Elsevier

Neuromuscular Disorders

Volume 14, Issues 8–9, September 2004, Pages 526-534
Neuromuscular Disorders

Workshop report
Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids 2–4 April 2004, Naarden, The Netherlands

https://doi.org/10.1016/j.nmd.2004.05.006Get rights and content

Introduction

Thirty-two participants representing parents, funding agencies and clinicians involved in the care of children with Duchenne Muscular Dystrophy (DMD) from Belgium, Canada, Denmark, Finland, France, Germany, Italy, the Netherlands, Spain, Sweden, the UK and the USA met in Naarden on 2–4th April 2004. The meeting was held under the auspices of the ENMC Clinical Trials Network, and with the additional support of the United Parent Project. The aims of the workshop were to define the need for clinical trials in DMD and develop a protocol for such trials, relating primarily to the use of steroids (prednisolone, prednisone and deflazacort) in DMD.

The first part of the meeting summarised the current state of practice on the use of steroids in DMD. Elizabeth Vroom (Netherlands) and Pat Furlong (USA) presented the views of parents surveyed by questionnaire by the United Parent Project. A major worry for parents was the lack of use of steroids at all in some countries, the multiplicity of steroid regimes used and the problems of getting firm information about which type of steroid or which regime for using steroids was best. This was reflected in the variation in practice amongst the participants at the Workshop, who between them used at least seven different regimes for giving steroids, and some did not use steroids at all.

Adnan Manzur (UK), co-author of the Cochrane report on the use of glucocorticosteroids in DMD described the major findings of this systematic review [1]. Only five randomised controlled trials of the use of steroids in DMD were published in sufficient detail to be able to be included in the review. These trials did, however, present evidence that use of daily prednisolone (0.75 mg/kg per day) or deflazacort (0.9 mg/kg per day) increased strength in DMD. Robert Griggs, Richard Moxley (USA) and Doug Biggar (Canada) were able to confirm that long-term follow up of cohorts of patients treated under one or other of these regimes and who mostly continued using steroids beyond the loss of independent ambulation shows that this increase in strength is mirrored by improvement in function (with age at loss of ambulation in the mid teens, preservation of respiratory function, lack of need for scoliosis surgery and possibly preservation of cardiac function) [2], [3], [4]. With long-term use of steroids, the per kilogram dose of corticosteroid tended to reduce with time. In some cases, this was in response to side effects such as weight gain or behaviour changes, but in the majority represented a tendency not to keep up strictly with change in weight over time.

Many different regimes for giving steroids in DMD have been suggested as a way to reduce the risk of the well-known side effects associated with the long-term use of daily steroids. The dose of 0.75 mg/kg per day was shown to be the most effective dose in the early randomised controlled trials, where dose response analysis showed that 0.35 mg/kg per day was not as effective as 0.75 mg/kg per day, while 1.2 mg/kg per day gave no additional benefit [5], [6]. Deflazacort 0.9 mg/kg per day is said to be the equivalent dose to 0.75 mg/kg per day of prednisolone, and appears to be equally as effective [7], [8]. Side effect profiles of the two regimes may differ slightly. Deflazacort appears to cause less weight gain, but is more likely to be associated with the development of asymptomatic cataracts. It is hard to assess the long-term differences in these regimes with respect to their effect on bone mineral density. Some studies have reported a high incidence of vertebral fractures with deflazacort, while other centres have not had this experience [2], [9]. By far the most commonly reported side effects in the published series have been weight gain and behavioural changes [10].

There are known to be many other possible side effects of long-term daily steroid use. These include adrenal suppression, susceptibility to infection, hypertension, impaired glucose tolerance, gastrointestinal irritation and skin fragility. None of the centres with long-term experience in the use of steroids in DMD represented at the meeting had seen these complications at a high frequency.

Concern about side effects has led to the development of various regimes to minimise these risks. Some are based on the premise that intermittent dosing allows the body to recover from the effects of steroids by allowing a period off the drug (alternate day regimes, regimes using 10 days on steroids and 10 or 20 days off, or vice versa, weekend only regimes, etc.) with or without a reduction in the overall dose given [11], [12], [13]. Other regimes (daily low dosing) aim to reduce the cumulative steroid dose [14].

Proponents of all of these regimes describe benefit from their use, and a number of case or cohort reports are available, but no systematic studies have been published. Anneke van der Kooi (Netherlands) presented on behalf of her colleagues from Groningen (Beenakker et al) the results of the first randomised double-blind placebo-controlled crossover trial of an intermittent regime of prednisone (10 days on 0.75 mg/kg per day and 20 days off versus placebo during 6 months) [15]. This demonstrated that prednisone slowed deterioration of muscle function and force in ambulant DMD patients. Although side effects were present, the quality of life was not affected. Nathalie Goemans (Belgium) presented the plans of the CINRG group led by Diane Escolar (USA) to test weekend high-dose prednisolone against daily prednisolone for 1 year. A trial is under way in Germany (presented by Rudolph Korinthenberg) under the auspices of the MD-NET to test the effect of adding cyclosporin A to an intermittent (10 days on/10 days off) regime of 0.75 mg/kg per day prednisolone.

