Journal of the Neurological Sciences 267 (2008) 174–176www.elsevier.com/locate/jns

Short communication

Antioxidant use in Friedreich ataxia

Lauren Myers a,b, Jennifer M. Farmer a,c,d, Robert B. Wilson d, Lisa Friedman a,b, Amy Tsou a,Susan L. Perlman e, Sub H. Subramony f, Christopher M. Gomez g, Tetsuo Ashizawa h,George R. Wilmot i, Katherine D. Mathews j, Laura J. Balcer a, David R. Lynch a,b,d,⁎

a Department of Neurology, University of Pennsylvania School of Medicine, United Statesb Department of Pediatrics, University of Pennsylvania School of Medicine, United States

c Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, United Statesd Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States

e University of California Los Angeles, Los Angeles, CA, United Statesf University of Mississippi, Jackson, MS, United States

g University of Minnesota, Minneapolis, MN, United Statesh University of Texas Medical Branch, Galveston, TX, United States

i Emory University, Atlanta, GA, United Statesj University of Iowa, Iowa City, IA, United States

Received 1 August 2007; received in revised form 3 October 2007; accepted 5 October 2007Available online 7 November 2007

Abstract

Many antioxidants have been suggested as potential treatments for Friedreich ataxia, but have not been tested in clinical trials. We foundthat a majority of patients in our cohort already use such antioxidants, including idebenone, which is not available at a pharmaceutical gradein the United States. Younger age, cardiomyopathy and shorter GAA repeat length were independent predictors of idebenone use, but nofactors predicted use of other antioxidants. This confirms that non-prescription antioxidant use represents a major confounder to formal trialsof existing and novel agents for Friedreich ataxia.© 2007 Elsevier B.V. All rights reserved.

Keywords: Ataxia; Idebenone; Clinical trial; Cerebellum

1. Introduction

Friedreich ataxia (FA) is an autosomal recessive disordercharacterized by progressive ataxia, dysarthria, diabetes,scoliosis and cardiomyopathy [1]. An expanded GAA tripletrepeat is found in both alleles of the FRDA gene in 97% ofpeople with FA [1,2]. The length of the shorter GAA repeatcorrelates with age of onset. Frataxin, the gene product of

⁎ Corresponding author. Division of Neurology, Children's Hospital ofPhiladelphia, 502 Abramson Building, Philadelphia, Pennsylvania 19104-4318, United States. Tel.: +1 215 590 2242; fax: +1 215 590 3779.

E-mail address: lynch@pharm.med.upenn.edu (D.R. Lynch).

0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.jns.2007.10.008

FRDA, chaperones iron in the mitochondrial matrix, andmay be involved in the assembly and repair of mitochondrialiron–sulfur clusters [3–5]. Loss of mitochondrial respiratoryfunction and the production of reactive oxygen species arepostulated to contribute to the disease. While someantioxidants improve biomarkers of disease activity [6,7],double blind clinical trials are necessary to determine theeffect of antioxidants on clinical measures in FA.

Since many antioxidants are available without a prescrip-tion, some patients use antioxidants in an attempt to slowdisease progression. We reviewed the data available from alarge multicenter study of FA to ascertain the prevalence ofantioxidant use in FA and the disease features associated

Table 1AUse of antioxidants in FA patients

Agent % taking Median dose Interquartile range Median dose/weight Interquartile range Median duration (years)

Vitamin E 53 800 IU 700–1200 11.3 IU/kg 8.2–20 IU/kg N1Coenzyme Q10 43 300 mg 200–400 3.9 mg/kg 2.2–7.7 mg/kg N1Idebenone 17 390 mg 225–450 6.8 mg/kg 4.4–10 mg/kg N1NAC 9 1100 mg 550–2250 29.5 mg/kg 15.8–52.4 mg/kg N1Selenium 7 200 mg 100–200 2.7 mg/kg 0.98–4.7 mg/kg N1

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with use of antioxidants. This information about medicationand supplement use in the FA population will be important inplanning future clinical trials.

2. Methods

We examined 217 patients with genetically confirmed FAat 7 sites: The University of Pennsylvania/Children'sHospital of Philadelphia (67); University of California, LosAngeles (73); Emory University (33); University ofMississippi Medical Center (16); University of Minnesota(17); University of Iowa (8); and the University of TexasMedical Branch (3). Patients were assessed with aquantitative neurological exam called the Friedreich AtaxiaRating Scale (FARS) [8]. Use of the antioxidants vitamin E,idebenone, coenzyme Q10, selenium, N-acetyl cysteine(NAC) and other medications were recorded, as well as thedosage and duration of therapy. Dosages were also convertedto dose per weight when possible.

2.1. Data analysis

Logistic regression analyses were used to define con-tributors to the use of antioxidants. Analyses were performedusing Stata 8.0 software (StataCorp, College Station, TX).Statistical significance was set at pb0.01 since multiplecomparisons were performed.

3. Results

The cohort had a mean age of 30.8±15.5 years, and 57%were women. Mean shorter GAA repeat length was 602±247. Forty one percent of subjects had cardiomyopathy, 76%

Table 1BLogistic regression analysis of clinical variables and antioxidant use

Agent Age Gender GAA repeatlength

Presence ofcardiomyopathy

FARSscore

Vitamin E 0.56 0.37 0.59 0.32 0.032CoQ 0.73 0.69 0.35 0.50 0.13Idebenone 0.0005⁎ 0.32 0.005⁎ 0.029 0.13NAC 0.24 0.41 0.073 0.97 0.54Selenium 0.32 0.54 0.14 0.62 0.025

⁎=Statistically significant. In panel A, the use of different antioxidants isdisplayed. In panel B, logistic regression was used to define the patientcharacteristics associated with a greater likelihood for use of eachantioxidant ( p values shown in table).

had scoliosis, and 5% had diabetes. Mean FARS score was66±23, typical of a barely ambulatory patient.

