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)

P Warner, C J Weir, C H Hansen, A Douglas, M Madhra, S G Hillier, P T K Saunders, J P Iredale, S Semple, B R Walker, H O D Critchley, P Warner, C J Weir, C H Hansen, A Douglas, M Madhra, S G Hillier, P T K Saunders, J P Iredale, S Semple, B R Walker, H O D Critchley

Abstract

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.

Keywords: STATISTICS & RESEARCH METHODS.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Figure 1
Figure 1
Participant time line(s). Notes: #Completes menstrual diary and undertakes menstrual collection for objective MBL assessment. *Each treatment cycle starts immediately after a menstrual period and finishes at the end of the following period. Treatment is for 5 days, targeted to start approximately 8 days before the period (GP, general practitioner; HMB, heavy menstrual bleeding; MBL, menstrual blood loss; mth, month; SPCRN, the Scottish Primary Care Research Network).

References

    1. NICE. Clinical Guideline 44; heavy menstrual bleeding 2007.
    1. Harlow SD, Campbell OM. Epidemiology of menstrual disorders in developing countries: a systematic review. BJOG 2004;111:6–16. 10.1111/j.1471-0528.2004.00012.x
    1. Santer M, Warner P, Wyke S. A Scottish postal survey suggested that prevailing clinical pre-occupation with heavy periods does not reflect the epidemiology of reported symptoms and problems. J Clin Epidemiol 2005;58:1206–10. 10.1016/j.jclinepi.2005.02.026
    1. Shapley P, Jordan K, Croft PR. An epidemiological survey of symptoms of menstrual loss in the community. BJGP 2004;54:359–63.
    1. Rahn DD, Abed H, Sung VW et al. . Systematic review highlights difficulty interpreting diverse clinical outcomes in abnormal uterine bleeding trials. J Clin Epidemiol 2011;64:293–300. 10.1016/j.jclinepi.2010.03.017
    1. Liu Z, Doan QV, Blumenthal P et al. . A systematic review evaluating health-related quality of life, work impairment, and health-care costs and utilization in abnormal uterine bleeding. Value Health 2007;10:183–94. 10.1111/j.1524-4733.2007.00168.x
    1. Stewart EA. Uterine fibroids. Lancet 2001;357:293–8. 10.1016/S0140-6736(00)03622-9
    1. Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 1990;94:435–8.
    1. Lethaby A, Shepperd S, Cooke I et al. . Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database Syst Rev 2000;(2):CD000329.
    1. NHMBA. First Annual Report: National Heavy Menstrual Bleeding Audit. 1st Annual Report RCOG, 2011.
    1. NHMBA. Third Annual Report: National Heavy Menstrual Bleeding Audit. 3rd Annual Report RCOG, 2013.
    1. ONS. Who is having babies? Office for National Statistics Statistical Bulletin 2009.
    1. Warner P, Guttinger A, Glasier AF et al. . Randomized placebo-controlled trial of CDB-2914 in new users of a levonorgestrel-releasing intrauterine system shows only short-lived amelioration of unscheduled bleeding. Hum Reprod 2010;25:345–53. 10.1093/humrep/dep377
    1. Abdel-Aleem H, d'Arcangues C, Vogelsong KM et al. . Treatment of vaginal bleeding irregularities induced by progestin only contraceptives. Cochrane Database Syst Rev 2007;(4):CD003449.
    1. Bhattacharya S, Middleton L, Tsourapas A et al. . Hysterectomy, endometrial ablation and Mirena(R) for heavy menstrual bleeding: a systematic review of clinical effectiveness and cost-effectiveness analysis. Health Technol Assess 2011;15:1–252. 10.3310/hta15190
    1. Roberts TE, Tsourapas A, Middleton LJ et al. . Hysterectomy, endometrial ablation, and levonorgestrel releasing intrauterine system (Mirena) for treatment of heavy menstrual bleeding: cost effectiveness analysis. BMJ 2011;342:d2202 10.1136/bmj.d2202
    1. Warner P, Critchley HO, Lumsden MA et al. . Referral for menstrual problems: cross sectional survey of symptoms, reasons for referral, and management. BMJ 2001;323:24–8. 10.1136/bmj.323.7303.24
    1. Santer M, Wyke S, Warner P. What aspects of periods are most bothersome for women reporting heavy menstrual bleeding? Community survey and qualitative study. BMC Womens Health 2007;7:8 10.1186/1472-6874-7-8
    1. NHMBA. Final Annual Report: National Heavy Menstrual Bleeding Audit. Final Annual Report RCOG, 2014.
    1. Critchley HO, Maybin JA. Molecular and cellular causes of abnormal uterine bleeding of endometrial origin. Semin Reprod Med 2011;29:400–9. 10.1055/s-0031-1287664
    1. Rae M, Mohamad A, Price D et al. . Cortisol inactivation by 11beta-hydroxysteroid dehydrogenase-2 may enhance endometrial angiogenesis via reduced thrombospondin-1 in heavy menstruation. J Clin Endocrinol Metab 2009;94:1443–50. 10.1210/jc.2008-1879
    1. Zhang MZ, Xu J, Yao B et al. . Inhibition of 11beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans. J Clin Invest 2009;119:876–85. 10.1172/JCI37398
    1. Smith SK, Abel MH, Kelly RW et al. . Prostaglandin synthesis in the endometrium of women with ovular dysfunctional uterine bleeding. Br J Obstet Gynaecol 1981;88:434–42. 10.1111/j.1471-0528.1981.tb01009.x
    1. Chataway J, Nicholas R, Todd S et al. . A novel adaptive design strategy increases the efficiency of clinical trials in secondary progressive multiple sclerosis. Mult Scler 2011;17:81–8. 10.1177/1352458510382129
    1. Krams M, Sharma A, Dragalin V et al. . Adaptive approaches in clinical drug development. Opportunities and challenges in design and implementation. Pharm Med 2009;23:139–48. 10.1007/BF03256762
    1. West MJ, Harrison PJ. Bayesian forecasting and dynamic models. 2nd edn New York: Springer–Verlag, 1997.
    1. Lukes AS, Muse KN, Richter HE et al. . Estimating a meaningful reduction in menstrual blood loss for women with heavy menstrual bleeding. Curr Med Res Opin 2010;26:2673–8. 10.1185/03007995.2010.526098
    1. Warner PE, Critchley HO, Lumsden MA et al. . Menorrhagia II: is the 80-mL blood loss criterion useful in management of complaint of menorrhagia? Am J Obstet Gynecol 2004;190:1224–9. 10.1016/j.ajog.2003.11.016
    1. Warner PE, Critchley HO, Lumsden MA et al. . Menorrhagia I: measured blood loss, clinical features, and outcome in women with heavy periods: a survey with follow-up data. Am J Obstet Gynecol 2004;190:1216–23. 10.1016/j.ajog.2003.11.015
    1. Yong EL, Glasier A, Hillier H et al. . Effect of cyclofenil on hormonal dynamics, follicular development and cervical mucus in normal and oligomenorrhoeic women. Hum Reprod 1992;7:39–43.
    1. Wyatt KM, Dimmock PW, Walker TJ et al. . Determination of total menstrual blood loss. Fertil Steril 2001;76:125–31. 10.1016/S0015-0282(01)01847-7

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