A trial designed to treat women with a diagnosis of ectopic pregnancy with a combination of methotrexate (standard treatment) and gefitinib (trial agent)
| ISRCTN | ISRCTN67795930 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN67795930 |
| EudraCT/CTIS number | 2015-005013-76 |
| Secondary identifying numbers | AC15004 |
- Submission date
- 15/09/2016
- Registration date
- 15/09/2016
- Last edited
- 06/11/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Pregnancy and Childbirth
Plain English summary of protocol
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
Contact information
Scientific
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
| Phone | +44 131 242 9492 |
|---|---|
| gem3@ed.ac.uk |
Study information
| Study design | Multi-centre double-blind randomised controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| 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) |
| Study acronym | GEM3 |
| Study objectives | 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(s) | Scottish A Research Ethics Committee, 29/02/2016, ref: 16/SS/0014 |
| Health condition(s) or problem(s) studied | 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | 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 study start date | 01/04/2016 |
| Completion date | 01/03/2022 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 50 Years |
| Sex | Female |
| Target number of participants | 338 |
| Total final enrolment | 328 |
| Key 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 |
| Key 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 |
| Date of first enrolment | 02/11/2016 |
| Date of final enrolment | 06/10/2021 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
51 Little France Crescent
Edinburgh
EH16 4SA
United Kingdom
Glasgow
G31 2ER
United Kingdom
Kilmarnock
KA2 0BE
United Kingdom
Dundee
DD2 1SG
United Kingdom
Bury St Edmunds
IP33 2QZ
United Kingdom
Burnley
BB10 2PQ
United Kingdom
South Tees
TS4 3BW
United Kingdom
Chesterfield
S44 5BL
United Kingdom
Norwich
NR4 7UY
United Kingdom
Chester
CH2 1UL
United Kingdom
Manchester
M13 9WL
United Kingdom
Birmingham
B9 5SS
United Kingdom
Aylesbury
HP21 8AL
United Kingdom
Larbert
FK5 4WR
United Kingdom
Cambridge
CB2 0QQ
United Kingdom
Wishaw
ML2 0DP
United Kingdom
Harlow
CM20 1QX
United Kingdom
Wolverhampton
WV10 0QP
United Kingdom
Redhill
RH1 5RH
United Kingdom
Camberley
GU16 7UJ
United Kingdom
Warrington
WA5 1QG
United Kingdom
Coventry
CV2 2DX
United Kingdom
Kirkcaldy
KY1 2SD
United Kingdom
Stoke-on-Trent
ST4 6QG
United Kingdom
Huntingdon
PE29 6NT
United Kingdom
London
SE1 7EH
United Kingdom
Nottingham
NG7 2UH
United Kingdom
Dartford
DA2 8DA
United Kingdom
Bristol
BS2 8EG
United Kingdom
Isleworth
TW7 6AF
United Kingdom
Crewe
CW1 4QJ
United Kingdom
Carshalton
SM5 1AA
United Kingdom
Peterborough
PE3 9GZ
United Kingdom
London
SE5 9RS
United Kingdom
Inverness
IV2 3UJ
United Kingdom
Uxbridge
UB8 3NN
United Kingdom
Birmingham
B15 2TG
United Kingdom
Sunderland
SR4 7TP
United Kingdom
Southend
SS0 0RY
United Kingdom
London
NW1 2BU
United Kingdom
Darlington
DL3 6HX
United Kingdom
Durham
DH1 5TW
United Kingdom
Scunthorpe
DN15 7BH
United Kingdom
Sheffield
S10 2JF
United Kingdom
Romford
RM7 0AG
United Kingdom
Worcester
WR5 1DD
United Kingdom
Gloucester
GL1 3NN
United Kingdom
Whiston
L35 5DR
United Kingdom
Barrow-in-Furness
LA14 4LF
United Kingdom
Burton
DE13 0RB
United Kingdom
London
W12 0HS
United Kingdom
Bristol
BS10 5NB
United Kingdom
London
E9 6SR
United Kingdom
Epsom
KT18 7EG
United Kingdom
Warwick
CV34 5BW
United Kingdom
Rotherham
S60 2UD
United Kingdom
Basildon
SS16 5NL
United Kingdom
London
NW3 2QG
United Kingdom
Cardiff
CF24 0JT
United Kingdom
Ashton-under-Lyme
OL6 9RW
United Kingdom
Wrexham
LL13 7TD
United Kingdom
Chertsey
KT16 0PZ
United Kingdom
Doncaster
DN2 5LT
United Kingdom
Sponsor information
University/education
The Queens Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ
Scotland
United Kingdom
| Phone | +44 121 415 91111 |
|---|---|
| accord@nhslothian.scot.nhs.uk | |
| Website | http://www.accord.ed.ac.uk |
"ROR" |
https://ror.org/03q82t418 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/08/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal. |
| IPD sharing plan | Anonymous data will be made available to other researchers upon request, for example for individual patient data meta-analysis, if the aim is to answer further resolved questions in a scientifically rigorous study design. Please contact Ann Doust (ann.doust@ed.ac.uk). This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it is important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data is used. #datasaveslives. You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation. (added 06/11/2023): BCTU operate a controlled-access model where we vet access requests (approved by CI), this ensures the data is delivered to only those who can demonstrate they have the plan and expertise to handle it appropriately. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 20/11/2018 | Yes | No | |
| Results article | 01/02/2023 | 06/02/2023 | Yes | No | |
| Results article | Secondary analysis | 13/05/2023 | 15/05/2023 | Yes | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Statistical Analysis Plan | version 2.0 | 23/02/2022 | 06/11/2023 | No | No |
Additional files
Editorial Notes
06/11/2023: The following changes were made to the trial record:
1. The statistical analysis plan was uploaded as an additional file.
2. The participant level data sharing statement was updated.
15/05/2023: Publication reference added.
06/02/2023: Publication reference added.
27/05/2022: The following changes have been made:
1. The recruitment end date has been changed from 30/09/2021 to 06/10/2021.
2. The total final enrolment has been added.
3. The intention to publish date has been changed from 28/03/2022 to 01/08/2022.
4. The IPD sharing statement has been added.
21/09/2021: Internal review.
13/04/2021: The recruitment end date was changed from 30/04/2021 to 30/09/2021.
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.
