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

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

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

Study Overview

• Status: Completed
• Conditions: Lambert-Eaton Myasthenic Syndrome; Eaton-Lambert Myasthenic Syndrome
• Intervention / Treatment: Drug: Continuous 3,4-DAP; Drug: Taper 3,4-DAP to 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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • University of California at Davis
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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: Placebo; 3,4-Diaminopyridine; 3,4-Pyridinediamine; Diamino-3,4-pyridine

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Jacobus Pharmaceutical

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (ACTUAL): February 1, 2014
• Study Completion (ACTUAL): July 1, 2015

Study Registration Dates

• First Submitted: December 24, 2011
• First Submitted That Met QC Criteria: January 13, 2012
• First Posted (ESTIMATE): January 19, 2012

Study Record Updates

• Last Update Posted (ACTUAL): July 11, 2017
• Last Update Submitted That Met QC Criteria: July 7, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: 3,4-DAP; LES; LEMS; Lambert-Eaton; Eaton-Lambert; myasthenia; myasthenic; DAP; diaminopyridine; 3,4-diaminopyridine
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Neoplasms; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Neoplasms by Site; Disease; Neuromuscular Diseases; Neurodegenerative Diseases; Nervous System Neoplasms; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neuromuscular Junction Diseases; Myasthenia Gravis; Syndrome; Lambert-Eaton Myasthenic Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Membrane Transport Modulators; Neuromuscular Agents; Potassium Channel Blockers; Amifampridine
• Other Study ID Numbers: JPC 3,4-DAPPER

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No