Metformin Hydrochloride in Preventing Esophageal Cancer in Patients With Barrett Esophagus
|Barrett Esophagus Esophageal Cancer||Drug: metformin hydrochloride Other: placebo||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
|Official Title:||Randomized Double Blind Placebo Controlled Trial of Barrett's Esophagus Chemoprevention With Metformin|
- Percent Change in Median pS6K1 Immunostaining Among Participants With Barrett Esophagus [ Time Frame: Baseline to 3 months ]The percent change in pS6K1 was calculated as month 3 pS6k1 values minus baseline pS6k1 values, then divide by baseline pS6k1 values and multiply by 100.
- Overall Adverse Event Rates [ Time Frame: Up to 30 days ]
Number of patients that experienced adverse events (grade 1 or above) as measured by NCI CTCAE (Common Terminology Criteria for Adverse Events) v. 4.0.
The data reported in the table include only the commonly occurring adverse events (3 or more events).
|Study Start Date:||June 2012|
|Study Completion Date:||September 2013|
|Primary Completion Date:||May 2013 (Final data collection date for primary outcome measure)|
Experimental: Arm I
Patients receive extended-release metformin hydrochloride PO QD on week 1, and BID on weeks 2-12 (QAM QPM on week 3) in the absence of unacceptable toxicity or disease progression.
Drug: metformin hydrochloride
Given PO QD and BID
Other Name: Glucophage
Placebo Comparator: Arm II
Patients receive extended-release placebo PO QD on week 1and BID on weeks 2-12 (QAM and QPM on week 3) in the absence of unacceptable toxicity or disease progression.
Given PO QD and BID
Other Name: PLCB
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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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01447927
|United States, Illinois|
|Hines Veterans Administration Hospital|
|Hines, Illinois, United States, 60141|
|United States, Minnesota|
|Rochester, Minnesota, United States, 55905|
|United States, Ohio|
|Case Comprehensive Cancer Center|
|Cleveland, Ohio, United States, 44106-5065|
|Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center|
|Cleveland, Ohio, United States, 44106|
|United States, Pennsylvania|
|University of Pittsburgh Medical Center - Shadyside Hospital|
|Pittsburgh, Pennsylvania, United States, 15232|
|University of Toronto|
|Toronto, Ontario, Canada, M5S 1A1|
|University of Puerto Rico|
|San Juan, Puerto Rico, 00936|
|Principal Investigator:||Amitabh Chak||Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center|