{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:37:19Z","timestamp":1790674639457,"version":"4.1.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T00:00:00Z","timestamp":1662076800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T00:00:00Z","timestamp":1662076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Natural history studies are increasingly recognized as having an important role in drug development for rare diseases. A phase 3, observational, retrospective, and non-interventional study was designed to establish a natural history control (NHC) cohort of patients with Barth syndrome (BTHS) to provide further analysis of the efficacy of elamipretide observed in an open-label extension (OLE) phase of the TAZPOWER trial, a clinical trial that tested the efficacy of 40\u00a0mg daily of elamipretide in patients with BTHS.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This was a retrospective, non-interventional study. A propensity score model was used to compare elamipretide-treated patients and NHCs. The analysis included 8 patients from the TAZPOWER OLE and 19 untreated NHCs (including 12 with serial echocardiographic assessments).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>For the 6-min walk test (6MWT, primary endpoint), the least squares (LS) mean difference between groups was 79.7\u00a0m (<jats:italic>P<\/jats:italic>\u2009=\u20090.0004) at week 64 and 91.0\u00a0m (<jats:italic>P<\/jats:italic>\u2009=\u20090.0005) at week 76 in favor of elamipretide. Significant improvements in muscle strength (secondary endpoint), as assessed by handheld dynamometry (HHD) were also observed with elamipretide, with LS mean differences of 40.8 Newtons at 64\u00a0weeks (<jats:italic>P<\/jats:italic>\u2009=\u20090.0002) and 56.7 Newtons at 76\u00a0weeks (<jats:italic>P<\/jats:italic>\u2009=\u20090.0005). Patients continuously treated with elamipretide also experienced statistically significant improvements in other secondary endpoints (i.e., 5 times sit-to-stand [5XSST], multi-domain responder index [MDRI]). The functional improvements were robust to sensitivity analyses. Left ventricular stroke volume increased from baseline in patients with elamipretide but decreased in NHCs.\n<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Overall, the study established a NHC for use in assessing the efficacy of therapeutic interventions in patients with BTHS and the results suggest that elamipretide may improve natural history of BTHS at least in part by attenuating the natural decline in heart function and provide meaningful improvements in heart function and functional capacity in patients with BTHS compared to NHCs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Highlights<\/jats:title>\n                <jats:p><jats:list list-type=\"bullet\">\n                  <jats:list-item>\n                    <jats:p>A matched Natural History Control (NHC) was used to evaluate elamipretide in BTHS<\/jats:p>\n                  <\/jats:list-item>\n                  <jats:list-item>\n                    <jats:p>Elamipretide may improve natural history of BTHS by attenuating natural decline in heart function<\/jats:p>\n                  <\/jats:list-item>\n                  <jats:list-item>\n                    <jats:p>Elamipretide was associated with meaningful clinical improvements in skeletal muscle and cardiovascular parameters that were not observed in NHCs<\/jats:p>\n                  <\/jats:list-item>\n                  <jats:list-item>\n                    <jats:p>The study established a NHC for use in assessing the efficacy of therapeutic interventions in BTHS<\/jats:p>\n                  <\/jats:list-item>\n                <\/jats:list><\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-022-02469-5","type":"journal-article","created":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T05:02:55Z","timestamp":1662094975000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome"],"prefix":"10.1186","volume":"17","author":[{"given":"Brittany","family":"Hornby","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William Reid","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Almuqbil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Manuel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Abbruscato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Carr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9940-9866","authenticated-orcid":false,"given":"Hilary J.","family":"Vernon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,2]]},"reference":[{"key":"2469_CR1","unstructured":"Ferreira C, Thompson R, and Vernon H (1993) Barth syndrome. In GeneReviews((R)) (Adam M P, Ardinger H H, Pagon R A, Wallace S E, Bean L J H, Stephens