Effect of Repeated Doses of YF476, Omeprazole and Placebo on Stomach Acidity in Healthy Volunteers

YF476: Effects of Repeated Dosing at 2 Dose Levels on 24-hour Ambulatory Gastric pH Compared With Placebo and Omeprazole in Healthy Volunteers

The objectives of this study were:

To compare repeated doses of YF476 at 2 dose levels, placebo and omeprazole with respect to their effect on basal- and food- stimulated gastric pH in healthy volunteers.

To compare repeated doses of YF476 at 2 dose levels, placebo and omeprazole with respect to their effect on basal and meal stimulated pH.

To assess the safety, tolerability and pharmacokinetics of repeated doses of YF476 in healthy volunteers.

Study Overview

• Status: Completed
• Conditions: Reflux Oesophagitis
• Intervention / Treatment: Drug: YF476; Drug: Omeprazole

Detailed Description

YF476 is clearly a potent and selective gastrin/CCK-B antagonist and should inhibit basal and meal-stimulated gastric acid secretion, enhance gastric emptying of a liquid meal and increase lower oesphageal sphincter pressure in man. Therefore YF476 might benefit patients with reflux oesophagitis.

YF476 has been well tolerated in healthy volunteers at single doses up to 100mg and remarkably well tolerated at repeat doses in animals up to 350 times the maximum dose planned for the proposed study. A range of doses of YF476 (25 and 100mg twice daily) will be administered to steady state. 24-hour ambulatory gastric pH will be monitored via an intragastric pH electrode to assess the effect of YF476 on basal and meal stimulated gastric pH. Although there is variability between subjects with respect to the effects of food and drug treatment on gastric pH, the methodology for measurement of ambulatory gastric pH is robust.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Hammersmith Medicines Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female aged 18-45 years.
• No clinically relevant abnormal findings in the clinical history or physical examination at the screening assessment which could interfere with the objectives of the study or make the subject's participation hazardous.
• No clinically relevant abnormal laboratory values at the screening evaluation (Attachment 2).
• A normal ECG at the screening examination.
• A body mass index (Quetelet index) in the range 19-30:

Body Mass Index = weight [kg]_ height [m]2

• Normal blood pressure and heart rate at the screening examination, i.e. BP 90-150mmHg systolic, 40-95mmHg diastolic; heart rate 40-100 beats/min in seated position.
• Subjects must be of sufficient intelligence to understand the nature of the study and any hazards of their participation in it. They must be able to communicate satisfactorily with the Investigator and to participate in, and comply with the requirements of, the entire study.
• Subjects must give their written consent to participate after reading the Information-for-Volunteers Leaflet and Consent Form, and after having the opportunity to discuss the study with the Investigator or his deputy.

Exclusion Criteria:

• Females who are pregnant or lactating, or who are sexually active and are not using a reliable method of contraception.
• Clinically relevant abnormal history or physical findings at the screening assessment, which could interfere with the objectives of the study or the safety of the subject's participation.
• Clinically relevant abnormalities of laboratory values or ECG at screening evaluation.
• Presence of acute or chronic illness or history of chronic illness sufficient to invalidate subject's participation in the study or make it unnecessarily hazardous.
• Impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes mellitus, coronary heart disease or history of any psychotic mental illness.
• Participation in other clinical studies of a new chemical entity or a prescription medicine within the previous 3 months.
• Presence or history of drug or alcohol abuse, or intake of more than 40 units of alcohol weekly.
• Loss of more than 400mL blood during the 3 months before the study, e.g. as a blood donor.
• Use of prescription medication during 30 days before the study.
• Use of an over-the-counter medicine during 7 days before the study
• Blood pressure or heart rate outside those values specified under inclusion criterion (f).
• Possibility that the subject will not cooperate with the requirements of the protocol.
• Evidence of drug abuse on urine testing at study entry.
• Positive test for hepatitis B or C or HIV 1 & 2.
• High risk of hepatitis or HIV infection.
• History of severe allergic disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamic measurements: continuous 24h ambulatory gastric pH and 24 h plasma gastrin	Recording started 0.5 h before the morning dose on Study Day 7 for measurement of gastric pH; meals taken at 4, 9, 13 & 22 h after the morning dose. Frequent blood samples for measurement of plasma gastrin.	6 weeks
Assessment of safety and tolerability	Physical examination, ECG and safety tests of blood/urine at screening, after the last dose and at follow up.	6 weeks
Pharmacokinetic analysis of plasma YF476 concentrations	Blood samples (8 mL) for assay of YF476 taken before each morning dose on Study Days 1-6 and at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 12.25, 12.5, 12.75, 13, 14.5, 15, 16, 17, 18, 20, 22 and 24h on Study Day 7 (where 0h is the time of the morning dose and 12h is the time of the evening dose)for calculation of Cmax, Tmax, AUC 0-24 h, T1/2.	6 weeks
Number of adverse events	Adverse events throughout the study	6 weeks

Collaborators and Investigators

• Sponsor: Trio Medicines Ltd.
• Collaborators: Ferring Pharmaceuticals
• Investigators: Study Director: Malcolm Boyce, Trio Medicines Limited

Study record dates

Study Major Dates

• Study Start: August 1, 1996
• Primary Completion (Actual): October 1, 1996
• Study Completion (Actual): October 1, 1996

Study Registration Dates

• First Submitted: May 10, 2012
• First Submitted That Met QC Criteria: May 14, 2012
• First Posted (Estimate): May 16, 2012

Study Record Updates

• Last Update Posted (Estimate): May 16, 2012
• Last Update Submitted That Met QC Criteria: May 14, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: healthy subjects; omeprazole; YF476; gastrin receptor antagonist; gastric pH
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Gastroenteritis; Intestinal Diseases; Esophageal Diseases; Peptic Ulcer; Duodenal Diseases; Esophagitis, Peptic; Esophagitis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Omeprazole
• Other Study ID Numbers: 96-018