Dexamethasone for Excessive Menstruation
Condition: Heavy Menstrual Bleeding
MeSH terms: Menorrhagia; Hemorrhage
Study type: Interventional
Phase: Phase 2

Summary: 
      This study builds on previous research which has provided compelling evidence that deficient
      activity of glucocorticoids in the endometrium is a cause of increased menstrual bleeding.
      This study aims to demonstrate that a glucocorticoid (dexamethasone), already in common use
      for other conditions, (eg to treat medical conditions such as asthma and rheumatoid arthritis
      in early pregnancy), will reverse the endometrial glucocorticoid deficiency and as a result
      reduce menstrual blood loss.

      The study is in two stages, a 12 month workup stage and a 3 year, response adaptive,
      dose-finding randomised controlled trial. The first stage involves two workup clinical
      studies to gather preliminary safety and efficacy data from first-in-Heavy Menstrual Bleeding
      use of oral dexamethasone. They will also provide methodological data for a series of
      simulation studies to determine a robust adaptive trial design specification.

      Workup study 1: is unblinded, six patients will be given Dexamethasone (0.75mg twice daily)
      for 5 days during two consecutive menstrual cycles and will have an endometrial biopsy and
      MRI on two occasions (in a nontreated cycle, and the second of the cycles treated with
      Dexamethasone). Workup study 2; is a doubleblind crossover trial of 14 women -2 treatment
      blocks of two cycles each, with either placebo or Dexamethasone (0.75mg twice daily),
      randomised to order of treatments blocks - placebo then Dexamethasone, or vice-versa.

      Adaptive trial: 54 month double-blind, placebo controlled trial of 108 women to evaluate the
      effect of Dexamethasone across a range of doses with the aim of identifying the optimal dose
      to be studied in a subsequent Phase III trial.

      Participants will be randomised to receive one of 6 active doses or placebo over 3 menstrual
      cycles.

      All studies will involve asking participants to complete menstrual diaries and to carry out
      menstrual blood loss collections to objectively measure blood loss.

      The investigators' proposed approach is novel use of synthetic glucocorticoid to "rescue"
      luteal phase deficiency of cortisol, and thus improve endometrial vasculature and hence
      vasoconstriction when menses commences, and thus reduce menstrual bleeding.
    

Detailed description: 
      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).
    

Intervention name(s): Dexamethasone; placebo
Intervention type(s): Drug; Drug
Intervention description(s): studies 1&2:0.75mg twice daily for 5 days, starting on day LH (Luteinising Hormone)+8 of menstrual cycle; Study 3 (adaptive) 0.2,0.4,0.5,0.75,0.8,0.9mg twice daily as above
Other intervention name(s): D07AB19
Intervention MeSH terms: Dexamethasone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Heavy menstrual bleeding (HMB); Dexamethasone; glucocorticoid