Condition category
Pregnancy and Childbirth
Date applied
15/09/2016
Date assigned
15/09/2016
Last edited
23/11/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Plain English summary as of 23/11/2018:
Background and study aims
An ectopic pregnancy occurs when a fertilised egg attaches itself somewhere other than inside the womb, usually in one of the fallopian tubes (the tubes connecting the ovaries and womb, which a mature egg travels down during ovulation). Sadly, there is no chance of this pregnancy surviving and if it is allowed to continue it could potentially be life-threatening to the mother. If an ectopic pregnancy is detected early enough, it can be treated with a single dose of a drug called methotrexate which stops the pregnancy developing. In some cases this single dose of methotrexate is not successful and a further dose of methotrexate is required or surgery may be needed. A more effective treatment is therefore needed to reduce the requirement for repeat doses of methotrexate or surgery. Previous studies using a drug called gefitinib (a drug used in lung cancer patients) in addition to methotrexate have shown promising results, as it appears to have a blocking effect on the cells found in an ectopic pregnancy. These studies were in a small number of women and so a larger study is needed to prove the effectiveness of this treatment. The aim of this study is to find out whether treatment using methotrexate and gefitinib is more effective than methotrexate alone.

Who can participate?
Women aged between 18 and 50 who are being treated for an ectopic pregnancy.

What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive an injection of methotrexate and then take tablets containing gefitinib once a day for seven days. Those in the second group receive an injection of methotrexate and then take tablets containing a placebo (dummy drug) once a day for seven days. Participants in both groups are then monitored until the resolution of the ectopic pregnancy defined by a serum hCG level of ≤15 IU/l or surgical removal of the ectopic pregnancy.

What are the possible benefits and risks of participating?
Not provided at time of registration

Where is the study run from?
Royal Infirmary of Edinburgh (lead site) and 70 other centres throughout the England, Scotland and Wales (UK)

When is the study starting and how long is it expected to run for?
April 2016 to December 2019

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Mrs Ann Doust
gem3@ed.ac.uk


Previous plan English summary:
Background and study aims
An ectopic pregnancy occurs when a fertilised egg attaches itself somewhere other than inside the womb, usually in one of the fallopian tubes (the tubes connecting the ovaries and womb, which a mature egg travels down during ovulation). Sadly, there is no chance of this pregnancy surviving and if it is allowed to continue it could potentially be life-threatening to the mother. If an ectopic pregnancy is detected early enough, it can be treated with a single dose of a drug called methotrexate which stops the pregnancy developing. In some cases this single dose of methotrexate is not successful and a further dose of methotrexate is required or surgery may be needed. A more effective treatment is therefore needed to reduce the requirement for repeat doses of methotrexate or surgery. Previous studies using a drug called gefitinib (a drug used in lung cancer patients) in addition to methotrexate have shown promising results, as it appears to have a blocking effect on the cells found in an ectopic pregnancy. These studies were in a small number of women and so a larger study is needed to prove the effectiveness of this treatment. The aim of this study is to find out whether treatment using methotrexate and gefitinib is more effective than methotrexate alone.

Who can participate?
Women aged between 18 and 50 who are being treated for an ectopic pregnancy.

What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive an injection of methotrexate and then take tablets containing gefitinib once a day for seven days. Those in the second group receive an injection of methotrexate and then take tablets containing a placebo (dummy drug) once a day for seven days. Participants in both groups are then monitored for three months in order to find out whether they required any additional treatment (surgery or further methotrexate).

What are the possible benefits and risks of participating?
Not provided at time of registration

Where is the study run from?
Royal Infirmary of Edinburgh (lead site) and 49 other centres throughout the England, Scotland and Wales (UK)

When is the study starting and how long is it expected to run for?
April 2016 to December 2018

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Ms Kirandeep Sunner
gem3@trials.bham.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Mrs Ann Doust

ORCID ID

Contact details

GEM3 Trial Management Team
The University of Edinburgh
Room S7128
2nd Floor Simpson Centre
Royal Infirmary of Edinburgh
51 Little France Crescent
Edinburgh
EH16 4SA
United Kingdom
+44131 242 9492
gem3@ed.ac.uk

Additional identifiers

EudraCT number

2015-005013-76

ClinicalTrials.gov number

Protocol/serial number

AC15004

Study information

Scientific title

Scientific title as of 22/11/2018:
A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3)

Previous scientific title:
A double blind placebo controlled trial of a combination of methotrexate and gefitinib versus methotrexate alone as a treatment for ectopic pregnancy

Acronym

GEM3

Study hypothesis

Study hypothesis as of 23/11/2018:
A combination of intramuscular methotrexate and oral gefitinib, an EGFR anatagonist, is more effective in preventing the need for surgery in the treatment of ectopic pregnancy than methotrexate alone.

Previous study hypothesis:
Combination of intramuscular methotrexate and oral gefitinib, an EGFR antagonist, is a more effective treatment for ectopic pregnancy than methotrexate alone.

Ethics approval

Scottish A Research Ethics Committee, 29/02/2016, ref: 16/SS/0014

Study design

Multi-centre double-blind randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Condition

Ectopic Pregnancy

Intervention

Participants will be randomly allocated to one of two study arms using a computer-based algorithm to avoid chance imbalances in stratification variables.

Arm 1: Participants are administered 50mg/m2 methotrexate as intramuscular injection and take a single tablet containing 250mg gefitinib daily for seven days.

Arm 2: Participants are administered 50mg/m2 methotrexate as intramuscular injection and take a single tablet containing a placebo daily for seven days.

