Developmental Clinical Studies - Reversing Endometrial Glucocorticoid Deficiency in Heavy Menstrual Bleeding

Background Menstrual bleeding complaints affect quality of life and comprise a substantial societal burden, including major impact on health care use and costs. Current medical therapy for heavy menstrual bleeding (HMB) is often ineffective and/or associated with unacceptable side effects. There is unmet clinical need for targeted, effective, medical treatment strategies for HMB. The investigators' findings from research into mechanisms in HMB has led to the conclusion that women with HMB have enhanced endometrial inactivation of cortisol by 11βHSD2 resulting in local endometrial glucocorticoid deficiency, changes in prostaglandin (PG) production, and altered structure and deficient vasoconstriction of the endometrial vasculature. The investigators therefore anticipate that luteal phase "rescue" of endometrial glucocorticoid deficiency will provide a novel approach to therapy for women with HMB. The synthetic glucocorticoid dexamethasone (Dex) is a potent cortisol surrogate and glucocorticoid receptor (GR) agonist that resists 11βHSD2 inactivation. In a non-human primate study the investigators have observed a striking reduction in menstrual blood loss after Dexamethasone administration.

Objectives The investigators aim to show proof-of-concept that Dexamethasone administration in women with HMB will improve the capacity of endometrial vasculature for efficient vasoconstriction when menses commences, and hence reduce menstrual bleeding. The investigators' proposal is a novel use of an existing, well-characterised medical treatment (Dex).

Methods The Investigators propose a parallel group randomised controlled trial in women with HMB comparing Dexamethasone (over a range of potential doses) to placebo treatment. The trial design will be response-adaptive, whereby randomisation probabilities change across time to ensure that maximum information is obtained in the critical region of the underlying dose-response curve (that containing the 'optimum' dose). This has the added advantage that relatively more and more women are randomised to the doses emerging as most effective. Such a design is the most parsimonious way to enable both robust demonstration of the therapeutic effect of Dexamethasone on HMB, and reliable identification of the optimal dose to take forward for future further study in a Phase III trial.

Work Up Stage Adaptive designs such as this require a work up stage to enable the simulation modelling necessary to determine a robust final design specification with adequate power (here, the expected number of patients required lies in the range 100-108). In addition this work up stage will allow two clinical studies to be executed. Data collected in these will inform the modelling and simulation, but will also enhance mechanistic and pharmacodynamic understanding of observed Dexamethasone effect, and will be an invaluable preliminary check of safety of this 'first-in-HMB' use of oral Dexamethasone. These studies will involve treating in total 20 women with HMB with two cycles of Dexamethasone (1.5mg daily).