Warner P, Weir C J, Hansen C H, Douglas A, Madhra M, Hillier S G, Saunders P T K, Iredale J P, Semple S, Walker B R, Critchley H O D
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK Edinburgh Health Services Research Unit, Edinburgh, UK.
BMJ Open. 2015 Jan 14;5(1):e006837. doi: 10.1136/bmjopen-2014-006837.
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.
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.
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.
ClinicalTrials.gov NCT01769820; EudractCT 2012-003405-98.
月经过多会降低个人生活质量，并带来巨大的社会负担。在月经过多的子宫内膜中，皮质醇（通过2型11β羟类固醇脱氢酶（11βHSD2））失活可能导致局部子宫内膜糖皮质激素缺乏，从而增加血管生成并损害血管收缩。我们提出，挽救黄体期子宫内膜糖皮质激素缺乏可能会减少月经出血。
DexFEM是一项针对月经过多女性的双盲反应适应性平行组安慰剂对照试验（将随机分配108名女性），积极治疗采用强效口服合成糖皮质激素地塞米松，其对11βHSD2失活具有相对抗性。参与者年龄超过18岁，两个筛查周期的平均实测月经失血量（MBL）≥50mL。主要结局是筛查后MBL的减少。次要终点是对治疗效果和可接受性的问卷调查评估。治疗将在三个治疗月经周期的黄体中期进行5天。将六剂低剂量地塞米松（每日两次，剂量范围为0.2至0.9mg）与安慰剂进行比较，以确定最佳剂量，以及其是否比安慰剂更具优势。通过允许随机化概率在入组阶段的五个时间点根据目前可用的反应数据进行“调整”，以倾向于预期能提供有关剂量反应最大额外信息的剂量，从而使统计效率最大化。将基线MBL作为协变量纳入的贝叶斯正态动态线性模型将确定最佳剂量（即MBL的减少量）。次要终点将使用广义动态线性模型进行分析。对于所有终点的每种剂量，将计算效应与安慰剂相比的95%可信区间。
地塞米松广泛使用，因此在安全性方面有充分的特征描述。已获得苏格兰A研究伦理委员会的伦理批准（12/SS/0147）。试验结果将通过开放获取的同行评审出版物、会议、临床网络、公开讲座和我们的网站进行传播。
ClinicalTrials.gov NCT01769820；EudractCT 2012-003405-98。
