Myasthenia Gravis, Generalized
Conditions
Keywords
MuSK antibody positive
Brief summary
Efficacy and safety of amifampridine phosphate in improving the activities of daily living for patients with antibody positive MuSK myasthenia gravis.
Detailed description
Randomized, double-blind, placebo-controlled, parallel group study is designed to evaluate the safety, tolerability and efficacy of amifampridine phosphate in patients with MuSK-MG. In addition, a sample of AChR-MG patients will be assess for efficacy and safety of amifampridine phosphate. Planned duration of participation for each patient is at least 38 days, excluding the screening period. Eligible patients will be titrated to an efficacious dose of amifampridine phosphate and those who demonstrate improvement will be randomized to either placebo or amifampridine, in a double-blind fashion, for 10 days.
Interventions
tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day
DRUGPlacebo Oral Tablet
tablets matching amifampridine phosphate, 3 to 4 times a day
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. Willing and able to provide written informed consent after the nature of the study has been explained and before the start of any research-related procedures. 2. Male or female ≥18 years of age. 3. Positive serologic test for anti-MuSK antibodies or anti-AChR antibodies as confirmed at Screening or by previous antibody test, with report available. 4. Confirmatory EMG or EMG report. 5. Myasthenia Gravis Foundation of America (MGFA) Class II to IV at Screening. 6. MG-ADL score of ≥6 at Screening, with more than 50% of this score attributed to non-ocular items. 7. Patients receiving steroids or pyridostigmine should not have any modification of drug regimen during the month before Screening. 8. Female patients of childbearing potential must have a negative pregnancy test (serum human chorionic gonadotropin \[HCG\] at screening); and must practice an effective, reliable contraceptive regimen during the study and for up to 30 days following discontinuation of treatment. 9. Ability to participate in the study based on overall health of the patient and disease prognosis, as applicable, in the opinion of the Investigator; and able to comply with all requirements of the protocol, including completion of study questionnaires.
Exclusion criteria
1. Epilepsy and currently on medication. 2. Concomitant use of medicinal products with a known potential to cause QTc prolongation. 3. Patients with long QT syndromes. 4. History of thymectomy within 12 months before Screening. 5. An electrocardiogram (ECG) within 6 months before starting treatment that shows clinically significant abnormalities, in the opinion of the Investigator. 6. Breastfeeding or pregnant at Screening or planning to become pregnant at any time during the study. 7. Patients receiving immunomodulatory treatment (e.g. plasma exchange \[PE\], therapeutic plasma exchange \[TPE\], intravenous immunoglobulin G \[IVIG\]) should not have any treatment in the previous 4 weeks prior to Randomization or at any time during the study. 8. Use of rituximab or other similar biologic medications for immunomodulation within 6 months prior to Screening. 9. Treatment with an investigational drug (other than amifampridine) or device within 30 days before Screening or while participating in this study. 10. Any medical condition that, in the opinion of the Investigator, might interfere with the patient's participation in the study, poses an added risk for the patient, or confound the assessment of the patient. 11. History of drug allergy to any pyridine-containing substances or any amifampridine excipient(s).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Last day (Day 0) of the Run-in period and at the post-treatment visit (i.e., day 10 or the time point at which a patient discontinued treatment early). | Myasthenia Gravis-Activities of Daily Living (MG-ADL) is a self-report scale to assess the patient's MG symptoms and functional performance of activities of daily living. The eight items are scored on a scale of 0-3 with 3 representing the most severe symptoms or impaired performance and 0 representing no symptoms or impaired performance. Each item was assessed by the patient at the last day (Day 0) of the Run-in period and at the post-treatment visit. The post-treatment result will be the result obtained on Day 10. If the patient discontinued treatment early, the post-treatment result may be obtained at an earlier time point. The total MG-ADL score was calculated as the sum of each item score, with a maximum score of 24 (most severe symptoms/impairment) and minimum score of 0 (least severe symptoms/impairment). The change from baseline (CFB) at Day 10 was assessed. A Wilcoxon-Mann-Whitney Rank Sum Test of equality of change from baseline distributions between subjects diagnos |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Last day (Day 0) of the Run-in period and at the post-treatment visit (i.e., day 10 or the time at which a patient discontinued treatment early). | Quantitative Myasthenia Gravis (QMG) assesses the patient's general body strength and fatigability. Each test item is scored on a scale of 0-3 with 3 representing the most severe symptom results and 0 representing no symptom results. Each item was assessed by the patient at Screening, the first (Day 1) and last day (Day 0) of the Run-in period and at the post-treatment visit. The post-treatment result will be the result obtained on Day 10. If the patient discontinued treatment early, the post-treatment result may be obtained at an earlier time point. The total QMG score was calculated as the sum of each item score, with a maximum score of 39 (most severe symptoms) and minimum score of 0 (least severe symptoms). The change from baseline (CFB) at Day 10 was assessed. A Wilcoxon-Mann-Whitney Rank Sum Test of equality of change from baseline distributions between subjects diagnosed with MuSK-MG treated with amifampridine and placebo was conducted. |
Countries
United States
Participant flow
Recruitment details
The study was conducted from 18 April 2018 - 24 April 2020 at 26 sites in the United States and Europe.
