Barrett's Esophagus
Conditions
Keywords
Barrett's Esophagus, Esophageal Adenocarcinoma, GERD, Acid Reflux
Brief summary
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
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.
Interventions
DRUGYF476
25 mg: one capsule to be taken by mouth once daily for 12 weeks.
DRUGPlacebo
Matching placebo: one capsule to be taken by mouth once daily for 12 weeks.
Sponsors
Trio Medicines Ltd.
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Ki67 Expression | Up to 3 months from baseline | The study is designed to examine change in tissue Ki67 expression, a marker of cellular proliferation. |
| Number of Participants That Experienced Change in Any Biomarker Expression | Up to 3 months from baseline | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants That Experienced Adverse Events | Up to 4 months from baseline | A measure of safety and tolerability. Participants with recorded adverse events were tallied. The events include any adverse events and/or severe adverse events. |
Countries
United Kingdom, United States
Participant flow
Pre-assignment details
3 subjects were screen failures. 24 out of 27 subjects were randomized.
Participants by arm
| Arm | Count |
|---|---|
| YF476 YF476 (gastrin-receptor antagonist)
YF476: 25 mg: one capsule to be taken by mouth once daily for 12 weeks. | 13 |
| Placebo Placebo pill (identical in appearance to YF476 pills)
Placebo: Matching placebo: one capsule to be taken by mouth once daily for 12 weeks. | 11 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Baseline Endoscopy showed low grade dysplasia or indefinite for dysplasia | 3 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Total | YF476 | Placebo |
|---|---|---|---|
| Age, Continuous | 66.3 years STANDARD_DEVIATION 7.1 | 64.4 years STANDARD_DEVIATION 7.2 | 68.6 years STANDARD_DEVIATION 6.6 |
| Aspirin Use | 5 Participants | 3 Participants | 2 Participants |
| Barrett's Esophagus length Placebo | 6 cm | — | 6 cm |
| Barrett's Esophagus length YF476 | 3 cm | 3 cm | — |
| BMI | 27.9 kg/m2 STANDARD_DEVIATION 4.1 | 28.9 kg/m2 STANDARD_DEVIATION 4.7 | 26.7 kg/m2 STANDARD_DEVIATION 3.1 |
| Current smoker | 0 Participants | 0 Participants | 0 Participants |
| Hiatal hernia size Placebo | 4 cm | — | 4 cm |
| Hiatal hernia size YF476 | 2 cm | 2 cm | — |
| Plasma CgA | 11.2 nmol/L STANDARD_DEVIATION 13 | 12.9 nmol/L STANDARD_DEVIATION 17.2 | 9.1 nmol/L STANDARD_DEVIATION 5 |
| Proton Pump Inhibitor (PPI) frequency Once daily | 14 Participants | 8 Participants | 6 Participants |
| Proton Pump Inhibitor (PPI) frequency Twice daily | 10 Participants | 5 Participants | 5 Participants |
| Race/Ethnicity, Customized Race, white | 24 Participants | 13 Participants | 11 Participants |
| Serum gastrin | 56.4 pmol/L STANDARD_DEVIATION 36 | 60.3 pmol/L STANDARD_DEVIATION 41.7 | 51.8 pmol/L STANDARD_DEVIATION 29.1 |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 21 Participants | 11 Participants | 10 Participants |
| Waist circumference | 96.8 cm STANDARD_DEVIATION 14.8 | 95.7 cm STANDARD_DEVIATION 17.8 | 98.1 cm STANDARD_DEVIATION 10.9 |
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 | 10 / 13 | 7 / 11 |
| serious Total, serious adverse events | 1 / 13 | 0 / 11 |
Outcome results
Primary
Mean Ki67 Expression
The study is designed to examine change in tissue Ki67 expression, a marker of cellular proliferation.
Time frame: Up to 3 months from baseline
Population: Analysis limited to those who completed study (10 subjects in the intervention group and 10 subjects in the placebo group).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| YF476 | Mean Ki67 Expression | 35.6 cells/mm2 | Standard Deviation 620.7 |
| Placebo | Mean Ki67 Expression | 307.8 cells/mm2 | Standard Deviation 640.3 |
Primary
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.
Time frame: Up to 3 months from baseline
Population: Analysis limited to those who completed study (10 subjects in the intervention group and 10 subjects in the placebo group).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| YF476 | Number of Participants That Experienced Change in Any Biomarker Expression | 10 Participants |
| Placebo | Number of Participants That Experienced Change in Any Biomarker Expression | 9 Participants |
Secondary
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.
Time frame: Up to 4 months from baseline
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| YF476 | Number of Participants That Experienced Adverse Events | Serious Adverse Event | 1 Participants |
| YF476 | Number of Participants That Experienced Adverse Events | Any Adverse Event | 10 Participants |
| Placebo | Number of Participants That Experienced Adverse Events | Serious Adverse Event | 0 Participants |
| Placebo | Number of Participants That Experienced Adverse Events | Any Adverse Event | 7 Participants |