- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02562066
Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes
March 8, 2021 updated by: Catalyst Pharmaceuticals, Inc.
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)
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.
Study Overview
Status
Completed
Conditions
Intervention / 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.
Study Type
Interventional
Enrollment (Actual)
20
Phase
- Phase 3
Expanded Access
No longer available outside the clinical trial.
See expanded access record.
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
California
-
Los Angeles, California, United States, 90095
- UCLA Department of Neurology
-
-
Maryland
-
Baltimore, Maryland, United States, 21287
- Johns Hopkins Pediatric Neurology
-
-
Massachusetts
-
Boston, Massachusetts, United States, 02115
- Boston Children's Hospital
-
-
Ohio
-
Columbus, Ohio, United States, 43221
- Ohio State University
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
2 years to 70 years (Child, Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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).
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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 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.
Other Names:
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.
|
Experimental: 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 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.
Other Names:
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.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Subject Global Impression (SGI) Score Summary: Mann-Whitney Main Effects Test Results; SGI Score Mixed Model Analysis
Time Frame: 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.
|
Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Motor Function Measure 32 (MFM-32) Score Summary: Mann-Whitney Main Effect Test Results, MFM-32 Score Mixed Model Analysis
Time Frame: 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.
|
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
Time Frame: 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.
|
Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Principal Investigator: Thomas Crawford, M.D., Johns Hopkins Pediatric Neurology
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
January 1, 2016
Primary Completion (Actual)
August 1, 2019
Study Completion (Actual)
October 1, 2019
Study Registration Dates
First Submitted
September 24, 2015
First Submitted That Met QC Criteria
September 25, 2015
First Posted (Estimate)
September 29, 2015
Study Record Updates
Last Update Posted (Actual)
April 2, 2021
Last Update Submitted That Met QC Criteria
March 8, 2021
Last Verified
February 1, 2021
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Nervous System Diseases
- Immune System Diseases
- Neoplasms
- Autoimmune Diseases of the Nervous System
- Autoimmune Diseases
- Neoplasms by Site
- Disease
- Genetic Diseases, Inborn
- Neuromuscular Diseases
- Neurodegenerative Diseases
- Nervous System Neoplasms
- Paraneoplastic Syndromes, Nervous System
- Paraneoplastic Syndromes
- Neuromuscular Junction Diseases
- Myasthenia Gravis
- Syndrome
- Lambert-Eaton Myasthenic Syndrome
- Myasthenic Syndromes, Congenital
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Peripheral Nervous System Agents
- Membrane Transport Modulators
- Neuromuscular Agents
- Potassium Channel Blockers
- Amifampridine
Other Study ID Numbers
- CMS-001
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Myasthenic Syndromes, Congenital
-
Ricardo MaselliCatalyst Pharmaceuticals, Inc.No longer availableCongenital Myasthenic SyndromeUnited States
-
argenxRecruitingCongenital Myasthenic SyndromeUnited States, Canada, France
-
Mayo ClinicCompletedCongenital Myasthenic SyndromeUnited States
-
Institut de Myologie, FranceAssistance Publique - Hôpitaux de ParisCompletedCongenital Myasthenic Syndrome
-
Lahey ClinicApproved for marketingLambert-Eaton Myasthenic Syndrome | Congenital Myasthenic SyndromeUnited States
-
Oregon Health and Science UniversityJacobus PharmaceuticalNo longer availableLambert-Eaton Myasthenic Syndrome (LEMS) | Congenital Myasthenia (CM)United States
-
Hadassah Medical OrganizationUnknown
-
Catalyst Pharmaceuticals, Inc.No longer availableLambert-Eaton Myasthenic Syndrome | Congenital Myasthenic Syndrome | Nystagmus, AcquiredUnited States
-
Vern C. Juel, M.D.No longer available
-
Institut de Myologie, FranceAssociation Française contre les Myopathies (AFM), ParisCompletedMyasthenia Gravis | Lambert-Eaton Myasthenic Syndrome | Congenital Myasthenic Syndrome | Autoimmune Myasthenia GravisFrance
Clinical Trials on amifampridine phosphate
-
Catalyst Pharmaceuticals, Inc.CompletedA Phase 3 Study of Amifampridine Phosphate in Patients With Lambert Eaton Myasthenic Syndrome (LEMS)Lambert Eaton Myasthenic SyndromeUnited States, Spain, Serbia, Russian Federation, Hungary, France, Germany, Poland
-
Catalyst Pharmaceuticals, Inc.CompletedMuscular Atrophy, SpinalItaly
-
Catalyst Pharmaceuticals, Inc.No longer availableLambert-Eaton Myasthenic Syndrome | Congenital Myasthenic Syndrome | Nystagmus, AcquiredUnited States
-
Catalyst Pharmaceuticals, Inc.Active, not recruitingMyasthenia Gravis, MuSKUnited States
-
Catalyst Pharmaceuticals, Inc.CompletedMyasthenia Gravis, GeneralizedUnited States
-
Catalyst Pharmaceuticals, Inc.TerminatedSpinal Muscular Atrophy Type 3Italy
-
Catalyst Pharmaceuticals, Inc.CompletedLambert-Eaton Myasthenic SyndromeUnited States
-
Leiden University Medical CenterNMD Pharma A/SRecruiting
-
University of Texas Southwestern Medical CenterCompletedHypertensionUnited States
-
Augusta UniversityRecruiting