TY - JOUR
T1 - Low dose dexamethasone as treatment for women with heavy menstrual bleeding
T2 - A response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM)
AU - Warner, Pamela
AU - Whitaker, Lucy Harriet Ravenscroft
AU - Parker, Richard Anthony
AU - Weir, Christopher John
AU - Douglas, Anne
AU - Hansen, Christian Holm
AU - Madhra, Mayank
AU - Hillier, Stephen Gilbert
AU - Saunders, Philippa Tansy Kemp
AU - Iredale, John Peter
AU - Semple, Scott
AU - Slayden, Ov Daniel
AU - Walker, Brian Robert
AU - Critchley, Hilary Octavia Dawn
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
KW - Abnormal uterine bleeding (AUB)
KW - Adaptive randomisation
KW - Bayesian
KW - Dexamethasone
KW - Endometrium
KW - Heavy menstrual bleeding (HMB)
KW - Menorrhagia
KW - Randomised controlled trial
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U2 - 10.1016/j.ebiom.2021.103434
DO - 10.1016/j.ebiom.2021.103434
M3 - Article
C2 - 34218053
AN - SCOPUS:85109023511
SN - 2352-3964
VL - 69
JO - EBioMedicine
JF - EBioMedicine
M1 - 103434
ER -