Patient case: 19-year-old female with long QT syndrome; genetic feature: KCNH2

Clinical trial: Expanded Access Study Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS), Congenital Myasthenic Syndrome (CMS), or Downbeat Nystagmus Patients

Summary: The primary objective of the study is:
  • To provide patients with LEMS/CMS/downbeat nystagmus access to amifampridine phosphate therapy until the product becomes commercially available.
  The secondary objective of the study is:
  • To assess the long-term safety of amifampridine phosphate in patients with LEMS/CMS/downbeat nystagmus


Eligibility: Inclusion Criteria:
  -  Male or female:
  -  2 years of age at 5 pediatric CMS study sites
  -  10 years of age at other study sites.
  -  Confirmed physician diagnosis of LEMS, CMS or downbeat nystagmus.
  -  Completion of anti-cancer treatment at least 3 months (90 days) before treatment.
  -  Negative urine pregnancy test for females of childbearing potential at Screening.
  -  If sexually active and of childbearing potential, willing to use 2 acceptable methods of contraception from screening visit until 3 months after the last dose of investigational product. No adequate clinical data on exposed pregnancies are available for amifampridine. No nonclinical safety data are available regarding the effects of amifampridine on reproductive function. Amifampridine phosphate should not be used during pregnancy. It is unknown whether amifampridine is excreted in human breast milk. The excretion of amifampridine in milk has not been studied in animals. Amifampridine phosphate should not be used during breastfeeding.
  -  Any subject currently participating in studies LMS-002, LMS-002EXT, or CMS 001 is immediately eligible for enrollment into study EAP-001, as long as inclusion/exclusion criteria are still met.
  -  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.
  Exclusion Criteria:
  -  History of epilepsy.
  -  CMS subtypes including slow-channel syndrome, LRP4 deficiency, and acetylcholinesterase deficiency.
  -  Known active brain metastasis. Patients with treated brain metastasis (radiotherapy and/or surgery) who have completed treatment for their brain metastasis >90 days before Screening, are neurologically stable (neurological symptoms grade <1), are on a stable dose of corticosteroids and have no evidence of new disease on magnetic resonance imaging (MRI) are eligible, provided they meet the other inclusion/exclusion criteria.
  -  Current use of dalfampridine (Ampyra®; 4-aminopyridine), and any form of 3,4 DAP other than the investigational product provided, such as amifampridine base and does not agree to discontinue use for the duration of the study.
  -  Use of guanidine hydrochloride within 7 days of starting amifampridine phosphate treatment.
  -  History of drug allergy to any pyridine-containing substances or any amifampridine phosphate excipients (i.e. microcrystalline cellulose, colloidal silicon dioxide or calcium stearate).
  -  Use of any other investigational product (other than 3,4 DAP or amifampridine phosphate) or investigational medical device within 30 days before starting treatment or requirement for any investigational agent before completion of all scheduled study assessments.
  -  An electrocardiogram (ECG) within 6 months before starting treatment that shows clinically significant abnormality(ies), in the opinion of the patient's personal physician.
  -  History of additional risk factors for torsade de pointes (e.g. history of surviving a near drowning due to loss of consciousness, family history of congenital QT syndrome, long QT syndrome, family history of unexplained early sudden death, or heart failure).
  -  Breastfeeding or pregnant or planning to become pregnant (self or partner). Male patients with breastfeeding partners are not excluded from the study.
  -  History of severe renal impairment or evidence of severe renal impairment at time of Screening on laboratory tests, specifically a creatinine clearance <30 mL/min (within 30 days) as calculated using the Cockcroft Gault formula.
  -  History at time of Screening of laboratory tests (within 30 days) indicating hepatic impairment:
  o In patients without liver metastases from cancer, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or total bilirubin >1.5 × upper limit of normal (ULN).
  -  Any condition that, in the view of the Principal Investigator, places the patient at high risk of poor treatment compliance or of not completing the study.

Relevance to patient case: not relevant