Gefitinib and methotrexate to resolve tubal ectopic pregnancy: the GEM3 RCT

Article history

The research reported in this issue of the journal was funded by the EME programme as project number 14/150/03. The contractual start date was in April 2016. The final report began editorial review in May 2022 and was accepted for publication in September 2022. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The EME editors and production house have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report.

Copyright statement

Copyright © 2023 Moakes et al. This work was produced by Moakes et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2023 Moakes et al.

Clinical background

Ectopic pregnancies (EPs) occur when the embryo implants outside the endometrial cavity, most commonly in the fallopian tube. It complicates 1–2% of all pregnancies and is a life-threatening emergency because it can cause the tube to rupture, eliciting a catastrophic maternal haemorrhage. 1 EPs are a significant contributor to maternal morbidity and mortality in both the developed and developing world. 2,3

Around 98% of EPs occur in a fallopian tube. Risk factors incurring the highest odds of an EP are those associated with pre-existing tubal injury, such as a previous EP, tubal ligation, tubal pathology (often resulting from pelvic infections) and prior tubal surgery. 4,5 Other risk factors include conception via in vitro fertilisation, smoking and the presence of an intrauterine device in situ. 4,5

Because of the emergent nature of an EP, prompt management is required. In most cases, laparoscopic surgery is carried out to remove the pregnancy, ideally before it ruptures. Laparoscopic excision will often involve en bloc removal of the affected fallopian tube. Urgent surgical management is mandated when there are clinical or ultrasound suspicions that the ectopic implantation has ruptured and there is active bleeding. However, if the EP is stable and there is no evidence of bleeding, medical management may be considered (as detailed below).

Laparoscopic excision of EP can be carried out safely. However, there are some rare risks, such as injury to internal viscera during the operation and small risks associated with having a general anaesthetic. Furthermore, there are many regions in the world where surgery is not easily accessed. Hence, there is an important clinical role for effective medical options to treat EP.

Current medical management of ectopic pregnancies with methotrexate

First proposed in 1991,6 medical management with a single intramuscular (IM) injection of methotrexate (MTX) is a recognised treatment for women with tubal EP without signs of rupture. 7

Medical management centres on the use of the chemotherapeutic agent MTX. MTX is a folate antagonist and this induces cell death because folate is a necessary ingredient of DNA synthesis (a substrate for the nucleoside thymidine). 8 For decades, it has been long recognised that trophoblast tissue is very sensitive to MTX. Since the late 1950s it has been used to treat choriocarcinoma (placental tumours). 8

The MTX treatment protocol involves an initial IM injection of MTX (50 mg/m²), following which serum human chorionic gonadotrophin (hCG) levels (uniquely secreted from gestational tissues) are monitored until it drops to <15 international units/litre (IU/l), which indicates a non-pregnant state. 9 If the serum hCG is not falling appropriately, a second dose of MTX may be given.

Low-grade evidence on the resolution rate of MTX treatment for EP suggests it is around 70% effective. 10 Treatment failure carries around a 21% risk of requiring a second dose of MTX and the subsequent risk of emergency laparoscopic surgery (where there are inherent risks of damage to visceral organs and an impact on subsequent fertility). In addition, EPs with higher hCG levels (>1000 IU/l) at the start of treatment with MTX, take a significant length of time to resolve and require multiple outpatient monitoring visits. There is a need for more effective medical treatments for tubal EP to reduce the need for additional MTX, to reduce the need for emergency surgery and to reduce the time to resolution associated with MTX management.

Gefitinib as a possible new treatment for ectopic pregnancies

Over the past decade we have generated preclinical11 evidence, and data from small clinical trials12–15 suggesting adding oral gefitinib to IM MTX may improve its effectiveness. 16

Gefitinib is an epidermal growth factor receptor (EGFR) inhibitor. 17,18 It could plausibly disrupt the ectopic implantation site, because placental tissue exhibits very high expression of EGFR and the developing placenta seems critically dependent on this cellular pathway for survival. 19–22

Gefitinib is used to treat non-small cell lung cancer where it is prescribed indefinitely after the primary cancer treatment. In 2004 postmarketing surveillance of 31,045 people exposed to gefitinib was reported to the Food and Drug Administration. 23 Common side effects include skin rash and diarrhoea. Gefitinib is associated with a rare but concerning side effect of interstitial lung disease (ILD) (0.3% incidence). However, it is possible that developing gefitinib-related ILD mainly happens when there is coexisting lung cancer. Also, the median time to developing related ILD is 42 days and major risk factors include being older than 55 and male sex. 23 Offering it to women who are younger (and unlikely to have lung cancer) and limiting the dose to 7 days would avoid all these risk factors. A short course of the drug is therefore likely to be very safe as a treatment option.

