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

Sponsor

KK Women's and Children's Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05341817

Collaborator

(none)

144

Enrollment

Location

Arms

Anticipated Duration (Months)

8.5

Patients Per Site Per Month

Study Details

Study Description

Brief 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:

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

Condition or Disease	Intervention/Treatment	Phase
Abortion in First Trimester	Drug: Letrozole Drug: Mifepristone	Phase 4

Detailed 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

144 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Care Provider)

Masking Description:

The treatment doctor during the Day 21-28 follow-up visit will be blinded to the treatment allocation of the study participant.

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jun 1, 2022

Anticipated Primary Completion Date :

Aug 1, 2023

Anticipated Study Completion Date :

Nov 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Letrozole Day 1: Oral letrozole 10mg under direct observation therapy (DOT) in the clinic Day 2: Oral letrozole 10mg to self-administer at home Day 3: Oral letrozole 10mg to self-administer at home or at the hospital. Vaginal misoprostol 800mcg given in the ward, followed by vaginal misoprostol 400mcg, approximately 4 hours later, if subject showed no signs of abortion	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.
Active Comparator: Control Day 1: Oral mifepristone 200mg (control) under direct observation therapy (DOT) in clinic Day 2: NIL medication to be self-administered at home Day 3: NIL medication to be self-administered at home. Vaginal misoprostol 800mcg given in the ward, followed by vaginal misoprostol 400mcg, approximately 4 hours later, if subject showed no signs of abortion	Drug: 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.

Arm

Intervention/Treatment

Experimental: Letrozole

Day 1: Oral letrozole 10mg under direct observation therapy (DOT) in the clinic Day 2: Oral letrozole 10mg to self-administer at home Day 3: Oral letrozole 10mg to self-administer at home or at the hospital. Vaginal misoprostol 800mcg given in the ward, followed by vaginal misoprostol 400mcg, approximately 4 hours later, if subject showed no signs of abortion

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.

Active Comparator: Control

Day 1: Oral mifepristone 200mg (control) under direct observation therapy (DOT) in clinic Day 2: NIL medication to be self-administered at home Day 3: NIL medication to be self-administered at home. Vaginal misoprostol 800mcg given in the ward, followed by vaginal misoprostol 400mcg, approximately 4 hours later, if subject showed no signs of abortion

Drug: 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.

Outcome Measures

Primary Outcome Measures

Rate of complete abortion by Day 21-28 [Day 21-28 of study procedure]
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)

Secondary Outcome Measures

Number of patients who require surgical evacuation of uterus for retained product of conception (POC) [Day 1-28 of study procedure]
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]
Number of doses of misoprostol administered for expulsion of product of conception (POC) [Day 3-4 of study procedure]
Time interval between administration of first dose of misoprostol and expulsion of product of conception (POC) [Day 3-4 of study procedure]
Number of patients who need blood transfusion [Day 1-28 of study procedure, After Day 28 of study procedure]
Number of patients who require analgesia according to the analgesic ladder [Day 1-4 of study procedure]
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]
Length of hospital stay [Day 1-28 of study procedure, After Day 28 of study procedure]
Number of patients who require unscheduled emergency department visit or hospital admission [Day 1-28 of study procedure, After Day 28 of study procedure]
Number of patients who develop severe allergic reactions [Day 1-28 of study procedure, After Day 28 of study procedure]
Any other adverse events [Day 1-28 of study procedure, After Day 28 of study procedure]

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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