Letrozole in Tubal Ectopic Pregnancy

Randomized Controlled Trial on Use of Letrozole in the Medical Management of Tubal Ectopic Pregnancies

This is a multi-centred randomized controlled trial on the addition of letrozole in the medical management of tubal ectopic pregnancies.

Tubal ectopic pregnancies are abnormal pregnancies in the Fallopian tube, rather than in the womb. They occurred in around 1-2% of all pregnancies. Methotrexate (MTX) given by the intramuscular route i.e. systemic, a commonly used drug for cancer , was a widely used alternative for management for unruptured tubal ectopic pregnancies and was recommended as first line treatment for selected women.

Letrozole, aromatase inhibitor, can suppose oestradiol level. Combination of letrozole with misprostol has shown to improve the complete abortion rate in miscarriage. As a result, addition of letrozole may cause a higher success rate in the medical treatment of ectopic pregnancy.

As the evidence of combination of MTX and letrozole in tubal ectopic pregnancies is not available, the objective of the present study is to evaluate the efficacy of combination of MTX and letrozole compared to MTX alone in women with tubal ectopic pregnancies.

Study Overview

• Status: Recruiting
• Conditions: Tubal Pregnancy
• Intervention / Treatment: Drug: Letrozole tablets; Other: Placebos

Detailed Description

Tubal ectopic pregnancies occur in around 1-2% of all pregnancies. Traditionally, surgery with salpingectomy was the mainstay of treatment; however, it comes with anaesthetic and operatives risks in addition to an increased cost for operative procedures. In recent years, systemic methotrexate (MTX), a dihydrofolate reductase inhibitor, has been a widely used alternative for management for unruptured tubal ectopic pregnancies. The success rate of systemic MTX at a doses of 50mg/m2 body surface area is around 70% which ranges from 65 to 95%, depending greatly on the level of human chorionic gonadotrophin (hCG), the size of adnexal mass and presence of fetal heart pulsation.

Use of systemic MTX as the first-line management has been proposed for women with unruptured ectopic pregnancy where the adnexal mass is smaller than 35mm, serum hCG level is less than 5000 IU/l and fetal heartbeat is absent.

Letrozole is a third generation non-steroidal reversible aromatase inhibitor. It can suppress oestradiol level up to 95% to 99% after administration according to pharmacodynamics and pharmacokinetics studies. Oestrogen is important in the support of early pregnancy, other than progesterone with well-known pivotal effect on the maintenance of early pregnancy.

Animal studies showed the combination of mifepristone and letrozole worked synergistically and induced almost 100% termination of pregnancies in rats. Letrozole induced 50% miscarriage rate in pregnant baboons. Letrozole combined with vaginal misoprostol regimen was associated with a higher complete abortion rate than misoprostol alone in pregnancies up to 63 days.

The use of letrozole in ectopic pregnancy has never been explored. It is hypothesized that letrozole can suppress serum oestradiol level, which in turn, may cause failure of pregnancy in ectopic pregnancy. The aim of this study is to investigate the clinical effectiveness of letrozole in addition to MTX in the medical treatment of ectopic pregnancy.

• Study Type: Interventional
• Enrollment (Anticipated): 214
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Evelyn Wong, MBBS; Phone Number: 22554517; Email: evelynwong.ew@gmail.com

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • Department of Obstetrics and Gynaecology, Queen Mary Hospital
    • Contact: Karen Chan, Prof; Phone Number: 22554647; Email: kklchan@hku.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 48 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Presence of heterogenous adnexal mass on USG suggestive of tubal ectopic pregnancy with hCG level >=1500 IU/L and <= 5000 IU/L
• Absence of fetal heart pulsation
• Mean diameter of adnexal mass <= 3.5cm
• Haemodynamically stable
• No significant abdominal pain

Exclusion Criteria:

• Presence of significant amount of free fluid in pelvis
• Allergic to MTX
• Deranged liver function test (AST/ ALT or GGT >= 2 upper limit of normal)
• Deranged renal function test (eGFR <= 45ml/min)
• Heterotopic pregnancies

