Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial

Lucy H.R. Whitaker; Lee J. Middleton; Jane P. Daniels; Alistair R.W. Williams; Lee Priest; Smita Odedra; Versha Cheed; Clive E. Stubbs; T. Justin Clark; Mary-Ann Lumsden; Dharani K. Hapangama; Siladitya Bhattacharya; Paul P. Smith; Elaine P. Nicholls; Neil Roberts; Scott I. Semple; Lucky Saraswat; Jane Walker; Rohan R. Chodankar; Hilary O.D. Critchley

doi:10.1016/j.eclinm.2023.101995

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial

Lucy H.R. Whitaker, Lee J. Middleton, Jane P. Daniels, Alistair R.W. Williams, Lee Priest, Smita Odedra, Versha Cheed, Clive E. Stubbs, T. Justin Clark, Mary-Ann Lumsden, Dharani K. Hapangama, Siladitya Bhattacharya, Paul P. Smith, Elaine P. Nicholls, Neil Roberts, Scott I. Semple, Lucky Saraswat, Jane Walker, Rohan R. Chodankar, Hilary O.D. Critchley^* (Corresponding Author)

^*Corresponding author for this work

University of Edinburgh

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Abstract

Background Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26–1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29–22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

Original language	English
Article number	101995
Number of pages	13
Journal	EClinicalMedicine
Volume	60
Early online date	18 May 2023
DOIs	https://doi.org/10.1016/j.eclinm.2023.101995
Publication status	Published - 1 Jun 2023

Bibliographical note

Acknowledgments
This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership (grant 12/206/52). Medical Research Council (MRC) Centre grants to the Centre for Reproductive Health (CRH) (G1002033 and MR/N022556/1) are also gratefully acknowledged. The views expressed in this publication are those of the authors and not necessarily those of the Medical Research Council, National Institute for Health Research, or Department of Health and Social Care. We thank our Collaborative Group (listed in the Supplementary Material) for their contribution to recruitment, randomisation and collection of data, and to our Trial Steering and Data Monitoring Committees (members listed in Supplementary Material).

Keywords

Heavy menstrual bleeding
Ulipristal acetate
Selective progesterone receptor modulator
Levonorgestrel-releasing intrauterine system
Randomised controlled trial
Fibroid
Leiomyoma
Adenomyosis endometrium
Uterus
Quality of life
Amenorrhoea
Ultrasound
Progesterone receptor modulator associated endometrial changes
Drug induced liver injury
Urgent safety measures

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Cite this

Whitaker, L. H. R., Middleton, L. J., Daniels, J. P., Williams, A. R. W., Priest, L., Odedra, S., Cheed, V., Stubbs, C. E., Clark, T. J., Lumsden, M.-A., Hapangama, D. K., Bhattacharya, S., Smith, P. P., Nicholls, E. P., Roberts, N., Semple, S. I., Saraswat, L., Walker, J., Chodankar, R. R., & Critchley, H. O. D. (2023). Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial. EClinicalMedicine, 60, Article 101995. https://doi.org/10.1016/j.eclinm.2023.101995

Whitaker, LHR, Middleton, LJ, Daniels, JP, Williams, ARW, Priest, L, Odedra, S, Cheed, V, Stubbs, CE, Clark, TJ, Lumsden, M-A, Hapangama, DK, Bhattacharya, S, Smith, PP, Nicholls, EP, Roberts, N, Semple, SI, Saraswat, L, Walker, J, Chodankar, RR & Critchley, HOD 2023, 'Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial', EClinicalMedicine, vol. 60, 101995. https://doi.org/10.1016/j.eclinm.2023.101995

