Ambulatory capacity and disease progression as measured by the 6-minute-walk-distance in Duchenne muscular dystrophy subjects on daily corticosteroids
Introduction
New developments in therapeutic approaches for Duchenne muscular dystrophy (DMD), moving into human trials, have exposed the urgent need for a better understanding of the contemporary natural history of this disease and the outcome measures currently used to assess therapeutic interventions [1].
Clinical trials for progressive and complex childhood orphan diseases such as DMD face specific challenges as efficacy of therapeutic interventions has to be assessed against the background of a decline affecting motor, cardiac and respiratory functions. The predictable clinical course of this disease has been altered by the use of corticosteroids, delaying loss of ambulation and decline of cardio-respiratory function [2], [3], [4], [5]. This treatment is considered as standard of care in ambulant DMD boys [6] and has to be integrated in the design of clinical trials. However, data are lacking on this modified disease evolution as measured by outcome measures currently used in trials. Moreover, inconsistency/variations in type of corticosteroids, dosage and regimen (daily, alternating days, 10 days on/off, weekly administration) across centres are an additional confounding factor in the interpretation of longitudinal data in the contemporary DMD population.
Most therapeutic approaches target the early stage of the disease, before muscle damage has evolved into an irreversible stage, underscoring the need for sensitive and reliable assessment tools to allow efficacy assessments of therapeutic intervention in the ambulatory stage of the disease. The 6-min walk test (6MWT), a measure of function and endurance has been accepted as a clinically meaningful outcome measure by the regulatory authorities in registration-directed clinical trials in neuromuscular and neurometabolic disorders [7]. A 6MWT adapted from the American Thoracic Society guidelines has been validated in DMD and is currently used as (primary) endpoint in therapeutic trials in ambulatory boys with DMD [8]. More recently, data are emerging on the evolution of this measure with time in heterogeneous cohorts of DMD boys outside clinical trials [9], [10], [11]. These data indicate that age and the stage of the disease influence the rate of decline and illustrate the heterogeneity in disease progression due to variability in phenotype and heterogeneity in corticosteroid treatment.
An additional challenge in the design of clinical trials of DMD and more specifically in trials with a specific gene-based approach, is the limited number of eligible patients available. The use of natural history cohorts as controls to assess the efficacy of interventions could palliate this issue. This underscores the need for additional data from large contemporary homogenous cohorts of steroid treated DMD to further understand the evolution and the variability of this outcome measure.
The aim of this study was to generate data on the contemporary natural history of DMD and to describe the clinical course and disease progression in the ambulatory stage of this disease by means of the 6MWT. For this purpose, we describe the 6-min-distance (6MWD) by age and its change over time in a homogenous population of steroid treated DMD boys receiving a similar standard of care in a single centre. We explore as well the 6MWD expressed in a percent predicted value, calculated using the age-height based Geiger equation, as proposed to account for growth and maturational influence [12], [13].
Section snippets
Participants
This study was an observational single centre cohort study reporting 6MWD collected as part of routine follow-up clinics from genetically confirmed and corticosteroid treated DMD boys attending the Leuven Neuromuscular Reference Center (NMRC) for clinical care and management.
All DMD subjects up to 17.5 years of age attending the NMRC between January 2007 and September 2012 were assessed for eligibility. Inclusion criteria were genetically proven diagnosis of DMD and being on chronic daily
Patient population
Sixty-five DMD subjects meeting the inclusion criteria were identified ranging from age 5.1 to 15.3 years with a mean age of 9.5 years.
All were on daily corticosteroids, with 90% of patients treated with deflazacort (DFZ). Patients that were initiated elsewhere on prednisone before joining follow-up at our NMRC (7%) were not changed from regimen, while a few patients (3%) switched from DFZ to prednisone in the course of their treatment. Glucocorticosteroids were started at a mean (SD) age of 6.8
Discussion
The aim of this study was to contribute to the understanding of the modified natural history of DMD in the context of corticosteroid treatment and to gain insights in the 6MWT, an outcome measure currently used as primary endpoint in registration directed trials, by reporting 6MWD from a homogenous cohort of corticosteroid treated DMD patients attending a single centre and receiving the same treatment and care.
Our study provides additional data on the age dependent biphasic pattern of evolution
Funding sources
NG was funded by the Clinical Research Foundation UZ Leuven, MvdH and AvI were funded by the “ Fonds voor Spierzieke Kinderen”. RW has a consultancy contract with Prosensa Therapeutics BV. GB is Senior Clinical Investigator of the Research Foundation-Flanders (FWO – Vlaanderen, Belgium).
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2020, Jornal de PediatriaCitation Excerpt :This can be observed in the 10MWT data, where the highest rate of progression occurs at the beginning of the second decade of life. Other authors, using data from the patients of previous studies,15,19–21 have developed models of DMD evolution, with potential improvement of the 6MWT up to 10 years of age, but with a subsequent rapid decline in performance. There have been few studies that described 10MWT or TR by age group.