Development of novel observer-reported outcome assessments in clinical trials of patients with Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration. An unmet need exists for a standardized, validated observer-rated instrument to augment efficacy and safety assessments in clinical trials of DMD therapies and further elucidate potential risks and benefits of treatment. Recently, regulatory authorities such as the European Medicines Agency and Food and Drug Administration clarified the possible add-on value of collecting such data in drug development. Two observer-reported outcome measures will be evaluated in the double-blind, randomized, placebo-controlled phase 3 ESSENCE trial (NCT02500381) of 2 investigational exon-skipping therapeutics in ambulant patients with DMD gene variants amenable to skipping exon 45 or 53. Observers (eg, parents/caregivers) will complete a Web-based questionnaire on how well a patient performs various daily tasks and a recreational activity the patient chooses. They will video record the patient performing daily activities (eg, walking, standing up) and attempting an activity the patient struggles with/recently lost ability to perform. Rigorous qualitative and quantitative validation methods will be used. In-depth concept elicitation and cognitive debriefing interviews with clinicians and caregivers, an inter-rater reliability study conducted with physical therapists, and physician and physical therapist interviews will provide feedback on the questionnaire and videos. Assessments will be collected every 12 weeks in the ESSENCE trial and in a natural history study. These study data will be used to quantitatively evaluate measurement properties of both instruments. Use of these novel assessments for observer-reported outcomes will allow measurement of disease progression in DMD patients on active study drug vs placebo, detect changes in physical functioning, supplement clinical information not captured by current DMD outcome measures, and may provide alternative end points for future DMD clinical trials.