Phase 1B Clinical Trial to Establish the Safety and Tolerability of a Multiple-Dose Regimen of Idebenone Administered to Patients With Friedreich's Ataxia

Background: Friedreich's ataxia (FRDA) is a progressive, autosomal recessive, multisystem degenerative disease for which there is currently no effective treatment. Recent studies have demonstrated that lipid-soluble antioxidants lead to a modest reversal of cardiomyopathy in patients with FRDA. It is possible that antioxidants may also prevent the progression of neurodegeneration. Objective: This will be a phase 1B, unblinded trial examining the toxicity and tolerability of the antioxidant idebenone given as a multiple-dose regimen for a short inpatient course and then long term to patients with FRDA. Study Population: We aim to enroll 15 patients divided evenly among three age cohorts: children (ages 5-11), adolescents (ages 12-17), and adults (age greater than or equal to 18). Design: Our primary objective is to examine the tolerability of idebenone given at a dose of 60 mg/kg/day for 72 hours (total of 9 doses) in an inpatient setting (NIH Clinical Center). This dose is below the maximum dose examined (75 mg/kg/day) that was well tolerated with no dose-limiting toxicity (DLT) in our phase 1A (protocol# 01-N-0167) study. The 72 hour course represents 5.5 half-lives of the drug based upon previous studies of the drug in healthy human subjects and our phase 1A data, thereby allowing the serum concentration of the drug to reach steady-state levels. This multiple dose regimen will allow us to examine accumulation of the drug and to examine tolerability of the drug at a steady-state concentration. The patients will then be followed by inpatient monitoring for an additional 43 hours, representing 3.3 half-lives, to allow relatively complete elimination of the drug. If no adverse events are noted during the inpatient phase of the trial, patients will resume taking the drug on an outpatient basis for 1 month to determine long-term tolerability and compliance. Outpatients will be followed through phone interviews by the NIH research team along with routine blood work every 2 weeks. Our secondary objective is to document the pharmacokinetics, specifically the apparent distribution volume (Vd), elimination half-life (t1/2), elimination clearance (CLE), and steady-state concentrations (CSS) of idebenone during the inpatient phase of the study. Outcome Parameters: Outcomes in this phase I trial are types and frequency of adverse events, if any, and compliance with the dosing regimen. Our secondary endpoint is pharmacokinetics of this dosing regimen. Future Directions: We hope to follow these phase I studies with a multicenter, double-blinded, placebo-controlled phase III trial using an ataxia scale developed for FRDA as the primary endpoint.