Eaton-Lambert Myasthenic Syndrome, Lambert-Eaton Myasthenic Syndrome
Conditions
Keywords
Lambert-Eaton, Eaton-Lambert, myasthenia, myasthenic, LEMS, LES, DAP, diaminopyridine, 3,4-diaminopyridine, 3,4-DAP
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.
Interventions
DRUGContinuous 3,4-DAP
Subjects were maintained on their usual personal dose and schedule of 3,4-DAP base
DRUGTaper 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
Sponsors
Jacobus Pharmaceutical
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
Countries
United States
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 details
52 patients were assessed for eligibility. 20 were ineligible. 32 were randomized and completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Continuous 3,4-Diaminopyridine (3,4-DAP) Subjects were administered their usual dosage on their regular personalized schedule | 14 |
| 3,4-DAP Taper to Placebo Subjects were administered decreasing amounts of 3,4-DAP on their regular personalized schedule | 18 |
| Total | 32 |
Baseline characteristics
| Characteristic | Total | Continuous 3,4-Diaminopyridine (3,4-DAP) | 3,4-DAP Taper to Placebo |
|---|---|---|---|
| Age at diagnosis | 48.9 years STANDARD_DEVIATION 14.76 | 44.1 years STANDARD_DEVIATION 13.79 | 52.7 years STANDARD_DEVIATION 14.76 |
| Age, Continuous | 55.5 years STANDARD_DEVIATION 15.77 | 50.7 years STANDARD_DEVIATION 15.97 | 59.3 years STANDARD_DEVIATION 14.99 |
| Body Mass Index (BMI) | 27.5 kg/m2 STANDARD_DEVIATION 5.39 | 27.3 kg/m2 STANDARD_DEVIATION 5.92 | 27.7 kg/m2 STANDARD_DEVIATION 5.14 |
| Compound Muscle Action Potential (CMAP) consistent with Lambert-Eaton Myasthenia (LEM) at screening | 17 Participants | 7 Participants | 10 Participants |
| Duration of diagnosis prior to randomization | 6.7 years STANDARD_DEVIATION 5.82 | 6.7 years STANDARD_DEVIATION 5.7 | 6.7 years STANDARD_DEVIATION 6.08 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 14 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 169.2 cm STANDARD_DEVIATION 7.67 | 168.5 cm STANDARD_DEVIATION 5.67 | 169.6 cm STANDARD_DEVIATION 8.98 |
| Number of 3,4-DAP individual daily doses at randomization | 5.0 number of daily doses | 4.5 number of daily doses | 5.0 number of daily doses |
| Positive P/Q type voltage-gated calcium channel (VGCC) antibodies at screening | 29 Participants | 12 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 11 Participants | 18 Participants |
| Sex: Female, Male Female | 21 Participants | 10 Participants | 11 Participants |
| Sex: Female, Male Male | 11 Participants | 4 Participants | 7 Participants |
| Time between symptom onset and diagnosis | 1.7 years STANDARD_DEVIATION 2.35 | 0.9 years STANDARD_DEVIATION 0.62 | 2.2 years STANDARD_DEVIATION 3 |
| Total Daily Dose of 3,4-DAP at randomization | 80 mg | 80.0 mg | 80.0 mg |
| Weight | 79.3 kg STANDARD_DEVIATION 18.73 | 78.0 kg STANDARD_DEVIATION 19.11 | 80.3 kg STANDARD_DEVIATION 18.95 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 18 |
| other Total, other adverse events | 5 / 14 | 12 / 18 |
| serious Total, serious adverse events | 0 / 14 | 1 / 18 |
Outcome results
Primary
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.
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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Continuous 3,4-Diaminopyridine (3,4-DAP) | Number of Participants With 30% or More Deterioration in Triple Timed Up & Go (3TUG) Test, Compared to Time-matched Baseline | 0 Participants |
| 3,4-DAP Taper to Placebo | Number of Participants With 30% or More Deterioration in Triple Timed Up & Go (3TUG) Test, Compared to Time-matched Baseline | 13 Participants |
p-value: <0.0001Fisher Exact
Secondary
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).
Time frame: Participants were followed for up to 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Continuous 3,4-Diaminopyridine (3,4-DAP) | Self-assessment of LEMS-related Weakness, W-SAS | -0.2 units on a scale | Standard Deviation 1.24 |
| 3,4-DAP Taper to Placebo | Self-assessment of LEMS-related Weakness, W-SAS | -2.4 units on a scale | Standard Deviation 0.85 |
p-value: 0.0001t-test, 2 sided