Patient case: 36-year-old female with Brugada syndrome; genetic feature: SCN5A

Clinical trial: 4-Aminopyridine in Episodic Ataxia Type 2

Summary: Episodic ataxia type 2 (EA2) is a rare familial neurological condition characterized by debilitating episodes of vertigo and imbalance. Since the serendipitous discovery of dramatic response of EA2 to acetazolamide, acetazolamide has been the first-line treatment for EA2. Yet, for those patients who do not respond to or cannot tolerate acetazolamide, there is no alternative treatment. The purpose of this randomized trial is to test whether 4-aminopyridine may reduce the ataxia episodes in EA2 as an alternative to acetazolamide. Funding Source - FDA OOPD

Detailed description: This study aims to determine whether 4-aminopyridine (4AP) can reduce attacks of ataxia in patients with episodic ataxia type 2 (EA2), a rare but often debilitating condition. Episodic ataxia (EA) is a group of inherited disorders characterized by recurrent, discrete episodes of vertigo and ataxia variably associated with progressive ataxia. EA2, the most common and the best characterized of all the EA syndromes, is caused by heterozygous mutations in CACNA1A, which encodes the main subunit of a neuronal voltage-gated calcium channel, Cav2.1.
  Although observational data suggest symptomatic resolution with acetazolamide in many EA2 patients, the investigators found in our patient databases that at least a third of the EA2 patients continue to suffer debilitating ataxia attacks, either because of incomplete control while on acetazolamide or because of intolerability or hypersensitivity to acetazolamide. For these patients there is no alternative intervention. 4-Aminopyridine (4AP) has been found to be helpful in a handful of patients with EA2. Recently, dalfampridine, an extended release formulation of 4AP (AMPYRA) by Acorda Therapeutics, received FDA approval to improve gait in multiple sclerosis.
  The investigators plan to recruit 20 subjects with genetically defined EA2 who suffer frequent ataxia episodes (at least 3 episodes a month) to conduct a randomized trial of 4AP to examine its efficacy and tolerability in EA2. Study subjects will be recruited at UCLA and the University of Rochester to participate in a randomized, double-blind, double-crossover trial of 4AP.Each treatment period is 2-months with a 1-week wash-out period in between each treatment period. Participating subjects will undergo standardized history and physical examination at the time of enrollment. Participants will log their ataxia attacks daily by interactive voice response (IVR) system and will be interviewed monthly for events and side effects/toxicity. Study visits will occur at the beginning and the end of the study.

Eligibility: Inclusion Criteria:
  Patients will be included if they:
  -  Have EA2 genetically confirmed to harbor mutations in CACNA1A
  -  Are ≥ 18 years of age
  -  Are not taking acetazolamide (because of intolerance, poor response, or allergy)
  -  Are able to maintain a daily log of ataxia episode(s) and report daily by using an Interactive Voice Recording System (IVR) throughout the study
  -  Experience ≥ 3 ataxia episodes per month during the two-month screening period to qualify for randomization
  Exclusion Criteria:
  Patients will be excluded if they:
  -  Have seizures or a history of seizures
  -  Have first-degree relatives with EA2 and seizures
  -  Have renal disease with impaired function (Creatinine clearance CrCl≤50ml/min)
  -  Are pregnant or breast feeding (women of childbearing age will be tested for pregnancy and must be using birth control)
  -  Are unable to comply with the study requirement

Relevance to patient case: not relevant