Idebenone for the treatment of Duchenne muscular dystrophy (Protocol)

Idebenone for the treatment of Duchenne muscular dystrophy (Protocol) Geng J, Dong J, Jiang K, Shen L, Wu T, Ni H, Shi LL, Wang G, Wu H This is a rep...
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Idebenone for the treatment of Duchenne muscular dystrophy (Protocol) Geng J, Dong J, Jiang K, Shen L, Wu T, Ni H, Shi LL, Wang G, Wu H

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2011, Issue 4 http://www.thecochranelibrary.com

Idebenone for the treatment of Duchenne muscular dystrophy (Protocol) Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . ABSTRACT . . . . . . . . . BACKGROUND . . . . . . . OBJECTIVES . . . . . . . . METHODS . . . . . . . . . ACKNOWLEDGEMENTS . . . REFERENCES . . . . . . . . APPENDICES . . . . . . . . WHAT’S NEW . . . . . . . . HISTORY . . . . . . . . . . CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST . SOURCES OF SUPPORT . . . .

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Idebenone for the treatment of Duchenne muscular dystrophy (Protocol) Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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[Intervention Protocol]

Idebenone for the treatment of Duchenne muscular dystrophy JinSong Geng1 , JianCheng Dong1 , Kui Jiang1 , LiHua Shen2 , Taixiang Wu3 , Hengjian Ni1 , Li Li Shi4 , GuoHua Wang5 , HuiQun Wu 6 1 Evidence-based Medicine Center, Medical School of Nantong University, Nantong, China. 2 Department of Neurology, Affiliated Hospital of Nantong University, Nantong, China. 3 Chinese Cochrane Centre, Chinese Clinical Trial Registry, Chinese Evidence-Based Medicine Centre, INCLEN Resource and Training Centre, West China Hospital, Sichuan University, Chengdu, China. 4 Nantong University Library, Evidence-based Medicine Center, Medical School of Nantong University, Nantong, China. 5 Institute of Nautical Medicine, Nantong University, Nantong, China. 6 Department of Medical Informatics, Medical School of Nantong University, Nantong, China

Contact address: JinSong Geng, Evidence-based Medicine Center, Medical School of Nantong University, 19 Qixiu Road, Nantong, Jiangsu, 226001, China. [email protected]. Editorial group: Cochrane Neuromuscular Disease Group. Publication status and date: Edited (no change to conclusions), published in Issue 4, 2011. Citation: Geng J, Dong J, Jiang K, Shen L, Wu T, Ni H, Shi LL, Wang G, Wu H. Idebenone for the treatment of Duchenne muscular dystrophy. Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD008647. DOI: 10.1002/14651858.CD008647. Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT This is the protocol for a review and there is no abstract. The objectives are as follows: To evaluate the efficacy of idebenone on muscle strength, muscle function, respiratory function, cardiac function and quality of life in people with Duchenne muscular dystrophy.

Idebenone for the treatment of Duchenne muscular dystrophy (Protocol) Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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BACKGROUND

Description of the condition Duchenne muscular dystrophy (DMD) is a life-limiting, X-linked neuromuscular disease with a prevalence rate of approximately 1 in 3,500 live male births. DMD is characterized by progressive skeletal muscle weakness and wasting, resulting in the loss of ambulation between ages of 7 and 13 years and death in the second or third decade from cardiac or respiratory failure (Klitzner 2005). Dystrophin, a 427 kDa cytoskeletal protein, is normally found at the inner surface of skeletal and cardiac muscle fibers. In humans, DMD is caused by defects in the dystrophin gene that prevent the production of dystrophin, leading to costamere disorganization, sarcolemmal fragility, muscle weakness and necrosis (Ervasti 2007). At present, there are still no effective interventions to alter significantly the progression of the disease. However, quality of life and life expectancy can be markedly improved if cardiopulmonary manifestations are adequately treated (Finsterer 2006). We should be optimistic that novel therapeutic agents may have a positive impact on this disease in the near future.

