Low dose dexamethasone as treatment for women with heavy menstrual bleeding: A response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM)

Pamela Warner, Lucy Harriet Ravenscroft Whitaker, Richard Anthony Parker, Christopher John Weir, Anne Douglas, Christian Holm Hansen, Mayank Madhra, Stephen Gilbert Hillier, Philippa Tansy Kemp Saunders, John Peter Iredale, Scott Semple, Ov Daniel Slayden, Brian Robert Walker, Hilary Octavia Dawn Critchley, Pamela Warner, Lucy Harriet Ravenscroft Whitaker, Richard Anthony Parker, Christopher John Weir, Anne Douglas, Christian Holm Hansen, Mayank Madhra, Stephen Gilbert Hillier, Philippa Tansy Kemp Saunders, John Peter Iredale, Scott Semple, Ov Daniel Slayden, Brian Robert Walker, Hilary Octavia Dawn Critchley

Abstract

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.

Keywords: Abnormal uterine bleeding (AUB); Adaptive randomisation; Bayesian; Dexamethasone; Endometrium; Heavy menstrual bleeding (HMB); Menorrhagia; Randomised controlled trial.

Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Participant time-line in study – 5 to 6 months from screening appointment
Fig. 2
Fig. 2
CONSORT diagram.
Fig. 3
Fig. 3
Primary outcome results: Posterior median difference, for each dexamethasone dose group minus placebo, in change in menstrual blood loss volume (mL), Rogue and 95% CrI Legend: Primary outcome is change in assayed MBL for an individual i.e. their treatment phase MBL– screening MBL. Normal dynamic linear model of change in MBL is adjusted for Screening MBL of each participant.
Fig. 4
Fig. 4
Treatment Review Questionnaire secondary outcome results: Difference in proportions responding as indicated - for each dexamethasone dose minus placebo - and 95% CrI Legend: The left-panel items ask participant to compare their most recent menstrual period (3rd), to before the trial, while the right-panel items ask for 'absolute' judgements. Estimates plotted in shaded area favour dexamethasone, while those plotted in unshaded area, favour placebo. Left panel n = 97, 95, 97 respectively, and right panel n = 97, 95, 96.

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