A Phase 3, Double-Blind, Placebo-Controlled Trial of Idebenone in Friedreich Ataxia

CLINICAL TRIALS

SECTION EDITOR: IRA SHOULSON, MD A Phase 3, Double-blind, Placebo-Controlled Trial of Idebenone in Friedreich Ataxia

David R. Lynch, MD, PhD; Susan L. Perlman, MD; Thomas Meier, PhD

Objective: To assess the efficacy of idebenone on neu- (FARS) score, performance measures, and activities of rological function in patients with Friedreich ataxia. daily living were the secondary efficacy variables.

Design: Randomized, double-blind, placebo- Results: Patients who received idebenone improved by controlled intervention trial. 2.5 points on mean ICARS score compared with baseline, while patients in the placebo group improved by 1.3 Setting: Children’s Hospital of Philadelphia and the Uni- points. Patients who took idebenone also improved by versity of California at Los Angeles. 1.6 points on the FARS, while patients taking placebo de- clined by 0.6 points. For both end points, the difference Participants: Seventy ambulatory pediatric patients (age, between the idebenone and placebo groups was not sta- 8-18 years) with a baseline International Cooperative tistically different. Ataxia Rating Scale (ICARS) score of 10 to 54. Conclusions: Idebenone did not significantly alter neu- Interventions: Participants were randomized into 1 of rological function in Friedreich ataxia during the 6-month 3 treatment arms: 450 or 900 mg of idebenone per day study. Larger studies of longer duration may be needed (in those with a body weight Յ or Ͼ45 kg, respectively; to assess the therapeutic potential of drug candidates on n=22); 1350 or 2250 mg of idebenone per day (n=24); neurological function in Friedreich ataxia. or placebo (n=24). Trial Registration: clinicaltrials.gov Identifier: Main Outcome Measures: Mean change from base- NCT00537680 line to week 24 in ICARS score was the primary efficacy variable. Mean change in Friedreich Ataxia Rating Scale Arch Neurol. 2010;67(8):941-947

RIEDREICH ATAXIA IS AN AU- the mitochondrial electron transport chain, tosomal recessive degenera- increasing the production of adenosine tri- tive disorder characterized by phosphate.8 In Friedreich ataxia, idebe- ataxia, areflexia, sensory loss, none may decrease cardiac hypertrophy and weakness, scoliosis, and car- improve cardiac function, with beneficial ef- diomyopathy. Diabetes mellitus, optic neu- fects observed at dose levels of 5 mg/kg per F 1,2 9-13 ropathy, and hearing loss are also seen. day. Data on neurological effects at this Most patients with Friedreich ataxia (97%) dose level are inconsistent.9-13 A 6-month, have expansions of a GAA repeat in the first double-blind, placebo-controlled phase 2 intron on both alleles of the gene encoding clinical trial (National Institutes of Health the mitochondrial protein frataxin,2,3 whose [NIH] Collaboration With Santhera in 4 Author Affiliations: expression is reduced in Friedreich ataxia. Ataxia [NICOSIA]) using higher doses of Departments of Neurology The size of the GAA-repeat expansion in- idebenone showed evidence of dose- and Pediatrics, University versely correlates with frataxin expression dependent improvement in secondary of Pennsylvania School and age at disease onset.3 Deficiency of fra- neurological end points compared with pla- of Medicine, and The Children’s taxin in cells leads to decreased activities of cebo.14 This was best noted on the Interna- Hospital of Philadelphia, iron-sulfur cluster–containing enzymes, ac- tional Cooperative Ataxia Rating Scale Philadelphia (Dr Lynch); cumulation of iron in the mitochondrial ma- (ICARS), with a similar pattern observed for Department of Neurology, trix, increased sensitivity to oxidative stress, the Activities of Daily Living and neuro- David Geffen School and impaired adenosine triphosphate pro- logical scales of the Friedreich’s Ataxia Rat- of Medicine, University 5-7 of California at Los Angeles, duction. ing Scale (FARS). Neurological improve- Los Angeles (Dr Perlman); and Idebenone, a synthetic analogue of co- ment was especially evident in ambulatory Santhera Pharmaceuticals, enzyme Q10, has potent antioxidant activ- patients with ICARS scores of 10 to 54 at Liestal, Switzerland (Dr Meier). ity and facilitates the flux of electrons along baseline. The trend to improvement was

