Idebenone in friedreich ataxia cardiomyopathy: Results from a 6 months phase III study

Background: Friedreich ataxia (FRDA) is commonly associated with hypertrophic cardiomyopathy, but little is known about the frequency or the severity of FRDA cardiomyopathy; there are no proven treatments for FRDA-related cardiac disease. In this 6-month, randomized, double-blind controlled study, we sought to determine whether idebenone improves cardiac function in patients with FRDA. Methods: Seventy pediatric subjects at The Children's Hospital of Philadelphia and the University of California at Los Angeles were treated with idebenone (450/900 mg/day or 1350/2250 mg/day) or placebo. Electrocardiograms were assessed at each visit, and echocardiograms were performed at baseline and week 24. Results: We found ECG abnormalities in 90% of patients. On echocardiogram, 81.4% of the total cohort had left ventricular hypertrophy as measured by increased left ventricular mass index (LVMi) and the mean ejection fraction (EF) was 56.9%. Longer PR intervals at baseline were marginally associated with longer GAA repeat length (R2=0.13, p=0.011). GAA repeat length did not clearly predict baseline EF (R2=0.0067, p=0.086) and left ventricular mass by M-mode (R2=0.34, p=0.045). LVMi, posterior wall thickness, EF and ECG parameters were not significantly improved by treatment with idebenone, independent of dose. However, age was a significant negative predictor of LVMi (R2=0.226, p<0.01). Notably, some changes in echocardiographic parameters during the treatment phase correlated with baseline status but not treatment group. All groups showed an overall decrease in LVMi and PWTd, without significant difference between groups. Conclusions: In patients with FRDA, idebenone did not decrease left ventricular hypertrophy or improve cardiac function when compared to placebo. The present studies do not provide evidence of benefit in this cohort. In addition, the normalization of several echocardiographic parameters in the placebo group suggests that echocardiography is limited in its use as an outcome measure in FRDA.