K, and Amemiya A, eds), Seattle (WA)"},{"key":"2469_CR2","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/1750-1172-8-70","volume":"8","author":"C Rigaud","year":"2013","unstructured":"Rigaud C, Lebre AS, Touraine R, Beaupain B, Ottolenghi C, Chabli A, Ansquer H, Ozsahin H, Di Filippo S, De Lonlay P, Borm B, Rivier F, Vaillant MC, Mathieu-Dramard M, Goldenberg A, Viot G, Charron P, Rio M, Bonnet D, Donadieu J. Natural history of barth syndrome: a national cohort study of 22 patients. Orphanet J Rare Dis. 2013;8:70.","journal-title":"Orphanet J Rare Dis"},{"key":"2469_CR3","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1750-1172-8-23","volume":"8","author":"SL Clarke","year":"2013","unstructured":"Clarke SL, Bowron A, Gonzalez IL, Groves SJ, Newbury-Ecob R, Clayton N, Martin RP, Tsai-Goodman B, Garratt V, Ashworth M, Bowen VM, McCurdy KR, Damin MK, Spencer CT, Toth MJ, Kelley RI, Steward CG. Barth syndrome. Orphanet J Rare Dis. 2013;8:23.","journal-title":"Orphanet J Rare Dis"},{"key":"2469_CR4","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1086\/514886","volume":"61","author":"P D'Adamo","year":"1997","unstructured":"D\u2019Adamo P, Fassone L, Gedeon A, Janssen EA, Bione S, Bolhuis PA, Barth PG, Wilson M, Haan E, Orstavik KH, Patton MA, Green AJ, Zammarchi E, Donati MA, Toniolo D. The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies. Am J Hum Genet. 1997;61:862\u20137.","journal-title":"Am J Hum Genet"},{"key":"2469_CR5","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/ng0496-385","volume":"12","author":"S Bione","year":"1996","unstructured":"Bione S, D\u2019Adamo P, Maestrini E, Gedeon AK, Bolhuis PA, Toniolo D. A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat Genet. 1996;12:385\u20139.","journal-title":"Nat Genet"},{"key":"2469_CR6","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.jpeds.2019.09.074","volume":"217","author":"PC Miller","year":"2020","unstructured":"Miller PC, Ren M, Schlame M, Toth MJ, Phoon CKL. A Bayesian analysis to determine the prevalence of barth syndrome in the pediatric population. J Pediatr. 2020;217:139\u201344.","journal-title":"J Pediatr"},{"key":"2469_CR7","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1038\/gim.2015.204","volume":"18","author":"WR Thompson","year":"2016","unstructured":"Thompson WR, DeCroes B, McClellan R, Rubens J, Vaz FM, Kristaponis K, Avramopoulos D, Vernon HJ. New targets for monitoring and therapy in Barth syndrome. Genet Med. 2016;18:1001\u201310.","journal-title":"Genet Med"},{"key":"2469_CR8","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1016\/j.ab.2009.01.032","volume":"387","author":"RH Houtkooper","year":"2009","unstructured":"Houtkooper RH, Rodenburg RJ, Thiels C, van Lenthe H, Stet F, Poll-The BT, Stone JE, Steward CG, Wanders RJ, Smeitink J, Kulik W, Vaz FM. Cardiolipin and monolysocardiolipin analysis in fibroblasts, lymphocytes, and tissues using high-performance liquid chromatography-mass spectrometry as a diagnostic test for Barth syndrome. Anal Biochem. 2009;387:230\u20137.","journal-title":"Anal Biochem"},{"key":"2469_CR9","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.ymgme.2014.03.007","volume":"112","author":"HJ Vernon","year":"2014","unstructured":"Vernon HJ, Sandlers Y, McClellan R, Kelley RI. Clinical laboratory studies in Barth Syndrome. Mol Genet Metab. 2014;112:143\u20137.","journal-title":"Mol Genet Metab"},{"key":"2469_CR10","first-page":"495","volume":"27","author":"DM Avdjieva-Tzavella","year":"2016","unstructured":"Avdjieva-Tzavella DM, Todorova AP, Kathom HM, Ivanova MB, Yordanova IT, Todorov TP, Litvinenko IO, Dasheva-Dimitrova AT, Tincheva RS. Barth syndrome in male and female siblings caused by a novel mutation in the Taz Gene. Genet Couns. 2016;27:495\u2013501.","journal-title":"Genet Couns"},{"key":"2469_CR11","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.ymgme.2012.01.015","volume":"106","author":"L Cosson","year":"2012","unstructured":"Cosson L, Toutain A, Simard G, Kulik W, Matyas G, Guichet A, Blasco H, Maakaroun-Vermesse Z, Vaillant MC, Le Caignec C, Chantepie A, Labarthe F. Barth syndrome in a female patient. Mol Genet Metab. 2012;106:115\u201320.","journal-title":"Mol Genet Metab"},{"key":"2469_CR12","doi-asserted-by":"publisher","first-page":"39217","DOI":"10.1074\/jbc.M606100200","volume":"281","author":"Y Xu","year":"2006","unstructured":"Xu Y, Malhotra A, Ren M, Schlame M. The enzymatic function of tafazzin. J Biol Chem. 2006;281:39217\u201324.","journal-title":"J Biol Chem"},{"key":"2469_CR13","doi-asserted-by":"publisher","first-page":"5202","DOI":"10.1091\/mbc.e05-03-0256","volume":"16","author":"K Brandner","year":"2005","unstructured":"Brandner K, Mick DU, Frazier AE, Taylor RD, Meisinger C, Rehling P. Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: implications for Barth Syndrome. Mol Biol Cell. 2005;16:5202\u201314.","journal-title":"Mol Biol Cell"},{"key":"2469_CR14","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1093\/cvr\/cvx014","volume":"113","author":"J Dudek","year":"2017","unstructured":"Dudek J, Maack C. Barth syndrome cardiomyopathy. Cardiovasc Res. 2017;113:399\u2013410.","journal-title":"Cardiovasc Res"},{"key":"2469_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101005","volume":"297","author":"AF Anzmann","year":"2021","unstructured":"Anzmann AF, Sniezek OL, Pado A, Busa V, Vaz FM, Kreimer SD, DeVine LR, Cole RN, Le A, Kirsch BJ, Claypool SM, Vernon HJ. Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by cardiolipin-interacting small molecules. J Biol Chem. 2021;297: 101005.","journal-title":"J Biol Chem"},{"key":"2469_CR16","doi-asserted-by":"publisher","first-page":"139","DOI":"10.15252\/emmm.201505644","volume":"8","author":"J Dudek","year":"2016","unstructured":"Dudek J, Cheng IF, Chowdhury A, Wozny K, Balleininger M, Reinhold R, Grunau S, Callegari S, Toischer K, Wanders RJ, Hasenfuss G, Brugger B, Guan K, Rehling P. Cardiac-specific succinate dehydrogenase deficiency in Barth syndrome. EMBO Mol Med. 2016;8:139\u201354.","journal-title":"EMBO Mol Med"},{"key":"2469_CR17","doi-asserted-by":"publisher","first-page":"3650","DOI":"10.1016\/j.bbadis.2018.08.041","volume":"1864","author":"IA Chatzispyrou","year":"2018","unstructured":"Chatzispyrou IA, Guerrero-Castillo S, Held NM, Ruiter JPN, Denis SW, L, I. J., Wanders, R. J., van Weeghel, M., Ferdinandusse, S., Vaz, F. M., Brandt, U., and Houtkooper, R. H. Barth syndrome cells display widespread remodeling of mitochondrial complexes without affecting metabolic flux distribution. Biochim Biophys Acta Mol Basis Dis. 2018;1864:3650\u20138.","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"2469_CR18","doi-asserted-by":"publisher","first-page":"2029","DOI":"10.1111\/bph.12461","volume":"171","author":"HH Szeto","year":"2014","unstructured":"Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171:2029\u201350.","journal-title":"Br J Pharmacol"},{"key":"2469_CR19","doi-asserted-by":"publisher","first-page":"1250","DOI":"10.1681\/ASN.2012121216","volume":"24","author":"AV Birk","year":"2013","unstructured":"Birk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, Seshan SV, Pardee JD, Szeto HH. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013;24:1250\u201361.","journal-title":"J Am Soc Nephrol"},{"key":"2469_CR20","doi-asserted-by":"publisher","first-page":"2017","DOI":"10.1111\/bph.12468","volume":"171","author":"AV Birk","year":"2014","unstructured":"Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c\/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol. 2014;171:2017\u201328.","journal-title":"Br J Pharmacol"},{"key":"2469_CR21","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1097\/FJC.0000000000000155","volume":"64","author":"W Dai","year":"2014","unstructured":"Dai W, Shi J, Gupta RC, Sabbah HN, Hale SL, Kloner RA. Bendavia, a mitochondria-targeting peptide, improves postinfarction cardiac function, prevents adverse left ventricular remodeling, and restores mitochondria-related gene expression in rats. J Cardiovasc Pharmacol. 2014;64:543\u201353.","journal-title":"J Cardiovasc Pharmacol"},{"key":"2469_CR22","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1007\/s43441-021-00302-y","volume":"55","author":"M Jahanshahi","year":"2021","unstructured":"Jahanshahi M, Gregg K, Davis G, Ndu A, Miller V, Vockley J, Ollivier C, Franolic T, Sakai S. The use of external controls in FDA regulatory decision making. Ther Innov Regul Sci. 2021;55:1019\u201335.","journal-title":"Ther Innov Regul Sci"},{"key":"2469_CR23","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/s41436-020-01006-8","volume":"23","author":"W Reid Thompson","year":"2021","unstructured":"Reid Thompson W, Hornby B, Manuel R, Bradley E, Laux J, Carr J, Vernon HJ. A phase 2\/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism. Genet Med. 2021;23:471\u20138.","journal-title":"Genet Med"},{"key":"2469_CR24","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s13023-019-1006-8","volume":"14","author":"B Hornby","year":"2019","unstructured":"Hornby B, McClellan R, Buckley L, Carson K, Gooding T, Vernon HJ. Functional exercise capacity, strength, balance and motion reaction time in Barth syndrome. Orphanet J Rare Dis. 2019;14:37.","journal-title":"Orphanet J Rare Dis"},{"key":"2469_CR25","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1002\/jcsm.12559","volume":"11","author":"A Karaa","year":"2020","unstructured":"Karaa A, Haas R, Goldstein A, Vockley J, Cohen BH. A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy. J Cachexia Sarcopenia Muscle. 