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

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.

• Number of patients who require surgical evacuation of uterus for retained product of conception (POC) [Срок оценки: Day 1-28 of study procedure]
• Number of patients who require repeated medical therapy for retained product of conception (POC) [Срок оценки: Day 1-28 of study procedure, After Day 28 of study procedure]
• Number of doses of misoprostol administered for expulsion of product of conception (POC) [Срок оценки: Day 3-4 of study procedure]
• Time interval between administration of first dose of misoprostol and expulsion of product of conception (POC) [Срок оценки: Day 3-4 of study procedure]
• Number of patients who need blood transfusion [Срок оценки: Day 1-28 of study procedure, After Day 28 of study procedure]
• Number of patients who require analgesia according to the analgesic ladder [Срок оценки: Day 1-4 of study procedure]
• Number of patients who experience minor side effects including pain, bleeding, fever, vomiting and diarrhoea [Срок оценки: Day 1-28 of study procedure, After Day 28 of study procedure]
• Length of hospital stay [Срок оценки: Day 1-28 of study procedure, After Day 28 of study procedure]
• Number of patients who require unscheduled emergency department visit or hospital admission [Срок оценки: Day 1-28 of study procedure, After Day 28 of study procedure]
• Number of patients who develop severe allergic reactions [Срок оценки: Day 1-28 of study procedure, After Day 28 of study procedure]
• Number of adverse events reported [Срок оценки: Day 1-28 of study procedure, After Day 28 of study procedure]