Clinical Study to Establish Better Outcome Measures for Dysferlinopathy in Preparation for Trials


The central aims of the study are to better prepare for clinical trials by defining the best outcome measures for assessing how effective prospective therapies in dysferlinopathy are and to gain a stronger understanding of disease progression.

On a mission to cure muscular dystrophies caused by dysferlin protein deficiency—which includes Limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi Myopathy type 1 (MMD1) which are collectively called Dysferlinopathy—the Jain Foundation initiated, funded and has been heavily involved in the analysis of the Clinical Outcome Study for Dysferlinopathy (COS). The central aims of the study are to better prepare for clinical trials by defining the best outcome measures for assessing how effective prospective therapies in dysferlinopathy are, and to gain a stronger understanding of disease progression.

In an exclusive interview with Rare Disease Report® (RDR®), co-principle investigators at the University of Newcastle in the United Kingdom, Anna Mayhew, PhD, and Volker Straub, MD, PhD and Laura Rufibach, PhD, Co-President of the Jain Foundation, provide details regarding the initial COS study (COS1), what has been learned so far, and how COS1 laid the groundwork for the upcoming second international natural history study of dysferlinopathy, COS2.

Rare Disease Report®: Can you provide some background on the COS1 study?

Mayhew: The initial COS study (COS1) started in 2012 and continued through March 2018. The grant of about 2 and a half million pounds funded by the Jain Foundation, included funding for data management, magnetic resonance imaging (MRI), patient expenses, as well as the collection of the natural history data.

We didn’t have any disease-specific functional outcome measures to work with, so we took what was available, reviewed those, and used the best assessment for the study visits. The study included the collection of natural history data mainly related to functional outcome measures and measures of muscle strength, as well as the assessment of respiratory function in these patients. Even though respiratory function hasn’t been considered to be a major problem for these patients, we wanted to double check the impact of the disease on respiratory muscles.

We had a set of timed functional tests, some of which had a very functional relationship, such as the time it takes it to get out of a chair, walk 3 meters, turn around and sit back down again, and the 6-minute walk test, which has been used a lot in other neuromuscular trials.

The study visits also included a medical assessment, laboratory tests, electrocardiogram (ECG), echocardiogram, as well as a plethora of MRI outcomes. Most of these [measures] were conducted initially at the screening and baseline visits to establish a firm baseline assessment, especially for patients who weren’t used to doing these tests before. These initial visits were followed by a 6-month, 1 year, 2 years, and 3 years assessment. A lot of time went into designing standard operating procedures and training the physiotherapists to ensure everyone was trained regardless of whether staff changed.

In terms of recruitment, 209 dysferlinopathy patients were recruited. As it was very important to include those who were able to walk, as well as those who were no longer walking, the study had about 75% who were walking and 25% who were not walking. The study consortium included 15 sites with 5 of those being in the United States, eight in Europe, 1 in Australia, and 1 in Japan.

We now have a vast quantity of data collected for each patient over 3 years. However, we didn’t wait until the end of the 3 years to begin data analysis; we began to review baseline data early on. Since the study began, we have conducted a lot of analysis, and out of that analysis has come several publications that are very important to the community, including the baseline paper, a letter regarding exercise in this group, and evaluation of muscle MRI. There is still more data to be analyzed, as well as more publications to be prepared.

A very important outcome of the COS1 study is that we started off without a clear picture of which outcomes were best for assessing dysferlinopathy, and we now find ourselves with the opportunity to make good recommendations moving forward and are able to deliver to industry a set of outcome measures we think are most suitable for assessing if any treatment would be effective or not in dysferlinopathy.

How will the COS2 study take this research a step further?

Rufibach: The main objectives of COS2 are to validate the findings from COS1 through further evaluation of the current COS patients and the recruitment of new participants, to better understand the transition from ambulant to non-ambulant, refine subgroup characteristics, and identify early indicators/predictors of decline.

Mayhew: We made some important changes during COS1 because we felt some of our outcome measures were not quite up to scratch, and that was particularly true for some of the functional outcome measures. During COS1, we developed a new functional outcome measure called the North Star Assessment for Dysferlinopathy (NSAD)—which is designed to assess function in both ambulant and non-ambulant patients—which allows us to plot their progression even if they lose ambulation during the study. Therefore, one of the main purposes of COS2 is to further establish the responsiveness and suitability of this new outcome measure.

We also felt we hadn’t nailed other aspects, particularly patient-reported outcome measures and quality of life measures. COS2 gives us further opportunity to hone these types of patient-reported outcome measures, which are so important to regulatory authorities to establish and assure they measure what really matters to the patients.

