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

PLoS One. 2020 Jun 18;15(6):e0232870. doi: 10.1371/journal.pone.0232870. eCollection 2020.

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.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Computer Simulation
  • Disease Progression
  • Exercise Test* / methods
  • Follow-Up Studies
  • Humans
  • Male
  • Muscular Dystrophy, Duchenne / diagnosis*
  • Muscular Dystrophy, Duchenne / drug therapy*
  • Muscular Dystrophy, Duchenne / physiopathology
  • Neuromuscular Agents / therapeutic use
  • Prognosis
  • Sample Size
  • Tadalafil / therapeutic use
  • Walking

Substances

  • Neuromuscular Agents
  • Tadalafil

Grants and funding

This study was conducted within the collaborative Trajectory Analysis Project (cTAP), a pre-competitive coalition of academic clinicians, drug developers, and patient foundations formed in 2015 to overcome the challenges of high variation in clinical trials in Duchenne muscular dystrophy. cTAP has received sponsorship from Astellas Pharma (Mitobridge), Catabasis, FibroGen Inc., Italfarmaco SpA, Pfizer Inc., PTC Therapeutics, Roche, Sarepta Therapeutics, Shire plc, Solid Biosciences, Wave Life Sciences, Parent Project Muscular Dystrophy, Charley’s Fund, and CureDuchenne, a founding patient advocacy partner and provider of initial seed funding to cTAP. Physical function testing at Universitaire Ziekenhuizen Leuven was funded by Fonds Spierzieke Kinderen. cTAP was involved in study design, analysis, manuscript preparation, and the decision to publish. James Signorovitch, Gautam Sajeev, Madeline Jenkins, Ibrahima Dieye, Zhiwen Yao, and Intekhab Hossain are employees of Analysis Group Inc., which received funding from the study sponsors via the Collaborative Trajectory Analysis Project (cTAP). David Cox and John Landry are shareholders and paid employees of Eli Lilly and Company. Susan J. Ward has received funding from the study sponsors via the Collaborative Trajectory Analysis Project (cTAP). The specific roles of these authors are articulated in the ‘author contributions’ section."