6 Minute Walk Test validated as an outcome measure in DMD

http://ptct.client.shareholder.com/releasedetail.cfm?ReleaseID=533918

 

This is consistent with what some specialists in the field mentioned all along and justifies using 6MWT as an outcome measure in clinical trials for DMD.

 

Observational Data from One-Year Follow-up Study Validate Six-Minute Walk Distance as an Outcome Measure in Duchenne and Becker Muscular Dystrophy

SOUTH PLAINFIELD, NJ – December 1, 2010 – Data published in the December issue of the medical journal Muscle and Nerve confirm the utility of six-minute walk distance (6MWD) as a clinically meaningful endpoint in dystrophinopathy, a disease continuum comprising Duchenne and Becker muscular dystrophy (DBMD). The data showed that boys with DBMD experience a significant decline in walking ability compared to healthy boys over one year, suggesting that slowing the loss of walking ability is a major treatment goal. The observational study, which provides the first longitudinal natural history data reflecting changes in 6MWD in patients with DBMD, was conducted at the University of California-Davis, sponsored by PTC Therapeutics and funded in part by a grant from Parent Project Muscular Dystrophy (PPMD).

"The data from the observational study show that the 6-minute walk test is a clinically meaningful outcome measure of walking ability in patients with Duchenne/Becker muscular dystrophy. Progressive loss of walking ability is a major disease manifestation that significantly impacts a patient's quality of life," stated Stuart Peltz, Ph.D., President and CEO of PTC Therapeutics. "The study results support our understanding of recently reported results from a Phase 2b clinical trial of ataluren in nonsense mutation Duchenne/Becker muscular dystrophy. In addition, the critical information provided by this study will help inform the design of future clinical trials in this disorder."

The six-minute walk test (6MWT) was originally developed as an integrated assessment of cardiac, respiratory, circulatory and muscular capacity, and it has been used as a primary outcome measure to support the registration of treatments for other neuromuscular disorders. In a prior short-term study, the 6MWT was established as a feasible, safe and reliable outcome measure in boys with DBMD. Because the short-term study did not provide longitudinal data, it was extended to assess changes in walking ability over a longer period.

RESULTS FROM THE OBSERVATIONAL STUDY
The goal of the one-year study was to determine the ability of the six-minute walk test (6MWT) to detect changes in walking ability in boys with DBMD and compare it to healthy boys of similar age, height and weight. Participants included 18 boys with DBMD and 22 healthy boys who had participated in the prior short-term study. At baseline, all participants were required to be 4 to 12 years of age and capable of walking 10 meters or more without assistive devices.

At 52 weeks, boys with DBMD experienced a loss of 57 meters in mean 6MWD compared with an improvement of 13 meters in healthy boys. The difference in average change in 6MWD between the two study arms was 70 meters (p=0.037). The decrease in 6MWD observed in boys with DBMD is consistent with results from a recently-reported registration-directed Phase 2b clinical trial of the investigational new drug ataluren in nonsense mutation DBMD, which showed that patients treated with placebo (n=57) experienced an average loss of 43 meters in 6MWD over 48 weeks.

The validity of change in 6MWD as a measure of disease progression was supported by the age-related pattern of changes over time. At baseline, boys with DBMD had significantly reduced walking ability compared to healthy boys at baseline. Though the data showed that young boys with or without the disorder may show improvements in 6MWD, these gains appear to be eclipsed by disease progression in boys with DBMD at about 7 years of age.

The results suggested high variability in disease progression, as measured by the 6MWT, among boys with DBMD. In healthy patients, the variability (standard deviation of the mean change in 6MWD) was 40 meters at one year. For boys with DBMD, variability was 83 meters among those who maintained ambulation and 104 meters among all boys at one year. Two boys with DBMD lost independent ambulation during the study. One boy was 10 years old and walked only 125 meters at baseline and was not receiving corticosteroids. The other boy was 9 years old and began the study with a 6MWD of 350 meters and received corticosteroids throughout the study.

"The 6-minute walk test has rapidly become the primary endpoint of choice for therapeutic trials involving ambulatory boys with Duchenne/Becker muscular dystrophy worldwide and these findings provide the first important longitudinal findings that will assist in the optimal design of these trials," said Craig McDonald, M.D., principal investigator of the observational study of outcome measures in DBMD and director of the NIDRR-funded Rehabilitation Research and Training Center in Neuromuscular Diseases, University of California Davis. "Importantly, the results showed that development-related improvements in walking ability in younger boys with DBMD were overtaken by the progressive muscle disorder as they grew older. Despite age-appropriate increases in height and weight and prevalent corticosteroid use, boys with DBMD experienced a significant loss of walking ability over one year. Treatments that can slow or prevent this progression will be of tremendous benefit in this form of muscular dystrophy."

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Exactly what is the protocol of the 6MWT?
I believe it's just the distance you can walk in 6 minutes.
I believe that the importance of the 6MWT is undeniable, but it would be unfortunate if it is consecrated as a sort of gold standard, at least when defining things like expected reduction in the distance walked as compared with the placebo group. What happened with the Ataluren trials is proof of this; the trial was aborted ONLY because there was a shortfall of 30 cms (less than 12 inches) between the goal set by the designers of the trial and the walking distance that the boys on the low dose were able to walk after almost one year. This was done even when the 6MWT itself proved beyond doubt that the ability to walk among boys taking the low dose drug was remarkably more resilient than among the placebo group (I believe there was a 30 meter difference).

The fanatical adherence to one single rule without any consideration for other factors has meant in this case that approval of Ataluren for DMD will be delayed for who knows how long, when anyone realizes that the drug (at the low dose) appears to be a great success in at least slowing down the progression of the disease.

Bernardo

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