Efficacy and safety of the combination of estetrol 15 mg/drospirenone 3 mg in a cyclic regimen for the treatment of endometriosis-associated pain and objective gynecological findings: a multicenter, placebo-controlled, double-blind, randomized study.

Objective: To evaluate the efficacy and safety of 24-week cyclic administration of estetrol (E4) (15 mg)/drospirenone (DRSP) (3 mg) in Japanese patients with endometriosis.
Design: A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
Setting: Twenty-five study centers in Japan.
Patient(s): A total of 162 Japanese women diagnosed with endometriosis.
Intervention(s): Participants were randomly allocated to the E4/DRSP group or the placebo group. In the E4/DRSP group, participants were orally administered one tablet containing E4 (15 mg) and DRSP (3 mg) daily for 24 days, followed by one placebo tablet for 4 days for a hormone-free interval, constituting a 1-cycle regimen. One placebo tablet was administered once daily for 28 days to participants in the placebo group. The treatments were continued for six cycles (24 weeks) throughout the confirmatory period.
Main Outcome Measure(s): Changes in visual analogue scale (VAS) scores for the most severe pelvic pain (lower abdominal and back pain) from baseline to six treatment cycles at the end of the confirmatory study period.
Result(s): Estetrol/drospirenone showed changes in the mean VAS scores for the most severe pelvic pain (-33.2 mm) from baseline to the end of the 6-cycle treatment. The between-group difference was significant (-8.5 mm; 2-sided 95% confidence interval, -16.1 to -0.9 mm), showing superiority to placebo. The responder rates, ≥30% and ≥50% reductions in the VAS scores from baseline, were higher in the E4/DRSP group than in the placebo group: 53.2% vs. 29.6% and 36.4% vs. 12.3%. Objective gynecological findings (induration of the cul-de-sac, pelvic tenderness, and limited uterine mobility) were significantly improved by E4/DRSP treatment, and the proportions of stable and worsened participants were significantly lower than in the placebo group. Estetrol/drospirenone decreased the size of endometriomas and improved quality of life, on the basis of quality of life-related questionnaires and global impression scores. No safety concerns were observed with E4/DRSP treatment. Few differences were observed in the proportion of participants with hemostasis parameters outside the reference range between the E4/DRSP and placebo groups.
Conclusion(s): Estetrol/drospirenone effectively treats endometriosis-associated pain and improves gynecological findings. Estetrol/drospirenone may be a safe, new option for endometriosis treatment with a potentially decreased risk of thromboembolic events.
Clinical Trial Registration Number: jRCT2011210027.
Competing Interests: Declaration of Interests T.H. reports a medical writing and clinical trial advisory fee payment on the basis of the medical expert contract from Fuji Pharma Co., Ltd., and case study meeting fee payment on the basis of the medical expert contracts and medical writing fees for other clinical trials other than this manuscript in accordance with the medical expert contract from Fuji Pharma Co., Ltd. T.K. reports a medical writing and clinical trial advisory fee payment on the basis of the medical expert contract from Fuji Pharma Co., Ltd. A.H. reports a medical writing and clinical trial advisory fee payment on the basis of clinical biostatistics expert contract from Fuji Pharma Co., Ltd., and clinical biostatistics educational seminar fee payment on the basis of clinical biostatistics expert contract from Fuji Pharma Co., Ltd. T.T. reports salary and article processing charges from Fuji Pharma Co., Ltd. M.N. reports salary and article processing charges from Fuji Pharma Co., Ltd.; and patent filed with regard to the improvement of cul-de-sac induration, pelvic tenderness, and uterine mobility in subjects with endometriosis complicated by adenomyosis (Fuji Pharma Co., Ltd., and Mithra Pharmaceuticals). T.M. reports salary and article processing charges from Fuji Pharma Co., Ltd. M.H. reports salary and article processing charges from Fuji Pharma Co., Ltd.; and patent filed with regard to the improvement of cul-de-sac induration, pelvic tenderness, and uterine mobility in subjects with endometriosis complicated by adenomyosis (Fuji Pharma Co., Ltd., and Mithra Pharmaceuticals). J.-M.F. is a member of the Board at Mithra Pharmaceuticals and received financial support for the supervision of this study and consulting fees. Y.O. reports a medical writing and clinical trial advisory fee payment on the basis of the medical expert contract from Fuji Pharma Co., Ltd., and case study meeting fee payment on the basis of the medical expert contracts from Fuji Pharma Co., Ltd.
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