2020;11:909\u201318.","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"2469_CR26","first-page":"135","volume":"9","author":"JA Patterson","year":"2014","unstructured":"Patterson JA, Amick RZ, Thummar T, Rogers ME. Validation of measures from the smartphone sway balance application: a pilot study. Int J Sports Phys Ther. 2014;9:135\u20139.","journal-title":"Int J Sports Phys Ther"},{"key":"2469_CR27","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1002\/jimd.12304","volume":"44","author":"SF Garbade","year":"2021","unstructured":"Garbade SF, Zielonka M, Komatsuzaki S, Kolker S, Hoffmann GF, Hinderhofer K, Mountford WK, Mengel E, Slama T, Mechler K, Ries M. Quantitative retrospective natural history modeling for orphan drug development. J Inherit Metab Dis. 2021;44:99\u2013109.","journal-title":"J Inherit Metab Dis"},{"key":"2469_CR28","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1097\/01823246-201324030-00004","volume":"24","author":"MJ Shoemaker","year":"2013","unstructured":"Shoemaker MJ, Curtis AB, Vangsnes E, Dickinson MG. Clinically meaningful change estimates for the six-minute walk test and daily activity in individuals with chronic heart failure. Cardiopulm Phys Ther J. 2013;24:21\u20139.","journal-title":"Cardiopulm Phys Ther J"},{"key":"2469_CR29","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1164\/rccm.201212-2191ED","volume":"187","author":"AE Holland","year":"2013","unstructured":"Holland AE, Nici L. The return of the minimum clinically important difference for 6-minute-walk distance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187:335\u20136.","journal-title":"Am J Respir Crit Care Med"},{"key":"2469_CR30","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1164\/rccm.201203-0480OC","volume":"186","author":"SC Mathai","year":"2012","unstructured":"Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:428\u201333.","journal-title":"Am J Respir Crit Care Med"},{"key":"2469_CR31","doi-asserted-by":"publisher","first-page":"e9","DOI":"10.1161\/CIR.0000000000000682","volume":"140","author":"SE Lipshultz","year":"2019","unstructured":"Lipshultz SE, Law YM, Asante-Korang A, Austin ED, Dipchand AI, Everitt MD, Hsu DT, Lin KY, Price JF, Wilkinson JD, Colan SD. Cardiomyopathy in children: classification and diagnosis: a scientific statement from the american heart association. Circulation. 2019;140:e9\u201368.","journal-title":"Circulation"},{"key":"2469_CR32","doi-asserted-by":"publisher","first-page":"H2122","DOI":"10.1152\/ajpheart.00479.2010","volume":"301","author":"CT Spencer","year":"2011","unstructured":"Spencer CT, Byrne BJ, Bryant RM, Margossian R, Maisenbacher M, Breitenger P, Benni PB, Redfearn S, Marcus E, Cade WT. Impaired cardiac reserve and severely diminished skeletal muscle O(2) utilization mediate exercise intolerance in Barth syndrome. Am J Physiol Heart Circ Physiol. 2011;301:H2122-2129.","journal-title":"Am J Physiol Heart Circ Physiol"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-022-02469-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-022-02469-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-022-02469-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T05:13:39Z","timestamp":1662095619000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-022-02469-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,2]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["2469"],"URL":"https:\/\/doi.org\/10.1186\/s13023-022-02469-5","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,2]]},"assertion":[{"value":"26 November 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 August 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 September 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The TAZPOWER trial was approved under the Johns Hopkins Institutional Review Board Protocol IRB00124162 and the NHC study was approved under the Johns Hopkins Institutional Review Board Protocol IRB00231209. The trials were conducted in accordance with consensus ethics principles derived from international ethics guidelines, including the Council for International Organizations of Medical Sciences International Ethical Guidelines and the International Conference on Harmonisation Good Clinical Practice guideline. The protocol was approved by the institutional review boards of the participating trial centers and all patients provided written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"AA and JC are employees of Stealth BioTherapeutics, Needham, MA. HJV received clinical trial and research funding from Stealth BioTherapeutics, Needham, MA.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"336"}}