A trial designed to treat women with a diagnosis of ectopic pregnancy with a combination of methotrexate (standard treatment) and gefitinib (trial agent)

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

https://www.ed.ac.uk/centre-reproductive-health/gem3

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

EudraCT number

2015-005013-76

ClinicalTrials.gov number

Protocol/serial number

AC15004

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)

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

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

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

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

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

Publication citations

10/09/2020: The following changes have been made: 1. The trial website has been added. 2. The target number of participants has been changed from 328 to 338. 3. The recruitment end date has been changed from 31/12/2019 to 30/04/2021. 4. The intention to publish date has been changed from 28/02/2020 to 28/03/2022. 5. Princess Royal Maternity Hospital, Crosshouse Hospital, Ninewells Hospital, West Suffolk Hospital, Burnley General Hospital, James Cook Hospital, Chesterfield Royal Hospital, Norfolk and Norwich University Hospital, Countess of Chester Hospital, St Mary's Hospital, Heartlands Hospital, Stoke Mandeville Hospital, Forth Valley Hospital, Addenbrookes Hospital, University Hospital Wishaw, Princess Alexandra Hospital, New Cross Hospital, East Surrey Hospital, Frimley Park Hospital, Warrington Hospital, University Hospital Coventry, Victoria Hospital, Royal Stoke Hospital, Hinchingbrooke Hospital, St Thomas' Hospital, The Queen's Medical Centre, Darent Valley Hospital, St Michael's Hospital, West Middlesex Hospital, Leighton Hospital, St Helier Hospital, Peterborough City Hospital, King's College Hospital, Raigmore Hospital, Hillingdon Hospital, Birmingham Women's Hospital, Sunderland Royal Hospital, Southend Hospital, University College London Hospital, Darlington Memorial Hospital, University Hospital of Durham, Scunthorpe General Hospital, Royal Hallamshire Hospital, Queen's Hospital Romford, Worcestershire Royal Hospital, Gloucestershire Royal Hospital, Whiston Hospital, Furness General Hospital, Queen's Hospital, Queen Charlotte and Chelsea Hospital, Southmead Hospital, Homerton Hospital, Epsom General Hospital, Warwick Hospital, Rotherham General Hospital, Basildon University Hospital, Royal Free Hospital, Cardiff Royal Infirmary, Tameside Hospital, Wrexham Maelor Hospital, St Peter's Hospital and Doncaster Royal Infirmary. 14/01/2020: The overall end date was changed from 03/02/2020 to 01/03/2022. 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 changged from"A double blind placebo controlled trial of a combination of methotrexate and gefitinib versus methotrexate alone as a treatment for ectopic pregnancy" to "A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3)". 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.