Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT01676077 |
| Other study ID # |
85750 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 2012 |
| Est. completion date |
March 2024 |
Study information
| Verified date |
July 2022 |
| Source |
Newcastle-upon-Tyne Hospitals NHS Trust |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The "Clinical Outcome Study for Dysferlinopathy" is being performed in centres in Europe (UK-
Newcastle; Spain- Barcelona, Sevilla; San Sebastian;Denmark, Copenhagen, Italy- Padova;
France- Paris,), USA (Charlotte, NC; Columbus, OH; St.Louis, MO, Stanford CA, Irvine CA and
Columbia NY), Chile (Santiago) Japan (Tokyo) and South Korea (Pusan). Oversight is provided
by Newcastle upon Tyne Hospitals Trust. Funding for this study is being provided by the Jain
Foundation, a non-profit foundation dedicated to finding therapies for
dysferlinopathies(LGMD2b/Miyoshi). The aim of this "Clinical Outcome Study" is to determine
the clinical outcome measures required for future clinical trials, characterize the disease
progression of dysferlinopathy and collect biological samples for the identification of
disease markers that are needed to non-invasively monitor the disease during clinical trials.
Without this information, effective clinical trials cannot be performed.
This study is recruiting a large number of genetically confirmed dysferlinopathy patients
aged 10 years or older, who are ambulant or non-ambulant. The study has reopened for a
further two years (COS2). Participants will be assessed at 4 further visits over 2 years via
medical, physiotherapy, and MRI/MRS assessments, as well as standard blood tests. Optionally,
the participants can donate blood samples and a skin sample for use in the identification of
disease markers and other approved research. There is a sub-study running in MRI at selected
sites.
Description:
Dysferlinopathy represents a rare group of muscular dystrophies, presenting a particular
challenge for the definition of natural history and "trial readiness". In the early days
after the cloning of the dysferlin gene, several papers described the clinical phenotype over
time of collections of patients leading to the recognition of the "core" phenotypes of
Miyoshi Myopathy (MM), LGMD2B and the rarer distal myopathy with anterior tibial involvement.
Most of these papers dealt with inbred populations with a limited number of mutations
represented. Subsequent studies have reported larger numbers of patients with outbred
mutations and extended the clinical spectrum to include onset as young as early childhood and
as late as old age, with a large group of patients in whom a clear distinction in their
pattern of muscle involvement into Miyoshi or LGMD was not possible, with involvement of both
the proximal and distal musculature in most patients, especially as the disease progresses. A
limitation of all of these studies however is that with few exceptions, again mainly in
inbred groups, long-term follow-up data are not presented and data on clinical progression
are collected in different ways making precise comparisons between their conclusions
difficult. Nonetheless, the studies overall are in agreement that dysferlinopathy is a
chronically progressive condition sometimes with periods where there is a plateauing of
muscle function, with variable age at wheelchair dependency and probably a low risk of
cardiac and respiratory complications compared to other types of muscular dystrophy.
Intriguing suggestions from these publications which require more systematic study include
the definition of a particularly good level of sporting prowess before the onset of symptoms
and the description of a subacute onset with muscle pain and swelling, both features, if
better understood, that potentially could help in our understanding of the pathogenesis of
the disease.
Recently, two as yet unpublished studies have addressed the topic of charting the natural
history of dysferlinopathy more systematically. In a study of 9 genetically confirmed LGMD2B
and MM patients studied over 18 months, Isabel Illa and colleagues found a significant
decline in muscle strength in a set of muscle groups measured by manual muscle testing, and
in knee flexion measured by quantitative muscle testing, accompanied by a detectable
deterioration on MRI imaging in biceps femori and tibialis posterior. Maggie Walter and
colleagues assessed the natural course of disease and efficacy of deflazacort treatment in 25
patients (between 25 and 63 years of age) with genetically confirmed dysferlinopathy in a
double-blind, cross-over trial. During the first year of the study, they assessed the natural
course of disease in 6-month intervals, evaluating MRC scores, quantitative strength
measurement by hand-held dynamometry (Citec, Groningen, Netherlands), and torque measurement
(M3 diagnose system, Fa. Schnell, Germany), Neuromuscular Symptoms Score (NSS), Timed
Function Tests (getting up from lying and sitting position, climbing 4 stairs, running 10m),
Vignos Scale, Hammersmith Motor Ability Score, and Global Assessment CGI Scale, quality of
life SF-36 scale and laboratory parameters (sodium, potassium, creatinine, urea, GOT, GPT,
gamma-GT, CK, blood count, ESR, CRP). Medication (placebo or deflazacort in a cross-over
design) was only started in the 2nd year of the study. All patients showed a decline in
muscle strength over one year, which was reflected in the tests performed.
It is reassuring that from these data we can conclude that it is likely that there will be
changes detectable with time in dysferlinopathy that could inform the design of future
clinical trials, but the optimal measurements have yet to be defined and mapped in a much
larger group of dysferlinopathy patients representing the entire clinical spectrum of this
diverse disease group. Extrapolating from the requirements for studies in other types of
muscular dystrophies, including the regulatory advice for establishing pivotal trials of
therapies in these disorders, these measures would need to include not only measures of
muscle strength, but also of function and some degree of patient reported outcomes. The
unpublished results of Isabel Illa and colleagues, as well as another small study of MRI in
dysferlinopathy, also show some hope for the use of MRI as a measure of change in muscle over
time which might be applicable as an outcome measure. Up until now, muscle MRI has been seen
more as a tool for delineating the pattern of muscles involved than for monitoring change -
the use of MRI for monitoring disease progression in a non-invasive manner is however
attracting a lot of current interest, though more study is needed especially in respect of
functional correlates and patient relevance.
The frequency of dysferlinopathy provides a further challenge to the collection of natural
history data. The relative frequency of different forms of muscular dystrophy depends to a
certain extent on the population studied. Dysferlinopathy appears to be a more common cause
of LGMD in Southern European populations than in Northern European ones. Founder mutations
exist in only a few small communities. There is little doubt that dysferlinopathy is
under-diagnosed and, in fact, the clinical diagnostic process by which dysferlinopathy is
diagnosed is also variable. Most laboratories still rely on the suggestion of the diagnosis
by muscle immunocytochemistry or (more reliably) immunoblotting. Some laboratories carry out
protein testing on monocytes as an alternative screening methodology. The gold standard for
dysferlinopathy diagnosis has however become DNA testing, with sequencing carried out in a
small number of commercial laboratories as well as a series of diagnostic laboratories in
Europe and the USA. The Jain Foundation (www.jain-foundation.org) can help guide those who
are unsure about their diagnosis through the process of getting a genetic analysis. Please
contact Sarah Shira at the Jain Foundation for help with diagnosis at +1 425 882 1492
With the perspective of different approaches to therapy in dysferlinopathy, a clearer
definition of the natural history of the disease and the delineation of suitable outcome
measures for clinical trials needs to be prioritised. The current protocol builds on existing
national and international networks to bring together a critical mass to address the
following specific aims:
1. To define the natural history of Dysferlinopathies with respect to age and nature of
onset, progression and presence of complications.
2. To determine the most suitable and robust outcomes measures for evaluation of disease
progression in patients with Dysferlinopathy at different stages of the disease.
3. To evaluate whether cardiac manifestations are clinically significant in patients with
Dysferlinopathy.
4. To explore if sodium MRI could be useful to identify muscle damage on skeletal muscle of
patients with Dysferlinopathy