tary running performance (Buyse 2009). Authors of this trial concluded that they had identified a novel potential therapeutic strategy for homologous human DMD. The 12-month Phase II Efficacy and Tolerability of Idebenone in Boys With Cardiac Dysfunction Associated With Duchenne Muscular Dystrophy (DELPHI) trial has evaluated the efficacy and tolerability of idebenone at a dose of 450 mg/day compared to placebo in children with DMD (NCT00654784). Clinical efficacy of idebenone was demonstrated by improvement in functional cardiac and respiratory parameters (including the primary endpoint) that were sensitive markers of cardiac disease and respiratory insufficiency (Buyse 2008). The post hoc subgroup analysis of the DELPHI trial, which was intended to verify any potential influence of glucocorticoids on early markers of respiratory weakness in people with DMD, indicated that the effect size of idebenone on peak expiratory flow (PEF) was significantly larger in glucocorticoidnaïve participants than in glucocorticoid users (Buyse 2009a). A phase III randomized, double-blind, placebo-controlled clinical study of idebenone is planned (Duchenne Muscular Dystrophy Long-term Idebenone Study, DELOS) , which aims to determine efficacy using a clinically meaningful early parameter of respiratory function in participants with DMD who are in their second decade (Buyse 2009b).

Description of the intervention Idebenone is an organic compound of the quinone family, promoted commercially as a synthetic analogue of coenzyme Q10 (CoQ10). Idebenone has been used for research in neurological disorders. Several studies have indicated that idebenone might exert some therapeutic effects in Alzheimer’s disease (Weyer 1997; Gutzmann 1998; Gutzmann 2002). However, one study (Thal 2003) suggested that idebenone failed to slow cognitive decline in Alzheimer’s disease. At present, no systematic review has been performed on this topic and no convincing conclusions can be drawn. In participants with Friedreich’s ataxia, a phase III study demonstrated that treatment with higher doses of idebenone was generally well tolerated and associated with improvement in neurological function and activities of daily living (ADL) (Di Prospero 2007). In addition, idebenone is currently being investigated in Leber’s hereditary optic neuropathy, MELAS syndrome (Mytochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes) and primary progressive multiple sclerosis. On 20 March 2007, the European Commission granted orphan designation (EU/3/07/437) to Santhera Pharmaceuticals (Germany) GmbH for idebenone in the treatment of DMD (Committee for orphan medicinal products 2007). Results of a long-term, blinded and placebo-controlled study in the dystrophin deficient mdx mouse demonstrated that long-term idebenone treatment initiated before the appearance of symptoms significantly prevented cardiac diastolic dysfunction, blocked the development of lethal acute heart failure during a dobutaminemediated stress protocol (i.e. improved contractile reserve), reduced cardiac inflammation and fibrosis, and improved volun-

How the intervention might work The beneficial effects of idebenone can be explained by its ability to protect against mitochondrial respiratory chain dysfunction and reduce oxidative stress (Buyse 2009; Gemperli 2009). Dystrophin and the dystrophin-associated proteins may be involved in cell survival signaling pathways that regulate antioxidant defense mechanisms (Disatnik 2000). Free radical production may be disrupted and contribute to the ensuing pathology (Tidball 2007). Excessive reactive oxygen species (ROS) production and simultaneous activation of abnormal Ca2+ signals amplify each other, finally culminating in a vicious cycle of damaging events, which may contribute to the abnormal stress sensitivity in dystrophic skeletal muscle (Shkryl 2009). With progression of weakness and wasting of striated skeletal muscles, inspiratory and expiratory muscles will eventually be impaired. Meanwhile, mitochondrial dysfunction and oxidative damage may be involved in the pathogenesis of heart failure (Williams 2007; Jung 2008). Furthermore, respiratory insufficiency may be worsened by left or right ventricular heart failure. Idebenone exerts its antioxidant function via various mechanisms. It can inhibit the oxidation of nicotinamide adenine dinucleotide (NADH)-dependent substrates (Rauchová 2008), decrease the generation of ROS (Rauchová 2006; Ranganathan 2009), reduce oxidative damage and mitochondrial swelling, and strongly increase glycerophosphate dehydrogenase (G3PDH) activity (Haefeli 2009).

Idebenone for the treatment of Duchenne muscular dystrophy (Protocol) Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Why it is important to do this review DMD is a devastating and still incurable neuromuscular disease. Increased oxidative stress within the cell that damages the sarcolemma is an important pathological characteristic of this dystrophin deficient disease. Several studies have proposed that idebenone may reduce oxidative stress and protect mitochondrial function. Meanwhile, preliminary data suggest beneficial effects on cardiac and respiratory function. Hence, idebenone seems to be a novel potential therapeutic strategy for DMD. The purpose of this review is to provide up-to-date evidence regarding the efficacy and adverse effects of idebenone in people with DMD.

