, multicentre, international. Country: Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, USA. |
|
| Participants |
Inclusion criteria:
Exclusion criteria:
Total participants randomised: 66 Group 1: n = 32 idebenone group Age, mean (SD): 13.5 (2.7) Weight, mean (SD): 55.3 (18.3) kg Height, mean (SD): 157.4 (11.3) cm Body mass index, mean (SD): 22.0 (5.9) kg/m² Ethnic origin, n (%):
Previous glucocorticoid use, n(%): 17 (55%) Time since last glucocorticoid use, mean (SD): 2.9 (1.8) years Patient in wheelchair, n(%): 28 (90%) Baseline PEF as % predicted (PEF%p), n(%):
Baseline respiratory function tests:
Group 2: n = 34 placebo group Age, mean (SD): 15.0 (2.5) Weight, mean (SD): 61.9 (18) kg Height, mean (SD): 162.4 (12.4) cm Body mass index, mean (SD): 23.4 (5.6) kg/m² Ethnic origin, n (%):
Previous glucocorticoid use, n(%): 19 (58%) Time since last glucocorticoid use, mean (SD): 4.3 (2.2) years Patient in wheelchair, n(%): 31 (94%) Baseline peak expiratory flow as % predicted (PEF%p), n(%):
Baseline respiratory function tests:
|
|
| Interventions |
Group 1: n = 32 idebenone group: Treatment consisted of film‐coated tablets of idebenone (Raxone or Catena, Santhera Pharmaceuticals, Liestal, Switzerland) (900 mg/day): 2 tablets (150 mg each) 3 times orally with meals for 52 weeks. Group 2: n = 34 placebo group: Treatment consisted of placebo (900 mg/day) 2 tablets (150 mg each) 3 times orally with meals for 52 weeks. Co‐interventions: not reported |
|
| Outcomes |
Forced vital capacity How measured: measured by a qualified, trained, and certified evaluator at each centre in accordance with standardised procedures and international guidelines, using a Pneumotrac Spirometer 6800 (Vitalograph), and reported as change from baseline in FVC%p and as change from baseline in absolute values (FVC (L)) Time points measured: baseline, 13, 26, 39, and 52 weeks Time points reported: baseline and 52 weeks Subgroups: none Quality of life How measured: measured using the Pediatric Quality of Life Inventory (PedsQL), which contains the following paediatric health‐related quality of life measurements: Physical, Emotional, Social and School Functioning. Item scaling in a 5‐point Likert scale from 0 (never) to 4 (almost always). 3‐point scale: 0 (not at all), 2 (sometimes), and 4 (a lot) for the young child (ages 5 to 7). Scores were transformed on a scale from 0 to 100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). Total score: sum of all the items over the number of items answered on all the scales. The overall scores ranged between 0 and 100, with 0 = worst outcome and 100 = best outcome. Reported as change from baseline. Time points measured: baseline and 52 weeks Time points reported: baseline and 52 weeks Subgroups: none Adverse events How measured: number of participants reporting serious adverse events and non‐serious adverse events Time points measured: not reported Time points reported: 52 weeks Subgroups: none Change in muscle function How measured: the change from baseline to week 52 in muscle strength as measured by hand‐held myometry (HHM) was performed following standardised procedures. As almost all participants were non‐ambulatory, only analyses of upper limb muscle strength were performed. The highest value of 3 consecutive measurements with an interval of at least 10 s were recorded. The HHM was measured using MicroFET2, a digital hand‐held muscle tester. The selected unit of measure was Newtons (N). Time points measured: not reported Time points reported: 52 weeks Subgroups: none Peak expiratory flow How measured: measured by a qualified, trained, and certified evaluator at each centre in accordance with standardised procedures and international guidelines, using participant's portable ASMA‐1 device (usb model 4000, Vitalograph, Maids Moreton, UK) and reported as change from baseline in PEF%p and as change from baseline in absolute values (PEF L/min). Time points measured: baseline and 52 weeks Time points reported: baseline, 13, 26, 39, and 52 weeks Subgroups: none Forced expiratory volume How measured: measured by a qualified, trained, and certified evaluator at each centre in accordance with standardised procedures and international guidelines, using participant's portable ASMA‐1 device (usb model 4000, Vitalograph, Maids Moreton, UK) and reported as change from baseline in FEV1%p and as change from baseline in absolute values (FEV1 (L)). Time points measured: baseline, 13, 26, 39, and 52 weeks Time points reported: baseline and 52 weeks Subgroups: none |
|
