Improving symptomatic treatment with pyridostigmine and amifampridine: a randomized double-blinded, placebo controlled crossover trial in patients with myasthenia gravis (IMPACT-MG)

Myasthenia gravis (MG) is a rare autoimmune disease characterized by muscle
fatigability due to autoantibodies aimed at components of the neuromuscular
junction, most commonly against the acetylcholine receptor (AChR). The initial
therapy for most patients is an oral acetylcholinesterase inhibitor, usually
pyridostigmine. Pyridostigmine is registered as a treatment for MG and has been
used by MG patients since the 1940s. However, no randomized controlled trials
evaluating the efficacy and side effects of pyridostigmine have ever been
completed. Currently one study evaluating the efficacy of pyridostigmine is
recruiting patients. However, only two doses of pyridostigmine are given on one
day making it less applicable to the clinical population.
Furthermore, amifampridine is commonly used in other diseases of the
neuromuscular junction, in particular Lambert-Eaton Myasthenic Syndrome (LEMS)
and congenital myasthenic syndromes. The potential use of amifampridine as
add-on in AChR positive MG has only been described in limited case reports. No
randomized controlled trial regarding the efficacy and side effects has ever
been performed on amifampridine as add-on in AChR positive MG.

The aim of this study is to investigate the efficacy and tolerability of
pyridostigmine monotherapy and amifampridine as add-on compared to placebo in
patients with MG.

A randomized, double-blind, placebo controlled, crossover intervention study
subdivided in part 1 and part 2 will be performed.

In the first part of the study patients will be randomly allocated to one of
two consecutive treatment periods in which patients either first receive
placebo and then pyridostigmine, or vice versa. The dose of pyridostigmine will
be based on the optimal pre-study dose according to the patient*s own
experience. Each treatment period lasts 5 days with a 2-day wash-out period
between each treatment period. Measurements will be performed at every last day
of a treatment period (day 5 and day 12).
At the end of the two treatment periods, patients restart their pre-study dose
of pyridostigmine. Patients can qualify for participation in part 2 based on
the Myasthenia Gravis Impairment Index (MGII) determined at inclusion. Patients
scoring >10 points, meaning that they still have some residual symptoms based
on the patient acceptable symptom state threshold for MGII, will move on to the
second part of the study.
In the second part of the study the effect of two doses of amifampridine as
add-on to pyridostigmine will be studied. Patients will be randomly assigned to
either one of three treatment sequences; 1) amifampridine 30 mg - amifampridine
60 mg - placebo or 2) amifampridine 60 mg - placebo - amifampridine 30 mg or 3)
placebo - amifampridine 30 mg - amifampridine 60 mg.
Again, each treatment period consists of 5 days and will be separated by a
2-day wash-out period. Measurements will be performed at every last day of
treatment (day 19, day 26 and day 33).
Patients will have the option to participate in a PK/PD Substudy to
characterize the PK and PD of amifampridine in AChR positive MG patients.
After the completion of part 2, patients will be given the option to continue
amifampridine. This will be provided off-label by prescription of the treating
physician as part of usual clinical care. For these patients, additional
measurements will be performed at 3 months and 6 months to determine long-term
efficacy and side effects.

The first part of the study lasts 2 weeks and the second part of the study 3
weeks. Patients will have to visit the hospital once for inclusion and six
times during the study (once a week with additionally a baseline visit at the
beginning of the study).
During the visits the MGII, MG-ADL, QMG, MG-QoL15r, EQ-5D-5L and TSQM-9 will be
obtained. For safety measures, control of vital signs will be performed and
blood samples will be taken. AChR antibody levels will be measured at baseline,
after part 1 and after part 2 of the study. Serum levels of pyridostigmine,
preferably trough levels, will be determined weekly during both parts of the
study. Serum levels, preferably trough levels, of amifampridine will be
determined weekly during part 2 of the study. An ECG will be performed at
baseline and weekly during part 2 of the study.
Patients are asked weekly to fill out a side effects questionnaire and the
number of times escape medication was used including the effect of these
adjustments on the symptoms.
Side effects of pyridostigmine can be caused by either muscarinic activation
(blurry vision, nausea, vomiting, diarrhea, low lung compliance,
bronchoconstriction, bronchorrhea, increased secretions in the tracheobronchial
and gastrointestinal system, bradycardia and urinary frequency and urgency) or
nicotinic activation (flaccid paralysis and tachycardia) which, in extremely
rare and severe cases, can result in a cholinergic crisis. Side effects are
transient and will diminish 3-4 hours after taking pyridostigmine.
Side effects of amifampridine include transient paresthesias and
gastrointestinal symptoms, such as nausea, diarrhea and abdominal pain.
Seizures have been reported, but only with doses of amifampridine above 100 mg
per day, which is higher than the doses used in the current study.
Patients included in the optional PKPD Substudy will stay in the hospital on
the day of the measurements, in total 3 days. The blood samples of the
different timepoints will be drawn from a peripheral intravenous cannula.
The burden for patients participating in the open label extension phase is
estimated to be low. It concerns an observational period with an observation
moment after 3 and 6 months. During this period, the patient is treated with
amifampridine as part of clinical care.