{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T04:21:02Z","timestamp":1770438062554,"version":"3.49.0"},"reference-count":15,"publisher":"BMJ","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2013,6,16]]},"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. tEPs with pretreatment serum human chorionic gonadotrophin (hCG) levels &lt;1000\u2005IU\/L respond well to outpatient medical treatment with intramuscular methotrexate (MTX). TEPs with hCG &gt;1000\u2005IU\/L take a significant time to resolve with MTX and require multiple outpatient monitoring visits. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. In preclinical studies, we found that EP implantation sites express high levels of EGFR and that gefitinib augments MTX-induced regression of pregnancy-like tissue. We performed a phase I toxicity study administering oral gefitinib and intramuscular MTX to 12 women with tEPs. The combination therapy did not cause significant toxicities and was well tolerated. We noted that combination therapy resolved the tEPs faster than MTX alone. We now describe the protocol of a larger single arm trial to estimate the efficacy and side effects of combination gefitinib and MTX to treat stable tEPs with hCG 1000\u201310\u2005000\u2005IU\/L<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and analysis<\/jats:title><jats:p>We propose to undertake a single-arm multicentre open label trial (in Edinburgh and Melbourne) and recruit 28 women with tEPs (pretreatment serum hCG 1000\u201310\u2005000\u2005IU\/L). We intend to give a single dose of intramuscular MTX (50\u2005mg\/m<jats:sup>2<\/jats:sup>) and oral gefitinib (250\u2005mg) daily for 7\u2005days. Our primary outcome is the resolution of EP to non-pregnant hCG levels &lt;15\u2005IU\/L without requirement of surgery. Our secondary outcomes are comparison of time to resolution against historical controls given MTX only, and safety and tolerability as determined by clinical\/biochemical assessment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Ethics and dissemination<\/jats:title><jats:p>Ethical approval has been obtained from Scotland A Research Ethics Committee (MREC 11\/AL\/0350), Southern Health Human Research Ethics Committee B (HREC 11180B) and the Mercy Health Human Research Ethics Committee (R12\/25). Data will be presented at international conferences and published in peer-reviewed journals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration number<\/jats:title><jats:p>ACTRN12611001056987.<\/jats:p><\/jats:sec>","DOI":"10.1136\/bmjopen-2013-002902","type":"journal-article","created":{"date-parts":[[2013,7,20]],"date-time":"2013-07-20T00:20:37Z","timestamp":1374279637000},"page":"e002902","source":"Crossref","is-referenced-by-count":10,"title":["Phase II single arm open label multicentre clinical trial to evaluate the efficacy and side effects of a combination of gefitinib and methotrexate to treat tubal ectopic pregnancies (GEM II): study protocol"],"prefix":"10.1136","volume":"3","author":[{"given":"Andrew W","family":"Horne","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika M","family":"Skubisz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann","family":"Doust","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W Colin","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Euan","family":"Wallace","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hilary O D","family":"Critchley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terrance G","family":"Johns","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane E","family":"Norman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siladitya","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jill","family":"Mollison","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Rassmusen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Tong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2013,7,18]]},"reference":[{"key":"2024051504431866000_3.7.e002902.1","doi-asserted-by":"publisher","DOI":"10.1136\/jfprhc-2011-0073"},{"key":"2024051504431866000_3.7.e002902.2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.d3397"},{"key":"2024051504431866000_3.7.e002902.3","unstructured":"RCOG. The management of tubal pregnancy. Green top Guideline No 21, published in May 2004 (reviewed 2010). http:\/\/www.rcog.org.uk\/files\/rcog-corp\/GTG21_230611.pdf"},{"key":"2024051504431866000_3.7.e002902.4","doi-asserted-by":"publisher","DOI":"10.1002\/uog.12401"},{"key":"2024051504431866000_3.7.e002902.5","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/des373"},{"key":"2024051504431866000_3.7.e002902.6","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmn012"},{"key":"2024051504431866000_3.7.e002902.7","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1506"},{"key":"2024051504431866000_3.7.e002902.8","unstructured":"Nilsson UW Johns TG Wilmann T . Effects of Gefinitb, an Epidermal Growth Factor Receptor Inhibitor, on Human Placental Cell Growth. Obstet Gynecol. In press."},{"key":"2024051504431866000_3.7.e002902.9","unstructured":"Skubisz MM Horne AW Johns TG . Combination Gefitinib and Methotrexate Compared with Methotrexate Alone to Treat Ectopic Pregnancy. 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