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This randomized, double-blind, controlled, outpatient two-period, two-treatment crossover study is designed to evaluate the efficacy and safety of amifampridine phosphate in patients (ages 2 and above) diagnosed with certain genetic subtypes of CMS and demonstrated open label (amifampridine phosphate) or history of sustained amifampridine benefit from treatment.
Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, blinded treatment effect will be assessed in a randomized fashion of continuation or cessation of drug (Placebo) starting with Period I (duration 7 days). Following experimental Period 1, patients will be returned to the stable dose administered at the end of the open-label run-in period for approximately 2 weeks, followed by cross over treatment in Period 2 dosing for 7 days. After completion of Period 2, patients will be eligible for expanded access with restoration of open-label amifampridine phosphate at the same dose and frequency as established in the run in phase of the study.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| amifampridine phosphate -placebo | Experimental | Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, half of the subjects will be randomized to receive amifampridine in Period I and then crossed over to receive placebo in Period II. Each randomized treatment period is 7 days in duration and is separated by a re-stabilization period of approximately two weeks where the subject will be returned to the stable dose administered at the end of the open-label run-in period. Dosing will be between 20 - 80 mg per day and frequency will be between 2-4 times per day. |
|
| placebo - amifampridine phosphate | Experimental | Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, half of the subjects will be randomized to receive placebo in Period I and then crossed over to receive amifampridine in Period II. Each randomized treatment period is 7 days in duration and separated by a re-stabilization period of approximately two weeks where the subject will be returned to the stable dose administered at the end of the open-label run-in period. Dosing will be between 20 - 80 mg per day and frequency will be between 2-4 times per day. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| amifampridine phosphate | Drug | Amifampridine phosphate tablets 10 mg will be provided in round, white-scored tablets, and containing amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet. |
| Measure | Description | Time Frame |
|---|---|---|
| Subject Global Impression (SGI) Score Summary: Mann-Whitney Main Effects Test Results; SGI Score Mixed Model Analysis | Subject Global Impression (SGI) rates the subject's impression of the effects of the study medication during the preceding week with max score =7 (most satisfied) and min score =1 (least satisfied). It will be completed at D0 (baseline for Study Period 1), D8, D21 (baseline for Study Period 2), and D29. Change from baseline (CFB) will be assessed for Study Period 1 (difference in SGI score from D0 to D8), Study Period 2 (difference in SGI score from D21 to D29) and the change in CFB from Study Period 1 to Study Period 2 (difference between CFB during Study Period 1 and CFB during Study Period 2). A Mann-Whitney-Wilcoxon test for equality of the CFB results in the two treatments in Period 1 and for the equality of the CFB results in the two treatment sequences will be conducted. A mixed effects liner model will be fit with the SGI raw scores as a response and study arm, treatment, period, age group and mutation type as fixed effect terms and patient as a random effect. | Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29 |
| Measure | Description | Time Frame |
|---|---|---|
| Motor Function Measure 32 (MFM-32) Score Summary: Mann-Whitney Main Effect Test Results, MFM-32 Score Mixed Model Analysis | Motor Function Measure 32 (MFM-32) evaluates the severity and progression of motor function in patients 7 years of age or older with max total score = 96 (best score) and min total score =0 (worst score). It will be completed at D0 (baseline for Study Period 1), D8, D21 (baseline for Study Period 2) and D29. CFB will be assessed for Study Period 1 (difference in MFM-32 from D0 to D8), Study Period 2 (difference in MFM-32 from D21 to D28) and the change in CFB from Study Period 1 to Study Period 2 (difference between CFB during Study Period 1 and CFB during Study Period 2). A Mann-Whitney-Wilcoxon test for equality of CFB results in the two treatments in Period 1 and for the equality of the CFB results in the two treatment sequences will be conducted. A mixed effects linear model will be fit to the overall MFM-32 score as the response variable and fixed effect terms for treatment, period, age group, genetic mutation type, and sequence*period and a random effect for patient. |
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Inclusion Criteria:
Individuals eligible to participate in this study must meet all of the following inclusion criteria:
Exclusion Criteria:
Individuals who meet any of the following exclusion criteria are not eligible to participate in the study:
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| Name | Affiliation | Role |
|---|---|---|
| Thomas Crawford, M.D. | Johns Hopkins Pediatric Neurology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UCLA Department of Neurology | Los Angeles | California | 90095 | United States | ||
| Johns Hopkins Pediatric Neurology |
Screening ensured patients met I/E criteria. Patients naïve to amifampridine began open-label titration until a stable dose and frequency was achieved for 7 days. Demonstrated efficacy (assessed by improvement on the MFM) was required to participate in the randomized portion of the study. Patients already on a stable dose with hostory of meaningful improvement were eligible immediately and transitioned to an equivalent dose of amifampridine phosphate for 7 days prior to randomization.
