Long Term Natural History Data in Ambulant Boys with Duchenne Muscular Dystrophy: 36-Month Changes

Abstract

The 6 minute walk test has been recently chosen as the primary outcome measure in international multicenter clinical trials in Duchenne muscular dystrophy ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment, age and 6 minute walk test values at baseline. Ninety-six patients from 11 centers were assessed at baseline and 12, 24 and 36 months after baseline using the 6 minute walk test and the North Star Ambulatory Assessment. Three boys (3%) lost the ability to perform the 6 minute walk test within 12 months, another 13 between 12 and 24 months (14%) and 11 between 24 and 36 months (12%). The 6 minute walk test showed an average overall decline of −15.8 (SD 77.3) m at 12 months, of −58.9 (SD 125.7) m at 24 months and −104.22 (SD 146.2) m at 36 months. The changes were significantly different in the two baseline age groups and according to the baseline 6 minute walk test values (below and above 350 m) (p<0.001). The changes were also significantly different according to steroid treatment (p = 0.01). Similar findings were found for the North Star Ambulatory Assessment. These are the first 36 month longitudinal data using the 6 minute walk test and North Star Ambulatory Assessment in Duchenne muscular dystrophy. Our findings will help not only to have a better idea of the progression of the disorder but also provide reference data that can be used to compare with the results of the long term extension studies that are becoming available.

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

“…The previously reported age dichotomy15, 26 observed for the general DMD population was confirmed for the subpopulation of patients with genotypes amenable to exon skipping (see Fig 3A). Consistent with previous reports, patients <7 years of age showed improvement over the first 2 years of observation, followed by a decline (although remaining above the baseline value by 25m) between months 24 and 36.…”

“…It has been previously suggested that disease severity may be affected by mutation type,25 and multiple publications have demonstrated an age‐dependent change in disease trajectory, showing that when younger than 7 years, boys with DMD experience a steady increase in 6MWT distance, whereas boys aged ≥7 years experience progressive decline 15, 26. In the current study, the pooled historical control data set was analyzed to further elucidate the effect of mutation type and age on disease progression to further the field's understanding of DMD disease progression and to identify the most comparable patient subset for comparison to the eteplirsen‐treated cohort.…”

“…Patient‐level historical control data were provided by E.M. on behalf of the Italian DMD Registry database,26 and N.G 15…”

“…Given that there is no control group in the open label, long‐term extension study, eteplirsen's effect on disease progression as measured by 6MWT was evaluated by comparison to matched historical controls from 2 DMD natural history cohorts: the Leuven Neuromuscular Reference Center (LNMRC) and the Italian Telethon registry 15, 26. These 2 investigator‐initiated studies are the only DMD natural history data sets that have prospectively and consistently collected 6MWT assessments for a substantial number of patients for 36 months or longer.…”

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

“…Disrupted muscle NO signaling impairs muscle blood flow regulation in dystrophindeficient mice (27) and results in markedly exaggerated fatigue after exercise (28). Severe muscle fatigue is also a prominent feature of human DMD, and its improvement is considered an important clinical outcome for therapies, such that the 6-min walk test is an important endpoint for clinical trials in DMD (29). Despite growing appreciation of the physiological implications of disrupted muscle NO production, it remains unclear whether impaired nNOS activation in dystrophin-deficient skeletal muscle is a consequence of disrupted scaffolding of nNOS to the DGC, or whether the DGC acts as a mechanosensor in a mechanosignaling pathway that regulates nNOS activity.…”