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Efficacy and safety of amifampridine phosphate in improving the activities of daily living for patients with antibody positive MuSK myasthenia gravis.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| amifamapridine phosphate tablets | Experimental |
| |
| placebo tablets | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Amifampridine Phosphate | Drug | tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 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). |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Renato Mantegazza, MD | Carlo Besta Neurologic Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cleveland Clinic | Cleveland | Ohio | 44195 | United States | ||
| Univerity of Pennsylvania |
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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).
The study was conducted from 18 April 2018 - 24 April 2020 at 26 sites in the United States and Europe.
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| ID | Title | Description |
|---|---|---|
| FG000 | Amifampridine Phosphate - MuSK | Amifampridine Phosphate: tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day MuSK - patients diagnosed with MuSK-MG |
| FG001 | Amifampridine Phosphate - AChR-MG | Amifampridine Phosphate: tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day AChR-MG- patients diagnosed with AChR-MG |
| FG002 | Placebo - MuSk | Placebo Oral Tablet: tablets matching amifampridine phosphate, 3 to 4 times a day MuSK - patients diagnosed with MuSK-MG |
| FG003 | Placebo - AChR-MG | Placebo Oral Tablet: tablets matching amifampridine phosphate, 3 to 4 times a day AChR-MG- patients diagnosed with AChR-MG |
| FG004 | Amifampridine Phosphate Only - MuSK | Patients receiving amifampridine during the open-label run-in period but were not randomized for the crossover portion of the study and diagnosed with MuSK-MG. |
| FG005 | Amifampridine Phosphate Only- AChR-MG | Patients receiving amifampridine during the open-label run-in period but were not randomized for the crossover portion of the study and diagnosed with AChR-MG. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
The analysis of baseline characteristics included all patients in the Safety population, who are those patients who enrolled and received at least one dose of amifampridine. Patients who began the run-in period belong to the Safety population whether they were randomized to treatment or not.
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| ID | Title | Description |
|---|---|---|
| BG000 | Amifampridine Phosphate | Amifampridine Phosphate: tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day |
| BG001 | Placebo | Placebo Oral Tablet: tablets matching amifampridine phosphate, 3 to 4 times a day |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | 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. | Posted | Mean | Standard Deviation | Score on a Scale |
Serious adverse events (SAEs) were recorded for each patient from the time informed consent was obtained at Screening and continues through four weeks after the last dose or at the early discontinuation visit, for a total of approximately 52 days. Non-serious AEs were recorded for each patient after the first administration of study drug through the last visit or at the early discontinuation visit, for a total of approximately 10 days.
Serious classification based on the FDA regulatory definition of a serious AE.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Amifampridine Phosphate | Amifampridine Phosphate: tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day. The AEs reported within this treatment arm are those experienced by all participants who received Amifampridine Phosphate at the time of onset of the AE. Because this study has a run-in period where all subjects received Amifampridine Phosphate, the number of at-risk subjects in this treatment arm is identical to the overall number of at-risk participants. That is, the at-risk count includes those randomized to the Amifampridine Phosphate-Placebo sequence, Placebo - Amifampridine Phosphate sequence and those that received Amifampridine Phosphate during the open-label Run-in period but were not randomized for the crossover portion of the study. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Myasthenia gravis | Nervous system disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal discomfort | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Gary Ingenito | Catalyst Pharmaceuticals, Inc. | 305-420-3200 | gingenito@catalystpharma.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 27, 2017 | Apr 13, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jan 27, 2020 | Apr 9, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D009157 | Myasthenia Gravis |
| ID | Term |
|---|---|
| D020361 | Paraneoplastic Syndromes, Nervous System |
| D009423 | Nervous System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D000077770 | Amifampridine |
| ID | Term |
|---|---|
| D015761 | 4-Aminopyridine |
| D000631 | Aminopyridines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
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| Placebo Oral Tablet | Drug | tablets matching amifampridine phosphate, 3 to 4 times a day |
|
| 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). |
| Philadelphia |
| Pennsylvania |
| 19104 |
| United States |
| BG002 | Amifampridine Phosphate Only | Patients receiving Amifampridine during the open-label Run-in period but were not randomized for the crossover portion of the study. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Weight | Mean | Standard Deviation | kg |
|
| Height | Mean | Standard Deviation | cm |
|
| 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). |
|
|
|
|
| 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. | 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. | Posted | Mean | Standard Deviation | Score on a Scale | 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). |
|
|
|
|
| 0 |
| 86 |
| 2 |
| 86 |
| 80 |
| 86 |
| EG001 | Placebo | Placebo Oral Tablet: tablets matching amifampridine phosphate, 3 to 4 times a day The AEs reported within this treatment arm are those experienced by participants who received Placebo at the time of onset of the AE. This includes those randomized to the Placebo - Amifampridine Phosphate sequence. | 0 | 36 | 0 | 36 | 7 | 36 |
| EG002 | Overall | Includes all participants who received study drug, including Amifampridine Phosphate during the open-label Run-in period or double-blind treatment period or Placebo during the double-blind treatment period. | 0 | 86 | 2 | 86 | 80 | 86 |
| Myasthenia gravis crisis | Nervous system disorders | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | Systematic Assessment |
|
| Hypoaesthesia oral | Gastrointestinal disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Paraesthesia oral | Gastrointestinal disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | Systematic Assessment |
|
| Peripheral coldness | Vascular disorders | Systematic Assessment |
|
| Tinnitus | Ear and labyrinth disorders | Systematic Assessment |
|
| Diplopia | Eye disorders | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Asthenia | General disorders | Systematic Assessment |
|
| Feeling cold | General disorders | Systematic Assessment |
|
| Feeling hot | General disorders | Systematic Assessment |
|
| Ear infection | Infections and infestations | Systematic Assessment |
|
| Hordeolum | Infections and infestations | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | Systematic Assessment |
|
| Sinusitis | Infections and infestations | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Mastication disorder | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Hypoaesthesia | Nervous system disorders | Systematic Assessment |
|
| Myasthenia gravis | Nervous system disorders | Systematic Assessment |
|
| Sensory disturbance | Nervous system disorders | Systematic Assessment |
|
| Speech disorder | Nervous system disorders | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Palpitations | Cardiac disorders | Systematic Assessment |
|
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| D010257 | Paraneoplastic Syndromes |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D019636 | Neurodegenerative Diseases |
| D020511 | Neuromuscular Junction Diseases |
| D009468 | Neuromuscular Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D011725 |
| Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| Post-Baseline (day 10 or time at which a patient discontinued treatment early) QMG Total Raw Score |
|
| CFB QMG Total Score |
|