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 vided as prepackaged kits marked with the appropriate treatment number. Group A received idebenone (150-mg idebe- 74 Screened 4 Excluded none tablets, Catena, Santhera Pharmaceuticals) at 450 mg per 3 ICARS score > 54 day (if Յ45-kg body weight at baseline) or 900 mg per day (if 1 Elevated liver Ͼ45-kg body weight at baseline); group B received idebenone function test result Յ Ͼ 70 Randomized at 1350 mg per day (if 45 kg) or 2250 mg per day (if 45 kg); and group C received placebo. These dosages correspond Center 1 Center 2 to doses in the range of approximately 10 to 20 mg/kg per day 12 Received placebo 12 Received placebo 11 Received 450 or 900 11 Received 450 or 900 (group A) and approximately 30 to 54 mg/kg per day (group mg/d of idebenone Allocation mg/d of idebenone B) for patients weighing 25 to 80 kg within each dose group. 12 Received 1350 or 2250 12 Received 1350 or 2250 The drug was administered in 3 divided doses with meals. mg/d of idebenone mg/d of idebenone

35 Completed treatment Follow-up 35 Completed treatment STUDY CONDUCT

35 Analyzed Analysis 35 Analyzed Within 8 weeks prior to randomization (at the baseline visit), patients attended a screening visit where informed consent/assent was obtained and inclusion/exclusion criteria were assessed. They Figure 1. Participant flow diagram. ICARS indicates International underwent a physical and neurological examination, including Cooperative Ataxia Rating Scale. an assessment of vital signs and electrocardiography, and a preg- nancy test for female patients of childbearing potential. Thereaf- only evident at idebenone doses approximately 3- to 10- ter, neurological efficacy assessments were undertaken at base- fold higher than the previously used daily 5-mg/kg dose. line (day 1) and weeks 12 and 24 (end of therapy). Safety The present study, Idebenone Effects on Neurological assessments were performed at weeks 4, 12, 24, and 28 (follow- ICARS Assessments (IONIA), is a double-blind, random- up); no follow-up visit was undertaken in patients who enrolled ized, placebo-controlled intervention trial of 6 months’ du- into the open-label extension. Patients maintained a diary, with daily documentation of study medication intake and recording ration evaluating the safety and efficacy on neurological of adverse events and concomitant medications. function of idebenone in ambulatory pediatric patients with Friedreich ataxia. OUTCOME MEASURES AND OBJECTIVES

