Ulipristal acetate versus conventional management of heavy menstrual bleeding

ISRCTN	ISRCTN20426843
DOI	https://doi.org/10.1186/ISRCTN20426843
Clinical Trials Information System (CTIS)	2014-003408-65
Protocol serial number	18534
Sponsor	NHS Lothian
Funder	National Institute for Health Research

Submission date: 25/03/2015
Registration date: 25/03/2015
Last edited: 23/04/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Urological and Genital Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Current plain English summary as of 29/05/2020:
Background and study aims
Heavy menstrual bleeding (HMB) refers to when a woman loses an excessive amount of blood over a number of periods. It’s not necessarily a symptom of there being something seriously wrong, but it can have a serious effect on a woman’s quality of life. Medication is the main treatment, but surgery is also an option for women when other treatment options have failed. There is a pressing need to develop safe, simple, acceptable, fertility-sparing medical treatments for HMB for women regardless of age, reproductive history and the presence of uterine fibroids (non-cancerous growths in the uterus). Limitations of current medical treatments are that they often do not work or have side effects that women find unacceptable. An exciting new 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.
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® or LNG-IUS – 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 structure of the uterus.

Who can participate?
Woman (aged at least 18) with HMB.

What does the study involve?
Participants are randomly allocated intone of two groups. Those in group 1 are treated with UPA. Those in group 2 are treated with LNG-IUS. The two groups are compared to see whether UPA works better in improving HMB compared with LNG-IUS after 12 months treatment. We also look at bleeding patterns, satisfaction with treatment and safety. Women are asked to complete questionnaires before treatment, and then after 3, 6 and 12 months of treatment.

What are the possible benefits and risks of participating?
The UCON trial is led by a team of experienced researchers, who have an excellent track record of both running clinical trials and investigating menstrual bleeding problems.
Women treated with UPA are monitored for side effects with scans and examining samples from the womb lining. A subgroup of participants who are taking UPA will also have detailed MR investigations of the womb to study womb structure, along with in depth examination of samples of the womb-lining (endometrium). Ultimately, there could be savings to the NHS from fewer operations to remove the womb (hysterectomy) or destroy its lining (endometrial ablation).

Where is the study run from?
Royal Infirmary of Edinburgh (lead site) and 4 other hospitals in the UK.

When is the study starting and how long is it expected to run for?
October 2014 to May 2021

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Professor Hilary Critchley, Hilary.Critchley@ed.ac.uk

Previous plain English summary:
Background and study aims
Heavy menstrual bleeding (HMB) refers to when a woman loses an excessive amount of blood over a number of periods. It’s not necessarily a symptom of there being something seriously wrong, but it can have a serious effect on a woman’s quality of life. Medication is the main treatment, but surgery is also an option for women when other treatment options have failed. There is a pressing need to develop safe, simple, acceptable, fertility sparing medical treatments for HMB for women regardless of age, reproductive history and the presence of uterine fibroids (non-cancerous growths in the uterus). Limitations of current medical treatments are that they often do not work or have side effects that women find unacceptable. An exciting new 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. Here, we aim to test whether the SPRM ulipristal acetate (UPA; Esmya®), works better than the levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena®) for the long term treatment of HMB.

Who can participate?
Woman (aged at least 18) with HMB.

What does the study involve?
Participants are randomly allocated intone of two groups. Those in group 1 are treated with UPA. Those in group 2 are treated with LNG-IUS. The two groups are compared to see whether UPA works better in improving HMB compared with LNG-IUS after 12 months treatment. We also look at bleeding patterns, satisfaction with treatment and safety. Women are asked to complete questionnaires before treatment, and then after 3, 6 and 12 months of treatment.

What are the possible benefits and risks of participating?
The UCON trial is led by a team of experienced researchers, who have an excellent track record of both running clinical trials and investigating menstrual bleeding problems. Women treated with UPA are monitored for side effects with scans and examining samples from the womb lining, as changes to the womb lining have been noted after 3 months. Furthermore, additional samples are taken from a smaller group of women also have a detailed MR investigation of the womb to measure uterine perfusion. This shows the effect of UPA on structure and blood supply of the uterus both in the presence and absence of fibroids. Ultimately, there could be savings to the NHS from fewer operations to remove the womb (hysterectomy) or destroy its lining (endometrial ablation).

Where is the study run from?
Royal Infirmary of Edinburgh (lead site) and 4 other hospitals in the UK.

