The Use of Letrozole or Mifepristone for Pretreatment of Medical Termination of Pregnancy

Abortion in First Trimester Clinical Trial

Official title:

The Use of Letrozole or Mifepristone for Pretreatment of Medical Termination of Pregnancy: a Randomized, Non-inferiority Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05341817
• Other study ID #: CIRB 202110-00035
• Status: Recruiting
• Phase: Phase 4
• Start date: November 22, 2022
• Est. completion date: November 2024

Study information

• Verified date: October 2023
• Source: KK Women's and Children's Hospital
• Contact: Meei Jiun Seet
• Phone: (+65) 8223 2674
• Email: Seet.Meei.Jiun[@]singhealth.com.sg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Medical termination of pregnancy (mTOP) generally involves using either a combined regimen consisting of mifepristone and misoprostol, or a misoprostol-only regimen. Complete abortion rates of first trimester mTOP with the use of misoprostol-only regimen varies between 74-88%. With the addition of mifepristone as pre-treatment drug, this improves success rates to 93-97%. Mifepristone, an anti-progesterone, is relatively expensive and is subject to stringent regulations for usage in addition to restricted access in many countries. Therefore, there is a need to find a cheaper and more readily available, yet effective alternative.

The use of letrozole (an aromatase inhibitor) in mTOP is postulated to suppress estradiol levels (an important factor in the maintenance of early pregnancy), therefore enhancing the effect of misoprostol in inducing abortion. Studies have shown that pre-treatment with letrozole achieves a complete abortion rate of 77-98%, similar to that in mifepristone-Misoprostol studies.

The investigators hypothesise that letrozole is equivalent to mifepristone for the pre-treatment of mTOP and propose to conduct a randomised, non-inferiority trial for mTOP up to 10 weeks gestation with two arms as detailed below:

1. Oral letrozole 10mg daily for 3 days, followed by vaginal misoprostol on Day 3 (Intervention group)

2. Oral mifepristone 200mg once on Day 1, followed by vaginal misoprostol 800mcg on Day 3. Then, 4 hours later, another dose of 400mcg PV misoprostol if no signs of abortion (Control group - current practice).

The investigators aim to include a total of 144 patients, 72 in each arm, to detect a non-inferiority margin of 15% with a power of 80% at 5% significance. The investigators primary outcome will be rate of complete abortion by Day 21-28 of mTOP.

This pilot RCT will provide preliminary data and preparation for larger grant application which will provide necessary evidence to enhance the care of women undergoing mTOP, with enhanced cost-savings and availability.

Description:

The standard of care for termination of pregnancy (TOP) has shifted from a predominantly surgical approach towards medical strategy. Medical termination of pregnancy (mTOP) has increased in popularity worldwide as it is cost savings, non-invasive and there is avoidance of risks associated with surgery.

In general, mTOP involves using either a combined regimen consisting of mifepristone and misoprostol which is the current gold standard of care, or a misoprostol-only regimen. The World Health Organisation (WHO) recommends the use of mifepristone for pre-misoprostol priming when mifepristone is available, and the alternative of misoprostol-only when mifepristone is not accessible. Compared with misoprostol alone, pre-treatment with mifepristone followed by misoprostol has been shown to improve the success rate of complete abortion. However, the widespread use of mifepristone is limited by the high cost of therapy and unavailability in many countries. Hence, there is an urgent unmet need for a cheaper and more readily available alternative.

Letrozole priming before mTOP has been proposed as an alternative to the use of mifepristone. The proposed mechanism is a reduction in serum estrogen levels, leading to a concomitant reduction in progesterone receptor concentration necessary for the maintenance of pregnancy. Several randomised controlled trials (RCTs) have been performed by comparing the effectiveness of using letrozole for mTOP priming before misoprostol versus misoprostol alone. The combination of letrozole with misoprostol has shown to be effective in improving the success rates of complete abortion up to 10 weeks gestation, compared with misoprostol alone. Given its low price, ready availability worldwide and common usage in the fields of ovulation induction and breast cancer, letrozole may be a potential alternative to mifepristone in mTOP priming. While medication costs vary from country to country, the cost of a course of letrozole is largely cheaper than mifepristone. Unfortunately, no study has been designed to specifically compare the effectiveness of letrozole versus mifepristone pre-treatment regimes in the management of mTOP. Independent examination of the pre-treatment effects of letrozole and misoprostol versus misoprostol alone in different studies (different population characteristics) restricted valid comparison between treatments. This forms the key motivation for the investigators' proposed study.

