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Gonadotropin-releasing hormone (GnRH) receptor antagonists provide fast symptom relief and show promise as a medical (non-surgical) treatment option and as a presurgical treatment to reduce leiomyoma size. The aim of this study was to evaluate the efficacy and safety of three dose levels of oral relugolix, a small molecule GnRH receptor antagonist, in Japanese women with uterine leiomyomas and heavy menstrual bleeding.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This phase 2, multicenter, double-blind, parallel-group study was conducted at 36 sites in Japan in women with uterine leiomyomas and heavy menstrual bleeding, defined as a pictorial blood loss assessment chart (PBAC) score of \u2265\u2009120 in one menstrual cycle. Patients were randomized 1:1:1:1 to relugolix 10, 20, or 40\u00a0mg, or placebo, orally once daily for 12 weeks. The primary endpoint was the proportion of patients with a total PBAC score of &lt;\u200910 from week 6 to 12. A sample size of 50 patients per group was estimated to provide\u2009\u2265\u200995% power, based on the comparison of relugolix 40\u00a0mg with placebo using a chi-square test with a significance level of 5% (two-sided).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      From November 2011 to September 2012, 216 patients were randomized and 214 patients (99.1%) were analyzed. The proportion (difference vs. placebo) of patients that achieved the primary endpoint in the placebo and 10-, 20-, and 40-mg relugolix groups were 0%, 20.8% (95% confidence interval [CI]: 9.3\u201332.3,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u2009.001), 42.6% (95% CI: 29.4\u201355.8,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u2009.001), and 83.3% (95% CI: 73.4\u201393.3,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u2009.001), respectively. Though treatment-emergent adverse events were similar between the 20- and 40-mg groups, the incidence rates were more frequent compared with the placebo group. Most of these adverse events were mild or moderate in intensity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Relugolix decreased menstrual blood loss in women with uterine leiomyomas in a dose\u2013response manner, and was generally well\u00a0tolerated.<\/jats:p>\n                    <jats:p>\n                      <jats:bold>Clinical trial registration:<\/jats:bold>\n                      ClinicalTrials.gov,\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01452659\">https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01452659<\/jats:ext-link>\n                      , NCT01452659 (registered 17\/10\/2011); JAPIC Clinical Trial Information,\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.jp\">https:\/\/www.clinicaltrials.jp<\/jats:ext-link>\n                      , JapicCTI-111590 (registered 31\/08\/2011).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12905-021-01475-2","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T03:02:58Z","timestamp":1635390178000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Relugolix for oral treatment of uterine leiomyomas: a dose-finding, randomized, controlled trial"],"prefix":"10.1186","volume":"21","clinical-trial-number":[{"clinical-trial-number":"nct01452659","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Hiroshi","family":"Hoshiai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshifumi","family":"Seki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeru","family":"Kusumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentarou","family":"Kudou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Tanimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"1475_CR1","doi-asserted-by":"publisher","first-page":"16043","DOI":"10.1038\/nrdp.2016.43","volume":"2","author":"EA Stewart","year":"2016","unstructured":"Stewart EA, Laughlin-Tommaso SK, Catherino WH, Lalitkumar S, Gupta D, Vollenhoven B. 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All participants provided written informed consent.  Ethical approval for the study, including the protocol and informed consent form, was obtained from the Institutional Review Board (IRB) at each study site: Chayamachi Ladies Clinic IRB, NPO Clinical Research Promotion Network Japan IRB, Jinsenkai Hanna Hospital IRB, Meiwa Hospital IRB, Shintokai Yokohama Minoru Clinic IRB, Ehime Prefectural Central Hospital IRB, International University of Health and Welfare-IRB, Hakataeki-higashi Clinic IRB, Chiba Kaihin Municipal Hospital IRB, Eiyukai Yasuda Hospital IRB, Sapporo Medical Association\u2019s IRB, Kenporen Osaka Central Hospital IRB, Kansai Rosai Hospital IRB, Yamate Dermatological Clinic IRB, Tokushukai Group IRB, Fukui General Hospital IRB, Toyama Prefectural Central Hospital IRB, Oita Red Cross Hospital IRB, Japan Organization of Occupational Health and Safety Ehime Rosai Hospital IRB, Japan Organization of Occupational Health and Safety Chiba Rosai Hospital IRB, Aso Co., Iizuka Hospital IRB, Fukui Prefectural Hospital IRB, and Ogikubo Hospital IRB.","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":"Hiroshi Hoshiai has received consultancy fees from Takeda Pharmaceutical Company Limited, and Yoshifumi Seki, Takeru Kusumoto, Kentarou Kudou, and Masataka Tanimoto are current and past employees of Takeda Pharmaceutical Company Limited.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"375"}}