Gastrointestinal Integrity After Naproxen + Rebamipide Versus Naproxen + Placebo

Phase 1

Completed

Conditions: Gastrointestinal Lesions

Interventions: Drug: Rebamipide effervescent granules
Drug: Placebo effervescent granules
Drug: Naproxen tablet

Registration Number: NCT02632812

Lead Sponsor: Biolab Sanus Farmaceutica

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 24

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rebamipide & Naproxen	Rebamipide effervescent granules	Rebamipide 100 mg effervescent granules (oral) Twice daily (total dose = 200 mg) for 7 days
Rebamipide & Naproxen	Naproxen tablet	Rebamipide 100 mg effervescent granules (oral) Twice daily (total dose = 200 mg) for 7 days
Placebo & Naproxen	Placebo effervescent granules	Sugar pill manufactured to mimic Rebamipide 100 mg effervescent granules (oral) Twice daily for 7 days
Placebo & Naproxen	Naproxen tablet	Sugar pill manufactured to mimic Rebamipide 100 mg effervescent granules (oral) Twice daily for 7 days

Primary Outcome Measures

Name	Time	Method
Endoscopic Score - Cryer Score	8 days	Cryer score according to gastroduodenal mucosal injury: 0 = Normal or erythema 1. = Any amount of submucosal hemorrhage or edema without erosions 2. = 1 erosion +- submucosal hemorrhage or edema 3. = 2-4 erosions +- submucosal hemorrhage or edema 4. = 5 or more erosions and/or a single ulcer +- submucosal hemorrhage or edema 5. = Multiple ulcers +- submucosal hemorrhage or edema - Ulcer
Endoscopic Score - Modified Lanza Score	8 days	Modified Lanza score according to gastroduodenal mucosal injury: 0 = No hemorrhage or erosion observed 1. = One or two hemorrhages or erosions observed in one gastric area 2. = Three to five hemorrhages or erosions observed in one gastric area 3. = 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 4. = Hemorrhages or erosions observed in three or more gastric areas; eleven or more hemorrhages or erosions observed widely in the entire stomach 5. = Ulcer
Histopathological Score	8 days	Histopathologic grade score developed for microscopic injury evaluation 0 = Normal gastric mucosa or mild chronic inflammation 1. = Chronic gastritis without activity 2. = Chronic gastritis with activity on antrum 3. = Chronic gastritis with activity on the body 4. = Chronic gastritis with activity on antrum and on the body
Intragastric pH	8 days
Presence of H. Pylori by Biopsy	8 days	Giemsa stain was used to diagnose H. pylori (positive = presence of H. pylori)
Prostaglandin Level (PGE2 Quantification)	8 days	Tissue prostaglandin concentration quantified by enzyme-linked immunosorbent assay (ELISA) using Cayman Chemical Monoclonal Prostaglandin E2 EIA Kit (item number 514010)