Trial of a Gastrin Receptor Antagonist in Barrett's Esophagus

• Sponsor: Columbia University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01298999
• Collaborator: Trio Medicines Ltd. (Industry)
• Enrollment: 27
• Locations: 2
• Arms: 2
• Duration (Months): 90
• Patients Per Site: 13.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Barrett's Esophagus	Drug: YF476; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Randomized Placebo-Controlled Trial of YF476, a Gastrin Receptor Antagonist, in Barrett's Esophagus
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Dec 1, 2017
• Actual Study Completion Date: Dec 1, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New York Presbyterian Hospital - Columbia	New York	New York	United States	10032
2	National Institute for Health Research	Cambridge		United Kingdom

Sponsors and Collaborators

• Columbia University
• Trio Medicines Ltd.

Investigators

• Principal Investigator: Julian A Abrams, MD, MS, Columbia University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 13, 2016

More Information

Publications

None provided.

• Responsible Party: Columbia University
• ClinicalTrials.gov Identifier: NCT01298999
• Other Study ID Numbers: AAAE9648; YFBE-001
• First Posted: Feb 18, 2011
• Last Update Posted: Nov 23, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Columbia University: Barrett's Esophagus; Esophageal Adenocarcinoma; GERD; Acid Reflux
• Additional relevant MeSH terms: Barrett Esophagus

Study Results

Participant Flow

Pre-assignment Detail	3 subjects were screen failures. 24 out of 27 subjects were randomized.

Arm/Group Title	YF476	Placebo
Arm/Group Description	YF476 (gastrin-receptor antagonist) YF476: 25 mg: one capsule to be taken by mouth once daily for 12 weeks.	Placebo pill (identical in appearance to YF476 pills) Placebo: Matching placebo: one capsule to be taken by mouth once daily for 12 weeks.
Period Title: Overall Study
STARTED	13	11
COMPLETED	10	10
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	YF476	Placebo	Total
Arm/Group Description	YF476 (gastrin-receptor antagonist) YF476: 25 mg: one capsule to be taken by mouth once daily for 12 weeks.	Placebo pill (identical in appearance to YF476 pills) Placebo: Matching placebo: one capsule to be taken by mouth once daily for 12 weeks.	Total of all reporting groups
Overall Participants	13	11	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.4 (7.2)	68.6 (6.6)	66.3 (7.1)
Sex: Female, Male (Count of Participants)
Female	2 15.4%	1 9.1%	3 12.5%
Male	11 84.6%	10 90.9%	21 87.5%
Race/Ethnicity, Customized (Count of Participants)
Race, white	13 100%	11 100%	24 100%
BMI (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	28.9 (4.7)	26.7 (3.1)	27.9 (4.1)
Waist circumference (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	95.7 (17.8)	98.1 (10.9)	96.8 (14.8)
Current smoker (Count of Participants)
Count of Participants [Participants]	0 0%	0 0%	0 0%
Proton Pump Inhibitor (PPI) frequency (Count of Participants)
Once daily	8 61.5%	6 54.5%	14 58.3%
Twice daily	5 38.5%	5 45.5%	10 41.7%
Aspirin Use (Count of Participants)
Count of Participants [Participants]	3 23.1%	2 18.2%	5 20.8%
Barrett's Esophagus length (cm) [Mean (Inter-Quartile Range) ]
YF476	3	3
Placebo	6	6
Hiatal hernia size (cm) [Mean (Inter-Quartile Range) ]
YF476	2	2
Placebo	4	4
Serum gastrin (pmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pmol/L]	60.3 (41.7)	51.8 (29.1)	56.4 (36.0)
Plasma CgA (nmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [nmol/L]	12.9 (17.2)	9.1 (5.0)	11.2 (13.0)

Outcome Measures

1. Primary Outcome

Title	Mean Ki67 Expression
Description	The study is designed to examine change in tissue Ki67 expression, a marker of cellular proliferation.
Time Frame	Up to 3 months from baseline

Outcome Measure Data

Analysis Population Description

Analysis limited to those who completed study (10 subjects in the intervention group and 10 subjects in the placebo group).

