Prospective Trial of Metformin - Chemoprevention Role

A Prospective Placebo-control Double-blind Randomized Trial of Metformin in Chemoprevention of Metachronous Colonic Neoplastic Polyps

The goal of this clinical research study is to learn if metformin extended release (ER) can prevent colonic adenomas from becoming cancerous. Metformin ER will be compared to a placebo.

Metformin ER is designed to block a protein in tumor cells that is important in tumor growth and blood vessel development. This may cause cell death or reduce the spread of the disease.

A placebo is not a drug. It looks like the study drug but is not designed to treat any disease or illness. It is designed to be compared with a study drug to learn if the study drug has any real effect.

Study Overview

• Status: Withdrawn
• Conditions: Colorectum
• Intervention / Treatment: Drug: Metformin ER; Other: Placebo

Detailed Description

Colonic adenomas are considered pre-cancerous, but they may change into colorectal cancer. Patients have a higher risk of developing additional adenomas if adenomas are found at the time of their follow-up colonoscopy.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 groups. You will have an equal chance of being assigned to either group.

If you are in Group 1, you will receive metformin ER

If you are in Group 2, you will receive a placebo.

Neither you nor the study staff will know if you are receiving the study drug or the placebo. However, if needed for your safety, the study staff will be able to find out what you are receiving.

Study Drug Administration:

You will take metformin ER/placebo tablets by mouth 1 time a day with food for 12-18 months (usually 12 months but sometimes up to 18 if the doctor thinks it is needed). This will allow time for at least 1 repeat follow-up colonoscopy.

The dose of metformin ER will be increased at Week 2 and again at Week 3. If you have side effects, the dose may be lowered if the doctor thinks it is needed.

Study Visit:

At 3-12 months or 3-18 months after you start taking metformin ER/placebo, you will have another colonoscopy and standard tissue collection for colonic adenoma(s). This tissue will be used for biomarker testing. Blood (about 3 tablespoons) will be drawn for testing on your blood sugar and for biomarker testing. You will need to fast for 8 hours before this test.

Your blood and tissue will also be used for research on the cause of colorectal cancer and biomarker testing.

Length of Treatment:

You may continue taking the study drug for 12 months. However, if your doctor thinks it is needed, a follow-up colonoscopy may be scheduled for you at either 15 or 18 months after enrollment. If this is the case, you will continue taking the drug for up to 18 months. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the study visit.

This is an investigational study. Metformin ER is FDA approved and commercially available for the treatment of type 2 diabetes. Its use to prevent colonic adenomas is investigational.

Up to 128 patients will take part in this study. All will be enrolled at MD Anderson.

• Study Type: Interventional
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age between 40 and 75 years
2. Polyp features suggesting high risk for recurrence include: piece-meal polypectomy, large (>10mm) neoplastic polyp, polyp with high grade dysplasia, or substantial number (>10) of neoplastic polyps.
3. ability to give informed consent
4. Patients should be registered on LAB10-0417
5. Diabetic patients are eligible but they may be excluded if they are taken Metformin, insulin or sulfonylureas

Exclusion Criteria:

1. Patients with renal insufficiency defined as serum creatinine >= 1.4 mg/dl for females and >= 1.5 mg/dl for males by the manufacturer.
2. Pregnant or nursing women
3. A malignancy currently under active therapy
4. Unstable angina, uncontrolled ischemic cardiac disease or symptomatic congestive heart failure (e.g. Class III or IV New York Heart Association's Functional Classification)
5. Current usage of Metformin
6. Current usage of insulin, sulfonylureas
7. History of lactic acidosis
8. Liver dysfunction including chronic active hepatitis and cirrhosis
9. Inability to give informed consent
10. Other investigational drugs within the past one year or concurrently
11. Known hypersensitivity or intolerance to Metformin
12. Contraindications for repeat colonoscopy
13. Inflammatory bowel disease
14. Rectosigmoiditis of any etiology

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin ER; Participants receive two tablets of Metformin ER 500 mg once daily for no more than twelve to eighteen months allowing time for at least one follow up colonoscopy. Dose will be reached in a gradual escalation scheme to improve gastrointestinal tolerance. If participants experience side effects during dose escalation regimen, they will be reduced to one tablet of 500 mg daily, and may continue taking 500 mg daily for the duration of the study.	Drug: Metformin ER; Starting dose: 500 mg by mouth daily for 1 week with weekly increases of 250 mg daily to target dose of 1000 mg daily.
Active Comparator: Placebo; Control group given matched Placebo once daily for no more than twelve to eighteen months allowing time for at least one follow up colonoscopy.	Other: Placebo; Placebo tablets by mouth 1 time a day.; Other Names: sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Ki-67-Stained Nuclei in Normal Rectal Mucosa	Primary endpoint defined as change in overall proliferation index between baseline and first return visit, that is, percentage of Ki-67-stained nuclei, in normal rectal mucosa. Tissue samples will be obtained at baseline colonoscopy and subsequent exams for analysis including Ki67, caspase 3, and various biomarkers and immunohistochemicals studies.	3 months

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Investigators: Principal Investigator: William Ross, MD, UT MD Anderson Cancer Center

Publications and helpful links

Helpful Links

• UT MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Anticipated): July 1, 2020

Study Registration Dates

• First Submitted: March 8, 2012
• First Submitted That Met QC Criteria: March 8, 2012
• First Posted (Estimate): March 12, 2012

Study Record Updates

• Last Update Posted (Estimate): April 5, 2013
• Last Update Submitted That Met QC Criteria: April 4, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Keywords: Chemoprevention; Placebo; Sugar pill; Metformin ER; Extended Release; Colorectum; Metachronous ctalColonic Neoplastic Polyps; Colonic adenoma(s); Pre-cancerous tumor(s) on the colon
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 2011-1100