Lambert-Eaton Myasthenic Syndrome
Conditions
Keywords
LEMS
Brief summary
This study evaluates the effect of withdrawing amifampridine phosphate treatment from patients with LEMS. One half of the patients will continue to receive amifampridine phosphate and the other half will receive placebo, during this double-blind study.
Detailed description
This was a randomized (1:1), double-blind, placebo-controlled, parallel-group, withdrawal study designed to evaluate the efficacy and safety of amifampridine phosphate in patients diagnosed with LEMS. The study was planned to include approximately 28 male and female patients. Prior to the study, patients were receiving unblinded treatment in the expanded access program (EAP-001). Patients had to be on a stable dose and frequency of amifampridine phosphate for at least 1 week prior to randomization into LMS-003. Screening and randomization (Day 0) may have been into a single visit. Patients who met eligibility criteria were randomized 1:1 to amifampridine phosphate (at the patient's optimal dose) or placebo on Day 0. Baseline assessments were obtained on Study Day 0, while the patient has been on open-label amifampridine phosphate and in relationship to the usual dosing schedule. Patients took blinded study medication on Day 1 through Day 3. On Day 4, a dose of blinded study medication was administered by the site study personnel. This was the same medication that the patient took on Day 1 through Day 3. The assessments listed below were performed following either the second, third, or fourth dose of medication taken on Day 4, and this should be the same dose after which Day 0 assessments were performed. For example, if the patient took their second dose of amifampridine in the clinic on Day 0 and had assessments started 40 minutes later, then on Day 4, that patient should be assessed after taking their second dose of investigational product (IP). Beginning with the next dose after all Day 0 baseline assessments were completed, the patient received IP through Day 4, with a clinic visit on the last day (Day 4) for assessments. The planned duration of participation for each patient was up to 12 days, including screening (up to 7 days), Day 0 assessments and randomization, and IP administration (Day 1 through Day 4).
Interventions
DRUGPlacebo Oral Tablet
Sponsors
Catalyst Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female ≥18 years of age and currently receiving amifampridine phosphate for LEMS. 2. Diagnosis of LEMS by antibody testing or electromyography (EMG). 3. Completion of anti-cancer treatment at least 3 months (90 days) prior to Screening. 4. If receiving peripherally acting cholinesterase inhibitors (e.g. pyridostigmine), a stable dose of cholinesterase inhibitors is required for at least 7 days prior to randomization and throughout the study. 5. If receiving permitted oral immunosuppressants (prednisone or other corticosteroid), a stable dose is required for at least 30 days prior to randomization and throughout the study. 6. Female patients of childbearing potential must practice an effective, reliable contraceptive regimen during the study. 7. Able to perform all study procedures and assessments. 8. Willing and able to travel to study site and attend all clinic study visits. 9. Willing and able to provide written informed consent.
Exclusion criteria
1. Clinically significant long corrected QT (QTc) interval on ECG in previous 12 months. 2. Seizure disorder. 3. Active brain metastases. 4. Unable to ambulate. 5. Pregnant or lactating females. 6. Any other condition which, in the opinion of the Investigator, might interfere with the patient's participation in the study or confound the assessment of the patient.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Quantitative Myasthenia Gravis (QMG) Score | change from baseline in QMG score at end of day 4 | The QMG is a physician-rated test including 13 assessments such as facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each assessment is graded as 0 (none), 1 (mild), 2 (moderate), or 3 (severe), for a total range of 0-39. A higher total score indicates a worse outcome. |
| Subject Global Impression (SGI) Score | change from baseline in SGI score at end of day 4 | The SGI is a 7-point scale on which the patient rates their global impression of the effects of a study treatment (1=terrible to 7=delighted). The SGI was assessed by the patient or the patient's parent/guardian/caregiver if the patient was unable to complete the SGI. The SGI has demonstrated concordance with the physician's assessment of improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinician's Global Impression of Improvement (CGI-I) at Day 4 Compared to Baseline | change from baseline in CGI-I score at end of day 4 | The CGI-I captures the Investigator's global impression of the patient's improvement or worsening from baseline status. The 7-point scale is scored by the Investigator based on changes in symptoms, behavior, and functional abilities. Each symptom is rated as 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), or 7 (very much worse). The total score can range from 0 to 49. A higher score indicates a worse outcome. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Triple Timed Up and Go Walk Test (3TUG) | change from baseline in 3TUG at end of day 4 | The 3TUG is a functional mobility test that requires a patient to stand up from a straight-backed armchair, walk 3 meters, turn around, walk back, and sit down in the chair. A modification of this is where the individual performs the test 3 times without pause, and the measurement is the average time required to complete each of the 3 repetitions. Based upon literature reports that a significant change in gait for a similar walk-test is an increase in time of more than 20%, this has been incorporated into the endpoint. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Amifampridine Phosphate amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days
Amifampridine Phosphate | 13 |
| Placebo (for Amifampridine Phosphate) placebo by mouth 3 to 4 times per day for 4 days
Placebo Oral Tablet | 13 |
| Total | 26 |
Baseline characteristics
| Characteristic | Amifampridine Phosphate | Placebo (for Amifampridine Phosphate) | Total |
|---|---|---|---|
| Age, Continuous | 54.9 years STANDARD_DEVIATION 11.51 | 53.4 years STANDARD_DEVIATION 13.46 | 54.2 years STANDARD_DEVIATION 12.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 12 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 16 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
| Weight | 77.62 kg STANDARD_DEVIATION 20.312 | 93.95 kg STANDARD_DEVIATION 15.449 | 85.78 kg STANDARD_DEVIATION 19.545 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 3 / 13 | 10 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
Primary
Quantitative Myasthenia Gravis (QMG) Score
The QMG is a physician-rated test including 13 assessments such as facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each assessment is graded as 0 (none), 1 (mild), 2 (moderate), or 3 (severe), for a total range of 0-39. A higher total score indicates a worse outcome.