Use of antioxidants was common among this cohort. Only36% of patients reported no antioxidant use, and 1% took allfive antioxidants queried (Tables 1A and 1B). Vitamin E wasthe most commonly taken antioxidant, followed by coen-zyme Q10. Side effects were quite limited and included easybruising with vitamin E (1 patient), increased cholesterollevels after starting CoQ10 in conjunction with cholesterollowering medicines (1 patient), and nausea with combinationNAC/selenium (1 patient). For comparison, symptomaticprescription medications taken by patients included baclofen(11%), buspirone (3%), gabapentin (6%) and amantidine(6%), showing that antioxidant use was far more prevalentthat prescription medication use.

We then examined whether antioxidant use was associ-ated with specific clinical features of FA patients. Antiox-idant use did not differ between sites (data not shown).Idebenone use was independently associated with youngerage and shorter GAA repeat size; presence of cardiomyop-athy was also independently associated with a higherprobability of taking idebenone with an odds ratio of 3.3(though this did not reach significance (pN0.01)). Inaddition, the median dose of idebenone (about 7 mg/kg) issimilar to that suggested to slow the progression ofcardiomyopathy [7]. When we reviewed the cumulativedata, 38% of children already took idebenone, and 72% ofchildren took at least one antioxidant. Better neurologicalexam score showed a trend toward increased use of eachantioxidant except NAC; this did not reach significance,suggesting that disease stage did not greatly influencetendency toward such therapies. No other features weresignificantly associated with an increased use of any otherspecific antioxidant.

4. Discussion

In the present study we determined that a majority ofFA patients use readily available antioxidants. Except foruse of idebenone, there were no predictors for use of otherspecific antioxidants in terms of genetic severity, gender, orage. While these agents are not clearly efficacious and maytheoretically counteract each other in certain situations [11],the level of antioxidant use seems quite high in comparisonto other neurodegenerative disorders. This may reflect thepublication of studies almost 10 years ago suggesting poten-tial efficacy of idebenone, the life threatening nature of

176 L. Myers et al. / Journal of the Neurological Sciences 267 (2008) 174–176

cardiomyopathy in FA, the relative justification in interven-ing in a childhood-onset (rather than adult-onset) disorder,and the biased nature of the referral population in the presentstudy. In the primary center in the present study (Universityof Pennsylvania/CHOP), almost 50% of patients live outsidenormal referral areas suggesting the possibility of bias. Still,in each of the centers, less than 10% of patients seen for FAdeclined participation, limiting further bias (data not shown).In addition, this referral population is likely the target offuture therapeutic trials, making the present observationsdirectly relevant for such studies.

The use of non-prescription medicines and alternativetherapies has been associated with a variety of factors inother settings [12–15]. Gender, racial and ethnic features,and disease severity have all been associated with alternativemedical approaches in selected populations. In our cohort,ethnic and racial features play little or no role because of thelimited racial distribution of FA, and we found no influenceof gender as a determining factor in antioxidant use. Diseaseseverity (as defined by FARS score) also played at mosta limited role. In contrast, use of idebenone was associatedwith younger age, shorter GAA repeat length and cardio-myopathy. Several studies suggest that idebenone may beefficacious in young patients with cardiomyopathy, and thedose used here by FA patients roughly matches that used inEuropean trials [7,9,10], suggesting that the use of idebenonein part reflects reading of the medical literature by physiciansand families. The association of idebenone use with shorterGAA repeat length when age is controlled likely reflects thesubpopulation of adults with late onset disease that are morereadily capable of obtaining idebenone. In the present cohort,antioxidant use was usually initiated by patients, thoughphysicians were generally consulted. This is revealed in ourdata by the absence of any site dependence in antioxidantuse.

The present data illustrate the need for systematic clinicaltrials when feasible, but also have important implications forthe design of clinical trials in FA, particularly if the agentunder consideration has antioxidant properties. Most pro-posed trials in FA will use a placebo control and requirediscontinuation of antioxidants in order to maximize detec-tion of a response to therapeutic agents (most of which havesome antioxidant abilities). As initial clinical trials may betargeted to children who are ambulatory (based on thepresumed superior responsiveness of such patients), our datademonstrate that most children are at present not eligible forsuch trials unless they discontinue present agents. However,the widespread use of antioxidants suggests that patients andcaregivers already believe that such agents are useful. Thus itmay be difficult to find patients who are antioxidant naive orwilling to discontinue antioxidant use for clinical trials. Thisdramatically limits the enrollment possibilities and thegeneralizability of results from such studies.

In considering the design of future trials, it may be nec-essary to minimize the number of individuals in placeboarms or to limit the time of such trials to avoid long-termwithholding of such agents. Alternatively, careful naturalhistory studies might allow use of historical controls usingantioxidants in some trials, or studies could utilize an activeplacebo arm containing low dose antioxidants. Some trialsmight allow for continued intake of current antioxidants withstable dosing. Accurate knowledge about the current healthpractices of potential study participants will allow studydesign to optimize enrollment and insure meaningful results.

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