Reevaluating measures of disease progression in facioscapulohumeral muscular dystrophy

Abstract

Recent advances in the understanding of the molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) have identified potential therapeutic targets. Consequently, an accurate understanding of disease progression in FSHD is crucial for the design of future clinical trials. Data from 228 subjects in 3 clinical trials and 1 natural history study were compared to examine disease progression in FSHD. All studies utilized the same techniques for manual muscle testing and maximum voluntary isometric contraction testing. Both techniques yield a total strength score that can be followed over time as an indicator of disease progression. Whereas natural history data showed a decrease in strength over 1 year, there was an apparent increase in strength at 6 months in 2 of the 3 clinical trials in both the placebo and treatment groups, that persisted for up to 1 year for maximum voluntary isometric contraction testing. Variability estimates from the clinical trial data were consistent with those seen in the natural history data. Patients in clinical trials in FSHD may have better outcomes than those in natural history studies, regardless of treatment assignment, emphasizing the importance of placebo groups and the need for caution when interpreting the strength results of controlled and uncontrolled trials.

Figure 1

A. Comparison of mean changes in composite strength scores among groups from the natural history study and the albuterol and MYO-029 RCTs. Results (mean ± standard error) are presented for composite MVICT score (left) and composite MMT score (right). B. Comparison of mean changes in composite MVICT scores among groups from the natural history study and the Dutch exercise/albuterol study. Results (mean ± standard error) are presented for subjects assigned to non-training (left) and training (right) compared to subjects in the natural history study. Alb = albuterol; MYO = MYO-029; NT = non-training; T = training

Figure 2

Progression of disease as measured by composite MVICT score (A) and composite MMT score (B) for 15 subjects entered in the natural history study (blue) that later participated in the albuterol RCT (pink=active, maroon=placebo). The slope is estimated from a linear mixed effects model (see text for details) and includes measurements up to the albuterol RCT baseline visit. The time scale on the X-axis is in relation to the baseline visit in the albuterol RCT (time zero). Alb = albuterol; CI = Confidence interval.