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

Phase 2

Completed

• Conditions: Lambert-Eaton Myasthenic Syndrome; Eaton-Lambert Myasthenic Syndrome
• Interventions: Drug: Taper 3,4-DAP to Placebo; Drug: Continuous 3,4-DAP

• Registration Number: NCT01511978
• Lead Sponsor: Jacobus Pharmaceutical

Brief Summary

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

Detailed Description

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.

Study Timeline

• Study First Submitted: 2011-12-24
• Study Start: 2012-01
• Study First Submitted QC: 2012-01-13
• Study First Posted: 2012-01-19
• Primary Completion: 2014-02
• Study Completion: 2015-07
• Results First Submitted: 2017-06-07
• Status Verified: 2017-07
• Results First Submitted QC: 2017-07-07
• Last Update Submitted: 2017-07-07
• Results First Posted: 2017-07-11
• Last Update Posted: 2017-07-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 32

Inclusion Criteria

1. Age 18 or over
2. 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
3. Established diagnosis of LEMS, with documentation provided
4. Continuous use of Jacobus 3,4-DAP for at least 3 months
5. Minimum of 3 doses per day with no single dose less than 10 mg of 3,4-DAP
6. 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]
7. Stable regimen of all LEMS-related treatments for at least 3 months
8. Stable daily regimen of other medications (prescription and over-the-counter) for a minimum of 1 month
9. Willing to chance being tapered off of 3,4-DAP
10. Fluency in English
11. If applicable, agreed to use birth control during heterosexual intercourse until at least 2 weeks after completion of study
12. A signed informed consent by the study subject

Exclusion Criteria

1. Last monoclonal antibody treatment (e.g. rituximab) was less than 6 months ago (i.e., recent treatment is an exclusion)
2. 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
3. Respiratory failure requiring intubation while on 3,4-DAP with no precipitating event or medication
4. Use of any investigational drug other than 3,4-DAP within the last 30 days
5. Pregnant or lactating
6. Current use of other aminopyridines (e.g.4-AP) or guanidine
7. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Taper 3,4-DAP to Placebo	Taper 3,4-DAP to Placebo	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
Continuous 3,4-DAP	Continuous 3,4-DAP	Subjects continued taking their usual individualized regimen of 3,4-DAP base, 30 to 100 mg daily divided into at least 3 doses.

Primary Outcome Measures

Name	Time	Method
Number of Participants With 30% or More Deterioration in Triple Timed Up & Go (3TUG) Test, Compared to Time-matched Baseline	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)	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.

Secondary Outcome Measures

Name	Time	Method
Self-assessment of LEMS-related Weakness, W-SAS	Participants were followed for up to 7 days	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).

Trial Locations

Locations (7)

University of California at Davis; 🇺🇸 Sacramento, California, United States

Indiana University; 🇺🇸 Indianapolis, Indiana, United States

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Duke University; 🇺🇸 Durham, North Carolina, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Baylor College of Medicine; 🇺🇸 Houston, Texas, United States