Upper extremity outcome measures in non-ambulant Duchenne muscular dystrophy patients

Rationale:
Duchenne muscular dystrophy (DMD) is a rare X-linked inherited muscle disease
caused by mutations in the dystrophin gene. In muscles, the absence of
dystrophin leads to inflammation, fibrosis and irreversible replacement of
muscle tissue with fat. As a consequence, DMD patients suffer from progressive
muscle weakness. Their lower extremities (LE) are affected earlier in the
disease course than the upper extremities (UE), which leads to wheelchair
dependence around the age of 12, and loss of the ability to move the hand to
the mouth in the following, early non-ambulant phase. For patients in the
advanced non-ambulant stages of the disease, the preservation of minimal
functioning of hand muscles can have a significant impact on participation in
daily life, for example due to the ability to use electronic devices, such as a
phone or game console.

Currently, no full market-approved drug is available for DMD. However, several
drugs are being tested or planned to be tested in clinical trials, and some
have obtained conditional approval. Almost all of these trials have focussed on
ambulant boys. Although the conduction of placebo controlled trials has
appeared feasible, several major problems have been identified.
First, it is difficult to include sufficient patients per trial due to the
rarity of the disease. This is even more applicable for drugs targeting
specific mutations. Secondly, the regulatory agencies require the use of
outcome measures that are unequivocally related to daily life functioning.
Development of such outcome measures has taken many years in ambulant patients,
but has only started recently in the early non-ambulant phase, and is lacking
in the advanced stage of the disease. Thirdly, the natural history of the
disease was shown to be very variable, and understanding of the underlying
mechanism is lacking. Finally, as the replacement of muscle by fat is
considered irreversible, all drugs need sufficient remaining muscle tissue to
target. Therefore, extrapolation of results obtained in ambulant boys towards
later stages of the disease is not considered appropriate by the regulators.
As a result, there is an urgent need to develop objective biomarkers with a
clear relation to clinical endpoints in order to limit the duration of clinical
trials, and to reduce the numbers of required participants. Additionally, more
advanced techniques to quantify UE motor function may more objectively and
better relate to activities in daily life. Finally, it is necessary to document
the natural history of the disease in non-ambulant patients and to better
understand the underlying causes of its variability.

At present, quantitative MRI (qMRI) is considered the most promising biomarker
reflecting essential muscle pathology in DMD. qMRI has been feasible and
reliable even in children from the age of five. The most studied parameter is
muscle fat fraction (FF). In the LE, the complex relation between FF in the
many muscles involved and the main clinical endpoint at that stage, i.e. loss
of ambulation, is currently studied by international research collaborations.
In UE, the relation between FF and function is supposed to be less complex, due
to the smaller number of muscles involved. The Performance of Upper Limb (PUL)
motor scale and DMD upper limb patient-reported outcome measure (DMD Upper Limb
PROM) have been validated as outcome measures for UE function in multiple
natural history studies. Limitations of the PUL are a ceiling effect in the
upper and lower regions of the score and observer-dependence. Microsoft Kinect
and Leap Motion are two innovative systems that do not have these limitations,
and that could provide better quantification of UE motor function in daily
life. The automated score generation may be more easily applied in multicentre
trials.

Primary objective:
1. To study the relation between muscle FF and two major clinical endpoints in
different phases of the disease in non-ambulant DMD patients.

Secondary objectives:
2. To explore the use of Microsoft Kinect and Leap Motion in relation to the
validated PUL scale, DMD Upper Limb PROM, and muscle FF, in non-ambulant DMD
patients.
o To compare accuracy between the use of one or two Leap Motion
sensors and study the effect of occlusions on submaximal movements.
3. To define biological parameters and qMRI characteristics other than FF, such
as diffusion tensor imaging (DTI), contractile cross-sectional area (CSA) and
transverse relaxation time (T2) of muscle, in relation to the variability in UE
function and UE muscle FF in non-ambulant DMD patients.

Study design and methods:
This observational study will be conducted at the Leiden University Medical
Center (LUMC). Patients will be included in the following groups:
- DMD_AA: Able to move the hand to the mouth with a 200 gram (200g) weighing
cup (supporting elbow on table is allowed) and Able to play for 10 minutes on a
game console.
- DMD_UA: Unable to move the hand to the mouth with a 200g weighing cup
(supporting elbow on table is allowed), but Able to play for 10 minutes on a
game console.
- DMD_UU: Unable to move the hand to the mouth with a 200g weighing cup
(supporting elbow on table is allowed) and Unable to play for 10 minutes on a
game console.

Patients in group DMD_AA and DMD_UA will undergo qMRI of the right upper arm
and hand, Kinect, Leap Motion, and functional tests at baseline, 12 months, and
18 months follow-up. Patients in group DMD_UU will undergo the tests at
baseline and 12 months follow-up. Clinical follow-up to determine loss of
either biceps or thenar clinical endpoint will be done by telephone calls for a
maximum of 4 years. Fifteen healthy age matched controls are needed for
calibration of DTI and CSA values. Ten will undergo the qMRI and clinical
assessment only once at baseline. Five healthy controls, aged 18 years and
older, will have an MRI scan also at 12 and 18 months for MRI quality control.
For the primary objective, qMRI will yield FF data of the biceps and thenar
muscles. These will be fitted to a logarithmic model, after which the resulting
data is analysed in a survival analysis with time varying covariates, together
with the dates on which the clinical endpoint was reached. This Clinical
Endpoints Model (CEM) yields a hazard ratio.
For the second objective all functional test results will be correlated to DMD
Upper Limb PROM results and biceps and thenar FF at baseline. Moreover, the
association between change in functional tests scores and DMD Upper Limb PROM
scores, biceps and thenar FF over the 1-year and 6-months follow-up periods
will be evaluated.
The third objective will be analysed using linear regression analyses, in which
the different biological parameters and qMRI characteristics will be used to
explain variability in UE function (i.e. Kinect, Leap Motion and DMD Upper Limb
PROM results), and in biceps and thenar FF.

Nature and extent of the burden and risks:
This study has no invasive procedures. Subjects with contraindications for MRI
will be excluded. There are no known risks known associated with the use of
MRI, Kinect and Leap Motion or the applied functional tests. Participants have
no direct personal benefit from participating in this study. The data will
support the design of future clinical trials in non-ambulant DMD patients.