| Notes | The study was sponsored by Santhera Pharmaceuticals. Height was derived from ulnar length. Change in absolute values of FVC and FEV1 available in online supplementary appendix. Respiratory tract infection‐related adverse events available in online supplementary appendix. Quality of life outcomes available from ClinicalTrials.gov. Change in muscle function available from ClinicalTrials.gov. Declarations of interest: GMB was investigator for clinical trials in DMD sponsored by Santhera Pharmaceuticals, Prosensa Therapeutics, and GlaxoSmithKline. TV was an investigator for clinical trials of DMD sponsored by PTC Therapeutics, GlaxoSmithKline, Prosensa, and Santhera Pharmaceuticals; he serves as a scientific advisory board member to Prosensa. US was an investigator for clinical trials sponsored by PTC Therapeutics, Lilly Pharma, Santhera Pharmaceuticals, Prosensa, and GlaxoSmithKline. CSMS has participated in trials sponsored by GlaxoSmithKline, Prosensa, and Santhera Pharmaceuticals. RSF has participated in studies of DMD sponsored by PTC Therapeutics, the US National Institutes of Health (UDP R01NS043264, Wellstone 5U54AR052646‐03, Imaging DMD R01‐AR056973, and FOR‐DMD U01 NS061799‐01A2), Lilly, Muscular Dystrophy Association, Sarepta; served as a member of the data and safety monitoring board for the Sarepta 201 study; and served as adviser to Catabasis. CMM has served as a consultant for trials unrelated to this scope of work for PTC Therapeutics, Prosensa, Sarepta, Eli Lilly, Pfizer, Halo Therapeutics, Cardero, and Mitokyne, and serves on external advisory boards related to DMD for PTC Therapeutics and Eli Lilly. TM is a regular employee of Santhera Pharmaceuticals. GMB and TM are co‐inventors of relevant patent applications. The other authors declare no competing interests. |
|
SIDEROS 2021.
| Study characteristics | ||
| Methods | A phase III double‐blind, randomised, placebo‐controlled study | |
| Participants | Patients with DMD receiving glucocorticoid steroids Inclusion criteria:
Exclusion criteria:
|
|
| Interventions | Idebenone 150 mg film‐coated tablet versus placebo | |
| Outcomes |
Primary endpoint:
To assess the efficacy of idebenone compared to placebo in delaying the loss of inspiratory muscle function as measured by changes in inspiratory flow reserve (IFR) using clinic‐based spirometry. To assess the time to clinically relevant events and disease milestones. Secondary endpoints: The secondary endpoints will be evaluated in the following order in a hierarchical manner.
|
|
| Notes | Source of monetary support: Santhera Pharmaceuticals (Switzerland) Limited. A press release was shared by the pharmaceutical company explaining that the trial was prematurely terminated on 2 October 2020. |
|
COPD: chronic obstructive pulmonary disease DMD: Duchenne muscular dystrophy FEV1: forced expiratory volume in 1 s FEV1%p: forced expiratory volume in 1 s as percentage predicted FVC: forced vital capacity FVC%p: forced vital capacity as percentage predicted MEP: maximum expiratory pressure MEP%p: maximum expiratory pressure as percentage predicted MIP: maximum inspiratory pressure MIP%p: maximum inspiratory pressure as percentage predicted NIV: non‐invasive ventilation PCF: peak cough flow PEF: peak expiratory flow PEF%p: peak expiratory flow as percentage predicted SD: standard deviation
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Bäckman 1988 | Wrong patient population. The study did not report respiratory function of participants at baseline, and we were unable to identify if included participants had respiratory decline. |
| Barcellona 2014 | Wrong study design. Observational pilot study evaluating the safety and tolerability of flavocoxid in ambulant DMD patients |
| Bertorini 1985 | Wrong patient population. The study did not report respiratory function of participants at baseline, and we were unable to identify if included participants had respiratory decline. |
| Bonati 2014 | Wrong patient population. The study did not report respiratory function of participants at baseline, and we were unable to identify if included participants had respiratory decline. |
| Buyse 2008 | Wrong patient population. The study did not report respiratory function of participants at baseline, and we were unable to identify if included participants had respiratory decline. |
| Buyse 2013 | Wrong patient population. The study did not report respiratory function of participants at baseline, and we were unable to identify if included participants had respiratory decline. |
| Buyse 2015a | Wrong study design. Combination of studies using idebenone |
| Buyse 2015b | Wrong study design. Combination of studies using idebenone |
| Buyse 2019 | Wrong study design. Combination of the extension programmes of the DELPHI and DELOS studies |
| DELPHI 2011 | Wrong patient population. The majority of participants did not have respiratory decline. A meta‐analysis was presented by the study authors of the DELPHI study using raw data from the trial as a poster in a conference on the subset of participants with respiratory decline, but no numerical data were available (Leinonen 2017). |
| Escolar 2012 | Wrong patient population. Participants did not have respiratory decline at baseline as considered for this review. |
| EUCTR2005‐002520‐33‐BE | Wrong patient population with no outcomes reported. There is no statement related to participant respiratory decline, considered in this review as an inclusion criterion. |
| EUCTR2017‐002213‐60‐GB | Wrong intervention. No antioxidant effect associated with the study drug |
| EUCTR2017‐004279‐30‐GB | Wrong study design. Observational extension study of the active arm of the SIDEROS trial |
