Ulipristal acetate versus conventional management of heavy menstrual bleeding
| ISRCTN | ISRCTN20426843 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN20426843 |
| EudraCT/CTIS number | 2014-003408-65 |
| Secondary identifying numbers | 18534 |
- 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
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
Scientific
University of Edinburgh
Medical School
Teviot Place
Edinburgh
EH8 9AG
United Kingdom
| Phone | +44 131 242 6858 |
|---|---|
| Hilary.Critchley@ed.ac.uk |
Study information
| Study design | Randomised; Interventional; Design type: Treatment |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a patient 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Ulipristal Acetate |
| Primary outcome measure | 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. |
| Secondary outcome measures | 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 |
| Overall study start date | 01/10/2014 |
| Completion date | 31/05/2021 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Female |
| Target number of participants | Planned Sample Size: 220; UK Sample Size: 220; Description: The Mechanistic Sub-study is carried out only at the Royal Infirmary of Edinburgh and will require a sample size of approximately 20 participants. Added 21/05/2020: As a consequence of the urgent safety measure relating to UPA (12-Feb-2018) we will aim to recruit enough women to ensure our primary analysis population is unaffected by enforced non-compliance with UPA or knowledge of the issues around UPA. This means we will now need to recruit 302 women in total into the study in total, with a target of 172 participants used in the primary analysis as per the original sample size target. |
| 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
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Edinburgh
EH16 4SA
United Kingdom
Glasgow
G4 0SF
United Kingdom
Liverpool
L8 7SS
United Kingdom
Aberdeen
AB25 2ZN
United Kingdom
Birmingham
B15 2TG
United Kingdom
Haslingden Rd
Blackburn
BB2 3HH
United Kingdom
M8 5RB
United Kingdom
Ynysmaerdy
Llantrisant
Pontypridd
CF72 8XR
United Kingdom
Llanfrechfa
Cwmbran
NP44 8YN
United Kingdom
KA2 0BE
United Kingdom
LL13 7TD
United Kingdom
Sponsor information
Hospital/treatment centre
ACCORD
The Queens Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ
Scotland
United Kingdom
"ROR" |
https://ror.org/03q82t418 |
|---|
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/03/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The final report will be written in accordance with funder (NIHR EME) guidelines and published via NIHR. |
| 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? |
|---|---|---|---|---|---|
| Protocol file | version 7.0 | 23/03/2020 | 06/02/2023 | No | No |
| Results article | results | 18/05/2023 | 31/05/2023 | Yes | No |
| Other publications | 22/05/2023 | 12/06/2023 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No | ||
| Results article | 01/10/2023 | 23/04/2025 | Yes | No |
Additional files
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
