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CMS Amifampridine Phosphate Study

Study Title:
A Phase 3, Multicenter, Double-blind, Placebo-controlled, Randomized, Outpatient Two-period Two-treatment Crossover Study to Evaluate the Efficacy and Safety of Amifampridine Phosphate (3,4 Diaminopyridine Phosphate) in Patients with Congenital Myasthenic Syndromes (CMS)


Study Start: January 2016
Study Type: Interventional

 
Background
Congenital myasthenic syndromes (CMS) are a group of heterogeneous inherited disorders caused by mutations in genes encoding proteins essential for the integrity of neuromuscular transmission. CMS is characterized by weakness of skeletal muscle with an onset typically at birth or early childhood. Children can have low muscle tone, difficulty in swallowing, and lack of control over facial and eye muscles responsible for actions such as eye movements and smiling. The drug amifampridine phosphate is being investigated in a clinical trial to improve muscle function.


Purpose
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 Details
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.

Primary Outcome Measures
  • Change from baseline in the subject global impression (SGI) scale [ Time Frame: Change from baseline in SGI scores at the end of week 5 (end of Period I) and change from baseline in SGI scores at the end of Week 8 (end of Period 2) ]
  • The CGI score is a 2-part observer-rated instrument that assesses 1) severity of the patient's disease (CGI S) at a given point in time and 2) change from baseline (CGI-I).
Secondary Outcome Measure
  • Change from baseline in the Motor Function Measure (MFM) scale [ Time Frame: Change from baseline in MFM scores at the end of week 5 (end of Period I) and at the end of Week 8 (end of Period 2) ] .

Eligibility

Eligible to participate in this study are male and females ages 2 to 70 years.


Inclusion criteria:
  1. Patient 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 2 years of age and older.
  3. Body weight ≥10 kg.
  4. Genetically-confirmed CMS involving acetylcholine receptor defect, Rapsyn deficiency, MuSK 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 amifampridine, improvement of >20% in MFM20 or MFM32 scores after open label period of up titration of dose
  7. In patients previously stabilized on amifampridine, 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.
  8. Female patients of childbearing potential must have a negative pregnancy test (serum human chorionic gonadotropin [HCG] at Screening); and must practice two forms of effective, reliable contraceptive regimen during the study. Acceptable methods of contraception include hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring), intrauterine device, barrier methods (diaphragm, condom) with spermicide, or surgical sterilization (tubal ligation).
  9. 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:
  1. CMS subtype diagnosis of acetylcholinesterase deficiency, slow-channel syndrome, LRP4 deficiency, and plectin deficiency
  2. Cardiac conduction defects on Screening electrocardiogram (ECG)
  3. Seizure disorder
  4. Abnormal liver function tests at Screening
  5. Abnormal kidney function tests at Screening
  6. Abnormal electrolyte values at Screening
  7. Pregnancy or breastfeeding at Screening or planning to become pregnant at any time during the study
  8. Any systemic bacterial or other infection, which is clinically significant in the opinion of the investigator and has not been treated with appropriate antibiotics
  9. Treatment with an investigational drug (other than amifampridine or amifampridine phosphate), device, or biological agent within 30 days before Screening or while participating in this study
  10. 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 confounds the assessment of the patient
  11. History of drug allergy to any pyridine-containing substances or any amifampridine or amifampridine phosphate excipient(s)
Contact: Gary Ingenito, M.D., Ph.D, Tel: +1 305-420-3200 ext 123, This e-mail address is being protected from spambots. You need JavaScript enabled to view it

Study Sites

United States, California
UCLA Department of Neurology, Los Angeles, California, United States, 90095
Contact: Angela Ho    310-825-3264    This e-mail address is being protected from spambots. You need JavaScript enabled to view it
Principal Investigator: Perry Shieh, MD, PhD
 
United States, Georgia, Children's Healthcare of Atlanta, Atlanta, Georgia, United States, 30342
Contact: Schauna Gillam    678-409-4612    This e-mail address is being protected from spambots. You need JavaScript enabled to view it
Contact: Sumit Verma, MD    404-785-4688    This e-mail address is being protected from spambots. You need JavaScript enabled to view it
 
United States, Maryland
Johns Hopkins Pediatric Neurology, Baltimore, Maryland, United States, 21287
Contact: Agnes King Rennie, CNA, MST    443-287-6294    This e-mail address is being protected from spambots. You need JavaScript enabled to view it   
Principal Investigator: Thomas Crawford, MD 
 
United States, Massachusetts
Boston Children's Hospital, Boston, Massachusetts, United States, 02115
Contact: Timothy Harrington    857-218-4677  This e-mail address is being protected from spambots. You need JavaScript enabled to view it   
Contact: Grace Ordonez    617-919-7384  This e-mail address is being protected from spambots. You need JavaScript enabled to view it   
Principal Investigator: Partha Ghosh, MD
        
United States, Ohio
Nationwide Children's Hospital, Columbus, Ohio, United States, 43205
Contact: Alana Mahley    614-355-2606    This e-mail address is being protected from spambots. You need JavaScript enabled to view it   
Principal Investigator: Samiah Al-Zaidy, MD  

Sponsors and Collaborators
Catalyst Pharmaceuticals, Inc.
 
Principal Investigator:  Sumit Verma, M.D., Children's Healthcare of Atlanta
Principal Investigator:  Thomas Crawford, M.D., Johns Hopkins Pediatric Neurology
 
Responsible Party:  Catalyst Pharmaceuticals, Inc.                
ClinicalTrials.gov Study ID:  NCT02562066