An Observational Study in Participants with Ryanodine Receptor 1-Related Myopathies (RYR1-RM) to Determine Optimal Endpoint Measurements.

Ryanodine receptor isoform 1-related myopathies (RYR1-RM) are rare, slowly
progressive neuromuscular
diseases. They are the most common class of congenital myopathies caused by
pathogenic variants in the ryanodine receptor
isoform 1 (RYR1) gene and encompass a heterogeneous spectrum of
histopathological and clinical subtypes. The RYR1-gene
encodes a major skeletal muscle Ca2+ release channel - RyR1. RyR1 is embedded
within the sarcoplasmic reticulum membrane
of skeletal muscle and is a critical component needed for effective skeletal
muscle excitation-contraction coupling. Mutations
within the RYR1 gene result in chronic Ca2+ leak from the sarcoplasmic
reticulum and primarily impair excitation-contraction
coupling. Chronic Ca2+ leak into the sarcoplasm may lead to increased
mitochondrial-related oxidative stress, RyR1 channel
oxidation, cellular injury, leading to myopathy. Affected individuals present
with mild to severe symptoms ranging from
delayed motor milestones, proximal muscle weakness, hypotonia, impaired
ambulation, joint contractures, and fatigue to
scoliosis, ophthalmoplegia, and respiratory involvement. Although RYR1-RM has
been associated with significant morbidities
and early mortality, there is currently no approved treatment for this
debilitating condition. Thus, there is a clear unmet need
for therapies to treat RYR1-RM. Rycals® are a novel class of Ca2+ channel
stabilizers that are currently in clinical development.
A RyR1 binding site was identified where the Rycal compound, ARM210 (S48168)
binds cooperatively with adenosine
triphosphate (ATP), stabilizes the closed state of the channel and prevents
pathological pore opening. ARM210 (S48168) is
expected to be a disease-modifying therapy for RYR1-RM patients whose only
defect is leaky RyR1. ARM210 (S48168) has
completed Phase I clinical studies in healthy volunteers. ARM210 (S48168) is
safe and well tolerated in single and multiple
dose studies and has now been tested in 7 patients with RYR1-RM. Before
progressing to Phase II there is a need to define
appropriate endpoints. This non-interventional study plans to provide evidence
to support the optimal endpoints for a Phase II
study.

Primary objective
* To determine the extent to which muscle strength is affected in patients with
RYR1-RM with autosomal dominant
mutations and describe measurements over time.

Secondary objectives
* To determine the extent to which fatigue and physical function is affected in
patients with RYR1-RM with autosomal
dominant mutations.
* To describe the demographic and clinical characteristics of patients with
RYR1-RM with autosomal dominant
mutations in the real-world setting.

Exploratory objective
* To evaluate the Syde® device for use in patients with RYR1-RM with autosomal
dominant mutations

This is an observational, prospective, multi-centre study to assess muscle
strength in participants with RYR1-RM with autosomal dominant mutations. The
study will consist of up to 4 visits, each taking place approximately 30 days
apart with the following windows of deviation to allow for flexibility in
participant scheduling defined as follows: Screening Visit (0 days), Visit 1
(±3 days), Visit 2 (-14/ +3 days) and End of Study Visit (-14/ +3 days).
Therefore, the length of time for a participant to complete all four visits
would range from a minimum of 59 days to a maximum of 99 days. The overall
duration of the study will be up to 9 months, from first data collection to
reporting of results.

Screening Visit (0 day)
* Informed consent;
* Inclusion/Exclusion (including MMT to assess muscle/motor function deficit,
10-MWT to assess ability to walk, and
FVC to assess pulmonary dysfunction);
* Demographics (medical records);
* Medical history (medical records) ;
* Medication use (medical records);
* Vital signs and ECG (medical records or primary data collection; note that
FVC will be evaluated as part of the
assessment of the exclusion criteria);
* Strength measurements using QMA and HHD (note that MMT will be conducted at
the start of the Screening Visit
as part of the assessment of the inclusion criteria);
* 1-Minute Sit-to-Stand Test;
* 4SCT;
* Full physical, neurological, and functional examination;
* PROMIS Questionnaires;
* IPAQ;
* Syde® device fitting;
* Symptom diary (initiation); and
* Adverse events (AE)/Serious adverse events (SAE).

Visit 1 (30 ± 3 days), Visit 2 (60 ± 3 days), and End of Study Visit (90 ± 3
days)
* Medication use (at Visit 1, Visit 2, and End of Study Visit);
* Strength measurements using QMA, HHD, and MMT (at Visit 1, Visit 2, and End
of Study Visit);
* 10-MWT (at Visit 1, Visit 2, and End of Study Visit);
* 1-Minute Sit-to-Stand Test (at Visit 1, Visit 2, and End of Study Visit);
* 4SCT (at Visit 1, Visit 2, and End of Study Visit);
* PROMIS Questionnaires;
* IPAQ (at End of Study Visit);
* Full physical, neurological, and functional examination (at End of Study
Visit);
* Syde® device removal (at Visit 1);
* Symptom Diary (patients will stop using the diary at End of Study Visit); and
* AE/SAE (at Visit 1, Visit 2, and End of Study Visit).

Physical risks following participation in the study are not anticipated.
This study involves strength measurements which should not pose a risk to
subjects. However, they may experience discomfort and tiredness from carrying
out the activities required for the physical assessment. Subjects will have the
option to take short breaks between assessments if needed.
Wearing the Syde® device should also not pose any risks to subjects. They might
feel some discomfort from wearing the device, but it is expected that this is
no more uncomfortable than wearing a watch, but in this case around the ankles.
Taking part in the study will cost extra time to subjects.