Trial design

The GEM3 trial was a placebo-controlled randomised, blinded, multicentre trial of a combination of MTX and gefitinib versus MTX and placebo as a treatment for EP. The trial had a favourable ethical opinion from Scotland A Research Ethics Committee (ref: 16/SS/0014).

Recruitment

GEM3 participants were recruited from early pregnancy units (EPU) in 50 of the 74 National Health Service (NHS) participating sites across the UK. Firstly, potential participants were referred to the local research teams by their attending clinician with their permission. All referred women were then approached by researchers who were trained in Good Clinical Practice and specifically in taking consent for this trial. Potential participants were provided with a Participant Information Sheet and given time to consider their involvement. All patients were told that participation in the trial was completely voluntary and that once recruited they could withdraw at any stage in the trial. Reassurance was given that participation or withdrawal would not affect their normal clinical care. If patients expressed an interest, written informed consent was sought and they were assessed for eligibility.

Eligibility criteria

Participants were assessed for eligibility by an appropriately trained doctor. The participants needed to meet the following criteria:

1. women aged between 18 and 50 years;

2. clinical decision made for treatment of tubal EP with MTX;

3. able to understand all information (written and oral) presented (using an interpreter if necessary) and provide signed consent;

4. diagnosis of either:

   1. definite tubal EP [extrauterine gestational sac with yolk sac and/or embryo, without cardiac activity on ultrasound scan (USS)];

   2. clinical decision of probable tubal EP [extrauterine sac-like structure of inhomogenous adnexal mass on USS with a background of suboptimal serum hCG concentrations (on at least 2 different days)];

5. pretreatment serum hCG level of 1000–5000 IU/l (within 1 calendar day of treatment);

6. clinically stable;

7. haemoglobin between 100 and 165 g/l within 1 calendar day of treatment;

8. able to comply with treatment and willing to participate in follow up. Participants could not be included if any of the following criteria were applicable:

   1. pregnancy of unknown location;

   2. evidence of intrauterine pregnancy;

   3. breastfeeding;

   4. hypersensitivity to gefitinib;

   5. EP mass on USS greater than 3.5 cm (mean dimensions);

   6. evidence of significant intra-abdominal bleed on USS, defined by echogenic free fluid above the uterine fundus or surrounding one ovary within 1 calendar day;

   7. significant abdominal pain, guarding/rigidity;

   8. clinically significant abnormal liver/renal/haematological indices within 3 calendar days of treatment;

   9. galactose intolerance;

   10. significant dermatological disease, for example, severe psoriasis/eczema;

   11. significant pulmonary disease, for example, severe/uncontrolled asthma;

   12. significant gastrointestinal illness, for example, Crohn’s disease/ulcerative colitis;

   13. participating in any other clinical trial of an investigational medicinal product (IMP);

   14. previous participation in GEM3;

   15. Japanese ethnicity, due to higher risk of ILD from use of gefitinib in this population.

Randomisation method and minimisation variables

Once final eligibility was confirmed and consent obtained, participants were randomised to GEM3 by the research staff at sites using a secure online randomisation service provided by the Birmingham Clinical Trials Unit. Participants were randomised in an equal (1:1) ratio to gefitinib or placebo and a bottle number was allocated. The bottle number was sent via email to the local Principal Investigator (PI), the trial pharmacist and the research nurse performing the randomisation. A ‘minimisation’ procedure, incorporating a random element, using a computer-based algorithm, was used to avoid chance imbalances in important prognostic variables. Strata used in the minimisation were as follows:

1. baseline hCG levels (<1500 IU/l, ≥1500 to 2500 IU/l, ≥2500 IU/l);

2. body mass index (BMI) (<25 kg/m², ≥25 kg/m²);

3. ectopic mass size (<2 cm, ≥2 cm);

4. recruiting centre.

