Gastrointestinal Integrity After Naproxen + Rebamipide Versus Naproxen + Placebo

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Gastrointestinal Lesions

Intervention / Treatment
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* Drug: Rebamipide effervescent granules
* Drug: Placebo effervescent granules
* Drug: Naproxen tablet


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events |  | 60 days |