Gastrointestinal Lesions
Conditions
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.
Interventions
DRUGRebamipide effervescent granules
Rebamipide effervescent granules 100mg (oral), twice daily for 7 days
DRUGPlacebo effervescent granules
Placebo effervescent granules (oral), twice daily for 7 days
DRUGNaproxen tablet
Naproxen tablet 550mg (tablet), twice daily for 7 days
Sponsors
Biolab Sanus Farmaceutica
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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) |
| 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) |
Secondary
| Measure | Time frame |
|---|---|
| Number of Adverse Events | 60 days |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rebamipide 200 mg Rebamipide 100 mg effervescent granules (oral) Twice daily (total dose = 200 mg)
Rebamipide effervescent granules
Naproxen tablet | 12 |
| Placebo Placebo effervescent granules (oral) Twice daily
Placebo effervescent granules
Naproxen tablet | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Placebo | Rebamipide 200 mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants | 24 Participants |
| Age, Continuous | 28.5 years | 23.5 years | 24.5 years |
| Region of Enrollment Brazil | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 12 | 3 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Endoscopic Score - Cryer Score
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
Time frame: 8 days
Population: All recruited volunteers completed the trial.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rebamipide & Naproxen | Endoscopic Score - Cryer Score | 4 Cryer score |
| Placebo & Naproxen | Endoscopic Score - Cryer Score | 4 Cryer score |
Primary
Endoscopic Score - Modified Lanza Score
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
Time frame: 8 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rebamipide & Naproxen | Endoscopic Score - Modified Lanza Score | 3.5 Modified Lanza score |
| Placebo & Naproxen | Endoscopic Score - Modified Lanza Score | 4 Modified Lanza score |
Primary
Histopathological Score
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
Time frame: 8 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rebamipide & Naproxen | Histopathological Score | Basal endoscopy | 1 Histopathologic grade score |
| Rebamipide & Naproxen | Histopathological Score | End of treatment endoscopy | 1 Histopathologic grade score |
| Placebo & Naproxen | Histopathological Score | Basal endoscopy | 1 Histopathologic grade score |
| Placebo & Naproxen | Histopathological Score | End of treatment endoscopy | 1 Histopathologic grade score |
Primary
Intragastric pH
Time frame: 8 days
Population: Intragastric PH measurement was not performed and for this reason it will not be available.
Primary
Presence of H. Pylori by Biopsy
Giemsa stain was used to diagnose H. pylori (positive = presence of H. pylori)
Time frame: 8 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rebamipide & Naproxen | Presence of H. Pylori by Biopsy | Basal endoscopy | 5 participants |
| Rebamipide & Naproxen | Presence of H. Pylori by Biopsy | End of treatment endoscopy | 6 participants |
| Placebo & Naproxen | Presence of H. Pylori by Biopsy | Basal endoscopy | 5 participants |
| Placebo & Naproxen | Presence of H. Pylori by Biopsy | End of treatment endoscopy | 6 participants |
Primary
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)
Time frame: 8 days
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Rebamipide & Naproxen | Prostaglandin Level (PGE2 Quantification) | Basal PGE2 concentration | 999 pg/mL (mean tissue PGE2 concentration) |
| Rebamipide & Naproxen | Prostaglandin Level (PGE2 Quantification) | End of treatment PGE2 concentration | 168 pg/mL (mean tissue PGE2 concentration) |
| Placebo & Naproxen | Prostaglandin Level (PGE2 Quantification) | Basal PGE2 concentration | 1005 pg/mL (mean tissue PGE2 concentration) |
| Placebo & Naproxen | Prostaglandin Level (PGE2 Quantification) | End of treatment PGE2 concentration | 241 pg/mL (mean tissue PGE2 concentration) |
Secondary
Number of Adverse Events
Time frame: 60 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rebamipide & Naproxen | Number of Adverse Events | 7 adverse events |
| Placebo & Naproxen | Number of Adverse Events | 7 adverse events |