{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T06:18:18Z","timestamp":1771568298133,"version":"3.50.1"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2019,2,21]],"date-time":"2019-02-21T00:00:00Z","timestamp":1550707200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,2,21]],"date-time":"2019-02-21T00:00:00Z","timestamp":1550707200000},"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":["Invest New Drugs"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Summary<\/jats:title>\n          <jats:p><jats:italic>Purpose<\/jats:italic> We investigated the safety, tolerability, pharmacokinetics, and efficacy of TAS-121, a novel, potent, and highly selective third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in Japanese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) previously treated with EGFR-TKI. <jats:italic>Methods<\/jats:italic> This was an open-label, non-randomized, multi-center, dose escalation, phase I study conducted in three phases (dose escalation, expansion, and extension phases). TAS-121 was administered orally once daily (QD) or twice daily (BID) under fasting conditions in a 21-day treatment cycle. The primary endpoint was dose-limiting toxicities (DLTs) during Cycle 1 of the dose escalation phase. <jats:italic>Results<\/jats:italic> In total, 134 patients received treatment. Five and three patients presented a DLT with the QD and BID regimens, respectively. The DLTs were drug-induced liver injury, platelet count decreased, urticaria, interstitial lung disease, and left ventricular failure. The maximum tolerated dose (MTD) was 10\u00a0mg\/day QD and 8\u00a0mg\/day BID in the dose escalation phase. The most common adverse drug reactions (ADRs) were dermatological toxicity (89.6%), platelet count decreased (67.2%), and pyrexia (44%) among all patients. Rate of discontinuations due to ADRs at the MTD level were 11.1% with TAS-121 10\u00a0mg\/day QD and 7.9% with TAS-121 8\u00a0mg\/day BID. Among 86\u00a0T790M-positive patients (confirmed by blood serum sampling in most patients), the objective response rate (ORR) was 28% and highest at 8\u00a0mg\/day BID (39%). Among 16\u00a0T790M-negative patients, the ORR was 19%. <jats:italic>Conclusions<\/jats:italic> TAS-121 was well tolerated up to the MTD and demonstrated antitumor activity in Japanese T790M-positive NSCLC patients. <jats:bold>Clinical trial registration:<\/jats:bold> JapicCTI-142651.<\/jats:p>","DOI":"10.1007\/s10637-019-00732-4","type":"journal-article","created":{"date-parts":[[2019,2,21]],"date-time":"2019-02-21T06:18:24Z","timestamp":1550729904000},"page":"1207-1217","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Phase I study of TAS-121, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with non-small-cell lung cancer harboring EGFR mutations"],"prefix":"10.1007","volume":"37","author":[{"given":"Makoto","family":"Nishio","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruyasu","family":"Murakami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuichiro","family":"Ohe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toyoaki","family":"Hida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuo","family":"Kasahara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumio","family":"Imamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohisa","family":"Baba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaoru","family":"Kubota","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukio","family":"Hosomi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuneo","family":"Shimokawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidetoshi","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazutaka","family":"Miyadera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohide","family":"Tamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,2,21]]},"reference":[{"key":"732_CR1","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1093\/jnci\/dji055","volume":"97","author":"H Shigematsu","year":"2005","unstructured":"Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, Fujisawa T, Feng Z, Roth JA, Herz J, Minna JD, Gazdar AF (2005) Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97:339\u2013346","journal-title":"J Natl Cancer Inst"},{"key":"732_CR2","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/j.ccr.2006.04.022","volume":"9","author":"H Ji","year":"2006","unstructured":"Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K, Mahmood U, Mitchell A, Sun Y, Al-Hashem R, Chirieac LR, Padera R, Bronson RT, Kim W, J\u00e4nne PA, Shapiro GI, Tenen D, Johnson BE, Weissleder R, Sharpless NE, Wong KK (2006) The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 9:485\u2013495","journal-title":"Cancer Cell"},{"key":"732_CR3","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1056\/NEJMoa040938","volume":"350","author":"TJ Lynch","year":"2004","unstructured":"Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129\u20132139","journal-title":"N Engl J Med"},{"key":"732_CR4","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1056\/NEJMoa0810699","volume":"361","author":"TS Mok","year":"2009","unstructured":"Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947\u2013957. https:\/\/doi.org\/10.1056\/NEJMoa0810699","journal-title":"N Engl J Med"},{"key":"732_CR5","doi-asserted-by":"publisher","first-page":"2380","DOI":"10.1056\/NEJMoa0909530","volume":"362","author":"M