{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:55:46Z","timestamp":1791896146529,"version":"4.3.4"},"reference-count":26,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T00:00:00Z","timestamp":1723161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"OGNI GIORNO","award":["RC 2022-23"],"award-info":[{"award-number":["RC 2022-23"]}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RC 2022-23"],"award-info":[{"award-number":["RC 2022-23"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background: A drug repositioning effort supported the possible use of the anti-HIV drug etravirine as a disease-modifying drug for Friedreich ataxia (FRDA). Etravirine increases frataxin protein and corrects the biochemical defects in cells derived from FRDA patients. Because of these findings, and since etravirine displays a favorable safety profile, we conducted a pilot open-label phase 2 clinical trial assessing the safety and potential efficacy of etravirine in FRDA patients. Methods: Thirty-five patients were stratified into three severity groups and randomized to etravirine 200 mg\/day or 400 mg\/day. They were treated for 4 months. Safety endpoints were the number and type of adverse events and number of dropouts. Efficacy endpoints were represented by changes in peak oxygen uptake and workload as measured by incremental exercise test, SARA score, cardiac measures, measures of QoL and disability. Data were collected 4 months before the start of the treatment (T \u2212 4), at the start (T0), at the end (T4) and 4 months after the termination of the treatment (T + 4). Results: Etravirine was reasonably tolerated, and adverse events were generally mild. Four months of etravirine treatment did not significantly increase the peak oxygen uptake but was associated with a change in the progression of the SARA score (p value &lt; 0.001), compared to the 4 months pre- and post-treatment. It also significantly increased peak workload (p value = 0.021). No changes in the cardiac measures were observed. Health and QoL measures showed a worsening at the suspension of the drug. Conclusions: In this open trial etravirine treatment was safe, reasonably well tolerated and appreciably improved neurological function and exercise performance. Even though a placebo effect cannot be ruled out, these results suggest that etravirine may represent a potential therapeutic agent in FRDA deserving testing in a randomized placebo-controlled clinical trial.<\/jats:p>","DOI":"10.3390\/children11080958","type":"journal-article","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T09:48:54Z","timestamp":1723196934000},"page":"958","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Pilot Phase 2 Randomized Trial to Evaluate the Safety and Potential Efficacy of Etravirine in Friedreich Ataxia Patients"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9986-9907","authenticated-orcid":false,"given":"Gabriella","family":"Paparella","sequence":"first","affiliation":[{"name":"Department of Conegliano, Scientific Institute IRCCS E. Medea, 31015 Conegliano, Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9756-0534","authenticated-orcid":false,"given":"Cristina","family":"Strag\u00e0","sequence":"additional","affiliation":[{"name":"Department of Conegliano, Scientific Institute IRCCS E. Medea, 31015 Conegliano, Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Pesenti","sequence":"additional","affiliation":[{"name":"Department of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca, 20126 Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Dal Molin","sequence":"additional","affiliation":[{"name":"Department of Conegliano, Scientific Institute IRCCS E. Medea, 31015 Conegliano, Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gian Antonio","family":"Martorel","sequence":"additional","affiliation":[{"name":"Department of Conegliano, Scientific Institute IRCCS E. Medea, 31015 Conegliano, Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasco","family":"Merotto","sequence":"additional","affiliation":[{"name":"Department of Conegliano, Scientific Institute IRCCS E. Medea, 31015 Conegliano, Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Genova","sequence":"additional","affiliation":[{"name":"Department of Conegliano, Scientific Institute IRCCS E. Medea, 31015 Conegliano, Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Piazza","sequence":"additional","affiliation":[{"name":"Department of Conegliano, Scientific Institute IRCCS E. Medea, 31015 Conegliano, Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Piccoli","sequence":"additional","affiliation":[{"name":"Department of Conegliano, Scientific Institute IRCCS E. Medea, 31015 Conegliano, Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5063-7403","authenticated-orcid":false,"given":"Elena","family":"Panzeri","sequence":"additional","affiliation":[{"name":"Department of Bosisio Parini, Scientific Institute IRCCS E. Medea, 23842 Bosisio Parini, Lecco, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5654-9615","authenticated-orcid":false,"given":"Alessandra","family":"Rufini","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Testi","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0319-3579","authenticated-orcid":false,"given":"Andrea","family":"Martinuzzi","sequence":"additional","affiliation":[{"name":"Department of Conegliano, Scientific Institute IRCCS E. Medea, 31015 Conegliano, Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1126\/science.271.5254.1423","article-title":"Friedreich\u2019s Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion","volume":"271","author":"Campuzano","year":"1996","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1212\/WNL.55.11.1719","article-title":"Oxidative Stress in Patients with Friedreich Ataxia","volume":"55","author":"Schulz","year":"2000","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"NS20180060","DOI":"10.1042\/NS20180060","article-title":"Role of Frataxin Protein Deficiency and Metabolic Dysfunction in Friedreich Ataxia, an Autosomal Recessive Mitochondrial Disease","volume":"2","author":"Clark","year":"2018","journal-title":"Neuronal Signal."