OBJECTIVES To evaluate the efficacy of idebenone on muscle strength, muscle function, respiratory function, cardiac function and quality of life in people with Duchenne muscular dystrophy.

METHODS

Criteria for considering studies for this review

Types of studies All relevant RCTs and quasi-RCTs will be eligible for inclusion. Quasi-RCTs are those using not truly random methods in the sequence generation process such as date of birth, date of admission, hospital or clinic record number. We will also include two-period cross-over trials. Types of participants

in muscle function from baseline as measured by functional rating scales like Hammersmith motor ability scale (HMAS) (Scott 1982), Brooke upper extremity scales (Brooke 1981), Vignos lower extremity scales (Vignos 1960) and Motor Function Measure (MFM) (Bérard 2005).

Secondary outcomes

1. Change in muscle strength from baseline after six months of treatment measured by manual muscle testing (MMT) such as Medical Research Council (MRC) strength scores (MRC 1976), and quantitative muscle testing (QMT) using equipment such as an isokinetic dynamometer or hand-held dynamometer. 2. Change in respiratory function from baseline as evaluated by percentage of expected forced vital capacity (FVC) for height and forced expiratory volume in one second (FEV1) after six months of treatment. 3. Change in cardiac function from baseline, such as fractional shortening (FS) or ejection fraction (EF) measured by echocardiography or gated magnetic resonance imaging or tissue doppler after six months of treatment. 4. Change in quality of life from baseline as measured by validated and recognized rating scales such as Short-Form 36 (SF36) (Ware 1993) and Barthel Index (BI) (Mahoney 1965) after six months of treatment. 5. Adverse events which lead to withdraw of treatment and serious adverse events which lead to hospitalization or death during the treatment and follow-up period. Participants with DMD have gradual loss of muscle function and concurrently develop progressive contractures over time. Six months to 12 months and greater than 12 months are appropriate times given the fact that studies of DMD therapeutics will be extremely long.

Search methods for identification of studies

We will include both ambulant and non-ambulant people with a definite diagnosis of DMD. Electronic searches Types of interventions We will consider trials comparing idebenone with placebo, other drug treatment and no treatment (e.g. standard care). Types of outcome measures

Primary outcomes

Primary outcomes will be measured after 12 months and will be change in timed functional testing from baseline, such as time taken to walk 30 feet and time to climb four stairs, and change

We will search the Neuromuscular Disease Group Specialized Register using the following terms: muscular dystrophy, duchenn*, dystrophin*; Idebenone, SNT-MC17, Catena. The strategy will be adapted to search MEDLINE (1966 to present), EMBASE (1980 to present), Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and databases of ongoing trials including Current Controlled Trials, the National Research Register (NRR) archive and the US National Institutes of Health.

Searching other resources

Idebenone for the treatment of Duchenne muscular dystrophy (Protocol) Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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We will search the bibliographies of any included studies that are identified for further references and will contact authors of identified trials for additional information and unpublished data.

Data collection and analysis Selection of studies Two review authors (Geng JS and Jiang K) will independently screen all the titles and abstracts of publications identified by the searches to assess their eligibility. They will exclude publications that do not meet the criteria at this stage. Following screening, they will assess the full text of eligible citations for inclusion. They will select trials and reach a final list of studies by consensus. The two authors will discuss and resolve any disagreements where possible. If there is no consensus, they will consult a third member of the team (Wu TX). Data extraction and management Two reviewers (Geng JS and Jiang K) will independently extract characteristics of each included trial including the risk of bias assessment, baseline characteristics and results for the outcome measures using the standard data extraction form developed by the Cochrane Neuromuscular Disease Group. When additional data are required, we may contact the authors for relevant information. For continuous data, the summary statistics required for each trial and each outcome are the mean change from baseline, the standard deviation (SD) of the mean change, and the number of participants for each group. When studies do not report changes from baseline, we will extract the mean, SD and the number of people for each group at each time point. If any of the continuous data which did not report the SD and this could not be deduced, then the standard error (SE) will be deduced and estimates from the individual studies. For dichotomous data, we will seek the numbers in each group at baseline and post-treatment and other measurement time points. For an intention-to-treat analysis, we will collect data for each outcome measure on every participant randomized, irrespective of compliance. For cross-over studies, we will extract the mean change from baseline and the SD or SE for each group. We will seek information about randomized participants excluded from the published analyses and if available incorporate it into the analysis. Assessment of risk of bias in included studies Two review authors (Geng JS and Shi LL) will assess the risk of bias of each trial according to the approaches described in The Cochrane Handbook for Systematic Reviews of Interventions 5.0.1 (Higgins 2008). We will construct ’Risk of bias’ tables using the