When is the study starting and how long is it expected to run for?
October 2014 to May 2021 (updated 22/05/2020, previously: February 2015 to September 2018)

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Professor Hilary Critchley
Hilary.Critchley@ed.ac.uk

Contact information

Prof Hilary OD Critchley
Scientific

University of Edinburgh
Medical School
Teviot Place
Edinburgh
EH8 9AG
United Kingdom

Phone	+44 131 242 6858
Email	Hilary.Critchley@ed.ac.uk

Study information

Primary study design	Interventional
Study design	Randomised; Interventional; Design type: Treatment
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	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)
Study acronym	UCON
Study objectives	Current study hypothesis as of 21/05/2020: The selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA; Esmya®), is more effective than the levonorgestrel-releasing intrauterine system (LNGIUS) for the long term treatment of heavy menstrual bleeding (HMB). We also aim to acquire an understanding of themechanism of action of UPA on the endometrium and its effects upon the vasculature and structure of the uterus. Previous study hypothesis: The selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA; Esmya®), is more effective than the levonorgestrel-releasing intrauterine system (LNGIUS, Mirena®) for the long term treatment of heavy menstrual bleeding (HMB). We also 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.
Ethics approval(s)	NRES Committee London - Bloomsbury, 18/11/2014, 14/LO/1602
Health condition(s) or problem(s) studied	Topic: Reproductive health and childbirth; Subtopic: Reproductive Health and Childb (all Subtopics); Disease: Menstrual Disorders
Intervention	1. Intervention: Ulipristal Acetate (UPA) 2. Reference/ Control group: levonorgestrel-releasing intrauterine system (LNG-IUS) Treatment duration:12 months. Follow-up: 12 month questionnaire. Gynaecology clinic appointment (UPA group receive 12 month ultrasound, blood sample, endometrial biopsy). LNG-IUS Group receive 12 month ultrasound and blood sample).
Intervention type	Drug
Phase	Phase III
Drug / device / biological / vaccine name(s)	Ulipristal Acetate
Primary outcome measure(s)	The primary outcome measure is the condition-specific Menorrhagia Multi-Attribute Scale (MMAS) designed and validated to capture the impact of HMB on women’s day-to-day life.
Key secondary outcome measure(s)	Current secondary outcome measures as of 21/05/2020: 1. Menstrual bleeding will be captured by validated Pictorial Blood Loss Assessment Chart (PBAC) 2. Cycle regularity and duration 3. Visual analogue scales (0-10) for pelvic pain during periods, intercourse and at other times. 4. Sexual Activity Questionnaire, a measure of sexual functioning, used in other HMB trials 5. General quality of life (EuroQoL – EQ-5D-5L) and ICECAP-A) 6. Satisfaction with treatment on a 5-point Likert scale 7. Participant rating of effect of treatment on HMB over 12 months measured on a 4-point Likert scale 8. Whether participant is willing to recommend the treatment to a friend 9. Surgical intervention (hysterectomy, endometrial ablation and other gynaecological surgery) 10. Adherence to trial treatments and reasons for changing treatment, as reported by the participant 11. Serious adverse events and reactions reported by participants, principally those that are serious and detailed in the respective Summary of Product Characteristics (SmPC) and those that are unexpected 12. Clinical measurements via pelvic ultrasound: uterine volume, evidence of adenomyosis, presence of fibroids, largest fibroid volume, endometrial thickness, endometrial appearance (regular/irregular), evidence of ovarian cysts 13. Clinical measurement via endometrial biopsy: primary diagnosis (normal/benign/hyperplasia/ malignant) and further sub-diagnoses if non-normal 14. Clinical measurement via blood samples: liver function (including alanine transaminase (ALT) and asparate aminotransferase (AST) and other tests according to local protocols) serum haemoglobin and oestradiol levels Functional Outcomes 15. Impact on endometrial tissue architecture including regulation of the vascular compartment 16. Impact on endometrial steroid responsiveness, proliferation, survival and inflammatory processes 17. Expression of genes implicated in pre-malignant change including tumour suppressors 18. Effects on uterine/ fibroid structure and vascularity as determined by MRI-DCE and high resolution structural MRI Previous secondary outcome measures: 1. Menstrual bleeding will be captured by validated Pictorial Blood Loss Assessment Chart (PBAC). The standard PBAC is a validated and well used assessment of menstrual blood loss in women. The PBAC will be supplemented by visual analogue scales for menstruation duration, regularity and pelvic pain 2. Uterine Fibroid Symptom and Quality of Life (UFS-QoL) instrument, which contains a health related quality of life (HRQoL) domain and a symptom domain. This instrument will be only given to women diagnosed with fibroids 3. Sexual Activity Questionnaire, a measure of sexual functioning, used in other HMB trials. The sexual activity questionnaire is a valid, reliable and acceptable measure for describing the sexual functioning of women in terms of pleasure and discomfort. It is quick and easy to administer and has good face validity delineating between the sexual functioning of pre and post-menopausal women 4. Satisfaction with treatment outcome measured on a 5-point Likert scale. Specific statements about the experience and the acceptability of the treatment and the beliefs about the value of the treatment will be elicited from the participants 5. Adherence to trial treatments, as reported by the participant 6. Serious adverse events and reactions reported by participants, principally those that are serious and detailed in the respective Summary of Product Characteristics (SmPC) and those that are unexpected 7. Clinical measurements to assess safety and efficacy will include serum haemoglobin as appropriate, oestradiol, pelvic ultrasound (endometrial appearance; fibroid volume) and endometrial biopsies (reported according to pre-agreed criteria by independent pathologists blinded to treatment allocations) 8. Impact on endometrial tissue architecture including regulation of the vascular compartment 9. Impact on endometrial steroid responsiveness, proliferation, survival and inflammatory processes 10. Expression of genes implicated in pre-malignant change including tumour suppressors 11. Effects on uterine/ fibroid structure and vascularity as determined by MRI-DCE and high-resolution structural MRI
Completion date	31/05/2021

