Fatigue Improvement Through Aerobic exercise and Cognitive behavioural Therapy in patients with Myasthenia Gravis (FIT to ACT - MG)

Myasthenia Gravis (MG) is a chronic antibody-mediated auto-immune disease
affecting the neuromuscular junction. MG is characterized by fluctuating
weakness and fatigability of the skeletal muscles. A frequent, persistent and
disabling symptom of MG is fatigue, present in ± 80% of patients and strongly
associated with a lower quality of life. Fatigue is defined as an experienced
lack of energy, physically and/or mentally. Limited data is available on the
treatment of fatigue in MG. Aerobic exercise therapy (AET) and
cognitive-behavioural therapy (CBT) have been proven effective in other
neuromuscular diseases, but literature on its effect on patients with MG is
scarce: only a short exercise program has been investigated in a small number
of fatigued MG patients. The pathophysiology of fatigue in MG is poorly
understood. Recent research indicates an important role for the cross-talk
between skeletal muscles and the brain, suggesting that fatigue arises from a
dysfunction of this *muscle-brain connection*. Fatigue can be regarded as a
behavioural adaptative signal from the brain, limiting physical activities in
order to protect muscles from further damage. This inactivity leads to a
reduction of muscle volume and strength, possibly causing a vicious cycle of
more fatigue and inactivity. We have recently found that serum levels of
C-Reactive Protein (CRP) correlate with fatigue in MG patients (unpublished
data, NL72266.058.20). We hypothesize that AET and CBT are effective
therapeutic interventions to treat fatigue in patients with MG.

The main objective is to investigate the effect of a 16-week AET or CBT program
on fatigue in patients with MG, compared to care as usual.

Prospective assessor-blinded randomized clinical trial.

A 16-week AET or CBT program, compared to care as usual.

For an individual participant, the overall study duration will be 52 weeks with
a total intervention duration of 16 weeks. Participants will have to visit
Leiden University Medical Center (LUMC) three times: 1) for inclusion, 2) for
baseline measurements after a four week observation period, and 3) follow-up at
20 weeks (after 16 weeks of intervention or usual care). Participants in the
AET group will have an additional visit for one supervised training session.

After inclusion, all participants will receive an activity tracker (Withings
Pulse HR) to enable remote monitoring of their physical activity. At baseline
(after a 4 week observation period) and at 20 weeks follow-up, all outcome
measures will be obtained, consisting of a number of questionnaires and a QMG
test (a measure of MG disease severity). In addition, blood samples will be
drawn for MG-related biomarkers and AChR and MuSK antibody status (in patients
with previously positive antibodies). Every participant will undergo an aerobic
fitness test, consisting of a short-term maximal field test on a calibrated
cycle ergometer (Steep Ramp Test), two times: 1) at baseline, prior to
randomisation, and 2) after 20 weeks. At 32 weeks and 52 weeks we will approach
every participant to digitally complete four questionnaires.

For participants in the AET group, the intake meeting with a physical therapist
will be on the same day as the baseline visit, immediately after randomisation.
AET will consist of three weekly sessions for a period of 16 weeks. Using
measurements from the baseline aerobic fitness test, the training schedule will
be adapted to the individual participants* aerobic capacity. To minimize the
number of visits to the LUMC, only the first training session will be
supervised by an experienced physical therapist at the LUMC. After that,
participants will perform the remaining workouts at home. One session per week
will be carried out independently at home, the other two sessions will be
digitally supervised via a digital connection (Zoom) by a trained professional.
Training activity will be monitored remotely using the activity tracker.

For participants in the CBT group, the intake meeting with a psychologist will
be online and in the same week as the baseline visit. The entire CBT program
will be conducted digitally through an online platform and will span 12-16
weeks. Every week or every two weeks, the psychologist gives feedback on the
finished sessions and provides new assignments. If necessary, the psychologist
will contact a participant by phone for additional support.

Participants will be given the option to undergo a quantitative muscle MRI of
the upper legs. The MRI is additional and not mandatory to participate in the
study. We will include a maximum of 10 participants per group. Participants in
this sub-study will undergo the MRI twice: before intervention at baseline and
after intervention at 20 weeks follow-up. The scan protocol will take a maximum
of 60 minutes in total. Muscle MRI can take place on another day than the
baseline and follow-up visits, depending on the preference of the participant,
but will never take place immediately after functional tests to avoid
post-exercise effects on the scans.

The risks of CBT are negligible. The aerobic fitness tests and AET may lead to
a temporary feeling of tiredness or muscle soreness in the following days. This
feeling is self-limiting and will decrease after repeated exercise. The risks
of venous blood withdrawal are that the puncture may be painful or that a
hematoma at the puncture site can arise, causing minor discomfort. The amount
of blood withdrawn is small and is not expected to give any problems. There are
no major known risks associated with the use of the MRI. Participants with
contraindications for MRI will be excluded.