Cochrane Collaboration software, Review Manager 5 (RevMan 2008). The risk of bias will be assessed as: yes (low risk of bias); no (high risk of bias); or unclear (uncertain risk of bias). The following characteristics will be evaluated: 1. Adequate sequence generation? 2. Allocation concealment? 3. Blinding? 4. Incomplete outcome data addressed? 5. Free of selective reporting? 6. Free of other bias? The assessment of the quality of the body of evidence will follow the methods recommended by Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group (Atkins 2004; Higgins 2008), which combines considerations of risk of bias, directness, heterogeneity, precision and publication bias. Using Gradeprofiler (version 3.2.2) (GRADEpro 2008), we will construct a ’Summary of findings’ table, which includes information on the individual selected outcomes, the amount of evidence available to make the judgement, the relative and absolute risks and the quality of the evidence used for each outcome to make the judgement. Outcomes to be included in the ’Summary of findings’ table will be: change in muscle function, change in muscle strength and incidence and severity of adverse effects. Measures of treatment effect Statistical methods used to measure treatment effect will be in accordance with The Cochrane Handbook for Systematic Reviews of Interventions 5.0.1 (Higgins 2008). For continuous data, the main outcomes of interest is the change in score from baseline to the final assessment. If the change from baseline results is not reported, we will calculate the statistics from baseline, if data are available. We will use the mean difference (MD) with 95% confidence intervals (CIs) where outcomes are measured in a standard way across studies. We will use standardized mean differences (SMD) with 95% CIs to summarise results across studies with outcomes that are conceptually the same but measured in different ways. For dichotomous data, we will use the risk ratio (RR) with 95% CIs. For cross-over studies, we will calculate the paired MD or the paired SMD between treatments and their SE. Unit of analysis issues For trials comparing more than two intervention groups, we will assess the relevant intervention group. Cross-over studies in which each participant acts as his or her own control and in which every participant receives every intervention have advantages over parallel group trials. The effect estimate for the meta-analysis will be the mean and SE of the differences between experimental and control groups. The effect estimate may

Idebenone for the treatment of Duchenne muscular dystrophy (Protocol) Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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be included in a meta-analysis using the generic inverse variance (GIV) method in RevMan. In cluster-randomized studies, groups of individuals are randomized to different interventions. The multi-level statistical models should be used in the analysis of cluster-randomized trials. Effect estimates and their SEs from correct analyses of cluster-randomized trials may be meta-analysed using the GIV method in RevMan. Dealing with missing data We will contact the chief investigators to request missing data. We will include in the review some studies that are lacking information on outcomes of interest, or summary data such as sample sizes, numbers of events, or SEs but we will not consider them in the meta-analysis. We will address the potential implications of missing data (e.g. loss to follow-up and no outcome obtained, receiving the wrong treatment, lack of compliance, or ineligibility) in the ’Discussion’. Assessment of heterogeneity We will test heterogeneity of intervention effects among trials using the standard Chi2 statistic (P value) or the I2 statistic. P values of less than 0.10 will be taken as evidence of heterogeneity. We will interpret I2 for heterogeneity as follows: • 0% to 40%: may not be important; • 30% to 60%: may represent moderate heterogeneity; • 50% to 90%: may represent substantial heterogeneity; • 75% to 100%: considerable heterogeneity. We will investigate heterogeneity among trials by excluding trials of the poorest quality in the analyses, and using the subgroup analysis as described below. Assessment of reporting biases We will draw a funnel plot to detect the possibility of publication bias in the meta-analysis if there are a reasonable number of studies (in accordance with methods developed by Cochrane Neuromuscular Disease Group: at least 10 is probably necessary for a clear pattern to emerge). Data synthesis If there is no substantial or considerable heterogeneity, we will synthesize the results in a meta-analysis. We will combine trial data using RevMan. We will used fixed-effect or random-effects models as appropriate. For cross-over studies, only outcomes where results from the paired t-tests are available will be included for meta-analysis. We will

