4-Aminopyridine in Episodic Ataxia Type 2 (4AP in EA2)

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

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.

Trial participants have frequent episodes of ataxia at baseline. The participants will document daily whether ataxia events occurred during the 2-month screening period and the 9-month study period by calling a toll-free number and participating in an Interactive Voice Response (IVR) system.

Participants will use IVR to log the impact (on a scale of 0-3) of ataxia events, if any, on their daily activities: (0) No impact (1) Mild (2) Moderate (3) Severe

Study Participants will use IVR daily to log the severity of ataxia events, if any, on a scale of 1-9: (1) mild (9) very severe

The study participant will respond by phone interview to the 11-item Treatment Satisfaction Questionnaire for Medication (TSQM Version 2) at the end of each of the four treatment periods.

The study participant will be interviewed by phone regarding toxicity using the [Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0] at two different time points (4 weeks, 8 weeks) of each 8-week Treatment Period. Spectrum and severity of toxicity and the prevalence among study participants will be documented.

The study participant will log side effects as they occur (reporting the seizures or other severe side effects immediately to Investigators) and will be interviewed by phone regarding side effects at two different time points (4 weeks, 8 weeks) of each 8-week Treatment Period. Spectrum of side effects and the prevalence among those treated will be documented.

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

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