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

• Main Authors: 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
• Format: Article
• Language: English
• Published: Elsevier 2021-07-01
• Series: EBioMedicine
• Subjects: Heavy menstrual bleeding (HMB); Randomised controlled trial; Dexamethasone; Adaptive randomisation; Endometrium; Bayesian
• Online Access: http://www.sciencedirect.com/science/article/pii/S2352396421002279

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.