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. 2018 Nov 20;19(1):643.
doi: 10.1186/s13063-018-3008-6.

A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3): trial protocol

James May  1 , Colin Duncan  2 , Ben Mol  3 , Siladitya Bhattacharya  4 , Jane Daniels  5 , Lee Middleton  6 , Catherine Hewitt  6 , Arri Coomarasamy  7 , Davor Jurkovic  8 , Tom Bourne  9 , Cecilia Bottomley  10 , Alexandra Peace-Gadsby  11 , Ann Doust  2 , Stephen Tong  12 , Andrew W Horne  13
Affiliations

A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3): trial protocol

James May et al. Trials. .

Abstract

Background: Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. Treatment options include surgery and medical management. Stable women with tEPs with pre-treatment serum human chorionic gonadotrophin (hCG) levels < 1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate. However, tEPs with hCG > 1000 IU/L can take significant time to resolve with methotrexate and require multiple outpatient monitoring visits. In pre-clinical studies, we found that tEP implantation sites express high levels of epidermal growth factor receptor. In early-phase trials, we found that combination therapy with gefitinib, an orally active epidermal growth factor receptor antagonist, and methotrexate resolved tEPs without the need for surgery in over 70% of cases, did not cause significant toxicities, and was well tolerated. We describe the protocol of a randomised trial to assess the efficacy of combination gefitinib and methotrexate, versus methotrexate alone, in reducing the need for surgical intervention for tEPs.

Methods and analysis: We propose to undertake a multi-centre, double-blind, placebo-controlled, randomised trial (around 70 sites across the UK) and recruit 328 women with tEPs (with pre-treatment serum hCG of 1000-5000 IU/L). Women will be randomised in a 1:1 ratio by a secure online system to receive a single dose of intramuscular methotrexate (50 mg/m2) and either oral gefitinib or matched placebo (250 mg) daily for 7 days. Participants and healthcare providers will remain blinded to treatment allocation throughout the trial. The primary outcome is the need for surgical intervention for tEP. Secondary outcomes are the need for further methotrexate treatment, time to resolution of the tEP (serum hCG ≤ 15 IU/L), number of hospital visits associated with treatment (until resolution or scheduled/emergency surgery), and the return of menses by 3 months after resolution. We will also assess adverse events and reactions until day of resolution or surgery, and participant-reported acceptability at 3 months.

Discussion: A medical intervention that reduces the need for surgery and resolves tEP faster would be a favourable treatment alternative. If effective, we believe that gefitinib and methotrexate could become standard care for stable tEPs.

Trial registration: ISRCTN Registry ISRCTN67795930 . Registered 15 September 2016.

Keywords: Clinical trial; Ectopic pregnancy; Epidermal growth factor receptor; Gefitinib; Gynaecology; Methotrexate; Reproductive medicine; Surgery.

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Conflict of interest statement

Ethics approval and consent to participate

Ethical approval was obtained from the Scotland A Research Ethics Committee (16/SS/0014) on 29 February 2016. Data will be presented at international conferences and published in peer-reviewed journals. We will make the information available to the public through national bodies and charities, e.g. the Ectopic Pregnancy Trust.

Consent for publication

Not applicable.

Competing interests

ST holds a patent that relates to the use of gefitinib to treat ectopic pregnancies. BM is supported by a NHMRC Practitioner Fellowship (GNT1082548). BWM reports consultancy for ObsEva, Merck KGaA, and Guerbet. CB is on the advisory panel for Clearblue, was Scientific Chair of the Association of Early Pregnancy Units 2015–2017, and is a Medical Advisor to the Ectopic Pregnancy Trust. TB receives departmental research support from Roche Diagnostics and Samsung Medison. AWH is on the Scientific Board of the Association of Early Pregnancy Units, and is a Trustee and Medical Advisor to the Ectopic Pregnancy Trust. The remaining authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
CONSORT flow diagram. MTX methotrexate
Fig. 2
Fig. 2
Schedule of enrolment, interventions, and assessments. hCG human chorionic gonadotrophin
See this image and copyright information in PMC

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