Arm/Group Title	YF476	Placebo
Arm/Group Description	YF476 (gastrin-receptor antagonist) YF476: 25 mg: one capsule to be taken by mouth once daily for 12 weeks.	Placebo pill (identical in appearance to YF476 pills) Placebo: Matching placebo: one capsule to be taken by mouth once daily for 12 weeks.
Measure Participants	10	10
Mean (Standard Deviation) [cells/mm2]	35.6 (620.7)	307.8 (640.3)

2. Primary Outcome

Title	Number of Participants That Experienced Change in Any Biomarker Expression
Description	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

Outcome Measure Data

Analysis Population Description

Analysis limited to those who completed study (10 subjects in the intervention group and 10 subjects in the placebo group).

Arm/Group Title	YF476	Placebo
Arm/Group Description	YF476 (gastrin-receptor antagonist) YF476: 25 mg: one capsule to be taken by mouth once daily for 12 weeks.	Placebo pill (identical in appearance to YF476 pills) Placebo: Matching placebo: one capsule to be taken by mouth once daily for 12 weeks.
Measure Participants	10	10
Count of Participants [Participants]	10 76.9%	9 81.8%

3. Secondary Outcome

Title	Number of Participants That Experienced Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	YF476	Placebo
Arm/Group Description	YF476 (gastrin-receptor antagonist) YF476: 25 mg: one capsule to be taken by mouth once daily for 12 weeks.	Placebo pill (identical in appearance to YF476 pills) Placebo: Matching placebo: one capsule to be taken by mouth once daily for 12 weeks.
Measure Participants	13	11
Serious Adverse Event	1 7.7%	0 0%
Any Adverse Event	10 76.9%	7 63.6%

Adverse Events

Time Frame	Throughout the course of treatment and up to four weeks after completion of the study drug course or placebo course - an average of 4 months.
Arm/Group Title	YF476		Placebo
Arm/Group Description	YF476 (gastrin-receptor antagonist) YF476: 25 mg: one capsule to be taken by mouth once daily for 12 weeks.		Placebo pill (identical in appearance to YF476 pills) Placebo: Matching placebo: one capsule to be taken by mouth once daily for 12 weeks.
All Cause Mortality
	YF476		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/11 (0%)
Serious Adverse Events
	YF476		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/13 (7.7%)		0/11 (0%)
Reproductive system and breast disorders
Scrotal abscess	1/13 (7.7%)	1	0/11 (0%)	0
Other (Not Including Serious) Adverse Events
	YF476		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/13 (76.9%)		7/11 (63.6%)
Endocrine disorders
Hypoglycemia	1/13 (7.7%)		0/11 (0%)
Gastrointestinal disorders
Diarrhea	3/13 (23.1%)		1/11 (9.1%)
Abdominal pain	2/13 (15.4%)		2/11 (18.2%)
Constipation	2/13 (15.4%)		1/11 (9.1%)
Nausea	1/13 (7.7%)		1/11 (9.1%)
Rectal bleeding	1/13 (7.7%)		1/11 (9.1%)
Acid reflux	0/13 (0%)		1/11 (9.1%)
Vomiting	0/13 (0%)		1/11 (9.1%)
Constipation	0/13 (0%)		1/11 (9.1%)
General disorders
Fatigue	1/13 (7.7%)		0/11 (0%)
Fever	1/13 (7.7%)		0/11 (0%)
Chest pain	1/13 (7.7%)		0/11 (0%)
Epistaxis	0/13 (0%)		1/11 (9.1%)
Mouth ulcer	1/13 (7.7%)		0/11 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	0/13 (0%)		2/11 (18.2%)
Arthralgia	1/13 (7.7%)		0/11 (0%)
Nervous system disorders
Headache	3/13 (23.1%)		3/11 (27.3%)
Dizziness	2/13 (15.4%)		1/11 (9.1%)
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis	2/13 (15.4%)		2/11 (18.2%)
Cough	0/13 (0%)		2/11 (18.2%)
Skin and subcutaneous tissue disorders
Rash	2/13 (15.4%)		1/11 (9.1%)

Limitations/Caveats

Relatively small sample size; study enrollment was limited to Barrett's esophagus without dysplasia, limited analysis of treatment related to later stages of disease progression; only one dose was tested which limits possibility that higher doses would have been more bioactive in Barrett's esophagus tissue.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.