{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:13:44Z","timestamp":1779254024972,"version":"3.51.4"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2020,8,19]],"date-time":"2020-08-19T00:00:00Z","timestamp":1597795200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,8,19]],"date-time":"2020-08-19T00:00:00Z","timestamp":1597795200000},"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":["Hepatol Int"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background and aims<\/jats:title>\n<jats:p>Pirfenidone (PFD), an oral antifibrotic drug, has been authorized by the EMA and FDA for treatment of idiopathic pulmonary fibrosis. Few studies have addressed its use in advanced liver fibrosis (ALF). We evaluated a prolonged-release formulation (PR-PFD) plus standard of care on disease progression in ALF.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>281 ALF patients from 12 centers receiving PR-PFD (600\u00a0mg bid) were screened; 122 completed 1\u00a0year of treatment. Additionally, 74 patients received only standard of care regimen. Average age was 64\u2009\u00b1\u200912\u00a0years, 58% female. 43.5% had fatty liver disease (NAFLD), 22.5% viral hepatitis C (VHC), 17% autoimmune hepatitis (AIH), and 17% alcoholic liver disease (ALD). Baseline fibrosis was F4 in 74% and F3 in 26%. Antifibrotic effects were assessed by transient elastography (Fibroscan<jats:sup>\u00ae<\/jats:sup>) and Fibro Test<jats:sup>\u00ae<\/jats:sup> (FT); Cytokines and PFD plasma levels were tracked and quality of life evaluated.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>We found a significant reduction in fibrosis in 35% of PR-PFD patients and only in 4.1% in non PR-PFD patients. Child\u2013Pugh score improved in 29.7%. Biochemical values remained stable; 40.6% and 43.3% decreased ALT or AST, respectively. TGF\u03b21 (pg\/mL) levels were lower in PFD-treated patients. PFD serum concentration (\u00b5g\/mL) was higher (8.2\u2009\u00b1\u20091.7) in fibrosis regression profile (FRP) patients compared to fibrosis progression profile (FPP) patients (4.7\u2009\u00b1\u20090.3\u00a0\u00b5g\/mL, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). 12% reported transient burning or nausea and 7% photosensitivity. Quality of life (Euro-Qol scale) improved from 62\u2009\u00b1\u20095 to 84\u2009\u00b1\u20093 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and from 32\u2009\u00b1\u20093 to 42\u2009\u00b1\u20092 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.008) (FACIT scale).<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>PR-PFD is efficacious and safe in ALF and associated with promising antifibrotic effects.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Trial registration<\/jats:title>\n<jats:p>Clinical trial number: NCT04099407.<\/jats:p>\n<\/jats:sec>","DOI":"10.1007\/s12072-020-10069-3","type":"journal-article","created":{"date-parts":[[2020,8,19]],"date-time":"2020-08-19T14:02:58Z","timestamp":1597845778000},"page":"817-827","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Benefits of prolonged-release pirfenidone plus standard of care treatment in patients with advanced liver fibrosis: PROMETEO study"],"prefix":"10.1007","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8205-5379","authenticated-orcid":false,"given":"Jorge Luis","family":"Poo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aldo","family":"Torre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Ram\u00f3n","family":"Aguilar-Ram\u00edrez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mauricio","family":"Cruz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"Mej\u00eda-Cu\u00e1n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eira","family":"Cerda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfredo","family":"Vel\u00e1zquez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ang\u00e9lica","family":"Pati\u00f1o","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Ram\u00edrez-Castillo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Cisneros","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco","family":"Bosques-Padilla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larissa","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frida","family":"Gasca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco","family":"Flores-Murrieta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Trevi\u00f1o","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graciela","family":"Tapia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Armendariz-Borunda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda E.","family":"Mu\u00f1oz-Espinosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,8,19]]},"reference":[{"key":"10069_CR1","first-page":"183","volume":"14","author":"R Perez-Tamayo","year":"1979","unstructured":"Perez-Tamayo R. Cirrhosis of the liver: a reversible disease? Pathol Annu 1979;14:183\u2013213","journal-title":"Pathol Annu"},{"issue":"5","key":"10069_CR2","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1016\/0016-5085(92)91739-Q","volume":"102","author":"JL Poo","year":"1992","unstructured":"Poo JL, Feldmann G, Erlinger S, Braillon A, Gaudin C, Dumont M, et al. Ursodeoxycholic acid limits liver histologic alterations and portal hypertension induced by bile duct ligation in the rat. Gastroenterology 1992;102(5):1752\u20131759","journal-title":"Gastroenterology"},{"key":"10069_CR3","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1016\/j.jhep.2011.09.024","volume":"56","author":"EL Ellis","year":"2012","unstructured":"Ellis EL, Mann DA. Clinical evidence for the regression of liver fibrosis. J Hepatol 2012;56:1171\u20131180","journal-title":"J Hepatol"},{"key":"10069_CR4","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1016\/S0140-6736(12)61425-1","volume":"381","author":"P Marcellin","year":"2013","unstructured":"Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013;381:468\u2013475","journal-title":"Lancet"},{"key":"10069_CR5","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1111\/j.1360-0443.2009.02521.x","volume":"104","author":"C Verrill","year":"2009","unstructured":"Verrill C, Markham H, Templeton A, Carr NJ, Sheron N. Alcohol-related cirrhosis: early abstinence is a key factor in prognosis, even in the most severe cases. Addiction 2009;104:768\u2013774","journal-title":"Addiction"},{"issue":"1","key":"10069_CR6","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/s12072-018-9897-3","volume":"13","author":"MB Bansal","year":"2019","unstructured":"Bansal MB, Chamroonkul N. Antifibrotics in liver disease: are we getting closer to clinical use? Hepatol Int 2019;13(1):25\u201339","journal-title":"Hepatol Int"},{"key":"10069_CR7","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/1755-1536-3-16","volume":"3","author":"J Macias-Barragan","year":"2010","unstructured":"Macias-Barragan J, Sandoval-Rodr\u00edguez A, Navarro-Partida J, Armend\u00e1riz-Borunda J. The multifaceted role of pirfenidone and its novel target. Fibrogenesis Tissue Repair 2010;3:16","journal-title":"Fibrogenesis Tissue Repair"},{"issue":"2","key":"10069_CR8","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1517\/14656566.2014.867328","volume":"15","author":"A Xaubet","year":"2014","unstructured":"Xaubet A, Serrano-Mollar A, Ancochea J. Pirfenidone for the treatment of idiopathic pulmonary fibrosis. Expert Opin Pharmacother 2014;15(2):275\u2013281","journal-title":"Expert Opin Pharmacother"},{"key":"10069_CR9","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.pupt.2009.03.003","volume":"22","author":"CM Rubino","year":"2013","unstructured":"Rubino CM, Bhavnani SM, Ambrose PG, Forrest A, Loutit JS. Effect of food and antacids on the pharmacokinetics of pirfenidone in older healthy adults. Pulm Pharmacol Ther 2013;22:279\u2013285","journal-title":"Pulm Pharmacol Ther"},{"issue":"3","key":"10069_CR10","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/S2213-2600(13)70065-1","volume":"1","author":"LJ Landells","year":"2013","unstructured":"Landells LJ, Naidoo B, Robertson J, Clark P. NICE guidance on pirfenidone for treating idiopathic pulmonary fibrosis. Lancet Respir Med 2013;1(3):191\u2013192","journal-title":"Lancet Respir Med."},{"issue":"11","key":"10069_CR11","doi-asserted-by":"publisher","first-page":"840","DOI":"10.7150\/ijms.11579","volume":"12","author":"DA Lopez-de la Mora","year":"2015","unstructured":"Lopez-de la Mora DA, Sanchez-Roque C, Montoya-Buelna M, Sanchez-Enriquez S, Lucano-Landeros S, Macias-Barragan J, et al. Role and new insights of pirfenidone in fibrotic diseases. Int J Med Sci 2015;12(11):840\u2013847","journal-title":"Int J Med Sci"},{"key":"10069_CR12","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1136\/gut.2006.107136","volume":"55","author":"J Armend\u00e1riz-Borunda","year":"2006","unstructured":"Armend\u00e1riz-Borunda J, Islas-Carbajal M, Meza-Garc\u00eda E, Rincon AR, Lucano S, Sandoval AS, et al. A pilot study in patients with established advanced liver fibrosis using pirfenidone. Gut 2006;55:1663\u20131665","journal-title":"Gut"},{"key":"10069_CR13","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/1471-230X-14-131","volume":"14","author":"L