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

Study Overview
=================
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.

Official Title
-----------------
Effect of Vitamin D Supplementation on 15-Prostaglandin Dehydrogenase Expression in Barrett's Esophagus

Conditions
-----------------
Short Segment Barrett's Esophagus, Long Segment Barrett's Esophagus

Intervention / Treatment
-----------------
* Drug: Omeprazole
* Drug: Vitamin D3
* Drug: Vitamin D3
* Procedure: upper endoscopy
* Drug: Metformin


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Indefinite, LGD or no dysplasia arm<br>Barrett's esophagus patients who have no dysplasia or low grade dysplasia | Drug: Omeprazole<br>* 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).<br>Drug: Vitamin D3<br>* 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.<br>* Other names: Cholecalciferol;Procedure: upper endoscopy<br>* 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.<br>|
| Experimental: high grade dysplasia<br>Barrett's esophagus with high grade dysplasia | Drug: Omeprazole<br>* 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).<br>Drug: Vitamin D3<br>* 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.<br>* Other names: Cholecalciferol;Procedure: upper endoscopy<br>* 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.<br>|
| Experimental: Indefinite, LGD or no dysplasia arm:Vitamin D/Metformin Subarm<br>Barrett's esophagus patients who have no dysplasia or low grade dysplasia | Drug: Omeprazole<br>* 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).<br>Drug: Vitamin D3<br>* 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.<br>* Other names: Cholecalciferol;Procedure: upper endoscopy<br>* 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.<br>Drug: Metformin<br>* 500mg for the first week, 1000mg during the second week, 1500mg during the third week, maximum dose of 2000mg in the fourth week<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Barrett's Esophagus, Vitamin D3, cholecalciferol, 15-Prostaglandin Dehydrogenase Expression, metformin