calculate the paired mean difference and SE of change score from baseline to the final assessment. The GIV method will be used to combine data from cross-over studies with those from parallel group trials. Subgroup analysis and investigation of heterogeneity Subgroup analysis of interest will be ambulant versus non-ambulant DMD participants. Outcomes that depend upon ambulation will only include participants who can ambulate at the commencement of the trial. However, we will not perform subgroup analysis unless we can extract sufficient data about these two participant types. Sensitivity analysis We will detect the robustness of the results of the meta-analysis according to methods developed by Cochrane Neuromuscular Disease Group as follows. (1) Repeat the analysis excluding unpublished studies if there are any. (2) Repeat the analysis excluding studies of the lowest quality. (3) If there are any very large studies, repeat the analysis excluding them to look at how much they dominate the results. (4) Repeat the analysis excluding other types of studies, depending on the degree to which there are choices about the inclusion/exclusion criteria (for example with/without trials that had different age groups, different dosages, or different cut-offs for severity of disability).

ACKNOWLEDGEMENTS We are grateful for technical assistance from the Cochrane Neuromuscular Disease Group. Editorial support from the Cochrane Neuromuscular Disease Group was funded by the TREAT NMD European Union Grant 036825. We sincerely thank Dr Michael Lunn for important advice on how to write and revise the protocol. We acknowledge the contribution of Ruth Brassington and Kate Jewitt (Managing Editors) for detailed comments which have contributed to this protocol. We thank Professor YouPing Li and Professor GuanJian Liu at the Chinese Cochrane Center and Chinese Evidence-based Medicine Center for guidance on how to teach and do research in evidence-based medicine. We acknowledge the help of teachers at Chinese Cochrane Center and Chinese Evidence-based Medicine Center, West China Hospital and Department of Medical Informatics, Medical School of Nantong University. We sincerely acknowledge the contribution from peer reviewers and consumers.

Idebenone for the treatment of Duchenne muscular dystrophy (Protocol) Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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REFERENCES

Additional references Atkins 2004 Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al.GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004; 328(7454):1490. [PUBMED: 15205295] Brooke 1981 Brooke MH, Griggs RC, Mendell JR, Fenichel GM, Shumate JB, Pellegrino RJ. Clinical trial in Duchenne dystrophy. I. The design of the protocol. Muscle and Nerve 1981;4(3):186–97. [PUBMED: 7017401] Buyse 2008 Buyse GM, Goemans N, Van der Mieren G, Erb M, D’hooge J, Herijgers P, et al.SNT-MC17/idebenone in Duchenne muscular dystrophy: long-term blinded controlled preclinical study in the mdx mouse followed by a 12 month double blind randomized controlled trial in humans. Neuromuscular Disorders 2008;18(9-10):832. [DOI: 10.1016/j.nmd.2008.06.378] Buyse 2009 Buyse GM, Van der Mieren G, Erb M, D’hooge J, Herijgers P, Verbeken E, et al.Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance. European Heart Journal 2009;30(1):116–24. [PUBMED: 18784063] Buyse 2009a Buyse GM, Goemans N, van den Hauwe M, de Groot IJM, Schara U, Ceulemans B, et al.Glucocorticoids influence therapeutic efficacy of idebenone (Catena ®) on peak expiratory flow in patients with Duchenne muscular dystrophy (DMD). Neuromuscular Disorders 2009;19(8-9): 610. [DOI: 10.1016/j.nmd.2009.06.208] Buyse 2009b Buyse GM, Meier T, Finkel RS. Design of an international phase III study with idebenone (Catena ®) in patients with Duchenne muscular dystrophy (DMD) - The DELOS study. Neuromuscular Disorders 2009;19(8-9):612. [DOI: 10.1016/j.nmd.2009.06.214] Bérard 2005 Bérard C, Payan C, Hodgkinson I, Fermanian J, MFM Collaborative Study Group. A motor function measure for neuromuscular diseases. Construction and validation study. Neuromuscular Disorders 2005;15(7):463–70. [PUBMED: 16106528] Committee for orphan medicinal products 2007 Committee for orphan medicinal products. Public summary of positive opinion for orphan designation of idebenone for the treatment of Duchenne muscular dystrophy. European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use 2007. [: Doc.Ref.: EMEA/ COMP/466948/2006]

