Clinical trial NCT04341545: Letrozole in Tubal Ectopic Pregnancy
Official title: Randomized Controlled Trial on Use of Letrozole in the Medical Management of Tubal Ectopic Pregnancies
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Tubal Pregnancy
Keywords: Tubal ectopic pregnancy
Methotrexate
Letrozole
Lead sponsor: Queen Mary Hospital, Hong Kong
Sponsor class: OTHER
Collaborators: name: Kwong Wah Hospital
name: Princess Margaret Hospital, Hong Kong
name: Pamela Youde Nethersole Eastern Hospital, Hong Kong
name: Queen Elizabeth Hospital, Hong Kong
name: Prince of Wales Hospital, Shatin, Hong Kong
First posted: 2020-04-10
Enrollment: 214
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomized into either receive letrozole or placebo capsules.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Treatment success
timeFrame: 2 months
Secondary outcomes:
measure: hCG normalization duration
timeFrame: 2 months
measure: Number of participants experienced side effects
timeFrame: 2 months
measure: Duration of hospitalization
timeFrame: 2 months
measure: Participant satisfaction: proportion of women who would recommend this treatment to a friend
timeFrame: 2 months
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Department of Obstetrics and Gynaecology, Queen Mary Hospital
Study officials:
affiliation: The University of Hong Kong
name: Ernest H.Y. Ng, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
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.
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.