Abstract: We identified more than 12 studies that used antioxidants in the treatment of Friedreich ataxia, but only two small RCTs, with a combined total of 72 participants, both fulfilled the selection criteria for this review and published results. One of these trials compared idebenone with placebo, the other compared high-dose versus low-dose coenzyme Q10 and vitamin E (the trialists considered the low-dose medication to be the placebo). We identified two other completed RCTs, which remain unpublished; the interventions in these trials were pioglitazone (40 participants) and idebenone (232 participants). Other RCTs were of insufficient duration for inclusion. In the included studies, the primary outcome specified for the review, change in a validated Friedreich ataxia rating score, was measured using the International Co-operative Ataxia Rating Scale (ICARS). The results did not reveal any significant difference between the antioxidant-treated and the placebo groups (mean difference 0.79 points, 95% confidence interval -1.97 to 3.55 points; low-quality evidence). The published included studies did not assess the first secondary outcome, change in cardiac status as measured by magnetic resonance imaging. Both studies reported changes in cardiac measurements assessed by echocardiogram. The ejection fraction was not measured in the larger of the included studies (44 participants). In the smaller study (28 participants), it was normal at baseline and did not change with treatment. End-diastolic interventricular septal thickness showed a small decrease in the smaller of the two included studies. In the larger included study, there was no decrease, showing significant heterogeneity in the study results; our overall assessment of the quality of evidence for this outcome was very low. Left ventricular mass (LVM) was only available for the smaller RCT, which showed a significant decrease. The relevance of this change is unclear and the quality of evidence low. There were no deaths related to the treatment with antioxidants. We considered the published included studies at low risk of bias in six of seven domains assessed. One unpublished included RCT, a year-long study using idebenone (232 participants), published an interim report in May 2010 stating that the study reached neither its primary endpoint, which was change in the ICARS score, nor a key cardiological secondary endpoint, but data were not available for verification and analysis. Low-quality evidence from two small, published, randomised controlled trials neither support nor refute an effect from antioxidants (idebenone, or a combination of coenzyme Q10 and vitamin E) on the neurological status of people with Friedreich ataxia, measured with a validated neurological rating scale. A large unpublished study of idebenone that reportedly failed to meet neurological or key cardiological endpoints, and a trial of pioglitazone remain unpublished, but on publication will very likely influence quality assessments and conclusions. A single study of idebenone provided low-quality evidence for a decrease in LVM, which is of uncertain clinical significance but of potential importance that needs to be clarified. According to low-quality evidence, serious and non-serious adverse events were rare in both antioxidant and placebo groups. No non-antioxidant agents have been investigated in RCTs of 12 months' duration.

Plain-language summary: We decided to review clinical trials that had participants who took antioxidants for at least 12 months, as Friedreich ataxia is a slowly progressing condition. A wide search of the medical literature found four randomised controlled trials, but only two of them had published results in medical journals. One trial, involving 28 participants, compared idebenone to a placebo. The other, involving 44 participants, compared high-dose and very low-dose combined coenzyme Q10 and vitamin E. The two unpublished trials studied pioglitazone in 40 participants and idebenone in 232 participants, but we had no data. According to low quality evidence from two small published trials included in the review, antioxidants did not improve neurological symptoms in Friedreich ataxia. An additional large, unpublished study of idebenone reportedly found no benefit from idebenone for heart or neurological symptoms, but data are not available for checking and analysis. When published this trial will very likely influence our quality assessments and conclusions. Although some measures of heart wall thickness and mass decreased in the smaller of the two published trials, the quality of this evidence was low or very low and the importance of these findings is not clear. . Numbers of serious or non-serious adverse events were low and similar with antioxidants and placebo. The only serious adverse event that required withdrawal of an antioxidant was increased bowel frequency in one person receiving coenzyme Q with vitamin E. The evidence in the review is up to date to February 2016.