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Female
Target sample size at registration	220
Total final enrolment	236
Key inclusion criteria	Current inclusion criteria as of 21/05/2020: 1. Aged 18 years or over 2. Menstrual bleeding that she perceives to be heavy and troublesome 3. Willing to receive medical treatment with either UPA or LNG-IUS 4. Willing to undergo two pelvic ultrasounds 5. If allocated to UPA, willing and eligible to undergo two endometrial biopsies with the possibility of a third and fourth (i.e. up to four biopsies) 6. If allocated to UPA mechanistic sub-study, willing and eligible to undergo three endometrial biopsies with the possibility of a fourth and fifth (i.e. up to five biopsies). If ‘No’ may be randomised to RCT if UPA endometrial biopsy consent given 7. Willing to use barrier contraception if allocated to UPA 8. Given written informed consent 9. Willing and eligible to undergo up to three magnetic resonance imaging scans If allocated to UPA, mechanistic sub-study only. If ‘No’ may still be randomised to RCT Previous inclusion criteria: 1. Females aged between 18 or over 2. Heavy menstrual bleeding at intervals of 25-42 days that she perceives to be heavy and troublesome 3. Willing to receive medical treatment with either UPA or LNGIUS 4. Willing to undergo two pelvic ultrasounds and at least one endometrial biopsy, but up to four if allocated to UPA 5. Willing to use barrier contraception if allocated to UPA 6. Given written informed consent 7. Willing to undergo one additional endometrial biopsy and at least three magnetic resonance imaging scan (if allocated to UPA, mechanistic substudy only)
Key exclusion criteria	Current exclusion criteria as of 21/05/2020: 1. Post-menopausal 2. A >14 week fibroid uterus and/or cavity length >11 cm confirmed by ultrasound scan 3. Submucosal fibroids >2cm diameter confirmed by ultrasound scan 4. Contraindications to UPA or LNG-IUS 5. Intention to continue current use of Cytochrome P450 (CYP3A4) inhibitors 6. Intention to continue current use of Cytochrome P450 (CYP3A4) inducers (e.g. Phenytoin, carbamazepine, rifampicin, St John’s Wort) 7. Intention to continue current use of P-glycoprotein substrates (e.g. digoxin) 8. A past, current or suspected diagnosis of endometrial hyperplasia or neoplasia 9. History of liver problems 10. Exclusion from the trial or initiating a new course of UPA if Alanine transaminase (ALT) or aspartate aminotransferase (AST) more than 2-times the upper limit of normal (ULN) 11. Epilepsy managed with carbamazepine, phenytoin 12. Significant renal impairment 13. Pregnant 14. Current plans to become pregnant within 12 months 15. Currently breastfeeding 16. Severe asthma that is not sufficiently controlled by oral glucocorticoids 17. Past or current known history of with uterine, cervical, ovarian or breast cancer. 18. Current use of progestagen-releasing intrauterine device (except if allocated within UCON) 19. Intention to continue regular use of Mefenamic acid 20. Intention to continue regular use of Tranexamic acid 21. Intention to continue regular use of GnRH analogues 22. Intention to continue regular use of Progestagen-only contraceptive 23. Intention to continue regular use of any combined oral contraceptive pills 24. Intention to continue regular use of hormonal replacement therapy Previous exclusion criteria: 1. A >14 week fibroid uterus and/or cavity length >11 cm confirmed by ultrasound scan 2. Submucosal fibroids >2cm diameter confirmed by ultrasound scan 3. Contraindications to UPA or LNGIUS 4. Current use of Cytochrome P450 (CYP3A4) inhibitors 5. Current use of Cytochrome P450 (CYP3A4) inducers 6.Current use of Pglycoprotein substrate (e.g.digoxin) 7. A past, current or suspected diagnosis of endometrial hyperplasia or endometrial neoplasia 8. Severe hepatic impairment 9. Suffer with epilepsy managed with carbamazepine, phenytoin 10. Significant renal impairment 11. Pregnant 12. Current plans to become pregnant within 12 months 13. Currently breastfeeding 14. Severe asthma that is not sufficiently controlled by oral glucocorticoidssteroids 15. Suffer with uterine, cervical, ovarian or breast cancer 16. Receiving Pglycoprotein substrates 17. Current use of progestagen releasing intrauterine device (except if allocated within UCON) 18. Continued regular use of Mefenamic acid 19. Continued regular use of Tranexamic acid 20. Continued regular use of GnRH analogues 21. Continued regular use of Progestagen only contraceptive 22. Continued regular use of any combined oral contraceptive pills
Date of first enrolment	01/04/2015
Date of final enrolment	28/02/2020

