Trial of a Gastrin Receptor Antagonist in Barrett's Esophagus

Study Overview
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Brief Summary
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The purpose of this study is to determine whether treatment with an experimental drug called YF476 in patients with Barrett's esophagus reduces the expression of tissue markers that are associated with an increased risk of developing esophageal cancer.

Detailed Description
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The association between gastro-esophageal reflux disease (GERD) and cancer of the esophagus is well-established. Barrett's esophagus (BE) is a condition in which the lining of the part of the esophagus changes to look like small intestine, and this change occurs in the setting of GERD. Patients with BE are at increased risk for developing esophageal cancer. It is recommended that all patients with BE take medicines called proton pump inhibitors (PPIs), which greatly reduce the acid produced by the stomach, in the hopes of reducing the risk of esophageal cancer. However, by reducing the acid level in the stomach, levels of a hormone called gastrin are increased. There is laboratory data to suggest that gastrin may have effects that actually promote the development of cancer, including esophageal cancer. The investigators previously showed that BE patients with very high gastrin levels are more likely to have either advanced precancerous changes (also called high grade dysplasia) or cancer of the esophagus. As such, the obvious question is raised: does gastrin promote the development of cancer in BE? YF476 is a new drug that blocks the effects of gastrin. Trials in healthy subjects have demonstrated that the drug is safe and well-tolerated. The investigators therefore propose to conduct a randomized placebo-controlled trial of YF476 in patients with Barrett's esophagus. The primary hypothesis is that treatment with YF476 will reduce the expression of tissue markers that are associated with an increased risk of developing esophageal cancer.

Official Title
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Randomized Placebo-Controlled Trial of YF476, a Gastrin Receptor Antagonist, in Barrett's Esophagus

Conditions
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Barrett's Esophagus

Intervention / Treatment
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* Drug: YF476
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years, with histologically confirmed diagnosis of Barrett's Esophagus without dysplasia Minimum of 1 cm circumferential Barrett's mucosa on endoscopy or at least 2 cm maximal contiguous extent of Barrett's mucosa Proton pump inhibitor use at least once daily for at least twelve months prior to enrolment, and stable dose of PPI for the three months before enrolment ECOG performance status ≤ 2 and Karnofsky ≥ 60% Normal organ and marrow function Use of adequate contraception during the study Willingness to comply with all treatment and follow up procedures Ability to understand and the willingness to sign a written informed consent document Up to date with all age appropriate cancer screening tests, as per American Cancer Society guidelines Exclusion Criteria: Histologically confirmed BE with high grade dysplasia, invasive carcinoma of the esophagus, low grade dysplasia Prior endoscopic therapy for BE History of esophageal or gastric surgery History of atrophic gastritis, pernicious anemia, or Zollinger-Ellison syndrome Participation in a trial of an investigational medicinal product within the previous 28 days Prolonged QTc interval >450 msec History of allergic reactions attributed to compounds of similar chemical composition to YF476 History of baseline findings of: diabetes mellitus requiring insulin therapy; pancreatitis; hepatitis B, hepatitis C or HIV; malabsorption syndrome or inability to swallow or retain oral medicine; major surgery ≤ 28 days prior to enrollment; ECOG performance status ≥ 2; or another cancer within 3 years except for basal carcinoma of the skin or cervical carcinoma in situ; any clinically significant and uncontrolled major morbidity Certain medicines and herbal remedies taken during the 7 days before the start of study drug Has evidence of cancer at the time of enrolment, or has surveillance tests planned within 21 weeks after enrollment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: YF476<br>YF476 (gastrin-receptor antagonist) | Drug: YF476<br>* 25 mg: one capsule to be taken by mouth once daily for 12 weeks.<br>* Other names: Netazepide;|
| Placebo Comparator: Placebo<br>Placebo pill (identical in appearance to YF476 pills) | Drug: Placebo<br>* Matching placebo: one capsule to be taken by mouth once daily for 12 weeks.<br>* Other names: Placebo Tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Ki67 Expression | The study is designed to examine change in tissue Ki67 expression, a marker of cellular proliferation. | Up to 3 months from baseline | 
| Number of Participants That Experienced Change in Any Biomarker Expression | Participants with changes in gene expression were assessed by RNA-sequencing (i.e., sample has sufficient RNA for analysis) between baseline and up to 3 months are tallied. | Up to 3 months from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Experienced Adverse Events | A measure of safety and tolerability. Participants with recorded adverse events were tallied. The events include any adverse events and/or severe adverse events. | Up to 4 months from baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Barrett's Esophagus, Esophageal Adenocarcinoma, GERD, Acid Reflux