METHODS The primary objective was to compare the efficacy of 24 weeks’ treatment with 2 different doses of idebenone with that of pla- STUDY DESIGN cebo on neurological impairment as assessed by the ICARS. Sec- ondary measures included the neurological examination of the The study was a double-blind, randomized, placebo- FARS; the Friedreich’s Ataxia Composite Test (FACT-Z3), de- controlled, parallel-group study investigating the safety, toler- rived from the Timed 25-Foot Walk test, the 9-hole peg test, ability, and efficacy of idebenone in the treatment of patients and the low-contrast letter acuity test; and the activities of daily with Friedreich ataxia conducted at 2 centers: Children’s Hos- living scale.15-18 pital of Philadelphia and the University of California at Los An- geles. Inclusion criteria included a diagnosis of Friedreich ataxia STATISTICAL ANALYSIS with confirmed GAA-expansion mutations (patients having point mutations were not eligible); age older than 7 and younger than The primary and secondary efficacy analyses were conducted 18 years at baseline evaluation; body weight above 25 kg; and in the intent-to-treat population, including all randomized pa- ability to walk at least 10 m without an accompanying person tients. The patients were analyzed as randomized regardless of (ICARS Walking Capacities score Յ6). Patients were ex- protocol deviations. The last observation carried forward method cluded if they had an ICARS score greater than 54 or less than was applied to impute missing data. Safety analysis included 10 at screening; were pregnant or breastfeeding; had clinically all randomized patients who received at least 1 dose of the trial significant abnormalities of hematology or biochemistry; or had medication and for whom safety assessments were available. participated in the previous phase 2 trial of idebenone.14 Pa- Unless specified, efficacy analyses for each group receiving tients being treated at screening with antioxidants (vitamin E, idebenone were compared against the placebo group using pair- coenzyme Q, and idebenone purchased from noncontrolled wise comparison based on an analysis of covariance model, with sources) were required to have a 1-month washout of these treatment as a factor and baseline value as a covariate testing a agents before the baseline visit. 2-sided alternative at a Bonferroni-adjusted ␣ level of 2.5%. With a minimum of 15 evaluable patients in each of the groups, an RANDOMIZATION anticipated effect size (difference between placebo and idebenone) of more than 6.2 ICARS points, and a common SD of Of 74 patients who were screened, 4 did not qualify for enroll- 5.0 points, the study would provide 85% power to reject the ment (3 patients had ICARS scores Ͼ54 and 1 patient had an null hypothesis of no difference between any idebenone dose abnormal liver function test result) (Figure 1). Seventy pa- and placebo with regard to the change from baseline to week tients were randomized 1:1:1 to 1 of 3 treatment arms using a 24 in ICARS using a pairwise comparison test. This effect size central block randomization scheme. A list of randomization is based on results from subgroup analysis of NICOSIA14 and numbers and corresponding treatment numbers was com- is greater than the expected yearly decline in ICARS score for puter generated by a third party (Fischer Services, Allschwil, patients with Friedrich ataxia. Switzerland). Patients and investigators were blinded to the al- A prespecified responder analysis derived from ICARS scores located study group. Treatment assignments were maintained was also conducted. Herein, each active treatment dose was com- by the third party and only made available after the trial was pared with placebo using a 2-sided ␹2 test on the intent-to- complete and the database locked. Study medication was pro- treat population. The responder analysis compared the num-

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Mean (SD), Range by Group

Idebenone

Placebo 450 or 900 mg 1350 or 2250 mg Total Characteristic (n=24) (n=22) (n=24) (N=70) Age, mean (SD), 13.7 (2.8), 13.15 (8.7-18.1) 13.9 (2.5), 14.5 (9.7-17.3) 13.4 (3.0), 12.9 (8.0-18.0) 13.7 (2.8), 13.9 (8.0-18.1) median (range), y Sex, No. (%) M 8 (33.3) 15 (68.2) 10 (41.7) 33 (47.1) F 16 (66.7) 7 (31.8) 14 (58.3) 37 (52.9) GAA-repeat length,a mean (SD), 738 (130), 717 (520-1000) 725 (109), 741 (521-900) 735 (128), 718 (486-970) 733 (121), 727 (486-1000) median (range) Disease duration,b mean (SD), 71.4 (47.4), 74.5 (1.1-196.9) 64.9 (32.3), 63.2 (0.8-124.7) 63.1 (33.6), 55.4 (6.4-134.7) 66.6 (38.3), 68.7 (0.8-196.9) median (range), mo Patients with previous use 3 (12.5) 3 (13.6) 6 (25.0) 12 (17.1) of idebenone, No. (%) Baseline ICARS scorec 35.6 (7.0), 24-48 36.0 (7.1), 23-49 34.0 (8.9), 16-52 35.2 (7.7), 16-52 Baseline FARS scorec 55.9 (10.4), 36-78 59.0 (8.2), 41-73 56.5 (11.6), 34-81 57.1 (10.1), 34-81 c Baseline FACT-Z2 score 0.03 (0.81), −1.4 to 2.2 −0.2 (0.91), −2.3 to 1.2 0.16 (0.99), −2.2 to 2.2 0.00 (0.91), −2.3 to 2.2 c Baseline FACT-Z3 score −0.08 (0.79), −1.4 to 1.8 −0.09 (0.79), −1.8 to 1.3 0.16 (0.85), −1.6 to 1.8 0.00 (0.81), −1.8 to 1.8 Baseline ADL scorec 9.7 (3.9), 3-16 10.5 (2.9), 3-14 9.5 (5.1), 0-19 9.9 (4.1), 0-19

