Ectopic pregnancy Pregnancy and Childbirth
Conditions
Interventions
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
Sponsors
University of Aberdeen
Eligibility
Sex/Gender
Female
Age
16 Years to 100 Years
Inclusion criteria
Inclusion criteria: 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 i.e. sequentially reducing low level hCGs where NICE guidance suggests expectant management can be offered. This is vital in an efficacy trial to ensure women with ectopic pregnancies where methotrexate is appropriate in line with NICE guidance is offered.
Exclusion criteria
Exclusion criteria: 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 methotrexate treatment that is listed in the relevant SmPC 26. Women taking strong CYP3A4 inhibitors or strong CYP3A4 inducers such as those listed in the British National Formulary (BNF: https://bnf.nice.org.uk/interactions/mifepristone/) **It is standard care to obtain full blood count, liver function tests and renal function (often known as urea and electrolytes) prior to methotrexate treatment (the NIMP). These are not required before clinical treatment with mifepristone. Because all trial participants will receive the NIMP as part of standard of care this is included as an exclusion criteria. It is acceptable to use a sample taken per standard of care for this purpose within the last 4 weeks.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Rate of surgery to treat tubal ectopic pregnancy (removal of Fallopian tube [salpingectomy]/incision of Fallopian tube to remove ectopic pregnancy (salpingostomy) by laparoscopy/laparotomy) measured using patient records at 12 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Second dose (injection) of methotrexate required measured using patient records within 12 weeks 2. Number of days to resolution of tubal ectopic pregnancy (return of hCG to <15IU/l, i.e. non pregnant levels) from treatment start to 12 weeks measured using patient records 3. The number of hospital visits related to their ectopic pregnancy/ treatment (until resolution of ectopic pregnancy to <15IU/l, or surgery to treat their tubal ectopic pregnancy or end of 12 week follow up period) measured using patient records 4. Safety (measured by recorded Serious Adverse Events, Serious Adverse Reactions and Suspected Unexpected Serious Adverse Reactions as classified and reported by the clinical team) up to 12 weeks 5. Patient acceptability and satisfaction measured by patient questionnaire at 7 days and 12 weeks 6. Return of menstrual cycle by 12 weeks (end of study period) measured by patient questionnaire Mechanistic outcomes: 7. Serum progesterone and hCG levels (baseline and post-treatment) including trajectory and rate of decline to non-pregnant levels (measured via standard care blood sample) t baseline and 12 weeks | — |
Countries
United Kingdom
Contacts
Public ContactClaire Cochran
Outcome results
None listed