background: This double-blind trial investigated the efficacy and safety of estradiol valerate/dienogest (E 2 V/DNG) for the treatment of heavy menstrual bleeding without recognizable organic pathology.methods: Otherwise healthy women with idiopathic heavy, prolonged or frequent menstrual bleeding, confirmed during a 90-day run-in phase, were randomized (2:1) according to a permuted-block, computer-generated schedule to E 2 V/DNG or placebo for 196 days at 34 centres in Europe and Australia. The primary efficacy end-point was the proportion of women with a 'complete' response (i.e. a return to 'menstrual normality') during a 90-day efficacy phase. Secondary end-points included changes in measured menstrual blood loss (MBL) and iron metabolism parameters. results:The intention-to-treat population comprised 231 women. The E 2 V/DNG response rate was much higher than with placebo (P , 0.0001). The mean reduction in MBL volume in E 2 V/DNG recipients was 69.4% (median 79.2%) versus 5.8% (median 7.4%) in placebo recipients. The between-treatment difference in MBL volume was 373 ml in favour of E 2 V/DNG (95% confidence interval 490, 255 ml; P , 0.0001). Significant improvements in iron metabolism parameters were observed with E 2 V/DNG but not placebo. Overall, 14 women (9.7%) treated with E 2 V/DNG and 5 (6.2%) treated with placebo prematurely discontinued treatment because of adverse events, headache being the most prevalent. Serious adverse events occurred in both the E 2 V/DNG and placebo groups (each n ¼ 2).conclusions: E 2 V/DNG is an effective treatment in women with heavy and/or prolonged menstrual bleeding without organic pathology. Further study of E 2 V/DNG compared with an active comparator is warranted. ClinicalTrials.gov identifier: NCT00307801.

Treatment with an OC containing E2V and DNG was well tolerated and was associated with stable E2 concentrations over 28 days. The pharmacokinetics of DNG were consistent with previous findings. Minimum serum concentrations of DNG increased only slightly during phases of the regimen during which DNG was administered.

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This study demonstrates a robust and thorough trial design leading to accurate and objective data collection. We recommend that future studies investigating heavy menstrual bleeding (HMB) should follow, and improve upon, this rigorous approach to menstrual trial data collection, not only to validate clinical results but also to improve the techniques used to acquire these results. We propose that the state-of-the-art methodology described here be used as the basis for new guidelines for the implementation of clinical trials in the area of HMB.