Warner P, Whitaker LHR, Parker RA, Weir CJ, Douglas A, Hansen CH, Madhra M, Hillier SG, Saunders PTK, Iredale JP, Semple S, Slayden OD, Walker BR, and Critchley HOD
Background: The symptom of heavy menstrual bleeding (HMB) diminishes quality-of-life for many mid-age women and imposes substantial societal burden. We investigated our hypothesis that HMB reflects impaired endometrial vasoconstriction due to endometrial glucocorticoid deficiency. Does reversing this deficiency, by short-term luteal-phase treatment with exogenous glucocorticoid (dexamethasone), ameliorate HMB?, Methods: In our Bayesian response-adaptive parallel-group placebo-controlled randomised trial, five pre-planned interim analyses used primary outcome data to adjust randomisation probabilities to favour doses providing most dose-response information. Participants with HMB, recruited from Lothian (Scotland) NHS clinics and via community invitations/advertisements, were aged over 18 years; reported regular 21-42 day menstrual cycles; and had measured menstrual blood loss (MBL) averaging ≥ 50 mL over two screening periods. Identically encapsulated placebo, or one of six Dexamethasone doses (0·2 mg, 0·4 mg, 0·5 mg, 0·6 mg, 0·75 mg, 0·9 mg), were taken orally twice-daily over five days in the mid-luteal phase of three menstrual cycles. Participants, investigators, and those measuring outcomes were masked to group assignment. Primary outcome, change in average MBL from screening to 'treatment', was analysed by allocated treatment, for all with data., Trial Registration: ClinicalTrials.gov NCT01769820; EudractCT 2012-003,405-98 FINDINGS: Recruitment lasted 29/01/2014 to 25/09/2017; 176 were screened, 107 randomised and 97 provided primary outcome data (n = 24,5,9,21,8,14,16 in the seven arms, placebo to 1·8 mg total daily active dose). In Bayesian normal dynamic linear modelling, 1·8 mg dexamethasone daily showed a 25 mL greater reduction in MBL from screening, than placebo (95% credible interval 1 to 49 mL), and probability 0·98 of benefit over placebo. Adverse events were reported by 75% (58/77) receiving dexamethasone, 58% (15/26) taking placebo. Three serious adverse events occurred, two during screening, one in a placebo participant. No woman withdrew due to adverse effects., Interpretation: Our adaptive trial in HMB showed that dexamethasone 1·8 mg daily reduced menstrual blood loss. The role of dexamethasone in HMB management deserves further investigation., Funding: UK MRC DCS/DPFS grant MR/J003611/1., Competing Interests: Declaration of Competing Interest PW, CHH, AD, LW & MM, PTKS, SGH, ODS, CJW and RAP have no competing interests to disclose. Other disclosures, all outside the current research study, are: BRW is a paid consultant for Actinogen Medical, an inventor on patents owned by the University of Edinburgh relating to manipulating and monitoring glucocorticoid action; receives royalties as editor of Davidson's Principles & Practice of Medicine published by Elsevier; and an honorarium as Chair of the MRC Population & Systems Medicine. SS receives support from GlaxoSmithKline for his research group. JPI is supported by the UK National Institute of Health Research (NIHR) and is Director of the University Hospitals Bristol Trust and University of Bristol NIHR Biomedical Research Centre. HODC reports clinical research support for laboratory consumables and staff from Bayer AG and she has also provided consultancy advice (but with no personal remuneration) for Bayer AG; Vifor Pharma; Gedeon Richter; Myovant. She receives royalties from Up-to-Date for article on Abnormal Uterine Bleeding., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)