Duchenne muscular dystrophy (DMD) is a disabling and life-threatening X-linked genetic disorder caused by defects in the gene for dystrophin that results in a progressive loss of functional muscle fibers and weakness with stereotypic functional consequences affecting mobility, progressive musculoskeletal deformities, upper limb impairment, impaired airway clearance and ventilation, cardiomyopathy, and premature death.[1, 2]
The past several years have seen increased interest by biopharmaceutical companies in conducting ground-breaking research and development into novel treatment agents for DMD. There is considerable hope that new disease-modifying therapies will slow disease progression, stabilize or improve function, and maintain quality of life. The DMD population targeted by such trials features patients who are old enough to be assessed reliably and still have sufficient muscle fibers available for therapeutics to demonstrate a measurable benefit over the typical 1-year clinical trial duration.
Bipedal ambulation constitutes an almost uniquely human characteristic and is the most commonly performed physical activity by humans. Previously, we modified the American Thoracic Society version of the 6-minute walk test (6MWT) for DMD and validated the 6-minute walk distance (6MWD) as a measure of disease progression in ambulatory DMD patients.[4-6] Given that ambulatory compromise is such an important component of the DMD disease process, improvement in the 6MWD with treatment relative to placebo constitutes clear evidence of therapeutic value. Thus, rather than being a surrogate endpoint, a change in the 6MWD can be defined as an important clinically meaningful endpoint that directly assesses how an ambulatory DMD patient functions. Evidence documenting the reliability of the 6MWT and the concurrent validity, sensitivity, and clinical meaningfulness of longitudinal changes in the 6MWD[4-6, 8, 9] has led to its common use as the primary clinical endpoint in ambulatory DMD trials worldwide.
Because loss of muscle function in DMD occurs against the background of normal childhood growth and development associated with increases in stride length, children with DMD who are <7 years of age may show increases in 6MWD over ∽1 year despite progressive muscular impairment.[6, 9, 10] Older DMD subjects demonstrate variable rates of decline in 6MWD. These findings emphasize the importance of age as a stratification factor in DMD clinical trials using the 6MWD. In addition, Henricson and colleagues showed that normalizing the data by converting 6MWD to a percent predicted 6MWD value may help to distinguish normal growth and development from disease-related progression and treatment effects. The results accumulated over the last several years have shown that the 6MWT offers advantages in DMD as an integrated global measure of ambulatory function that is influenced by lower extremity strength, biomechanical inefficiencies, endurance, and cardiorespiratory status.
Longitudinal 6MWD natural history data provide information on how DMD patient ambulation changes over time (change scores), as well as an understanding of how the variability of the 6MWT (standard deviation) changes over time. This information can be used in clinical trial design for novel therapeutics. Such data for the change score and the standard deviation (SD) of the change score allow for more accurate statistical powering of clinical trials. Furthermore, as we gain understanding of the natural history of DMD we will ultimately be able to use these and future data for patients who receive standard-of-care treatment as historical controls. This will allow comparisons of treated subjects with historical controls for determination of efficacy in trials targeting rare populations with genetic-based treatments.
To determine the clinical relevance of a treatment effect for a given endpoint one must know what constitutes a minimal clinically important difference (MCID). For the 6MWD applied to DMD this has been estimated to be ∽30 m using 2 statistical distribution approaches. Knowledge of the MCID difference in 6MWD and the relevant variability of the change score make it possible to design clinical trials of appropriate power and size.
The aim of this report of placebo-treated patients from the phase 2b ataluren clinical trial (PTC Therapeutics)[12, 13] is to: (1) determine the contemporary natural history of common clinical measures of disease progression in ambulatory DMD subjects [6MWD, timed function tests (TFTs), and quantitative strength using hand-held myometry]; (2) estimate the probability of clinically meaningful disease progression (defined as persistent 10% worsening in 6MWD) and evaluate baseline predictors of subsequent 10% worsening; and (3) assess the relationship between baseline 6MWD and future loss of ambulation.