Interventions

Treatment allocations

Participants were commenced on the trial intervention on the day they were randomised. They commenced on one tablet of 250 mg gefitinib or matched placebo each day for 7 days (or until resolution of EP if this occurred prior to 7 days).

Blinding

Participants, investigators, research nurses and other attending clinicians all remained blind to the trial drug allocation for the duration of their participation.

In case of any serious adverse event (SAE), the general recommendation was to initiate management and care of the participant as though the woman was taking gefitinib. Cases that were considered serious, unexpected and possibly, probably or definitely related to the trial intervention [suspected unexpected serious adverse reaction (SUSAR)], were unblinded as appropriate, if deemed necessary. In any other circumstances, participants, investigators and research nurses and midwives remained blind to drug allocation whilst the participant remained in the trial.

The trial statisticians were unblinded to the trial drug allocation following approval of the Statistical Analysis Plan (SAP) and after the database had been locked for analysis.

Trial appointments

Trial participants attended routine clinical care appointments as per their local Trust policy for the treatment of an EP. Most EPUs advised review on day 4, 7 and then weekly post randomisation. At each visit, adverse events (AEs), symptoms, extra visits to hospital, further doses of MTX and need for surgery were captured and recorded on the database.

Adherence monitoring

Adherence to treatment was assessed by both participant’s self-reported account of total number of tablets taken and clinician reported data on whether the MTX injection was given. We predefined adherence as participants who received their initial MTX injection and at least 75% of their allocated treatment (gefitinib or placebo) prior to resolution (up to a maximum of 7 daily doses if resolution had not occurred by 7 days post randomisation). Women who were considered adherent as per this definition comprised the per-protocol cohort.

Co-enrolment

Participants were not permitted to participate in other IMP trials but were permitted to take part in non-IMP (e.g. questionnaire/tissue collection) studies.

Participant withdrawal

A participant was considered for withdrawal from the trial treatment if, in the opinion of the investigator or the care providing clinician or clinical team, it was medically necessary to do so. Participants could also voluntarily withdraw from treatment at any time, however, women were encouraged to continue follow-up following withdrawal from trial treatment to minimise attrition bias.

Participants could voluntarily withdraw their consent to study participation at any time. If a participant did not return for a scheduled visit, attempts were made to contact her and where possible, review adherence and safety data. Reasons for withdrawal were captured where possible. If a participant explicitly withdrew consent to have any further data recorded their decision was respected and recorded on the electronic data capture system. All communication surrounding the withdrawal was noted in the patient’s medical notes and no further data collected for that participant.

Outcomes and assessments

Adverse events and serious adverse events

All AEs, from consent until resolution of EP (hCG ≤ 15 IU/l or surgical intervention), whether observed directly or reported by the patient, were collected and recorded. Common known side effects of gefitinib were not reported as AEs (unless they met the definition of seriousness) but were captured directly onto the database at each visit. These common side effects were abdominal pain, diarrhoea, nausea, vomiting, rash, fatigue, dizziness and mouth ulcers. Trial participants were asked about the occurrence of AEs and SAEs at each study visit. All SAEs were emailed or faxed to the sponsor’s office within 24 hours of the research staff becoming aware of the event and onward reported to Astra Zeneca. The local PI (or other nominated clinician) had to assign seriousness, severity, causality and expectedness (if deemed related) to the SAE before reporting. SAEs categorised by the local investigator as both suspected to be related to the trial drug and unexpected were classified as SUSARs, and were subject to expedited reporting. In the case of any SAEs, management and care of the women was initiated as though the woman was taking gefitinib. All AEs and SAEs have been MedDRA coded (version 24.1) for consistency of reporting.

Statistical considerations

Statistical analysis

A comprehensive SAP was drawn up prior to any analysis. In brief, categorical data were summarised with frequencies and percentages. Continuous variables were summarised with means and standard deviations unless there was evidence of skew, where medians and interquartile ranges (IQR) were presented. In the first instance, participants were analysed in the treatment group to which they were randomised [intention to treat (ITT)], irrespective of adherence with the treatment protocol. All estimates of differences between groups were presented with 95%, two-sided confidence intervals (CIs), adjusted for the minimisation variables (where possible).

