Myasthenic Syndromes, Congenital
Conditions
Brief summary
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.
Detailed description
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.
Interventions
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.
DRUGPlacebo
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.
Sponsors
Catalyst Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Individuals eligible to participate in this study must meet all of the following inclusion criteria: 1. Patient's or parent 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, or the patient's legal guardian or caregiver with durable power of attorney can provide written informed consent. An assent form must also be signed if in the judgement of the IRB the children are capable of providing assent. 2. Male or female age 2 and above. 3. Body weight ≥10 kg. 4. Genetically-confirmed CMS involving acetylcholine receptor defect, Rapsyn deficiency, MuSK deficiency, Dok-7 deficiency, SYT2 deficiency,SNAP25B deficiency, and fast channel syndrome. 5. MFM 20 or 32 score equal or less than 48 or 76, respectively, at Screening. 6. In patients naïve to 3,4-DAP or amifampridine phosphate, improvement of \>20% in MFM20 or MFM32 scores after open label period of up titration of dose 7. In patients previously stabilized on 3,4-DAP or amifampridine phosphate, history of meaningful improvement in motor function (in opinion of investigator) 8. Willingness of patients receiving pyridostigmine, prednisone, albuterol, ephedrine, or fluoxetine to remain on a stable dose of these medications throughout the study interval. 9. Female patients of childbearing potential must have a negative pregnancy test (serum human chorionic gonadotropin \[HCG\] at Screening); and must practice effective, reliable contraceptive regimen during the study. 10. 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.
Exclusion criteria
Individuals who meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subject Global Impression (SGI) Score Summary: Mann-Whitney Main Effects Test Results; SGI Score Mixed Model Analysis | Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Motor Function Measure 32 (MFM-32) Score Summary: Mann-Whitney Main Effect Test Results, MFM-32 Score Mixed Model Analysis | Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29 | 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. |
| Motor Function Measure 20 (MFM-20) Score Mixed Model Analysis, MFM-20 Score Mixed Model Analysis | Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29 | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 8 |
| 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. | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | Amifampridine Phosphate - Placebo | Placebo - Amifampridine Phosphate | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 5 Participants | 12 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Continuous | 12.59 years STANDARD_DEVIATION 15.7 | 27.35 years STANDARD_DEVIATION 25 | 19.97 years STANDARD_DEVIATION 21.56 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 7 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 8 Participants | 5 Participants | 13 Participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 11 / 20 | 6 / 20 |
| serious Total, serious adverse events | 1 / 20 | 1 / 20 |
Outcome results
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.
Time frame: Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amifampridine Phosphate - Placebo | Subject Global Impression (SGI) Score Summary: Mann-Whitney Main Effects Test Results; SGI Score Mixed Model Analysis | Study Period 1: CFB in SGI Score at Day 8 | -0.13 Scores on a scale | Standard Deviation 1.81 |
| Amifampridine Phosphate - Placebo | Subject Global Impression (SGI) Score Summary: Mann-Whitney Main Effects Test Results; SGI Score Mixed Model Analysis | Study Period 2 : CFB in SGI Score at Day 29 | -0.75 Scores on a scale | Standard Deviation 1.75 |
| Placebo - Amifampridine Phosphate | Subject Global Impression (SGI) Score Summary: Mann-Whitney Main Effects Test Results; SGI Score Mixed Model Analysis | Study Period 1: CFB in SGI Score at Day 8 | -1.75 Scores on a scale | Standard Deviation 2.12 |
| Placebo - Amifampridine Phosphate | Subject Global Impression (SGI) Score Summary: Mann-Whitney Main Effects Test Results; SGI Score Mixed Model Analysis | Study Period 2 : CFB in SGI Score at Day 29 | -1.14 Scores on a scale | Standard Deviation 1.68 |
Comparison: A Mann-Whitney-Wilcoxon test for equality of the change from baseline (CFB) in the two treatments in Period 1 will be presented.p-value: 0.085Wilcoxon (Mann-Whitney)
Comparison: A mixed effects linear model will be fit to the data with SGI raw 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.95% CI: [-0.97, 2.09]Mixed Models Analysis
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.
Time frame: Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amifampridine Phosphate - Placebo | Motor Function Measure 20 (MFM-20) Score Mixed Model Analysis, MFM-20 Score Mixed Model Analysis | Study Period 1: CFB in Overall MFM-20 Score at Day 8 | -1.50 Score on a Scale | Standard Deviation 4.2 |
| Amifampridine Phosphate - Placebo | Motor Function Measure 20 (MFM-20) Score Mixed Model Analysis, MFM-20 Score Mixed Model Analysis | Study Period 2: CFB in Overall MFM-20 Score at Day 29 | -0.75 Score on a Scale | Standard Deviation 0.5 |
| Placebo - Amifampridine Phosphate | Motor Function Measure 20 (MFM-20) Score Mixed Model Analysis, MFM-20 Score Mixed Model Analysis | Study Period 1: CFB in Overall MFM-20 Score at Day 8 | -0.50 Score on a Scale | Standard Deviation 6.36 |
| Placebo - Amifampridine Phosphate | Motor Function Measure 20 (MFM-20) Score Mixed Model Analysis, MFM-20 Score Mixed Model Analysis | Study Period 2: CFB in Overall MFM-20 Score at Day 29 | 1.50 Score on a Scale | Standard Deviation 2.12 |
Comparison: A Mann-Whitney-Wilcoxon test for equality of the change from baseline (CFB) in the two treatments in Period 1 will be presented.p-value: 0.8Wilcoxon (Mann-Whitney)
Comparison: 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.95% CI: [-5.25, 6.5]Mixed Models Analysis
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.
Time frame: Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amifampridine Phosphate - Placebo | Motor Function Measure 32 (MFM-32) Score Summary: Mann-Whitney Main Effect Test Results, MFM-32 Score Mixed Model Analysis | Study Period 1: CFB in Overall MFM-32 Score at Day 8 | 3.00 Score on a Scale | Standard Deviation 3.92 |
| Amifampridine Phosphate - Placebo | Motor Function Measure 32 (MFM-32) Score Summary: Mann-Whitney Main Effect Test Results, MFM-32 Score Mixed Model Analysis | Study Period 2: CFB in Overall MFM-32 Score at Day 29 | 0.75 Score on a Scale | Standard Deviation 2.22 |
| Placebo - Amifampridine Phosphate | Motor Function Measure 32 (MFM-32) Score Summary: Mann-Whitney Main Effect Test Results, MFM-32 Score Mixed Model Analysis | Study Period 1: CFB in Overall MFM-32 Score at Day 8 | -0.17 Score on a Scale | Standard Deviation 4.58 |
| Placebo - Amifampridine Phosphate | Motor Function Measure 32 (MFM-32) Score Summary: Mann-Whitney Main Effect Test Results, MFM-32 Score Mixed Model Analysis | Study Period 2: CFB in Overall MFM-32 Score at Day 29 | -0.60 Score on a Scale | Standard Deviation 0.89 |
Comparison: A Mann-Whitney-Wilcoxon test for equality of the change from baseline (CFB) in the two treatments in Period 1 will be presented.p-value: 0.376Wilcoxon (Mann-Whitney)
Comparison: 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.95% CI: [-2.31, 4.58]Mixed Models Analysis