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Trial registered on ANZCTR


Registration number
ACTRN12614000838617
Ethics application status
Approved
Date submitted
19/06/2014
Date registered
7/08/2014
Date last updated
22/11/2019
Date data sharing statement initially provided
22/11/2019
Date results information initially provided
22/11/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Investigating the Prevention of Endometrial CAncer with Metformin (PECAM Study)
Scientific title
Investigating the Prevention of Endometrial CAncer with Metformin (PECAM Study)- a study involving postmenopausal women with hormone receptor positive breast cancer who are currently on tamoxifen therapy for at least 6 weeks.
Secondary ID [1] 284834 0
NIL
Universal Trial Number (UTN)
U1111-1158-2065
Trial acronym
PECAM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Endometrial cancer 292221 0
Breast cancer 292222 0
Condition category
Condition code
Cancer 292557 292557 0 0
Womb (Uterine or endometrial cancer)
Cancer 292558 292558 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Metformin 850mg oral twice daily for 12 months commencing with commencement of tamoxifen. Adherence will be monitored by return tablet count.
Intervention code [1] 289626 0
Prevention
Intervention code [2] 289627 0
Treatment: Drugs
Comparator / control treatment
Placebo will be identical tablets to the metformin 850mg tablets
Control group
Placebo

Outcomes
Primary outcome [1] 292420 0
The primary outcome is the effect of metformin therapy on the expression of genes in endometrial tissue on biopsy encoding:
1) proteins in the LKB1/AMPK pathway, which inhibits cell proliferation;
2) mammalian target of rapamycin (mTOR), which stimulates endometrial growth;
3) the cytochrome P450 enzyme, aromatase, which is essential for oestrogen biosynthesis in the endometrium, and hence endometrial growth.
These are co-primary outcomes as they are dependent variables
Timepoint [1] 292420 0
12 months
Secondary outcome [1] 308905 0
The effects of metformin, versus placebo, after 52 weeks of treatment on endometrial thickness, assessed by TVU+ saline infusion sonohysterography (SIS), and development of any other endometrial abnormalities on TVU (polyps, hyperplasia, subendometrial thickening or fibroids).


Timepoint [1] 308905 0
12 months
Secondary outcome [2] 308990 0
The effects of metformin, versus placebo, after 52 weeks of treatment on endometrial histopathology of the endometrial biopsy tissue.
Timepoint [2] 308990 0
12 months
Secondary outcome [3] 308991 0
Associations between the effects of metformin on the endometrium ( by transvaginal ultrasound) and clinical characteristics and biochemistry, including fasting glucose, insulin, adiponectin and leptin ( by blood tests).
Timepoint [3] 308991 0
12 months
Secondary outcome [4] 308992 0
The association between TVU+SIS findings and endometrial pathology on biopsy.
Timepoint [4] 308992 0
12 months

Eligibility
Key inclusion criteria
Postmenopausal women, aged < 75 years, who are currently taking tamoxifen therapy for at least 6 weeks for treatment of hormone receptor positive breast cancer.
Minimum age
18 Years
Maximum age
74 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Women who are premenopausal / perimenopausal / > 75 years old
2. Women with advanced breast cancer and likely to have progression of their disease within the study period, as assessed by their treating oncologist.

3. Women with any of the following on screening:

a)Use of any systemic hormones in the last 6 months;
b) serious endocrine disorder with systemic disease;
c) alcohol consumption greater than 3 standard drinks per day;
d) known acute or chronic renal, liver disease or cardiovascular disease;
e) insulin dependent diabetes mellitus or use of an oral hypoglycemic agent;


4. <6 months amenorrhoea so that the likelihood of ovulatory cycles during the study will be small.

5. EH with atypia or ECa on endometrial biopsy or hysteroscopy and curettage.
6. Women who, in the opinion of the investigator, are a poor medical or psychiatric risk for treatment in a research protocol.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
1:1 randomization.

Allocation concealment will be strictly maintained. The investigators, study centre personnel and participants will remain blinded throughout the study.

The investigators, study centre personnel and participants will remain blinded throughout the study.

In order to maintain allocation concealment, a piece of paper with the group allocation (metformin or placebo) assigned to each study number in the randomization list will be put into opaque envelopes numbered consecutively 1- 120. Randomization will occur when the envelope with the patient’s study number on it is opened.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be independently computer generated and stratified by body mass index (BMI) such that there will be equal numbers of women with BMI > 30kg/m2 per group.

Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary study outcome is the effect of metformin on the pathway whereby metformin inhibits mTOR action, the pathway whereby it stimulates p53 and inhibits the cell cycle, and the pathway whereby it inhibits aromatase expression via AMPK and sequestration of CRTC2 in the endometrium of women at high risk of, or who have, EH.
In an earlier study, hyperproliferative and hyperplastic endometrial tissue from 24 women receiving tamoxifen exhibited higher phosphorylation levels at specific amino residues of AKT in the order of (2.6 to 3.5 fold) and for mTOR (10 to 20 fold) compared with benign endometrial tissue from non treated patients (n=28). Our hypothesis is that metformin therapy will reverse this effect.
Based on our previous research, we anticipate about 20% of women will not have evaluable endometrial biopsy samples. Thus, taking a pragmatic approach, we will recruit 130 women and randomise half (65) to each treatment. Allowing for a conservative 20% non completion rate and 20% unevaluable samples, we aim to have evaluable endometrial tissue and study data for 40 women per treatment arm.
The distribution of the data will be examined and non normally distributed data will be transformed. Baseline levels in the treatment groups will be examined. If there are no significant between- group differences at baseline, comparison of between-group differences at the end of the study would be by t-test (or non-parametric equivalent). If there is any chance baseline difference, then an analysis of variance will be performed, adjusting for the baseline difference.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 8315 0
3004 - St Kilda Road Melbourne