Di Prospero 2007 Di Prospero NA, Baker A, Jeffries N, Fischbeck KH. Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial. Lancet Neurology 2007;6(10):878–86. [PUBMED: 17826341] Disatnik 2000 Disatnik MH, Chamberlain JS, Rando TA. Dystrophin mutations predict cellular susceptibility to oxidative stress. Muscle and Nerve 2000;23(5):784–92. [PUBMED: 10797403] Ervasti 2007 Ervasti JM. Dystrophin, its interactions with other proteins, and implications for muscular dystrophy. Biochimica et Biophysica Acta 2007;1772(2):108–17. [PUBMED: 16829057] Finsterer 2006 Finsterer J. Cardiopulmonary support in Duchenne muscular dystrophy. Lung 2006;184(4):205–15. [PUBMED: 17006747] Gemperli 2009 Gemperli A, Hufschmid M, Courdier-Fruh I, Haefeli R, Erb M, Dallmann R, et al.Restoring mitochondrial function in Duchenne muscular dystrophy by idebenone. Neuromuscular Disorders 2009;19(8):616–7. [DOI: 10.1016/j.nmd.2009.06.228] GRADEpro 2008 Jan Brozek, Andrew Oxman, Holger Schünemann. GRADEpro. 3.2 for Windows. Jan Brozek, Andrew Oxman, Holger Schünemann, 2008. Gutzmann 1998 Gutzmann H, Hadler D. Sustained efficacy and safety of idebenone in the treatment of Alzheimer’s disease: update on a 2-year double-blind multicenter study. Journal of Neural Transmission. Supplementum 1998;54:301–10. [PUBMED: 9850939] Gutzmann 2002 Thal LJ, Grundman M, Berg J, Ernstrom K, Margolin R, Pfeiffer E, et al.Idebenone treatment fails to slow cognitive decline in Alzheimer’s disease. Neurology 2003;61(11): 1498–502. [PUBMED: 14663031] Haefeli 2009 Haefeli R, Gemperli A, Güven N. Effects of idebenone on mitochondrial function in cells from muscular dystrophy patients and healthy individuals. Neuromuscular Disorders 2009;19(8-9):613. [DOI: 10.1016/j.nmd.2009.06.216] Higgins 2008 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.

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Jung 2008 Jung C, Martins AS, Niggli E, Shirokova N. Dystrophic cardiomyopathy: amplification of cellular damage by Ca2+ signalling and reactive oxygen species-generating pathways. Cardiovascular Research 2008;77(4):766–73. [PUBMED: 18056762] Klitzner 2005 American Academy of Pediatrics Section on Cardiology, Cardiac surgery. Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Pediatrics 2005;116(6):1569–73. [PUBMED: 16322188] Mahoney 1965 Mahoney FI, Barthel DW. Functional evaluation. The Barthel index. Maryland State Medical Journal 1965;14: 61–5. [PUBMED: 14258950] MRC 1976 Medical Research Council. Aids to the investigation of peripheral nerve injuries. London: HMSO, 1976. NCT00654784 NCT00654784. Efficacy and Tolerability of Idebenone in Boys With Cardiac Dysfunction Associated With Duchenne Muscular Dystrophy (DELPHI). http:// www.clinicaltrials.gov/ct2/show/NCT00654784 (Accessed 2 February 2010). [: NCT00654784] Ranganathan 2009 Ranganathan S, Harmison GG, Meyertholen K, Pennuto M, Burnett BG, Fischbeck KH. Mitochondrial abnormalities in spinal and bulbar muscular atrophy. Human Molecular Genetics 2009;18(1):27–42. [PUBMED: 18824496] Rauchová 2006 Rauchová H, Vrbacký M, Bergamini C, Fato R, Lenaz G, Houšt k J, et al.Inhibition of glycerophosphate-dependent H2 O2 generation in brown fat mitochondria by idebenone. Biochemical and Biophysical Research Communications 2006; 339(1):362–6. [PUBMED: 16300743] Rauchová 2008 Rauchová H, Drahota Z, Bergamini C, Fato R, Lenaz G. Modification of respiratory-chain enzyme activities in brown adipose tissue mitochondria by idebenone (hydroxydecyl-ubiquinone). Journal of Bioenergetics and Biomembranes 2008;40(2):85–93. [PUBMED: 18055285] RevMan 2008 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.0. Copenhagen: The Nordic

