AMETHYST: A multicentre, double-blind, placebo-controlled randomised trial comparing a combination of mifepristone and methotrexate versus methotrexate and placebo as a medical treatment for tubal ectopic pregnancy
Ectopic pregnancy
Randomisation to AMETHYST takes place after fully informed consent is received by a locally delegated member of staff. Randomisation is double blinded, computer-generated randomisation in a 1:1 ratio to mifepristone or placebo, minimised on centre, baseline hCG levels and ectopic size. The intervention is 600 mg mifepristone when used alongside standard medical treatment for tubal ectopic pregnancy (methotrexate) compared to placebo when used alongside standard medical treatment for tubal ectopic pregnancy (methotrexate). For the purposes of the study, methotrexate is defined as the non-investigational medicinal product (NIMP). Participants will take a single dose of 600 mg mifepristone (or identical placebo), with no dose adjustment. The dose will be taken orally as three individual capsules. The mifepristone and placebo will be administered by clinical staff (doctors, nurses or midwives), ideally within the same appointment that the methotrexate is administered, or as soon as possible on the same day (within 12 hours maximum). All participants will be followed up for 12 weeks (post IMP/ Placebo administration). The trial follow-up is at days 1, 4, 7, 11 and thereafter weekly (up to 12 weeks) until hCG levels drop to non-pregnant levels. This mirrors Standard of Care, where women are asked to attend for these routine follow-up visits to monitor the success of methotrexate and identify the need for any further treatment. Patient acceptability and satisfaction will be assessed via questionnaire at 7 days and 12 weeks after randomisation. The 12-week questionnaire will also ask about return of menstrual cycle since the ectopic pregnancy.
1. Women aged 16 years and older 2. Ultrasound diagnosis of likely tubal ectopic pregnancy defined as extrauterine gestational sac with yolk sac and/or embryo, without cardiac activity or extrauterine sac-like structure or inhomogeneous adnexal mass with no evidence of normally sited intrauterine pregnancy on ultrasound scan; includes interstitial ectopic pregnancy within diagnosis of tubal ectopic pregnancy 3. Minimum of two hCG measurements, taken at least two days apart, with a plateau or suboptimal rising pattern according to clinical judgment 4. Deemed suitable by clinical team for methotrexate treatment 5. Where the woman wishes to opt for methotrexate treatment 6. Methotrexate treatment planned to be administered within 24 hours of decision to proceed with methotrexate treatment 7. A pre-treatment serum hCG of 1000 to 5000 IU/L* 8. Where an individual woman’s initial pre-treatment serum hCG level(s) is 8.1. Clinically stable (Early Warning Score as per local policy of no more than 2) 8.2. Haemoglobin at baseline between 100 and 165 g/L 8.3. Able to attend outpatient follow up as per local clinical protocol for methotrexate treatment *hCG testing is a routine part of standard of care and diagnostic process in confirming an ectopic pregnancy. Sites will take pre-treatment hCG as per their usual clinical process and this result will be recorded for the purposes of the trial. The most recent hCG will be used as the baseline hCG for analysis purposes, but we will also ask sites to provide all pre-treatment hCGs to the study team in the baseline CRF so that the trajectory of pre-treatment hCGs can also be analysed alongside post-treatment results. None of the hCG blood tests are required specifically for the purposes of the trial – we will collect only results taken as part of standard of care, but for eligibility purposes pre-treatment levels of 1000-5000 IU/L are mandated. This is to avoid recruitment of women whose ectopic pregnancy may already be resolving
1. Evidence of normally sited (intrauterine) pregnancy 2. Breastfeeding 3. Immediate pre-treatment hCG 4. Women with any hCG measurement >5000 IU/L 5. Women eligible for and opt for expectant management 6. Clinically unstable (any component of Early Warning Score of 3 or more) 7. Women with a pregnancy of unknown location 8. Women with uterine ectopic pregnancy (such as caesarean scar or intramural) 9. Women with non-tubal extrauterine ectopic pregnancy (such as abdominal or ovarian ectopic pregnancy) 10. Women with heterotopic pregnancy 11. Women with ectopic pregnancy mass on ultrasound of greater than or equal to 3.5cm (see ESHRE guidelines on how to measure ectopic pregnancy mass) 12. Women with ectopic pregnancy mass with visible fetal pole heart pulsation [live ectopic pregnancy] 13. Evidence of ruptured ectopic pregnancy including evidence of significant free fluid on ultrasound (see ESHRE guidelines), or severe abdominal pain or where clinician deems unsuitable for medical management 14. Significantly abnormal liver/ renal/ haematological indices** including pre-existing blood dyscrasia as per usual clinical care in deciding if appropriate to offer methotrexate as per local policies 15. Active pulmonary disease 16. Severe, acute or chronic infections and immunodeficiency syndrome 17. Inherited porphyria 18. Significant gastrointestinal medical illnesses including chronic liver disease and gastric/peptic ulcer disease as per usual clinical care in deciding if appropriate to offer methotrexate as per local policies 19. Known allergy to methotrexate (the NIMP) or mifepristone (IMP) 20. Adrenal insufficiency 21. Known serious conditions being treated with systemic corticosteroids 22. Severe uncontrolled asthma 23. Women lacking capacity to consent 24. Participating in any active intervention phase or other clinical trial of an investigational medicinal product 25. Any contraindication for mifepristone treatment (excluding tubal ectopic pregnancy) or methotrex