Despite the multiplicity of steroid regimes that have been devised and are in use across the world, none has to date been tested systematically against daily steroids at the proven effective dose to look at difference or equivalence of efficacy and the difference in rate of significant side effects. Without this information, patients are being advised on steroid dosages without evidence-based facts as to the likely outcomes, based usually on personal experience of the advising physician. As it can now be concluded that the long-term use of daily steroids, introduced when patients are still ambulant and before they have lost major function, alters the natural history of the disease, the issue of ensuring that children are receiving an adequate dose becomes more imperative. It was decided therefore that the key hypothesis for development of a trial protocol should be that alternative regimes to daily steroids have a similar level of efficacy but a different side effect profile. After much discussion, it was agreed that the trial should test 0.75 mg/kg per day of prednisolone administered in a 10 days on/10 days off regime against 0.75 mg/kg per day. Additional arms of the trial (if sufficient patient numbers were available) would look at 0.9 mg/kg per day of deflazacort and 0.5 mg/kg per day of prednisolone.

Tony Swan (UK) summarised the statistical considerations involved in designing such a trial. Primary outcomes relating to function and side effects will need to be chosen to have the power to identify equivalence of effect and difference in side effects. This will require analysis of the likely variance in any of the likely measures chosen.

Small group discussions on the second day of the workshop addressed the design of the protocol in more detail, relating to the collection of outcome data and to the definition, management and prophylaxis of adverse events. A key aim for these discussions was to arrive at protocols that would be as simple as possible and allow for uniform data collection for the optimal management of children with DMD treated with steroids within or outside the context of a trial. Consideration was given to agreed protocols already in use such as the Utah dystrophinopathy project (http://dystrophy.genetics.utah.edu/) the German MD-NET (www.md-net.org) and the Scandinavian reference programme for DMD so that additional work for busy clinics could be avoided as much as possible. As only a minority of children with DMD will by definition be enrolled in a trial, it was also intended that the protocols used would be relevant to routine follow up and provide a framework for the care of any child with DMD using steroids. The parent representatives at the meeting emphasised the value of agreeing to collect long-term follow up data as well as collect data strictly within a trial, and this was also a focus of a small discussion group (see below). These protocols will be available through the ENMC website (www.enmc.org).

In the second part of the workshop, the meeting split to allow small groups to discuss development of specific areas of a trial protocol.

Section snippets

Session 1. Functional outcome measures

Michelle Eagle (UK) and Birgit Steffensen (Denmark) led a group discussing the kinds of functional outcome measures relevant to DMD. The ideal functional outcome measures would reflect real issues relevant to the disease, be simple to administer and to standardise across different evaluators, and be validated in previous studies. The conclusions of this session are summarised in Table 1.

Measures of function can be considered as three main groups.

Session 2. Strength outcome measures

Michelle Eagle and Birgit Steffensen also co-ordinated the discussion on outcome measures related to changes in muscle strength. The main debate was around the use of manual muscle testing (used in most previous trials in DMD) or quantitative muscle testing (as validated by the CINRG group [19]), and about how many muscles to test. The issue of testing respiratory muscle strength was also discussed. The outcome of these discussions is summarised in Table 1.

Session 3. Quality of life and related issues

Francesco Muntoni (UK) and Michael Rose (UK) led the session on quality of life (QOL) assessment, measurement of behavioural changes and caregiver burden. No long-term studies have systematically looked into these issues in children with DMD, and specific measures for this disorder are not available. Nonetheless, it was agreed that any long-term trial of steroid regimes should incorporate at least a generic measure or measures of QOL with separate child and parents questionnaires. The ideal

Session 4. Implications for cardiology

John Bourke (UK), Giovanni Nigro (Italy) and Denis Duboc (France) led a session on cardiological issues. As cardiomyopathy is an almost universal finding in DMD, the effect of steroid treatment in this group on cardiac function will be important to consider [20]. Long-term cohort studies of boys treated with daily deflazacort suggest that there may be a cardioprotective effect of steroids [3], and no-one had any data to suggest that steroid treatment was detrimental to heart function. In the

Session 5. Monitoring for side effects

The discussions on side effects were split into three groups. The conclusions of these discussions are presented in Table 2.

Session 6. Long-term monitoring

It was the unanimous decision of the meeting that a long-term follow up strategy was essential and that assessments should be made as simple as possible to reflect this need. Functional measures, and in particular noting of milestones of disease progression are essential in this context. Apart from the measures already noted, monitoring of development of respiratory failure and the need for nocturnal ventilation, and the development and need for treatment of scoliosis would be additional needs

Session 7. Funding options

An important feature of this workshop was the participation of parent groups and various funding agencies (the Association Francaise contre les myopathies (AFM, France), Muscular Dystrophy Association (MDA, USA), United Parent Project, and Telethon (Italy)). Working together to fund multinational efforts such as this was recognised as the only viable option, and there was considerable support for this initiative. The group suggested that a planning application could be submitted to the NIH. The

Conclusions and workshop outcomes

  • 1.

    It was agreed that the evidence for the use of daily steroids in DMD is now established and that trials of other treatments should be against this ‘gold standard’.

  • 2.

    Many measures can be put in place to monitor for, minimise or treat predictable side effects and these should be standardised as much as possible. Guidelines developed from this meeting will be available through the ENMC website and are summarised in Table 2.

  • 3.

    Patient information material is crucial and should be distributed through the

Acknowledgements

This Workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors: Association Française contre les Myopathies (France); Deutsche Gesellschaft für Muskelkranke (Germany); Telethon Foundation (Italy); Muscular Dystrophy Campaign (UK); Muskelsvindfonden (Denmark); Prinses Beatrix Fonds (The Netherlands); Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland); Österreichische Muskelforschung (Austria);

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References (23)

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