This study will determine the highest amount of idebenone that can be taken without harmful
side effects in children, teenagers, and adults with Friedreich's ataxia, a progressive
degenerative disease that affects several body systems. Studies in France and Canada showed
that patients with Friedreich's ataxia who took idebenone had a decrease in the size of
their left ventricle (main pumping chamber of the heart), which is often enlarged in this
disease. It is possible that idebenone may also prevent the progression of nervous system
degeneration in Friedreich's ataxia.
Patients 5 years of age and older with Friedreich's ataxia may be eligible for this study.
Candidates are screened with a blood test and review of their medical records, including
Participants undergo the following procedures during a 6-day hospital admission to the NIH
- Placement of an intravenous catheter (plastic tube inserted into a vein) for collecting
blood samples after drug administration
- Blood and urine tests
- Heart examination, including electrocardiogram (EKG), to assess heart function and
- Idebenone therapy: Patients take three tablets a day (at 7 AM, 1 PM and 7 PM) on days
2, 3 and 4 of hospitalization. Blood samples are collected through the IV tube at 0.5,
1, 2, 4, and 6 hours after the first dose on day 2, then at 1 hour after the first and
third doses every day, and then at 1, 2, 4, 8, 12, 24, 36, and 48 hours after the last
dose on day 4 to determine how the body uses and eliminates the drug.
- Monitoring for drug side effects: Patients have frequent checks of vital signs (blood
pressure, pulse, temperature, breathing rate) and a brief physical examination to check
for drug side effects from the start of drug therapy on day 2 until at least 43 hours
after the last dose on day 4.
Patients who experience no difficulties are discharged from the hospital after the sixth day
with a 1-month supply of medication to take 3 times a day at home. They are contacted by
phone every 2 weeks while taking the medication to check side effects. Blood tests are also
done every 2 weeks to check for any abnormalities.
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
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.
Diagnosis of FRDA with confirmed FRDA mutations.
Age greater than or equal to five years.
No exposure to idebenone or coenzyme Q(10) for a period of at least one week before onset
of the medication phase of the study.
Written, informed consent (and assent, if applicable).
History of hypersensitivity reaction to idebenone or coenzyme Q(10).
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
Lactose intolerant individuals (because of the lactose content in the tablet ingredients).
Age less than five years old.
Platelet count, lymphocyte count or hemoglobin below the lower limit of normal.
Alkaline phosphatase, SGOT, or SGPT greater than 1.5 x the upper limit of normal.
Bilirubin greater than 1.2 g/dl.
Creatinine greater than 1.5 x 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.