Pre-Surgical Metformin in Uterine Malignancy (Premium): A Multi-Centre, Randomised Double-Blind, Placebo-Controlled Phase 3 Trial

Abstract

Background: Endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumour growth in vitro. Pre-surgical window studies allow rapid in vivo assessment of anti-tumour activity. Previous window studies found short-term metformin treatment reduced endometrial cancer proliferation but these lacked methodological rigor, particularly control arms for comparison. PREMIUM was designed to definitively determine the anti-proliferative effect of metformin in vivo using a robust window study design. Methods: A randomised, double-blind, placebo-controlled phase 3 trial was conducted in five hospitals in England. Eligible women had biopsy-proven atypical endometrial hyperplasia or endometrioid endometrial cancer and were not receiving anti-diabetic medication. Women were computer-randomised (1:1) using the permuted block method (block size 30) to metformin (850mg daily for three days, increased to twice daily thereafter) or placebo for 1-5 weeks, until the evening before surgery. Participants and researchers were blinded to treatment group allocation. The primary outcome was post-treatment immunohistochemical expression of Ki-67 in the hysterectomy specimen; a modified intention-to-treat analysis included all women taking at least one dose of study drug and undergoing tumour biopsy within 72 hours of treatment discontinuation. Safety analysis included all women receiving at least one dose of drug. Findings: Between February 2015-2017, 93 women were randomised to metformin (n=47) or placebo (n=46), with five withdrawals (four without taking any drug and one because of no post-treatment biopsy). Eighty-eight women were included in the final analysis (metformin n=45, placebo n=43). There was no overall difference in post-treatment Ki-67 between the metformin and placebo arms, in an ANCOVA analysis adjusting for baseline Ki-67 expression (mean difference -0·57%, 95% CI -7·57% to 6·42%, p=0·87). Women receiving metformin reported significantly more adverse events than those receiving placebo (37 [82·2%] vs. 25 [58·1%], p=0·001), especially nausea and vomiting (17 [37·8%] vs. 6 [13·6%], p=0·015), diarrhoea (23 [51·1%] vs. 6 [13·6%], p=0·0003) and anorexia (9 [20·0%] vs. 0 [0·0%], p=0·003), but did not discontinue treatment.. Interpretation: Short term treatment with standard diabetic doses of metformin does not reduce tumour proliferation in women with endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings. Future studies should focus on primary and secondary prevention of endometrial cancer and pursue longer treatment windows. Clinical Trial Number: The study was registered on UK and European clinical trials databases (ISRCTN 88589234, EudraCT number 2014-000991-25) and is closed to recruitment. Funding Statement: National Institute for Health Research Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All participants provided written, informed consent. The trial was approved by the North West Research Ethics Committee (14/NW/1236), Medicine and Healthcare Products Regulatory Authority (MHRA, reference 21387/0232/001-0001) and local Research and Development departments.