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/ana.24595","article-title":"Compound Heterozygous FXN Mutations and Clinical Outcome in Friedreich Ataxia","volume":"79","author":"Galea","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/jnc.12317","article-title":"Clinical Features of Friedreich\u2019s Ataxia: Classical and Atypical Phenotypes","volume":"126","author":"Parkinson","year":"2013","journal-title":"J. Neurochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nrneurol.2009.26","article-title":"Diagnosis and Treatment of Friedreich Ataxia: A European Perspective","volume":"5","author":"Schulz","year":"2009","journal-title":"Nat. Rev. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1177\/0883073812448230","article-title":"Clinical Features of Friedreich Ataxia","volume":"27","author":"Delatycki","year":"2012","journal-title":"J. Child Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/mds.27604","article-title":"Drug Repositioning Screening Identifies Etravirine as a Potential Therapeutic for Friedreich\u2019s Ataxia","volume":"34","author":"Alfedi","year":"2019","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/acn3.660","article-title":"Safety, Pharmacodynamics, and Potential Benefit of Omaveloxolone in Friedreich Ataxia","volume":"6","author":"Lynch","year":"2018","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1002\/ana.25934","article-title":"Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study)","volume":"89","author":"Lynch","year":"2021","journal-title":"Ann. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1002\/mds.27979","article-title":"Safety and Efficacy of Interferon \u03b3 in Friedreich\u2019s Ataxia","volume":"35","author":"Vavla","year":"2020","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1212\/01.wnl.0000219042.60538.92","article-title":"Scale for the Assessment and Rating of Ataxia: Development of a New Clinical Scale","volume":"66","author":"Baliko","year":"2006","journal-title":"Neurology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/S0895-4356(98)00094-8","article-title":"The Italian SF-36 Health Survey: Translation, Validation and Norming","volume":"51","author":"Apolone","year":"1998","journal-title":"J. Clin. Epidemiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"815","DOI":"10.2471\/BLT.09.067231","article-title":"Developing the World Health Organization Disability Assessment Schedule 2.0","volume":"88","author":"Chatterji","year":"2010","journal-title":"Bull. World Health Organ."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1590\/S0066-782X2010005000155","article-title":"Reference Values for Cardiopulmonary Exercise Testing for Sedentary and Active Men and Women","volume":"96","author":"Herdy","year":"2011","journal-title":"Arq. Bras. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s00421-014-3013-8","article-title":"Cardiorespiratory Fitness, Respiratory Function and Hemodynamic Responses to Maximal Cycle Ergometer Exercise Test in Girls and Boys Aged 9-11 Years: The PANIC Study","volume":"115","author":"Lintu","year":"2015","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.apmr.2010.04.007","article-title":"Exercise Capacity and Idebenone Intervention in Children and Adolescents with Friedreich Ataxia","volume":"91","author":"Drinkard","year":"2010","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1002\/mds.26552","article-title":"Long-Term Effect of Epoetin Alfa on Clinical and Biochemical Markers in Friedreich Ataxia","volume":"31","author":"Puorro","year":"2016","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1093\/eurjpc\/zwaa134","article-title":"Safety and Feasibility of Upper Limb Cardiopulmonary Exercise Test in Friedreich Ataxia","volume":"29","author":"Pane","year":"2022","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_20","unstructured":"R Core Team (2024, August 06). R: A Language and Environment for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.tips.2021.01.003","article-title":"Drug Repurposing for Rare Diseases","volume":"42","author":"Roessler","year":"2021","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Rufini, A., Malisan, F., Cond\u00f2, I., and Testi, R. (2022). Drug Repositioning in Friedreich Ataxia. Front. Neurosci., 16.","DOI":"10.3389\/fnins.2022.814445"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"392","DOI":"10.3109\/23744235.2015.1133927","article-title":"Long-Term Efficacy and Safety of Etravirine-Containing Regimens in a Real-Life Cohort of Treatment-Experienced HIV-1-Infected Patients","volume":"48","author":"Allavena","year":"2016","journal-title":"Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1002\/mds.23879","article-title":"Annual Change in Friedreich\u2019s Ataxia Evaluated by the Scale for the Assessment and Rating of Ataxia (SARA) Is Independent of Disease Severity","volume":"27","author":"Marelli","year":"2012","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1136\/jnnp-2017-316964","article-title":"Friedreich and Dominant Ataxias: Quantitative Differences in Cerebellar Dysfunction Measurements","volume":"89","author":"Mariotti","year":"2018","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1002\/mds.27605","article-title":"Etravirine in Friedreich\u2019s Ataxia: Lessons from HIV?","volume":"34","author":"Lynch","year":"2019","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/11\/8\/958\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:32:44Z","timestamp":1760110364000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/11\/8\/958"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,9]]},"references-count":26,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["children11080958"],"URL":"https:\/\/doi.org\/10.3390\/children11080958","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,9]]}}}