Vitamin D Supplementation on 15-Prostaglandin Dehydrogenase Expression in Barrett's Esophagus

• ClinicalTrials.gov Identifier: NCT01465113
• Recruitment Status: Completed
• First Posted: November 4, 2011
• Last Update Posted: March 10, 2016
• Sponsor: Case Comprehensive Cancer Center
• Information provided by (Responsible Party): Case Comprehensive Cancer Center

Tracking Information

• First Submitted Date: November 1, 2011
• First Posted Date: November 4, 2011
• Last Update Posted Date: March 10, 2016
• Study Start Date: May 2010
• Actual Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 2, 2011)

• Arm 1(no or low grade dysplasia): 15-Prostaglandin dehydrogenase expression [ Time Frame: after 12 weeks of vitamin D supplement ]
  To determine whether vitamin D supplementation induces 15-Prostaglandin dehydrogenase expression as measured by RT-PCR in Barrett's esophagus
• Arm 2 (high grade dysplasia): 15-Prostaglandin dehydrogenase expression [ Time Frame: after 2 weeks of vitamin D supplement ]
  To determine whether vitamin D supplementation induces 15-Prostaglandin dehydrogenase expression as measured by RT-PCR in Barrett's esophagus

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 15, 2011)

• decreased prostaglandin E2 expression in Barrett's esophagus [ Time Frame: after 2 or 12 weeks of vitamin D supplement ]
  To determine whether vitamin D supplementation leads to decreased prostaglandin E2 expression in Barrett's esophagus
• effects on cyclooxygenase-2 expression [ Time Frame: after 2 or 12 weeks after vitamin D supplement ]
  To determine whether vitamin D supplementation affects cyclooxygenase-2 expression in Barrett's esophagus
• 15-Prostaglandin dehydrogenase expression differences between RT-PCR and immunohistochemistry [ Time Frame: after 2 or 12 weeks after vitamin D supplement ]
  To determine whether 15-Prostaglandin dehydrogenase expression in Barrett's esophagus differs between RT-PCR and immunohistochemistry
• effects on levels of Ki-67 [ Time Frame: after 2 or 12 weeks after vitamin D supplement ]
  To determine whether vitamin D supplementation affects levels of Ki-67, a marker for proliferation, in Barrett's esophagus
• effects on levels of caspase [ Time Frame: after 2 or 12 weeks of vitamin D supplement ]
  To determine whether vitamin D supplementation affects levels of caspase, a marker for apoptosis, in Barrett's esophagus
• effects on insulin resistance [ Time Frame: after 2 or 12 weeks of vitamin D supplement ]
  To determine whether vitamin D supplementation affects insulin resistance in Barrett's esophagus

Original Secondary Outcome Measures (submitted: November 2, 2011)

• decreased prostaglandin E2 expression in Barrett's esophagus [ Time Frame: after 2 or 12 weeks of vitamin D supplement ]
  To determine whether vitamin D supplementation leads to decreased prostaglandin E2 expression in Barrett's esophagus
• affects on cyclooxygenase-2 expression [ Time Frame: after 2 or 12 weeks after vitamin D supplement ]
  To determine whether vitamin D supplementation affects cyclooxygenase-2 expression in Barrett's esophagus
• 15-Prostaglandin dehydrogenase expression differs between RT-PCR and immunohistochemistry [ Time Frame: after 2 or 12 weeks after vitamin D supplement ]
  To determine whether 15-Prostaglandin dehydrogenase expression in Barrett's esophagus differs between RT-PCR and immunohistochemistry
• affects on levels of Ki-67 [ Time Frame: after 2 or 12 weeks after vitamin D supplement ]
  To determine whether vitamin D supplementation affects levels of Ki-67, a marker for proliferation, in Barrett's esophagus
• affects on levels of caspase [ Time Frame: after 2 or 12 weeks of vitamin D supplement ]
  To determine whether vitamin D supplementation affects levels of caspase, a marker for apoptosis, in Barrett's esophagus
• affects on insulin resistance [ Time Frame: after 2 or 12 weeks of vitamin D supplement ]
  To determine whether vitamin D supplementation affects insulin resistance in Barrett's esophagus

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Vitamin D Supplementation on 15-Prostaglandin Dehydrogenase Expression in Barrett's Esophagus
• Official Title: Effect of Vitamin D Supplementation on 15-Prostaglandin Dehydrogenase Expression in Barrett's Esophagus
• Brief Summary: This study is being conducted to determine if vitamin D supplementation increases the level of a protein that may be involved in decreasing the risk of esophageal cancer in patients with Barrett's esophagus. Subjects with Barrett's esophagus will take vitamin D supplementation for 2-12 weeks depending on the severity of their condition, and receive an upper endoscopy procedure before and after vitamin D supplementation trial.
• Detailed Description: 28-day run-in phase during which subjects are treated with a proton pump inhibitor (omeprazole 20 mg po q day or an equivalent dose of another proton pump inhibitor). The purpose of the run-in phase is to minimize esophagitis, which can cause histologic changes that can be confused with dysplasia. After the run-in phase, subjects will undergo an upper endoscopy for Barrett's surveillance or Barrett's mapping as part of routine clinical care. At the time of endoscopy, research biopsies will be obtained for the study. Subjects eligible and continuing in the study will take vitamin D3 (Cholecalciferol) 50,000 IU capsules once weekly with or without daily metformin for a total of two or twelve weeks depending on the severity of Barrett's esophagus. After completion of vitamin D3 subjects will return for an EGD (endoscopy) and biopsies for the research study.
• Study Type: Interventional
• Study Phase: Early Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention

Condition

• Short Segment Barrett's Esophagus
• Long Segment Barrett's Esophagus

Intervention

• Drug: Omeprazole
  28-day run-in phase during which subjects are treated with a proton pump inhibitor (omeprazole 20 mg po q day or an equivalent dose of another proton pump inhibitor).
• Drug: Vitamin D3
  These patients (indefinite for dysplasia, LGD, or no dysplasia) will take vitamin D3 50,000 IU once a week for 12 weeks following the upper endoscopy.
  Other Name: Cholecalciferol
• Drug: Vitamin D3
  Due to the risk of progression, subjects with Barrett's esophagus with high grade dysplasia will take vitamin D3 50,000 IU once a week for 2 weeks.
  Other Name: Cholecalciferol
• Procedure: upper endoscopy
  After the run-in phase subjects will undergo an upper endoscopy for Barrett's surveillance or Barrett's mapping as part of routine clinical care. At the time of endoscopy, in addition to large cup forceps biopsies obtained for surveillance or mapping as part of standard care, research biopsies will be obtained for the study. Following vitamin D3 supplementation, all subjects will undergo a repeat upper endoscopy for additional large cup forceps biopsies for measurement of post-treatment mucosal levels.
• Drug: Metformin
  500mg for the first week, 1000mg during the second week, 1500mg during the third week, maximum dose of 2000mg in the fourth week

Study Arms

• Experimental: Indefinite, LGD or no dysplasia arm
  Barrett's esophagus patients who have no dysplasia or low grade dysplasia
  Interventions:

  • Drug: Omeprazole
  • Drug: Vitamin D3
  • Procedure: upper endoscopy
• Experimental: high grade dysplasia
  Barrett's esophagus with high grade dysplasia
  Interventions:

  • Drug: Omeprazole
  • Drug: Vitamin D3
  • Procedure: upper endoscopy
• Experimental: Indefinite, LGD or no dysplasia arm:Vitamin D/Metformin Subarm
  Barrett's esophagus patients who have no dysplasia or low grade dysplasia
  Interventions:

  • Drug: Omeprazole
  • Drug: Vitamin D3
  • Procedure: upper endoscopy
  • Drug: Metformin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 1, 2016): 26
• Original Estimated Enrollment (submitted: November 2, 2011): 20
• Actual Study Completion Date: February 2016
• Actual Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Known diagnosis of short-segment or long-segment Barrett's esophagus as previously made by upper endoscopy showing salmon-colored distal esophageal mucosa and biopsies revealing intestinal metaplasia with goblet cells. Potential study subjects may be contacted by mailings or phone calls or may be approached in clinic. Additionally, potential study subjects may be approached using a web-based recruitment tool. Informed consent will be obtained by a research coordinator or study investigator.
• Subjects may be taking calcium supplements or have previous history of hypercalcemia
• Subjects may have diabetes mellitus
• Subjects may have a history of prior malignancy except for esophageal adenocarcinoma
• Willing to donate 90 mL of blood and endoscopic mucosal biopsies for research

The following additional inclusion criteria apply for patients in the Vitamin D/metformin sub-arm of the low grade dysplasia/no dysplasia arm:

• At least 2 cm circumferential Barrett's esophagus segment length (C2M2 by Prague C & M criteria)
• Normal renal function (defined as creatinine within normal institutional limits)

Exclusion Criteria:

• Pregnancy
• Known chronic liver disease (Child's B cirrhosis)
• Known chronic kidney disease (creatinine ≥ 3.0)
• Esophageal adenocarcinoma
• Allergic reaction to omeprazole
• Allergic reaction to vitamin D
• Unable or unwilling to provide informed consent
• Known hypercalcemia
• Previous ablative therapy for Barrett's esophagus
• Patients on a stable (>/=4 week duration) dose of >2000 IU/day (or equivalent) of vitamin D supplementation

The following additional exclusion criteria apply for patients in the Vitamin D/metformin sub-arm of the no dysplasia/low grade dysplasia arm:

• Allergic reaction to metformin
• History of diabetes mellitus
• History of lactic acidosis
• History of B12 deficiency
• Participants may not be using metformin, cimetidine (Tagamet) furosemide (Lasix), nifedipine (Cardizem), or any other drug contraindicated for use with metformin.
• Treatment with other oral hypoglycemic agents
• Participants planning to undergo elective radiologic studies involving intravascular administration of iodinated contrast materials.
• Known chronic kidney disease with creatinine greater than normal institutional limits

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01465113
• Other Study ID Numbers: CASE12209
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Case Comprehensive Cancer Center
• Study Sponsor: Case Comprehensive Cancer Center
• Collaborators: Not Provided

Investigators

• Principal Investigator: Linda Cummings, MD; Case Comprehensive Cancer Center

• PRS Account: Case Comprehensive Cancer Center
• Verification Date: March 2016