Pre-assignment details
A screening visit was conducted to ensure that each patient met inclusion/exclusion criteria. Those patients successfully completing screening had procedures/assessments conducted at the start of the Run-in period (Day 1, before starting study medication) and during run-in, until stable dose and frequency of amifampridine is established for at least 7 days, and at least a 2-point improvement in MG-ADL score was achieved from the start of Run-in to be eligible for randomization (Day 0).
Participants by arm
| Arm | Count |
|---|---|
| Amifampridine Phosphate Amifampridine Phosphate: tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day | 34 |
| Placebo Placebo Oral Tablet: tablets matching amifampridine phosphate, 3 to 4 times a day | 36 |
| Amifampridine Phosphate Only Patients receiving Amifampridine during the open-label Run-in period but were not randomized for the crossover portion of the study. | 16 |
| Total | 86 |
Baseline characteristics
| Characteristic | Amifampridine Phosphate | Placebo | Amifampridine Phosphate Only | Total |
|---|---|---|---|---|
| Age, Continuous | 53.1 years STANDARD_DEVIATION 14.92 | 53.5 years STANDARD_DEVIATION 12.61 | 45.9 years STANDARD_DEVIATION 11.31 | 51.9 years STANDARD_DEVIATION 13.52 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 15 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 34 Participants | 1 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 164.7 cm STANDARD_DEVIATION 7.64 | 163.5 cm STANDARD_DEVIATION 10.75 | 163.6 cm STANDARD_DEVIATION 7.37 | 164.0 cm STANDARD_DEVIATION 8.99 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 31 Participants | 34 Participants | 13 Participants | 78 Participants |
| Sex: Female, Male Female | 24 Participants | 28 Participants | 14 Participants | 66 Participants |
| Sex: Female, Male Male | 10 Participants | 8 Participants | 2 Participants | 20 Participants |
| Weight | 84.6 kg STANDARD_DEVIATION 21.11 | 84.3 kg STANDARD_DEVIATION 27.27 | 76.1 kg STANDARD_DEVIATION 32.28 | 82.9 kg STANDARD_DEVIATION 25.96 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 86 | 0 / 36 | 0 / 86 |
| other Total, other adverse events | 80 / 86 | 7 / 36 | 80 / 86 |
| serious Total, serious adverse events | 2 / 86 | 0 / 36 | 2 / 86 |
Outcome results
Primary
Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results
Myasthenia Gravis-Activities of Daily Living (MG-ADL) is a self-report scale to assess the patient's MG symptoms and functional performance of activities of daily living. The eight items are scored on a scale of 0-3 with 3 representing the most severe symptoms or impaired performance and 0 representing no symptoms or impaired performance. Each item was assessed by the patient at the last day (Day 0) of the Run-in period and at the post-treatment visit. The post-treatment result will be the result obtained on Day 10. If the patient discontinued treatment early, the post-treatment result may be obtained at an earlier time point. The total MG-ADL score was calculated as the sum of each item score, with a maximum score of 24 (most severe symptoms/impairment) and minimum score of 0 (least severe symptoms/impairment). The change from baseline (CFB) at Day 10 was assessed. A Wilcoxon-Mann-Whitney Rank Sum Test of equality of change from baseline distributions between subjects diagnos
Time frame: Last day (Day 0) of the Run-in period and at the post-treatment visit (i.e., day 10 or the time point at which a patient discontinued treatment early).