Time frame: change from baseline in QMG score at end of day 4
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amifampridine Phosphate | Quantitative Myasthenia Gravis (QMG) Score | Day 4 | 7.9 scores on a scale | Standard Deviation 4.94 |
| Amifampridine Phosphate | Quantitative Myasthenia Gravis (QMG) Score | Change from baseline | 0.1 scores on a scale | Standard Deviation 3.07 |
| Amifampridine Phosphate | Quantitative Myasthenia Gravis (QMG) Score | Baseline | 7.8 scores on a scale | Standard Deviation 4.2 |
| Placebo (for Amifampridine Phosphate) | Quantitative Myasthenia Gravis (QMG) Score | Baseline | 8.5 scores on a scale | Standard Deviation 5.43 |
| Placebo (for Amifampridine Phosphate) | Quantitative Myasthenia Gravis (QMG) Score | Day 4 | 15.0 scores on a scale | Standard Deviation 5.9 |
| Placebo (for Amifampridine Phosphate) | Quantitative Myasthenia Gravis (QMG) Score | Change from baseline | 6.5 scores on a scale | Standard Deviation 4.82 |
p-value: 0.0004Least square means
Primary
Subject Global Impression (SGI) Score
The SGI is a 7-point scale on which the patient rates their global impression of the effects of a study treatment (1=terrible to 7=delighted). The SGI was assessed by the patient or the patient's parent/guardian/caregiver if the patient was unable to complete the SGI. The SGI has demonstrated concordance with the physician's assessment of improvement.
Time frame: change from baseline in SGI score at end of day 4
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amifampridine Phosphate | Subject Global Impression (SGI) Score | Baseline | 6.1 scores on a scale | Standard Deviation 0.86 |
| Amifampridine Phosphate | Subject Global Impression (SGI) Score | Day 4 | 5.3 scores on a scale | Standard Deviation 1.65 |
| Amifampridine Phosphate | Subject Global Impression (SGI) Score | Change from baseline to Day 4 | -0.8 scores on a scale | Standard Deviation 1.74 |
| Placebo (for Amifampridine Phosphate) | Subject Global Impression (SGI) Score | Baseline | 5.8 scores on a scale | Standard Deviation 0.9 |
| Placebo (for Amifampridine Phosphate) | Subject Global Impression (SGI) Score | Day 4 | 2.4 scores on a scale | Standard Deviation 1.76 |
| Placebo (for Amifampridine Phosphate) | Subject Global Impression (SGI) Score | Change from baseline to Day 4 | -3.5 scores on a scale | Standard Deviation 2.18 |
p-value: 0.000395% CI: [1.53, 4.38]Fixed effects linear model
Secondary
Change in Clinician's Global Impression of Improvement (CGI-I) at Day 4 Compared to Baseline
The CGI-I captures the Investigator's global impression of the patient's improvement or worsening from baseline status. The 7-point scale is scored by the Investigator based on changes in symptoms, behavior, and functional abilities. Each symptom is rated as 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), or 7 (very much worse). The total score can range from 0 to 49. A higher score indicates a worse outcome.
Time frame: change from baseline in CGI-I score at end of day 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amifampridine Phosphate | Change in Clinician's Global Impression of Improvement (CGI-I) at Day 4 Compared to Baseline | 3.8 scores on a scale | Standard Deviation 0.8 |
| Placebo (for Amifampridine Phosphate) | Change in Clinician's Global Impression of Improvement (CGI-I) at Day 4 Compared to Baseline | 5.5 scores on a scale | Standard Deviation 1.27 |
p-value: 0.002Wilcoxon Rank Sum Test
Other Pre-specified
Triple Timed Up and Go Walk Test (3TUG)
The 3TUG is a functional mobility test that requires a patient to stand up from a straight-backed armchair, walk 3 meters, turn around, walk back, and sit down in the chair. A modification of this is where the individual performs the test 3 times without pause, and the measurement is the average time required to complete each of the 3 repetitions. Based upon literature reports that a significant change in gait for a similar walk-test is an increase in time of more than 20%, this has been incorporated into the endpoint.
Time frame: change from baseline in 3TUG at end of day 4
Population: The number and proportion of patients with a ≥20% increase in 3TUG average time
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amifampridine Phosphate | Triple Timed Up and Go Walk Test (3TUG) | 1 Participants |
| Placebo (for Amifampridine Phosphate) | Triple Timed Up and Go Walk Test (3TUG) | 8 Participants |
p-value: 0.0112Fisher Exact