Ephedrine as add-on therapy for patients with myasthenia gravis

Myasthenia gravis is a rare autoimmune neuromuscular condition which initially
responds favourably to symptomatic treatment with acetylcholinesterase
inhibitors (AChIs) that act on the neuromuscular junction (NMJ). The second
line of treatment usually consists of high doses of immunomodulating or
immunosuppressive drugs, which may have serious side effects. A potential
alternative is the short-acting drug ephedrine which - together with AChIs or
low-dose prednisone - may postpone (or even abolish) the need for high-dose
immunomodulating or immunosuppressive therapies.

The main objective of this pilot study of n-of-one trials is to determine the
effect of add-on treatment with ephedrine for all participants enrolled in this
small series of n-of-one trials. Secondary objectives include determining the
effect in individual patients in the trial, feasibility of a larger series of
n-of-one trials to investigate efficacy and adverse effects of oral add-on
treatment for myasthenia gravis. We will also evaluate patients*, physicians*
and pharmacists* experiences with this trial design and record adverse effects
of add-on treatment with ephedrine.

The study consists of an inclusion phase and 4 n-of-one trials, followed by an
evaluation phase and an optional open label extension phase. N-of-one trials
are double-blind, multiple crossover single patient trials in which the order
of treatment allocation is randomised over the cycles of the trial. Based on
their individual results of the n-of-one trial, patients can decide whether to
continue with ephedrine. In this case, they will be asked to participate in the
open label extension phase to determine the long term efficacy of add-on
treatment with ephedrine. Patients* experiences with (the burden of) n-of-one
trials will be explored by interviews.

During the randomised, double-blind multiple crossover phase, add-on treatment
with 25 mg ephedrine 2 times daily will be compared to add-on treatment with
placebo 2 times daily. Effect of treatment will be measured both objectively
(Quantitative Myasthenia Gravis (QMG) score, MG Composite) and subjectively
(Myasthenia Gravis-Activities of Daily Living (MG-ADL) profile and VAS score of
muscle strength). Adverse effects will be measured by a symptom questionnaire.
Patients will continue to use their pre-study dose of pyridostigmine or
low-dose prednisone throughout the n-of-one trial.

Each n-of-one trial lasts 10 weeks. In week 1 and 2 of every n-of-one trial,
each patient will visit the hospital for a full day to establish whether the
treatment is safe for that patient. VAS score of muscle strength, all adverse
effects (questionnaire) and vital signs are measured 30, 60 and 120 minutes
after ephedrine administration, an ECG will additionally be performed 60
minutes after administration.
During the 6-week blinded multiple crossover phase, patients will receive 3
weeks of ephedrine and 3 weeks of placebo add-on treatment (week 1-6). The
order of treatment will be randomised over each of the 3 crossover cycles (e.g.
AB-BA-BA). Patients will fill out adverse event questionnaires twice a week (+
baseline; 13 adverse event questionnaires in total), visit their neurologist
once a week (+ baseline; 7 hospital visits), answer an ADL questionnaire once a
week (+ baseline: 7) and give a VAS score once a week (+ baseline: 7).
In week 8, patients will have a follow-up consultation with their neurologist
to discuss the results of the n-of-one trial. Based on the results and
experience in the multiple crossover phase, patients can decide whether they
want to continue ephedrine after the trial. During the qualitative evaluation
phase (week 9 or 10), patients will be interviewed by telephone by one of the
researchers to explore their experiences with the n-of-one trial.
If a patient has decided to continue treatment with ephedrine after the
n-of-one trial, we will ask them to participate in the open label extension
phase. This will consist of three outpatient visits at 2, 4 and 6 months
afterwards. An n-of-one trial directly assesses benefits and risks of treatment
for individual patients. This means that treatment decisions can be made based
on the results of an individual patient*s results of the n-of-one trial. If
ephedrine treatment is effective in a patient, his or her functional status and
quality of life may improve.
Adverse effects of ephedrine treatment include palpitations, anxiety, nausea,
restlessness and insomnia. These will be recorded and monitored throughout the
trial.