…but proves the importance and feasibility of randomized controlled trials in rare disease.
A 36-month study into the effects of ciclosporin (cyclosporine) A both alone and in combination with intermittent prednisone for the treatment of ambulant patients with Duchenne muscular dystrophy (DMD) was published in November 2010 in Lancet Neurology. Although the trial found no evidence of a beneficial effect of the drug, it is nevertheless an important milestone in DMD trials, proving that with the close collaboration of all stakeholder groups it is possible to perform meaningful randomized controlled clinical trials with sufficient statistical power even in rare diseases like DMD.
Ciclosporin A is one of the essential immunosuppressive drugs used in many immune and non-immune childhood diseases, and two previous open-label trials had reported enhanced muscle strength in boys with Duchenne muscular dystrophy after daily treatment with the drug. More recently, a positive treatment effect of low dose ciclosporin A was also confirmed in mdx mice. The coordinating investigator of the current trial was Rudolf Korinthenberg at the Division of Neuropaediatrics and Muscle Disorders at Freiburg University. The trial was supported financially by the German government and the patient organization aktion benni & co. and in kind by Novartis Pharma (provision of study medication) and the Deutsche Gesellschaft für Muskelkranke (provision of myometers). A total of 146 patients were recruited over 36 months into a double-blind, randomized, placebo-controlled multicentre study at 11 trial sites across Germany and in Austria and Switzerland that are part of the German muscular dystrophy network (MD-NET). The trial concluded that ciclosporin A alone or in combination with intermittent prednisone does not improve muscle strength or functional abilities in ambulant boys with Duchenne muscular dystrophy, but is safe and well tolerated.
‘Trials that prove a drug has no benefit are of course extremely disappointing for everyone and often don’t get much publicity,’ explained study coordinator Janbernd Kirschner. ‘But this is still a very important result that has many implications for future trials in DMD and other rare diseases. We did this trial because two previous trials had reported that ciclosporin had a positive effect on muscle strength, and we hoped to prove that effect. Instead, we proved the drug had no effect. Those previous trials were open-label studies, meaning the doctors and patients knew the drug that was being used, and the patients receiving the drug were not compared against a group receiving a placebo. Our study enrolled a much larger number of boys and neither the doctors nor the patients knew which patients were getting the drug. The fact that it showed no benefit just goes to show how important it is that these randomized, placebo-controlled trials are carried out whenever possible to get a definitive answer about any drug proposed as a treatment for DMD. With a lesser evidence base, we could have been giving our DMD boys a drug that was having no benefit at all and that has some risks associated with it. Equally importantly, we have clearly shown that it is possible to perform meaningful randomized controlled clinical trials with sufficient statistical power even in rare diseases like DMD – which is very promising in terms of the future therapies that are now coming to trial.’
This trial therefore sends an important message about the feasibility of trials in rare diseases, and with the increasing interest from pharmaceutical companies in the rare disease field this is a very timely message. But as commercial interest and financial resources can still remain scarce, it is important to note that planning and carrying out such a trial requires close cooperation between researchers, clinicians, patient groups, public funding sources and industry partners. The German muscular dystrophy network MD-NET and the support of patient organizations was instrumental in this trial. Future multinational studies, even those with industry sponsors, will also need to take advantage of networks of trial sites, the support of patient groups, and the assistance of patient registries for recruitment.
The full published paper is available online at
Kirschner J et al. Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial. Lancet Neurol. 2010 Nov;9(11):1053-9.