The primary outcome was analysed using a mixed-effects log-binomial model to generate an adjusted risk ratio (RR) and an adjusted risk difference (RD) (using an identity link function), including centre as a random effect. Statistical significance of the treatment group parameter was determined (p-value generated) through examination of the associated chi-squared statistic (obtained from the log-binomial model, which produced the RR).

Binary secondary outcomes were analysed as per the primary outcome. Time to hCG resolution was considered in a competing risk framework to account for participants who had surgical intervention for their EP. 26 A cumulative incidence function was used to estimate the probability of occurrence (hCG resolution) over time. A Fine-Gray model was then used to estimate a subdistribution adjusted hazard ratio (HR) directly from the cumulative incidence function. In addition, a further Cox proportional hazard model was fitted and applied to the cause-specific (non-surgical resolution) hazard function and used to generate an adjusted HR. 27 Return to menses was analysed using a Cox regression model. Number of hospital visits associated with treatment was analysed using a Poisson regression model, including centre as a random effect to generate an adjusted incidence rate ratio (IRR). Acceptability of treatment was analysed using an ordinal logistic regression model, including centre as a random effect to generate an adjusted odds ratio (OR).

Sensitivity and supportive analyses of the primary outcome included a per-protocol analysis, an analysis that excluded any women found to violate the inclusion/exclusion criteria post randomisation and an analysis to investigate the small amount of missing primary outcome data by means of a ‘tipping point’ approach, which explored the possibility that missing responses were ‘missing not at random’. Unadjusted models were utilised. Firstly all women with missing outcome data were considered as having not met the primary outcome (i.e. surgical intervention was no). Two scenarios were then considered. In the first scenario, in women who had missing data in the gefitinib group, ‘events’ (i.e. surgical intervention was changed from no to yes) were sequentially added to this group until the number of events added was equal to the number of women with missing outcome data in that group. With the addition of each event, an unadjusted model was run and the RR stored. The tipping point for the gefitinib group occurred when enough events have been added such that the upper/lower limit of the CI from the corresponding model differed from that of the primary ITT finding (in regards to whether the CI crossed the null value of one), should the tipping point exist. A second scenario was then considered, which repeated this process in the placebo group. A sensitivity analysis for time to hCG resolution was also conducted where the threshold for resolution was considered as 30 IU/l.

Preplanned subgroup analyses (limited to the primary outcome measure only) were completed for the following: baseline serum hCG levels (<1500 IU/l, ≥1500 to <2500 IU/l, ≥2500 IU/l), BMI (<25 kg/m², ≥25 kg/m²) and ectopic size on ultrasound (<2 cm, or ≥2 cm). The effects of these subgroups were examined by adding the subgroup by treatment group interaction parameters to the regression model. p-values from the tests for statistical heterogeneity were presented alongside the effect estimate and estimates of uncertainty within each subgroup. In addition to this, ratios were provided to quantify the difference between the treatment effects estimated within each subgroup.

Interim analyses of effectiveness and safety end points were performed on behalf of the Data Monitoring and Ethics Committee (DMEC) on an approximately annual basis during the period of recruitment. These analyses were performed with the use of the Haybittle–Peto principle28 and hence no adjustment was made in the final p-values to determine significance.

All analyses were performed in SAS^® (version 9.4 SAS Institute Inc., Cary, North Carolina 27513, USA) or Stata^® (version 17.0 StataCorp LP, College Station, TX, USA).

Amendments to the project

During the course of the trial we submitted 22 substantial amendments and six non-substantial amendments. Please see details in Table 3.

Trial oversight

Study oversight was provided by a Trial Steering Committee (TSC), chaired by Professor Ying Cheong (University of Southampton) and a DMEC, chaired by Professor Usha Menon (University College London). The TSC provided independent supervision for the trial, providing advice to the Chief and Co-Investigators on all aspects of the trial throughout the study. The DMEC adopted the DAMOCLES charter29 to define its terms of reference and operation in relation to oversight of the GEM3 trial.

