YF476 in Barrett's Esophagus

Study Overview
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Brief Summary
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A phase 2, randomised, double-blind, out-patient trial to determine if YF476 is a safe and effective treatment in patients with Barrett's esophagus.

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: YF476 placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged >18 years, with histologically confirmed diagnosis of Barrett's esophagus (BE) without dysplasia. A prior endoscopy with biopsies read as indefinite for dysplasia is permitted if biopsies from the most recent endoscopy prior to study entry demonstrated BE without dysplasia. Minimum of 1 cm circumferential Barrett's mucosa on endoscopy or at least 2 cm maximal contiguous extent of Barrett's mucosa, as measured from the top of the gastric folds to the squamocolumnar junction (Prague criteria C>1, any M or any C, M>2). Proton pump inhibitor use at least once daily, for at least 12 months prior to enrolment, and stable dose of PPI for the 3 months before enrolment. Any PPI, dose, and frequency allowable. ECOG performance status <2 and Karnofsky >60% Normal organ and marrow function, defined as white blood cells >3 x 10e9, absolute neutrophil count >1.5 x 10e9, platelets >100 x 10e9, creatinine <1.5 mg/dL, total bilirubin <1.5 mg/dL, AST <100 U/L, ALT <100 U/L. Use of adequate contraception during the study, as follows; Post-menopausal women must have had their last menstrual period at least 1 year ago. Pre-menopausal women, who are sexually-active, must have had a hysterectomy or bilateral oophorectomy; or must use an intrauterine device (IUD), or spermicide with a diaphragm, cap or condom. Streroid contraceptives such as 'the pill' are not allowed unless in combination with one of the aforementioned barrier contraceptive methods. Men must use a condom and spermicide. 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, (Columbia University only), and no cancer screening tests planned for the next 21 weeks. Exclusion Criteria: Histologically confirmed BE with high-grade dysplasia. Histologically confirmed diagnosis of invasive carcinoma of the esophagus. Histologically confirmed BE with low-grade dysplasia that has been diagnosed by at least 2 expert gastrointestinal pathologists. Prior endoscopic therapy for BE. Any history of esophageal or gastric surgery. History of atrophic gastritis, pernicious anemia, or Zollinger-Ellison syndrome. Participation in a trial of an IMP within the previous 28 days. Prolonged QTc interval >450 msec. History of allergic reactions attributed to compounds of similar chemical composition of YF476. History of baseline findings of: diabetes mellitus requiring insulin therapy pancreatitis (baseline amylase and/or lipase >2.0 x ULN) hepatitis B, hepatitis C or HIV malabsorption syndrome or inability to swallow or retain oral medicine major surgery <28 days prior to enrolment ECOG performance status >2 another cancer within 3 years except for basal carcinoma of the skin or cervical carcinoma in-situ also, any clinically significant and uncontrolled major morbidity including but not limited to: serious cardiac disease (unstable angina, s/p myocardial infarction <1 month); respiratory disease (advanced COPD or pulmonary fibrosis); uncontrolled hypertension; active systemic infection; or psychiatric illness/social situations that would limit compliance with study requirements. Certain medicines and herbal remedies taken during the 7 days before the start of the study drug. A history of cancer >3 years from the time of enrolment, and the patient is not up to date with surveillance for that cancer (based on the American Cancer Society guidelines, Columbia University only), has evidence of cancer at the time of enrolment, or has surveillance tests planned within 21 weeks after enrolment.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Patients will take 25 mg YF476 once daily for 12 weeks | Drug: YF476<br>* gastrin receptor antagonist<br>* Other names: netazepide;|
| Placebo Comparator: YF476 Placebo<br>Patients will take matching placebo once daily for 12 weeks | Drug: YF476 placebo<br>* placebo<br>* Other names: netazepide placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Ki67 Biomarker Expression | Esophagogastroduodenoscopy (EGD) was performed to enable taking biopsies for assessment of Ki67 expression, a marker of cellular proliferation. Ki67 expression was assessed by immunohistochemistry and calculating the number of Ki67 positive cells per mm^2 of Barrett's epithelium. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expression of Biomarkers Potentially Associated With Esophageal Adenocarcinoma (EAC) | Blood samples were taken for assay of biomarkers associated with esophageal adenocarcinoma. Changes in biomarker expression were derived from RNA-Sequencing and calculated as log-fold change comparing the treatment group to the placebo group. The nature of how results are derived by RNA-sequencing means summary statistics cannot be generated individually for each arm and a value has not been calculated for each individual participant. Therefore, results are reported as the relative change in biomarker expression in the treatment arm compared to the placebo arm. | Week 12 | 
| Abundance of Biomarkers of Gastric Acid Suppression | Blood samples were taken to assess the effects of YF476 on fasting serum gastrin, a marker of gastric acid suppression | Week 4, Week 6, Week 8, Week 12 and Follow-up (4 weeks after stopping YF476 treatment) | 
| Abundance of Biomarkers of ECL Cell Hyperplasia | Blood samples were taken to assess the effects of YF476 on fasting plasma CgA, a marker of ECL cell hyperplasia | Week 4, Week 6, Week 8, Week 12 and Follow-up (4 weeks after stopping YF476 treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acid reflux, intragastric pH, gastrin, hypergastrinemia