Lead Investigator: Mark Peterson, Vertex Pharmaceuticals
Title of Proposal Research: Identifying and quantifying predictors of disease progression in common measures of physical function among boys with Duchenne Muscular Dystrophy (DMD)
Vivli Data Request: 5981
Funding Source: None
Potential Conflicts of Interest: Researcher is a full-time employee of Vertex Pharmaceuticals (Boston, MA), which is interested in developing therapies for Duchenne Muscular Dystrophy. Since the data sets requested from Vivli are focused primarily on natural history and disease progression in DMD, and not on evaluating the safety or efficacy of a competitor product, there is minimal risk of a conflict of interest affecting the proposed analyses.
Summary of the Proposed Research:
Duchenne Muscular Dystrophy (DMD) is a pediatric, neuromuscular, genetic disease marked by the progressive weakness and degeneration of skeletal muscles and cardiac muscles that causes gradual loss of ambulation (LOA), cardiopulmonary failure, and results in early death.
DMD is caused by genetic mutations that interfere with the production of the dystrophin protein normally found in skeletal muscles and cardiac muscles. Dystrophin plays an important role in muscle strength and helps to prevent muscle injury.
Because genetic mutations that cause DMD are found on the X chromosome, DMD affects primarily males. Females with similar genetic mutations usually do not have DMD. This study will therefore focus on males with DMD. There are approximately 10,000 males in the United States (US) with DMD, and it is estimated that 400 boys are born each year in the US with DMD.
To preserve muscle function, the current standard of care for DMD involves long-term systemic corticosteroids initiated at a young age. More recently, interventions such as antisense nucleotides (ASOs) and gene therapies have been proposed to restore partial dystrophin expression and improve muscle function.
ASOs are nucleic acid therapies that attempt to bypass some of the genetic mutations that cause DMD and allow patients to produce smaller amounts of dystrophin. Gene therapies are intended to provide a smaller version of the dystrophin protein (eg, mini- or micro-dystrophin) or to correct the genetic mutations that cause DMD and allow patients to produce some dystrophin themselves.
Early intervention is thought to be important to halting potentially irreversible muscle damage in DMD, making it critical to understand and model predictable disease progression from the time of onset of neuromuscular manifestations around ages 3 to 5 until complete LOA around ages 12 to 16.
The development of model structures to describe disease progression is necessary to provide quantitative constructs from which to make comparisons between changes observed in clinical trials of therapies for DMD and changes that may be expected in the absence of such therapies (ie, natural history of disease progression). Such knowledge and comparisons to changes observed in placebo groups of clinical trials or in non-interventional studies focused on natural history could reduce the need for patients with DMD to participate in future clinical trials with a placebo group.
Given the heterogeneity in measures of function during disease progression reported thus far in the DMD literature, a model-based approach may enable the quantification of disease progression, partition any variability observed into variation attributable to changes within the same patient over time (ie, intra-patient) and variation attributable to differences between patients (ie, inter-patient), providing an opportunity to reduce unexplained variability using predictive covariates.
Requested Studies:
A Prospective Natural History Study of Progression of Physical Impairment, Activity Limitation and Quality of Life in Duchenne Muscular Dystrophy.
Sponsor: CureDuchenne
Study ID: NCT01753804
Sponsor ID: PRO-DMD-01
An Exploratory Study to Assess Two Doses of GSK2402968 in the Treatment of Ambulant Boys With Duchenne Muscular Dystrophy
Sponsor: CureDuchenne
Study ID: NCT01462292
Sponsor ID: 114876
A Phase III, Randomized, Double Blind, Placebo-controlled Clinical Study to Assess the Efficacy and Safety of GSK2402968 in Subjects With Duchenne Muscular Dystrophy
Sponsor: CureDuchenne
Study ID: NCT01254019
Sponsor ID: 114044
A Phase II, Double Blind, Exploratory, Parallel-group, Placebocontrolled Clinical Study to Assess Two Dosing Regimens of GSK2402968 for Efficacy, Safety, Tolerability and Pharmacokinetics in Ambulant Subjects With Duchenne Muscular Dystrophy
Sponsor: CureDuchenne
Study ID: NCT01153932
Sponsor ID: 114117
A Study of Tadalafil for Duchenne Muscular Dystrophy
Sponsor: Eli Lilly and Company
Sponsor ID: H6D-MC-LVJJ