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)

摘要

Introduction 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 and analysis 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. Ethics and dissemination 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. Trial registration number ClinicalTrials.gov NCT01769820; EudractCT 2012-003405-98. Background Heavy menstrual bleeding (HMB) is defined as excessive menstrual blood loss that interferes with the woman's physical, emotional, social or material quality-of-life.1 The prevalence of excessive menstrual bleeding in developing countries is reported as 4–9%.2 Community surveys of UK menstruating women have found 35–52% prevalence of reporting ‘heavy periods’ in the past 6?months,3 ,4 and 25% annual cumulative incidence of reporting periods as ‘heavy’,4 but with respect to putative HMB, only 15% who report both heavy periods and that their periods are ‘a marked/severe problem’.3 Annually, 1 million UK women seek help for HMB,1 and an estimated 3.5 million work days are lost.5 Conservative estimates of annual direct and indirect economic costs of menstrual bleeding problems in the USA are US$1 billion and US$12 billion, respectively (in year 2005$).6 Surgical treatments for HMB (hysterectomy, endometrial ablation) end fertility, and hysterectomy is high-cost major surgery. Among those aged 30–40 years, uterine fibroids are often the cause of HMB,7 frequently necessitating surgery. In the US 10–15% of women aged 25–64 have hysterectomy for fibroids8 costing $3 billion annually.6 Hysterectomy remains a common intervention even in the absence of large fibroids.9 It is estimated in England and Wales, that annually about 80?000 women are referred for the first time to hospital with HMB and approximately 28?000 (35%) undergo surgical treatment.10 A national 4-year audit has reported that in the year following first attendance at hospital for HMB, 43% of women received surgery (8183 followed up).11 However, given half of all UK-born babies (47%) are to women aged 30 or older,12 fertility-ending surgery is not always acceptable. Medical therapy for HMB is either ineffective,10 or associated with unacceptable side effects. The Levonorgestrel intrauterine system (LNG-IUS), a hormonal contraceptive now licensed as treatment for HMB, is unsuitable for women seeking to become pregnant. LNG-IUS can cause amenorrhoea, or for other users there is ongoing and unpredictable unscheduled bleeding, and these consequences can be unacceptable to women.13 The audit reported that in the first year after attendance for HMB, oral medication and IUS were received by 29% and 33%, respectively, but these were the ‘final’ treatment for only 12% (over half switched from oral medication) and 22% (one third switched from IUS).11 IUS and systemic progestin therapies for HMB are discontinued by up to one in five users due to side effects.14 A recent meta-analysis concludes that LNG-IUS is less cost-effective than hysterectomy for HMB.15 ,16 HMB often occurs in combination with other symptoms.17 ,18 The aud