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

• Sponsor: Jacobus Pharmaceutical (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01511978
• Collaborator: (none)
• Enrollment: 32
• Locations: 7
• Arms: 2
• Duration (Months): 42
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Lambert-Eaton Myasthenic Syndrome; Eaton-Lambert Myasthenic Syndrome	Drug: Continuous 3,4-DAP; Drug: Taper 3,4-DAP to Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• 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).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 (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
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Jul 1, 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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

1. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	University of California at Davis	Sacramento	California	United States	95817
2	Indiana University	Indianapolis	Indiana	United States	46202
3	Duke University	Durham	North Carolina	United States	27710
4	Oregon Health & Science University	Portland	Oregon	United States	97239
5	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
6	Baylor College of Medicine	Houston	Texas	United States	77030
7	University of Utah	Salt Lake City	Utah	United States	84132

Sponsors and Collaborators

• Jacobus Pharmaceutical

Investigators

• Study Director: Kathy L Aleš, MD, Jacobus Pharmaceutical

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jacobus Pharmaceutical
• ClinicalTrials.gov Identifier: NCT01511978
• Other Study ID Numbers: JPC 3,4-DAPPER
• First Posted: Jan 19, 2012
• Last Update Posted: Jul 11, 2017
• Last Verified: Jul 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• 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: Lambert-Eaton Myasthenic Syndrome; Syndrome; Amifampridine

Study Results

Participant Flow

Recruitment Details	Participants were referred by active Investigational New Drug (IND) holders involved with the Jacobus Pharmaceutical Company's 3,4-diaminopyridine (3,4-DAP) free base compassionate distribution program.
Pre-assignment Detail	52 patients were assessed for eligibility. 20 were ineligible. 32 were randomized and completed the study.

Arm/Group Title	Continuous 3,4-DAP	Taper 3,4-DAP to Placebo
Arm/Group Description	Subjects were administered their usual dosage on their regular personalized schedule	Subjects were administered decreasing amounts of 3,4-DAP on their regular personalized schedule
Period Title: Overall Study
STARTED	14	18
COMPLETED	14	18
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Continuous 3,4-Diaminopyridine (3,4-DAP)	3,4-DAP Taper to Placebo	Total
Arm/Group Description	Subjects were administered their usual dosage on their regular personalized schedule	Subjects were administered decreasing amounts of 3,4-DAP on their regular personalized schedule	Total of all reporting groups
Overall Participants	14	18	32
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.7 (15.97)	59.3 (14.99)	55.5 (15.77)
Sex: Female, Male (Count of Participants)
Female	10 71.4%	11 61.1%	21 65.6%
Male	4 28.6%	7 38.9%	11 34.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 5.6%	1 3.1%
Not Hispanic or Latino	14 100%	17 94.4%	31 96.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 21.4%	0 0%	3 9.4%
White	11 78.6%	18 100%	29 90.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	168.5 (5.67)	169.6 (8.98)	169.2 (7.67)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	78.0 (19.11)	80.3 (18.95)	79.3 (18.73)
Body Mass Index (BMI) (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	27.3 (5.92)	27.7 (5.14)	27.5 (5.39)
Age at diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.1 (13.79)	52.7 (14.76)	48.9 (14.76)
Time between symptom onset and diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	0.9 (0.62)	2.2 (3.00)	1.7 (2.35)
Duration of diagnosis prior to randomization (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	6.7 (5.70)	6.7 (6.08)	6.7 (5.82)
Positive P/Q type voltage-gated calcium channel (VGCC) antibodies at screening (Count of Participants)
Count of Participants [Participants]	12 85.7%	17 94.4%	29 90.6%
Compound Muscle Action Potential (CMAP) consistent with Lambert-Eaton Myasthenia (LEM) at screening (Count of Participants)
Count of Participants [Participants]	7 50%	10 55.6%	17 53.1%
Total Daily Dose of 3,4-DAP at randomization (mg) [Median (Full Range) ]
Median (Full Range) [mg]	80.0	80.0	80
Number of 3,4-DAP individual daily doses at randomization (number of daily doses) [Median (Full Range) ]
Median (Full Range) [number of daily doses]	4.5	5.0	5.0

