Pharmacological treatments for Friedreich ataxia.

2026-05-12
The Cochrane database of systematic reviews 2026(5)
- Shane Lyons
- Mary Kearney
- Michael C Fahey
- Prashant Janjal
- Massimo Pandolfo
- Patricia Patton

PubMed: 42117563
DOI: 10.1002/14651858.cd007791.pub5

Study Design

Type: Meta-Analysis
Sample size: n = 574
Population: 574 participants with genetically-confirmed Friedreich ataxia, aged 8 to 70 years, mean age 25.9 years, 68% severe ataxia, 32% moderate ataxia, both sexes
Methods: Cochrane systematic review with meta-analysis of RCTs and quasi-RCTs of pharmacological treatments (including vitamins), studies lasting at least 12 months, searched CENTRAL, MEDLINE, Embase, etc. up to 4 February 2025
Duration: 12 months
Funding: Independent

Rationale

Friedreich ataxia (FRDA) is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, and slowly progressing to wheelchair dependency, usually in the late teens or early twenties. Scoliosis, pes cavus and cardiomyopathy are often present at diagnosis. As the disease progresses, individuals usually develop slurred speech, auditory impairment (especially in a noisy environment), urinary tract morbidity, diabetes, anxiety, depression, muscle spasticity and visual disturbances. Cardiac abnormalities cause premature death in 60% of people with FRDA. There is no easily defined clinical or biochemical marker to assess progression and no known curative treatment. This is the third update of a review published in 2009 and updated in 2012 and 2016.

Objectives

To assess the effects of pharmacological treatments for people with Friedreich ataxia (FRDA) after 12 months of treatment.

Search methods

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.

Eligibility criteria

We were interested in randomised controlled trials (RCTs) and quasi-RCTs of pharmacological treatments (including vitamins) in people with genetically-confirmed FRDA. To be included in the review, studies had to last at least 12 months.

Outcomes

We assessed the following outcomes after 12 months of treatment: change in score on a validated ataxia rating scale; change in interventricular septal thickness in diastole (IVSTd) by cardiac magnetic resonance imaging or echocardiogram; change in activities of daily living (ADL) using a validated questionnaire; change in upper limb dexterity; and change in cardiopulmonary exercise testing (CPET). We also assessed treatment-related adverse events with medication continued for the study period, and treatment-emergent adverse events leading to cessation of medication or death during the study period.

Risk of bias

Using the Cochrane risk of bias tool RoB 2, we assessed the risk of bias in the seven outcomes reported in our summary of findings tables.

Synthesis methods

We synthesised the results of the studies for each outcome using meta-analysis, where possible. We calculated the mean difference (MD) or standardised mean difference (SMD) for continuous outcomes, and the risk ratio (RR) for dichotomous outcomes, all with 95% confidence intervals (CIs). We used GRADE to assess the certainty of evidence for our prespecified outcomes as high, moderate, low or very low.

Included studies

We included eight RCTs in this updated review. We included seven of them in meta-analysis, and these studies enroled a total of 574 participants, with sample sizes ranging from 29 to 232 participants per study. One study was international, with centres in North America, Europe and Australia. There were four other multicentre studies (three in Europe and one in North America). Single-centre studies were conducted in the UK, Italy and France. Participants in the studies ranged from eight to 70 years of age at enrolment, with the mean age in each study being between 18 years and 35 years (with an unweighted pooled mean age across studies of 25.9 years). All of the studies enroled both males and females, with the proportion of female participants ranging from 21% to 58%. Sixty-eight per cent of participants had severe ataxia, while the other 32% had moderate ataxia. The studies tested epoetin alpha, CoQ10 and vitamin E, idebenone, leriglitazone, omaveloxolone, and RT001. One study tested pioglitazone but has not published any results. Four of the studies were pharmaceutical-industry-controlled.

Synthesis of results

Meta-analysis of seven studies demonstrated that pharmacological treatment probably makes little or no difference to scores on the ataxia rating scale after 12 months of treatment (SMD 0.02, 95% CI -0.23 to 0.26; I² = 42%; 7 studies, 513 participants; moderate-certainty evidence). The evidence was very uncertain about the effects of treatment on IVSTd (MD -0.51, 95% CI -1.10 to 0.09; I² = 80%; 2 studies, 72 participants; very low-certainty evidence) and on ADL (MD -0.59, 95% CI -1.39 to 0.21; I² = 24%; 3 studies, 167 participants; very low-certainty evidence). Meta-analysis of three studies showed that treatment probably improves upper limb dexterity (SMD -0.42, 95% CI -0.73 to -0.11; I² = 0%; 3 studies, 166 participants; moderate-certainty evidence). We are very uncertain about the effect of pharmacological treatment on CPET (SMD -0.16, 95% CI -0.46 to 0.13; I² = 0%; 3 studies, 181 participants; very low-certainty evidence). We are very uncertain whether pharmacological treatment has any effect on treatment-related adverse events (RR 0.88, 95% CI 0.63 to 1.22; I² = 0%; 2 studies, 104 participants; very low-certainty evidence). There were only 104 participants in this analysis out of a total of 545 participants, so the result may have little relevance. Meta-analysis of six studies found that there may be little to no difference between pharmacological treatment and placebo in treatment-emergent adverse events leading to cessation of medication or death (RR 1.24, 95% CI 0.44 to 3.48; I² = 0%; 6 studies, 313 participants; low-certainty evidence). Our certainty in the evidence ranged from very low to moderate. We downgraded all outcomes by one or two levels for imprecision, with further downgrades for inconsistency (for the outcomes of IVSTd, ADL, CPET) and suspected publication bias (for the outcomes of IVSTd, ADL, CPET and adverse events).

Authors' conclusions

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.

Funding

The authors in this review received no funding.

Registration

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.

Research Insights

Vitamin E→Improved Activities of Daily Living
The evidence was very uncertain about the effects of treatment on ADL (MD -0.59, 95% CI -1.39 to 0.21; I² = 24%; 3 studies, 167 participants; very low-certainty evidence).
Effect
Neutral
Effect size
Small
Vitamin E→Improved Ataxia Rating Scale Score
Meta-analysis of seven studies demonstrated that pharmacological treatment probably makes little or no difference to scores on the ataxia rating scale after 12 months of treatment (SMD 0.02, 95% CI -0.23 to 0.26; I² = 42%; 7 studies, 513 participants; moderate-certainty evidence).
Effect
Neutral
Effect size
Small
Vitamin E→Improved Cardiopulmonary Exercise Testing
We are very uncertain about the effect of pharmacological treatment on CPET (SMD -0.16, 95% CI -0.46 to 0.13; I² = 0%; 3 studies, 181 participants; very low-certainty evidence).
Effect
Neutral
Effect size
Small
Vitamin E→Reduced Interventricular Septal Thickness in Diastole
The evidence was very uncertain about the effects of treatment on IVSTd (MD -0.51, 95% CI -1.10 to 0.09; I² = 80%; 2 studies, 72 participants; very low-certainty evidence).
Effect
Neutral
Effect size
Small