Prognostic factors for changes in the timed 4-stair climb in patients with Duchenne muscular dystrophy, and implications for measuring drug efficacy: A multi-institutional collaboration

Abstract

The timed 4-stair climb (4SC) assessment has been used to measure function in Duchenne muscular dystrophy (DMD) practice and research. We sought to identify prognostic factors for changes in 4SC, assess their consistency across data sources, and the extent to which prognostic scores could be useful in DMD clinical trial design and analysis. Data from patients with DMD in the placebo arm of a phase 3 trial (Tadalafil DMD trial) and two real-world sources (Universitaire Ziekenhuizen, Leuven, Belgium [Leuven] and Cincinnati Children's Hospital Medical Center [CCHMC]) were analyzed. One-year changes in 4SC completion time and velocity (stairs/second) were analyzed. Prognostic models included age, height, weight, steroid use, and multiple timed function tests and were developed using multivariable regression, separately in each data source. Simulations were used to quantify impacts on trial sample size requirements. Data on 1-year changes in 4SC were available from the Tadalafil DMD trial (n = 92) Leuven (n = 67), and CCHMC (n = 212). Models incorporating multiple timed function tests, height, and weight significantly improved prognostic accuracy for 1-year change in 4SC (R2: 29%-36% for 4SC velocity, and 29%-34% for 4SC time) compared to models including only age, baseline 4SC and steroid duration (R2:8%-17% for 4SC velocity and 2%-13% for 4SC time). Measures of walking and rising ability contributed important prognostic information for changes in 4SC. In a randomized trial with equal allocation to treatment and placebo, adjustment for such a prognostic score would enable detection (at 80% power) of a treatment effect of 0.25 stairs/second with 100-120 patients, compared to 170-190 patients without prognostic score adjustment. Combining measures of ambulatory function doubled prognostic accuracy for 1-year changes in 4SC completion time and velocity. Randomized clinical trials incorporating a validated prognostic score could reduce sample size requirements by approximately 40%. Knowledge of important prognostic factors can also inform adjusted comparisons to external controls.

Fig 1. Study design.

Changes in timed 4-stair climb (4SC) were evaluated over approximate 1-year follow-up intervals (8–16 months). 4SC, 4-stair climb; BMI, body mass index.

Fig 2. Power to detect a treatment effect of 0.25 stairs/second with and without adjustment for prognostic score under different trial arm sample sizes, assuming the SD of Δ4SC velocity is 0.6.

Δ4SC, annualized change in 4-stair climb; SD, standard deviation. Δ4SC velocity = (4SC velocity at outcome visit - 4SC velocity at baseline visit)/ time in years between outcome and baseline visits. Δ4SC velocity > 0 indicates improved performance; Δ4SC velocity < 0 indicates worsened performance. R-squared due to prognostic model assumed to be 0.35 in all scenarios. While a SD of Δ4SC velocity of 0.6 was used for this illustration, a similar pattern of greater power to detect a treatment effect when adjustment is made for the prognostic score also holds for lower and higher SDs of Δ4SC velocity (S3 and S4 Figs).