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Continuous 3,4-Diaminopyridine (3,4-DAP)	3,4-DAP Taper to Placebo
Arm/Group Description	Subjects were continued on their usual pre-randomization 3,4-DAP dosing regimen.	Subjects were tapered off of their pre-randomization 3,4-DAP dosing regimen over 3 days with up to an additional 16 hours of placebo.
Measure Participants	14	18
Count of Participants [Participants]	0 0%	13 72.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Continuous 3,4-Diaminopyridine (3,4-DAP), 3,4-DAP Taper to Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	3,4-DAP	3,4-DAP Taper to Placebo
Arm/Group Description	Subjects were administered their usual dosage on their regular personalized schedule.	Subjects were administered decreasing amounts of 3,4-DAP on their regular personalized schedule
Measure Participants	14	18
Mean (Standard Deviation) [units on a scale]	-0.2 (1.24)	-2.4 (0.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Continuous 3,4-Diaminopyridine (3,4-DAP), 3,4-DAP Taper to Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	Adverse events were collected during the inpatient stay of up to 7 days on the clinical research unit and then weekly with standard telephone follow-up and diary entries for one month following discharge from the clinical research unit.
Adverse Event Reporting Description	The return of Lambert-Eaton Myasthenic Syndrome (LEMS)-related signs and symptoms in a withdrawal design was anticipated and therefore adverse events were categorized as (1) treatment emergent adverse events, (2) treatment emergent adverse events excluding LEMS-related signs and symptoms, and (3) LEMS-related signs and symptoms adverse events
Arm/Group Title	Continuous 3,4-Diaminopyridine (3,4-DAP)		3,4-DAP Taper to Placebo
Arm/Group Description	Subjects were administered their usual dosage on their regular personalized schedule		Subjects were administered decreasing amounts of 3,4-DAP on their regular personalized schedule
All Cause Mortality
	Continuous 3,4-Diaminopyridine (3,4-DAP)		3,4-DAP Taper to Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/18 (0%)
Serious Adverse Events
	Continuous 3,4-Diaminopyridine (3,4-DAP)		3,4-DAP Taper to Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		1/18 (5.6%)
Infections and infestations
pneumonia	0/14 (0%)	0	1/18 (5.6%)	1
Other (Not Including Serious) Adverse Events
	Continuous 3,4-Diaminopyridine (3,4-DAP)		3,4-DAP Taper to Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/14 (35.7%)		12/18 (66.7%)
Gastrointestinal disorders
Abdominal discomfort	0/14 (0%)		2/18 (11.1%)
Abdominal pain lower	0/14 (0%)		1/18 (5.6%)
Cheilitis	0/14 (0%)		1/18 (5.6%)
Nausea	0/14 (0%)		1/18 (5.6%)
Gastritis	1/14 (7.1%)		0/18 (0%)
General disorders
Pyrexia	0/14 (0%)		1/18 (5.6%)
Injection site bruising	1/14 (7.1%)		0/18 (0%)
Instillation site irritation	1/14 (7.1%)		0/18 (0%)
Immune system disorders
Seasonal allergy	0/14 (0%)		1/18 (5.6%)
Infections and infestations
Respiratory tract infection	0/14 (0%)		2/18 (11.1%)
Nasopharyngitis	1/14 (7.1%)		1/18 (5.6%)
Sinusitis	0/14 (0%)		1/18 (5.6%)
Oral herpes	1/14 (7.1%)		0/18 (0%)
Investigations
Blood glucose increased	0/14 (0%)		1/18 (5.6%)
Electrocardiogram QT prolonged	0/14 (0%)		1/18 (5.6%)
Metabolism and nutrition disorders
Gout	0/14 (0%)		1/18 (5.6%)
Musculoskeletal and connective tissue disorders
Back pain	1/14 (7.1%)		1/18 (5.6%)
Sjogren	0/14 (0%)		1/18 (5.6%)
Musculoskeletal stiffness	1/14 (7.1%)		0/18 (0%)
Nervous system disorders
Headache	1/14 (7.1%)		1/18 (5.6%)
Dizziness	0/14 (0%)		1/18 (5.6%)
Paresthesia	0/14 (0%)		1/18 (5.6%)
Sinus headache	0/14 (0%)		1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/14 (7.1%)		1/18 (5.6%)
Skin and subcutaneous tissue disorders
Rash	0/14 (0%)		1/18 (5.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first publication shall be a multicenter publication submitted after conclusion of the Study at all sites. If a multicenter publication is not submitted within 12 months, PIs may use results. The only other disclosure restriction on the PI is that the Sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period of 30 days for confidential review. This period may be extended by 60 days at Sponsor's request.