The study was conducted from 08 February 2016 - 24 January 2019 and was conducted at six sites in the United States and two sites in Canada, although one site (Montreal Neurological Institute and Hospital) did not enroll any patients.
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| ID | Title | Description |
|---|---|---|
| FG000 | Amifampridine Phosphate - Placebo | Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, half of the subjects will be randomized to receive amifampridine in Period I and then crossed over to receive placebo in Period II. Each randomized treatment period is 7 days in duration and is separated by a re-stabilization period of approximately two weeks where the subject will be returned to the stable dose administered at the end of the open-label run-in period. Dosing will be between 20 - 80 mg per day and frequency will be between 2-4 times per day. Amifampridine Phosphate: Amifampridine phosphate tablets 10 mg will be provided in round, white-scored tablets, and containing amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet. Placebo: A placebo equivalent will be provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo will be administered consistent with the dose regimen of amifampridine phosphate. |
| FG001 | Placebo - Amifampridine Phosphate | Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, half of the subjects will be randomized to receive placebo in Period I and then crossed over to receive amifampridine in Period II. Each randomized treatment period is 7 days in duration and separated by a re-stabilization period of approximately two weeks where the subject will be returned to the stable dose administered at the end of the open-label run-in period. Dosing will be between 20 - 80 mg per day and frequency will be between 2-4 times per day. amifampridine phosphate: Amifampridine phosphate tablets 10 mg will be provided in round, white-scored tablets, and containing amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet. Placebo: A placebo equivalent will be provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo will be administered consistent with the dose regimen of amifampridine phosphate. |
| FG002 | Amifampridine Phosphate Only | Patients receiving amifampridine during the open-label run-in period but were not randomized for the crossover portion of the study. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Safety population: All randomized patients who have received at least one dose of study medication. Note that subjects in the Amifampridine Phosphate Only arm are excluded from this analysis, as they were not randomized for inclusion in the crossover portion of the study.
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| ID | Title | Description |
|---|---|---|
| BG000 | Amifampridine Phosphate - Placebo | Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, half of the subjects will be randomized to receive amifampridine in Period I and then crossed over to receive placebo in Period II. Each randomized treatment period is 7 days in duration and is separated by a re-stabilization period of approximately two weeks where the subject will be returned to the stable dose administered at the end of the open-label run-in period. Dosing will be between 20 - 80 mg per day and frequency will be between 2-4 times per day. Amifampridine Phosphate: Amifampridine phosphate tablets 10 mg will be provided in round, white-scored tablets, and containing amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet. Placebo: A placebo equivalent will be provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo will be administered consistent with the dose regimen of amifampridine phosphate. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Subject Global Impression (SGI) Score Summary: Mann-Whitney Main Effects Test Results; SGI Score Mixed Model Analysis | Subject Global Impression (SGI) rates the subject's impression of the effects of the study medication during the preceding week with max score =7 (most satisfied) and min score =1 (least satisfied). It will be completed at D0 (baseline for Study Period 1), D8, D21 (baseline for Study Period 2), and D29. Change from baseline (CFB) will be assessed for Study Period 1 (difference in SGI score from D0 to D8), Study Period 2 (difference in SGI score from D21 to D29) and the change in CFB from Study Period 1 to Study Period 2 (difference between CFB during Study Period 1 and CFB during Study Period 2). A Mann-Whitney-Wilcoxon test for equality of the CFB results in the two treatments in Period 1 and for the equality of the CFB results in the two treatment sequences will be conducted. A mixed effects liner model will be fit with the SGI raw scores as a response and study arm, treatment, period, age group and mutation type as fixed effect terms and patient as a random effect. | The Full Analysis Set consists of all randomized patients who receive at least one dose of study medication and have at least one post-treatment efficacy assessment. | Posted | Mean | Standard Deviation | Scores on a scale | Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29 |
Serious adverse events (SAEs) were recorded for each patient from the time informed consent was obtained and continues through four weeks after the last dose or at the early discontinuation visit, for a total of approximately 14 weeks. Non-serious AEs were recorded for each patient after informed consent is obtained and the first administration of study drug (on Day 1 of run-in) through the last visit or at the early discontinuation visit, for a total of approximately 10 weeks .
