Key messages
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For people with a progressive genetic condition called Friedreich ataxia, which affects nerves and muscles, taking medicine for a year probably has little to no effect on measures of ataxia (problems with co-ordination and balance) or speech, although it probably improves upper limb dexterity (the ability to co-ordinate the action of the arms, hands and fingers).
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We are uncertain whether taking medicine has any effect on heart health, the ability to perform daily tasks, or the body's response to exercise in people with Friedreich ataxia.
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From the available evidence, it is very uncertain whether the medicines cause any unwanted effects.
What is Friedreich ataxia?
Friedreich ataxia is a rare inherited condition affecting the nerves and muscles, which usually appears in childhood, at between 5 and 15 years of age. It causes clumsiness of movement, which progresses to unsteadiness in standing and walking, and to being dependent on a wheelchair by the late teens or early twenties. It can be associated with a curved spine (scoliosis), foot deformity (a high arch) and heart problems. As the disease progresses, slurred speech, hearing difficulties, problems going to the toilet, muscle spasticity, depression, anxiety and visual disturbances are common. Heart problems are a cause of early death in nearly two-thirds of people with Friedreich ataxia.
Clinical examination and laboratory tests are not very useful for judging the progression of the disease, which makes it difficult to understand the results of studies with Friedreich ataxia patients.
What are the possible options for treating Friedreich ataxia?
There is currently no cure for Friedreich ataxia. Various medicines have been tried. A new medicine, omaveloxolone, was recently approved in the USA and Europe for people over 16 years of age with Friedreich ataxia.
What did we want to find out?
We wanted to know if any of the medicines tested in randomised clinical trials help improve the lives of people with Friedreich ataxia. Randomised clinical trials are studies where some people take medicine and others take placebo, which is a substance that has no medical benefit but looks the same as the active medicine. No-one involved with the study knows who is taking medicine and who is taking placebo.
This is the third update of a Cochrane review that was first published in 2009.
What did we do?
We searched for randomised clinical trials that compared medicine to placebo in people with Friedreich ataxia and lasted at least 12 months. We combined the results of the studies and rated our confidence in this evidence, based on factors such as study methods and the number of people involved.
What did we find?
We found eight studies, seven of which reported results after taking medicine or placebo for 12 months. The studies included a total of 574 people, whose average ages were between 18 and 35 years. Most of the participants (68%) had severe ataxia, while 32% had moderate ataxia.
The studies took place in Europe, North America and Australia. Four of them were carried out by the pharmaceutical industry (i.e. by companies who make the medicines).
Two studies used a medicine called idebenone, and each of the others used a different medicine: co-Q10 with vitamin E, epoetin alpha, omaveloxolone, leriglitazone, pioglitazone, and RT001.
We found that, after one year, there was probably little to no difference in the level of ataxia that people experienced, regardless of whether they took medicine or placebo (7 studies, 513 people).
We are very uncertain whether medicine has any effect on heart health (based on measuring the thickness of the heart muscle) or the ability to do daily tasks or how people score on special tests designed to measure the body's response to exercise.
We found that medicine probably improves upper limb dexterity after one year (3 studies (testing leriglitazone, epoetin alpha and omaveloxolone), 166 people).
With regard to safety, we are very uncertain whether the medicines cause any more unwanted effects than placebo. We found that there may be little to no difference between people taking medicine and people taking placebo in terms of the number of who either stopped taking the medicine or placebo, or the number of who died during the study years (6 studies, 313 people).
What are the limitations of the evidence?
Our confidence in the effect of medicine on ataxia is only moderate. This is because the results were not very precise. We are only moderately confident about the effect of medicine on upper limb dexterity because this was only reported in small studies. We had very little confidence in the other outcomes because of the small numbers of people in the studies. The studies reported varied results, and some studies did not publish the results for all the assessments that were carried out.
It is difficult to measure an individual's perceptions of the positive effects of any new medicine, which may vary depending on their expectations prior to starting the medicine and whether their illness is early or advanced.
How up to date is this evidence?
The evidence is current to 4 February 2025.
Vollständige Zusammenfassung lesen
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.
Zielsetzungen
To assess the effects of pharmacological treatments for people with Friedreich ataxia (FRDA) after 12 months of treatment.
Suchstrategie
To identify studies for inclusion in this review, we searched CENTRAL, MEDLINE, Embase, CINAHL Plus, TRIP, Orphanet, WHO International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov. We also checked reference lists of relevant studies and contacted study authors. The most recent search was on 4 February 2025.
Auswahlkriterien
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.
Datensammlung und ‐analyse
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.
Hauptergebnisse
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.
Schlussfolgerungen der Autoren
In this updated Cochrane systematic review, meta-analysis of results on the ataxia rating scale showed that pharmacological treatments probably make little or no difference compared with placebo after 12 months of treatment. Given this result, the probable improvement that we found in upper limb dexterity was unexpected. Treatment-emergent adverse events leading to cessation of medication or death may be no more common in treatment groups than placebo groups as there were few adverse events detected in the treated groups. However, the studies may not have detected all rare and serious adverse events.
Finanzierung
The authors in this review received no funding.
Registrierung
Protocol (2009) DOI: 10.1002/14651858.CD007791
Original review (2009) DOI: 10.1002/14651858.CD99791.pub2
Update (2012) DOI: 10.1002/14651858.CD007791.pub3
Update (2016) DOI: 10.1002/14651858.CD007791.pub4