16 Abbreviations: ADL, activities of daily living; FACT-Z2, Friedreich’s Ataxia Composite Test (contains only the Timed 25-Foot Walk and the 9-hole pegboard test) ; FACT-Z3, Friedreich’s Ataxia Composite Test; FARS, Friedreich Ataxia Rating Scale; ICARS, International Cooperative Ataxia Rating Scale. a Repeat length of the shorter GAA allele. b The time since diagnosis is based on the medical history case report form pages. Missing day of onset is imputed to 15, missing day and month of onset are imputed to June 30, and missing year of onset is considered missing. Twenty-four participants in the placebo group; 22 in the 450- or 900-mg idebenone group; and 22 in the 1350- or 2250-mg group. c For intent-to-treat population.

ber and percentage of patients in each treatment arm showing involvement and another had an episode of idiopathic (1) a 2.5-point or greater improvement on ICARS and (2) a thrombocytopenic purpura. Both patients had a history 5-point or greater improvement on ICARS, the latter corre- of the respective condition. The events were classified as sponding to the annual rate of decline in untreated patients with 19 unrelated and resolved spontaneously while they con- Friedreich ataxia. Additional subgroup analyses were per- tinued taking the study medication. Most adverse events formed on the primary efficacy end point for the study population split by the median ICARS score at baseline, disease du- occurred equally between patients taking idebenone and ration of shorter or longer than 5 years prior to study start, sex, those taking placebo (eTable, available at http://www previous use of idebenone, GAA value reported at screening .archneurol.com), except for gastrointestinal tract irri- (Յ800 vs Ͼ800), and study site. tations (defined as nausea, upper abdominal pain, diar- rhea, abdominal pain, vomiting, and dyspepsia). These RESULTS were more frequent in patients in the high-dose (n=14) compared with the low-dose (n=7) and placebo (n=10) groups, but this difference was not statistically signifi- RESULTS OF RANDOMIZATION cant. No safety effects were identified following the with- drawal of antioxidants at trial initiation. Seventy patients (35 patients/center) were randomized to 1 of 3 treatments (Figure 1), and the characteristics of each group were compared (Table 1). Disease severity was simi- CHARACTERIZATION OF EFFICACY VARIABLES lar in the groups based on GAA-repeat length, disease du- AT SCREENING AND BASELINE ration, and baseline neurological scores. The groups dif- fered by sex (P=.049, ␹2 test for between-treatment Although many measures have been developed and used comparison), as group A contained more men. The demo- to assess ataxia, few have been tested under clinical trial graphic characteristics of the cohort were similar to those conditions. We examined the difference between the of the NICOSIA study in age, GAA-repeat length, and sex. screening and baseline values for the primary outcome As efficacy parameters were available from all patients for measure (ICARS score) and 2 other neurological mea- analysis, no data imputation was required. sures, the FARS and the FACT-Z3 (Figure 2). The correlation between scores at these 2 visits was very high SAFETY AND TOLERABILITY for all 3 parameters, with Pearson correlation coeffi- cients of 0.88 (ICARS), 0.89 (FARS), and 0.95 (FACT- Ͻ As seen previously, idebenone was safe and well toler- Z3)(P .001 for all 3 comparisons). This indicates the ated, and all subjects completed the treatment period. Two high reliability of these assessments at screening and base- patients in group B experienced serious adverse events: line visits, which were up to 8 weeks apart, and shows 1 patient experienced chest pain not related to cardiac that these outcome measures are reproducible enough

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40 – 1.0

30 – 2.0 Baseline – 3.0 20 Change in ICARS Score – 4.0 10 – 5.0 Placebo 450 or 900 mg/d 1350 or 2250 mg/d

