Randomized Double Blind Placebo Controlled Trial of Barrett's Esophagus Chemoprevention With Metformin
I. To compare the percent change in the mean pS6K1 immunostaining from baseline in mucosal
Barrett esophagus (BE) biopsies among patients assigned to 2,000 mg metformin hydrochloride
once daily (QD) versus placebo as determined from Barrett mucosal biopsy samples obtained
pre- and post-intervention.
I. To evaluate adverse events associated with the two intervention arms.
I. To assess the effects of metformin hydrochloride 2,000 mg QD versus placebo on the
changes in pS6K1 using traditional IHC categories.
II. To assess the effects of metformin hydrochloride 2,000 mg QD versus placebo on absolute
change in pS6K1.
III. To assess changes in serum markers (metformin hydrochloride, fasting insulin, HOMA-IR,
IGF-1, IGF-2, IGFBP-1, IGFBP-3, fasting leptin, and fasting adiponectin) as determined from
serum samples obtained pre- and post-intervention.
IV. To assess changes in proliferation (Ki-67) and apoptosis (cleaved caspase 3) as
determined from Barrett mucosal biopsy samples obtained pre- and post-intervention.
V. To assess changes in molecular mediators of the insulin pathway (p-IRS-1, p-AKT^Serine
473) as determined from Barrett mucosal biopsy samples obtained pre- and post-intervention.
VI. To assess changes in relative activity of AMPK (phosphorylated AMPK/total AMPK ratio)
and molecular mediators of AMP kinase (p-mTOR, pS6K1^Serine 235) as determined from Barrett
mucosal biopsy samples obtained pre- and post-intervention.
VII. To assess changes in Programmed Cell Death 4 expression and miR-21 as determined from
Barrett mucosal biopsy samples pre- and post-intervention.
VIII. To establish a biospecimen repository archive for future correlative studies.
OUTLINE: This is a multicenter study.
Patients are stratified according to nonsteroidal anti-inflammatory drugs use (regular vs no
regular), body mass index (≥ 30 kg/m² vs < 30 kg/m²), gender (male vs female), and length of
Barrett (2.00 to 4.99 cm vs ≥ 5.00 cm). Patients are randomized to 1 of 2 treatment arms.
Arm I: Patients receive extended-release metformin hydrochloride orally (PO) once daily (QD)
on week 1, and twice daily (BID) on weeks 2-12 (every morning [QAM] and every evening [QPM]
on week 3) in the absence of unacceptable toxicity or disease progression.
Arm II: Patients receive extended-release placebo PO QD on week 1 and BID on weeks 2-12 (QAM
and QPM on week 3) in the absence of unacceptable toxicity or disease progression.
Blood, tissue, and mucosal tissue samples are collected at baseline and after completion of
study treatment for pS6K1 analysis and other serum, mucosal, and molecular markers studies
by IHC, ELISA, western blotting, and high-performance liquid chromatography (HPLC) methods.
After completion of study treatment, patients are followed up for 30 days.
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention
Percent change in mean pS6K1 immunostaining among participants with Barrett esophagus
The standard deviation for the distribution will be estimated using a 1-sided t-test with a significance level of 0.05. If data are not normally distributed, the Wilcoxon Rank-Sum test will be used.
Baseline to 3 months
Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
United States: Food and Drug Administration
|Mayo Clinic||Rochester, Minnesota 55905|
|Case Comprehensive Cancer Center||Cleveland, Ohio 44106-5065|
|Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center||Cleveland, Ohio 44106-5065|
|University of Pittsburgh Medical Center - Shadyside Hospital||Pittsburgh, Pennsylvania 15213-2582|
|Hines Veterans Administration Hospital||Hines, Illinois 60141|