Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding: the UCON randomised controlled trial and mechanism of action study
Authors: Whitaker Lucy HR , Middleton Lee J , Priest Lee , Odedra Smita , Cheed Versha , Nicholls Elaine P , Williams Alistair RW , Roberts Neil , Stubbs Clive E , Tryposkiadis Konstantios , Bensoussane Hannah , Chodankar Rohan , Murray Alison A , Nicol Moira , Tsolova Aleksandra O , Yin Kaiming , Cruz Marcos , Leow Hui Wei , Kershaw Lucy E , McLenachan Suzanne L , McKillop Graham , Walker Jane , Semple Scott I , Clark T Justin , Lumsden Mary Ann , Hapangama Dharani K , Saraswat Lucky , Bhattacharya Siladitya , Smith Paul , Daniels Jane , Critchley Hilary OD 
Published: November 2023

Background
Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. The levonorgestrel-releasing intrauterine system is an effective long-term treatment but is discontinued by many due to unpredictable bleeding, or adverse effects. The selective progesterone receptor modulator ulipristal acetate is used to treat symptomatic fibroids but long-term efficacy for the symptom of heavy menstrual bleeding, irrespective of presence of fibroids, is unknown.

Objectives
To determine whether ulipristal acetate is more effective at reducing the burden of heavy menstrual bleeding than levonorgestrel-releasing intrauterine system after 12 months of treatment in women with and without fibroids. We investigated mechanism of action of ulipristal acetate in a subset of 20 women.

Design
Randomised, open-label, parallel group, multicentre trial with embedded mechanistic study.

Setting
Ten UK hospitals.

Participants
Women with heavy menstrual bleeding aged 18 and over with no contraindications to levonorgestrel-releasing intrauterine system or ulipristal acetate.

Interventions
Three 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or continuous levonorgestrel-releasing intrauterine system following allocation in a 1 : 1 ratio using a web-based minimisation procedure.

Main trial outcome measures
Primary outcome was quality-of-life measured by menorrhagia multi-attribute scale at 12 months. Secondary outcomes included menstrual bleeding and patient satisfaction. Impact on fibroid size, endometrial appearance and liver function was also collected.

Mechanistic study outcome
Cellular markers for endometrial cell structure and function, determined from endometrial biopsies; volume of uterus and fibroids and microcirculation parameters were determined from magnetic resonance images.

Results
Sample size was increased from 220 to 302 as a result of temporary halt to recruitment due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate and the COVID-19 pandemic led to a premature closure of recruitment, with 118 women randomised to each treatment and 103 women completing 12-month menorrhagia multi-attribute scale scores prior to this point. Primary outcome scores substantially improved in both arms, but at 12 months there was no evidence of a difference between those receiving three cycles of ulipristal acetate [median score category: 76–99, interquartile range (51–75 to 100), n = 53] and levonorgestrel-releasing intrauterine system [median score category: 76–99, interquartile range (51–75 to 100), n = 50; adjusted odds ratio 0.55, 95% confidence interval 0.26 to 1.17; p = 0.12]. Rates of amenorrhoea were much higher in those allocated ulipristal acetate compared with the levonorgestrel-releasing intrauterine system (12 months: 64% vs. 25%, adjusted odds ratio 7.12, 95% confidence interval 2.29 to 22.2). There was no evidence of a difference in other participant-reported outcomes. There were no cases of endometrial malignancy and no hepatotoxicity due to ulipristal acetate use.

Mechanistic study results
Ulipristal acetate produced a reversible reduction in endometrial cell proliferation, as well as reversible alteration of other endometrial cellular markers. Ulipristal acetate did not produce a reduction in the volume of the uterus irrespective of coexisting fibroids, nor an effect on uterine microvascular blood flow.

Limitations
The urgent safety measures and premature closure of recruitment impacted final sample size.

Conclusions
We found no evidence of a difference in quality of life between the two treatments, but ulipristal acetate was superior to levonorgestrel-releasing intrauterine system at inducing amenorrhoea. Ulipristal acetate currently has restricted availability due to concerns regarding hepatotoxicity.

Future work
There is a need to develop new, safe, effective and fertility-sparing medical treatments for heavy menstrual bleeding. The observed acceptability and effectiveness of ulipristal acetate warrants further research into the selective progesterone receptor modulator class of pharmacological agents.

Study registration
This trial is registered as ISRCTN 20426843.