0 20 40 60 Idebenone B 0.0 90 FARS Score – 0.5 80 – 1.0

70 – 1.5

60 – 2.0 – 2.5 50 – 3.0 Change in ICARS Score Baseline 40 – 3.5

30 – 4.0

– 4.5 20 Baseline 12 24

10 Week

0 20 40 60 80 100 Figure 3. Analysis of the primary efficacy parameter (International Cooperative Ataxia Rating Scale score [ICARS] score). Mean change between week 24 and baseline (A) and mean change between week 12 and baseline 2.0 and week 24 and baseline (B). Error bars represent the standard error of the mean. FACT-Z3 Score 1.5

1.0

0.5 ICARS) of 2.5 (group A) and 2.4 (group B) points, not significantly different compared with placebo (which im- 0.0 proved by 1.3 points) (Figure 3A). Moreover, the mean Baseline – 0.5 difference between the idebenone groups and placebo was driven by one investigation site (based on a site-specific – 1.0 improvement in the idebenone groups), and no dose correlation was seen between the idebenone groups. The im- – 1.5 provement in the placebo group was particularly promi- – 2.0 nent between baseline and week 12 and reduced during – 3 – 2 – 1 0 1 2 Screening the second 12-week study period (Figure 3B). In contrast to ICARS, a slight worsening on the FARS, a secondary neurological outcome measure, was observed for Figure 2. Scatterplots comparing screening and baseline ataxia scale scores

in all patients (N=70). FACT-Z3 indicates Friedreich’s Ataxia Composite Test; patients taking placebo. Although patients receiving ide- FARS, Friedreich Ataxia Rating Scale; and ICARS, International Cooperative benone improved on the FARS (ie, reduced mean FARS Ataxia Rating Scale. score), the difference between the idebenone and placebo groups was not significant (Figure 4A). Like- to be useful in assessing neurological progression in Fried- wise, no clear differences were seen in the FACT-Z3 or reich ataxia. activities of daily living scales between the study groups (Figure 4B and C). EFFECT OF IDEBENONE ON NEUROLOGICAL The change in ICARS score between baseline and week STATUS OF FRIEDREICH ATAXIA 24 for patients correlated with the change in FARS score (Pearson correlation coefficient r=0.62, PϽ.001) and When the 3 study groups were compared for the change FACT-Z3 (r=−0.26, P=.033). No differences were seen between baseline and week 24, subjects taking idebe- in these correlations between the different treatment none showed a mean improvement (ie, reduction on groups (Figure 5).

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0.0 5

– 1.0 0

– 2.0

Change in FARS Score Change in FARS – 5 – 3.0 Change in FARS Score Change in FARS – 10 – 4.0 Placebo Idebenone – 15 450 or 900 mg/d B 1350 or 2250 mg/d

0.2 – 20

0.1 1.5 Score 3

0.0 1.0

– 0.1 Change in FACT-Z Score

3 0.5

– 0.2

0.0

C Change in FACT-Z 2.0 – 0.5

1.0 – 1.0 – 15 – 10 – 5 0 5 10 15 Change in ICARS Score

0.0

Change in ADL Score Figure 5. Scatterplot for changes between week 24 and baseline for ataxia scale

scores in all patients (N=70). FACT-Z3 indicates Friedreich’s Ataxia Composite Test; FARS, Friedreich Ataxia Rating Scale; and ICARS, International Cooperative Ataxia Rating Scale. – 1.0 Placebo 450 or 900 mg/d 1350 or 2250 mg/d Idebenone 12; 33% by 2.5 points and 25% by 5 points at week 24). Thus, no statistically significant differences were noted Figure 4. Mean changes between week 24 and baseline for the secondary between placebo and idebenone therapy. efficacy parameters. ADL indicates activities of daily living; FACT-Z3, Friedreich’s The present results seem paradoxical based on the en- Ataxia Composite Test; and FARS, Friedreich Ataxia Rating Scale. Error bars 14 represent the standard error of the mean. couraging results of a previous phase 2 study that suggested that idebenone might be most effective in less affected patients. Thus, we examined the change in ICARS RESPONDER ANALYSIS scores in 2 subgroups split by the median ICARS at baseline (Table 2). The improvement on ICARS in the ide- We also analyzed the data for the number and percent- benone and placebo groups was generally larger in pa- age of patients who improved by 2.5 or 5 points on ICARS tients with lower ICARS scores at baseline (ie, milder affected over the course of the study (Figure 6). These levels patients) compared with the subgroup with a higher range were selected as being roughly the amount of progres- of ICARS scores at baseline. Similar analysis separating sub- sion expected to occur during 6 or 12 months, respec- groups by disease duration (Ͼ or Յ 5 years) or age showed tively, in untreated patients with Friedreich ataxia,19 and a congruent picture with greater improvement with both therefore improvement of this magnitude would be con- placebo and idebenone seen in the subgroup with shorter sidered clinically meaningful. At 24 weeks of therapy, disease duration or younger age (data not shown). These more than 50% of subjects taking idebenone improved analyses indicate that improvements in mean ICARS scores, by 2.5 points and almost 40% by 5 points, but there was whether with idebenone or placebo, were greater in pa- also a high number of responders in the placebo group tients with shorter disease duration, younger age, or lower (58% improved by 2.5 points and 41% by 5 points at week ICARS scores prior to the study.

