Author Profile

Craig M. McDonald

Affiliation: Department of Physical Medicine and Rehabilitation, University of California, Sacramento, California, USA

Professor and Chair

Recent Posts

Duchenne Regulatory Science Consortium Meeting on Disease Progression Modeling for Duchenne Muscular Dystrophy

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Introduction: The Duchenne Regulatory Science Consortium (D-RSC) was established to develop tools to accelerate drug development for DMD.  The resulting tools are anticipated to meet validity requirements outlined by qualification/endorsement pathways at both the U.S. Food and Drug Administration (FDA) and European Medicines Administration (EMA), and will be made available to the drug development community. The initial goals of the consortium include the development of a disease progression model, with the goal of creating a model that would be used to forecast changes in clinically meaningful endpoints, which would inform clinical trial protocol development and data analysis. 

Methods: In April of 2016 the consortium and other experts met to formulate plans for the development of the model. 

Conclusions: Here we report the results of the meeting, and discussion as to the form of the model that we plan to move forward to develop, after input from the regulatory authorities.

Prednisone and Deflazacort in Duchenne Muscular Dystrophy: Do They Play a Different Role in Child Behavior and Perceived Quality of Life?

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The aim of this study was to determine whether prednisone and deflazacort play a different role in child behavior and perceived health related psychosocial quality of life in ambulant boys with Duchenne Muscular Dystrophy. As part of a prospective natural-history study, parents of sixty-seven ambulant boys with DMD (27 taking prednisone, 15 taking deflazacort, 25 were steroid naïve) completed the Child Behavior Checklist (CBCL) for assessment of behavioral, emotional and social problems and both parents and boys with DMD completed the PedsQL™4.0 generic core scale short form. Boys with DMD had higher rates of general behavioral problems than age-matched peers. No significant differences were found among the groups for any of the CBCL syndrome scales raw scores, including internalizing and externalizing behaviors; however, on average boys taking deflazacort demonstrated more withdrawn behaviors than those taking prednisone, while on average the boys taking prednisone demonstrated more aggressive behaviors than boys taking deflazacort. Age, internalizing and externalizing behaviors accounted for 39 and 48% of the variance in psychosocial quality of life for both parents and boys with DMD, respectively. Overall, the use of steroids was not associated with more behavioral problems in boys with DMD. As behavior played a significant role in psychosocial quality of life, comprehensive assessment and treatment of behavioral problems is crucial in this population.

The 6-Minute Walk Test and Person-Reported Outcomes in Boys with Duchenne Muscular Dystrophy and Typically Developing Controls: Longitudinal Comparisons and Clinically-Meaningful Changes Over One Year

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INTRODUCTION:

Data is currently lacking anchoring a 30-meter longitudinal change in walking ability by 6-minute walk test (6MWT) in Duchenne muscular dystrophy as a minimal clinically important difference and “clinically meaningful” person-reported outcomes (PROs) at differing levels of ambulatory ability.

METHODS:

We describe correlation between measures, 1-year change in measures, and correlation of 1-year changes between measures for the six-minute walk test (6MWT), 10-meter run/walk velocity, PedsQL and POSNA Pediatric Outcomes Data Collection Instrument (PODCI) in 24 4-12 year old. ambulatory DMD and 36 typical controls, and determine if minimal clinically important differences (MCID) of PROs contribute to different estimates of 6-minute walk distance (6MWD) change at differing levels of ability.

RESULTS:

PedsQL total and physical function and PODCI global, transfer/mobility and sports/physical function PROs demonstrated significant differences between DMD and controls (p<0.00001). In DMD, 6MWD and 10-meter run/walk velocity were correlated with PODCI domain scores, with the transfer/mobility scale showing the strongest relationship (r=0.79 and r=0.76). In DMD, 6MWD distance and 10-meter run/walk velocity weakly correlated with PedsQL domain scores. In DMD, 6MWD, 10-meter run/walk velocity, and PODCI global and transfer and basic mobility demonstrated significant one-year change and exceeded the amount of change representing MCID. In DMD, 6MWD change highly correlated with change in PODCI global and PODCI transfer/mobility scores (r=0.76 and r=0.93). PODCI global and PODCI transfer/mobility scales provided the best estimates of 6MWT performance. A “meaningful” 4.5 point change in a low PODCI transfer / basic mobility score of 30 to 34.5 was associated with a 5.6m 6MWD change from 150.3 to 155.9m. At PODCI levels closer to normative levels for healthy controls, the change in 6MWD distance associated with a “meaningful” change in PODCI scores was almost 46m.

DISCUSSION:

At lower levels of function, smaller increases in 6MWD result in meaningful change in quality of life (QoL) instrument scores. At higher levels of function, larger increases may be necessary to achieve the same QoL change score.

Percent-Predicted 6-Minute Walk Distance in Duchenne Muscular Dystrophy to Account for Maturational Influences

We recently described a modified version of the 6-minute walk test (6MWT) for Duchenne muscular dystrophy (DMD) based partly on the American Thoracic Society (ATS) guidelines. This measure has shown reliability, validity and utility as a primary outcome measure in DMD clinical trials. Because loss of muscle function in DMD occurs against the background of normal childhood growth and development, younger children with DMD can show increase in distance walked during 6MWT over ~1 year despite progressive muscular impairment. In this study, we compare 6-minute walk distance (6MWD) data from DMD boys (n=17) and typically developing control subjects (n=22) to existing normative data from age- and sex-matched children and adolescents. An age- and height-based equation fitted to normative data by Geiger and colleagues was used to convert 6MWD to a percent-predicted (%-predicted) value in boys with DMD. Analysis of %-predicted 6MWD data represents a method to account for normal growth and development, and shows that gains in function at early ages represents stable rather than improving abilities in boys with DMD. Boys with DMD from 4-7 years of age maintain a stable 6MWD approximately 80% of that of typically developing peers, with the deficit progressing at a variable rate thereafter.