Flores-Contreras","year":"2014","unstructured":"Flores-Contreras L, Sandoval-Rodr\u00edguez AS, Mena-Enriquez MG, Lucano-Landeros S, Arellano-Olivera I, \u00c1lvarez-\u00c1lvarez A, et al. Treatment with pirfenidone for 2\u00a0years decreases fibrosis, cytokine levels and enhances CB2 gene expression in patients with chronic hepatitis C. BMC Gastroenterol 2014;14:131","journal-title":"BMC Gastroenterol"},{"key":"10069_CR14","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1016\/j.jhep.2013.11.016","volume":"60","author":"T Poynard","year":"2014","unstructured":"Poynard T, Vergniol J, Ngo Y, Foucher J, Munteanu M, Merrouche W, et al. Staging chronic hepatitis C in seven categories using fibrosis biomarker (FT\u2122) and transient elastography (FibroScan\u00ae). J Hepatol 2014;60:706\u2013714","journal-title":"J Hepatol"},{"key":"10069_CR15","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1053\/j.gastro.2017.03.017","volume":"152","author":"JK Lim","year":"2017","unstructured":"Lim JK, Flamm SL, Singh S, Falck-Ytter YT, Clinical Guidelines Committee of the American Gastroenterological Association. American Gastroenterological Association Institute Guideline on the role of elastography in the evaluation of liver fibrosis. Gastroenterology 2017;152:1536\u20131543","journal-title":"Gastroenterology"},{"key":"10069_CR16","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/j.jhep.2014.04.044","volume":"61","author":"C Cassinotto","year":"2014","unstructured":"Cassinotto C, Lapuyade B, Mouries A, Hiriart JB, Vergniol J, Gaye D, et al. Non-invasive assessment of liver fibrosis with impulse elastography: comparison of Supersonic Shear Imaging with ARFI and FibroScan R. J Hepatol 2014;61:550\u2013557","journal-title":"J Hepatol"},{"issue":"5","key":"10069_CR17","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1515\/cclm-2018-0357","volume":"57","author":"SM Haghgoo","year":"2019","unstructured":"Haghgoo SM, Sharafi H, Alavian SM. Serum cytokines, adipokines and ferritin for non-invasive assessment of liver fibrosis in chronic liver disease: a systematic review. Clin Chem Lab Med 2019;57(5):577\u2013610","journal-title":"Clin Chem Lab Med"},{"issue":"4","key":"10069_CR18","doi-asserted-by":"publisher","first-page":"240","DOI":"10.5114\/ceh.2018.80125","volume":"4","author":"D Piotrowski","year":"2018","unstructured":"Piotrowski D, S\u0105czewska-Piotrowska A, Jaroszewicz J, Boro\u0144-Kaczmarska A. Predictive power of model for end-stage liver disease and Child\u2013Turcotte\u2013Pugh score for mortality in cirrhotic patients. Clin Exp Hepatol 2018;4(4):240\u2013246","journal-title":"Clin Exp Hepatol."},{"key":"10069_CR19","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.3758\/BRM.41.4.1149","volume":"41","author":"F Faul","year":"2009","unstructured":"Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods 2009;41:1149\u20131160","journal-title":"Behav Res Methods"},{"key":"10069_CR20","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1055\/s-0033-1341478","volume":"63","author":"N Huang","year":"2013","unstructured":"Huang N, Ding L, Wang J, Zhang QY, Liu X, Lin HD, et al. Pharmacokinetics, safety and tolerability of pirfenidone and its major metabolite after single and multiple oral doses in healthy Chinese subjects under Fed conditions. Drug Res (Sturg) 2013;63:388\u2013395","journal-title":"Drug Res (Sturg)"},{"issue":"1","key":"10069_CR21","doi-asserted-by":"publisher","first-page":"01A","DOI":"10.1096\/fj.16-0101ufm","volume":"30","author":"V Kale","year":"2016","unstructured":"Kale V, Tharit Manoi T, Porter C, Atkinson S. Drug interaction of pirfenidone with commonly prescribed pharmaceutical drugs. FASEB J 2016;30(1):01A","journal-title":"FASEB J"},{"issue":"7","key":"10069_CR22","doi-asserted-by":"publisher","first-page":"944","DOI":"10.2310\/JIM.0b013e3181891512","volume":"56","author":"J Armend\u00e1riz-Borunda","year":"2008","unstructured":"Armend\u00e1riz-Borunda J, Rinc\u00f3n AR, Mu\u00f1oz-Valle JF, Bueno-Topete M, Oreg\u00f3n-Romero E, Islas-Carbajal MC, et al. Fibrogenic polymorphisms (TGF-beta, PAI-1, AT) in Mexican patients with established liver fibrosis. Potential correlation with pirfenidone treatment. J Investig Med 2008;56(7):944\u2013953","journal-title":"J Investig Med."