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 COMMENT benone groups were −10.8 to −1.7 points [dose A] and −12.5 to −3.1 points [dose B]). The inclusion criteria for this study The major finding of the present 6-month study is that (IONIA) were directed to match this population, and the idebenone did not significantly improve the neurologi- baseline ICARS score matched that of the ambulatory cal status of pediatric patients with Friedreich ataxia com- NICOSIA subgroup, but the effect size was smaller than pared with placebo. Thus, the present short-term study that noted in NICOSIA and not different from placebo. A does not provide evidence for efficacy of idebenone in greater responsiveness of patients with an earlier disease the treatment of ataxia in this disorder. stage to both placebo and idebenone did appear in the pre- The present design is derived from a prespecified sub- sent study. The IONIA study differs in its design from the group analysis of the data of a previous study (NICOSIA)14 NICOSIA study in several ways. Two centers participated in which ambulatory patients (33 of 48) undergoing treat- in the present study, with ratings performed by individu- ment with higher doses of idebenone had improved neu- als highly experienced in grading Friedreich ataxia.16 Fu- rological function as measured by the ICARS, while pa- ture studies might include more sites, in which variability tients taking placebo worsened (in NICOSIA the 95% among raters will be an issue, but also could resolve the confidence intervals for change from baseline in the ide- site specificity noted in the present study. The data from the present study show that the ICARS, FARS, and FACT-Z3 composite are all likely to be useful A Baseline to week 12 Baseline to week 24 in multicenter trials for Friedreich ataxia, as these mea- 70 sures all appeared to change in parallel, providing evi- 60 dence of their concurrent validity. Thus, while the sen-

50 sitivity of these scales to change is limited and each has a variety of limitations (including items that are redun- 40 dant or irrelevant), they appear valid under clinical trial 30 conditions. Still, although these measures change in par- Patients, % 20 allel, the improvement in the placebo group was particu-

10 larly prominent in the ICARS measurement. This had not been noted in the NICOSIA study.14 As evaluations were 0 performed more frequently in the present study than the NICOSIA study, one possible explanation would be prac- B tice effects in the performance of measures by the sub- 70 ject. This could be addressed in future studies by longer

60 study durations, additional “run-in” visits, or different spacing of the efficacy evaluations. Another contribut- 50 ing factor is suggested by the greater improvement in all 40 groups in younger patients. As ICARS scores improve by 30 several units per year until roughly age 11 to 12 years, Patients, % 20 some of the improvement seen across all groups (including placebo) may reflect naturally occurring increases in 10 motor abilities.20 In addition, though the execution of this 0 Placebo 450 or 900 mg/d 1350 or 2250 mg/d trial included systematic attempts to match assessment conditions at each visit, the high level of day-to-day vari- Idebenone ability in neurological function might have influenced results. Figure 6. Responder analysis. Percentage of patients improving by 2.5 or more points (A) or 5 or more points (B) on the International Cooperative The improvement in the placebo group was particu- Ataxia Rating Scale. larly great from baseline to week 12, with a notable drop-

Table 2. Change in ICARS Scores in Patients With Friedreich Ataxia by ICARS Score at Baseline

