Lambert Eaton Myasthenic Syndrome
Conditions
Brief summary
A Phase 3 study to evaluate the efficacy and safety of Amifampridine Phosphate in patients with Lambert-Eaton Myasthenic Syndrome (LEMS).
Detailed description
This multicenter, double-blind, placebo-controlled, randomized (1:1) discontinuation study is a 4-part study designed to evaluate the efficacy and safety of multiple dose administration of amifampridine phosphate in patients with LEMS. Data from parts 2 and 3 (the double-blind parts of the study) are presented in this record.
Interventions
Amifampridine, 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets), for 2 weeks.
DRUGPlacebo
Matching placebo tablets administered 3-4 times a day (to the individual patient's tablet count of active at baseline) over 2 weeks.
Sponsors
Catalyst Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Individuals eligible to participate in this study must meet all of the following inclusion criteria: * ≥18 years of age * Confirmed diagnosis of LEMS * Normal respiratory function * Normal swallowing function * If receiving peripherally acting cholinesterase inhibitors a stable dose is required for at least 7 days prior to Screening. * If receiving oral immunosuppressants a stable dose is required for at least 90 days prior to Screening. * Negative pregnancy test for females of childbearing potential * If sexually active, willing to use 2 acceptable methods of contraception * Willing to perform all study procedures as physically possible. * Willing and able to provide written informed consent after the nature of the study has been explained and prior to the start of any research-related procedures.
Exclusion criteria
Individuals who meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days | Assessment at Baseline and Day 14 | The QMG is a physician-rated test including 13 assessments, including facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each of the 13 items is scored from 0 (none) to 3 (severe). The total score can range from 0 to 39. Increased QMG total score correlates to worsening symptoms of LEMS. |
| Change in SGI Score | Assessment at Baseline and Day 14 | Subject Global Impression (SGI) is a measure of changes in subject's perception of change in overall wellbeing. The patient is asked to use the 7-point scale below to rate their impression of the effects of the study medication during the preceding 3 days on their physical well being. 1. Terrible 2. Mostly dissatisfied 3. Mixed 4. Partially satisfied 5. Mostly satisfied 6. Pleased 7. Delighted |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days | Assessment at Baseline and Day 14 | The T25FW test, a component of the Multiple Sclerosis Functional Composite, was a quantitative mobility and leg function performance test based on a timed 25-foot walk (National Multiple Sclerosis Society). The patient was directed to walk a clearly marked 25-foot course as quickly and safely as possible. Following a rest of at least 5 minutes, the timed 25-foot walk was repeated. Patients could use assistive devices, such as canes, crutches, or walkers. All data were normalized to the number of feet per minute, so if the patient walked 25 feet in less than a minute, the result was a speed greater than 25 feet/minute. The measurement for the T25FW test was the average speed, expressed in feet/minute, of the 2 completed walks. |
| Change in CGI-I Score | Baseline and Day 14 | The Investigator completed the 7-point CGI I, based on changes in symptoms, behavior, and functional abilities, at the protocol-specified time points compared to the patient's condition at Day 0. 1. = Very much improved 2. = Much improved 3. = Minimally improved 4. = No change 5. = Minimally worse 6. = Much worse 7. = Very much worse |
Countries
France, Germany, Hungary, Poland, Russia, Serbia, Spain, United States
Participant flow
Recruitment details
The study was conducted at 13 clinical sites in 8 countries, including France, Germany, Hungary, Poland, Russia, Serbia, Spain, and the United States. The study was conducted from 03Jun2011 to 08Jul2016.
Pre-assignment details
Open-label Run-in (Part 1): titration to the optimal amifampridine dose (well tolerated and resulted in a ≥3 point improvement in QMG score from Screening for patients without previous amifampridine use) for each individual patient. Patients who did not receive amifampridine prior to Run-in and who did not reach the optimal dose were discontinued.
Participants by arm
| Arm | Count |
|---|---|
| Part 2 and Part 3 Placebo Matching placebo tablets, administered 3-4 times a day for 2 weeks.
Placebo tablets indistinguishable from amifampridine phosphate tablets. The placebo was administered consistent with the dose and dose regimen of amifampridine phosphate. | 22 |
| Part 2 and Part 3 Amifampridine Phosphate Matching amifampridine phosphate tablets, 10 mg, administered 3-4 times a day for 2 weeks.
Amifampridine Phosphate: 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets). | 16 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | rescue tx after part 2, entered part 4 | 1 | 0 |
Baseline characteristics
| Characteristic | Part 2 and Part 3 Placebo | Part 2 and Part 3 Amifampridine Phosphate | Total |
|---|---|---|---|
| Age, Continuous | 51.5 years STANDARD_DEVIATION 17.57 | 51.6 years STANDARD_DEVIATION 12.05 | 51.5 years STANDARD_DEVIATION 15.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 12 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| If yes, number of continuous days of amifampridine exposure immediately prior to enrollment | 1287.1 days STANDARD_DEVIATION 1525.73 | 2143.3 days STANDARD_DEVIATION 3080.16 | 1544.0 days STANDARD_DEVIATION 1957.36 |
| 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 21 Participants | 13 Participants | 34 Participants |
| Sex: Female, Male Female | 14 Participants | 9 Participants | 23 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 15 Participants |
| Was the patient taking amifampridine (base or phosphate) immediately prior to enrollment? No | 15 Participants | 13 Participants | 28 Participants |
| Was the patient taking amifampridine (base or phosphate) immediately prior to enrollment? Yes | 7 Participants | 3 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 16 |
| other Total, other adverse events | 6 / 21 | 3 / 16 |
| serious Total, serious adverse events | 0 / 22 | 0 / 16 |
Outcome results
Primary
Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days
The QMG is a physician-rated test including 13 assessments, including facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each of the 13 items is scored from 0 (none) to 3 (severe). The total score can range from 0 to 39. Increased QMG total score correlates to worsening symptoms of LEMS.
