Ulipristal acetate versus conventional management of heavy menstrual bleeding (HMB; including uterine fibroids): a randomised controlled trial and exploration of mechanism of action (UCON trial)

BACKGROUND: The definitive treatment for the subjective symptom of heavy menstrual bleeding (HMB) has traditionally been surgery. There is a pressing need to develop safe, simple, acceptable, fertility-sparing medical treatments for HMB applicable to women regardless of age, reproductive history and the presence of uterine fibroids. Limitations of current medical treatments are that they are ineffective or associated with side-effects that women find unacceptable. A class of drugs, called selective progesterone receptor modulators (SPRMs), offer the potential to revolutionise the way we treat HMB by addressing the unmet need of sustainable long-term medical therapy. Menstrual disorder impacts significantly on quality of life, which can be assessed using one of a number of well validated questionnaires. HYPOTHESIS AND AIMS: We aim to test the hypothesis that the SPRM, ulipristal acetate (UPA; Esmya®), is more effective than the levonorgestrel-releasing intra-uterine system (LNG-IUS, Mirena®, Levosert) for the long-term treatment of HMB. Further, we aim to acquire an understanding of the mechanism of action of UPA on the endometrium and its effects upon the vasculature and structure of the uterus. DESIGN: Multicentre, randomised controlled trial with an embedded mechanistic evaluation of UPA. POPULATION: Women who present to primary and secondary care with HMB. Participants will be recruited from the gynaecological, out-patient clinics of participating centres, fitting around their current service provision. INTERVENTIONS: 5mg of daily oral UPA for 3 courses of 12 weeks, or will be fitted a LNG-IUS. PRIMARY CLINICAL OUTCOME: Validated Menorrhagia Multi-attribute Assessment Scale (MMAS) to assess impact of HMB on women's life, measured at 12 months. This is now an accepted primary outcome for randomised trials of interventions to improve HMB. SECONDARY CLINICAL OUTCOMES INCLUDE: Menstrual bleeding, Cycle regularity and duration, pelvic pain, uterine fibroid Symptom and quality of Life, sexual activity, general quality of life questionnaires, satisfaction with treatment outcome, effect of treatment on HMB, surgical intervention, adherence to trial treatments, serious adverse events and reactions reported by participants, Clinical measurements via pelvic ultrasound, endometrial biopsy and blood samples. MECHANISTIC OUTCOMES (subset of UPA group only): Study of impact of UPA on cell fate including markers of steroid responsiveness, inflammation, survival and proliferation and complemented with imaging of the uterus using high resolution Magnetic Resonance Imaging (MRI) of the uterine matrix and fibroids and Dynamic Contrast Enhanced (DCE-MRI) to measure uterine perfusion. SAMPLE SIZE: To demonstrate a clinically meaningful difference between UPA and LNG-IUS of 0.5 of a SD in MMAS score, with 90% power (p=0.05), approximately 220 patients in total are required (allowing for a 20% loss to follow-up). The embedded mechanistic component of the research will require 20 samples in the UPA group which will give >90% power to detect cell count changes. Statistical analysis will be by intention-to-treat. MMAS scores will be analysed using a linear regression model with baseline score included as a covariate. All effect sizes will be presented with 95% confidence intervals. EXPECTED RECRUITMENT RATE: Recruitment will take place over 24 months from at least 5 centres. All centres have HMB clinics, are experienced in recruiting to RCTs and the BCTU has a track record of completing RCTs in women's health. OUTLINE OF THE MAIN STAGES OF THE UCON TRIAL AND EXPECTED DURATIONS Months 1-6: site approvals and training. Months 7-30 Recruitment. Months 9-42 Follow-up. Months 43-48 Analysis and write-up.