Gastrointestinal Integrity After Naproxen + Rebamipide Versus Naproxen + Placebo

Double-blind Trial on the Gastrointestinal Integrity Evaluation After Daily Naproxen 1100 mg + Rebamipide 200mg for 7 Days Versus Naproxen 1100mg + Placebo for 7 Days

This is a double-blind, placebo-controlled, randomized, parallel trial to evaluate if rebamipide reduces the number of gastric events caused by naproxen. Sample size is 24 participants (12 per treatment group), male or female, aged 18 years-old and above.

Primary objective is to compare rebamipide effervescent granules 100 mg twice daily, plus naproxen (coated tablets) 550 mg twice daily to placebo plus naproxen 550 mg twice daily, for seven days, in reduction of gastric events caused by naproxen. Secondary objective is to evaluate safety and tolerability of rebamipide after multiple administrations.

Participants will receive either rebamipide + naproxen or placebo + naproxen, as above, during 7 consecutive days, which will be accompanied by a follow-up visit.

Gastric integrity will be assessed, before and after treatment, by endoscopy, with stomach biopsies and detection of H. pylori. Additionally, detection of occult blood in the stool will be performed, before and after treatment.

From the above-mentioned biopsies, dosage of prostaglandin E2 and histopathological analysis will be performed.

Study Overview

• Status: Completed
• Conditions: Gastrointestinal Lesions
• Intervention / Treatment: Drug: Rebamipide effervescent granules; Drug: Naproxen tablet; Drug: Placebo effervescent granules

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female study participants, aged 18 years-old and above; women cannot be pregnant or breastfeeding;
• Body mass index (BMI) greater than or equal to 19 and less than or equal to 28.75 Kg/m2;
• Good health conditions or without significant diseases, according to best medical judgement, according to protocol requirements and study evaluations: medical history, blood pressure and heart rate measurements, physical examination, electrocardiogram (ECG) and screening laboratory tests;
• Ability to understand the nature and objectives of the trial, including risks and adverse events; willingness to cooperate with the researcher and proceed according to all study requirements, which shall be confirmed by Informed Consent Form signature.

Exclusion Criteria:

• Known hypersensitivity to the investigational products (naproxen or rebamipide) or chemically related compounds; history of serious adverse reactions or hypersensitivity to any drug;
• Subject does not present intact superior gastrointestinal mucosa, i.e., presenting bleeding, ulcers and apparent injuries in baseline endoscopy;
• Subject has achlorhydria (intragastric pH > 6.5);
• History or presence of hepatic or gastrointestinal diseases, or other condition that interferes with drug absorption, distribution, excretion or metabolism;
• Chronic therapy with any drugs, except oral contraceptives;
• History of hepatic, kidney, lungs, gastrointestinal, epileptic, hematologic or psychiatric disease; hypotension or hypertension, of any etiology, that requires pharmacological treatment; history of myocardial infarction, angina and/or heart failure;
• Occult blood in the stool before treatment;
• Electrocardiographic findings that, at investigator criteria, are not recommended for study participation;
• Deviations on screening laboratory results that are considered as clinically relevant by the principal investigator;
• History of drugs and alcohol addiction or excessive alcohol consumption (> 35 g/day);
• Use of regular medications within 2 weeks prior study enrollment or use of any medications within one week prior to study enrollment, except oral contraceptives or cases which, based on drug's or metabolite's half-life, complete elimination can be assumed;
• Treatment, within 6 months before the trial, with any drugs known to have a well-established toxic potential to major organs;
• Participation in any other experimental research or administration of any experimental drug within 6 months before this trial;
• Any condition, according to investigator's best judgement, that prevents the subject to participate in the trial;
• Pregnancy, labor or miscarriage with 12 weeks before admission predicted date.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rebamipide & Naproxen; Rebamipide 100 mg effervescent granules (oral) Twice daily (total dose = 200 mg) for 7 days	Drug: Rebamipide effervescent granules; Rebamipide effervescent granules 100mg (oral), twice daily for 7 days; Drug: Naproxen tablet; Naproxen tablet 550mg (tablet), twice daily for 7 days
Placebo Comparator: Placebo & Naproxen; Sugar pill manufactured to mimic Rebamipide 100 mg effervescent granules (oral) Twice daily for 7 days	Drug: Naproxen tablet; Naproxen tablet 550mg (tablet), twice daily for 7 days; Drug: Placebo effervescent granules; Placebo effervescent granules (oral), twice daily for 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endoscopic Score - Cryer Score	Cryer score according to gastroduodenal mucosal injury: 0 = Normal or erythema; = Any amount of submucosal hemorrhage or edema without erosions; = 1 erosion +- submucosal hemorrhage or edema; = 2-4 erosions +- submucosal hemorrhage or edema; = 5 or more erosions and/or a single ulcer +- submucosal hemorrhage or edema; = Multiple ulcers +- submucosal hemorrhage or edema - Ulcer	8 days
Endoscopic Score - Modified Lanza Score	Modified Lanza score according to gastroduodenal mucosal injury: 0 = No hemorrhage or erosion observed; = One or two hemorrhages or erosions observed in one gastric area; = Three to five hemorrhages or erosions observed in one gastric area; = Hemorrhages or erosions observed in two gastric areas, six or more hemorrhages or erosions observed in one gastric area, with the total number not exceeding ten in the entire stomach; = Hemorrhages or erosions observed in three or more gastric areas; eleven or more hemorrhages or erosions observed widely in the entire stomach; = Ulcer	8 days
Histopathological Score	Histopathologic grade score developed for microscopic injury evaluation 0 = Normal gastric mucosa or mild chronic inflammation; = Chronic gastritis without activity; = Chronic gastritis with activity on antrum; = Chronic gastritis with activity on the body; = Chronic gastritis with activity on antrum and on the body	8 days
Intragastric pH		8 days
Presence of H. Pylori by Biopsy	Giemsa stain was used to diagnose H. pylori (positive = presence of H. pylori)	8 days
Prostaglandin Level (PGE2 Quantification)	Tissue prostaglandin concentration quantified by enzyme-linked immunosorbent assay (ELISA) using Cayman Chemical Monoclonal Prostaglandin E2 EIA Kit (item number 514010)	8 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of Adverse Events	60 days

Collaborators and Investigators

• Sponsor: Biolab Sanus Farmaceutica

Publications and helpful links

General Publications

• Gagliano-Juca T, Moreno RA, Zaminelli T, Napolitano M, Magalhaes AF, Carvalhaes A, Trevisan MS, Wallace JL, De Nucci G. Rebamipide does not protect against naproxen-induced gastric damage: a randomized double-blind controlled trial. BMC Gastroenterol. 2016 Jun 4;16(1):58. doi: 10.1186/s12876-016-0472-x.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: November 23, 2015
• First Submitted That Met QC Criteria: December 14, 2015
• First Posted (Estimate): December 17, 2015

Study Record Updates

• Last Update Posted (Actual): March 20, 2017
• Last Update Submitted That Met QC Criteria: January 31, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Gastrointestinal Agents; Protective Agents; Anti-Ulcer Agents; Antioxidants; Gout Suppressants; Naproxen; Rebamipide
• Other Study ID Numbers: GDN 025/14

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No