For Trial Participants

What is the GEM3 study?

GEM3 is a double blind placebo controlled trial of a combination of methotrexate and gefitinib versus methotrexate alone as a treatment for ectopic pregnancy.

Who can participate?

Women between the age of 18 and 50 years diagnosed with ectopic pregnancy where treatment for Methotrexate has been confirmed. 

Please contact your local GEM3 trial team for more information.

What does the study involve?

You will be given a copy of the information sheet to keep. You will have as long as you need to decide whether or not to take part. If you decide to take part you will be asked by a member of the research team to signa consent form. To confirm you are eligible to take part, we will look at your blood and ultrasound results with your permission. We will ask you some questions about your medical history and medications you are taking. If a doctor confirms that you can take part in the trial you will be randomised to a treatment. You will then be given seven tablets (either gefitinib or placebo (dummy drug) and you will be asked to take one a day for the next seven days. No-one will know what treatment you have been given as the tablets look exactly the same.

You will be followed up as you normally would at your hospital so there are no extra visits. This usually involves blood tests to measure your hormone levels at around days 4, 7, 11 and then weekly until your hormone level is back to a pre pregnancy level. After day 14, we will repeat some blood tests just to make sure that the drug combination has not caused any harm to your liver or kidneys. This will be with a routine blood test. We will follow you up until your pregnancy hormone blood results are back to a pre-pregnancy level.  After 3 months a member of the research team will contact you by telephone to answer some questions about your experience with the treatment and to find out when your periods returned. This should only take about 5 minutes of your time. We will ask your permission to access your medical records for 5 years following the study to look and see if you have any pregnancies in the years following your ectopic pregnancy and note what happened with these pregnancies. This will be done remotely looking at your medical records.

EDINBURGH ONLY: If the treatment does not work and you need to have an operation to remove your ectopic pregnancy we will ask permission to take a small piece of the tissue that is routinely removed during the operation.

Background to the study

Ectopic pregnancies are pregnancies that implant in maternal tissues other than the specialised endometrium of the uterus, most often in one of the Fallopian tubes. They are still one of the leading causes of maternal death in the first trimester. This is because placental trophoblastic cells are invasive by nature, and outside of the relatively controlled environment of the uterus are able to erode into maternal blood vessels and cause sometimes fatal internal bleeding. Ectopic pregnancies are common, accounting for approximately 2% of all pregnancies (Lancet. 2005 366(9485):583-91). Rates are thought to be rising due to increasing IVF use, increasing maternal age and pelvic infections.

Thus, ectopic pregnancy is a significant gynaecological disease. While prompt diagnosis and management make deaths in the developed world rare, maternal mortality from this condition is still significant. In The United Kingdom, 6 deaths occurred as a result of ectopic pregnancies between 2006-2008 (CEMACE 2011). In the developing world, women diagnosed with an ectopic pregnancy have up to 100 times increased mortality compared to the developed world (Obstet Gynecol 2004;103:692-697). Lack of timely access to life saving surgery and limited medical only options are likely contributors to this significant mortality rate.

What are the possible risks and benefits to participating?

Methotrexate and gefitinib have similar side effects, the most common of which are nausea, diarrhoea and a skin rash. Other possible side effects include: vomiting, poor appetite, weightloss, acne, dry skin, itch and a feeling of listlessness. An allergic reaction is always a possibility when taking any medication. If you experience any shortness of breath, wheezing, difficulty breathing, facial numbness, swelling or a rash, please notify a doctor as soon as possible.

The most serious known side effect of gefitinib is the development of Interstitial Lung Disease(ILD). This is a condition where the lungs are damaged by inflammation and become abnormally thickened. If severe, it can stop the lungs working properly. ILD occurs in approximately three in 1000 people taking the drug indefinitely (e.g. cancer patients who take this drug for life).These figures have been calculated from 92,000 people taking gefitinib who already have lung cancer. Therefore, it is possible that the lung cancer in combination with the drug may have contributed to the development of ILD. All the evidence available would suggest that seven doses of the gefitinib tablet should be safe, and the risk of developing ILD from this exceedingly low. Besides having lung cancer, those most likely to develop ILD were those older than 55 years, male, smokers and people of Japanese ethnicity.

By excluding most of these risk factors in our participants, including those with existing respiratory disease, and by giving gefitinib for a maximum of seven days, we believe the risk of developing ILD is minimal. The usual practice for anyone taking methotrexate alone for ectopic pregnancy is to avoid getting pregnant (use contraception) and not to breastfeed for three months. This advice also applies to gefitinib and methotrexate.

Study set-up details

 

GEM3 started recruiting in 2016, the recruitment period will last for 24 months over approximately 50 sites in the UK (number dependent on rate of recruitment). 328 patients will be recruited into the main study, an additional 30 women will be recruited into a separate related mechanistic study (Edinburgh only). The treatment duration for each patient will be seven days. Each patient will be followed up after 3 months and a blood sample will b e collected once between 14 and 21 days after the start of treatment. Long term follow up (up to 5 years) to determine future pregnancies will be carried out via medical records. 

The GEM3 Chief Investigator is Professor Andrew Horne.

The GEM3 study is being co-ordinated by Birmingham Clinical Trials Unit, and is co-sponsored by the University of Edinburgh and NHS Lothian ACCORD.

The study has been funded by the National Institute for Health Research Efficacy and Mechanism Evaluation Programme. (NIHR HTA Ref: 14/150/03).

ISTRCTN: 67795930