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Report on the 124Th ENMC International Workshop. Treatment Neuromuscular Disorders 14 (2004) 526–534 www.elsevier.com/locate/nmd 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 K. Bushbya,*, F. Muntonib, A. Urtizbereac, R. Hughesd, R. Griggse aInstitute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne NE3 4YQ, UK bHammersmith Hospital, Imperial College, London W12 ONN, UK cInstitute de Myologie, 75013 Paris, France dDepartment of Clinical Neurosciences, Guys Hospital, London SE1 1UL, UK eUniversity of Rochester Medical Centre, New York, NY 14642, USA Received 13 May 2004 Keywords: Duchenne muscular dystrophy; Corticosteroids; Medical management; Prednisolone; Deflazacort 1. Introduction between them used at least seven different regimes for giving steroids, and some did not use steroids at all. Thirty-two participants representing parents, funding Adnan Manzur (UK), co-author of the Cochrane report agencies and clinicians involved in the care of children with on the use of glucocorticosteroids in DMD described Duchenne Muscular Dystrophy (DMD) from Belgium, the major findings of this systematic review [1]. Only five Canada, Denmark, Finland, France, Germany, Italy, the randomised controlled trials of the use of steroids in DMD Netherlands, Spain, Sweden, the UK and the USA met in were published in sufficient detail to be able to be included Naarden on 2–4th April 2004. The meeting was held under in the review. These trials did, however, present evidence the auspices of the ENMC Clinical Trials Network, and with that use of daily prednisolone (0.75 mg/kg per day) or the additional support of the United Parent Project. The aims deflazacort (0.9 mg/kg per day) increased strength in DMD. of the workshop were to define the need for clinical trials in Robert Griggs, Richard Moxley (USA) and Doug Biggar DMD and develop a protocol for such trials, relating (Canada) were able to confirm that long-term follow up of primarily to the use of steroids (prednisolone, prednisone cohorts of patients treated under one or other of these and deflazacort) in DMD. regimes and who mostly continued using steroids beyond The first part of the meeting summarised the current state the loss of independent ambulation shows that this increase of practice on the use of steroids in DMD. Elizabeth Vroom in strength is mirrored by improvement in function (with (Netherlands) and Pat Furlong (USA) presented the views of age at loss of ambulation in the mid teens, preservation of parents surveyed by questionnaire by the United Parent respiratory function, lack of need for scoliosis surgery and Project. A major worry for parents was the lack of use of possibly preservation of cardiac function) [2–4]. With long- steroids at all in some countries, the multiplicity of steroid term use of steroids, the per kilogram dose of corticosteroid regimes used and the problems of getting firm information tended to reduce with time. In some cases, this was in response to side effects such as weight gain or behaviour about which type of steroid or which regime for using changes, but in the majority represented a tendency not to steroids was best. This was reflected in the variation in keep up strictly with change in weight over time. practice amongst the participants at the Workshop, who Many different regimes for giving steroids in DMD have * Corresponding author. Tel.: þ44-191-241-8757; fax: þ44-191-241- been suggested as a way to reduce the risk of the well-known 8799. side effects associated with the long-term use of daily E-mail address: [email protected] (K. Bushby). steroids. The dose of 0.75 mg/kg per day was shown to be 0960-8966/$ - see front matter q 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2004.05.006 K. Bushby et al. / Neuromuscular Disorders 14 (2004) 526–534 527 the most effective dose in the early randomised controlled Without this information, patients are being advised on trials, where dose response analysis showed that 0.35 mg/kg steroid dosages without evidence-based facts as to the likely per day was not as effective as 0.75 mg/kg per day, while outcomes, based usually on personal experience of 1.2 mg/kg per day gave no additional benefit [5,6]. Deflaza- the advising physician. As it can now be concluded that cort 0.9 mg/kg per day is said to be the equivalent dose to the long-term use of daily steroids, introduced when patients 0.75 mg/kg per day of prednisolone, and appears to be equally are still ambulant and before they have lost major function, as effective [7,8]. Side effect profiles of the two regimes may alters the natural history of the disease, the issue of ensuring differ slightly. Deflazacort appears to cause less weight gain, that children are receiving an adequate dose