title: Low-dose dexamethasone as a treatment for women with heavy menstrual bleeding: protocol for response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM).
abstract: BACKGROUND
  Heavy menstrual bleeding (HMB) diminishes individual quality-of-life and poses substantial societal burden. In HMB endometrium, inactivation of cortisol (by enzyme 11β hydroxysteroid dehydrogenase type 2 (11βHSD2)), may cause local endometrial glucocorticoid deficiency and hence increased angiogenesis and impaired vasoconstriction. We propose that 'rescue' of luteal phase endometrial glucocorticoid deficiency could reduce menstrual bleeding.
  
  
  METHODS
  DexFEM is a double-blind response-adaptive parallel-group placebo-controlled trial in women with HMB (108 to be randomised), with active treatment the potent oral synthetic glucocorticoid dexamethasone, which is relatively resistant to 11βHSD2 inactivation. Participants will be aged over 18 years, with mean measured menstrual blood loss (MBL) for two screening cycles ≥50 mL. The primary outcome is reduction in MBL from screening. Secondary end points are questionnaire assessments of treatment effect and acceptability. Treatment will be for 5 days in the mid-luteal phases of three treatment menstrual cycles. Six doses of low-dose dexamethasone (ranging from 0.2 to 0.9 mg twice daily) will be compared with placebo, to ascertain optimal dose, and whether this has advantage over placebo. Statistical efficiency is maximised by allowing randomisation probabilities to 'adapt' at five points during enrolment phase, based on the response data available so far, to favour doses expected to provide greatest additional information on the dose-response. Bayesian Normal Dynamic Linear Modelling, with baseline MBL included as covariate, will determine optimal dose (re reduction in MBL). Secondary end points will be analysed using generalised dynamic linear models. For each dose for all end points, a 95% credible interval will be calculated for effect versus placebo.
  
  
  BACKGROUND
  Dexamethasone is widely used and hence well-characterised safety-wise. Ethical approval has been obtained from Scotland A Research Ethics Committee (12/SS/0147). Trial findings will be disseminated via open-access peer-reviewed publications, conferences, clinical networks, public lectures, and our websites.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01769820; EudractCT 2012-003405-98.
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: P
authors.initials: P
authors.lastname: Warner
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK Edinburgh Health Services Research Unit, Edinburgh, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Weir
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: C H
authors.initials: CH
authors.lastname: Hansen
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: A
authors.initials: A
authors.lastname: Douglas
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK.
authors.forename: M
authors.initials: M
authors.lastname: Madhra
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK.
authors.forename: S G
authors.initials: SG
authors.lastname: Hillier
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK.
authors.forename: P T K
authors.initials: PT
authors.lastname: Saunders
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Iredale
authors.affiliation: Clinical Research Imaging Centre, University of Edinburgh, Edinburgh, UK British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: S
authors.initials: S
authors.lastname: Semple
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: B R
authors.initials: BR
authors.lastname: Walker
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK.
authors.forename: H O D
authors.initials: HO
authors.lastname: Critchley
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism; D000328:Adult; D001499:Bayes Theorem; D002985:Clinical Protocols; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004311:Double-Blind Method; D004717:Endometrium / Q000187:drug effects*; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008595:Menorrhagia / Q000188:drug therapy*; D008597:Menstrual Cycle; D008598:Menstruation / Q000187:drug effects*; D012107:Research Design
chemical_list: D005938:Glucocorticoids; D003907:Dexamethasone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D006854:Hydrocortisone
keywords: STATISTICS & RESEARCH METHODS