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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 | Treatment administered to the patient at the time of onset of the AE. Includes patients who received amifampridine phosphate during the run-in period who were not randomized for inclusion in the crossover portion of the study. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pyrexia | General disorders | MedDRA 19.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ear haemorrhage | Ear and labyrinth disorders | MedDRA 19.1 | 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 26, 2017 | Feb 8, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Aug 20, 2019 | Feb 8, 2021 | SAP_001.pdf |
| ID | Term |
|---|---|
| D020294 | Myasthenic Syndromes, Congenital |
| ID | Term |
|---|---|
| D020511 | Neuromuscular Junction Diseases |
| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D030342 | Genetic Diseases, Inborn |
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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 | Drug | A placebo equivalent will be provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo will be administered consistent with the dose regimen of amifampridine phosphate. |
|
| Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29 |
| Motor Function Measure 20 (MFM-20) Score Mixed Model Analysis, MFM-20 Score Mixed Model Analysis | Motor Function Measure 20 (MFM-20) evaluates the severity and progression of motor function in patients 2 to 6 years of age with max total score = 60 (best score) and min total score =0 (worst score). It will be completed at D0 (baseline for Study Period 1), D8, D21 (baseline for Study Period 2) and D29. CFB will be assessed for Study Period 1 (difference in MFM-20 from D0 to D8), Study Period 2 (difference in MFM-20 from D21 to D28) and the change in CFB from Study Period 1 to Study Period 2 (difference between CFB during Study Period 1 and CFB during Study Period 2). A Mann-Whitney-Wilcoxon test for equality of CFB results in the two treatments in Period 1 and for the equality of the CFB results in the two treatment sequences will be conducted. A mixed effects linear model will be fit to the overall MFM-32 score as the response variable and fixed effect terms for treatment, period, age group, genetic mutation type, and sequence*period and a random effect for patient. | Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29 |
| Baltimore |
| Maryland |
| 21287 |
| United States |
| Boston Children's Hospital | Boston | Massachusetts | 02115 | United States |
| Ohio State University | Columbus | Ohio | 43221 | United States |
| BG001 | Placebo - Amifampridine Phosphate | Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, half of the subjects will be randomized to receive placebo in Period I and then crossed over to receive amifampridine in Period II. Each randomized treatment period is 7 days in duration and separated by a re-stabilization period of approximately two weeks where the subject will be returned to the stable dose administered at the end of the open-label run-in period. Dosing will be between 20 - 80 mg per day and frequency will be between 2-4 times per day. amifampridine phosphate: Amifampridine phosphate tablets 10 mg will be provided in round, white-scored tablets, and containing amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet. Placebo: A placebo equivalent will be provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo will be administered consistent with the dose regimen of amifampridine phosphate. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
|
|
|
|
| Secondary | Motor Function Measure 32 (MFM-32) Score Summary: Mann-Whitney Main Effect Test Results, MFM-32 Score Mixed Model Analysis | Motor Function Measure 32 (MFM-32) evaluates the severity and progression of motor function in patients 7 years of age or older with max total score = 96 (best score) and min total score =0 (worst score). It will be completed at D0 (baseline for Study Period 1), D8, D21 (baseline for Study Period 2) and D29. CFB will be assessed for Study Period 1 (difference in MFM-32 from D0 to D8), Study Period 2 (difference in MFM-32 from D21 to D28) and the change in CFB from Study Period 1 to Study Period 2 (difference between CFB during Study Period 1 and CFB during Study Period 2). A Mann-Whitney-Wilcoxon test for equality of CFB results in the two treatments in Period 1 and for the equality of the CFB results in the two treatment sequences will be conducted. A mixed effects linear model will be fit to the overall MFM-32 score as the response variable and fixed effect terms for treatment, period, age group, genetic mutation type, and sequence*period and a random effect for patient. | The Full Analysis Set consists of all randomized patients who receive at least one dose of study medication and have at least one post-treatment efficacy assessment. | Posted | Mean | Standard Deviation | Score on a Scale | Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29 |
