Barrett's Esophagus
Conditions
Keywords
acid reflux, intragastric pH, gastrin, hypergastrinemia
Brief summary
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.
Interventions
DRUGYF476
gastrin receptor antagonist
DRUGYF476 placebo
placebo
Sponsors
Columbia University
University of Cambridge
Trio Medicines Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Ki67 Biomarker Expression | Baseline and Week 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Expression of Biomarkers Potentially Associated With Esophageal Adenocarcinoma (EAC) | Week 12 | 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. |
| Abundance of Biomarkers of Gastric Acid Suppression | Week 4, Week 6, Week 8, Week 12 and Follow-up (4 weeks after stopping YF476 treatment) | Blood samples were taken to assess the effects of YF476 on fasting serum gastrin, a marker of gastric acid suppression |
| Abundance of Biomarkers of ECL Cell Hyperplasia | Week 4, Week 6, Week 8, Week 12 and Follow-up (4 weeks after stopping YF476 treatment) | Blood samples were taken to assess the effects of YF476 on fasting plasma CgA, a marker of ECL cell hyperplasia |
Countries
United Kingdom, United States
Participant flow
Pre-assignment details
Three patients were enrolled but failed screening due to elevated lipase, prolonged QTc or being diagnosed with lymphoma.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Patients will take 25 mg YF476 once daily for 12 weeks
YF476: gastrin receptor antagonist | 13 |
| YF476 Placebo Patients will take matching placebo once daily for 12 weeks
YF476 placebo: placebo | 11 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Baseline biopsies showed indefinite for dysplasia | 2 | 0 |
| Overall Study | Baseline biopsies showed low grade dysplasia | 1 | 0 |
| Overall Study | Recurrent metastatic prostate cancer | 0 | 1 |
Baseline characteristics
| Characteristic | Treatment | YF476 Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 9 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 2 Participants | 6 Participants |
| Fasting plasma CgA concentration (marker of ECL cell hyperplasia) | 12.93 nmol/L STANDARD_DEVIATION 17.21 | 9.12 nmol/L STANDARD_DEVIATION 4.98 | 11.18 nmol/L STANDARD_DEVIATION 13 |
| Fasting serum gastrin concentration (marker of gastric acid suppression) | 66.74 pmol/L STANDARD_DEVIATION 41.736 | 51.85 pmol/L STANDARD_DEVIATION 29.104 | 56.45 pmol/L STANDARD_DEVIATION 35.997 |
| Ki67 expression | 1539 cells/mm^2 STANDARD_DEVIATION 514 | 1556 cells/mm^2 STANDARD_DEVIATION 622 | 1548 cells/mm^2 STANDARD_DEVIATION 559 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 11 Participants | 24 Participants |
| Region of Enrollment United Kingdom | 6 participants | 6 participants | 12 participants |
| Region of Enrollment United States | 7 participants | 5 participants | 12 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 11 |
| other Total, other adverse events | 13 / 13 | 11 / 11 |
| serious Total, serious adverse events | 1 / 13 | 0 / 11 |
Outcome results
Primary
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.
