P.2.8 The 6-min walk test and clinical endpoints in Duchenne MD: Reliability, validity, and clinically-important differences

Introduction : An international clinical trial enrolled 174 ambulatory males ⩾5 years old with nonsense mutation Duchenne muscular dystrophy (DMD). Pre-treatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCID) of the 6-min walk test (6MWT), and other endpoints. Methods : Eligibility criteria included nonsense-mediated severe dystrophinopathy, males ⩾5 years, and ambulatory (defined as ability to walk >75 m on the 6MWT). A total of 174 patients, 70% of whom were treated with corticosteroids, were randomized into three treatment groups for the PTC124-GD-007 Ataluren clinical trial and evaluated initially at screening and baseline visits. The 6 min walk distance (6MWD) was defined as primary endpoint and other secondary and exploratory endpoints included timed function tests ¨C TFTs (time to stand from supine, time to climb 4 stairs, time to run/walk 10 m, and methods during TFTs), quantitative strength by hand-held myometry (knee extensors, knee flexors, elbow extensors, and elbow flexors), the PedsQL physical functioning scale, and energy expenditure index determined by heart rate measurement during the 6-min walk test. Results : The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 m based on two statistical distribution methods. Discussion : The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints demonstrating the sensitivity of this endpoint. The 6MWD showed an MCID of approximately 30 m – similar to the magnitude of change observed in previous registration trials focused on other clinical populations. The 6MWD is a reliable, valid and clinically meaningful primary endpoint and an optimal primary endpoint for DMD clinical trials that are therapeutically focused on preservation of ambulatory functioning and slowing disease progression.