Background: Friedreich's ataxia (FA) is a progressive, autosomal recessive, multisystem degenerative disease for which there is currently no effective treatment. Recent studies have suggested that lipid-soluble antioxidants lead to a modest reversal of cardiomyopathy in patients with FA. It is possible that antioxidants may also prevent the progression of neurodegeneration. Objective: This will be a 6 month phase 2 double-blind, placebo-controlled trial to assess the safety and efficacy of idebenone administered to adolescents and children with FA. Study Population: We aim to enroll 48 subjects composed of children (ages 9-11) and adolescents (ages 12-17) with FA divided evenly among 4 treatment arms (placebo, low, intermediate, and high dose idebenone). Design: Our primary objective is to examine the change in the level of oxidative stress by measuring the oxidative marker 8-hydroxy-2-deoxyguanosine from baseline and after 6 months of treatment with placebo or varying doses of idebenone. Following informed consent and assent, patients will undergo an initial medical history and physical followed by specific neurological, functional, and cardiac testing over a two-day outpatient visit. Patients will provide blood and urine samples for safety laboratory and biochemical analysis. Each patient will be randomized to one of 4 treatment arms and will be provided with a 6 month supply of study drug or placebo which will be administered three times a day. Patients will have follow-up laboratory monitoring after 1 and 3 months and at the end of the study. Additionally, patients will also have an EKG, vital signs, including orthostatics, and a physical examination performed after 1 and 3 months by their primary care physician. Patients will return after 6 months for follow-up exam, testing, and laboratory monitoring over a two-day outpatient visit. Outcome Parameters: The primary endpoint in this phase 2 trial is the change in the level of the oxidative stress marker 8-hydroxy-2-deoxyguanosine. Secondary endpoints include types and frequency of adverse events, if any, compliance with the dosing regimen, and measurements of the following: International Cooperative Ataxia Rating Scale (ICARS), Friedreich's ataxia Rating Scale (FARS), force control, gait analysis, quantitative sensation testing, fine motor control, health related quality of life score (SF-10), functional capacity, aerobic capacity, left ventricular wall mass, noninvasive measures of systolic and diastolic ventricular function, metabolic markers, markers of mitochondrial DNA damage, and gene expression profiling. Future Directions: We hope that the results of this phase 2 study will assist us in developing a multi-center, double-blinded, placebo-controlled phase III trial.
- INCLUSION CRITERIA: Diagnosis of FA with confirmed FRDA mutations. Age from nine up to but not over eighteen years. Weight between 30 to 80 kilograms. Ambulatory (assistance devices permitted). Willing to participate in all aspects of trial design and follow-up. All subjects agree and commit to the use of 2 reliable methods of birth control for the duration of the study if sexually active. Neurologically symptomatic. No exposure to idebenone, coenzyme Q10, or other dietary supplements for a period of at least one month before enrollment in the study. EXCLUSION CRITERIA: History of a hypersensitivity reaction to idebenone or coenzyme Q10. Pregnant or lactating women. All women of child-bearing potential must have negative serum pregnancy prior to the medication phase of the study. If a minor has a positive pregnancy test, we will inform her but not inform her parents unless we are asked to by the minor. Platelet count, white blood cell count or hemoglobin below the lower limit of normal. Alkaline phosphatase, SGOT, or SGPT greater than 1.5 times the upper limit of normal. Bilirubin greater than 1.5 g/dl. Creatinine greater than 1.5 times the upper limit of normal based upon the pediatric reference range provided by the testing laboratory. Clinically significant medical disease that, in the judgment of the investigators, would expose the patient to undue risk of harm or prevent the patient from completing the study.