Public and patient involvement

We have been supported throughout the trial by the Ectopic Pregnancy Trust (EPT) and, in particular, its chair. Public and patient involvement was crucial in improving the acceptability of the GEM3 trial and promoting engagement of gynaecologists. We engaged with EPT throughout, improving our understanding of the needs of patients with EP. Members of the EPT commented on all patient-facing materials to ensure that they were clear and comprehensive. We organised three research site team training days during the course of the trial and EPT patient representatives spoke at each of these meetings (e.g. on how best to counsel participants when approaching them about the trial). We will engage with the EPT regarding the dissemination of our results, providing a plain English summary of the findings. This will be distributed via the EPT’s website and on their social media channels. Any future research groups taking forward the research recommendations from this project would benefit from engaging with the EPT.

Recruitment

Screening of participants commenced on 2 November 2016 and the last woman was randomised on 6 October 2021 (Figure 1). Recruitment was paused during the COVID-19 pandemic from 20 March 2020 until 2 June 2020 but otherwise the pandemic had limited impact on the trial process and data collection. Three hundred twenty-eight women were recruited from 50 sites, the contribution from each site can be seen in Table 4. The complete flow of participants through the GEM3 trial is shown in Figure 1. Initially, 699 were considered for participation, of which, 540 women were considered eligible. Of these women, 328 women were randomised, 212 were not randomised for various reasons (details in Figure 1). A total of 165 participants were assigned to gefitinib and 163 to placebo. Three women withdrew from GEM3 and there were no deaths. Reasons for trial withdrawal are provided in Table 5.

FIGURE 1.

CONSORT diagram.

Pregnancy

Two participants were found to have intrauterine pregnancies following randomisation to the trial. These pregnancies were found to be unviable. These participants were withdrawn from the trial.

Participant characteristics

At enrolment, baseline characteristics were well balanced between groups (Table 6). The mean age was 31.7 years (SD 5.5 years), mean BMI was 26.8 kg/m² (SD 6.1 kg/m²), the median pretreatment hCG levels were 1994.0 (IQR 1487.0–2819.0), and 25% had a starting ectopic size ≥ 2 cm measured on USS.

Adherence to treatment

Nearly all women received their initial MTX injection (99%), of the three women who did not receive their initial injection reasons can be seen in Table 7. The median number of tablets taken was 7.0 (IQR 7.0–7.0) in both groups. One hundred fifty-five of 165 (94%) women in the gefitinib group were considered adherent, in comparison to 152 of 162 (94%) women in the placebo group.

Primary outcome

For the primary ITT analysis, there was no evidence of a difference in the primary outcome. The surgical intervention rate in the gefitinib group was 30% (50/165) and 29% (47/160) in the placebo arm (adjusted RR 1.15, 95% CI 0.85 to 1.58; adjusted RD −0.01, 95% CI −0.10 to 0.09; p = 0.37) (Table 8).

Sensitivity and supportive analyses had minimal impact on effect estimates as described below. In the per-protocol analysis of the primary outcome comparison, including only the 306 women defined as adherent who had primary outcome data available, the effect estimates changed only marginally. Similarly, when the analysis population was limited to women who were not found to violate the inclusion/exclusion criteria (post randomisation), the point estimates and CIs were almost identical to the ITT analysis. Finally, the sensitivity analyses to assess the impact of missing data using a ‘tipping point’ approach (as summarised in Figure 2) support the conclusion that our primary outcome analysis was robust to the small amount of missing data. A tipping point analysis was not conducted in the gefitinib group since there were no missing primary outcome data in this group.

FIGURE 2.

Tipping point analysis in the placebo group.

Subgroup analysis was performed for the three prespecified variables used in the minimisation algorithm, namely baseline hCG levels (key subgroup), BMI and ectopic size. There was no evidence for varying effective in each subgroup analysis performed. The proportion of women who required surgical intervention in each subgroup is shown in Table 9.

