Adenomatous PolypPhase 2NCT01312467
Trial of Metformin for Colorectal Cancer Risk Reduction for History of Colorectal Adenomas and Elevated BMI
A Phase 2 study testing metformin hydrochloride in people with Adenomatous Polyp and Colorectal Cancer, run by National Cancer Institute (NCI) at 4 sites in 2 countries.
Trial summary
The purpose of this study is to find out whether METFORMIN decreases protein markers in colorectal tissue. This is a phase IIA study of the pharmacodynamics, safety and tolerability of Metformin in decreasing colorectal mucosa in patients with a history of colorectal adenomas in the past 3 years and a BMI >= 30, with… Read more about this study
- Who is it for?
- Ages 35 to 80 years
- Conditions the study is for
- Adenomatous Polyp, Colorectal Cancer, Obesity
- What is being tested?
- metformin hydrochloride
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 45 participants
- Where
- 4 sitesin 2 countries
- Study dates
- Mar 2011to Dec 2014
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- History of prior colorectal adenomas within the past 3 years; only patients who have had adenomas endoscopically removed are eligible; documentation of colorectal adenomas must be determined via review of pathology reports
- Body mass index (BMI) >= 30; rounded to the nearest whole integer
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Leukocytes ≥ 3,000/μL (>= 2,500/μL for African-American participants)
- Absolute neutrophil count >= 1,500/μL (>= 1,000/μL for African-American participants)
- Platelets >= 100,000/μL
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- Total bilirubin within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 X institutional upper limit of normal (ULN)
- Creatinine within normal institutional limits
- Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
- A serum pregnancy test must be performed and be negative in all women of childbearing potential within 2 weeks prior to starting treatment
- Ability to understand and willingness to sign a written informed consent document
Who cannot join
- History of colorectal cancer or other cancer(s) (except for non-melanoma skin cancers) within the last 3 years
- Family history of hereditary intestinal polyp disorder (e.g., familial adenomatous polyposis [FAP], hereditary non-polyposis colorectal cancer [HNPCC], Putz-Jegher's disease)
- Participants with diabetes
- History of vitamin B12 deficiency or megaloblastic anemia
- History of lactic acidosis
- Diet or other medications for weight loss
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- Diseases associated with weight loss: anorexia, bulimia, or nausea
- Treatment with medications that may increase metformin levels: cationic drugs, e.g., digoxin, amiloride, procainamide, trimethoprim, vancomycin, triamterene, and morphine
- Treatment with other oral hypoglycemic agents
- Participants who have undergone full bowel resection, ablation or other local therapies
- Participants may not be receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin
- Participants with human immunodeficiency virus (HIV), cirrhosis of any cause, NASH (nonalcoholic steatohepatitis), or hepatitis (auto-immune or infectious)
- Kidney disease or renal insufficiency (defined as serum creatinine > 1.4 mg/dL for females or > 1.5 mg/dL for males)
- Metabolic acidosis, acute or chronic, including ketoacidosis
- Uncontrolled intercurrent illness including, but not limited to:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness/social situations that would limit compliance with study requirements
- Renal failure
- Hepatic failure
- Sepsis
- Hypoxia
- Pregnant or breastfeeding women are excluded
- Participants anticipating elective surgery during the study period
- Contraindication to colonoscopy/flexible sigmoidoscopy
- Participants may not be using metformin, cimetidine (Tagament) furosemide (Lasix), nifedipine (Cardizem), Ranitidine (Zinetac or Zantac), digoxin (Lanoxin), Quinidine or any other drug contraindicated for use with metformin
- Chronic alcohol use or a history of alcohol abuse
- Participants with any medical psychosocial condition that, in the opinion of the investigator, could jeopardize participation in and compliance with the study criteria
- Participants that regularly use aspirin (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), calcium, and cyclooxygenase (Cox)-2 inhibitors are not eligible for enrollment; however, patients that use aspirin 81 mg daily, or aspirin 325 mg, NSAIDs, calcium, or Cox-2 inhibitors at a frequency < 10 times per month are eligible
Trial locations and contacts
4 sites in 2 countries.
4 sites in 2 countries
United States3 sites
Veterans Administration Long Beach Medical Center
Long Beach, California, 90822
University of California Medical Center At Irvine-Orange Campus
Orange, California, 92868
Kaiser Permanente - Sacramento
Sacramento, California, 95825
About this study
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
The purpose of this study is to find out whether METFORMIN decreases protein markers in colorectal tissue. This is a phase IIA study of the pharmacodynamics, safety and tolerability of Metformin in decreasing colorectal mucosa in patients with a history of colorectal adenomas in the past 3 years and a BMI >= 30, with decimals rounded to the nearest whole integer. Metformin as a potential chemopreventive agent for inhibition of the relevant molecular pathways involved in human colorectal carcinogenesis.