|
|
|
|
| Secondary | Motor Function Measure 20 (MFM-20) Score Mixed Model Analysis, MFM-20 Score Mixed Model Analysis | Motor Function Measure 20 (MFM-20) evaluates the severity and progression of motor function in patients 2 to 6 years of age with max total score = 60 (best score) and min total score =0 (worst score). It will be completed at D0 (baseline for Study Period 1), D8, D21 (baseline for Study Period 2) and D29. CFB will be assessed for Study Period 1 (difference in MFM-20 from D0 to D8), Study Period 2 (difference in MFM-20 from D21 to D28) and the change in CFB from Study Period 1 to Study Period 2 (difference between CFB during Study Period 1 and CFB during Study Period 2). A Mann-Whitney-Wilcoxon test for equality of CFB results in the two treatments in Period 1 and for the equality of the CFB results in the two treatment sequences will be conducted. A mixed effects linear model will be fit to the overall MFM-32 score as the response variable and fixed effect terms for treatment, period, age group, genetic mutation type, and sequence*period and a random effect for patient. | The Full Analysis Set consists of all randomized patients who receive at least one dose of study medication and have at least one post-treatment efficacy assessment. | Posted | Mean | Standard Deviation | Score on a Scale | Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29 |
|
|
|
|
| 0 |
| 20 |
| 1 |
| 20 |
| 11 |
| 20 |
| EG001 | Placebo | Treatment administered to the patient at the time of onset of the AE. | 0 | 20 | 1 | 20 | 6 | 20 |
| Parainfluenzae virus infection | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Rhinovirus infection | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA 19.1 | Systematic Assessment |
|
| Ear pain | Ear and labyrinth disorders | MedDRA 19.1 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Food poisoning | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Paraesthesia oral | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Retching | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Allergy to animal | Immune system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Conjunctivitis | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hypoaesthesia | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Migraine | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Agitation | Psychiatric disorders | MedDRA 19.1 | Systematic Assessment |
|
| Anger | Psychiatric disorders | MedDRA 19.1 | Systematic Assessment |
|
| Irritability | Psychiatric disorders | MedDRA 19.1 | Systematic Assessment |
|
| Menstruation irregular | Reproductive system and breast disorders | MedDRA 19.1 | Systematic Assessment |
|
| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Acne | Skin and subcutaneous tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Haematoma | Vascular disorders | MedDRA 19.1 | Systematic Assessment |
|
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| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D011725 |
| Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| Study Period 2: CFB in Overall MFM-32 Score at Day 29 |
|
|
A mixed effects linear model will be fit to the data with Overall MFM-32 scores as the response and fixed effect terms for treatment, period, age group, mutation type and sequence*period, and a random effect for patient. The LSMeans for the estimated difference between treatments in Period 1 along with a 95% confidence interval for this difference. |
| Mixed Models Analysis |
| Mean Difference (Net) |
| 1.14 |
| 2-Sided |
| 95 |
| -2.31 |
| 4.58 |
Results show the LSMeans for the estimated difference between treatments in Period 1 along with a 95% confidence interval for this difference. |
| Other |
| Study Period 2: CFB in Overall MFM-20 Score at Day 29 |
|
|
A mixed effects linear model will be fit to the data with Overall MFM-20 scores as the response and fixed effect terms for treatment, period, age group, mutation type and sequence*period, and a random effect for patient. The LSMeans for the estimated difference between treatments in Period 1 along with a 95% confidence interval for this difference. |
| Mixed Models Analysis |
| Mean Difference (Net) |
| 0.63 |
| 2-Sided |
| 95 |
| -5.25 |
| 6.50 |
Results show the LSMeans for the estimated difference between treatments in Period 1 along with a 95% confidence interval for this difference. |
| Other |