Individualized trajectories of upper arm disease progression in Duchenne muscular dystrophy patients

Duchenne muscular dystrophy (DMD) is a rare, progressive neuromuscular disorder
that primarily affects boys and men due to recessive X-linked mutations in the
dystrophin gene, which results in progressive degeneration of the muscle
fibers, with fibrosis, fat replacement and eventually atrophy of the muscles.
The clinical course of DMD is characterized by progressive muscle weakness and
cardiac and/or respiratory failure eventually cause a premature death.

To date, no medicinal products have received full marketing authorization for
Duchenne. Several antisense oligonucleotide (AON) mediated exon skipping
therapies are currently being studied with systemic dosing, mainly in ambulant
DMD patients. In the LUMC, new preclinical research is focused on another
delivery method of therapy for DMD patients: intramuscular injections. Firstly
because so far, results of systemic delivery of AONs have been limited due to
relatively poor delivery of AONs to target tissues. The proof-of-concept
studies with local intramuscular AONs (AVI-4658 and PRO051) showed safe and
induced dystrophin synthesis. Based on these promising results, the exon-skip
group from prof. dr. Annemieke Aartsma-Rus (Human Genetics, LUMC) is currently
working on optimal dosing and frequency of intramuscular injections of AONs in
animal models. Secondly because local therapy would reduce the risk of
off-target effects. The research group of prof. dr. N. Geijssen (Anatomy and
Embryology, LUMC) is working on a novel intramuscular CRISPR-Cas9 endonuclease
therapy with an unique way of delivery by the method of iTOP.

The aim of both approaches is the development of a therapy using local
intramuscular injections in selected muscles with the goal to preserve muscle
function. To overcome the lack of treatment development in non-ambulant
patients we aim to design a clinical trial targeting the elbow flexor (EF)
muscles.

To be able to measure response to local intramuscular therapy, careful
characterization of the natural history of the disease in the EF muscles, using
relevant biomarkers, in relationship to function, is needed in younger and
ambulant patients to expand previous findings. Moreover, longitudinal
trajectories are needed to determine the *window of opportunity* for treatment
of the EF muscles and to help us to determine the inclusion- and exclusion
criteria for prospective trials. Finally, as the trial is envisioned to be a
self-controlled trial, data about the symmetry between the trajectories of both
EF muscles (left vs. right) are needed.

Main objective
1. To assess the longitudinal trajectories of upper arm flexor muscle MRI
parameters, muscle force and upper arm function in a cohort of ambulant and
non-ambulant DMD patients, to assess the value of this muscle as target for
intramuscular therapy.

Secondary objectives
2. To assess (establish) the relation of these trajectories to a major disease
milestone, ie the loss of hand to mouth movement.
3. To assess the relationship between arm function and patient*s perspective on
performance of activities of the daily living and experienced health related
quality of life.
4. To assess the annual decline of each parameter for both the left and right
arm, to substantiate the feasibility of a self-controlled trial design.
5. To define the inclusion and exclusion criteria and primary endpoint for
participants in the self-controlled trial.

The study design of this study is an observational, prospective cohort study
and will be conducted at the LUMC. Patients will undergo a MRI of both upper
arms, functional tests (by hand-held-dynamometry (HHD), Biodex, Myotools and
assessment of the Performance of the Upper Limb (PUL)), the functional
questionnaire *DMD upper limb patient-reported outcome measure (PROM)* and the
QoL questionnaire *PedsQL Neuromuscular* at baseline, 6 months, 12 months and
24 months follow-up. Clinical follow-up will be done by telephone calls every
six months to determine if the elbow flexor endpoint has been reached and to
assess the PROM upper limb DMD.

For every included study patient under treatment at the LUMC, we will try to
incorporate the study visits in the in their (yearly) routine follow-up visit
at the hospital as much as possible. Their routine visit will then be
lengthened with roughly 2 hours to undergo the MRI examination, functional
assessments and questionnaires. Several functional tests mentioned above are
already part of their routine follow-up visits, except the measurements by the
Myotools and Biodex. For every included study patient under treatment at
another hospital, we will ask the study patients to visit the LUMC
independently from their routine follow-up visits. We expect their visits to
take up a maximum duration of 2,5 hours (including short breaks and time for
reposition).

The maximum duration of follow-up is 4 years. The physical follow-up ends for
each patient after the 24 month follow-up visit. The study will be ended when
all patients have finished their telephonic follow-up.

This study has no invasive procedures. Subjects with contraindications for MRI
will be excluded. There are no known risks associated with the use of MRI or
the functional tests (HHD, Biodex, Myotools, PUL2.0). The burden for each
participant (and his parents) will consist of roughly 1,5 - 2,5 hours per study
visit (at 0, 6, 12 and 24 months), and a maximum of five telephonic follow-up
calls, with a maximum duration of 15 minutes. Participants have no direct
personal benefit from participating in this study. However, the results of this
study will support the design of a future clinical trial for a new local
intramuscular therapy for Duchenne patients.