Barrett EsophagusPhase 2NCT01447927
Metformin Hydrochloride in Preventing Esophageal Cancer in Patients With Barrett Esophagus
A Phase 2 study testing metformin hydrochloride in people with Barrett Esophagus and Esophageal Cancer, run by National Cancer Institute (NCI) at 7 sites in 3 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Barrett Esophagus, Esophageal Cancer
- What is being tested?
- metformin hydrochloride
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 93 participants
- Where
- 7 sitesin 3 countries
- Study dates
- Jun 2012to Sep 2013
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 41Show fewer
- 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
Who cannot join
None listed.
Trial locations and contacts
7 sites in 3 countries.
7 sites in 3 countries
United States5 sites
Case Comprehensive Cancer Center
Cleveland, Ohio, 44106-5065
Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
Cleveland, Ohio, 44106
Hines Veterans Administration Hospital
Hines, Illinois, 60141
University of Pittsburgh Medical Center - Shadyside Hospital
Pittsburgh, Pennsylvania, 15232
Mayo Clinic
Rochester, Minnesota, 55905
About this study
Official title: 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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- To evaluate adverse events associated with the two intervention arms.
TERTIARY OBJECTIVES:
- 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.
- 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.
- Conditions
- Barrett Esophagus, Esophageal Cancer
- Being tested
- metformin hydrochloride, placebo
- Medical subject headings
- Barrett Esophagus, Esophageal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
metformin hydrochlorideDrug
Also called Glucophage
Given PO QD and BID
placeboOther
Also called PLCB
Given PO QD and BID
| Study group | Role | What they receive |
|---|---|---|
| Arm I | Experimental | 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. Receives: Drug: metformin hydrochloride |
| Arm II | Placebo comparator | 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. Receives: Other: placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent Change in Median pS6K1 Immunostaining Among Participants With Barrett Esophagus
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.
Measured: Baseline to 3 months
Secondary outcomes (1)
Overall Adverse Event Rates
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).
Measured: Up to 30 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Oct 2011 (estimated)
- Study startJun 2012
- Primary completionMay 2013
- Study completionSep 2013
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.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Barrett EsophagusStudies 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
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 93 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Amitabh Chak, Principal investigator, Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01447927
- Sponsor's protocol ID
- NCI-2011-03451
- Other IDs
- MAY10-15-03, MAYO-MAY10-15-03, CDR0000698069
- Status last verified
- Jun 2014
- First submitted
- 5 Oct 2011
- Last updated
- 21 Jul 2014
- Results posted
- Yes, on ClinicalTrials.gov
Publications
Chak A, Buttar NS, Foster NR, Seisler DK, Marcon NE, Schoen R, Cruz-Correa MR, Falk GW, Sharma P, Hur C, Katzka DA, Rodriguez LM, Richmond E, Sharma AN, Smyrk TC, Mandrekar SJ, Limburg PJ; Cancer Prevention Network. Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's esophagus. Clin Gastroenterol Hepatol. 2015 Apr;13(4):665-72.e1-4. doi: 10.1016/j.cgh.2014.08.040. Epub 2014 Sep 15.
PubMed 25218668
Study at a glance
From the registry record, last updated by the sponsor on 21 Jul 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Double Blind Placebo Controlled Trial of Barrett's Esophagus Chemoprevention With Metformin
- ClinicalTrials.gov ID
- NCT01447927
- Acronym / sponsor ID
- NCI-2011-03451
- Conditions
- Barrett Esophagus, Esophageal Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 93 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Jun 2012
- Primary completion
- May 2013 (actual)
- Study completion
- Sep 2013 (actual)
- First posted
- 6 Oct 2011 (estimated)
- Results
- Posted 21 Jul 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
PRIMARY OBJECTIVES:
- 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:
- To evaluate adverse events associated with the two intervention arms.
TERTIARY OBJECTIVES:
- 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.
- 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 design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm I | Experimental | Drug: metformin hydrochloridePatients 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. |
| Arm II | Placebo comparator | Other: placeboPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (41 listed)
- 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)
Key exclusion criteria (0 listed)
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: GlucophageGiven PO QD and BID | Drug | Arm I |
| placeboAlso: PLCBGiven PO QD and BID | Other | Arm II |
Primary outcome
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.
1 secondary outcome
Overall Adverse Event Rates
Time frame: Up to 30 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jul 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 25218668Chak A, Buttar NS, Foster NR, Seisler DK, Marcon NE, Schoen R, Cruz-Correa MR, Falk GW, Sharma P, Hur C, Katzka DA, Rodriguez LM, Richmond E, Sharma AN, Smyrk TC, Mandrekar SJ, Limburg PJ; Cancer Prevention Network. Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's esophagus. Clin Gastroenterol Hepatol. 2015 Apr;13(4):665-72.e1-4. doi: 10.1016/j.cgh.2014.08.040. Epub 2014 Sep 15.
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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.
Amitabh Chak principal investigator
Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
7 sites in 3 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 Barrett Esophagus and Esophageal Cancer, run by National Cancer Institute (NCI) at 7 sites in 3 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 41 inclusion and 0 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 21 Jul 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in United States, Canada, Puerto Rico. 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. Some participants in this study may receive a placebo. 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 21 Jul 2014). 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?
Percent Change in Median pS6K1 Immunostaining Among Participants With Barrett Esophagus (time frame: Baseline to 3 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01447927, which also lists 1 linked publication.
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 21 Jul 2014.