Read the detailed description
PRIMARY OBJECTIVES:
- 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.
SECONDARY OBJECTIVES:
- 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.
TERTIARY OBJECTIVES:
- 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.
OUTLINE:
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.
- Conditions
- Adenomatous Polyp, Colorectal Cancer, Obesity
- Being tested
- metformin hydrochloride
- Medical subject headings
- Adenomatous Polyps, Colorectal Neoplasms, Obesity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
metformin hydrochlorideDrug
Also called Glucophage
| Study group | Role | What they receive |
|---|---|---|
| Prevention (metformin hydrochloride) | Experimental | 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. Receives: Drug: metformin hydrochloride |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Activated S6serine235 (i.e., the Ratio of pS6serine235/S6serine235)
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.
Measured: From baseline to 12 weeks
Secondary outcomes (3)
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)
Data not collected.
Measured: Up to 16 weeks
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)
Data not collected.
Measured: Up to 16 weeks
Safety and Tolerability of Metformin Hydrochloride Treatment
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.
Measured: Up to 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Mar 2011 (estimated)
- Study startMar 2011
- Primary completionMar 2014
- Study completionDec 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Adenomatous PolypStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 45 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Jason Zell, Principal investigator, University of California Medical Center At Irvine-Orange Campus
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01312467
- Sponsor's protocol ID
- NCI-2011-01744
- Other IDs
- NCI-2011-01744, UCI 10-31, 2010-7705, UCI09-13-01, P30CA062203, N01CN35160
- Status last verified
- Feb 2019
- First submitted
- 7 Mar 2011
- Last updated
- 5 Mar 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 5 Mar 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01312467
- Acronym / sponsor ID
- NCI-2011-01744
- Conditions
- Adenomatous Polyp, Colorectal Cancer, Obesity
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 45 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Mar 2011
- Primary completion
- Mar 2014 (actual)
- Study completion
- Dec 2014 (actual)
- First posted
- 10 Mar 2011 (estimated)
- Results
- Posted 25 Jun 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to find out whether METFORMIN decreases protein markers in colorectal tissue. This is a phase IIA study of the pharmacodynamics, safety and tolerability of Metformin in decreasing colorectal mucosa in patients with a history of colorectal adenomas in the past 3 years and a BMI >= 30, with decimals rounded to the nearest whole integer. Metformin as a potential chemopreventive agent for inhibition of the relevant molecular pathways involved in human colorectal carcinogenesis.
Detailed description
PRIMARY OBJECTIVES:
- 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.
SECONDARY OBJECTIVES:
- 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.
TERTIARY OBJECTIVES:
- 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.
OUTLINE:
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 design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Prevention (metformin hydrochloride) | Experimental | Drug: metformin hydrochloridePatients 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. |
Who may qualify
- Ages
- 35 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- History of prior colorectal adenomas within the past 3 years; only patients who have had adenomas endoscopically removed are eligible; documentation of colorectal adenomas must be determined via review of pathology reports
- Body mass index (BMI) >= 30; rounded to the nearest whole integer
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Leukocytes ≥ 3,000/μL (>= 2,500/μL for African-American participants)
- Absolute neutrophil count >= 1,500/μL (>= 1,000/μL for African-American participants)
Key exclusion criteria (32 listed)
- History of colorectal cancer or other cancer(s) (except for non-melanoma skin cancers) within the last 3 years
- Family history of hereditary intestinal polyp disorder (e.g., familial adenomatous polyposis [FAP], hereditary non-polyposis colorectal cancer [HNPCC], Putz-Jegher's disease)
- Participants with diabetes
- History of vitamin B12 deficiency or megaloblastic anemia
- History of lactic acidosis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| metformin hydrochlorideAlso: Glucophage | Drug | Prevention (metformin hydrochloride) |
Primary outcome
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.
3 secondary outcomes
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
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
Safety and Tolerability of Metformin Hydrochloride Treatment
Time frame: Up to 16 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Mar 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jason Zell principal investigator
University of California Medical Center At Irvine-Orange Campus
4 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing metformin hydrochloride in people with Adenomatous Polyp and Colorectal Cancer, run by National Cancer Institute (NCI) at 4 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Jun 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Activated S6serine235 (i.e., the Ratio of pS6serine235/S6serine235) (time frame: From baseline to 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Mar 2019.