Secondary outcome results

There were no differences in the secondary outcomes (Table 10). The median time to resolution of the EP (defined as serum hCG declining to ≤ 15 IU/l) for those where medical management successfully resolved the EP was 28.0 days (IQR 23.5–36.0, n = 108) in the gefitinib group and 28.0 (IQR 21.0–36.5, n = 108) days in the placebo group (cause specific HR of 0.96, 95% CI 0.69 to 1.33; subdistribution HR 1.03, 95% CI 0.75 to 1.40) (Figure 3). A second dose of MTX was administered to 12% (20/165) of participants in the gefitinib group and 14% (23/162) in the placebo group (adjusted RR 0.86, 95% CI 0.57 to 1.28). The number of hospital visits was similar in both groups. The median number of days before a return to menses was similar in both groups: 24.0 days (IQR 24.0–38.0, n = 132) in the gefitinib group versus 24.0 (IQR 24.0–38.0, n = 134) in the placebo group (adjusted HR 1.08, 95% CI 0.83 to 1.40). Both treatments had high rates of satisfaction (percentage of women who were very, or mostly satisfied was 77% in the gefitinib group and 76% in the placebo group).

FIGURE 3.

Cumulative incidence function plot for time to hCG ≤ 15 IU/l (by treatment group).

Adverse events

The number of women who experienced a SAE was 3% (5/165) in the gefitinib group and 4% (6/162) in the placebo group (p = 0.74). One woman in the gefitinib group experienced a SUSAR as a result of a likely reaction to MTX. The proportions of women who reported diarrhoea or a rash were higher in the gefitinib group compared to the placebo group (Table 11). Further details of all AEs and SAEs are presented below in Tables 12 and 13.

Equality, diversity and inclusion

As this trial took place in a semi-emergency setting with restrictive inclusion criteria we were unable to target specific under-represented groups. However, we were open to recruitment across 74 sites in Scotland, England and Wales, some rural and some inner city, and the ethnic diversity of the PIs and research staff at these sites was broad. In addition, we had PIs ranging from experienced consultants to nurse practitioners, encouraging nurses to take on PI roles as the EPUs (where the recruitment was carried out) were often managed by nursing staff. Of the 328 women recruited to this trial 248 of these were White (76%); 38 were Asian (12%) and 21 were Black (6%).

Implications for practice

The key findings of GEM3 are clear: women with a tubal EP should not be offered combination of gefitinib and MTX because it is no more effective than treatment with MTX alone. However, our trial has generated high-quality evidence on the success rates of IM treatment with MTX – how long it takes for the EP to resolve and how many will need rescue surgery (failed medical treatment). These data will be immediately useful for patient counselling (to help them choose either surgery or medical management) and for inclusion in early pregnancy guidelines.

Recommendations for future research

In our opinion, no further research is required to evaluate the role of gefitinib in the management of women with tubal EPs. Questions that remain unaddressed relate to the use of combination treatment for other extrauterine and uterine EPs, such as caesarean scar pregnancies, or in the management of choriocarcinoma.

Contributions of authors

Catherine A Moakes (https://orcid.org/0000-0002-0473-0532) (Trial Statistician) performed the analyses for the trial, contributed to the interpretation of the trial and the drafting of the report.

Stephen Tong (https://orcid.org/0000-0002-2319-0586) (Professor of Obstetrics and Gynaecology) contributed to the design, delivery, analysis and interpretation of all components of GEM3, the first draft and overall editing of the final report.

Lee J Middleton (https://orcid.org/0000-0003-4621-1922) (Senior Statistician) contributed to the design of GEM3, oversaw the statistical analysis, contributed to the interpretation of the trial and the drafting of the report.

W Colin Duncan (https://orcid.org/0000-0002-7170-5740) (Professor of Reproductive Medicine and Science) contributed to the design, delivery, analysis and interpretation of all components of GEM3, the first draft and overall editing of the final report.

Ben W Mol (https://orcid.org/0000-0001-8337-550X) (Professor of Obstetrics and Gynaecology) contributed to the design, delivery, analysis and interpretation of all components of GEM3, the first draft and overall editing of the final report.

Lucy H R Whitaker (https://orcid.org/0000-0002-7678-6551) (NES/CSO Clinical Lecturer in Obstetrics and Gynaecology) contributed to the editing of the final report.

Davor Jurkovic (https://orcid.org/0000-0001-6487-5736) (Consultant Gynaecologist) contributed to the editing of the final report.

Arri Coomarasamy (https://orcid.org/0000-0002-3261-9807) (Professor of Gynaecology) contributed to the editing of the final report.

Natalie Nunes (https://orcid.org/0000-0003-1801-6281) (Consultant Obstetrician and Gynaecologist) contributed to the editing of the final report.