Time frame: Assessment at Baseline and Day 14
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days | Day 14 | 7.9 QMG Score | Standard Deviation 2.85 |
| Placebo | Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days | Baseline | 5.6 QMG Score | Standard Deviation 3.99 |
| Placebo | Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days | Change from Baseline | 2.2 QMG Score | Standard Deviation 2.93 |
| Amifampridine Phosphate | Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days | Baseline | 6.4 QMG Score | Standard Deviation 3.22 |
| Amifampridine Phosphate | Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days | Day 14 | 6.7 QMG Score | Standard Deviation 4.09 |
| Amifampridine Phosphate | Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days | Change from Baseline | 0.3 QMG Score | Standard Deviation 2.6 |
p-value: 0.0452Mixed Models Analysis
Primary
Change in SGI Score
Subject Global Impression (SGI) is a measure of changes in subject's perception of change in overall wellbeing. The patient is asked to use the 7-point scale below to rate their impression of the effects of the study medication during the preceding 3 days on their physical well being. 1. Terrible 2. Mostly dissatisfied 3. Mixed 4. Partially satisfied 5. Mostly satisfied 6. Pleased 7. Delighted
Time frame: Assessment at Baseline and Day 14
Population: FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in SGI Score | Baseline | 5.9 SGI score | Standard Deviation 1.22 |
| Placebo | Change in SGI Score | Day 14 | 3.2 SGI score | Standard Deviation 1.7 |
| Placebo | Change in SGI Score | Change from Baseline | -2.7 SGI score | Standard Deviation 2.29 |
| Amifampridine Phosphate | Change in SGI Score | Baseline | 5.6 SGI score | Standard Deviation 1.26 |
| Amifampridine Phosphate | Change in SGI Score | Day 14 | 4.9 SGI score | Standard Deviation 1.57 |
| Amifampridine Phosphate | Change in SGI Score | Change from Baseline | -0.7 SGI score | Standard Deviation 1.82 |
Comparison: Estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline SGI score as fixed effects and patient as a random effect. The model assumed time effect to be random between patientsp-value: 0.0028Mixed Models Analysis
Secondary
Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days
The T25FW test, a component of the Multiple Sclerosis Functional Composite, was a quantitative mobility and leg function performance test based on a timed 25-foot walk (National Multiple Sclerosis Society). The patient was directed to walk a clearly marked 25-foot course as quickly and safely as possible. Following a rest of at least 5 minutes, the timed 25-foot walk was repeated. Patients could use assistive devices, such as canes, crutches, or walkers. All data were normalized to the number of feet per minute, so if the patient walked 25 feet in less than a minute, the result was a speed greater than 25 feet/minute. The measurement for the T25FW test was the average speed, expressed in feet/minute, of the 2 completed walks.
Time frame: Assessment at Baseline and Day 14
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days | Day 14 | 244 feet/minute | Standard Deviation 116 |
| Placebo | Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days | Change from Baseline | -10.4 feet/minute | Standard Deviation 53.1 |
| Placebo | Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days | Baseline | 255 feet/minute | Standard Deviation 111 |
| Amifampridine Phosphate | Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days | Day 14 | 253 feet/minute | Standard Deviation 126 |
| Amifampridine Phosphate | Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days | Change from Baseline | -1.46 feet/minute | Standard Deviation 52.5 |
| Amifampridine Phosphate | Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days | Baseline | 254 feet/minute | Standard Deviation 126 |
Comparison: Estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline T25FW walking speed as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.p-value: 0.6274Mixed Models Analysis
Secondary
Change in CGI-I Score
The Investigator completed the 7-point CGI I, based on changes in symptoms, behavior, and functional abilities, at the protocol-specified time points compared to the patient's condition at Day 0. 1. = Very much improved 2. = Much improved 3. = Minimally improved 4. = No change 5. = Minimally worse 6. = Much worse 7. = Very much worse
Time frame: Baseline and Day 14
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in CGI-I Score | Baseline | 2.5 CGI-I score | Standard Deviation 0.98 |
| Placebo | Change in CGI-I Score | Day 14 | 4.8 CGI-I score | Standard Deviation 1.45 |
| Amifampridine Phosphate | Change in CGI-I Score | Baseline | 2.6 CGI-I score | Standard Deviation 0.63 |
| Amifampridine Phosphate | Change in CGI-I Score | Day 14 | 3.6 CGI-I score | Standard Deviation 1.5 |
Comparison: Estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction as fixed effects and patient as a random effect. The model assumed time effect to be random between patientsp-value: 0.0267Mixed Models Analysis