becomes more but is more likely to be associated with the development of imperative. It was decided therefore that the key hypothesis asymptomatic cataracts. It is hard to assess the long-term for development of a trial protocol should be that alternative differences in these regimes with respect to their effect on regimes to daily steroids have a similar level of efficacy but a bone mineral density. Some studies have reported a high different side effect profile. After much discussion, it was incidence of vertebral fractures with deflazacort, while other agreed that the trial should test 0.75 mg/kg per day of centres have not had this experience [2,9]. By far the most prednisolone administered in a 10 days on/10 days off regime commonly reported side effects in the published series have against 0.75 mg/kg per day. Additional arms of the trial (if been weight gain and behavioural changes [10]. sufficient patient numbers were available) would look at There are known to be many other possible side effects of 0.9 mg/kg per day of deflazacort and 0.5 mg/kg per day of long-term daily steroid use. These include adrenal suppres- prednisolone. sion, susceptibility to infection, hypertension, impaired Tony Swan (UK) summarised the statistical consider- glucose tolerance, gastrointestinal irritation and skin ations involved in designing such a trial. Primary outcomes fragility. None of the centres with long-term experience in relating to function and side effects will need to be chosen to the use of steroids in DMD represented at the meeting had have the power to identify equivalence of effect and seen these complications at a high frequency. difference in side effects. This will require analysis of the Concern about side effects has led to the development of likely variance in any of the likely measures chosen. various regimes to minimise these risks. Some are based on Small group discussions on the second day of the the premise that intermittent dosing allows the body to workshop addressed the design of the protocol in more recover from the effects of steroids by allowing a period off detail, relating to the collection of outcome data and to the the drug (alternate day regimes, regimes using 10 days on definition, management and prophylaxis of adverse events. steroids and 10 or 20 days off, or vice versa, weekend only A key aim for these discussions was to arrive at protocols regimes, etc.) with or without a reduction in the overall dose that would be as simple as possible and allow for uniform given [11–13]. Other regimes (daily low dosing) aim to data collection for the optimal management of children with reduce the cumulative steroid dose [14]. DMD treated with steroids within or outside the context of a Proponents of all of these regimes describe benefit from trial. Consideration was given to agreed protocols already in their use, and a number of case or cohort reports are use such as the Utah dystrophinopathy project (http:// available, but no systematic studies have been published. dystrophy.genetics.utah.edu/) the German MD-NET (www. Anneke van der Kooi (Netherlands) presented on behalf of md-net.org) and the Scandinavian reference programme for her colleagues from Groningen (Beenakker et al) the results DMD so that additional work for busy clinics could be of the first randomised double-blind placebo-controlled avoided as much as possible. As only a minority of children crossover trial of an intermittent regime of prednisone (10 with DMD will by definition be enrolled in a trial, it was days on 0.75 mg/kg per day and 20 days off versus placebo also intended that the protocols used would be relevant to during 6 months) [15]. This demonstrated that prednisone routine follow up and provide a framework for the care of slowed deterioration of muscle function and force in any child with DMD using steroids. The parent representa- ambulant DMD patients. Although side effects were present, tives at the meeting emphasised the value of agreeing to the quality of life was not affected. Nathalie Goemans collect long-term follow up data as well as collect data (Belgium) presented the plans of the CINRG group led by strictly within a trial, and this was also a focus of a small Diane Escolar (USA) to test weekend high-dose predniso- discussion group (see below). These protocols will be lone against daily prednisolone for 1 year. A trial is under available through the ENMC website (www.enmc.org). way in Germany (presented by Rudolph Korinthenberg) In the second part of the workshop, the meeting split to under the auspices of the MD-NET to test the effect of allow small groups to discuss development of specific areas adding cyclosporin A to an intermittent (10 days on/10 days of a trial protocol.
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