Maemondo","year":"2010","unstructured":"Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T, North-East Japan Study Group (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380\u20132388. https:\/\/doi.org\/10.1056\/NEJMoa0909530","journal-title":"N Engl J Med"},{"key":"732_CR6","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/S1470-2045(11)70393-X","volume":"13","author":"R Rosell","year":"2012","unstructured":"Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Mu\u00f1oz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L, Spanish Lung Cancer Group in collaboration with Groupe Fran\u00e7ais de Pneumo-Canc\u00e9rologie and Associazione Italiana Oncologia Toracica (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239\u2013246. https:\/\/doi.org\/10.1016\/S1470-2045(11)70393-X","journal-title":"Lancet Oncol"},{"key":"732_CR7","doi-asserted-by":"publisher","first-page":"3327","DOI":"10.1200\/JCO.2012.44.2806","volume":"31","author":"LV Sequist","year":"2013","unstructured":"Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31:3327\u20133334. https:\/\/doi.org\/10.1200\/JCO.2012.44.2806","journal-title":"J Clin Oncol"},{"key":"732_CR8","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2016-000060","volume":"1","author":"F Morgillo","year":"2016","unstructured":"Morgillo F, Della Corte CM, Fasano M, Ciardiello F (2016) Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open 1:e000060","journal-title":"ESMO Open"},{"key":"732_CR9","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1200\/JCO.2012.43.3912","volume":"31","author":"K Ohashi","year":"2013","unstructured":"Ohashi K, Maruvka YE, Michor F, Pao W (2013) Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol 31:1070\u20131080. https:\/\/doi.org\/10.1200\/JCO.2012.43.3912","journal-title":"J Clin Oncol"},{"key":"732_CR10","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1158\/1078-0432.CCR-12-2246","volume":"19","author":"HA Yu","year":"2013","unstructured":"Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M, Riely GJ (2013) Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 19:2240\u20132247. https:\/\/doi.org\/10.1158\/1078-0432.CCR-12-2246","journal-title":"Clin Cancer Res"},{"issue":"11 Suppl","key":"732_CR11","doi-asserted-by":"publisher","first-page":"Abstract C111","DOI":"10.1158\/1535-7163.TARG-13-C111","volume":"12","author":"K Ito","year":"2013","unstructured":"Ito K, Miyadera K, Aoyagi Y, Kato M, Yonekura K, Iwasawa Y, Utsugi T (2013) In vitro characterization of TAS-121, a novel, highly potent, and mutant-specific EGFR-TKI. Mol Cancer Ther 12(11 Suppl):Abstract C111. https:\/\/doi.org\/10.1158\/1535-7163.TARG-13-C111","journal-title":"Mol Cancer Ther"},{"key":"732_CR12","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1038\/nm.3854","volume":"21","author":"KS Thress","year":"2015","unstructured":"Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y, Ercan D, Matthews SE, Cantarini M, Barrett JC, J\u00e4nne PA, Oxnard GR (2015) Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med 21:560\u2013562. https:\/\/doi.org\/10.1038\/nm.3854","journal-title":"Nat Med"},{"key":"732_CR13","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1097\/JTO.0000000000000688","volume":"10","author":"TM Kim","year":"2015","unstructured":"Kim TM, Song A, Kim DW, Kim S, Ahn YO, Keam B, Jeon YK, Lee SH, Chung DH, Heo DS (2015) Mechanisms of acquired resistance to AZD9291: a mutation-selective, irreversible EGFR inhibitor. J Thorac Oncol 10:1736\u20131744. https:\/\/doi.org\/10.1097\/JTO.0000000000000688","journal-title":"J Thorac Oncol"},{"key":"732_CR14","doi-asserted-by":"publisher","first-page":"2073","DOI":"10.1093\/annonc\/mdv319","volume":"26","author":"D Planchard","year":"2015","unstructured":"Planchard D, Loriot Y, Andr\u00e9 F, Gobert A, Auger N, Lacroix L, Soria JC (2015) EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol 26:2073\u20132078. https:\/\/doi.org\/10.1093\/annonc\/mdv319","journal-title":"Ann Oncol"},{"key":"732_CR15","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1007\/s40487-017-0043-5","volume":"5","author":"ES Kim","year":"2017","unstructured":"Kim ES, Halmos B, Kohut IF, Patel T, Rostorfer RD, Spira AI, Cseh A, McKay J, Wallenstein G, Mileham KF (2017) Efficacy and safety results of the afatinib expanded access program. Oncol Ther 5:103\u2013110. https:\/\/doi.org\/10.1007\/s40487-017-0043-5","journal-title":"Oncol Ther"},{"key":"732_CR16","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1056\/NEJMoa1612674","volume":"376","author":"TS Mok","year":"2017","unstructured":"Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA, AURA3 Investigators (2017) Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 376:629\u2013640. https:\/\/doi.org\/10.1056\/NEJMoa1612674","journal-title":"N Engl J Med"},{"key":"732_CR17","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1111\/ajco.12687","volume":"14","author":"DC Aw","year":"2018","unstructured":"Aw DC, Tan EH, Chin TM, Lim HL, Lee HY, Soo RA (2018) Management of epidermal growth factor receptor tyrosine kinase inhibitor-related cutaneous and gastrointestinal toxicities. Asia Pac J Clin Oncol 14:23\u201331. https:\/\/doi.org\/10.1111\/ajco.12687","journal-title":"Asia Pac J Clin Oncol"},{"key":"732_CR18","doi-asserted-by":"publisher","first-page":"i3","DOI":"10.1093\/annonc\/mdx702","volume":"29","author":"WH