Metformin in non-diabetic women with endometrial cancer

ISRCTN	ISRCTN81570194
DOI	https://doi.org/10.1186/ISRCTN81570194
Secondary identifying numbers	METFORM01

Submission date: 20/12/2011
Registration date: 22/05/2012
Last edited: 29/01/2019

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Endometrial cancer, or cancer of the lining of the womb, has become the most common cancer of the reproductive tract in British women. Obese women are at increased risk of the disease and are also more likely to die from it. The recent obesity epidemic means that more women than ever before are developing the disease. Endometrial cancer can usually be cured by surgery but for obese or elderly women, surgery may be dangerous. It also leaves a woman infertile. There is an urgent need to prevent this cancer and to develop effective non-surgical treatments.
Metformin is one of the drugs used to treat diabetes. Recently, its role in the treatment of cancer has been explored. Diabetics who take metformin for many years are less likely to develop and die from cancer than those who do not. They are also more likely to respond well to chemotherapy if cancer does develop. Metformin has been shown to slow down the growth of breast, prostate, colon and endometrial cancers in the laboratory. Early studies in breast cancer patients have had promising results but metformin has never been tested in patients with endometrial cancer before.
This study will test metformin in patients with atypical endometrial hyperplasia (pre-cancer) and endometrial cancer. Women with atypical endometrial hyperplasia or endometrial cancer will receive metformin for one to four weeks while they wait for their surgery. The effects of metformin will then be assessed by comparing the characteristics of the endometrial tumour, taken at diagnosis, with those of the tumour removed at surgery. We will look at how fast the cells are multiplying and the proportion of cells undergoing cell death, and try to determine whether metformin affects key cancer pathways. It is hoped that the results of this small study will inform the design of a larger one.

Who can participate?
Non-diabetic women, aged 18 years or more who have recently been diagnosed with atypical endometrial hyperplasia or type I endometrial cancer.

What does the study involve?
Women taking part in the study will take metformin tablets twice a day for one to four weeks while they wait for their hysterectomy (Metformin Group). Other women taking part in the study will receive no treatment with metformin (Control Group). Both groups of women will have blood samples and a sample of the lining of the womb (endometrial biopsy) taken at recruitment and at hysterectomy. Those women who took metformin will be asked to report their experiences of taking the tablets by filling out a questionnaire.

What are the possible risks and benefits of participating?
There will be no direct benefit to those taking part. But there should be benefits in future for women with endometrial cancer because this study will help us decide whether metformin is useful in the treatment of this disease.
The main risk of taking metformin is mild tummy upset, nausea or diarrhoea, but this is usually short-lived. Women can not drink alcohol while they are on metformin tablets. Rarely, patients taking metformin have become very unwell because of and allergic reaction (anaphylaxis) or kidney failure (lactic acidosis). Participants will be closely monitored to prevent this happening and tablets will be stopped immediately and appropriate medical treatment started if there are any concerns.

Where is the study run from?
St Marys Hospital, Tameside Hospital and the Royal Oldham Hospital in Greater Manchester (UK).

When is the study starting and how long is it expected to run for?
The study will start mid 2012 and is likely to run for two to three years.

Who is funding the study?
1. Central Manchester University Hospitals NHS Foundation Trust - Experimental Medicine Scheme Grant (2011)
2. Wellbeing of Women Research Training Fellowship (2012)

Who is the main contact?
Dr Emma Crosbie
emma.crosbie@manchester.ac.uk
Dr Vanitha Sivalingam
Vanitha.sivalingam@manchester.ac.uk

Contact information

Dr Emma Crosbie
Scientific

NIHR Clinical Lecturer in Gynaecological Oncology
University of Manchester
St Mary's Hospital
Hathersage Road
Manchester
M13 9WL
United Kingdom

