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
A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3)
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 50 mg/m2 methotrexate as intramuscular injection and take a single tablet containing 250 mg gefitinib daily for 7 days.
Arm 2: Participants are administered 50 mg/m2 methotrexate as intramuscular injection and take a single tablet containing a placebo daily for 7 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, methotrexate
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
01/03/2022
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
338
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
30/04/2021
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Royal Infirmary of Edinburgh
NHS Lothian
51 Little France Crescent
Edinburgh
EH16 4SA
United Kingdom
Trial participating centre
Princess Royal Maternity Hospital
NHS Greater Glasgow and Clyde
Glasgow
G31 2ER
United Kingdom
Trial participating centre
Crosshouse Hospital
NHS Ayrshire and Arran
Kilmarnock
KA2 0BE
United Kingdom
Trial participating centre
Ninewells Hospital
NHS Tayside
Dundee
DD2 1SG
United Kingdom
Trial participating centre
West Suffolk Hospital
West Suffolk NHS Foundation Trust
Bury St Edmunds
IP33 2QZ
United Kingdom
Trial participating centre
Burnley General Hospital
East Lancashire Hospitals NHS Trust
Burnley
BB10 2PQ
United Kingdom
Trial participating centre
James Cook Hospital
South Tees Hospital NHS Foundation Trust
South Tees
TS4 3BW
United Kingdom
Trial participating centre
Chesterfield Royal Hospital
Chesterfield Royal NHS Foundation Trust
Chesterfield
S44 5BL
United Kingdom
Trial participating centre
Norfolk and Norwich University Hospital
Norfolk and Norwich University Hospital NHS Trust
Norwich
NR4 7UY
United Kingdom
Trial participating centre
Countess of Chester Hospital
The Countess of Chester Hospital NHS Foundation Trust
Chester
CH2 1UL
United Kingdom
Trial participating centre
St Mary's Hospital
Central Manchester University Hospital NHS Foundation Trust
Manchester
M13 9WL
United Kingdom
Trial participating centre
Heartlands Hospital
Heart of England NHS Foundation Trust
Birmingham
B9 5SS
United Kingdom
Trial participating centre
Stoke Mandeville Hospital
Buckinghamshire Healthcare NHS Trust
Aylesbury
HP21 8AL
United Kingdom
Trial participating centre
Forth Valley Hospital
NHS Forth Valley
Larbert
FK5 4WR
United Kingdom
Trial participating centre
Addenbrookes Hospital
Cambridge University Hospital NHS Foundation Trust
Cambridge
CB2 0QQ
United Kingdom
Trial participating centre
University Hospital Wishaw
NHS Lanarkshire
Wishaw
ML2 0DP
United Kingdom
Trial participating centre
Princess Alexandra Hospital
The Princess Alexandra Hospital NHS Trust
Harlow
CM20 1QX
United Kingdom
Trial participating centre
New Cross Hospital
The Royal Wolverhampton NHS Trust
Wolverhampton
WV10 0QP
United Kingdom
Trial participating centre
East Surrey Hospital
Surrey and Sussex NHS Trust
Redhill
RH1 5RH
United Kingdom
Trial participating centre
Frimley Park Hospital
Frimley Park Hospital NHS Trust
Camberley
GU16 7UJ
United Kingdom
Trial participating centre
Warrington Hospital
Warrington and Halton Hospitals NHS Foundation Trust
Warrington
WA5 1QG
United Kingdom
Trial participating centre
University Hospital Coventry
University Hospitals Coventry and Warwickshire NHS Trust
Coventry
CV2 2DX
United Kingdom
Trial participating centre
Victoria Hospital
NHS Fife
Kirkcaldy
KY1 2SD
United Kingdom
Trial participating centre
Royal Stoke Hospital
University Hospitals North Midlands NHS Trust
Stoke-on-Trent
ST4 6QG
United Kingdom
Trial participating centre
Hinchingbrooke Hospital
North West Anglia NHS Foundation Trust
Huntingdon
PE29 6NT
United Kingdom
Trial participating centre
St Thomas' Hospital
Guys and St Thomas' NHS Foundation Trust
London
SE1 7EH
United Kingdom
Trial participating centre
The Queen's Medical Centre
Nottingham University NHS Trust
Nottingham
NG7 2UH
United Kingdom
Trial participating centre
Darent Valley Hospital
Dartford and Gravesham NHS Trust
Dartford
DA2 8DA
United Kingdom
Trial participating centre
St Michael's Hospital
University Hospitals Bristol NHS Foundation Trust
Bristol
BS2 8EG
United Kingdom
Trial participating centre
West Middlesex Hospital
Chelsea and Westminster Hospitals NHS Foundation Trust
Isleworth
TW7 6AF
United Kingdom
Trial participating centre
Leighton Hospital
Mid Cheshire Hospitals NHS Foundation Trust
Crewe
CW1 4QJ
United Kingdom
Trial participating centre
