A multi-centre, double-blind, placebo-controlled randomised trial comparing a combination of methotrexate and mifepristone versus methotrexate alone as a medical treatment for tubal ectopic pregnancy (Short title - AMETHYST Trial: Adding Mifepristone to mETHotrexate for ectopic pregnancY STudy)

BACKGROUND Ectopic pregnancy (EP) affects 1 in 90 pregnancies and is the leading cause of death in the first trimester of pregnancy. An EP is a pregnancy implanted in an abnormal location, usually within the Fallopian tube (tubal EP; tEP). As the EP grows, the Fallopian tube is at risk of rupture which can cause life-threatening internal bleeding. Historically, the only treatment was surgery to remove the affected Fallopian tube. More recently, advances in ultrasound and biochemical markers of pregnancy have enabled diagnosis at an earlier stage so medical or expectant management can be offered. NICE(NG126) endorses medical treatment with methotrexate (MTX), an antifolate drug. Although 40% of women with tEP are now treated medically, 15% need a second injection of MTX and 30% will require surgery to remove the EP. We propose that an antiprogesterone drug, mifepristone, could improve the efficacy of MTX treatment compared to MTX alone. Mifepristone is routinely used in the management of miscarriage and termination of pregnancy. Evidence suggests there could be a role for mifepristone in tEP but a definitive trial is needed. AIM To determine if the combination of mifepristone and MTX is more effective than MTX alone with placebo in reducing the need for surgical intervention in clinically stable women with tEP. We will explore how mifepristone affects the trajectory of key pregnancy hormones (progesterone and hCG) and whether any treatment effect is moderated and/or mediated by the woman’s own baseline levels of pregnancy hormones. METHODS - DESIGN: Multicentre, double blind, placebo-controlled randomised controlled trial POPULATION: Clinically stable women aged 16 years and over with tEP and hCG level of 1000-5000 IU/L who have opted for standard medical treatment with single dose intramuscular methotrexate (50mg/m2) INTERVENTION: 600mg mifepristone (3 tablets taken once) COMPARATOR Matched placebo (3 tablets taken once) ASSESSMENT: Assessments will follow a protocol mirroring usual clinical care. Assessment of clinical suitability and hCG and progesterone levels in maternal serum at baseline, on days 1,4,7,11 and then weekly until hCG <15 IU/L (non-pregnant). Assessment of safety/tolerability by symptoms and examination. Assessment of acceptability by questionnaire on day 7. Menstrual cycle data by telephone questionnaire at 3 months. We will seek permission to log future fertility data PRIMARY CLINICAL OUTCOME: The need for surgical intervention for tEP SECONDARY CLINICAL OUTCOMES: The need for a second dose of MTX; time to non-pregnant hCG levels (days); number of treatment-associated hospital visits; safety/tolerability; patient acceptability SAMPLE SIZE: To detect a target difference of 15%, (absolute risk reduction from 30% to 15%) in the rate of surgical intervention with 90% power and alpha error 5% will require 161 participants per group, 328 in total allowing for 2% attrition rate. TIMELINES Approvals and set up Month (M) 1-9; Recruitment M10-33; Follow up M13-36; Analysis M37-45. ANTICIPATED IMPACT AND DISSEMINATION The results of this trial will impact clinical management and guidelines worldwide. If mifepristone is effective, this will lead to further research on its efficacy as a standalone treatment for EP and its potential use in resource poor settings. Findings will be disseminated in medical journals, conferences, via mainstream and social media planned in conjunction with PPI partners and third sector organisations.