| EUCTR2019‐004602‐94‐BE | Wrong intervention. No antioxidant effect associated with the study drug |
| Fenichel 1988 | Wrong patient population. The study did not report respiratory function of participants at baseline, and we were unable to identify if included participants had respiratory decline. |
| Hunter 1983 | Wrong study design. Cross‐over randomised controlled trial |
| Mendell 1979 | Wrong patient population. The study did not report respiratory function of participants at baseline, and we were unable to identify if included participants had respiratory decline. |
| Nagy 2019 | Wrong patient population. The study did not report respiratory function of participants at baseline, and we were unable to identify if included participants had respiratory decline. |
| NCT00308113 | Wrong patient population with no outcomes reported. There is no statement related to participant respiratory decline, considered in this review as an inclusion criterion. |
| NCT03603288 | Wrong study design. Observational extension study of the active arm of the SIDEROS trial |
| Stern 1981 | Wrong patient population. The study did not report respiratory function of participants at baseline, and we were unable to identify if included participants had respiratory decline. |
| Stern 1982 | Wrong patient population. The study did not report respiratory function of participants at baseline, and we were unable to identify if included participants had respiratory decline. |
| SYROS 2019 | Wrong study design. Observational study based on the expanded access programme of the drug idebenone following the DELOS study |
| Tamari 1982 | Wrong patient population. The study did not report respiratory function of participants at baseline, and we were unable to identify if included participants had respiratory decline. |
DMD: Duchenne muscular dystrophy
Characteristics of ongoing studies [ordered by study ID]
SUNIMUD.
| Study name | Sunphenon EGCg (epigallocatechin‐gallate) in Duchenne muscular dystrophy |
| Methods | Randomised controlled parallel trial |
| Participants |
Inclusion criteria:
Exclusion criteria:
|
| Interventions | Sunphenon EGCg (epigallocatechin‐gallate) 50 mg hard capsule or placebo |
| Outcomes |
Primary endpoint(s):
Secondary objective: to compare secondary clinical endpoints between the EGCg and the placebo group Time point(s) of evaluation of this endpoint: after 12 and 36 months Secondary endpoint(s):
Time point(s) of evaluation of this endpoint: after 36 months |
| Starting date | 25 June 2010 |
| Contact information | Name: Paul Friedmann Address: Chariteplatz 1 10117 Berlin, Germany Telephone: 4930450539755 Email: friedemann.paul@charite.de |
| Notes | Source of monetary support: aktion benni & co. Deutsche Gesellschaft für Muskelkranke e.V. It is unclear whether patients with respiratory decline will be included in this study. |
DMD: Duchenne muscular dystrophy
Differences between protocol and review
Change in the outcomes
We divided the outcome 'any adverse events' into 'serious adverse events' and 'non‐serious adverse events' in order to maximise the use of the available data.
We extracted and analysed data for the outcome 'change in muscle function' in two separate groups of muscles.
We planned to pilot our data extraction form on at least one study, but only one eligible study provided data.
Methods not implemented
We were not able to assess possible small‐study effects; however, we performed judgements on publication bias (see Quality of the evidence).
We were not able to carry out the subgroup analyses planned in the protocol as we found no studies with these characteristics.
We were not able to carry out sensitivity analyses because we did not find unpublished studies or studies with an overall high risk of bias.
Clarification of selected studies
We noted that we included studies that involved both eligible and ineligible participants (e.g. a subset of participants in the respiratory decline phase of DMD) if data for eligible participants were presented separately.
Contributions of authors
| Roles and responsibilities (protocol and review stage) | |
| Guarantor of the review | LIG |
| Draft the protocol | LIG, PRR, CMEL, JVAF, MRH |
| Develop and run the search strategy | LIG, CMEL, MRH, JVAF |
| Obtain copies of studies | CMEL, JVAF |
| Select which studies to include (2 people) | LIG, PRR, MRH, JVAF |
| Extract data from studies (2 people) | LIG, PRR, JVAF |
| Enter data into Review Manager 5 | LIG, PRR, JVAF |
| Carry out the analysis | LIG, PRR, JVAF |
| Interpret the analysis | LIG, PRR, MRH, JVAF |
| Draft the final review | LIG, PRR, CMEL, MRH, JVAF |
| Update the review | LIG, PRR, CMEL, MRH, JVAF |
Sources of support
Internal sources
-
Instituto Universitario Hospital Italiano, Argentina
Provided support for LIG and PRR as Research Fellows
Provided the salary for JVAF and CMEL as staff for the Cochrane Centre
-
Servicio de Neurología ‐ Hospital Italiano de Buenos Aires, Argentina
Provided support for the participation of MRH
External sources
-
None, Other
None
Declarations of interest
LIG: none known.
