Dexamethasone for Excessive Menstruation (dexFEM)

This study is not yet open for participant recruitment.
Verified January 2013 by University of Edinburgh
Sponsor:
Collaborator:
NHS Lothian
Information provided by (Responsible Party):
Hilary Critchley, University of Edinburgh
ClinicalTrials.gov Identifier:
NCT01769820
First received: December 19, 2012
Last updated: January 16, 2013
Last verified: January 2013
  Purpose

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: 36 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.


Condition Intervention Phase
Heavy Menstrual Bleeding
Drug: Dexamethasone
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Developmental Clinical Studies - Reversing Endometrial Glucocorticoid Deficiency in Heavy Menstrual Bleeding

Resource links provided by NLM:


Further study details as provided by University of Edinburgh:

Primary Outcome Measures:
  • Change or difference in mean laboratory measured menstrual blood loss(MBL) [ Time Frame: 3-4months ] [ Designated as safety issue: No ]

    study1:Change in mean MBL between baseline and Dexamethasone treatment cycles. Study2:Difference in mean MBL between placebo and Dexamethasone treatment cycles.

    Study3 (adaptive):Change in mean MBL between baseline and cycles during randomised (Dexamethasone/placebo) treatment



Secondary Outcome Measures:
  • Menstrual diary score for volume of menstrual period [ Time Frame: 3-4months ] [ Designated as safety issue: No ]
  • Satisfaction with treatment by means of a participant completed treatment review questionnaire [ Time Frame: 3-4months ] [ Designated as safety issue: No ]
    Participants will be asked to complete a treatment review questionnaire at the end of their study participation to elicit subjective assessment of the effect of the study treatment.

  • Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: 3-4months ] [ Designated as safety issue: Yes ]
    Participants will be asked about the occurrence of adverse events at each study visit and at each contact with the research team.Adverse events will be recorded from time of consent to 30 days after last treatment dose.

  • Examine effect of treatment on Period pain via participant self-report questionnaire [ Time Frame: 3-4months ] [ Designated as safety issue: No ]
    Participants will be asked to assess levels of period pain in the menstrual diaries and in the pre and post treatment questionnaires.

  • Mechanistic examination of response to Dexamethasone [ Time Frame: 2 months ] [ Designated as safety issue: No ]
    study 1 only:mechanistic variables comparing an un-treated and a treated cycle via MRI scan and endometrial biopsy


Estimated Enrollment: 128
Study Start Date: January 2013
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Dexamethasone
Study 1, and study2(2 arms); Dexamethasone 1.5mg daily Study 3 (adaptive -7 arms): Dexamethasone of 0.4, 0.8, 1.0, 1.2, 1.5, and 1.8 mg total dose per day
Drug: Dexamethasone
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 Name: D07AB19
Placebo Comparator: Placebo
Placebo
Drug: placebo

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).

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Complaint of HMB, including women with fibroids
  • Pre-menopausal
  • Age 18 years and over
  • Describing menstrual cycles every 21- 42 days
  • Provide written informed consent prior to any study related procedures
  • If of childbearing potential either agree to practice a non-hormonal method of contraception for duration of study or have a partner with a vasectomy
  • Workup (Study 1 or 2)- MBL for single screening period is >= 50mL
  • Adaptive Trial (Study 3)- average MBL for two screening menstrual collections is >= 50mL

Exclusion Criteria:

  • Currently breast-feeding
  • History or current uterus, cervix, ovarian or breast cancer
  • Known severe coagulation disorder
  • Glucocorticoid treatment or sex steroid administration by any route in previous 1 month
  • Taking prohibited medication -
  • Thyroid, renal or liver dysfunction
  • Diabetes mellitus
  • Treated moderate/severe hypertension
  • Psychotic depressive illness
  • Rare hereditary galactose intolerance, lactase deficiency or glucose galactose malabsorption (due to lactose content of trial medication)
  • Has a problem with alcohol or drug abuse
  • Has a mental condition rendering her unable to understand the nature and scope of the study
  • Participation in treatment phase in any earlier DexFEM study (1 or 2)
  • Is currently enrolled in an investigational drug or device study or participated in such a study within the previous 30 days and is still in exclusion period
  • workup study 1, only, an additional exclusion criterion of any contra-indication to MRI
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01769820

Contacts
Contact: Hilary Crithcley, MBChB; MD 0044 131 2426858 hilary.critchley@ed.ac.uk

Locations
United Kingdom
University of Edinburgh Not yet recruiting
Edinburgh, United Kingdom, EH16 4TJ
Contact: Anne Douglas    0044 131 650 3231    anne.douglas@ed.ac.uk   
Principal Investigator: Hilary Critchley         
Sub-Investigator: Pamela Warner         
Sub-Investigator: Christopher Weir, PhD         
Sub-Investigator: Stephen Hillier         
Sub-Investigator: John Iredale         
Sub-Investigator: Phillipa Saunders         
Sub-Investigator: Scott Semple         
Sub-Investigator: Brian Walker         
Sponsors and Collaborators
University of Edinburgh
NHS Lothian
Investigators
Principal Investigator: Hilary Critchley, MBChB MD University of Edinburgh
  More Information

Publications:
Responsible Party: Hilary Critchley, Professor of Reproductive Medicine, University of Edinburgh
ClinicalTrials.gov Identifier: NCT01769820     History of Changes
Other Study ID Numbers: dexfemv2
Study First Received: December 19, 2012
Last Updated: January 16, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University of Edinburgh:
Heavy menstrual bleeding (HMB)
Dexamethasone
glucocorticoid

Additional relevant MeSH terms:
Menstruation Disturbances
Hemorrhage
Menorrhagia
Pathologic Processes
Uterine Hemorrhage
Uterine Diseases
Genital Diseases, Female
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Glucocorticoids
BB 1101
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 16, 2014