To address the aforementioned knowledge gaps, this study aims to conduct a non-inferior RCT to investigate whether pre-treatment with letrozole before misoprostol is comparable to mifepristone pre-treatment before misoprostol mTOP in patients up to 10 weeks gestation. Women will be randomly assigned (1:1) to either receive 10 mg letrozole daily for 3 days followed by 800 μg misoprostol, or 200 mg mifepristone followed by 800 μg misoprostol 2 days later. This RCT is designed as a non-inferiority trial. Thus, the investigators expect that no significant differences in abortion outcomes will be observed between the two groups.

The primary outcome is complete abortion rates. Secondary outcomes include time-to-abortion interval, the number of misoprostol doses required, healthcare resource utilisation and side effects.

Specific Aim 1: To compare complete abortion rates at day 21-28 of mTOP in patients using letrozole/misoprostol regime versus mifepristone/misoprostol regime. The investigators hypothesise that letrozole will achieve similar complete abortion rates as mifepristone when used as priming of mTOP. Complete abortion will be defined as no further intervention required e.g. medical or surgical treatment for retained products of conception.

Specific Aim 2: To determine if letrozole/misoprostol regime results in better healthcare resource utilisation than mifepristone/misoprostol regime. The investigators hypothesise that letrozole is a resource-efficient alternative as measured by length of hospital stay, need for emergency department attendance and need for additional medical/surgical treatment.

The successful completion of this RCT will provide the data necessary to show the non-inferiority of letrozole compared against mifepristone. This will lead to the introduction of a more cost-effective and more accessible mTOP service for patients, as letrozole is cheaper and more widely available as compared to mifepristone. The expansion of mTOP regimes may help to save hospital resources with less reliance on surgical methods (manpower and expertise, logistics, and cost etc.) in the long run.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 144
• Est. completion date: November 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 21 Years and older

Eligibility

Inclusion Criteria:

• 21 years and above

• Patient requesting for medical termination of pregnancy (mTOP)

• Patient eligible for legal abortion according to the Termination of Pregnancy Act (Chapter 324)

• Gestational age =10 weeks (on day 1 of mifepristone or letrozole administration) as confirmed by the first trimester dating scan

• Singleton pregnancy

• Patient is agreeable to undergo surgical evacuation or repeat medical therapy if treatment fails

• Willing and able to provide written, informed consent

Exclusion Criteria:

• History or evidence of adrenal pathology, steroid-dependent cancer, porphyria, poorly controlled hypertension, bronchial asthma, thromboembolism and severe cardiac/renal/liver disease

• Haemoglobin level of <9.5 g/L

• Presence of an intrauterine contraceptive device

• Breastfeeding

• Reported allergic reaction to mifepristone, misoprostol or letrozole,

• Participating in another trial of investigational medicinal products during the current pregnancy

Related Conditions & MeSH terms

• Abortion in First Trimester

Intervention

Drug:
• Letrozole
Letrozole priming before mTOP is used as an alternative to the use of mifepristone. Women randomly assigned (1:1) to the Letrozole arm will receive 10 mg letrozole daily for 3 days followed by 800 µg misoprostol.
• Mifepristone
Mifepristone priming before mTOP is the current standard of care. Women randomly assigned (1:1) to the Control arm will receive 200 mg mifepristone followed by 800 µg misoprostol 2 days later.

Locations

Country	Name	City	State
Singapore	KK Women's and Children's Hospital	Singapore

Sponsors (1)

Lead Sponsor	Collaborator
KK Women's and Children's Hospital

Country where clinical trial is conducted

Singapore, 

References & Publications (25)

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Abubeker FA, Lavelanet A, Rodriguez MI, Kim C. Medical termination for pregnancy in early first trimester (</= 63 days) using combination of mifepristone and misoprostol or misoprostol alone: a systematic review. BMC Womens Health. 2020 Jul 7;20(1):142. doi: 10.1186/s12905-020-01003-8. — View Citation

Allen R, O'Brien BM. Uses of misoprostol in obstetrics and gynecology. Rev Obstet Gynecol. 2009 Summer;2(3):159-68. — View Citation

