Title: GEM3: A multi-centre double-blind placebo-controlled randomised trial of a combination of methotrexate and gefitinib versus methotrexate alone as a treatment for ectopic pregnancy
Funder: Chief Scientist Office, Scotland

Abstract: BACKGROUND: Tubal ectopic pregnancy (EP) affects 1-2% of UK pregnancies and is potentially life threatening. Until two decades ago, EP was often diagnosed late, resulting in emergency surgery as the only treatment option. Transvaginal ultrasound and serum hCG measurement now allow early diagnosis and enable use of systemic methotrexate (MTX) that avoids surgery in selected women. Currently, 40% of EPs are initially managed medically, and the treatment is widely endorsed by NICE (CG154). However, 30% of these women will require subsequent ‘rescue’ surgery, while another 15% will require repeat MTX, and monitoring is prolonged. Surveys of women and clinical staff highlight the need for more effective treatments for EP. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. We have performed preclinical studies showing that gefitinib enhances MTX clearance of pregnancy tissue, and completed Phase I and II trials (GEM1 & 2) suggesting that combining MTX and gefitinib in the management of EP is safe, well tolerated, and may reduce the need for surgery. AIMS: To assess whether the combination of MTX and gefitinib is more effective than MTX alone in reducing the need for surgical intervention in clinically stable women with EP, and to explore molecular mechanisms of the actions of MTX and gefitinib on EP tissues to inform future developments in treatment. DESIGN: Multicentre RCT with mechanistic study. POPULATION: Clinically stable women with EP and serum hCG 1000–5000 IU/L. INTERVENTIONS: Single-dose intramuscular MTX (50mg/m2) injection (usual care) with either 7 daily doses oral gefitinib (250mg) or matched placebo. ASSESSMENTS: Assessments will follow a standardised protocol. Assessment of clinical stability and measurement of serum hCG concentrations on days 4, 7, 11, and then weekly, until hCG < or =15 IU/L (non-pregnant level). Assessment of safety/tolerability by symptoms±examination, and by serum haematology/biochemistry (day 14-21 post-treatment if abnormal until return to normal). Assessment of acceptability by questionnaire and menstrual cycle data at 3 months. We will seek permission to log future fertility data. PRIMARY CLINICAL OUTCOME: Need for surgical intervention for treatment of EP. SECONDARY CLINICAL OUTCOMES: Additional MTX; time to hCG resolution (days); number of treatment-associated hospital visits; safety/tolerability; patient acceptability. MECHANISTIC OUTCOMES: Measurement in tubal implantation site biopsies from a separate cohort of women given MTX and gefitinib <12hrs prior to planned surgery for EP of 1) phosphorylated EGFR/Akt and other adaptor molecules 2) target genes known to be up-regulated by EGFR, and 3) markers of apoptosis/cell proliferation. SAMPLE SIZE: Based on data from Phase I and II trials, and from an Edinburgh/Imperial 2012 cohort given standard medical treatment, the study has been designed to detect an absolute reduction of 15% (30% to 15%) in surgical intervention rate with 90% power and alpha error 5%. This would require 328 participants (161 per group, allowing for 2% loss to follow-up). 30 additional women who opt to have their EP treated surgically will be recruited for the mechanistic study. EXPECTED RECRUITMENT RATE: Recruitment over 24 mths from ~50 centres (rate based on data from 21 UK sites). MAIN STAGES OF TRIAL: Mths 1-6: site approvals/training. Mths 7-30: recruitment. Mths 9-42: follow-up. Mths 43-48: analysis/write-up.

Lay abstract: Tubal ectopic pregnancy (EP) occurs where an embryo implants in a Fallopian tube rather than the uterus. If the pregnancy continues to grow there is commonly stretching and ultimately rupture of the tube causing life-threatening, internal bleeding. Fortunately, in countries where ultrasound scans and pregnancy hormone (hCG) blood testing are widely available, most EP are now diagnosed before they rupture. Management of an unruptured EP depends on symptoms, pregnancy size, presence of internal bleeding, and hCG measurement. When a patient has a high risk of rupture as evident from severe symptoms, a large EP, internal bleeding or a high hCG level, then surgery is the best treatment. In the remaining women, a methotrexate (MTX) injection is a suitable treatment. However, in 30% of women, MTX treatment is unsuccessful (with surgery still required). In 15% of women, it is partially effective (2nd dose of MTX required). For many women, treatment is prolonged (many hospital visits) adding to emotional distress. A more effective treatment is necessary to reduce the need for emergency surgery, the requirement of repeat treatment and the prolonged time to complete treatment. Gefitinib is a drug taken by mouth that is licensed to treat a type of lung cancer. We have performed three small studies using MTX and gefitinib. In the first study (laboratory based), we found that EP tissue responds to gefitinib and that it improves the effect of MTX. In the second and third studies (called GEM1 and GEM2), we found that giving MTX and gefitinib together to women with EP may reduce the need for surgery and hospital visits. Using the drugs together did not cause any important side effects. These findings now require further study in a large trial and we need to reach a better understanding of how gefitinib works. We therefore propose a clinical trial to compare using MTX and gefitinib together with using MTX and placebo (dummy drug), and to study how gefitinib works in the body. All of the women who agree to participate in the trial will receive MTX (normal treatment dose) and also be randomly allocated to take either a gefitinib, or a placebo tablet, once a day for 7 days. We will assess whether the two drugs together are better than MTX with placebo at treating the EP without the need for surgery. We will also compare how long the hCG level takes to decrease, the number of hospital visits and the need for further MTX, as well as safety and patient acceptability between the study groups. To monitor treatment response, we will collect blood samples twice in the first week after treatment then weekly to measure hCG levels until they drop to non-pregnant levels. The trial will recruit 328 women from ~50 UK hospitals. To examine how MTX and gefitinib affects the pregnancy tissue, we will also randomise a further 30 women who opt to have their EP treated surgically (to take MTX and gefitinib). This will allow us to examine the microscopic effect of MTX and gefitinib on EP cells. We believe that the drugs together will be of greater benefit to women with EP in terms of fewer operations, hospital visits and blood tests. The trial will be led by researchers who have an excellent track record of running clinical trials and investigating early pregnancy problems, and overseen by independent committees. The project will take 3.5 years, with most of the budget allocated to the staff coordinating/analysing the trial.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH