Pharmacological treatments for Friedreich ataxia

  • Review
  • Intervention

Authors


Abstract

Background

Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, and pes cavus. Heart abnormalities cause premature death in 60% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the second update of a review first published in 2009 and previously updated in 2012.

Objectives

To assess the effects of pharmacological treatments for Friedreich ataxia.

Search methods

On 29 February 2016 we searched The Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, EMBASE and CINAHL Plus. On 7 March 2016 we searched ORPHANET and TRIP. We also checked clinical trials registers for ongoing studies.

Selection criteria

We considered randomised controlled trials (RCTs) or quasi-RCTs of pharmacological treatments (including vitamins) in people with genetically-confirmed Friedreich ataxia. The primary outcome was change in a validated Friedreich ataxia neurological score after 12 months. Secondary outcomes were changes in cardiac status as measured by magnetic resonance imaging or echocardiography, quality of life, mild and serious adverse events, and survival. We excluded trials of duration shorter than 12 months.

Data collection and analysis

Three review authors selected trials and two review authors extracted data. We obtained missing data from the two RCTs that met our inclusion criteria. We collected adverse event data from included studies. We used standard methodological procedures expected by Cochrane.

Main results

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 We identified two other completed RCTs, which remain unpublished; the interventions in these trials were pioglitazone (40 participants) and idebenone (232 participants).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.

Authors' conclusions

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

Pharmacological treatments for Friedreich ataxia

Review question

We reviewed the evidence about the effect of antioxidants and other medicines for Friedreich ataxia.

Background

Friedreich ataxia is a rare inherited neurological condition, which first presents between 5 and 15 years of age. It initially causes clumsiness of movement, and progresses to unsteadiness in standing and walking, with wheelchair dependency by late teens or early twenties. Speech usually becomes slurred. A specific faulty gene must be inherited from each parent for the disease to develop in their child (autosomal recessive inheritance). Other major problems which can develop include a curved spine (scoliosis), foot deformity (a high arch), and heart problems, which are a cause of death in 60% of people. Friedreich ataxia has no known effective treatment. Clinical examination and laboratory tests are not very useful for assessing disease progression, and this in turn makes interpreting clinical trial results difficult.

Antioxidants are thought to reduce damage to cells from harmful 'free radicals'. Antioxidants occur naturally in foods in very low levels. Recent studies have found conflicting results about the effect that the antioxidants idebenone, coenzyme Q10 and vitamin E have on the heart in Friedreich ataxia, as measured by thickening of the interventricular septum (the wall between two chambers of the heart), and increased left ventricular mass (the left ventricle is the chamber of the heart that pumps blood around the body).

Study characteristics

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.

Key results and quality of the evidence

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.