Locations

Countries of recruitment

United Kingdom
England
Scotland
Wales

Study participating centres

Royal Infirmary of Edinburgh (lead site)

51 Little France Drive
Edinburgh
EH16 4SA
United Kingdom

Glasgow Royal Infirmary

84 Castle Street
Glasgow
G4 0SF
United Kingdom

Liverpool Women's Hospital

Crown Street
Liverpool
L8 7SS
United Kingdom

Aberdeen Royal Infirmary

Foresterhill
Aberdeen
AB25 2ZN
United Kingdom

Birmingham Women’s Hospital

Mindelsohn Way
Birmingham
B15 2TG
United Kingdom

Royal Blackburn Teaching Hospital

East Lancashire Hospitals NHS Trust
Haslingden Rd
Blackburn
BB2 3HH
United Kingdom

Pennine Acute Hospitals Trust

Oldham
M8 5RB
United Kingdom

Cwm Taf University Health Board

Royal Glamorgan Hospital
Ynysmaerdy
Llantrisant
Pontypridd
CF72 8XR
United Kingdom

Aneurin Bevan University Health Board

Llanfrechfa Grange Hospital
Llanfrechfa
Cwmbran
NP44 8YN
United Kingdom

NHS Ayrshire and Arran

Kilmarnock
KA2 0BE
United Kingdom

Betsi Cadwaladr University Health Board

Bangor
LL13 7TD
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	Requests for data generated during the UCON study will be considered by the University of Birmingham Clinical Trials Unit (BCTU). Data will typically be available 6 months after the primary publication. Only scientifically sound proposals from appropriately qualified Research Groups will be considered for data sharing. The request will be reviewed by the BCTU Data Sharing Committee in discussion with the CI and, where appropriate (or in absence of the CI) any of the following: the Trial Sponsor, the relevant Trial Management Group (TMG), and independent TSC. Requests can be made to BCTU-Info@adf.bham.ac.uk A formal Data Sharing Agreement (DSA) may be required between respective organisations once the release of the data is approved and before data can be released. Data will be fully de-identified (anonymised) unless the DSA covers the transfer of participant-identifiable information. Any data transfer will use a secure and encrypted method.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	18/05/2023	31/05/2023	Yes	No
Results article		01/10/2023	23/04/2025	Yes	No
HRA research summary			28/06/2023	No	No
Other publications		22/05/2023	12/06/2023	Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Protocol file	version 7.0	23/03/2020	06/02/2023	No	No
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Additional files

ISRCTN20426843_PROTOCOL_V7.0_23Mar20.pdf: Protocol file

Editorial Notes

23/04/2025: Publication reference added.
12/06/2023: Publication reference added.
31/05/2023: Publication reference added.
16/02/2023: The following changes were made to the trial record:
1. IPD sharing statement added.
2. The intention to publish date was changed from 30/09/2022 to 30/03/2023.
06/02/2023: Protocol uploaded (not peer reviewed).
24/05/2022: The total final enrolment number was added and the intention to publish date was changed from 31/05/2022 to 30/09/2022.
01/06/2020: The iPD sharing statement was added to the publication and dissemination plan.
29/05/2020: The following changes were made to the trial record:
1. The secondary outcome measures were changed.
2. The plain English summary was updated.
22/05/2020: The following changes were made to the trial record:
1. The overall start date was changed from 24/02/2015 to 01/10/2014.
2. The plain English summary was updated to reflect the change.
21/05/2020: The following changes were made to the trial record:
1. The study hypothesis was changed.
2. The overall end date was changed from 30/09/2018 to 31/05/2021.
3. The recruitment end date was changed from 30/04/2017 to 28/02/2020.
4. The intention to publish date was added.
5. The secondary outcome measures were changed.
6. The trial website was added.
7. The inclusion criteria were changed.
8. The exclusion criteria were changed.
9. The target number of participants was updated.
10. The trial participating centres "Royal Blackburn Teaching Hospital, Pennine Acute Hospitals Trust, Cwm Taf University Health Board, Aneurin Bevan University Health Board, NHS Ayrshire and Arran, Betsi Cadwaladr University Health Board" were added.
12/04/2017: Internal review