Lessons for future clinical trials in adults with Becker muscular dystrophy: Disease progression detected by muscle magnetic resonance imaging, clinical and patient-reported outcome measures

Abstract

Background and purpose: Because Becker muscular dystrophy (BMD) is a heterogeneous disease and only few studies have evaluated adult patients, it is currently still unclear which outcome measures should be used in future clinical trials.

Methods: Muscle magnetic resonance imaging, patient-reported outcome measures and a wide range of clinical outcome measures, including motor function, muscle strength and timed-function tests, were evaluated in 21 adults with BMD at baseline and at 9 and 18 months of follow-up.

Results: Proton density fat fraction increased significantly in 10/17 thigh muscles after 9 months, and in all thigh and lower leg muscles after 18 months. The 32-item Motor Function Measurement (MFM-32) scale (-1.3%, p = 0.017), North Star Ambulatory Assessment (-1.3 points, p = 0.010) and patient-reported activity limitations scale (-0.3 logits, p = 0.018) deteriorated significantly after 9 months. The 6-min walk distance (-28.7 m, p = 0.042), 10-m walking test (-0.1 m/s, p = 0.032), time to climb four stairs test (-0.03 m/s, p = 0.028) and Biodex peak torque measurements of quadriceps (-4.6 N m, p = 0.014) and hamstrings (-5.0 N m, p = 0.019) additionally deteriorated significantly after 18 months. At this timepoint, domain 1 of the MFM-32 was the only clinical outcome measure with a large sensitivity to change (standardized response mean 1.15).

Discussion: It is concluded that proton density fat fraction imaging of entire thigh muscles is a sensitive outcome measure to track progressive muscle fat replacement in patients with BMD, already after 9 months of follow-up. Finally, significant changes are reported in a wide range of clinical and patient-reported outcome measures, of which the MFM-32 appeared to be the most sensitive to change in adults with BMD.

Keywords: BMD; Dixon; magnetic resonance imaging; quantitative MRI; trial readiness.

FIGURE 1

Boxplots of percentage change in PDFF of all thighs (left) and lower leg muscles (right) of adults with Becker muscular dystrophy over 18 months. PDFF, proton density fat fraction.

FIGURE 2

Correlations between PDFF and clinical outcome measures at baseline. The grey areas around the regression lines are 95% confidence intervals. Quantitative strength measurements with dynamometry of the quadriceps and hamstrings muscle groups are correlated with the PDFF of the quadriceps and hamstrings muscle groups, respectively. All other clinical outcome measures are correlated with the total thigh muscles PDFF. Only domain 3 of MFM‐32 did not correlate significantly with PDFF. MFM‐32, Motor Function Measurement scale; PDFF, proton density fat fraction.

FIGURE 3

Patterns of fat replacement within thigh muscles of patients with Becker muscular dystrophy at baseline. The PDFF percentage is shown for each of the 17 thigh muscles on the y‐axis, with the x‐axis representing the length of the muscle in centimetres from proximal (left, negative) to distal (right, positive). The most voluminous slice of the muscle is centred at muscle length ‘0’ on the x‐axis to enable easy visual comparison of the same parts of muscles from patients with varying thigh lengths in one graph. Each coloured line represents an individual patient, consisting of about 50–250 individual PDFF measurements from all (2 mm thick) Dixon MRI slices covering that muscle. These lines were smoothed with a generalized additive model function with confidence intervals shown as grey bars around the lines, to aid in visual representation. Thigh muscles were grouped together according to similarities in the predominant observable fat replacement patterns: (a) muscles with more pronounced fat replacement distally, (b) muscles with more pronounced fat replacement proximally, (c) muscles with more fat replacement in their centre than at the origin/insertion (resembling a downward facing parabola) and (d) muscles with little coherence between patients and thus an ‘undefined’ pattern.