{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:25:40Z","timestamp":1792794340945,"version":"4.5.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":97,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ObsEva","id":[{"id":"https:\/\/ror.org\/04vsvp708","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100024087","name":"Theramex","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100024087","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016288","name":"Kissei","doi-asserted-by":"publisher","award":["5\/4\/150\/5"],"award-info":[{"award-number":["5\/4\/150\/5"]}],"id":[{"id":"10.13039\/100016288","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fonds National de la Recherche Scientifique"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>STUDY QUESTION<\/jats:title>\n                    <jats:p>Was the efficacy of linzagolix, observed at 6\u2009months in women with endometriosis-associated pain, maintained when administered for an additional 6\u2009months?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SUMMARY ANSWER<\/jats:title>\n                    <jats:p>Efficacy from this extension study complements the results of the main trial, by showing that linzagolix is effective at reducing endometriosis-associated pain for a majority of women.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                    <jats:p>In the pivotal EDELWEISS 3 randomized controlled trial, the efficacy and safety of 24\u2009weeks of once-daily oral linzagolix (a GnRH antagonist) were reported in women with endometriosis-related pain. Risks of bone mineral density (BMD) loss and vasomotor symptoms were minimized in both groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                    <jats:p>EDELWEISS 3 was a prospective, randomized, double-blind study. Subjects completing the 6-month treatment period in EDELWEISS 3 were invited to participate in the present extension study: EDELWEISS 6. Only subjects who had completed the full 6-month treatment course in the main study and who met the inclusion criteria were eligible for entry into the extension study. Among 486 patients who completed the 6-month study, 353 participated in the extension study from March 2020 to February 2023. The current extension study started at Month 6 of the main EDELWEISS 3 phase-3 trial. Upon the end of treatment in the extension study (6-month treatment period from Month 6 to Month 12), subjects entered a post-treatment follow-up period of 6\u2009months. The current report describes outcomes from the extension treatment period (up to 12\u2009months) and subsequent follow-up of 6\u2009months with no investigational medicinal product. The co-primary endpoints were the reduction in dysmenorrhea and non-menstrual pelvic pain at Month 12.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                    <jats:p>Premenopausal women with moderate-to-severe endometriosis who previously completed the full 6-month treatment period in the main study and met the inclusion criteria were eligible for the extension study. All subjects (n\u2009=\u2009353), whether given placebo or not in the main study, received either 75\u2009mg linzagolix alone or 200\u2009mg combined with hormonal add-back therapy (ABT) once daily for the additional 6\u2009months, i.e. those who were given a placebo during the main study were randomized to either group and those who had received active treatment continued with the same treatment (placebo\/75\u2009mg linzagolix [n\u2009=\u200957], placebo\/200\u2009mg linzagolix plus ABT [n\u2009=\u200957], 75\u2009mg linzagolix [n\u2009=\u2009118], and 200\u2009mg linzagolix plus ABT [n\u2009=\u2009121]). Pain was measured daily on a verbal rating scale and recorded in an electronic diary. The trial was performed in clinics and university hospitals in the USA and Europe.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                    <jats:p>By Month 12, of the 353 women who were treated and analyzed, the proportion of subjects with a significant reduction in dysmenorrhea and stable or decreased use of analgesics was 55.9% in the 75\u2009mg linzagolix group and 91.0% in the 200\u2009mg+ABT linzagolix group. The proportion of subjects with a significant reduction in non-menstrual pelvic pain and stable or decreased use of analgesics was 59.5% in the 75\u2009mg linzagolix group and 67.6% in the 200\u2009mg+ABT linzagolix group. A steady reduction in mean daily dyschezia, dyspareunia, and overall pelvic pain scores was observed in both linzagolix groups from baseline to Month 12, with a more marked reduction in the 200\u2009mg+ABT linzagolix group. Quality of life was assessed using the EHP-30 questionnaire. At Month 12, clear improvements (total score reductions) were observed in both linzagolix groups, with greater improvements in five out of five dimensions in the 200\u2009mg+ABT linzagolix group. Changes in body mass index were minimal, with no clinically meaningful modifications from Month 6 to Month 12. Adverse events including hot flushes were encountered in fewer than 1% of subjects. During the off-treatment follow-up period of 6\u2009months, some of the improvements were maintained for several months.