Tom Holland (https://orcid.org/0000-0001-5727-0659) (Consultant Gynaecologist) contributed to the editing of the final report.

Fiona Clarke (https://orcid.org/0000-0003-0298-9601) (Consultant Obstetrician and Gynaecologist) contributed to the editing of the final report.

Lauren C Sutherland (https://orcid.org/0000-0001-5465-8586) (Trial Co-ordinator) was responsible for the day-to-day management, delivery of the trial, drafting the report and overall editing of the final report.

Ann M Doust (https://orcid.org/0000-0001-8726-7186) (Research Manager) contributed to the design of GEM3, was responsible for the day-to-day management and delivery of the trial, contributed to drafting the report and overall editing of the final report.

Jane P Daniels (https://orcid.org/0000-0003-3324-6771) (Professor of Clinical Trials) contributed to the design, delivery and interpretation of the trial and editing of the final report.

Andrew W Horne (https://orcid.org/0000-0002-9656-493X) (Professor of Gynaecology and Reproductive Sciences and Chief Investigator) contributed to the design, delivery, analysis and interpretation of all components of GEM3, the first draft and overall editing of the final report.

Members of the GEM3 Collaborative Group

Co-investigators

Stephen Tong, Co-investigator, University of Melbourne, Melbourne, Australia

Ben Mol, Co-investigator, Monash University, Melbourne

Colin Duncan, Co-investigator, University of Edinburgh, Edinburgh

Jane Daniels, Co-investigator, University of Nottingham, Nottingham

Professor Arri Coomarasamy, University of Birmingham, Birmingham

Mrs Alexandra Peace-Gadsby, Ectopic Pregnancy Trust

Lee J Middleton, University of Birmingham, Birmingham

Mr Davor Jurkovic, University College Hospital, London

Miss Cecilia Bottomley, Chelsea and Westminster Hospital, London

Professor Tom Bourne, Imperial College, London

Trial Management Group

Andrew W Horne (Chair), Chief Investigator, University of Edinburgh, Edinburgh

Stephen Tong, Co-investigator, University of Melbourne, Melbourne, Australia

Jane Daniels, Co-investigator, University of Nottingham, Nottingham

Ben Mol, Co-investigator, Monash University, Melbourne

Colin Duncan, Co-investigator, University of Edinburgh, Edinburgh

Catherine A Moakes, Statistician, University of Birmingham, Birmingham

Lee J Middleton, Senior Statistician, University of Birmingham, Birmingham

Ann M Doust, Research Manager, University of Edinburgh, Edinburgh

Frances Collins, Trial/Lab Manager, University of Edinburgh, Edinburgh

Lauren Sutherland, Trial Co-ordinator, University of Edinburgh, Edinburgh

Clive Stubbs, Team Lead, Birmingham Clinical Trials Unit, University of Birmingham, Birmingham

