This study will determine the highest dose of idebonone that can safely be given to patients
with Friedrich's ataxia, an inherited degenerative disease that causes loss of muscle
coordination, speech problems, weakness and sensory loss. Enlargement of the left ventricle
(the large pumping chamber of the heart) is also common in this disease. In studies in
France and Canada, patients with Friedrich's ataxia who were given idebonone, an antioxidant
similar to the dietary supplement coenzyme Q, had a decrease in the size of their left
Patients 5 years and older with Friedrich's ataxia may be eligible for this study. Pregnant
and lactating women may not participate. Candidates will be screened with a medical history
and physical examination and a review of genetic studies. Patients who have not had genetic
studies will be offered genetic counseling and testing to confirm or rule out Friedrich's
Participants will be admitted to the NIH Clinical Center for 3 days. They will have blood
and urine tests and a heart evaluation, including an echocardiogram-a procedure that uses
sound waves to produce images of the heart, and an electrocardiogram-a study of the
electrical activity of the heart. When these tests have been completed, patients will take
an idebonone capsule. They will be monitored for side effects for 72 hours. Blood samples
will be collected through an intravenous catheter (flexible plastic tube placed in a vein)
0.5, 1, 2, 3, 4, 6, 12, 24, 48 and 72 hours after the drug is taken to determine how long it
takes for the drug to be eliminated from the body.
Patients will return for a follow-up visit within 1 to 8 weeks. Those who experienced no
serious side effects may receive another, higher dose of the drug, with at least 6 days
Friedreich's ataxia (FRDA) is a progressive, autosomal recessive, multisystem degenerative
disease for which there is currently no effective treatment. Recent studies suggest that
lipid-soluble antioxidants may prevent the progression of neurodegeneration and lead to some
reversal of cardiomyopathy.
This will be a phase Ia, unblinded, dose-escalation trial examining the toxicity and
tolerability of the antioxidant idebenone in patients with FRDA. Our primary objective is
to determine the maximum tolerated single dose of idebenone in patients with FRDA. Our
secondary objective is to document the pharmacokinetics of single-dose idebenone in this
population. We aim to enroll 48 patients divided evenly among three age cohorts: children
(ages 5-11), adolescents (ages 12-17), and adults (age greater than or equal to 18). Each
age cohort will be studied independently. Three patients from each cohort will receive one
day of oral idebenone followed by inpatient monitoring for 72 hours. If dose-limiting
toxicity (DLT) is not observed during the 72-hour study period, three new patients will
receive the next highest dose. If one of three patients experiences DLT, three new patients
will receive the same dose. Within each cohort, the dose will be escalated until the
maximum tolerated dose (MTD) is established. The MTD will be defined as one dose below that
which resulted in DLT in any two patients within a cohort.
Subsequent to the completion of this phase Ia trial, we plan to further refine the MTD for
each age group in a phase Ib trial in which we will examine multiple-dose regimens over a
longer study period. We hope to follow these phase I studies with a double-blinded,
placebo-controlled phase II trial to further evaluate safety and to estimate the efficacy of
idebenone using cardiac parameters as our primary endpoints. In addition, we are currently
in the process of validating a clinical evaluation scale for FRDA that we hope to employ in
measuring neurological parameters as a secondary endpoint in the phase II trial.
Diagnosis of FRDA with confirmed FRDA mutations.
Age greater than or equal to five years old.
No exposure to idebenone or coenzyme Q10 for a period of at least one week prior to onset
of the medication phase of the study.
Written, informed consent (and assent, if applicable).
History of a hypersensitivity reaction to idebenone or coenzyme
Pregnant or lactating women. All women of child-bearing potential must have negative
serum pregnancy prior to the medication phase of the study.
Age less than five years old.
Platelet count, lymphocyte count or hemoglobin below the lower limit of normal.
Alkaline phosphatase, SGOT, SGPT greater than 1.5 times the upper limit of normal.
Bilirubin greater than 1.2 g/dl.
Creatinine greater than 1.5 times the upper limit of normal.
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.