IMPACT-MG
(2026)Objective
To evaluate the efficacy and safety of add-on amifampridine modified release (MR) in patients with AChR-positive myasthenia gravis (MG) with insufficient symptom control on pyridostigmine.
Study Summary
• No significant association between pharmacokinetic parameters and MGII
• Adverse events more common with amifampridine 30mg (60%) and 60mg (75%) vs placebo (30%); 3 patients discontinued early due to AEs; no serious adverse events reported
Intervention
Amifampridine MR 30mg/day or 60mg/day vs placebo added to stable pyridostigmine, in a 3-period crossover (5 days per period, 2-day washouts)
Inclusion Criteria
Adults ≥18 years with AChR antibody–positive ocular or generalized MG (MGFA class I–IV), on stable pyridostigmine, with MGII score >10, who either completed part 1 (pyridostigmine vs placebo) or failed the initial 2-day pyridostigmine washout.
Study Design
Arms: Amifampridine MR 30 mg/day + pyridostigmine vs Amifampridine MR 60 mg/day + pyridostigmine vs Placebo + pyridostigmine (n=20 total, crossover design with all patients receiving all 3 treatments)
Patients per Arm: 20 patients total (crossover; all received all 3 treatments)
Outcome
• No statistically significant association between PK parameters and MGII
• Higher AE rates with amifampridine (30mg: 60%; 60mg: 75%) vs placebo (30%); paresthesia, fatigue, numbness, dizziness, and sleep disturbances most common; 3 early discontinuations; no SAEs
Bottom Line
Add-on amifampridine MR (30 mg or 60 mg daily) was NOT superior to pyridostigmine alone for symptom control in AChR-positive MG, and was associated with a higher incidence of adverse events. Routine add-on use of amifampridine in this population is not supported.
Major Points
- First RCT to evaluate add-on amifampridine MR in AChR-positive MG inadequately controlled on pyridostigmine (Class I evidence).
- Neither 30 mg nor 60 mg daily amifampridine MR showed superiority over placebo on the primary outcome (MGII).
- Adverse events were dose-related and more frequent with amifampridine (60% at 30 mg, 75% at 60 mg) than placebo (30%); paresthesia, fatigue, numbness, dizziness, and sleep disturbances predominated.
- Three patients discontinued amifampridine early due to adverse events; no serious adverse events occurred.
- No statistically significant PK/PD association between amifampridine exposure and MGII change.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, 3-period crossover trial (part 2 of IMPACT-MG, investigator-initiated)
- Randomization
- Yes
- Blinding
- Double-blind (participants and investigators); identical-appearing tablets and bottles; allocation known only to study pharmacist until database lock; blinding success assessed by investigator and patient perception
- Sample Size
- 20
- Follow-up
- 3 treatment periods of 5 days each separated by 2-day washouts; protocol amended to add observational visits at 3 and 6 months
- Centers
- 1
- Countries
- Netherlands
Primary Outcome
Definition: Difference in Myasthenia Gravis Impairment Index (MGII) score between each amifampridine MR dose and placebo
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Placebo + pyridostigmine (reference) | Amifampridine MR 30 mg and 60 mg + pyridostigmine | - (−4.1 to 2.0 (30 mg vs placebo); −4.7 to 1.4 (60 mg vs placebo)) | 0.681 (30 mg vs placebo); 0.379 (60 mg vs placebo) |
Limitations & Criticisms
- Small sample size (n=20) at a single tertiary center limits external validity and statistical power.
- Short 5-day treatment periods may underestimate benefits that could accrue with longer exposure.
- Use of modified-release formulation (amifampridine base MR), most common in the Netherlands, may not reflect the immediate-release amifampridine phosphate salt authorized for LEMS elsewhere.
- Crossover design with brief washout could carry minor period or carryover effects despite the Latin square balancing.
Citation
Neurology 2026;106:e214715. doi:10.1212/WNL.0000000000214715