St Helier Hospital
Epsom and St Helier University Hospitals NHS Trust
Carshalton
SM5 1AA
United Kingdom
Trial participating centre
Peterborough City Hospital
North West Anglia Foundation Trust
Peterborough
PE3 9GZ
United Kingdom
Trial participating centre
King's College Hospital
King's College Hospital NHS Foundation Trust
London
SE5 9RS
United Kingdom
Trial participating centre
Raigmore Hospital
NHS Highland
Inverness
IV2 3UJ
United Kingdom
Trial participating centre
Hillingdon Hospital
Hillingdon Hospitals NHS Foundation Trust
Uxbridge
UB8 3NN
United Kingdom
Trial participating centre
Birmingham Women's Hospital
Birmingham Women's and Children's NHS Foundation Trust
Birmingham
B15 2TG
United Kingdom
Trial participating centre
Sunderland Royal Hospital
City Hospitals Sunderland NHS Trust
Sunderland
SR4 7TP
United Kingdom
Trial participating centre
Southend Hospital
Southend University Hospital NHS Foundation Trust
Southend
SS0 0RY
United Kingdom
Trial participating centre
University College London Hospital
University College London Hospital NHS Foundation Trust
London
NW1 2BU
United Kingdom
Trial participating centre
Darlington Memorial Hospital
County Durham and Darlington NHS Foundation Trust
Darlington
DL3 6HX
United Kingdom
Trial participating centre
University Hospital of Durham
County Durham and Darlington NHS Foundation Trust
Durham
DH1 5TW
United Kingdom
Trial participating centre
Scunthorpe General Hospital
Northern Lincolnshire and Goole Hospitals NHS Foundation Trust
Scunthorpe
DN15 7BH
United Kingdom
Trial participating centre
Royal Hallamshire Hospital
Sheffield Teaching Hospitals NHS Foundation Trust
Sheffield
S10 2JF
United Kingdom
Trial participating centre
Queen's Hospital Romford
Barking, Havering and Redbridge University Hospitals NHS Trust
Romford
RM7 0AG
United Kingdom
Trial participating centre
Worcestershire Royal Hospital
Worcester Acute Hospital NHS Trust
Worcester
WR5 1DD
United Kingdom
Trial participating centre
Gloucestershire Royal Hospital
Gloucestershire Hospitals NHS Foundation Trust
Gloucester
GL1 3NN
United Kingdom
Trial participating centre
Whiston Hospital
St Helen's and Knowsley Teaching Hospital NHS Trust
Whiston
L35 5DR
United Kingdom
Trial participating centre
Furness General Hospital
University Hospital of Morecombe Bay NHS Foundation Trus
Barrow-in-Furness
LA14 4LF
United Kingdom
Trial participating centre
Queen's Hospital
University Hospitals of Derby and Burton NHS Foundation Trust
Burton
DE13 0RB
United Kingdom
Trial participating centre
Queen Charlotte and Chelsea Hospital
Imperial College Healthcare NHS Trust
London
W12 0HS
United Kingdom
Trial participating centre
Southmead Hospital
North Bristol NHS Trust
Bristol
BS10 5NB
United Kingdom
Trial participating centre
Homerton Hospital
Homerton University NHS Foundation Trust
London
E9 6SR
United Kingdom
Trial participating centre
Epsom General Hospital
Epsom and St Helier University Hospitals NHS Trust
Epsom
KT18 7EG
United Kingdom
Trial participating centre
Warwick Hospital
South Warwickshire NHS Foundation Trust
Warwick
CV34 5BW
United Kingdom
Trial participating centre
Rotherham General Hospital
The Rotherham NHS Foundation Trust
Rotherham
S60 2UD
United Kingdom
Trial participating centre
Basildon University Hospital
Basildon and Thurrock University Hospitals NHS Foundation Trust
Basildon
SS16 5NL
United Kingdom
Trial participating centre
Royal Free Hospital
Royal Free London NHS Foundation Trust
London
NW3 2QG
United Kingdom
Trial participating centre
Cardiff Royal Infirmary
Cardiff and Vale University Health Board
Cardiff
CF24 0JT
United Kingdom
Trial participating centre
Tameside Hospital
Tameside and Glossop Integrated Care NHS Foundation Trust
Ashton-under-Lyme
OL6 9RW
United Kingdom
Trial participating centre
Wrexham Maelor Hospital
Betsi Cadwaladr University Health Board
Wrexham
LL13 7TD
United Kingdom
Trial participating centre
St Peter's Hospital
Ashford and St Peter's Hospitals NHS Foundation Trust
Chertsey
KT16 0PZ
United Kingdom
Trial participating centre
Doncaster Royal Infirmary
Doncaster and Bassetlaw Teaching Hospitals NHS Foundation Trust
Doncaster
DN2 5LT
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
Funders
Funder type
Government
Funder name
National Institute for Health Research
Alternative name(s)
NIHR
Funding Body Type
government organisation
Funding Body Subtype
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
28/03/2022
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