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Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes

Primary Purpose

Myasthenic Syndromes, Congenital

Status

Completed

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

amifampridine phosphate

Placebo

About this trial

This is an interventional treatment trial for Myasthenic Syndromes, Congenital

Eligibility Criteria

2 Years - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Individuals eligible to participate in this study must meet all of the following inclusion criteria:

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.
Male or female age 2 and above.
Body weight ≥10 kg.
Genetically-confirmed CMS involving acetylcholine receptor defect, Rapsyn deficiency, MuSK deficiency, Dok-7 deficiency, SYT2 deficiency,SNAP25B deficiency, and fast channel syndrome.
MFM 20 or 32 score equal or less than 48 or 76, respectively, at Screening.
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
In patients previously stabilized on 3,4-DAP or amifampridine phosphate, history of meaningful improvement in motor function (in opinion of investigator)
Willingness of patients receiving pyridostigmine, prednisone, albuterol, ephedrine, or fluoxetine to remain on a stable dose of these medications throughout the study interval.
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.
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 exclusion criteria are not eligible to participate in the study:

CMS subtype diagnosis of acetylcholinesterase deficiency, slow-channel syndrome, LRP4 deficiency, and plectin deficiency.
Cardiac conduction defects on Screening ECG.
Seizure disorder.
Abnormal liver function tests at Screening.
Abnormal kidney function tests at Screening.
Abnormal electrolyte values at Screening.
Pregnancy or breastfeeding at Screening or planning to become pregnant at any time during the study.
Any systemic bacterial or other infection, which is clinically significant in the opinion of the investigator and has not been treated with appropriate antibiotics.
Treatment with an investigational drug (other than amifampridine phosphate), device, or biological agent within 30 days before Screening or while participating in this study.
Any other 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.
History of drug allergy to any pyridine-containing substances or any amifampridine phosphate excipient(s).

Sites / Locations

UCLA Department of Neurology
Johns Hopkins Pediatric Neurology
Boston Children's Hospital
Ohio State University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

amifampridine phosphate -placebo

placebo - amifampridine phosphate

Arm 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, 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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

Full Information

NCT ID

NCT02562066

First Posted

September 24, 2015

Last Updated

March 8, 2021

Sponsor

Catalyst Pharmaceuticals, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT02562066

Brief Title

Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes

Official Title

A Phase 3, Double-blind, Outpatient Crossover Study to Evaluate the Efficacy and Safety of Amifampridine Phosphate (3,4 Diaminopyridine Phosphate) in Patients With Congenital Myasthenic Syndromes (CMS)

Study Type

Interventional

2. Study Status

Record Verification Date

February 2021

Overall Recruitment Status

Completed

Study Start Date

January 2016 (undefined)

Primary Completion Date

August 2019 (Actual)

Study Completion Date

October 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Catalyst Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myasthenic Syndromes, Congenital

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

20 (Actual)

8. Arms, Groups, and Interventions

Arm Title

amifampridine phosphate -placebo

Arm Type

Experimental

Arm Description

Arm Title

placebo - amifampridine phosphate

Arm Type

Experimental

Arm 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, 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.

Intervention Type

Drug

Intervention Name(s)

amifampridine phosphate

Other Intervention Name(s)

3,4 diaminopyridine phosphate, Firdapse™

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

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.

Primary Outcome Measure Information:

Title

Subject Global Impression (SGI) Score Summary: Mann-Whitney Main Effects Test Results; SGI Score Mixed Model Analysis

Description

Time Frame

Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29

Secondary Outcome Measure Information:

Title

Motor Function Measure 32 (MFM-32) Score Summary: Mann-Whitney Main Effect Test Results, MFM-32 Score Mixed Model Analysis

Description

Time Frame

Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29

Title

Motor Function Measure 20 (MFM-20) Score Mixed Model Analysis, MFM-20 Score Mixed Model Analysis

Description

Time Frame

Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Individuals eligible to participate in this study must meet all of the following inclusion criteria: 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. Male or female age 2 and above. Body weight ≥10 kg. Genetically-confirmed CMS involving acetylcholine receptor defect, Rapsyn deficiency, MuSK deficiency, Dok-7 deficiency, SYT2 deficiency,SNAP25B deficiency, and fast channel syndrome. MFM 20 or 32 score equal or less than 48 or 76, respectively, at Screening. 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 In patients previously stabilized on 3,4-DAP or amifampridine phosphate, history of meaningful improvement in motor function (in opinion of investigator) Willingness of patients receiving pyridostigmine, prednisone, albuterol, ephedrine, or fluoxetine to remain on a stable dose of these medications throughout the study interval. 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. 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 exclusion criteria are not eligible to participate in the study: CMS subtype diagnosis of acetylcholinesterase deficiency, slow-channel syndrome, LRP4 deficiency, and plectin deficiency. Cardiac conduction defects on Screening ECG. Seizure disorder. Abnormal liver function tests at Screening. Abnormal kidney function tests at Screening. Abnormal electrolyte values at Screening. Pregnancy or breastfeeding at Screening or planning to become pregnant at any time during the study. Any systemic bacterial or other infection, which is clinically significant in the opinion of the investigator and has not been treated with appropriate antibiotics. Treatment with an investigational drug (other than amifampridine phosphate), device, or biological agent within 30 days before Screening or while participating in this study. Any other 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. History of drug allergy to any pyridine-containing substances or any amifampridine phosphate excipient(s).

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Thomas Crawford, M.D.

Organizational Affiliation

Johns Hopkins Pediatric Neurology

Official's Role

Principal Investigator

Facility Information:

Facility Name

UCLA Department of Neurology

City

Los Angeles

State/Province

California

ZIP/Postal Code

90095

Country

United States

Facility Name

Johns Hopkins Pediatric Neurology

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21287

Country

United States

Facility Name

Boston Children's Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Ohio State University

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43221

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes

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