Cochrane Centre, The Cochrane Collaboration, The Cochrane Collaboration, 2008. Scott 1982 Scott OM, Hyde SA, Goddard C, Dubowitz V. Quantitation of muscle function in children: a prospective study in Duchenne muscular dystrophy. Muscle and Nerve 1982;5 (4):291–301. [PUBMED: 7099196] Shkryl 2009 Shkryl VM, Martins AS, Ullrich ND, Nowycky MC, Niggli E, Shirokova N. Reciprocal amplification of ROS and Ca 2+ signals in stressed mdx dystrophic skeletal muscle fibers. Pflügers Archiv-European Journal of Physiology 2009;458(5): 915–28. [PUBMED: 19387681] Thal 2003 Thal LJ, Grundman M, Berg J, Ernstrom K, Margolin R, Pfeiffer E, et al.Idebenone treatment fails to slow cognitive decline in Alzheimer’s disease. Neurology 2003;61(11): 1498–502. [PUBMED: 14663031] Tidball 2007 Tidball JG, Wehling-Henricks M. The role of free radicals in the pathophysiology of muscular dystrophy. Journal of Applied Physiology 2007;102(4):1677–86. [PUBMED: 17095633] Vignos 1960 Vignos PJ Jr, Spencer GE Jr, Archibald KC. Management of progressive muscular dystrophy in childhood. JAMA 1963; 184:89–96. [PUBMED: 13997180] Ware 1993 Ware JE Jr, Snow KK, Kosinski M, Gandek B. SF-36 health survey: manual and interpretation guide.. SF-36 health survey: manual and interpretation guide. Boston: The Medical Outcome Trust, New England Medical Center, 1993. Weyer 1997 Weyer G, Babej-Dölle RM, Hadler D, Hofmann S, Herrmann WM. A controlled study of 2 doses of idebenone in the treatment of Alzheimer’s disease. Neuropsychobiology 1997;36(2):73–82. [PUBMED: 9267856] Williams 2007 Williams IA, Allen DG. The role of reactive oxygen species in the hearts of dystrophin-deficient mdx mice. American Journal of Physiology - Heart and Circulatory Physiology 2007; 293(3):H1969–77. [PUBMED: 17573457] ∗ Indicates the major publication for the study

Idebenone for the treatment of Duchenne muscular dystrophy (Protocol) Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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APPENDICES

Appendix 1. MEDLINE (OvidSP) search strategy 1 randomized controlled trial.pt. 2 controlled clinical trial.pt. 3 randomized.ab. 4 placebo.ab. 5 drug therapy.fs. 6 randomly.ab. 7 trial.ab. 8 groups.ab. 9 or/1-8 10 exp animals/ not humans.sh. 11 9 not 10 12 exp muscular dystrophies/ or muscular dystrophy, duchenne/ 13 duchenne.tw. 14 Dystrophin/ 15 dystrophin$1.tw. 16 or/12-15 17 idebenone.mp. 18 exp Quinones/ 19 ide.mp. 20 snt-mc17.mp. 21 catena.mp. 22 or/17-21 23 11 and 16 and 22

WHAT’S NEW

Date

Event

Description

1 March 2011

Amended

Contact details updated.

HISTORY Protocol first published: Issue 8, 2010

Idebenone for the treatment of Duchenne muscular dystrophy (Protocol) Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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CONTRIBUTIONS OF AUTHORS Geng JS - Drafting protocol and review versions; search for trials; selection of trials for inclusion/exclusion; assessment of risk of bias in included studies; extraction of data; interpretation of data analyses; updating review. Dong JC - Data extraction and management; drafting review versions; updating review. Jiang K - Drafting protocol versions; selection of trials for inclusion/exclusion; extraction of data. Shen LH - Updating review. Wu TX - Arbiter of selection of trials for inclusion/exclusion; methodology expert. Ni HJ - Obtaining copies of trial reports. Shi LL - Assessment of risk of bias in included studies. Wang GH - - Updating review. Wu HQ - Updating review.

DECLARATIONS OF INTEREST None known.

SOURCES OF SUPPORT Internal sources • Medical School of Nantong University, China.

External sources • No sources of support supplied

Idebenone for the treatment of Duchenne muscular dystrophy (Protocol) Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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