Time frame: Baseline and Week 12
Population: 3 patients in the treatment arm and 1 patient in the placebo arm were withdrawn from the study due to reasons unrelated to the treatment. Therefore, Week 12 data show results from 10 patients per arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in Ki67 Biomarker Expression | Baseline | 1539 cells/mm^2 | Standard Deviation 514 |
| Treatment | Change in Ki67 Biomarker Expression | Week 12 | 1575 cells/mm^2 | Standard Deviation 620.7 |
| YF476 Placebo | Change in Ki67 Biomarker Expression | Baseline | 1556 cells/mm^2 | Standard Deviation 622 |
| YF476 Placebo | Change in Ki67 Biomarker Expression | Week 12 | 1864 cells/mm^2 | Standard Deviation 640.3 |
Secondary
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
Time frame: Week 4, Week 6, Week 8, Week 12 and Follow-up (4 weeks after stopping YF476 treatment)
Population: After 6 patients (3 per treatment) had their Week 4 and 8 visits, the protocol was amended so that those visits were replaced by a single visit at Week 6 in order to reduce the total number of visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Abundance of Biomarkers of ECL Cell Hyperplasia | Week 4 | 3.9 nmol/L | Standard Deviation 1.8 |
| Treatment | Abundance of Biomarkers of ECL Cell Hyperplasia | Week 12 | 2.9 nmol/L | Standard Deviation 2.5 |
| Treatment | Abundance of Biomarkers of ECL Cell Hyperplasia | Week 8 | 3.8 nmol/L | Standard Deviation 1.8 |
| Treatment | Abundance of Biomarkers of ECL Cell Hyperplasia | Follow-up | 19.8 nmol/L | Standard Deviation 26.1 |
| Treatment | Abundance of Biomarkers of ECL Cell Hyperplasia | Week 6 | 1.8 nmol/L | Standard Deviation 0.9 |
| YF476 Placebo | Abundance of Biomarkers of ECL Cell Hyperplasia | Follow-up | 11.9 nmol/L | Standard Deviation 7.2 |
| YF476 Placebo | Abundance of Biomarkers of ECL Cell Hyperplasia | Week 4 | 8.8 nmol/L | Standard Deviation 3.7 |
| YF476 Placebo | Abundance of Biomarkers of ECL Cell Hyperplasia | Week 6 | 16.9 nmol/L | Standard Deviation 9.8 |
| YF476 Placebo | Abundance of Biomarkers of ECL Cell Hyperplasia | Week 8 | 10.9 nmol/L | Standard Deviation 6 |
| YF476 Placebo | Abundance of Biomarkers of ECL Cell Hyperplasia | Week 12 | 10.6 nmol/L | Standard Deviation 7.4 |
Secondary
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
Time frame: Week 4, Week 6, Week 8, Week 12 and Follow-up (4 weeks after stopping YF476 treatment)
Population: After 6 patients (3 per treatment) had their Week 4 and 8 visits, the protocol was amended so that those visits were replaced by a single visit at Week 6 in order to reduce the total number of visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Abundance of Biomarkers of Gastric Acid Suppression | Week 6 | 103.3 pmol/L | Standard Deviation 89.9 |
| Treatment | Abundance of Biomarkers of Gastric Acid Suppression | Week 12 | 146.8 pmol/L | Standard Deviation 112.8 |
| Treatment | Abundance of Biomarkers of Gastric Acid Suppression | Week 8 | 234.3 pmol/L | Standard Deviation 156.5 |
| Treatment | Abundance of Biomarkers of Gastric Acid Suppression | Follow-up | 94.9 pmol/L | Standard Deviation 78.8 |
| Treatment | Abundance of Biomarkers of Gastric Acid Suppression | Week 4 | 242.6 pmol/L | Standard Deviation 142.3 |
| YF476 Placebo | Abundance of Biomarkers of Gastric Acid Suppression | Follow-up | 64.7 pmol/L | Standard Deviation 37.7 |
| YF476 Placebo | Abundance of Biomarkers of Gastric Acid Suppression | Week 4 | 43.6 pmol/L | Standard Deviation 9.9 |
| YF476 Placebo | Abundance of Biomarkers of Gastric Acid Suppression | Week 6 | 63.9 pmol/L | Standard Deviation 32.2 |
| YF476 Placebo | Abundance of Biomarkers of Gastric Acid Suppression | Week 8 | 96.4 pmol/L | Standard Deviation 54.2 |
| YF476 Placebo | Abundance of Biomarkers of Gastric Acid Suppression | Week 12 | 49.2 pmol/L | Standard Deviation 20.4 |
Secondary
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.
Time frame: Week 12
Population: 3 patients in the treatment arm were withdrawn from the study due to reasons unrelated to the treatment. Therefore, results are reported for 10 patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment | Expression of Biomarkers Potentially Associated With Esophageal Adenocarcinoma (EAC) | CCK2R, Week 12 | -1.19 relative log-fold change |
| Treatment | Expression of Biomarkers Potentially Associated With Esophageal Adenocarcinoma (EAC) | PTGS2, Week 12 | 0.31 relative log-fold change |
| Treatment | Expression of Biomarkers Potentially Associated With Esophageal Adenocarcinoma (EAC) | DCLK1, Week 12 | -0.34 relative log-fold change |