How are you going to more effectively measure patient-reported outcome measures and quality of life measures in COS2?

Mayhew: At the time we started the COS project, there weren’t patient-reported outcome measures specifically for dysferlinopathy, so we used some already in existence. We have been pleased with the performance of some of these measures and for others not.

When we make decisions about what patient-reported outcomes measures to use, we make sure we involve patient groups and get the opinion of those affected by this disease, as well as clinicians. It’s important that a disease outcome measure—patient-reported or not—fits the purpose. It needs to be robust, it needs to measure things effectively, but most importantly, it needs to be clinically relevant. We have had very good feedback from the dysferlinopathy patient groups over the years about what works and what doesn’t, what is acceptable and what isn’t acceptable.

For COS2, we have spent a lot of time deciding whether we should develop something completely new or use something that is already in existence, but imperfect. We have decided to go with something already in existence. We’ve had some good collaborations with other groups in France that have developed neuromuscular-specific quality of life outcome measures that are specifically designed for slow-progressing neuromuscular diseases like dysferlinopathy that we think may be useful in assessing dysferlinopathy.

One of the other new things we are now putting into COS2 is a very focused care discussion with the patients. A large amount of attention has been given to the importance of standards of care for spinal muscular atrophy and Duchenne muscular dystrophy, which are much better-described conditions. Standards of care don’t currently exist for LGMD2B and Miyoshi Myopathy, but it is something we have our eyes on in the future. This care discussion will allow us to begin to benchmark what standards of care might look like for this patient population.

How will COS2 lay the groundwork for future clinical trials?

Straub: All of this really is for trial readiness—making sure there is a cohort of patients in this rare disease field to incentivize investors to look at drug development. While we won’t directly test any therapeutic intervention, there is interest in drug companies to use this cohort for drug development problems.

The potential of such interest is very exciting for us and the main incentive for the Jain Foundation. We can show potential drug developers we know how to assess these patients and we know what’s meaningful—that’s what this study is mainly about.

Rufibach: COS is already providing multiple benefits to the dysferlinopathy community and helping to prepare for clinical trials. The patient and clinical community is gaining a greater sense of purpose and momentum by being involved in and observing COS results.

Improving clinical trial design for dysferlinopathy will put the community in a strong position to ensure that a safe and effective therapy will make it all the way through the approval process. In addition, COS is magnifying interest from drug companies by eliminating uncertainties.

With the recent deal made between Myonexus and Sarepta for the further development of gene therapies for selected LGMD subtypes (including LGMD2B/dysferlinopathy), we anticipate that the data from COS will be mined repeatedly to ensure effective trial design.

What is the projected timeline for COS2?

Straub: We are currently hoping to get all the approvals in place to start within the next couple of months (late Fall 2018).

Rufibach: COS2 will evaluate 200 patients at 4 visits over 2 years using the best assessments from COS1 and the evaluation of some new assessments. The participants will include some individuals from COS1, as well as newly recruited individuals.

The 15 sites from 8 countries slated to be involved in COS2, subject to the finalization of regulatory and contractual approvals, are listed below along with their principal investigators:

  • Newcastle University, Newcastle upon Tyne, UK: Dr. Volker Straub
  • Nationwide Children’s Hospital, Columbus, OH: Dr. Jerry Mendell
  • Stanford University, Stanford, CA: Dr. John Day
  • Columbia University, New York, NY: Dr. Matt Harms
  • UC Irvine, Irivine, CA: Dr. Tahseen Mozaffar
  • Carolinas Medical Center, Charlotte, NC: Dr. Elena Bravvers
  • Washington University, St. Louis, MO: Dr. Alan Pestronk
  • Hospital Sant Pau, Barcelona, Spain: Drs. Jordi Díaz-Manera & Isabel Illa
  • University of Padova, Padova, Italy: Drs. Elena Pegoraro & Claudio Semplicini
  • Institut de Myologie, Paris, France: Dr. Tanya Stojkovic
  • Hospital Universitario, Sevilla, Spain: Dr. Carmen Paradas
  • National Center of Neurology and Psychiatry, Tokyo, Japan: Drs. Shin’ichi Takeda & Madoka Mori-Yoshimura
  • Clínica Dávila, Santiago, Chile: Dr. Jorge Bevilaqua
  • Hospital Universitario, San Sebastian, Spain: Dr. Roberto Fernandez Torron
  • Rigshospitalet, Copenhagen, Denmark: Dr. John Vissing

If you have patients you suspect have dysferlinopathy, or with whom you would like to share information about COS2 participation or membership in the Dysferlin Registry, please contact the Jain Foundation at

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