Behroozi-Lak T, Derakhshan-Aydenloo S, Broomand F. Evaluation of effect of letrozole prior to misoprostol in comparison with misoprostol alone in success rate of induced abortion. J Gynecol Obstet Hum Reprod. 2018 Mar;47(3):113-117. doi: 10.1016/j.jogoh.2017.11.002. Epub 2017 Nov 6. — View Citation

Blum J, Raghavan S, Dabash R, Ngoc Nt, Chelli H, Hajri S, Conkling K, Winikoff B. Comparison of misoprostol-only and combined mifepristone-misoprostol regimens for home-based early medical abortion in Tunisia and Vietnam. Int J Gynaecol Obstet. 2012 Aug;118(2):166-71. doi: 10.1016/j.ijgo.2012.03.039. Epub 2012 Jun 8. — View Citation

Chai J, Ho PC. A pilot study on the combined use of letrozole, mifepristone and misoprostol in termination of first trimester pregnancy up to 9 weeks' gestation. Eur J Obstet Gynecol Reprod Biol. 2013 Dec;171(2):291-4. doi: 10.1016/j.ejogrb.2013.09.017. Epub 2013 Sep 25. — View Citation

Chawdhary R, Rana A, Pradhan N. Mifepristone plus vaginal misoprostol vs vaginal misoprostol alone for medical abortion in gestation 63 days or less in Nepalese women: a quasi-randomized controlled trial. J Obstet Gynaecol Res. 2009 Feb;35(1):78-85. doi: 10.1111/j.1447-0756.2008.00864.x. — View Citation

Creinin MD, Shore E, Balasubramanian S, Harwood B. The true cost differential between mifepristone and misoprostol and misoprostol-alone regimens for medical abortion. Contraception. 2005 Jan;71(1):26-30. doi: 10.1016/j.contraception.2004.07.011. — View Citation

Dahiya K, Ahuja K, Dhingra A, Duhan N, Nanda S. Efficacy and safety of mifepristone and buccal misoprostol versus buccal misoprostol alone for medical abortion. Arch Gynecol Obstet. 2012 Apr;285(4):1055-8. doi: 10.1007/s00404-011-2110-8. Epub 2011 Oct 19. — View Citation

Fekih M, Fathallah K, Ben Regaya L, Bouguizane S, Chaieb A, Bibi M, Khairi H. Sublingual misoprostol for first trimester termination of pregnancy. Int J Gynaecol Obstet. 2010 Apr;109(1):67-70. doi: 10.1016/j.ijgo.2009.11.008. Epub 2010 Jan 6. — View Citation

Jain JK, Dutton C, Harwood B, Meckstroth KR, Mishell DR Jr. A prospective randomized, double-blinded, placebo-controlled trial comparing mifepristone and vaginal misoprostol to vaginal misoprostol alone for elective termination of early pregnancy. Hum Reprod. 2002 Jun;17(6):1477-82. doi: 10.1093/humrep/17.6.1477. — View Citation

Lee VC, Gao J, Lee KF, Ng EH, Yeung WS, Ho PC. The effect of letrozole with misoprostol for medical termination of pregnancy on the expression of steroid receptors in the placenta. Hum Reprod. 2013 Nov;28(11):2912-9. doi: 10.1093/humrep/det345. Epub 2013 Aug 26. — View Citation

Lee VC, Tang OS, Ng EH, Yeung WS, Ho PC. A pilot study on the use of letrozole with either misoprostol or mifepristone for termination of pregnancy up to 63 days. Contraception. 2011 Jan;83(1):62-7. doi: 10.1016/j.contraception.2010.05.014. Epub 2010 Jun 23. — View Citation

Lee VC, Yeung TW, Tang OS, Ng EH, Yeung WS, Ho PC. Effect of letrozole on uterine artery Doppler flow indices prior to first-trimester termination of pregnancy: a randomized controlled trial. Ultrasound Obstet Gynecol. 2012 Oct;40(4):392-7. doi: 10.1002/uog.11115. — View Citation

Lee VCY, Ng EHY, Yeung WSB, Ho PC. Misoprostol with or without letrozole pretreatment for termination of pregnancy: a randomized controlled trial. Obstet Gynecol. 2011 Feb;117(2 Pt 1):317-323. doi: 10.1097/AOG.0b013e3182073fbf. — View Citation

Medical management of abortion. Geneva: World Health Organization; 2018. Available from http://www.ncbi.nlm.nih.gov/books/NBK536779/ — View Citation

