The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study

Abstract

Introduction: Duchenne muscular dystrophy (DMD) subjects ≥5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data (N = 57) provided insight into the natural history of the 6-minute walk test (6MWT) and other endpoints.

Methods: Evaluations performed every 6 weeks included the 6-minute walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand-held myometry.

Results: Baseline age (≥7 years), 6MWD, and selected TFT performance are strong predictors of decline in ambulation (Δ6MWD) and time to 10% worsening in 6MWD. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters. Only 1 of 42 (2.3%) subjects able to stand from supine lost ambulation.

Conclusion: Findings confirm the clinical meaningfulness of the 6MWD as the most accepted primary clinical endpoint in ambulatory DMD trials.

Keywords: 6-minute walk test; Duchenne muscular dystrophy; ambulation; dystrophinopathy; myometry; natural history; prediction of loss of function; timed function tests.

FIGURE 1

Change in strength for 5 strength measures by myometry obtained every 6 weeks for 48 weeks (mean ± SEM) in DMD patients (n = 57).

FIGURE 2

(a) Change in baseline time to stand from supine in seconds (mean ± SEM) for steroid-treated patients ≥7 years old (n = 32) and <7 years old (n = 6) with DMD over 48 weeks of evaluation. (b) Change in time to climb 4 stairs in seconds (mean ± SEM) for steroid-treated patients ≥7 years old (n = 34) and <7 years old (n = 6) with DMD over 48 weeks of evaluation. (c) Change in baseline time to run/walk 10 m in seconds (mean ± SEM) for steroid-treated patients ≥7 years old (n = 34) and <7 years old (n = 6) with DMD over 48 weeks of evaluation.

FIGURE 3

Relationship between percent change in 6MWD and percent change in 10-m run/walk test.

FIGURE 4

(a) Change in 6MWD over 48 weeks in 57 placebo-treated DMD patients. (b) Change in percent predicted 6MWD using age and height − calculated value over 48 weeks in 57 placebo-treated patients.

FIGURE 5

Change from baseline 6MWD in meters (mean ± SEM) over 48 weeks by baseline 6MWD level (<350 m vs. ≥350 m).

FIGURE 6

(a) 6MWD in meters (mean ± SEM) for all placebo-treated patients. (b) Percent predicted 6MWD (mean ± SEM) using age and height − calculated value for all placebo-treated patients. (c) Change in 6MWD in meters (mean ± SEM) for steroid-treated DMD patients <7 years old (n = 6) and ≥7 years old (N = 34). (d) Change in percent predicted 6MWD (mean + SEM) using age and height − calculated value for steroid-treated DMD patients <7 years old (n = 6) and ≥7 years old (N = 34).

FIGURE 7

(a) 6MWD in meters (mean ± SEM) for DMD patients <7 years old treated with steroids (n = 6) and steroid-naive patients (N = 8). (b) 6MWD in meters (mean ± SEM) for DMD patients ≥7 years old treated with steroids (N = 34) and steroid-naive subjects (N = 9).

FIGURE 8

Time to persistent 10% 6MWD worsening in 57 DMD patients. Note that the relative proportion of patients who reached the 10% progression milestone was constant over 48 weeks (26.3% patients declined 10% or more during the first 24 weeks; 23.8% of the remaining patients declined 10% or more from weeks 24–48).

FIGURE 9

(a) Kaplan–Meier analysis of time to 10% progression in 6MWD by time to stand for 3 groups (time to stand <4 s, 4 to < 8 s, and ≥8 s/cannot stand). (b) Kaplan–Meier analysis of time to 10% worsening in 6MWD by time to climb 4 stairs for 3 groups (time to climb 4 stairs <3 s, 3 to <6 s, and ≥6 s/cannot climb). (c) Kaplan–Meier analysis of time to 10% worsening in 6MWD by time to run/walk 10 m for 3 groups (10-m run/walk <5 s, 5 to <10 s, and ≥10 seconds).

FIGURE 10

(a) Kaplan–Maier survival for time to 10% progression on 6MWD for 3 groups, based on initial 6MWD (<325 m, 325 to <410 m, and ≥410 m). (b) Kaplan–Meier analysis of time to 10% worsening in 6MWD based on initial percent predicted 6MWD at baseline for 3 groups (percent predicted 6MWD <55%, percent predicted 6MWD 55% to <80%, and percent predicted 6MWD ≥80%).