Sensitivity of Different Clinical Outcome Measures in Assessing Adults With Becker Muscular Dystrophy: A 3-Year Natural History Study

Abstract

Background and objectives: Slow and highly variable disease progression in Becker muscular dystrophy (BMD) stresses the need to develop sensitive outcome measures for clinical trials. We evaluated responsiveness of different outcome measures in adult patients with BMD over 3 years and explored if the sensitivity of outcome measures can be increased by selecting on phenotype or genotype.

Methods: Genetically confirmed patients with BMD were recruited via the Dutch Dystrophinopathy Database. Functional tests included North Star Ambulatory Assessment (NSAA), Timed Tests, Performance of the Upper Limb version 1.2, and pulmonary function yearly and echocardiography biennially. Mean changes and standardized response means (SRMs) were calculated per year. Outcome measures with SRM ≥0.80 were considered to have a high responsiveness to change. Two genetic subgroups-deletion of exons 45-47 and variants affecting the neuronal nitric oxide synthesis (nNOS) binding site-and one functional subgroup-NSAA between 10 and 32 at baseline-were analyzed separately.

Results: Thirty-six patients with BMD were included (mean age 41.2 years, range 18.6-67.3, 27 ambulant at baseline). A high responsiveness was observed for the rise from floor velocity (RFFv) at 3-year follow-up (SRM -0.91, n = 16), while the SRMs for the other outcome measures were <0.8 at all time points. In the functional subgroup, a high responsiveness was observed for RFFv at 1-year follow-up (SRM -0.82, n = 10), along with 4-stair climb velocity (4SCv) (SRM -1.03, n = 11) and NSAA (SRM -0.82, n = 13) at 2-year follow-up. Genetic subgroups did not significantly differ in age at loss of ambulation (LoA). Upper limb and pulmonary function were preserved beyond LoA. Decline of cardiac function was independent of skeletal muscle function.

Discussion: RFFv was the only outcome measure sensitive to change at 3-year follow-up. Selecting on phenotype resulted in a high responsiveness for RFFv at 1-year follow-up and for 4SCv and NSAA at 2-year follow-up. NSAA could be performed in more participants compared with RFFv and therefore seems preferable in clinical trials for ambulant patients. Despite limitations in sample size, the results suggest that clinical trials in the ambulant population could be enriched by selecting on phenotype.

Figure 1. Kaplan-Meier Plots of Age at First Symptoms, Diagnosis, and Loss of Ambulation for the Genetic Subgroups

Different colors indicate the groups of participants with a deletion of exons 45–47 (del 45–47) in green vs other pathogenic variants in yellow (A), those with a pathogenic variant predicted to affect the nNOS binding site (nNOS−) in red, and those with other pathogenic variants in blue (B). nNOS = neuronal nitric oxide synthesis.

Figure 2. Individual Disease Trajectories for RFFv, NSAA, and 4SCv

Different colors indicate the groups of participants with a deletion of exons 45–47 (del 45–47) in yellow vs other pathogenic variants in green (A), those with a pathogenic variant predicted to affect the nNOS binding site (nNOS−) in red, and those with other pathogenic variants in blue (B), and 3 groups based on baseline NSAA (C). A velocity of zero is assigned to participants who lost to ability to perform the test. 4SCv = 4-stair climb velocity; nNOS = neuronal nitric oxide synthesis; NSAA = North Star Ambulatory Assessment; RFFv = rise from floor velocity.

Figure 3. Longitudinal Cardiac, Pulmonary, and Upper Limb Function in BMD Patients

Panels A–C show individual trajectories of the PUL1.2 (A), LV GLS (B), and FVC%pred (C), colored by NSAA score at first measurement. Panel D shows LV GLS quantified using ultrasound in relation to NSAA score at the corresponding time point. Arrows indicate the trajectory from first to second measurement. BMD = Becker muscular dystrophy; FVC%pred = Forced Vital Capacity % predicted; LV GLS = left ventricular global longitudinal strain; NSAA = North Star Ambulatory Assessment.