Jordan Doust, Data manager, University of Edinburgh, Edinburgh

Principal Investigators and recruiting sites

Sherif Saleh, Aberdeen Maternity Hospital, Aberdeen

Miriam Baumgarten, Addenbrookes Hospital, Cambridge

Ben Galea, Addenbrookes Hospital, Cambridge

Sinha Sanjay, Furness General Hospital, Barrow-in-Furness

Malar Raja, Basildon University Hospital, Basildon

Thangamma Katimada-Annaiah, Bedford Hospital, Bedford

Pratima Gupta, Heartlands Hospital, Birmingham

Justin Chu, Birmingham Women’s Hospital, Birmingham

Faye Rodger, Borders General Hospital, Melrose

Fiona Clarke, Burnley General Hospital, Burnley

Satya Duvvur, Queen’s Hospital, Burton-On-Trent

Monique Latibeaudiere, Cardiff Royal Infirmary, Cardiff

Natalie Nunes, West Middlesex Hospital, Isleworth

Victoria Finney, Countess of Chester Hospital, Chester

Janet Cresswell, Chesterfield Royal Hospital, Chesterfield

Feras Izzat, University Hospital Coventry, Coventry

Rebecca Thompson, Leighton Hospital, Crewe

Sonal Anderson, University Hospital Crosshouse, Kilmarnock

Fouzia Memon, Cumberland Infirmary, Cumberland

Jerry Oghoetouma, Darlington Memorial Hospital, Darlington

Gabriel Awadzi, Darent Valley Hospital, Dartford

Manju Sindhu, Doncaster Royal Infirmary, Doncaster

Binita Pande, Ninewells Hospital, Dundee

Velur Sindhu, University Hospital of Durham, Durham

Lucy Whitaker, Royal Infirmary of Edinburgh, Edinburgh

Mayank Madhra, Royal Infirmary of Edinburgh, Edinburgh

Sangeetha Devarajan, Epsom and St Helier Hospitals, Epsom

Jananki Putran, Princess Alexandra Hospital, Harlow

Shahzya Huda, Forth Valley Hospital, Larbert

Sridevi Sankharan, Frimley Park Hospital, Camberley

Chitra Kumar, Princess Royal Maternity Hospital, Glasgow

Kelly Bingham, Gloucestershire Royal Hospital, Gloucester

Shruti Mohan, Hillingdon Hospital, Hillingdon

Hema Nosib, Hinchingbrooke Hospital, Hinchingbrooke

Sandra Watson, Homerton Hospital, Homerton

Kate Stewart, Raigmore Hospital, Inverness

Jackie Ross, King’s College Hospital, London

Punukollu Durgadevi, Victoria Hospital, Fife

Penny Robshaw, Liverpool Women’s Hospital, Liverpool

Ursula Winters, St Mary’s Hospital, Manchester

Gautam Raje, Norfolk and Norwich University Hospital, Norwich

Shilpa Deb, The Queen’s Medical Centre, Nottingham

Rebecca McKay, Peterborough City Hospital, Peterborough

Joanne Page, Derriford Hospital, Plymouth

Krupa Madhvani, Poole Hospital, Poole

Tom Bourne, Queen Charlotte and Chelsea Hospital, London

Mona Sharma, Queen’s Hospital, Romford

Radwan Faraj, Rotherham General Hospital, Rotherham

Emma Kirk, Royal Free Hospital, London

Renee Behrens, Royal Hampshire County Hospital, Winchester

Gourab Misra, Royal Stoke Hospital, Stoke-On-Trent

Sujan Sen, Scunthorpe General Hospital, Scunthorpe

Jo Fletcher, Royal Hallamshire Hospital, Sheffield

Pinky Khatri, James Cook Hospital, South Tees

Umo Esen, South Tyneside District Hospital, South Tyneside

Sundararajah Raajkumar, Southend Hospital, Southend-On Sea

Susannah Hogg, Southmead Hospital, Bristol

Abigail Oliver, St Michael’s Hospital, Bristol

Ngozi Izuwah-Njoku, St Peter’s Hospital, Chertsey

Tom Holland, St Thomas’ Hospital, London

Sucheta Iyengar, Stoke Mandeville Hospital, Aylesbury

Amna Ahmed, Sunderland Royal Hospital, Sunderland

Catherine Wykes, East Surrey Hospital, Redhill

Millicent Anim-Somuah, Tameside Hospital, Tameside

Davor Jurkovic, University College Hospital, London

James Davis, Manor Hospital, Walsall

Vinita Raheja, Wansbeck General Hospital, Wansbeck

Helena Nik, Warrington Hospital, Warrington

Rita Arya, Warrington Hospital, Warrington

Suganya Sukumaran, Warwick Hospital, Warwick

Barkha Sinha, West Suffolk Hospital, Bury St Edmunds

Sandhya Rao, Whiston Hospital, Whiston

Rajalakshmi Rajagopal, University Hospital Wishaw, Wishaw

Sakunthala Tirumuru, New Cross Hospital, Wolverhampton

Mamta Pathak, Worcestershire Royal Hospital, Worcester

Geeta Kumar, Wrexham Maelor Hospital, Wrexham

Sponsor

ACCORD – NHS Lothian and University of Edinburgh

Monitoring and Audit team led by Elizabeth Craig and Lorn MacKenzie

Ethics statement

The trial was approved by Scotland A REC committee (ref: 16/SS/0014) on 29 February 2016.

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to anonymised data may be granted following review.

Patient data

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it is important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data is used. #datasaveslives. You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Disclaimers

This report presents independent research. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the MRC, the EME programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the EME programme or the Department of Health and Social Care.