MRH: is a paediatric neurologist in an academic hospital and provides care to children with Duchenne muscular dystrophy.
PRR: none known.
CMEL: none known.
JVAF: none known.
New
References
References to studies included in this review
DELOS 2015 {published data only}
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- Mayer OH, Leinonen M, Hasham S, Meier T, Voit T, Buyse G for the DELOS study group. Impact of idebenone on respiratory burden, including risk of bronchopulmonary complications, in Duchenne muscular dystrophy. Journal of Neuromuscular Diseases 2018;5(Suppl 1):48-9. [Google Scholar]
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SIDEROS 2021 {published data only}
- Buyse G, Mayer OH, Donisa-Dreghici R, Couttet F, Wolff J, Coppard N. A phase III double-blind, randomized, placebo controlled study (SIDEROS) assessing the efficacy of idebenone in slowing the rate of respiratory function loss in patients with Duchenne muscular dystrophy receiving glucocorticoid steroids. Journal of Neuromuscular Diseases 2016;3(S1):S103-4. [Google Scholar]
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- NCT02814019. A Phase III double-blind study with idebenone in patients with Duchenne muscular dystrophy (DMD) taking glucocorticoid steroids. clinicaltrials.gov/ct2/show/NCT02814019 (first received 27 June 2016).
- Santhera Pharmaceuticals Holding AG. Santhera to discontinue phase 3 SIDEROS study and development of Puldysa® in Duchenne muscular dystrophy (DMD) and focus on vamorolone. www.santhera.com/assets/files/press-releases/2020-10-06_SiderosPuldysa_e_final.pdf (accessed 2 August 2021).
References to studies excluded from this review
Bäckman 1988 {published data only}
- Bäckman E, Nylander E, Johansson I, Henriksson K, Tagesson C. Selenium and vitamin E treatment of Duchenne muscular dystrophy: no effect on muscle function. Acta Neurologica Scandinavica 1988;78(5):429-35. [DOI] [PubMed] [Google Scholar]
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Bertorini 1985 {published data only}
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Bonati 2014 {published data only}
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Buyse 2008 {published data only}
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Buyse 2015a {published data only}
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Buyse 2015b {published data only}
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Buyse 2019 {published data only}
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DELPHI 2011 {published data only}
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Escolar 2012 {published data only}
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EUCTR2005‐002520‐33‐BE {published data only}
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EUCTR2017‐002213‐60‐GB {published data only}
- EUCTR2017-002213-60-GB. A study to investigate the safety, tolerability, and efficacy of SGT-001 in male adolescents and children with Duchenne muscular dystrophy. www.clinicaltrialsregister.eu/ctr-search/trial/2017-002213-60/GB (first received 11 December 2018).
EUCTR2017‐004279‐30‐GB {published data only}
- EUCTR2017-004279-30-GB. A phase III open-label extension study to assess the long-term safety and efficacy of idebenone in patients with Duchenne muscular dystrophy (DMD) who completed the SIDEROS study. www.clinicaltrialsregister.eu/ctr-search/trial/2017-004279-30/GB (first received 9 May 2018).
EUCTR2019‐004602‐94‐BE {published data only}
- EUCTR2019-004602-94-BE. A 3-part, randomized, double blind, adaptive seamless phase 1-3 study to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of BIO101 in non-ambulatory patients with a genetically confirmed diagnosis of Duchenne muscular dystrophy and evidence of respiratory deterioration. clinicaltrialsregister.eu/ctr-search/trial/2019-004602-94/BE (first received 3 February 2020).
Fenichel 1988 {published data only}
- Fenichel G, Brooke M, Griggs R, Mendell J, Miller J, Moxley R, et al. Clinical investigation in Duchenne muscular dystrophy: penicillamine and vitamin E. Muscle & Nerve 1988;11(11):1164-8. [DOI] [PubMed] [Google Scholar]
Hunter 1983 {published data only}
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Mendell 1979 {published data only}
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Nagy 2019 {published data only}
- Nagy S, Hafner P, Schmidt S, Rubino-Nacht D, Schadelin S, Bieri O, et al. Tamoxifen in Duchenne muscular dystrophy (TAMDMD): study protocol for a multicenter, randomized, placebo-controlled, double-blind phase 3 trial. Trials 2019;20:637. [DOI] [PMC free article] [PubMed] [Google Scholar]
NCT00308113 {published data only}
- NCT00308113. CoQ10 and prednisone in non-ambulatory DMD. clinicaltrials.gov/ct2/show/NCT00308113 (first received 29 March 2006).
NCT03603288 {published data only}
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