A Trial of Metformin for Colorectal Cancer Risk Reduction Among Patients With a History of Colorectal Adenomas and Elevated Body Mass Index
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|ClinicalTrials.gov Identifier: NCT01312467|
Recruitment Status : Completed
First Posted : March 10, 2011
Results First Posted : June 25, 2015
Last Update Posted : June 25, 2015
|Condition or disease||Intervention/treatment||Phase|
|Adenomatous Polyp Colorectal Cancer Obesity||Drug: metformin hydrochloride Other: pharmacological study Other: laboratory biomarker analysis||Phase 2|
I. To determine if a 12-week intervention of oral metformin (metformin hydrochloride) treatment among obese patients with a history of colorectal adenomas results in at least a 35% decrease in colorectal mucosa activated pS6serine235 from baseline as assessed via immunostaining.
I. To assess the effect of metformin on additional relevant biomarkers in serum: metformin levels; fasting insulin-like growth factor (IGF)-1, insulin-like growth factor binding protein (IGFBP)-1, IGFBP-3; fasting leptin; fasting Adiponectin; fasting and 2 hour post-prandial insulin and glucose.
II. To examine the correlation among biomarkers (serum, tissue). III. To assess the independent effects of treatment on each biomarker, using multivariate regression models to account for clinical and biomarker data.
IV. To document the safety and tolerability of metformin in the study population.
I. To assess the effect of metformin on additional relevant biomarkers in tissue via immunostaining. This will include the effects on levels of colorectal mucosa proliferation estimated by: phosphorylated AMPK (pAMPK), phosphorylated AKTserine 473 (pAKT), phosphorylated mTOR, phosphorylated insulin receptor (pIR), phosphorylated IGF-1 (pIGF-1) receptor, and Ki-67.
II. To cross-validate immunostaining results with Western blotting experiments in a subset of consecutive patients for the following endpoints: phosphorylated S6serine235 (pS6serine235), phosphorylated AMPK (pAMPK), phosphorylated AKTserine 473 (pAKT), phosphorylated mTOR, phosphorylated insulin receptor (pIR), phosphorylated IGF-1 (pIGF-1) receptor, and Ki-67.
Patients receive metformin hydrochloride orally (PO) once daily (QD) during week 1 and then twice daily (BID) during weeks 2-12. Treatment continues for 12 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study therapy, patients are followed up for 4 weeks.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||45 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase IIa Trial of Metformin for Colorectal Cancer Risk Reduction Among Patients With a History of Colorectal Adenomas and Elevated Body Mass Index|
|Study Start Date :||March 2011|
|Primary Completion Date :||March 2014|
|Study Completion Date :||March 2014|
Experimental: Prevention (metformin hydrochloride)
Patients receive metformin hydrochloride PO QD during week 1 and then BID during weeks 2-12. Treatment continues for 12 weeks in the absence of disease progression or unacceptable toxicity.
Drug: metformin hydrochloride
Other Name: GlucophageOther: pharmacological study
Other Name: pharmacological studiesOther: laboratory biomarker analysis
- Change in Activated S6serine235 (i.e., the Ratio of pS6serine235/S6serine235) [ Time Frame: From baseline to 12 weeks ]Tissue S6Ser235 immunostaining was analyzed by the study pathologist using Histo Score (HScore) analysis at baseline and post- metformin (Week 12). The Hscore is determined by estimation of the percentage of cells positively stained with mild, moderate, or strong staining intensity. The final score is determined by weighted estimate, as follows: Hscore = (# cell stained with High intensity/total # cells)x3 + (# cells stained with median intensity/total # cells)x2 + (# cells stained with low intensity/total # cells)x1. Mean and standard deviation of the change in the histo score (H score) of pS6serine235 from baseline were calcuated.
- Effects of Metformin Hydrochloride on Colorectal Mucosa Proliferation (Ki-67, Phosphorylated IGF-1 Receptor, Phosphorylated Insulin Receptor, Phosphorylated AKT, Phosphorylated mTOR, and Phosphorylated AMP Kinase) [ Time Frame: Up to 16 weeks ]We are in the process of identifying and securing funding to complete the secondary and tertiary endpoints. Once the information is available, we will provide those results with any relevant post-hoc analyses.
- Effects of Metformin Hydrochloride on Serum (Fasting and 2 Hour Postprandial Insulin and Glucose, Fasting IGF-1, IGFBP-1, IGFBP-3, Leptin, Adiponectin and Metformin Levels) [ Time Frame: Up to 16 weeks ]We are in the process of identifying and securing funding to complete the secondary and tertiary endpoints. Once the information is available, we will provide those results with any relevant post-hoc analyses.
- Safety and Tolerability of Metformin Hydrochloride Treatment [ Time Frame: Up to 16 weeks ]
All participants will be evaluable for toxicity from the time of their first dose of metformin. Since toxicities in this study are measured as categorical data, primary analysis shall be by tests of binomial proportions (e.g., Mantel-Haenszel chi-squared statistic). This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0 for toxicity and Serious Adverse Event reporting.
We are in the process of identifying and securing funding to complete the secondary and tertiary endpoints. Once the information is available, we will provide those results with any relevant post-hoc analyses.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01312467
|United States, California|
|Veterans Administration Long Beach Medical Center|
|Long Beach, California, United States, 90822|
|University of California Medical Center At Irvine-Orange Campus|
|Orange, California, United States, 92868|
|Kaiser Permanente - Sacramento|
|Sacramento, California, United States, 95825|
|Jewish General Hospital|
|Montreal, Quebec, Canada, H3T 1E2|
|Principal Investigator:||Jason Zell||University of California Medical Center At Irvine-Orange Campus|