A Phase 3 Study of Amifampridine Phosphate in Patients With Lambert Eaton Myasthenic Syndrome (LEMS)

Study Overview
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Brief Summary
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A Phase 3 study to evaluate the efficacy and safety of Amifampridine Phosphate in patients with Lambert-Eaton Myasthenic Syndrome (LEMS).

Detailed Description
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This multicenter, double-blind, placebo-controlled, randomized (1:1) discontinuation study is a 4-part study designed to evaluate the efficacy and safety of multiple dose administration of amifampridine phosphate in patients with LEMS. Data from parts 2 and 3 (the double-blind parts of the study) are presented in this record.

Official Title
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A Phase 3, Double-blind, Placebo-controlled, Randomized Discontinuation Study Followed by Open-label Extension Evaluating Efficacy and Safety of Amifampridine Phosphate in Patients With Lambert-Eaton Myasthenic Syndrome (LEMS)

Conditions
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Lambert Eaton Myasthenic Syndrome

Intervention / Treatment
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* Drug: Amifampridine Phosphate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals eligible to participate in this study must meet all of the following inclusion criteria: ≥18 years of age Confirmed diagnosis of LEMS Normal respiratory function Normal swallowing function If receiving peripherally acting cholinesterase inhibitors a stable dose is required for at least 7 days prior to Screening. If receiving oral immunosuppressants a stable dose is required for at least 90 days prior to Screening. Negative pregnancy test for females of childbearing potential If sexually active, willing to use 2 acceptable methods of contraception Willing to perform all study procedures as physically possible. Willing and able to provide written informed consent after the nature of the study has been explained and prior to the start of any research-related procedures. Exclusion Criteria: Individuals who meet any of the following exclusion criteria are not eligible to participate in the study: History of epilepsy or seizure. Known active brain metastasis. Use of Fampridine (4-aminopyridine), and any form of 3,4-diaminopyridine other than the IP provided, such as amifampridine base or Firdapse, during the study. Use of medications known to lower the epileptic threshold within 7 days or 5 half-lives. Use of medications which inhibit neuromuscular junction function within 7 days or 5 half-lives. Use of IVIG, plasmapheresis (plasma exchange), or immunoadsorption within 90 days Use of guanidine hydrochloride within 7 days Use of rituximab within 12 months History of drug allergy to any pyridine-containing substances or any amifampridine phosphate excipient(s). Use of any other investigational productwithin 30 days Treatment with a concomitant medication that prolongs the QT/QTc interval within 7 days or 5 half-lives. Treatment with sultopride (4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethylsulfonyl-2-methoxybenzamide) within 7 days. An abnormal electrocardiogram (ECG). Documented history of arrhythmias. History of additional risk factors for torsade de pointes. Breastfeeding or pregnant or planning to become pregnant (self or partner) at any time during the study. Likely or expected to require treatment for cancer within 3 months (90 days) after entering. History of severe renal impairment or evidence of severe renal impairment Any condition that places the patient at high risk of poor treatment compliance or of not completing the study. History of uncontrolled asthma.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching placebo tablets administered 3-4 times a day (to the individual patient's tablet count of active at baseline) over 2 weeks. | Drug: Placebo<br>* Matching placebo tablets administered 3-4 times a day (to the individual patient's tablet count of active at baseline) over 2 weeks.<br>|
| Experimental: Amifampridine Phosphate<br>Amifampridine, 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets), for 2 weeks. | Drug: Amifampridine Phosphate<br>* Amifampridine, 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets), for 2 weeks.<br>* Other names: 3,4-DAP phosphate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days | The QMG is a physician-rated test including 13 assessments, including facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each of the 13 items is scored from 0 (none) to 3 (severe). The total score can range from 0 to 39. Increased QMG total score correlates to worsening symptoms of LEMS. | Assessment at Baseline and Day 14 | 
| Change in SGI Score | Subject Global Impression (SGI) is a measure of changes in subject's perception of change in overall wellbeing. The patient is asked to use the 7-point scale below to rate their impression of the effects of the study medication during the preceding 3 days on their physical well being. Terrible Mostly dissatisfied Mixed Partially satisfied Mostly satisfied Pleased Delighted | Assessment at Baseline and Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days | The T25FW test, a component of the Multiple Sclerosis Functional Composite, was a quantitative mobility and leg function performance test based on a timed 25-foot walk (National Multiple Sclerosis Society). The patient was directed to walk a clearly marked 25-foot course as quickly and safely as possible. Following a rest of at least 5 minutes, the timed 25-foot walk was repeated. Patients could use assistive devices, such as canes, crutches, or walkers. All data were normalized to the number of feet per minute, so if the patient walked 25 feet in less than a minute, the result was a speed greater than 25 feet/minute. The measurement for the T25FW test was the average speed, expressed in feet/minute, of the 2 completed walks. | Assessment at Baseline and Day 14 | 
| Change in CGI-I Score | The Investigator completed the 7-point CGI I, based on changes in symptoms, behavior, and functional abilities, at the protocol-specified time points compared to the patient's condition at Day 0. = Very much improved = Much improved = Minimally improved = No change = Minimally worse = Much worse = Very much worse | Baseline and Day 14 |