Hsu","year":"2018","unstructured":"Hsu WH, Yang JC, Mok TS, Loong HH (2018) Overview of current systemic management of EGFR-mutant NSCLC. Ann Oncol 29:i3\u2013i9. https:\/\/doi.org\/10.1093\/annonc\/mdx702","journal-title":"Ann Oncol"},{"key":"732_CR19","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1016\/j.immuni.2012.05.008","volume":"36","author":"A Zlotnik","year":"2012","unstructured":"Zlotnik A, Yoshie O (2012) The chemokine superfamily revisited. Immunity 36:705\u2013716. https:\/\/doi.org\/10.1016\/j.immuni.2012.05.008","journal-title":"Immunity"},{"key":"732_CR20","doi-asserted-by":"publisher","first-page":"3375","DOI":"10.1200\/JCO.2016.66.7162","volume":"34","author":"GR Oxnard","year":"2016","unstructured":"Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M, Yang JC, Barrett JC, J\u00e4nne PA (2016) Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 34:3375\u20133382. https:\/\/doi.org\/10.1200\/JCO.2016.66.7162","journal-title":"J Clin Oncol"},{"key":"732_CR21","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1001\/jamaoncol.2015.5009","volume":"2","author":"LV Sequist","year":"2016","unstructured":"Sequist LV, Piotrowska Z, Niederst MJ, Heist RS, Digumarthy S, Shaw AT, Engelman JA (2016) Osimertinib responses after disease progression in patients who had been receiving rociletinib. JAMA Oncol 2:541\u2013543. https:\/\/doi.org\/10.1001\/jamaoncol.2015.5009","journal-title":"JAMA Oncol"}],"container-title":["Investigational New Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10637-019-00732-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10637-019-00732-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10637-019-00732-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,11]],"date-time":"2023-03-11T18:38:15Z","timestamp":1678559895000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10637-019-00732-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,21]]},"references-count":21,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["732"],"URL":"https:\/\/doi.org\/10.1007\/s10637-019-00732-4","relation":{},"ISSN":["0167-6997","1573-0646"],"issn-type":[{"value":"0167-6997","type":"print"},{"value":"1573-0646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,21]]},"assertion":[{"value":"4 December 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 January 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 February 2019","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":"Makoto Nishio has received grants and\/or honoraria for speakers bureau from Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical.Haruyasu Murakami has received honoraria for speakers bureau from AstraZeneca and Chugai Pharmaceutical.Yuichiro Ohe has received grants and\/or honoraria for speakers bureau from AstraZeneca; Bayer; Bristol-Myers Squibb; Boehringer Ingelheim; Chugai Pharmaceutical; Daiichi Sankyo; Dainippon-Sumitomo; Ignyta; Japan Agency for Medical Research and Development; Kyorin; Eli Lilly; Ministry of Health, Labour and Welfare; MSD; Nipponkayaku; Novartis; Pfizer; and Taiho Pharmaceutical; and has worked as a consultant for AstraZeneca, Chugai Pharmaceutical, and Eli Lilly.Toyoaki Hida has received grants and\/or honoraria for speakers bureau from Astellas, AstraZeneca, Clovis Oncology, Novartis, and Taiho Pharmaceutical.Hiroshi Sakai has received honoraria for speakers bureau from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical.Kazuo Kasahara has received grants from Boehringer Ingelheim and honoraria for speakers bureau from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, and Taiho Pharmaceutical.Fumio Imamura has received grants and honoraria for speakers bureau from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, and Taiho Pharmaceutical.Tomohisa Baba has received honoraria for speakers bureau from AstraZeneca, Nippon Boehringer Ingelheim, and Taiho Pharmaceutical, and has worked as a consultant for AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, and Ono Pharmaceutical.Kaoru Kubota has received grants and honoraria for speakers bureau and has worked as a consultant for Taiho Pharmaceutical.Yukio Hosomi has received grants and\/or honoraria for speakers bureau\n              from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, Kyowa Hakko Kirin, and Taiho Pharmaceutical.Tsuneo Shimokawa has received grants from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Serono, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical.Hidetoshi Hayashi has received research support and\/or honoraria for speakers bureau from AbbVie Inc., AC MEDICAL Inc., Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, EPS Associates, GlaxoSmithKline, Japan Clinical Research Operations, Kyowa Hakko Kirin, Merck Serono, MSD, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, PAREXEL International, Pfizer Japan, PPD-SNBL, Quintiles, Taiho Pharmaceutical, Takeda Pharmaceutical, Transnational Japan, and Yakult Honsha, and has worked as a consultant for AstraZeneca and Eli Lilly.Kazutaka Miyadera is an employee of Taiho Pharmaceutical Co., Ltd.Tomohide Tamura has received honoraria for speakers bureau from Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly, Kyowa Hakko Kirin, MSD, Ono Pharmaceutical, Taiho Pharmaceutical, and Yakult Honsha.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}