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

Primary Purpose

Lambert-Eaton Myasthenic Syndrome, Eaton-Lambert Myasthenic Syndrome

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Continuous 3,4-DAP

Taper 3,4-DAP to Placebo

About this trial

This is an interventional treatment trial for Lambert-Eaton Myasthenic Syndrome focused on measuring Lambert-Eaton, Eaton-Lambert, myasthenia, myasthenic, LEMS, LES, DAP, diaminopyridine, 3,4-diaminopyridine, 3,4-DAP

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University of California at Davis
Indiana University
Duke University
Oregon Health & Science University
Vanderbilt University Medical Center
Baylor College of Medicine
University of Utah

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Continuous 3,4-DAP

Taper 3,4-DAP to Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).

Full Information

NCT ID

NCT01511978

First Posted

December 24, 2011

Last Updated

July 7, 2017

Sponsor

Jacobus Pharmaceutical

1. Study Identification

Unique Protocol Identification Number

NCT01511978

Brief Title

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

Acronym

DAPPER

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2017

Overall Recruitment Status

Completed

Study Start Date

January 2012 (undefined)

Primary Completion Date

February 2014 (Actual)

Study Completion Date

July 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Jacobus Pharmaceutical

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Lambert-Eaton Myasthenic Syndrome, Eaton-Lambert Myasthenic Syndrome

Keywords

Lambert-Eaton, Eaton-Lambert, myasthenia, myasthenic, LEMS, LES, DAP, diaminopyridine, 3,4-diaminopyridine, 3,4-DAP

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

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

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

32 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Continuous 3,4-DAP

Arm Type

Active Comparator

Arm Description

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

Arm Title

Taper 3,4-DAP to Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Continuous 3,4-DAP

Other Intervention Name(s)

3,4-Diaminopyridine, 3,4-Pyridinediamine, Diamino-3,4-pyridine

Intervention Description

Subjects were maintained on their usual personal dose and schedule of 3,4-DAP base

Intervention Type

Drug

Intervention Name(s)

Taper 3,4-DAP to Placebo

Other Intervention Name(s)

3,4-Diaminopyridine, 3,4-Pyridinediamine, Diamino-3,4-pyridine, Placebo

Intervention Description

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

Primary Outcome Measure Information:

Title

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

Description

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)

Secondary Outcome Measure Information:

Title

Self-assessment of LEMS-related Weakness, W-SAS

Description

Time Frame

Participants were followed for up to 7 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kathy L Aleš, MD

Organizational Affiliation

Jacobus Pharmaceutical

Official's Role

Study Director

Facility Information:

Facility Name

University of California at Davis

City

Sacramento

State/Province

California

ZIP/Postal Code

95817

Country

United States

Facility Name

Indiana University

City

Indianapolis

State/Province

Indiana

ZIP/Postal Code

46202

Country

United States

Facility Name

Duke University

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

Facility Name

Oregon Health & Science University

City

Portland

State/Province

Oregon

ZIP/Postal Code

97239

Country

United States

Facility Name

Vanderbilt University Medical Center

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

Facility Name

Baylor College of Medicine

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

University of Utah

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84132

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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

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