Effect of Netazepide on Omeprazole-induced Changes in Chromogranin A and Gastrin

NCT02620696 | Completed Phase 1

• 1 other identifier: T-013
• Study Type: interventional
• Target: 48
• Locations: 0 countries
• Sites: N/A

Brief Summary

Hypergastrinaemia induced by proton pump inhibitor (PPI) treatment is reported to cause ECL-cell and parietal-cell hyperplasia, and rebound hyperacidity and dyspepsia after PPI withdrawal. The objective of the study was to determine the dosage regimen of netazepide, a gastrin/CCK2 receptor antagonist, required to inhibit the trophic effects of PPI-induced hypergastrinaemia. Six groups of 8 healthy subjects participated in a randomised, double-blind, placebo-controlled exploratory study of esomeprazole 40 mg daily for 28 days, and netazepide 1, 5 or 25 mg, or placebo daily during the last 14 days of esomeprazole dosing, or 14 days after esomeprazole withdrawal. Serum gastrin and plasma chromogranin A (CgA) were measured regularly from study start until at least 1 week after the last dose. Dyspepsia was monitored after esomeprazole withdrawal.

Conditions

ECL-cell Hyperplasia; Parietal-cell Hyperplasia; Rebound Hyperacidity; Dyspepsia

Outcome Measures

Primary Outcomes (2)

• Plasma chromogranin A (CgA) concentrations

  We separated serum or plasma from blood, and stored samples at -20°C until assay by ELISA (serum gastrin: Immulite 2000, DPC. CV = 6.9%; plasma CgA: DAKO. CV = 7.2%) and validated HPLC/MS method (plasma netazepide: lower limit of quantification 0.5 ng/mL) (Redrup et al 2002).

  8 weeks

• Serum gastrin concentrations

  We separated serum or plasma from blood, and stored samples at -20°C until assay by ELISA (serum gastrin: Immulite 2000, DPC. CV = 6.9%; plasma CgA: DAKO. CV = 7.2%) and validated HPLC/MS method (plasma netazepide: lower limit of quantification 0.5 ng/mL) (Redrup et al 2002).

  8 weeks

Secondary Outcomes (4)

• Dyspepsia scores

  8 weeks

• Antacid usage

  8 weeks

• Safety assessed by Vital signs, ECG variables, physical examinations, laboratory variables

  5 weeks

• Tolerability assessed by Adverse events

  8 weeks

Study Arms (6)

Treatment 1

EXPERIMENTAL

* esomeprazole 40 mg daily for 28 days (Days 1-28) * netazepide placebo daily from Days 1-42

Drug: netazepide

Treatment 2

EXPERIMENTAL

* esomeprazole 40 mg daily for 28 days (Days 1-28) * netazepide 25 mg daily for 14 days (Days 15-28) * netazepide placebo daily from Days 1-14, and from Days 29-42

Drug: netazepide

Treatment 3

EXPERIMENTAL

* esomeprazole 40 mg daily for 28 days (Days 1-28) * netazepide 25 mg daily for 14 days (Days 29-42) * netazepide placebo daily from Days 1-28

Drug: netazepide

Treatment 4

EXPERIMENTAL

* esomeprazole 40 mg daily for 28 days (Days 1-28) * netazepide placebo daily from Days 1-28

Drug: netazepide

Treatment 5

EXPERIMENTAL

* esomeprazole 40 mg daily for 28 days (Days 1-28) * netazepide 1 mg daily for 14 days (Days 15-28) * netazepide placebo daily from Days 1-14

Drug: netazepide

Treatment 6

EXPERIMENTAL

* esomeprazole 40 mg daily for 28 days (Days 1-28) * netazepide 5 mg daily for 14 days (Days 15-28) * netazepide placebo daily from Days 1-14

Drug: netazepide

Interventions

netazepide DRUG

Also known as: YF476

Treatment 1; Treatment 2; Treatment 3; Treatment 4; Treatment 5; Treatment 6

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy men, post-menopausal women or pre-menopausal women, using one of the following methods of contraception: abstinence; condom and spermicide; intra-uterine device; or hysterectomy or tubal ligation
• Age 18-75 years
• A body mass index (Quetelet index) in the range 18.0-30.9 Body Mass Index = weight (kg)/height (m2)
• Negative test for H. pylori
• No history of dyspepsia symptoms
• No history of peptic ulcer or oesophagitis
• No history of treatment with a histamine H2 antagonist, proton pump inhibitor or antacid
• Normal serum gastrin (no greater than 5% above the upper limit of the HMR laboratory reference range for gastrin)
• Non-smokers or social smokers (defined as 10 or fewer cigarettes per week)
• Sufficient intelligence to understand the nature of the trial and any hazards of participating in it. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire trial
• Willingness to give written consent to participate after reading the Information and Consent Form, and after having the opportunity to discuss the trial with the investigator or delegate.

You may not qualify if:

• Women who are pregnant or lactating.
• Clinically relevant abnormal history, physical findings, ECG (\> 450 msec), or laboratory values at the pre-trial screening assessment that could interfere with the objectives of the trial or the safety of the subject.
• Presence of acute or chronic illness or history of chronic illness sufficient to invalidate the subject's participation in the trial or make it unnecessarily hazardous.
• Severe adverse reaction to any drug
• Use, during the 14 days before the baseline visit, of a prescription medicine, especially one that inhibits or induces CYP3A4/5, CYP2C8 or CYP2C9, a hormone contraceptive and hormone replacement therapy.
• Use, during the 14 days before the baseline visit, of herbal products, such as St John's wort.
• Use of an over-the-counter medicine during the 7 days before the baseline visit, with the exception of paracetamol (up to 4 g daily).
• Participation in another trial of a new chemical entity or a prescription medicine, or loss of more than 400 mL blood, within the previous 3 months.
• Presence or history of drug or alcohol abuse.

Sponsors & Collaborators

• Trio Medicines Ltd.: lead

MeSH Terms

Conditions

Dyspepsia

Interventions

YF 476

Condition Hierarchy (Ancestors)

Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Malcolm Boyce

  Hammersmith Medicines Research

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2015
• First Posted: December 3, 2015
• Study Start: November 1, 2009
• Primary Completion: September 1, 2010
• Study Completion: September 1, 2010
• Last Updated: December 3, 2015

Record last verified: 2015-12

Data Sharing

• IPD Sharing: Will not share