Challenges of clinical trial design for DMD

Abstract

The natural history of Duchenne Muscular Dystrophy (DMD) is undoubtedly a shifting target, as shown by numerous recent studies [1–3]. And by “natural history” it is intended DMD-with-all-the-intervention-available-to-date, which are summarised and elucidated in the standard of care documents published by Bushby and colleagues [4,5]. The natural history of this disorder goes hand in hand with the on-going evolution of therapies; hence this phenomenon needs to be respected and factored into the design of clinical trials. Applying metrics based on old knowledge of the condition without taking into account new interventions, risks making clinical trial design poorly adapted or obsolete, and recruitment into studies is very challenging. For example, most ambulant patients are now on glucocorticoid therapy, and the age of starting steroids is indeed shifting towards a younger age as shown in the UK clinical practice [6]; hence, designing studies with steroid therapy as an exclusion criterion in the young ambulant population risks making recruitment virtually impossible in most specialised centres. This could in turn skew recruitment and introduce recruitment biases. Furthermore, cardiac medications used prophylactically (i.e. beta blockers and ACE-inhibitors) are increasingly supported by evidence that their use is beneficial for DMD patients [7–9], although a consensus on what is the optimal age for commencing therapy is still lacking. An on-going 5-year clinical trial funded by the British Heart Foundation testing ACE-inhibitor (perindopril) combined with beta-blocker therapy (bisoprolol) is targeting DMD boys 7–12 years of age who have not developed signs of cardiomyopathy (EudraCT number: 2007-005932-10). This study will likely strengthen the body of literature in support of early intervention [10] and indeed prevention; hence, clinical trial design will have to become permissive towards heart medication given prophylactically. However, at least in animal models, medications targeting angiotensin not only impact on cardiac load, but appear also beneficial for skeletal muscle [11] making it difficult to assess if such medications introduce a bias into skeletal muscle-based trial outcome. A similar scenario will apply to anti-oxidative treatment such as ibedenone; with the recently published study [12] supporting the beneficial effect on respiratory function it is expected that soon enough many patients will be treated with ibedenone alongside steroids, although the study results were obtained on steroid-naive patients and it is unknown to what degree the two drugs are complementary.