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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Jacobus Pharmaceutical
ClinicalTrials.gov Identifier:
NCT01511978
First received: December 24, 2011
Last updated: July 7, 2017
Last verified: July 2017
  Purpose
Hypothesis: 3,4-Diaminopyridine base (3,4-DAP) improves Lambert-Eaton Myasthenic Syndrome (LEMS)-related weakness.

Condition Intervention Phase
Lambert-Eaton Myasthenic Syndrome Eaton-Lambert Myasthenic Syndrome Drug: Continuous 3,4-DAP Drug: Taper 3,4-DAP to Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: Inpatient Double-Blind Placebo-Controlled Withdrawal Study of 3,4-Diaminopyridine Base (3,4-DAP) in Subjects With Known Lambert-Eaton Myasthenic Syndrome

Resource links provided by NLM:


Further study details as provided by Jacobus Pharmaceutical:

Primary Outcome Measures:
  • Number of Participants With 30% or More Deterioration in Triple Timed Up & Go (3TUG) Test, Compared to Time-matched Baseline [ Time Frame: 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:
  • Self-assessment of LEMS-related Weakness, W-SAS [ Time Frame: 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).


Enrollment: 32
Study Start Date: January 2012
Study Completion Date: July 2015
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 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.
Drug: Continuous 3,4-DAP
Subjects were maintained on their usual personal dose and schedule of 3,4-DAP base
Other Names:
  • 3,4-Diaminopyridine
  • 3,4-Pyridinediamine
  • Diamino-3,4-pyridine
Placebo Comparator: 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
Drug: Taper 3,4-DAP to Placebo
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
Other Names:
  • 3,4-Diaminopyridine
  • 3,4-Pyridinediamine
  • Diamino-3,4-pyridine
  • Placebo

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01511978

Locations
United States, California
University of California at Davis
Sacramento, California, United States, 95817
United States, Indiana
Indiana University
Indianapolis, Indiana, United States, 46202
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27710
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
Jacobus Pharmaceutical
Investigators
Study Director: Kathy L Aleš, MD Jacobus Pharmaceutical
  More Information

Responsible Party: Jacobus Pharmaceutical
ClinicalTrials.gov Identifier: NCT01511978     History of Changes
Other Study ID Numbers: JPC 3,4-DAPPER
Study First Received: December 24, 2011
Results First Received: June 7, 2017
Last Updated: July 7, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jacobus Pharmaceutical:
Lambert-Eaton
Eaton-Lambert
myasthenia
myasthenic
LEMS
LES
DAP
diaminopyridine
3,4-diaminopyridine
3,4-DAP

Additional relevant MeSH terms:
Syndrome
Lambert-Eaton Myasthenic Syndrome
Paraneoplastic Syndromes, Nervous System
Paraneoplastic Syndromes
Disease
Pathologic Processes
Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Neurodegenerative Diseases
Neuromuscular Junction Diseases
Neuromuscular Diseases
Autoimmune Diseases
Immune System Diseases
3,4-diaminopyridine
4-Aminopyridine
Potassium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 24, 2017