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                    <jats:p>Efficacy was originally compared between the linzagolix and placebo groups from the main study, however, it would have been useful to have results from comparative studies with estro-progestogens or progestogens, to ascertain whether a GnRH antagonist has significant benefits over traditional first-line medications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                    <jats:p>Linzagolix, when administered orally once daily at a dose of 200\u2009mg in combination with ABT, offers an additional option for effective, safe, and well-tolerated medical treatments for endometriosis that can be proposed in cases of estro-progestogen or progestogen inefficacy, as it can be used for a longer term, improving quality of life and reducing the need for analgesics and opioids. The risks of bone mineral loss and vasomotor symptoms were minimized due to the ABT. The 75\u2009mg dose alone could be suitable for chronic treatment of endometriosis-associated pain without the need for concomitant hormonal ABT and may offer an option for some women, although further research is needed to confirm this finding.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY FUNDING, COMPETING INTEREST(S)<\/jats:title>\n                    <jats:p>Funding for the EDELWEISS 6 study was provided by Geneva, Switzerland. Analysis of data was partially supported by ObsEva (Geneva, Switzerland), Theramex (London, UK), and Kissei (Japan). Grant 5\/4\/150\/5 was awarded to M.-M.D. by the Fonds National de la Recherche Scientifique (FNRS). J.D. was a member of the scientific advisory board of ObsEva and Preglem until 2023 and reports consulting fees from ObsEva, Gedeon Richter, and Theramex. C.M.B. declares consulting fees (paid to University of Oxford) from Myovant for an advisory board and from Theramex; payment or honoraria (paid to University of Oxford) for talks at different meetings from [Theramex and Gedeon Richter]; support for attending meetings and\/or travel (paid to University of Oxford) from [Gedeon Richter]; being a member of the independent data monitoring board for the EDELWEIS 3 trial and member of the advisory board for Myovant for Spirit 1 and 2 trials (funds for both were paid to University of Oxford); being Chair of the ESHRE Endometriosis Guideline Committee (unpaid) and a member of the Medical Advisory Board Endometriosis UK (unpaid). F.P. has received fees and honoraria for lectures from Theramex. A.W.H. declares consultancy fees (paid to institution) from Roche Diagnostics, Gesynta, and Theramex; lecture fees from Gedeon Richter and Theramex; grant funding from the EU, UKRI, NIHR, CSO, Wellbeing of Women and Roche Diagnostics; UK Patent 2217921-2; participation on a Data Safety Monitoring Board for PANDA DMC; and roles as Trustee and Medical Advisor to Endometriosis UK, and Specialty Advisor to the Scottish Government\u2019s Chief Medical Officer for Obstetrics and Gynaecology. S.B. has received consulting fees and honoraria for lectures from Theramex. S.P.R. reports consulting fees and honoraria for lectures from Gedeon Richter and Theramex. F.C.H. reports consulting fees and honoraria for lectures, presentations, or educational events from Theramex and Gedeon Richter; and honoraria for participation in a data safety monitoring board for Organon. HT has received grants from Abbvie, reports consulting fees from ObsEva and Gedeon Richter and stock options from DotLab; declares a patent on endometriosis biomarkers, owned by Yale University (US10\u00a0982\u00a0282). M.P. was a principal investigator in the ObsEva-sponsored EDELWEISS trials and has received fees and honoraria from Theramex. E.B. and S.H. are employees of Theramex. M.-M.D. has received fees for lectures from Gedeon Richter and Theramex.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>TRIAL REGISTRATION NUMBER<\/jats:title>\n                    <jats:p>NCT04335591 (ClinicalTrials.gov).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/hropen\/hoag030","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T11:41:59Z","timestamp":1775216519000},"source":"Crossref","is-referenced-by-count":3,"title":["Linzagolix, with and without add-back therapy, in women with endometriosis-associated pain: results from EDELWEISS 6, a double-blind randomized extension and withdrawal study"],"prefix":"10.1093","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2528-206X","authenticated-orcid":false,"given":"Jacques","family":"Donnez","sequence":"first","affiliation":[{"name":"Department of Gynecology, Universit\u00e9 Catholique de Louvain , 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