Funding & Sponsors
Funding source category [1] 289442 0
Government body
Name [1] 289442 0
National Health and Medical Research Council of Australia
Address [1] 289442 0
Building Level 1, 16 Marcus Clarke St, Canberra ACT 2601, Australia
Country [1] 289442 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Rd Clayton VIC Australia 3168
Country
Australia
Secondary sponsor category [1] 288132 0
None
Name [1] 288132 0
none
Address [1] 288132 0
Country [1] 288132 0
Other collaborator category [1] 278009 0
Individual
Name [1] 278009 0
Dr Mitchell Chipman
Address [1] 278009 0
Victorian Breast Oncology Group
Level 2,166 Gipps Street,East Melbourne Vic 3002
Country [1] 278009 0
Australia
Other collaborator category [2] 278010 0
Individual
Name [2] 278010 0
A/Prof Shane White
Address [2] 278010 0
Medical Oncologist, Suite 13, Warringal Medical Centre, 214 Burgundy Street, Heidelberg, Victoria, 3081
Country [2] 278010 0
Australia
Other collaborator category [3] 278011 0
Other Collaborative groups
Name [3] 278011 0
Camberwell Ultrasound for Women
Address [3] 278011 0
64 Auburn Grove, Hawthorn East VIC 3123,
Country [3] 278011 0
Australia
Other collaborator category [4] 278012 0
Individual
Name [4] 278012 0
Dr Kristy Brown
Address [4] 278012 0
MIMR-PHI Institute
27-31 Wright Street, Clayton VIC 3168
Country [4] 278012 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291201 0
Monash University Human Research Ethics Committee
Ethics committee address [1] 291201 0
Monash University
Wellington Rd
Clayton VIC 3168
Ethics committee country [1] 291201 0
Australia
Date submitted for ethics approval [1] 291201 0
Approval date [1] 291201 0
17/02/2014
Ethics approval number [1] 291201 0
CF13/3870. 2013001982

Summary
Brief summary
The aim of this study is to determine if we can prevent the development of uterine cancer in women who need to take tamoxifen therapy.

We will investigate whether metformin, commonly used to treat diabetes, blocks cell pathways by which tamoxifen (and oestrogen) stimulates growth of the lining of the uterus.

This study will enable us to determine if there is a potential role for metformin
a) to prevent changes to the uterine lining in women treated with tamoxifen
b) possibly prevent cancer of the uterus

This study also offers a unique opportunity for us to determine whether all women with breast cancer should have ultrasound of their uterus before starting tamoxifen and after one year of therapy.

Reasons for the study:
Over 75% of women diagnosed with breast cancer in Australia have hormone sensitive cancer. Of these, at least 1/3 will be treated with a drug called tamoxifen, which blocks oestrogen action. A recent large study has shown that 10 years of tamoxifen therapy is more effective than 5 years in prolonging survival.

However, a downside of tamoxifen therapy is a 75% increase in the risk of uterine (endometrial) cancer.

Presently there is no treatment to prevent endometrial cancer in women treated with tamoxifen, or for that matter for women in general. Endometrial cancer, the most common gynaecologic cancer, affects approximately 1 in 73 Australian women by the age of 75 years and 1 in 52 by the age of 85 years.

We do know that:
tamoxifen is associated with a 7 fold increase in endometrial cancer over 5 years
most women who develop an endometrial abnormality on tamoxifen do so in the first year of treatment
1 in 5 women have an endometrial abnormality before starting tamoxifen (this increases the risk for tamoxifen-induced changes)


We will recruit women with hormone receptor positive breast cancer who are
postmenopausal,
less than 75 years old
not diabetic.
Trial website
http://womenshealth.med.monash.edu.au
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 49330 0
Prof Susan Davis
Address 49330 0
Women's Health Research Program,
Department of Epidemiology and Preventive Medicine
School of Public Health and Preventive Medicine
Monash University
99 Commercial Rd, Melbourne VIC 3004
Country 49330 0
Australia
Phone 49330 0
+61399030827
Fax 49330 0
Email 49330 0
susan.davis@monash.edu
Contact person for public queries
Name 49331 0
Prof Susan Davis
Address 49331 0
Women's Health Research Program,
Department of Epidemiology and Preventive Medicine
School of Public Health and Preventive Medicine
Monash University
99 Commercial Rd, Melbourne VIC 3004
Country 49331 0
Australia
Phone 49331 0
+61399030827
Fax 49331 0
Email 49331 0
susan.davis@monash.edu
Contact person for scientific queries
Name 49332 0
Prof Susan Davis
Address 49332 0
Women's Health Research Program,
Department of Epidemiology and Preventive Medicine
School of Public Health and Preventive Medicine
Monash University
99 Commercial Rd, Melbourne VIC 3004
Country 49332 0
Australia
Phone 49332 0
+61399030827
Fax 49332 0
Email 49332 0
susan.davis@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 5811 0
Davis SR1, Robinson PJ1, Jane F1, White S2, Brown KA3, Piessens S4, Edwards A4, McNeilage J5, Woinarski J5, Chipman M6, Bell RJ1. The benefits of adding metformin to tamoxifen to protect the endometrium-A randomized placebo-controlled trial. Clin Endocrinol (Oxf). 2018 Nov;89(5):605-612. doi: 10.1111/cen.13830. Epub 2018 Sep 9.
Attachments [1] 5811 0
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary