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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01543750
Recruitment Status : Withdrawn
First Posted : March 5, 2012
Last Update Posted : November 16, 2020
University of Rochester
University of South Florida
Information provided by (Responsible Party):
University of California, Los Angeles

Brief 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

Condition or disease Intervention/treatment Phase
Episodic Ataxia Type 2 Drug: 4-Aminopyridine Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase 2 Study of 4-Aminopyridine for the Treatment of Episodic Ataxia Type 2

Arm Intervention/treatment
Experimental: Study Medication
4-aminopyridine 10mg twice daily for 8 weeks
Drug: 4-Aminopyridine
Experimental: Placebo
placebo twice daily for 8 weeks
Drug: Placebo

Primary Outcome Measures :
  1. the frequency of ataxia episodes [ Time Frame: 11 months ]
    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.

Secondary Outcome Measures :
  1. impact on daily activities [ Time Frame: 11 months ]

    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

  2. duration of ataxia episodes [ Time Frame: 11 months ]
    Study Participants will use IVR daily to log the duration of ataxia events, if any, in hours.

  3. severity of ataxia episodes [ Time Frame: 11 months ]

    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

  4. treatment satisfaction [ Time Frame: 9 months ]
    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.

  5. Toxicity [ Time Frame: 9 months ]
    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.

  6. Side Effects [ Time Frame: 9 months ]
    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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01543750

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United States, California
University of California, Los Angeles (UCLA)
Los Angeles, California, United States, 90095
United States, Florida
University of South Florida
Tampa, Florida, United States, 33612
United States, New York
University of Rochester School of Medicine
Rochester, New York, United States, 14642
Sponsors and Collaborators
University of California, Los Angeles
University of Rochester
University of South Florida
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Principal Investigator: Joanna C Jen, MD PhD University of California, Los Angeles

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Responsible Party: University of California, Los Angeles Identifier: NCT01543750    
Other Study ID Numbers: CINCH-EA2
R01FD003923 ( U.S. FDA Grant/Contract )
First Posted: March 5, 2012    Key Record Dates
Last Update Posted: November 16, 2020
Last Verified: November 2020
Keywords provided by University of California, Los Angeles:
episodic ataxia
CACNA1A mutations
Additional relevant MeSH terms:
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Cerebellar Ataxia
Nystagmus, Pathologic
Neurologic Manifestations
Nervous System Diseases
Cerebellar Diseases
Brain Diseases
Central Nervous System Diseases
Ocular Motility Disorders
Cranial Nerve Diseases
Eye Diseases
Potassium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action