title: Improving clinical trial design for Duchenne muscular dystrophy.
abstract: BACKGROUND
  Currently, the most promising therapies for Duchenne muscular dystrophy (DMD) are exon skipping and stop codon read-through, two strategies aimed at restoring the expression of dystrophin. A phase 3 clinical trial with drisapersen, a drug designed to induce exon 51-skipping, has failed to show significant improvement of the primary outcome measure, the six-minute walk test.
  
  
  CONCLUSIONS
  Here, we review some key points that should be considered when designing clinical trials for these new therapies. First, younger patients have more functional abilities and more muscle fibers to preserve than older patients and therefore are better subjects for trials designed to demonstrate the success of new treatments. Second, the inclusion of patients on corticosteroids both in the treatment and placebo groups is of concern because the positive effect of corticosteroids might mask the effect of the treatment being tested. Additionally, the reasonable expectation from these therapies is the slowing of disease progression rather than improvement. Therefore, the appropriate clinical endpoints are the prolongation of the ability to stand from the floor, climb stairs, and walk, not an increase in muscle strength or function. Hence, the time frames for the detection of new dystrophin, which occurs within months, and the ability to demonstrate a slowing of disease progression, which requires years, are strikingly different. Finally, placebo-controlled trials are difficult to manage if years of blindness are required to demonstrate a slowing of disease progression. Thus, accelerated/conditional approval for new therapies should be based on surrogate biochemical outcomes: the demonstration of de novo dystrophin production and of its beneficial effect on the functional recovery of muscle fiber. These data suggest that clinical trials for DMD patients must be adapted to the particular characteristics of the disease in order to demonstrate the expected positive effect of new treatments.
authors: Laboratory of Musculoskeletal Cell Biology, Istituto Ortopedico Rizzoli, IRCCS, Via Di Barbiano 1/10, 40136, Bologna, Italy. luciano.merlini@ior.it.
authors: Luciano
authors: L
authors: Merlini
authors: Laboratory of Musculoskeletal Cell Biology, Istituto Ortopedico Rizzoli, IRCCS, Via Di Barbiano 1/10, 40136, Bologna, Italy. sabatelli@area.bo.cnr.it.|CNR National Research Council of Italy, Institute of Molecular Genetics, Bologna, Italy. sabatelli@area.bo.cnr.it.
authors: Patrizia
authors: P
authors: Sabatelli
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000379:methods*; D018450:Disease Progression; D004359:Drug Therapy, Combination; D016189:Dystrophin / Q000235:genetics; D005091:Exons; D006801:Humans; D008297:Male; D053580:Muscle Strength; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D009841:Oligonucleotides / Q000627:therapeutic use*; D058996:Quality Improvement; D012107:Research Design; D016896:Treatment Outcome; D016138:Walking
chemical_list: D000305:Adrenal Cortex Hormones; D016189:Dystrophin; D009841:Oligonucleotides; C525434:PRO051