Mean (SEM) by Baseline ICARS Score

ՅMedian ϾMedian

Idebenone Idebenone P Value, Յ vs Ͼ Median

450 or 1350 or 450 or 1350 or 450 or 1350 or ICARS Placebo 900 mg 2250 mg Placebo 900 mg 2250 mg 900 mg of 2250 mg of Score (n=11) (n=11) (n=14) (n=13) (n=11) (n=10) Placebo Idebenone Idebenone Baseline 29.2 (0.99) 30.3 (1.02) 28.1 (1.31) 41.1 (1.08) 41.6 (1.44) 42.1 (2.00) .12 .19 .63 Change from baseline to week 24 −2.8 (1.07) −4.3 (1.22) −2.8 (1.43) 0.0 (1.30) −0.7 (2.32) −1.8 (1.28) P valuea .49 .97 .78 .49

Abbreviation: ICARS, International Cooperative Ataxia Rating Scale. a Comparison with placebo for change from baseline to week 24.

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 off in the level of improvement by week 24, while the during study recruitment. We would like to acknowl- improvement seen in the idebenone treatment groups in- edge the excellent coordination of the multicenter study creased from week 12 to week 24. If the study had been by Bonnie Johnson, Kimberly Schadt, Lisa Friedman, Erin longer, a treatment effect may have been revealed. The Paulsen (from the Children’s Hospital of Philadelphia), study duration of 6 months in evaluating neuroprotec- Sharone Trifskin, and Lynn Kessler (University of Cali- tion in a chronically progressive neurological disease may fornia at Los Angeles). We thank Mikael Saulay (Averion represent an important limitation. International, Allschwil, Switzerland) for conducting sta- Although idebenone did not significantly alter neu- tistical analyses, which were also independently re- rological function as measured in this study, idebenone peated by Dr Lynch. treatment may affect features of Friedreich ataxia not captured in this study. Data from several studies indicate that idebenone can ameliorate cardiac hypertrophy of pa- REFERENCES tients with Friedreich ataxia, but there is still insuffi- cient evidence whether these improvements in cardiac 1. Harding AE. Friedreich’s ataxia: a clinical and genetic study of 90 families with anatomy translate into a demonstrable clinical benefit. an analysis of early diagnostic criteria and interfamilial clustering of clinical features. Finally, in Friedreich ataxia, idebenone is commonly as- Brain. 1981;104(3):589-620. 2. Schulz JB, Boesch S, Bürk K, et al. Diagnosis and treatment of Friedreich ataxia: sociated with a relief of the fatigue, a multifactorial symp- a European perspective. Nat Rev Neurol. 2009;5(4):222-234. tom that may not necessarily be well captured in mea- 3. Dürr A, Cossee M, Agid Y, et al. Clinical and genetic abnormalities in patients sures of ataxia. with Friedreich’s ataxia. N Engl J Med. 1996;335(16):1169-1175. While previous studies suggest that idebenone treat- 4. Campuzano V, Montermini L, Lutz Y, et al. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet. 1997; ment results in a potential clinical benefit for patients with 6(11):1771-1780. Friedreich ataxia, this study did not show statistically sig- 5. Rötig A, de Lonlay P, Chretien D, et al. Aconitase and mitochondrial iron- nificant differences between placebo and idebenone treat- sulphur protein deficiency in Friedreich ataxia. Nat Genet. 1997;17(2):215- ment in neurological end points after treatment for 6 217. months. Larger studies of longer duration may be needed 6. Delatycki MB, Camakaris J, Brooks H, et al. Direct evidence that mitochondrial iron accumulation occurs in Friedreich ataxia. Ann Neurol. 1999;45(5):673- to assess neurological efficacy of drug candidates in Frie- 675. dreich ataxia. 7. Lodi R, Cooper JM, Bradley JL, et al. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad SciUSA. 1999;96 Accepted for Publication: January 26, 2010. (20):11492-11495. 