Effectiveness of 3,4-Diaminopyridine in Lambert-Eaton Myasthenic Syndrome

Study Overview
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Brief Summary
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Hypothesis: 3,4-Diaminopyridine base (3,4-DAP) improves Lambert-Eaton Myasthenic Syndrome (LEMS)-related weakness.

Detailed Description
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The objectives of the study were to confirm the safety and to test the efficacy of 3,4-DAP in the treatment of LEMS-related weakness. This was a phase 2 randomized double-blind placebo-controlled withdrawal study in subjects with known clinically active LEMS who had been on a chronic stable dose of compassionate distribution Jacobus 3,4-DAP provided through FDA-approved individual investigator-held INDs.

Official Title
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Inpatient Double-Blind Placebo-Controlled Withdrawal Study of 3,4-Diaminopyridine Base (3,4-DAP) in Subjects With Known Lambert-Eaton Myasthenic Syndrome

Conditions
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Lambert-Eaton Myasthenic Syndrome, Eaton-Lambert Myasthenic Syndrome

Intervention / Treatment
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* Drug: Continuous 3,4-DAP
* Drug: Taper 3,4-DAP to Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 or over Ambulatory while taking 3,4-DAP, i.e. the patient was able to perform the timed up and go (TUG), either with or without an assistive device Established diagnosis of LEMS, with documentation provided Continuous use of Jacobus 3,4-DAP for at least 3 months Minimum of 3 doses per day with no single dose less than 10 mg of 3,4-DAP The patient needed to wait about 15 to 30 minutes to experience an unequivocal improvement in a LEMS-induced dysfunction after they take their first dose of 3,4-DAP in the morning [a patient who remains in bed past this point by choice may still be eligible] Stable regimen of all LEMS-related treatments for at least 3 months Stable daily regimen of other medications (prescription and over-the-counter) for a minimum of 1 month Willing to chance being tapered off of 3,4-DAP Fluency in English If applicable, agreed to use birth control during heterosexual intercourse until at least 2 weeks after completion of study A signed informed consent by the study subject Exclusion Criteria: Last monoclonal antibody treatment (e.g. rituximab) was less than 6 months ago (i.e., recent treatment is an exclusion) Clinically significant or poorly controlled condition that in the opinion of the study personnel might pose an unacceptable risk to the patient if entered into the study Respiratory failure requiring intubation while on 3,4-DAP with no precipitating event or medication Use of any investigational drug other than 3,4-DAP within the last 30 days Pregnant or lactating Current use of other aminopyridines (e.g.4-AP) or guanidine Did not display a sufficiently large response to 3,4-DAP during the baseline observation period in the CRU to detect a decline during withdrawal of 3,4-DAP

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
Interventional Model Description: This was a multicenter, randomized, double-blind, placebo-controlled withdrawal study to assess the safety and efficacy of 3,4-DAP in subjects on a stable regimen of all LEMS-related treatments, including 3,4-DAP, for a minimum of 3 months prior to study entry. Subjects who met all study entry criteria were randomized in a 1:1 ratio to continue their current treatment regimen (Group A, continuous 3,4-DAP) or tapered withdrawal from 3,4-DAP (Group B, taper to placebo).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Continuous 3,4-DAP<br>Subjects continued taking their usual individualized regimen of 3,4-DAP base, 30 to 100 mg daily divided into at least 3 doses. | Drug: Continuous 3,4-DAP<br>* Subjects were maintained on their usual personal dose and schedule of 3,4-DAP base<br>* Other names: Diamino-3,4-pyridine;|
| Placebo Comparator: Taper 3,4-DAP to Placebo<br>Subjects were tapered over 3 days from their usual individualized regimen of 3,4-DAP base (30 to 100 mg daily divided into at least 3 doses) to placebo with up to an additional 16 hours of placebo before resuming their usual pre-study regimen of 3,4-DAP base | Drug: Taper 3,4-DAP to Placebo<br>* Subjects were tapered over 3 days from their usual regimen of 3,4-DAP base to placebo with up to an additional 16 hours of placebo before resuming their usual pre-study regimen of 3,4-DAP base<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With 30% or More Deterioration in Triple Timed Up & Go (3TUG) Test, Compared to Time-matched Baseline | The 3TUG time obtained 2 hours after the last dose of the withdrawal period (i.e., at time of theoretical peak drug effect) was compared to the average time-matched 3TUG tests performed during 2 days of baseline observation prior to randomization. The study endpoint was a change of more than 30% in the final post-dose 3TUG during the withdrawal period and was based on blinded readings of video recordings of 3TUG tests. | Baseline period (days 0, 1, 2); Randomized treatment period (starting with last dose of day 2, and days 3, 4, 5, and ending with first dose on day 6 when pre-randomization regimen was resumed, or rescue, if indicated sooner) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Self-assessment of LEMS-related Weakness, W-SAS | The last post-dose self-assessment of LEMS-related weakness from the withdrawal period with categories of much much weaker (-3), much weaker (-2), somewhat weaker (-1), about the same (0), somewhat stronger (1), much stronger (2), and much much stronger (3). | Participants were followed for up to 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lambert-Eaton, Eaton-Lambert, myasthenia, myasthenic, LEMS, LES, DAP, diaminopyridine, 3,4-diaminopyridine, 3,4-DAP