Pyridostigmine and Amifampridine for Myasthenia Gravis (IMPACT-MG)

Leiden University Medical Center (LUMC)

Status and phase: Enrolling; Phase 3

Conditions: Myasthenia Gravis

Treatments: Drug: Amifampridine (base) with modified release; Drug: Placebo; Drug: Pyridostigmine

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT05919407

NL78666.058.21

Details and patient eligibility

About

A randomized, double-blind, placebo controlled, crossover intervention study evaluating the effect of pyridostigmine (part 1) and amifampridine (part 2) in Myasthenia Gravis (MG).

Full description

In the first part of the study, patients who are currently using pyridostigmine will be randomly allocated to one of two consecutive treatment periods in which patients either first receive placebo and then their usual dose of pyridostigmine, or vice versa. 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).

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 substudy to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of amifampridine in AChR positive MG patients.

Enrollment: 24 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Age >18 years

2. AChR positive myasthenia gravis (ocular or generalized)

3. Current use of pyridostigmine

4. MGFA Clinical Classification I-IV

5. Receiving a stable dose of MG treatment (other than pyridostigmine). If applicable:

   1. A stable steroid regimen for 1 month
   2. Nonsteroidal immunosuppressants: i. Azathioprine, mycophenolate mofetil, cyclosporine or other nonsteroid immunosuppressive agents start > 3 months ago and a stable regimen for 1 month. ii. Rituximab start > 6 months ago, complement inhibitors and Fc receptor inhibitors start > 6 months ago and a stable regimen for 3 months.

Additional inclusion criteria for part 2 To be eligible for participation in part 2 of the study patients must score >10 points on the MGII questionnaire at inclusion.

We will include a maximum of 5 patients with a MGFA class I (i.e. 20 percent of the total number of included patients) to ensure that this study accurately reflects the clinical population.

Exclusion criteria

1. Use of intravenous immunoglobulin or plasma exchange <4 weeks or planned during the trial.
2. Thymectomy < 6 months, or thymectomy (expected) to take place during the trial
3. Use of other acetylcholinesterase inhibitors than pyridostigmine
4. Pregnancy, lactation or intention to become pregnant during the study
5. Treatment with amifampridine is contraindicated. Contraindications include a history of epilepsy, uncontrolled asthma, inherited QT syndrome / a prolonged QT interval (as indicated by ECG), any drug known to cause QT c-prolongation, any drug known to lower the epileptic threshold, a known hypersensitivity reaction to the active substance or to any of the excipients.
6. The patient is unable to fill out the study questionnaires or be interviewed in Dutch, or is unable to undergo the tests needed for the study, or is unable to give informed consent for participation in the study.
7. The investigator can exclude patients for this trial which are deemed not suitable for any reason.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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24 participants in 4 patient groups, including a placebo group

Pyridostigmine

Experimental group

Description:

The dose of pyridostigmine will be based on the patient's prior experience with pyridostigmine under the assumption that the patient already gained sufficient experience during their disease course to know which dose is effective for them as patients are advised by their treating neurologist to continually adjust their dose based on their symptoms and side effects.

Treatment:

Drug: Pyridostigmine

Placebo (pyridostigmine)

Placebo Comparator group

Description:

Same as "Experimental", however capsules contain placebo.

Treatment:

Drug: Placebo

Drug: Placebo

Amifampridine (base) with modified release

Experimental group

Description:

Patients will receive amifampridine 2 dd 15 mg and amifampridine 2 dd 30 mg as add-on to the pre-study dose of pyridostigmine.

Treatment:

Drug: Amifampridine (base) with modified release

Placebo (amifampridine)

Placebo Comparator group

Description:

Same as "Experimental", however capsules contain placebo.

Treatment:

Drug: Placebo

Drug: Placebo