Naghshineh E, Allame Z, Farhat F. The effectiveness of using misoprostol with and without letrozole for successful medical abortion: A randomized placebo-controlled clinical trial. J Res Med Sci. 2015 Jun;20(6):585-9. doi: 10.4103/1735-1995.165964. — View Citation

Nash CM, Philp L, Shah P, Murphy KE. Letrozole pretreatment prior to medical termination of pregnancy: a systematic review. Contraception. 2018 Jun;97(6):504-509. doi: 10.1016/j.contraception.2017.11.003. Epub 2017 Nov 14. — View Citation

Ngoc NT, Blum J, Raghavan S, Nga NT, Dabash R, Diop A, Winikoff B. Comparing two early medical abortion regimens: mifepristone+misoprostol vs. misoprostol alone. Contraception. 2011 May;83(5):410-7. doi: 10.1016/j.contraception.2010.09.002. Epub 2010 Oct 18. — View Citation

Rezai Z, Heydari Bazardehi S S, Ghasemi Nezhad A, Sadeghi A S, Ghorbani Yekta B. (2014). Letrozole and misoprostol versus misoprostol alone for termination of pregnancy: a randomized clinical trial. Tehran Univ Med J, 71 (11), 700-706

Sedgh G, Bearak J, Singh S, Bankole A, Popinchalk A, Ganatra B, Rossier C, Gerdts C, Tuncalp O, Johnson BR Jr, Johnston HB, Alkema L. Abortion incidence between 1990 and 2014: global, regional, and subregional levels and trends. Lancet. 2016 Jul 16;388(10041):258-67. doi: 10.1016/S0140-6736(16)30380-4. Epub 2016 May 11. — View Citation

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Yeung TW, Lee VC, Ng EH, Ho PC. A pilot study on the use of a 7-day course of letrozole followed by misoprostol for the termination of early pregnancy up to 63 days. Contraception. 2012 Dec;86(6):763-9. doi: 10.1016/j.contraception.2012.05.009. Epub 2012 Jun 18. — View Citation

Yung SSF, Lee VCY, Chiu PCN, Li HWR, Ng EHY, Yeung WSB, Ho PC. The effect of 7 days of letrozole pretreatment combined with misoprostol on the expression of progesterone receptor and apoptotic factors of placental and decidual tissues from first-trimester abortion: a randomized controlled trial. Contraception. 2016 Apr;93(4):323-330. doi: 10.1016/j.contraception.2015.12.005. Epub 2015 Dec 19. — View Citation

Zhuo Y, Cainuo S, Chen Y, Sun B. The efficacy of letrozole supplementation for medical abortion: a meta-analysis of randomized controlled trials. J Matern Fetal Neonatal Med. 2021 May;34(9):1501-1507. doi: 10.1080/14767058.2019.1638899. Epub 2019 Jul 29. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of complete abortion by Day 21-28	Rate of complete abortion by Day 21-28 (defined as no further intervention required e.g. medical or surgical treatment for retained products of conception)	Day 21-28 of study procedure
Secondary	Number of patients who require surgical evacuation of uterus for retained product of conception (POC)		Day 1-28 of study procedure
Secondary	Number of patients who require repeated medical therapy for retained product of conception (POC)		Day 1-28 of study procedure, After Day 28 of study procedure
Secondary	Number of doses of misoprostol administered for expulsion of product of conception (POC)		Day 3-4 of study procedure
Secondary	Time interval between administration of first dose of misoprostol and expulsion of product of conception (POC)		Day 3-4 of study procedure
Secondary	Number of patients who need blood transfusion		Day 1-28 of study procedure, After Day 28 of study procedure
Secondary	Number of patients who require analgesia according to the analgesic ladder		Day 1-4 of study procedure
Secondary	Number of patients who experience minor side effects including pain, bleeding, fever, vomiting and diarrhoea		Day 1-28 of study procedure, After Day 28 of study procedure
Secondary	Length of hospital stay		Day 1-28 of study procedure, After Day 28 of study procedure
Secondary	Number of patients who require unscheduled emergency department visit or hospital admission		Day 1-28 of study procedure, After Day 28 of study procedure
Secondary	Number of patients who develop severe allergic reactions		Day 1-28 of study procedure, After Day 28 of study procedure
Secondary	Number of adverse events reported		Day 1-28 of study procedure, After Day 28 of study procedure