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title = "Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial",

abstract = "Background Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26–1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29–22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).",

keywords = "Heavy menstrual bleeding, Ulipristal acetate, Selective progesterone receptor modulator, Levonorgestrel-releasing intrauterine system, Randomised controlled trial, Fibroid, Leiomyoma, Adenomyosis endometrium, Uterus, Quality of life, Amenorrhoea, Ultrasound, Progesterone receptor modulator associated endometrial changes, Drug induced liver injury, Urgent safety measures",

author = "Whitaker, {Lucy H.R.} and Middleton, {Lee J.} and Daniels, {Jane P.} and Williams, {Alistair R.W.} and Lee Priest and Smita Odedra and Versha Cheed and Stubbs, {Clive E.} and Clark, {T. Justin} and Mary-Ann Lumsden and Hapangama, {Dharani K.} and Siladitya Bhattacharya and Smith, {Paul P.} and Nicholls, {Elaine P.} and Neil Roberts and Semple, {Scott I.} and Lucky Saraswat and Jane Walker and Chodankar, {Rohan R.} and Critchley, {Hilary O.D.}",

note = "Acknowledgments This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership (grant 12/206/52). Medical Research Council (MRC) Centre grants to the Centre for Reproductive Health (CRH) (G1002033 and MR/N022556/1) are also gratefully acknowledged. The views expressed in this publication are those of the authors and not necessarily those of the Medical Research Council, National Institute for Health Research, or Department of Health and Social Care. We thank our Collaborative Group (listed in the Supplementary Material) for their contribution to recruitment, randomisation and collection of data, and to our Trial Steering and Data Monitoring Committees (members listed in Supplementary Material).",

year = "2023",

month = jun,

day = "1",

doi = "10.1016/j.eclinm.2023.101995",

language = "English",

volume = "60",

journal = "EClinicalMedicine",

issn = "2589-5370",

publisher = "Lancet Publishing Group",

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TY - JOUR

T1 - Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON)

T2 - a randomised controlled phase III trial

AU - Whitaker, Lucy H.R.

AU - Middleton, Lee J.

AU - Daniels, Jane P.

AU - Williams, Alistair R.W.

AU - Priest, Lee

AU - Odedra, Smita

AU - Cheed, Versha

AU - Stubbs, Clive E.

AU - Clark, T. Justin

AU - Lumsden, Mary-Ann

AU - Hapangama, Dharani K.

AU - Bhattacharya, Siladitya

AU - Smith, Paul P.

AU - Nicholls, Elaine P.

AU - Roberts, Neil

AU - Semple, Scott I.

AU - Saraswat, Lucky

AU - Walker, Jane

AU - Chodankar, Rohan R.

AU - Critchley, Hilary O.D.

N1 - Acknowledgments This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership (grant 12/206/52). Medical Research Council (MRC) Centre grants to the Centre for Reproductive Health (CRH) (G1002033 and MR/N022556/1) are also gratefully acknowledged. The views expressed in this publication are those of the authors and not necessarily those of the Medical Research Council, National Institute for Health Research, or Department of Health and Social Care. We thank our Collaborative Group (listed in the Supplementary Material) for their contribution to recruitment, randomisation and collection of data, and to our Trial Steering and Data Monitoring Committees (members listed in Supplementary Material).

PY - 2023/6/1

Y1 - 2023/6/1

N2 - Background Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26–1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29–22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

AB - Background Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26–1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29–22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

KW - Heavy menstrual bleeding

KW - Ulipristal acetate

KW - Selective progesterone receptor modulator

KW - Levonorgestrel-releasing intrauterine system

KW - Randomised controlled trial

KW - Fibroid

KW - Leiomyoma

KW - Adenomyosis endometrium

KW - Uterus

KW - Quality of life

KW - Amenorrhoea

KW - Ultrasound

KW - Progesterone receptor modulator associated endometrial changes

KW - Drug induced liver injury

KW - Urgent safety measures

U2 - 10.1016/j.eclinm.2023.101995

DO - 10.1016/j.eclinm.2023.101995

M3 - Article

SN - 2589-5370

VL - 60

JO - EClinicalMedicine

JF - EClinicalMedicine

M1 - 101995

ER -

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial

Abstract

Bibliographical note

Keywords

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