Lyons S; Department of Neurology, University Hospital Waterford, Ireland.
Kearney M; Fahey MC; Janjal P; Pandolfo M; Patton P
Cochrane Database of Systematic Reviews. 5:CD007791, 2026 05 12.VI 1
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.
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.
