Letrozole Versus Mifepristone and Misoprostol in Silent Miscarriage

A Randomized Double-blind Placebo-controlled Trial Comparing Letrozole Versus Mifepristone As Pre-treatment Before Medical Management of First Trimester Silent Miscarriage Using Misoprostol

Management of first trimester silent miscarriage can be by expectant, medical or surgical management. Surgical management by suction evacuation is associated with surgical risks (including risks to the womb that can affect further pregnancy), anaesthetic risks and hospital stay. Medical management of first trimester silent miscarriage using misoprostol is another common option that can reduce the risk of bleeding and those associated with surgery. However, the current standard management of using misoprostol for the management of first trimester miscarriage only has a success rate of 70-80%, which is suboptimal.

Recent large studies have shown that adding mifepristone pre-treatment before misoprostol in the management of silent miscarriage can improve the success rates of complete miscarriage after medical management. There are 2 problems with mifepristone. Firstly, it is not widely available in many countries for cultural and religious reasons because it is labelled as an 'abortifacient'. Secondly, it is expensive. One tablet of Mifepristone costs $500 HK dollars. There is a need to look for an alternative to mifepristone.

Letrozole is an aromatase inhibitor which can reduce estrogen levels. Some studies have shown that it can improve the success rate of medical management of silent miscarriage and termination of pregnancy. It is safe, more widely available and cheaper than mifepristone.

This is a randomized double blinded trial comparing the use of mifepristone versus letrozole as pre-treatment in the medical management of first trimester silent miscarriage using misoprostol.

Study Overview

• Status: Not yet recruiting
• Conditions: Silent Miscarriage
• Intervention / Treatment: Drug: Letrozole; Drug: Mifepristone

Detailed Description

This is a randomized double blinded trial comparing the use of mifepristone versus letrozole as pre-treatment in the medical management of first trimester silent miscarriage using misoprostol.

Both groups will receive misoprostol (which is the standard management for medical management of silent miscarriage locally), but they will be randomized to either adding mifepristone or letrozole as pre-treatment. Mifepristone is usually taken once 2 days before misoprostol, whereas letrozole is taken 10mg daily for 3 days before misoprostol. Placebo of letrozole and mifepristone will be given to maintain double blindness of the groups.

• Study Type: Interventional
• Enrollment (Estimated): 884
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jennifer Ko; Phone Number: 22554647; Email: jenko@hku.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosed with silent miscarriage <= 12 weeks of gestation by ultrasonography
• Single intrauterine gestational sac
• No heavy per-vaginal bleeding
• No severe abdominal pain
• No features of intrauterine infection
• Able to understand the proposed research and able to comply with instructions
• Having given voluntary written informed consent

Exclusion Criteria:

• Known allergy to mifepristone, misoprostol or letrozole
• On drugs with potential drug interactions with mifepristone e.g. aspirin, clopidogrel, anti-coagulants etc.
• Suspected ectopic or molar pregnancy or multiple pregnancy
• Distorted uterine cavity by uterine septum or submucosal fibroids
• Presence of intrauterine contraceptive device
• History of bleeding tendencies e.g. haemorrhagic diseases, current anti-coagulant treatment
• Previous history of retained products of gestation/ failed medical management of miscarriage
• Opt for expectant or surgical management of miscarriage

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Letrozole; Letrozole 10mg per day from day 1-3 orally, placebo mifepristone Sublingual misoprostol 800 microgram on day 3	Drug: Letrozole; Letrozole pre-treatment in addition to misoprostol as medical management for silent miscarriage
Active Comparator: Mifepristone; Mifepristone 200mg orally on day 1, placebo letrozole on day 1-3 Sublingual misoprostol 800 microgram on day 3	Drug: Mifepristone; Mifepristone pre-treatment in addition to misoprostol as medical management for silent miscarriage; Other Names: Mifepristone, RU486

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational sac expulsion	Gestational sac expulsion by the first follow up visit after 2 weeks of misoprostol administration and no additional surgical or medical intervention within 30 days after randomization	2 weeks, 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time of tissue expulsion	Time of tissue expulsion	6 weeks
Return of normal menses	Return of normal menses without additional intervention	6 weeks
Requirement of repeated intervention	Requirement of repeated intervention including repeated course of medical treatment or surgery	6 weeks
Unplanned re-admission	Number of unplanned re-admission	6 weeks
Analgesics	Use of analgesics	6 weeks
Side effects	Vomiting	6 weeks
Side effects	Nausea	6 weeks
Side effects	Fever	6 weeks
Side effects	Diarrhoea	6 weeks
Side effects	Abdominal pain on a visual analog scale	6 weeks
Vaginal bleeding	Duration and amount of vaginal bleeding	6 weeks
Complications	Including severe vaginal bleeding requiring transfusion, infection	6 weeks
Return of menstruation	Timing of return of menses	6 weeks
Women's satisfaction	Client satisfaction questionnaire	6 weeks
Women's satisfaction	EQ-5D-5L questionnaire	6 weeks

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Collaborators: Queen Mary Hospital, Hong Kong; Princess Margaret Hospital, Canada; Kwong Wah Hospital; Pamela Youde Nethersole Eastern Hospital
• Investigators: Principal Investigator: Jennifer Ko, The University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Estimated): December 6, 2024
• Primary Completion (Estimated): December 5, 2027
• Study Completion (Estimated): June 5, 2028

Study Registration Dates

• First Submitted: December 6, 2024
• First Submitted That Met QC Criteria: December 9, 2024
• First Posted (Estimated): December 13, 2024

Study Record Updates

• Last Update Posted (Estimated): December 13, 2024
• Last Update Submitted That Met QC Criteria: December 9, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: mifepristone; misoprostol; letrozole; silent miscarriage
• Additional Relevant MeSH Terms: Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Pregnancy Complications; Abortion, Spontaneous; Abortion, Missed; Contraceptive Agents, Hormonal; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Abortifacient Agents; Reproductive Control Agents; Steroid Synthesis Inhibitors; Hormone Antagonists; Estrogen Antagonists; Aromatase Inhibitors; Luteolytic Agents; Contraceptive Agents, Female; Contraceptive Agents; Contraceptives, Oral; Contraceptives, Oral, Synthetic; Abortifacient Agents, Steroidal; Contraceptives, Postcoital, Synthetic; Contraceptives, Postcoital; Menstruation-Inducing Agents; Letrozole; Mifepristone
• Other Study ID Numbers: UW22-530

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No plan at the current moment

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No