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 - Funding Information:
Direct project funding for the research was received from the UK Medical Research Council DCS/DPFS scheme, grant number: MR/J003611/1 (https://mrc.ukri.org/) [HODC is CI for the grant, while PW, CJW, BRW, SGH, PTKS, SS and JPI were all co-applicants. The grant funded employment on the project of co-authors CHH, AD, RAP, LW & MM]. DexFEM was also indirectly supported by core funding to various affiliate institutions:, ??UoE MRC Centre for Reproductive Health [MRC core grants G1002033 2011?2016)PIs PTKS and HODC); MR/N022556/1 2016?2021 (renewal of core grant, no named PIs) - both https://mrc.ukri.org/], ??UoE Centre for Inflammation Research [MRC core grants from G0901697 2011?2017 (PI JPI); G9900991 2005?2010 (no DexFEM PI); both https://mrc.ukri.org/], ??Oregon National Primate Research Facility https://www.ohsu.edu/onprc [core grants over the time from ODS undertaking proof-of-concept study, until present - National Institutes of Health RR000163 PI J E Robertson, NIH P51 OD011092 PI P Bar-Gillespie (https://www.nih.gov/grants-funding)], ??SPCRN is supported by the Chief Scientist Office of the Scottish Government, ??SHARE is supported by NHS Research Scotland, the Universities of Scotland and the Chief Scientist Office of the Scottish Government, None of the funders listed above had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. BRW is a Wellcome Trust Senior Investigator (grant 107049/Z/15/Z https://wellcome.org/grant-funding) and has received programmatic grant support from British Heart Foundation. SS has been supported by a British Heart Foundation Centre of Research Excellence (2009?2014), CJW and RAP are partly supported by NHS Lothian grant to the UoE Edinburgh Clinical Trials Unit. We are grateful for the valuable contributions to DexFEM of:, The women who participated in the trial, DexFEM research team: Catherine Murray, Sharon McPherson, Moira Nicol, Alison Murray; Sheila Milne, Anne Houghton, Barbara Hamilton, NHS Lothian Pharmacy Services: Hazel Milligan, Ruaridh Buchan, Tayside Pharmaceuticals: Baxter Millar, ACCORD (sponsor) ? Ray French, Marise Bucukoglu, Bernadette Gallagher, Liz Craig, Heather Charles, UoE Edinburgh Clinical Trials Unit (ECTU): Gina Cranswick, Garry Milne, Jacqueline Stephen, Michelle Steven and other ECTU staff, NHS Lothian: Gerry Beattie, Ailsa Gebbie, Sharon Cameron;, Scottish Primary Care Research Network (SPCRN) [now rebranded to NRS Primary Care Network]: Ellen Drost; Morag Place, SHARE: Shobna Vasishta, Louise Dow, UoE Technology Transfer Office: Giles Dudley, Emma Mickley, Trial Steering Committee (TSC): Mary Ann Lumsden, Siladitya Bhattacharya, Dharani Hapangama;, Data Monitoring Committee (DMC): Justin Clark, Ertan Saridogan, Rebecca Reynolds, Adrian Mander, Data sharing: The full study database will be available, subject to approval of requests/proposals by a DexFEM user group including HODC, PW, CJW. Data will be fully anonymised (including removal of exact dates) and full supporting documentation will be provided (e.g. CRF, PIS, protocol, SAP, data dictionary). Access will be via Edinburgh DataShare https://datashare.is.ed.ac.uk/ and approved requests will be issued with a time-limited, renewable, data sharing agreement.
Funding Information:
BRW is a Wellcome Trust Senior Investigator (grant 107049/Z/15/Z https://wellcome.org/grant-funding ) and has received programmatic grant support from British Heart Foundation.
Funding Information:
• SPCRN is supported by the Chief Scientist Office of the Scottish Government
Funding Information:
• UoE MRC Centre for Reproductive Health [MRC core grants G1002033 2011–2016)PIs PTKS and HODC ); MR/N022556/1 2016–2021 (renewal of core grant, no named PIs) - both https://mrc.ukri.org/]
Funding Information:
SS has been supported by a British Heart Foundation Centre of Research Excellence (2009–2014)
Funding Information:
DexFEM was also indirectly supported by core funding to various affiliate institutions:
Funding Information:
• SHARE is supported by NHS Research Scotland, the Universities of Scotland and the Chief Scientist Office of the Scottish Government
Funding Information:
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.
Funding Information:
Direct project funding for the research was received from the UK Medical Research Council DCS/DPFS scheme, grant number: MR/J003611/1 ( https://mrc.ukri.org/ ) [ HODC is CI for the grant, while PW, CJW, BRW, SGH, PTKS, SS and JPI were all co-applicants. The grant funded employment on the project of co-authors CHH, AD, RAP, LW & MM].
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
VL - 69
JO - EBioMedicine
JF - EBioMedicine
SN - 2352-3964
M1 - 103434
ER -