A Prospective Natural History Study of the Progression of Physical Impairment, Activity Limitation and Quality of Life in Duchenne Muscular Dystrophy (DMD)

Duchenne Muscular Dystrophy (DMD) is an inheritable (X-chromosome linked)
lethal childhood disease with an incidence of approximately 1 in 3,500 newborn
boys (Emery, 1993). DMD is caused by alterations in the gene coding for the
protein dystrophin which leads to little or no dystrophin being produced.
Dystrophin is essential for the integrity and functioning of muscle fibres
(Hoffman EP, 1988).
First signs of muscle weakness typically occur before the age of 4 years and
gradually progress to include skeletal muscles in the arms, legs and trunk.
Over time, heart muscle and respiratory muscles are affected.
Even with more recent clinical interventions, such as glucocorticosteroid
treatment and ventilatory support, DMD patients are usually wheelchair-bound by
their mid-teens and generally die in their twenties/early thirties.
Although specific treatments for DMD have not reached the clinic yet, the
natural history of the disease has been changed by targeting known
manifestations and complications. Specifically, corticosteroid, respiratory,
cardiac, orthopaedic and rehabilitative interventions have led to improvements
in function, quality of life, health and longevity. There will be further
advances and more effective treatment of the underlying pathology of DMD,
currently exon skipping with AONs seems to be the most promising.
In order to assess the clinical effectiveness of specific treatments it is
vital to understand how the commonly used evaluations of DMD change over time
as the boy grows and develops. Also, as treatments are developed for the rarer
exon mutations, the number of boys that can be included in clinical trials will
become very small and so reference to the natural history of the disease will
be important in the bid to understand whether an intervention is effective or
not.
A variety of outcome measures are in current use in ambulant and non-ambulant
DMD boys. Outcome measures in ambulant boys which give high test-retest
correlations include the 6 minute walking distance test (6MWD), timed
functional tests (10 m walk/run, stair climb, stair descend and supine to
stand) and muscle strength testing using hand-held myometry. Outcome measures
in non-ambulatory boys have been less well studied and developed and include a
variety of functional scales and measures of Quality of Life as well as
assessments of upper limb muscle strength with myometry and also pulmonary
function testing. In order to develop the most meaningful outcome measures it
is important to understand how the measures change as the child grows and ages
and these changes translate into quality of life. It will also be possible to
study of the value of the outcome measures in predicting life altering events,
such as the loss of independent ambulation. There are further novel
developments on the application of serum biomarkers as an outcome, such as
MMP-9, TIMP-1 and miRNA*s which appear to correlate with disease progression.
Finally, clinical trials in DMD patients require careful monitoring for safety,
but many of the common blood parameters are not validated for DMD patients, in
particular those related to inflammation, liver and kidney function. This study
provides the opportunity to gain comprehensive background data essential for
safe clinical trials in this population at a low burden.
Therefore the main purpose of this prospective natural history study is to
expand the study of various outcome measures, particularly those for
non-ambulant boys and those in younger boys. The information gained will in
turn inform the design of future clinical trials.
The aim of the design of this protocol has been to minimize as far as possible
the burden for each subject in participating in this study. The evaluations
proposed do not differfrom those that are commonly used in DMD clinics in
Europe and the USA. The intention is to gather more data on all of the
measures in a natural history setting in order to contribute to the ongoing
global efforts towards a consensus on the best measures to use to evaluate the
progression of DMD.

•To characterize the natural history and progression of DMD to help inform the
design of future studies
•To capture biomarkers of safety and disease progression
•To provide comparative data for the development of rare exons for which formal
controlled trials are not feasible

This is a prospective study. All DMD patients that fulfil the
inclusion/exclusion criteria are eligible although the study is weighted
towards ambulant subjects aged 3 years or older. There will be 7 study visits
- baseline, then at 6, 12, 18, 24, 30 and 36 months.
Subjects will be in the study for a maximum of 3 years.

Evaluations (for a schedule of procedures at each site visit: please see
protocol appendix 1):

Completion of these evaluations will depend on age and ambulancy of the
individual subjects:

For the ambulatant subjects at each visit:
•6 minute walking distance (6MWD) + accelerometry in centres where Locometrix
is available
•Patient reported outcomes questionnaire - DMD FOS
•North Star Assessment
•Timed tests i.e. rise from floor, 10m walk/run, stair climb

In addition, for the very young subjects, ages 3 to approximately 5 yrs, there
will likely be an assessment of their development and motor skills using an
appropriate test or tests. The test/s to be used will be specified prior to
recruitment of subjects aged 3-5 yrs.

For the non-ambulant subjects at each visit, measures to include:
•Egen Klassification - measures functional ability (transfer, standing etc)

For all subjects:
•Myometry - to measure muscle strength - at each visit
•Goniometry - to measure range of movement - at each visit
•Myotools i.e. moviplate, pinch and hand grip in centres with the equipment and
training - at each visit
•Blood sampling at 4 time points: baseline, 12, 24 and 36 months (or when
subject leaves the study). The samples will be frozen and stored at the central
lab for future analysis. Some biomarkers from the following list will be
measured in the samples; MCP-1, Complement Factor C3, IL-6, CRP, cystatin C,
E-selectin, ppVWF, GLDH, MMP-9, TIMP-1, micro RNAs.
•Urinalysis sampling at 4 time points i.e. at baseline then at 12, 24 and 36
months or when subject leaves study if before 24 months: glucose, albumin,
protein, cystatin C, alpha1 microglobulin, KIM-1.
•ECG - if done at site, then it will be requested that the data is entered into
theeCRF
•Echocardiogram - if an ECHO is done at site it will be requested that the data
is entered into the eCRF
•Spirometry (FVC, FEV1, PCF and PF) - if done at site it will be requested that
the data is entered into the eCRF
•Sniff pressure test (SNIP) - where required equipment is at site
•DEXA - if done at site it will be requested that the data is entered into the
CRF
• Pulmonary function (appr. twice a year)
• PROM questionnaire (to asses ability to perform daily life activities)
• Performance Upper Limb

For all subjects at each visit:
•Asked about concomitant medication
•Assessment of illness/missed days at school/falls etc
•Assessment of *procedure related* events
•Vital signs
•Weight, height and BMI
•Physical examination including major events notable for disease progression
•Assessment of other treatments and/or hospital visits since last visit e.g.
physiotherapy, surgery

The aim of the design of this protocol has been to minimize as far as possible
the burden for each subject in participating in this study.
The evaluations proposed do not differ from those that are commonly used in DMD
clinics in Europe and the USA and the visits are in line with routine patient
management.
Some subjects, at some visits, may find it difficult to undertake/complete
particular tasks as specified in the protocol. In these cases, the Investigator
is asked, where appropriate, to enter any data generated and to record the
reasons why the subject has not been able to undertake or complete the task in
the e-CRF.
The intention is to gather more data on all of the measures in a natural
history setting in order to contribute to the ongoing global efforts towards a
consensus on the best measures to use to evaluate the progression of DMD.