Imaging Muscle Performance during ACtion to guide Therapy

Spinraza has been recently approved as the first drug ever to treat patients
with SMA. The current pipeline and encouraging results from several phase 1-2
studies suggest that in the coming years multiple other drugs will become
available. A major challenge we now face is the lack of sensitive outcome
measure that can detect early effects of usually very expensive treatment and
provide patients with a personalized treatment approach. We hypothesize that
the IMPACT-platform is a sensitive tool to capture early effects of
pharmacological treatment in patients with SMA

The development and validation of the IMPACT-platform, a diagnostic 7T-imaging
platform of dynamic exercise to determine early effects of pharmacological
treatment on motor unit recruitment and ATP metabolism in arm muscles of
patients with SMA by using 31-Phosphorus Magnetic Resonance Spectroscopy (31P
MRS).

Longitudinal observational cohort study

Subjects will visit the UMCU 5 times, in the spinraza cohort 4 visits and in
the Pyridostigmine cohort 2 visits will be planned to coincide with
regular/ordinary check-up visits to the outpatient clinic of the Spieren voor
Spieren Children*s Center or department of Neurology. Patients will be asked to
perform one practise test outside the scanner and three arm exercise tests
within the scanner in total.
Subjects will fill out a questionnaire about functional status, physical
activity level and fatigue at home three times during the study. Data
concerning anthropometrics, motor function and muscle strength will be obtained
where possible from standard care physical therapy assessments or additionally
assessed by the researcher. Standard care comprehends multidisciplinary
examination 2-4 times per year including similar motor function tests, muscle
strength assessments and questionnaires which generally takes about 3 hours.
The SMA expertise center in the UMCU is the national referral center for
patients with SMA with regards to treatment and trial participation. Patients
from all parts of the Netherlands visit the UMCU 1-4 times a year. 31P
MRS is a safe and reliable technique for subjects without
contra-indications for undergoing MRI and is widely used in clinical
examination and scientific research to non-invasively obtain in-vivo
measurements of the concentrations of phosphorus-containing metabolites in the
human body. A comparable ongoing study report no AEs and good feasibility (METC
nr. 17/776). Patients included in this study will have no contra-indications
for performing an exercise at maximum intensity and they will be screened for
contra-indications before undergoing MRS examination. To ensure safety and
feasibility, the IMPACT-protocol will be extensively pilot-tested in healthy
subjects according METC-protocol nr. 15-466. After successful field-testing in
healthy subjects, two patients with SMA will be included for field testing. The
criteria of the Nederlandse Vereniging voor Kindergeneeskunde (Dutch
association of Paediatrics) concerning research involving children will be
strictly applied. Subjects will not experience direct benefits by participating
in this study. However, by the end of this study, patients and clinicians will
gain more insight in the early effects of pharmacological treatment which will
help them to decide about treatment possibilities.