PK, PD and Safety Comparative Trial of Isosorbide Mononitrate Gel in Healthy Participants and With Anal Fissure

Study Overview
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Brief Summary
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This is a Phase I trial to evaluate Pharmacokinetics, Pharmacodynamics and Safety of Isosorbide Mononitrate gel for usage in participants with anal fissure and healthy volunteers. Three doses will be used in patients with anal fissure (0.5%, 1.0% or 2.0%) and healthy volunteers will receive 2.0% dose. All treatment will last 7 days.

Detailed Description
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This is a Phase I, open-label, parallel trial to evaluate Pharmacokinetics, Pharmacodynamics and Safety of Isosorbide Mononitrate gel for usage in participants with anal fissure and healthy volunteers. Investigational product will be randomly assigned as follows: healthy volunteers will receive 2g (2.0%) of investigational product at a single dose, and will undergo a washout period of 7 days; subsequently, they will receive 2g of investigational product once daily, for 7 consecutive days; participants with anal fissure will receive 2g of investigational product, either at 0.5%, 1.0% or 2.0%, at a single dose, and will undergo a washout period of 7 days; subsequently, they will receive 2g of investigational product, either at 0.5%, 1.0% or 2.0%, once daily, for 7 consecutive days.

Official Title
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Pharmacokinetics, Pharmacodynamics and Safety Comparative Trial of Isosorbide Mononitrate Gel in Participants With Anal Fissure and Healthy Volunteers.

Conditions
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Anal Fissure

Intervention / Treatment
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* Drug: Isosorbide Mononitrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects aged ≥ 18 years-old; Body mass index (BMI) ≥ 19 Kg/m2 and ≤ 35 Kg/m2; For healthy volunteers: 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; For participants with the condition under study: anal fissure; 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; Chronic therapy with any drugs, except oral contraceptives and medication authorized by principal investigator (each case to be individually evaluated); History of hepatic, kidney, lungs, gastrointestinal, epileptic, hematologic or psychiatric disease; hypotension or hypertension, or any other co-morbidity that requires priority immediate treatment ot that, at principal investigator discretion, might interfere with study participation or expose study participant to risks other than predicted; Deviations on screening laboratory results that are considered as clinically relevant by the principal investigator; Smoking; 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 six months before this trial; Donation or loss of 450 mL of blood (or more) within 3 months before the trial, or 4 donations within 12 months before the 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isosorbide Mononitrate 2.0% healthy<br>Isosorbide Mononitrate gel 2.0% - 2g Anorectal usage Once daily Healthy volunteers | Drug: Isosorbide Mononitrate<br>* Healthy volunteers will receive 2g (2.0%) of investigational product at a single dose, and will undergo a washout period of 7 days; subsequently, they will receive 2g of investigational product once daily, for 7 consecutive days. Participants with anal fissure will receive 2g of investigational product, either at 0.5%, 1.0% or 2.0%, at a single dose, and will undergo a washout period of 7 days; subsequently, they will receive 2g of investigational product, either at 0.5%, 1.0% or 2.0%, once daily, for 7 consecutive days.<br>|
| Experimental: Isosorbide Mononitrate 0.5% anal fissure<br>Isosorbide Mononitrate gel 0.5% - 2g Anorectal usage Once daily Participants with anal fissure | Drug: Isosorbide Mononitrate<br>* Healthy volunteers will receive 2g (2.0%) of investigational product at a single dose, and will undergo a washout period of 7 days; subsequently, they will receive 2g of investigational product once daily, for 7 consecutive days. Participants with anal fissure will receive 2g of investigational product, either at 0.5%, 1.0% or 2.0%, at a single dose, and will undergo a washout period of 7 days; subsequently, they will receive 2g of investigational product, either at 0.5%, 1.0% or 2.0%, once daily, for 7 consecutive days.<br>|
| Experimental: Isosorbide Mononitrate 1.0% anal fissure<br>Isosorbide Mononitrate gel 1.0% - 2g Anorectal usage Once daily Participants with anal fissure | Drug: Isosorbide Mononitrate<br>* Healthy volunteers will receive 2g (2.0%) of investigational product at a single dose, and will undergo a washout period of 7 days; subsequently, they will receive 2g of investigational product once daily, for 7 consecutive days. Participants with anal fissure will receive 2g of investigational product, either at 0.5%, 1.0% or 2.0%, at a single dose, and will undergo a washout period of 7 days; subsequently, they will receive 2g of investigational product, either at 0.5%, 1.0% or 2.0%, once daily, for 7 consecutive days.<br>|
| Experimental: Isosorbide Mononitrate 2.0% anal fissure<br>Isosorbide Mononitrate gel 2.0% - 2g Anorectal usage Once daily Participants with anal fissure | Drug: Isosorbide Mononitrate<br>* Healthy volunteers will receive 2g (2.0%) of investigational product at a single dose, and will undergo a washout period of 7 days; subsequently, they will receive 2g of investigational product once daily, for 7 consecutive days. Participants with anal fissure will receive 2g of investigational product, either at 0.5%, 1.0% or 2.0%, at a single dose, and will undergo a washout period of 7 days; subsequently, they will receive 2g of investigational product, either at 0.5%, 1.0% or 2.0%, once daily, for 7 consecutive days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics, area under the curve time zero - last (AUC t0-last) |  | 7 days | 
| Pharmacokinetics, area under the curve time zero - infinite (AUC t0-inf) |  | 7 days | 
| Pharmacokinetics, constant of elimination (Ke) |  | 7 days | 
| Pharmacokinetics, half-life (t1/2) |  | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, by number of adverse events |  | 7 days | 
| Safety, by blood pressure measurement |  | 7 days | 
| Anorectal muscle contractility, by anorectal manometry |  | 7 days |