The Minimal Clinical Important Difference (MCID) in Annual Rate of Change of Timed Function Tests in Boys with DMD

Abstract

Background: Duchenne muscular dystrophy (DMD) is a rare x-linked recessive genetic disorder affecting 1 in every 5000–10000 [1, 2]. This disease leads to a variable but progressive sequential pattern of muscle weakness that eventually leads to loss of important functional milestones such as the ability to walk. With promising drugs in development to ameliorate the effects of muscle weakness, these treatments must be associated with a clinically meaningful functional change. Objective: The objective of this analysis is to determine both distribution, minimal detectable change (MDC), and anchor-based, minimal clinically important difference, (MCID) of 12 month change values in standardized time function tests (TFT) used to monitor disease progression in DMD. Method: This is a retrospective analysis of prospectively collected data from a multi-center prospective natural history study with the Cooperative International Neuromuscular Research Group (CINRG). This study calculated MDC and MCID values for 3 commonly used timed function tests typically used to monitor disease progression; supine to stand (STS), 10 meter walk/run(10MWT), and 4 stair climb(4SC). MDC used standard error of measurement (SEM) while MCID measurements used the Vignos scale as an anchor to determine clinical change in functional status. Results: All 3 TFT were significantly important clinical endpoints to detect MDC and MCID changes. MDC and MCID 12 month changes were significant in 10MWT(–0.138, –0.212), Supine to Stand (–0.026, –0.023) and 4 stair climb (–0.034, –0.035) with an effect size greater or close to 0.2. Conclusion: The 3 TFT are clinically meaningful endpoints used to establish change in DMD. MCID values were higher than MDC values indicating that an anchor-based approach using Vignos as a clinically meaningful loss of lower extremity abilities is appropriate to assess change in boys with DMD.

Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy

“…The differences in TTSTAND velocity (0.06 rises per second for vamorolone, 6 mg/kg per day, vs placebo and 0.05 rises per second for vamorolone, 2 mg/kg per day, vs placebo) were clinically meaningful (>0.02 rises per second). 13 The differences in 6MWT (42 m for vamorolone, 6 mg/kg per day, vs placebo and 37 m for vamorolone, 2 mg/kg per day, vs placebo) were also clinically meaningful (>30 m). 14 This trial also validated previous open-label findings of normal growth trajectories over an 18-month period 10 and 30month period 11 in vamorolone-treated boys with DMD.…”

Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy

“…These were considered as means across all follow-up visits after baseline and outcomes at the month 36 visit alone. Based on previous studies, the minimal clinically important difference was 0.023 rise/s for rise from the floor velocity, 0.212 m/s for 10-m walk or run velocity, and a distance of 28 m to 36 m for the 6-minute walk test . Other secondary efficacy outcomes included time from the baseline visit to disease milestones, including loss of ambulation (scored as unable [item 2] on the North Star Ambulatory Assessment) and loss of ability to rise from the floor.…”

A longitudinal study of creatine kinase and creatinine levels in Duchenne muscular dystrophy

“…28,30,33 Moreover, other markers, namely timed function tests, already have been shown in the literature to predict loss of ambulation. [34][35][36][37] Future studies could expand on our findings to elucidate the predictive or therapeutic utility of these biomarkers for assessing motor functional changes in patients with DMD. Specifically, changes in these biomarkers could be assessed against muscle mass imaging markers (eg, lean body mass changes on dual-energy X-ray absorptiometry scan), as well as more granular motor function assessment scales (eg, the North Star Ambulatory Assessment), or compared with functional motor outcomes that have been demonstrated to predict loss of ambulation.…”

“…There is inherent variability in these biomarkers, depending on time of day, exercise, and dietary intake 28,30,33 . Moreover, other markers, namely timed function tests, already have been shown in the literature to predict loss of ambulation 34–37 . However, CK, serum Cr, and especially urine Cr, when assessed for trend in individuals, can give the clinician and researcher a fuller picture of the individual's status.…”