Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes
Condition: Myasthenic Syndromes, Congenital
MeSH terms: Lambert-Eaton Myasthenic Syndrome; Myasthenic Syndromes, Congenital; Syndrome
Intervention: amifampridine phosphate; Placebo
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.; 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.
Intervention MeSH terms: Amifampridine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 20.0
Sex: All
Minimum age: 2 Years
Maximum age: 70 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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 exclusion criteria are not eligible to
        participate in the study:

          1. CMS subtype diagnosis of acetylcholinesterase deficiency, slow-channel syndrome, LRP4
             deficiency, and plectin deficiency.

          2. Cardiac conduction defects on Screening 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 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
             confound the assessment of the patient.

         11. History of drug allergy to any pyridine-containing substances or any amifampridine
             phosphate excipient(s).