8. Sugiyama Y, Fujita T. Stimulation of the respiratory and phosphorylating activi- Correspondence: David R. Lynch, MD, PhD, Division of ties in rat brain mitochondria by idebenone (CV-2619), a new agent improving Neurology, Children’s Hospital of Philadelphia, 502 cerebral metabolism. FEBS Lett. 1985;184(1):48-51. Abramson Bldg, Philadelphia, PA 19104-4318 (lynch 9. Hausse AO, Aggoun Y, Bonnet D, et al. Idebenone and reduced cardiac hyper- @pharm.med.upenn.edu). trophy in Friedreich’s ataxia. Heart. 2002;87(4):346-349. Author Contributions: Study concept and design: Lynch 10. Buyse G, Mertens L, Di Salvo G, et al. Idebenone treatment in Friedreich’s ataxia: neurological, cardiac, and biochemical monitoring. Neurology. 2003;60(10): and Meier. Acquisition of data: Lynch and Perlman. Analy- 1679-1681. sis and interpretation of data: Lynch and Meier. Drafting 11. Mariotti C, Solari A, Torta D, Marano L, Fiorentini C, Di Donato S. Idebenone treat- of the manuscript: Lynch and Meier. Critical revision of ment in Friedreich patients: one-year-long randomised placebo-controlled trial. the manuscript for important intellectual content: Lynch, Neurology. 2003;60(10):1676-1679. 12. Artuch R, Aracil A, Mas A, et al. Friedreich’s ataxia: idebenone treatment in early Perlman, and Meier. Statistical analysis: Lynch. Admin- stage patients. Neuropediatrics. 2002;33(4):190-193. istrative, technical, and material support: Lynch and Meier. 13. Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, Sidi D, Munnich A, Rotig Study supervision: Lynch. A. Effect of Idebenone on cardiomyopathy in Friedreich’s ataxia: a preliminary Financial Disclosure: The present work was sponsored study. Lancet. 1999;354(9177):477-479. by Santhera Pharmaceuticals. Dr Lynch has also re- 14. Di Prospero NA, Baker A, Jeffries N, Fischbeck KH. Neurological effects of high- dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo- ceived grant funding for other projects from the Na- controlled trial. Lancet Neurol. 2007;6(10):878-886. tional Institutes of Health, the Muscular Dystrophy As- 15. Trouillas P, Takayanagi T, Hallett M, et al; The Ataxia Neuropharmacology Com- sociation, and the Friedreich’s Ataxia Research Alliance. mittee of the World Federation of Neurology. International Cooperative Ataxia Dr Perlman has also received grant funding for other Rating Scale for pharmacological assessment of the cerebellar syndrome. J Neu- rol Sci. 1997;145(2):205-211. projects from the National Institutes of Health, the HighQ/ 16. Lynch DR, Farmer JM, Tsou AY, et al. Measuring Friedreich ataxia: complemen- CHDI Foundation, the National Ataxia Foundation, the tary features of examination and performance measures. Neurology. 2006; Muscular Dystrophy Association, and the Friedreich 66(11):1711-1716. Ataxia Research Alliance. Dr Meier is an employee of San- 17. Subramony SH, May W, Lynch D, et al; Cooperative Ataxia Group. Measuring thera Pharmaceuticals. Dr Lynch had complete access to Friedreich ataxia: interrater reliability of a neurologic rating scale. Neurology. 2005; 64(7):1261-1262. all data and conducted statistical analyses indepen- 18. Lynch DR, Farmer JM, Wilson RL, Balcer LJ. Performance measures in Fried- dently of the sponsor. reich ataxia: potential utility as clinical outcome tools. Mov Disord. 2005;20 Online-Only Materials: The eTable is available at http: (7):777-782. //www.archneurol.com. 19. Fahey MC, Corben L, Collins V, Churchyard AJ, Delatycki MB. How is disease progress in Friedreich’s ataxia best measured? a study of four rating scales. Additional Contributions: The authors thank the pa- J Neurol Neurosurg Psychiatry. 2007;78(4):411-413. tients and families who participated in the study as well 20. Sival DA, Brunt ER. The International Cooperative Ataxia Rating Scale shows strong as the Friedreich Ataxia Research Alliance for support age-dependency in children. Dev Med Child Neurol. 2009;51(7):571-572.

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