Participants will be monitored as per local standards care for an ectopic pregnancy post randomisation so they will have their routine blood tested which includes checking safety bloods and measurement of hCG levels. In addition to this the trial requires participants to have an additional safety blood to ensure that the treatment is not causing any untoward effects. Once the hCG level has dropped to 15iu/L the research team will call the participant 3 months after resolution to complete the 3 month questionnaire.

Intervention type

Drug

Phase

Phase III

Drug names

Gefitinib

Primary outcome measure

Primary outcome measure as of 23/11/2018:
Surgical intervention for treatment of the index EP (salpingectomy/salpingostomy by laparoscopy/laparotomy) is measured using patient notes at each visit until resolution of EP.

Previous primary outcome measure:
Need for surgical intervention for treatment of ectopic pregnancy is determined through interviews with patients at clinic appointments and at the 3 month follow up telephone call.

Secondary outcome measures

Secondary outcome measures as of 23/11/2018:
1. The need for a second dose of MTX is measured using medical notes at each visit.
2. Number of days to resolution of tEP is measured using blood test at baseline and then at resolution is defined by serum hCG levels falling to non-pregnancy levels (hCG ≤ 15 IU/L), which corresponds to a negative urinary pregnancy test using the most sensitive assays.
3. Number of treatment-associated hospital visits until resolution or emergency ‘rescue’ surgery is measured using patient interviews at each hospital visit.
4. Return to menses, assessed 3 months post-resolution by telephone interview.
5. Safety and tolerability: women will be assessed clinically (at each contact as per local policies) and biochemically (haematological, renal, and liver function tests between days 14–21 post-treatment) and these will be repeated if deemed clinically significant.
6. Acceptability of treatment: assessed 3 months post-resolution by participant-reported Likert scores via a telephone interview

Previous secondary outcome measures:
1. Need for additional methotrexate treatment is determined through interviews with patients at clinic appointments
2. Time to hCG resolution (days) from randomisation to hCG level of ≤15 iu/L calculated from the day of diagnosis to the day the hCG dropped to 15iu/L, is determined through blood testing at baseline and throughout the trial based on local trust policy
3. Number of treatment-associated hospital visits until resolution or scheduled/emergency surgery is determined through medical record review at 3 months
4. Safety/tolerability is assessed through blood testing undertaken within 3 days of randomisation and 14-21 days post randomisation and patient interviews at clinic visits 14-21 days post randomisation
5. Acceptaibility of treatment is assessed using the Likert score after 3 months through a follow up telephone call at 3 months
6. Return to menses is assessed after 3 months post resolution of the ectopic pregnancy through a follow up telephone call at 3 months

Overall trial start date

01/04/2016

Overall trial end date

03/02/2020

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Clinical decision made for treatment of tubal EP with MTX
2. Able to understand all information (written and oral) presented (using an interpreter if necessary) and provide signed consent
3. Women 18-50 years at time of randomisation
4. Diagnosis of either:
4.1. Definite tubal EP (extrauterine gestational sac with yolk sac and/or embryo, without cardiac activity on USS) or
4.2. Clinical decision of probable tubal EP (extrauterine sac-like structure or inhomogeneous adnexal mass on USS with a background of sub optimally rising serum hCG concentrations (on at least 2 different days)
5. Pre-treatment 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 3 calendar days of treatment
8. Able to comply with treatment and willing to participate in follow up

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

328

Participant exclusion criteria

1. Women with a Ppregnancy of unknown location (PUL)
2. Evidence of intrauterine pregnancy
3. Breastfeeding
4. Hypersensitivity to gefitinib
5. Women with mean EP mass on ultrasound greater than 3.5cm (mean dimensions)
6. Women with evidence of intrauterine pregnancy
7. Evidence of significant intra-abdominal bleed on ultrasound USS defined by echogenic free fluid above the uterine fundus or surrounding ovary within 1 calendar day of treatment
8. Significant abdominal pain, guarding/rigidity
9. Clinically significant abnormal liver/renal/haematological indices noted within 3 calendar days of treatment
10. Galactose intolerance
11. Significant pre-existing dermatological disease eg severe psoriasis/eczema
12. Significant pulmonary disease eg severe/uncontrolled asthma
13. Significant gastrointestinal medical illness eg Crohn’s disease/ulcerative colitis
14. Participating in any other clinical trial of an investigational medicinal product
15. Previous participation in GEM3
16. Women of Japanese ethnicity

Recruitment start date

02/11/2016

Recruitment end date

31/12/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Royal Infirmary of Edinburgh
51 Little France Crescent
Edinburgh
EH16 4SA
United Kingdom

Sponsor information

Organisation

University of Edinburgh and NHS Lothian ACCORD

Sponsor details

The Queens Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom
+44 121 415 91111
accord@nhslothian.scot.nhs.uk

Sponsor type

Other

Website

http://www.accord.ed.ac.uk

Funders

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal.

IPD sharing plan:
The current data sharing plans for the current study are unknown and will be made available at a later date

Intention to publish date

28/02/2020

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

1. 2018 protocol in: https://www.ncbi.nlm.nih.gov/pubmed/30458863

Publication citations

Additional files

Editorial Notes

23/11/2018: The following changes were made: 1. The study hypothesis was updated 2. The plain English summary was updated. 3. The primary outcome measure was updated. 4. The secondary outcome measure was updated. 22/11/2018: The following changes were made: 1. The contact details were updated. 2. The scientific title was updated. 3. Publication reference added. 14/11/2018: The following changes were made: 1. The recruitment end date was changed from 01/10/2018 to 31/12/2019. 2. The overall trial end date was changed from 03/12/2018 to 03/02/2020. 3. The intention to publish date was changed from 31/12/2019 to 28/02/2020. 03/11/2016: The recruitment start date has been updated from 01/10/2016 to 02/11/2016. 19/09/2016: Verified study information with principal investigator.