Phone	+44 (0)161 701 6912
Email	emma.crosbie@manchester.ac.uk

Study information

Study design	Non-randomised controlled pre-surgical window study
Primary study design	Interventional
Secondary study design	Non randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	Proof of mechanism pre-surgical window trial of metformin in non-diabetic women with endometrial carcinoma: a feasibility study
Study objectives	Metformin reduces cellular proliferation in type 1 endometrial cancer.
Ethics approval(s)	North West Haydock Research Ethics Committee, 19/08/2011, ref: 11/NW/0442
Health condition(s) or problem(s) studied	Type 1 or endometrioid adenocarcinoma of the endometrium
Intervention	Current interventions as of 06/09/2013: Metformin Group Participants in the Metformin group will receive 850 mg metformin hydrochloride twice daily by mouth for one to four weeks between recruitment into the trial and surgery for endometrial cancer. They will discontinue their metformin the night before surgery. They will be asked to complete a tolerability of metformin treatment questionnaire two weeks after surgery. They do not require any other follow up as a result of participation in this study. Control Group Participants in the Control group will NOT receive Metformin during the one to four week period between recruitment and surgery. They do not require any follow up after their surgery. Previous interventions: Metformin Group Participants in the Metformin group will receive 850mg metformin hydrochloride twice daily by mouth for two to four weeks between recruitment into the trial and surgery for endometrial cancer. They will discontinue their metformin the night before surgery. They will be asked to complete a tolerability of metformin treatment questionnaire two weeks after surgery. They do not require any other follow up as a result of participation in this study. Control Group Participants in the Control group will NOT receive Metformin during the two to four week period between recruitment and surgery. They do not require any follow up after their surgery.
Intervention type	Other
Primary outcome measure	Test for Ki-67
Secondary outcome measures	Test for: 1. Phospho-H3 2. Cleaved caspase-3 and cleaved PARP 3. AKT, phosphorylated AKT 4. ERK1,2, phosphorylated ERK 1,2 5. PTEN, strathmin 6. Phosphorylation status of key signal transduction molecules (mTOR pathway) 7. Insulin receptor/phosphorylated insulin receptor 8. Fasting serum glucose, insulin, IGFBP-1 and C-peptide levels 9. Tolerability of metformin treatment
Overall study start date	03/01/2012
Completion date	02/01/2015

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Female
Target number of participants	30
Key inclusion criteria	Current inclusion criteria as of 06/09/2013: 1. Biopsy-proven atypical endometrial hyperplasia or type 1 endometrial carcinoma 2. Scheduled for surgical treatment in 1 or more weeks time 3. Written informed consent to participate in the trial 4. Females aged 18 years or older Previous inclusion criteria: 1. Biopsy-proven type 1 endometrial carcinoma 2. Scheduled for surgical treatment in 2 or more weeks time 3. Written informed consent to participate in the trial 4. Females aged 18 years or older
Key exclusion criteria	Current exclusion criteria as of 06/09/2013: 1. Already receiving metformin treatment 2. Type 1 or 2 diabetes mellitus on drug treatment 3. Renal or hepatic impairment 4. Unable to comply with treatment protocol Previous exclusion criteria: 1. Already receiving metformin treatment 2. Type 1 or 2 diabetes mellitus 3. Renal or hepatic impairment 4. Unable to comply with treatment protocol
Date of first enrolment	03/01/2012
Date of final enrolment	02/01/2015

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

NIHR Clinical Lecturer in Gynaecological Oncology

Manchester
M13 9WL
United Kingdom

Sponsor information

Central Manchester University Hospitals NHS Foundation Trust (UK)
Hospital/treatment centre

c/o Dr Lynne Webster
Head of Research Office
Research and Innovation Division
Postgraduate Medical Centre
Oxford Road
Manchester
M13 9WL
England
United Kingdom

Website	http://www.cmft.nhs.uk/
"ROR"	https://ror.org/00he80998

Funders

Funder type

University/education

University of Manchester (UK)
Government organisation / Universities (academic only)

Alternative name(s): The University of Manchester, University of Manchester UK, University of Manchester in United Kingdom, UoM
Location: United Kingdom

Central Manchester University Hospitals NHS Foundation Trust, Experimental Medicine Scheme Grant (UK)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	02/02/2016	29/01/2019	Yes	No
HRA research summary			28/06/2023	No	No

Editorial Notes

29/01/2019: Publication reference added
07/03/2017: No publications found in PubMed, verifying study status with principal investigator
17/04/2014: The trial has completed recruitment.