Population: The analysis of primary outcome data was based on the Full Analysis Set population, which included all randomized patients who received at least one dose of study medication (amifampridine or placebo post randomization) and had at least one post-treatment efficacy assessment. Patients who discontinued with no post-randomization data (no Day 0 and no Day 10 data) were excluded from all efficacy analyses but were included in the safety analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amifampridine Phosphate - MuSK | Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Baseline (Day 0) MG-ADL Total Raw Score | 4.96 Score on a Scale | Standard Deviation 2.915 |
| Amifampridine Phosphate - MuSK | Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | CFB MG-ADL Total Score | 1.04 Score on a Scale | Standard Deviation 2.98 |
| Amifampridine Phosphate - MuSK | Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Post-Baseline(Day 10 or time at which a patient discontinued treatment) MG-ADL Total Raw Score | 6.00 Score on a Scale | Standard Deviation 3.658 |
| Placebo - MuSK | Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Post-Baseline(Day 10 or time at which a patient discontinued treatment) MG-ADL Total Raw Score | 6.11 Score on a Scale | Standard Deviation 3.19 |
| Placebo - MuSK | Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Baseline (Day 0) MG-ADL Total Raw Score | 3.86 Score on a Scale | Standard Deviation 2.103 |
| Placebo - MuSK | Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | CFB MG-ADL Total Score | 2.25 Score on a Scale | Standard Deviation 3.658 |
| Amifampridine Phosphate - AChR | Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Post-Baseline(Day 10 or time at which a patient discontinued treatment) MG-ADL Total Raw Score | 4.71 Score on a Scale | Standard Deviation 3.147 |
| Amifampridine Phosphate - AChR | Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | CFB MG-ADL Total Score | -1.43 Score on a Scale | Standard Deviation 2.225 |
| Amifampridine Phosphate - AChR | Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Baseline (Day 0) MG-ADL Total Raw Score | 6.14 Score on a Scale | Standard Deviation 3.388 |
| Placebo - AChR | Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Post-Baseline(Day 10 or time at which a patient discontinued treatment) MG-ADL Total Raw Score | 10.38 Score on a Scale | Standard Deviation 3.583 |
| Placebo - AChR | Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Baseline (Day 0) MG-ADL Total Raw Score | 7.00 Score on a Scale | Standard Deviation 4.175 |
| Placebo - AChR | Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | CFB MG-ADL Total Score | 3.38 Score on a Scale | Standard Deviation 2.825 |
Comparison: A Wilcoxon-Mann-Whitney Rank Sum Test of equality of change from baseline distributions between subjects diagnosed with MuSK-MG treated with amifampridine and placebo was conducted.p-value: 0.2196Wilcoxon (Mann-Whitney)
Secondary
Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results
Quantitative Myasthenia Gravis (QMG) assesses the patient's general body strength and fatigability. Each test item is scored on a scale of 0-3 with 3 representing the most severe symptom results and 0 representing no symptom results. Each item was assessed by the patient at Screening, the first (Day 1) and last day (Day 0) of the Run-in period and at the post-treatment visit. The post-treatment result will be the result obtained on Day 10. If the patient discontinued treatment early, the post-treatment result may be obtained at an earlier time point. The total QMG score was calculated as the sum of each item score, with a maximum score of 39 (most severe symptoms) and minimum score of 0 (least severe symptoms). The change from baseline (CFB) at Day 10 was assessed. A Wilcoxon-Mann-Whitney Rank Sum Test of equality of change from baseline distributions between subjects diagnosed with MuSK-MG treated with amifampridine and placebo was conducted.
Time frame: Last day (Day 0) of the Run-in period and at the post-treatment visit (i.e., day 10 or the time at which a patient discontinued treatment early).
Population: The analysis of secondary outcome data was based on the Full Analysis Set population, which included all randomized patients who received at least one dose of study medication (amifampridine or placebo post randomization) and had at least one post-treatment efficacy assessment. Patients who discontinued with no post-randomization data (no Day 0 and no Day 10 data) were excluded from all efficacy analyses but were included in the safety analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amifampridine Phosphate - MuSK | Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Post-Baseline (day 10 or time at which a patient discontinued treatment early) QMG Total Raw Score | 11.19 Score on a Scale | Standard Deviation 5.367 |
| Amifampridine Phosphate - MuSK | Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Baseline (Day 0) QMG Total Raw Score | 10.00 Score on a Scale | Standard Deviation 3.873 |
| Amifampridine Phosphate - MuSK | Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | CFB QMG Total Score | 1.19 Score on a Scale | Standard Deviation 3.99 |
| Placebo - MuSK | Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Post-Baseline (day 10 or time at which a patient discontinued treatment early) QMG Total Raw Score | 10.16 Score on a Scale | Standard Deviation 3.648 |
| Placebo - MuSK | Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Baseline (Day 0) QMG Total Raw Score | 8.64 Score on a Scale | Standard Deviation 3.744 |
| Placebo - MuSK | Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | CFB QMG Total Score | 1.80 Score on a Scale | Standard Deviation 3.948 |
| Amifampridine Phosphate - AChR | Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Baseline (Day 0) QMG Total Raw Score | 10.57 Score on a Scale | Standard Deviation 3.359 |
| Amifampridine Phosphate - AChR | Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | CFB QMG Total Score | 0.29 Score on a Scale | Standard Deviation 3.039 |
| Amifampridine Phosphate - AChR | Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Post-Baseline (day 10 or time at which a patient discontinued treatment early) QMG Total Raw Score | 10.86 Score on a Scale | Standard Deviation 3.024 |
| Placebo - AChR | Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | CFB QMG Total Score | 0.86 Score on a Scale | Standard Deviation 2.673 |
| Placebo - AChR | Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Post-Baseline (day 10 or time at which a patient discontinued treatment early) QMG Total Raw Score | 14.43 Score on a Scale | Standard Deviation 3.952 |
| Placebo - AChR | Quantitative Myasthenia Gravis (QMG) Total Score Summary Statistics by Time Point and MG Type: Wilcoxon-Mann-Whitney Rank Sum Test Results | Baseline (Day 0) QMG Total Raw Score | 14.13 Score on a Scale | Standard Deviation 4.155 |
Comparison: A Wilcoxon-Mann-Whitney Rank Sum Test of equality of change from baseline distributions between subjects diagnosed with MuSK-MG treated with amifampridine and placebo was conducted.p-value: 0.3736Wilcoxon (Mann-Whitney)