},{"key":"10069_CR23","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.cyto.2015.10.006","volume":"77","author":"M Dirchwolf","year":"2016","unstructured":"Dirchwolf M, Podhorzer A, Marino M, Shulman C, Cartier M, Zunino M, et al. Immune dysfunction in cirrhosis: distinct cytokines phenotypes according to cirrhosis severity. Cytokine 2016;77:14\u201325","journal-title":"Cytokine"},{"key":"10069_CR24","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/nrneph.2016.48","volume":"12","author":"X Meng","year":"2016","unstructured":"Meng X, Nikolic-Paterson DJ, Lan HY. TGF-\u03b2: the master regulator of fibrosis. Nat Rev Nephrol 2016;12:325\u2013338","journal-title":"Nat Rev Nephrol"},{"issue":"4","key":"10069_CR25","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1016\/j.jhep.2017.11.020","volume":"68","author":"J Hartl","year":"2018","unstructured":"Hartl J, Ehlken H, Sebode M, Peiseler M, Krech T, Zenouzi R, et al. Usefulness of biochemical remission and transient elastography in monitoring disease course in autoimmune hepatitis. J Hepatol 2018;68(4):754\u2013763","journal-title":"J Hepatol"},{"key":"10069_CR26","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/S0168-8278(86)80075-7","volume":"2","author":"F Piccinino","year":"1986","unstructured":"Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy: a multicenter retrospective study on 68,276 biopsies. J Hepatol 1986;2:165\u2013173","journal-title":"J Hepatol"},{"issue":"2","key":"10069_CR27","doi-asserted-by":"publisher","first-page":"124","DOI":"10.20892\/j.issn.2095-3941.2018.0018","volume":"15","author":"C Li","year":"2018","unstructured":"Li C, Li R, Zhang W. Progress in non-invasive detection of liver fibrosis. Cancer Biol Med 2018;15(2):124\u2013136","journal-title":"Cancer Biol Med."},{"issue":"21","key":"10069_CR28","doi-asserted-by":"publisher","first-page":"2617","DOI":"10.3748\/wjg.15.2617","volume":"15","author":"D Lau-Corona","year":"2009","unstructured":"Lau-Corona D, Pineda LA, Avil\u00e9s HH, Guti\u00e9rrez-Reyes G, Farfan-Labonne BE, N\u00fa\u00f1ez-Nateras R, et al. Effective use of FibroTest to generate decision trees in hepatitis C. World J Gastroenterol 2009;15(21):2617\u20132622","journal-title":"World J Gastroenterol"},{"issue":"5","key":"10069_CR29","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1002\/hep.29557","volume":"67","author":"Z Mauro","year":"2018","unstructured":"Mauro Z, Crespo G, Montironi C, Londo\u00f1o MC, Virginia Hern\u00e1ndez-Gea V, Ruiz P, et al. Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C. Hepatology 2018;67(5):183\u20131694","journal-title":"Hepatology"},{"issue":"5","key":"10069_CR30","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1111\/liv.13974","volume":"39","author":"N Chalasani","year":"2019","unstructured":"Chalasani N, Abdelmalek MF, Loomba R, Kowdley KV, McCullough AJ, Dasarathy S, et al. Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with NASH. Liver Int 2019;39(5):924\u2013932","journal-title":"Liver Int."},{"key":"10069_CR31","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1023\/A:1013240225965","volume":"47","author":"P Angulo","year":"2002","unstructured":"Angulo P, MacCarty RL, Sylvestre PB, Jorgensen RA, Wiesner RH, LaRusso NA, et al. Pirfenidone in the treatment of primary sclerosing cholangitis. Dig Dis Sci 2002;47:157\u2013161","journal-title":"Dig Dis Sci"}],"container-title":["Hepatology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12072-020-10069-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12072-020-10069-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12072-020-10069-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T00:21:14Z","timestamp":1629332474000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12072-020-10069-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,19]]},"references-count":31,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,9]]}},"alternative-id":["10069"],"URL":"https:\/\/doi.org\/10.1007\/s12072-020-10069-3","relation":{},"ISSN":["1936-0533","1936-0541"],"issn-type":[{"value":"1936-0533","type":"print"},{"value":"1936-0541","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,19]]},"assertion":[{"value":"10 January 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 June 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The study was conducted in compliance with the International Standard GCP procedures and the principles of the Declaration of Helsinki. The protocol and informed consent form were approved by a local IRBs and registered in clinical trials.gov (NCT04099407).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent was obtained from all patients for being included in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}