Metformin Hydrochloride in Preventing Esophageal Cancer in Patients With Barrett Esophagus

June 19, 2014 updated by: National Cancer Institute (NCI)

Randomized Double Blind Placebo Controlled Trial of Barrett's Esophagus Chemoprevention With Metformin

This randomized phase II trial studies how well metformin hydrochloride works in preventing esophageal cancer in patients with Barrett esophagus. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of metformin hydrochloride may keep esophageal cancer from forming.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

I. To evaluate adverse events associated with the two intervention arms.

TERTIARY OBJECTIVES:

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
93

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5S 1A1
        • University of Toronto
  • Puerto Rico
      • San Juan, Puerto Rico, 00936
        • University of Puerto Rico
  • United States
    • Illinois
      • Hines, Illinois, United States, 60141
        • Hines Veterans Administration Hospital
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
      • Cleveland, Ohio, United States, 44106-5065
        • Case Comprehensive Cancer Center
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15232
        • University of Pittsburgh Medical Center - Shadyside Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically confirmed diagnosis of Barrett esophagus, with no dysplasia, indeterminate for dysplasia, or low-grade dysplasia as defined by the presence of specialized columnar epithelium on histology and >= 2 cm of involvement on endoscopy
  • Adequate Barrett mucosa, which is defined as >= 1 out of 4 research samples (i.e., >= 25%) with >= 50% intestinal metaplasia in biopsies required to satisfy the endpoints of the study
  • No history of esophageal carcinoma or other cancer(s) (except for non-melanoma skin cancers)
  • No erosive esophagitis or ulcerative esophagitis, unless treatment with a proton pump inhibitor (PPI) results in healed erosions or ulcers prior to entry endoscopy

  • No history of high-grade dysplasia or cancer (confirmed locally by esophagogastroduodenoscopy [EGD] and Pathology reports)

    • No ulcer, plaque, nodule, stricture, or other luminal irregularity within the Barrett segment, unless clinical biopsy produces no evidence of high-grade dysplasia or cancer
  • ECOG performance status =< 1
  • Hemoglobin >= 10 g/dL
  • Leukocytes >= 3,000/mL (>= 2,500/mL for African-American participants)
  • Absolute neutrophil count >= 1,500/mL (>= 1,000/mL for African-American participants)
  • Platelets >= 100,000/mL
  • Total bilirubin =< institutional upper limit of normal (ULN)
  • AST (SGOT) and ALT (SGPT) =< 1.5 times institutional ULN
  • Creatinine =< institutional ULN
  • Willingness to provide tissue samples for research purposes
  • No contraindication to esophagogastroduodenoscopy (EGD)
  • Willingness, for both men and women, to use adequate contraception (hormonal or barrier method of birth control; surgical intervention; abstinence) prior to study entry and for the duration of study participation
  • A negative (serum or urine) pregnancy test done =< 7 days prior to Pre-Registration, for women of childbearing potential only
  • No pregnant or nursing women
  • No participants with diabetes mellitus
  • No history of vitamin B12 deficiency or megaloblastic anemia
  • No history of lactic acidosis
  • No diseases associated with weight loss: anorexia, bulimia, or nausea
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin

  • No participants with HIV, cirrhosis of any cause, NASH (non-alcoholic steatohepatitis), or hepatitis (auto-immune or infectious)

    • For participants diagnosed with any other hepatic impairment, consult with protocol principal investigator (PI)
  • No metabolic acidosis, acute or chronic, including ketoacidosis
  • No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; this includes significant medical conditions including renal failure, hepatic failure, sepsis, and hypoxia
  • No genetics disorders such as family history of hereditary gastrointestinal polyp disorder (e.g., familial adenomatous polyposis [FAP], hereditary non-polyposis colorectal cancer [HNPCC], Peutz-Jegher disease)
  • No chronic alcohol use or a history of alcohol abuse (defined as ingestion of >= 3 drinks per day)
  • No kidney disease or renal insufficiency (defined as serum creatinine outside the normal institutional limits)
  • Currently on a proton pump inhibitor (PPI) >= 4 weeks (any PPI taken at least once daily is acceptable)
  • No medication(s) for weight loss ≤ 2 months prior to Pre-Registration
  • No treatment with medications that may increase metformin hydrochloride levels: cationic drugs, e.g., digoxin, amiloride, procainamide, ranitidine, trimethoprim, quinidine, quinine, vancomycin, triamterene, and morphine
  • No treatment with other oral hypoglycemic agents
  • No participant use of metformin, cimetidine (Tagamet), furosemide (Lasix), or nifedipine (Cardizem), or any other drug contraindicated for use with metformin
  • No receipt of any other investigational agents =< 3 months prior to Pre-Registration, except innocuous agents with no known interaction with the study agent (e.g., standard dose multivitamins or topical agents for limited skin conditions), at the discretion of the Protocol Lead Investigator at each Participating Site

  • No participants who have undergone ablation or other local therapies (e.g., percutaneous dilatational tracheostomy [PDT], cryotherapy, radiofrequency, argon plasma coagulation [APC], or multipolar electrocoagulation [MPEC])

    • Patients treated with endoscopic mucosal resection [EMR] allowed
  • No participants anticipating elective surgery during the study period
  • No participants planning to undergo elective radiologic studies involving intravascular administration of iodinated contrast materials

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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 Names:
  • 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.
Other: placebo
Given PO QD and BID
Other Names:
  • PLCB

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
Baseline to 3 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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).
Up to 30 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
National Cancer Institute (NCI)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Amitabh Chak, Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2012

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 1, 2013

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 1, 2013

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 5, 2011

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 5, 2011

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 6, 2011

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 21, 2014

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 19, 2014

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2014

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NCI-2011-03451
  • MAY10-15-03
  • MAYO-MAY10-15-03
  • CDR0000698069

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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