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
Experimental: Letrozole; Participants will be given letrozole 10mg daily for one week after standard medical management for tubal ectopic pregnancy by methotrexate injection. Subsequently they will receive the standard management for medical management of tubal ectopic prengnacies.	Drug: Letrozole tablets; Letrozole 10mg daily for one week.; Other Names: Letrozole
Placebo Comparator: Placebo; Participants will be given identical looking placebo for one week and receive the same standard management for medical management of tubal ectopic pregnancies.	Other: Placebos; Placebo 4 tablets a day for one week.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment success	Proportion of women with treatment success defined as normalization of serum hCG level <10IU/L without additional medical or surgical intervention	2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
hCG normalization duration	Duration of time until hCG normalization measured in days	2 months
Number of participants experienced side effects	Side effects after letrozole	2 months
Duration of hospitalization	Duration of hospitalization	2 months
Participant satisfaction: proportion of women who would recommend this treatment to a friend	Treatment satisfaction measured as proportion of women who would recommend this treatment to a friend	2 months

Collaborators and Investigators

• Sponsor: Queen Mary Hospital, Hong Kong
• Collaborators: Queen Elizabeth Hospital, Hong Kong; Prince of Wales Hospital, Shatin, Hong Kong; Kwong Wah Hospital; Pamela Youde Nethersole Eastern Hospital, Hong Kong; Princess Margaret Hospital, Hong Kong
• Investigators: Study Director: Ernest H.Y. Ng, MD, The University of Hong Kong

Publications and helpful links

General Publications

• Shi L, Shi SQ, Given RL, von Hertzen H, Garfield RE. Synergistic effects of antiprogestins and iNOS or aromatase inhibitors on establishment and maintenance of pregnancy. Steroids. 2003 Nov;68(10-13):1077-84. doi: 10.1016/j.steroids.2003.09.002.
• 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.
• 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.
• Panelli DM, Phillips CH, Brady PC. Incidence, diagnosis and management of tubal and nontubal ectopic pregnancies: a review. Fertil Res Pract. 2015 Oct 15;1:15. doi: 10.1186/s40738-015-0008-z. eCollection 2015.
• Diagnosis and Management of Ectopic Pregnancy: Green-top Guideline No. 21. BJOG. 2016 Dec;123(13):e15-e55. doi: 10.1111/1471-0528.14189. Epub 2016 Nov 3. No abstract available. Erratum In: BJOG. 2017 Dec;124(13):e314.
• Odejinmi F, Huff KO, Oliver R. Individualisation of intervention for tubal ectopic pregnancy: historical perspectives and the modern evidence based management of ectopic pregnancy. Eur J Obstet Gynecol Reprod Biol. 2017 Mar;210:69-75. doi: 10.1016/j.ejogrb.2016.10.037. Epub 2016 Oct 29.
• Albrecht ED, Aberdeen GW, Pepe GJ. The role of estrogen in the maintenance of primate pregnancy. Am J Obstet Gynecol. 2000 Feb;182(2):432-8. doi: 10.1016/s0002-9378(00)70235-3.
• National Collaborating Centre for Ws, Children's H. National Institute for Health and Clinical Excellence: Guidance. Ectopic Pregnancy and Miscarriage: Diagnosis and Initial Management in Early Pregnancy of Ectopic Pregnancy and Miscarriage. London: Rcog National Collaborating Centre for Women's and Children's Health.; 2012.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Anticipated): December 30, 2024
• Study Completion (Anticipated): March 31, 2025

Study Registration Dates

• First Submitted: April 7, 2020
• First Submitted That Met QC Criteria: April 9, 2020
• First Posted (Actual): April 10, 2020

Study Record Updates

• Last Update Posted (Actual): April 10, 2023
• Last Update Submitted That Met QC Criteria: April 6, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Methotrexate; Letrozole; Tubal ectopic pregnancy
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Pregnancy Complications; Pregnancy, Ectopic; Cardiac Complexes, Premature; Pregnancy, Tubal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: UW 20-005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Other researchers may contact the chief investigator for the request of individual participant data.

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