Study to Compare the Pharmacokinetics Profiles of Four Racecadotril Products

Study Overview
=================
Brief Summary
-----------------
This study is designed to compare the pharmacokinetics of four products used for treatment of acute diarrhea.

Detailed Description
-----------------
The study will be a single dose, randomized, four -way, four-sequence crossover study in 24 healthy subjects, with equal numbers of males and females (minimum of 10 of either gender). Subjects who drop out will not be replaced. The four doses of medication given in the study (a single dose in each of the four study periods) will be separated by a washout period of at least 7 calendar days. In each study period, 17 blood samples for pharmacokinetic analysis will be taken over 12 hours. Blood samples will be centrifuged and concentrations of thiorphan (the active metabolite) in plasma will be measured using a validated chromatographic assay. Pharmacokinetic parameters will be calculated from plasma concentration data.

Official Title
-----------------
An Open-Label, Fasting, Crossover, Single-Dose Pharmacokinetic Study of Four Formulations of Racecadotril

Conditions
-----------------
Diarrhea

Intervention / Treatment
-----------------
* Drug: Racecadotril
* Drug: Racecadotril
* Drug: Racecadotril
* Drug: Racecadotril


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female subjects (equal numbers of males and females) Volunteers aged of at least 18 years but not older than 55 years Subjects will have a Body Mass Index (BMI) within protocol-specified parameters. Non- or ex-smokers; an ex-smoker being defined as someone who completely stopped smoking for at least 12 months before day 1 of this study. Clinical laboratory values within the laboratory's stated normal range; if not within this range, they must be without any clinical significance Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on physical examination and/or clinical laboratory evaluations Has signed and dated the informed consent document, indicating that the subject has been informed of all pertinent aspects of the study Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures Exclusion Criteria: Seated pulse rate and blood pressure within protocol-specified parameters. Relationship to persons involved directly with the conduct of the study (i.e., principal investigator; sub-investigators; study coordinators; other study personnel; employees or contractors of the sponsor or Johnson & Johnson subsidiaries; and the families of each) Females who are pregnant or are lactating Females of childbearing potential or males with a female partner of childbearing potential who refuse to use an acceptable contraceptive regimen throughout the entire duration of the study History of significant hypersensitivity to racecadotril or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs Use of certain drugs/medications within protocol-specified timeframes Medical history or condition that may, per protocol or in the opinion of the investigator, adversely affect the safety of the study subject or compromise study results.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FCT<br>A single 2 x100 mg dose of an experimental Racecadotril Film-coated tablet (FCT) administered orally with 240 ml of water, with a 7- day washout between visits. | Drug: Racecadotril<br>* Film-coated tablet<br>* Other names: Not yet marketed;|
| Experimental: RPB<br>A single 2 x100 mg dose of an experimental Racecadotril Powder Blend administered orally with 240 ml of water, with a 7- day washout between visits. | Drug: Racecadotril<br>* Racecadotril Powder Blend<br>* Other names: Not yet marketed;|
| Active Comparator: TFT<br>A single 2 x 100 mg dose of a marketed Tiorfast® capsule administered orally with 240 ml of water, with a 7-day washout between visits. | Drug: Racecadotril<br>* Marketed Capsule<br>* Other names: Tiorfast®;|
| Active Comparator: TFR<br>A single 175 mg dose of a marketed Tiorfanor® 175 mg FCT administered orally with 240 ml of water, with a 7-day washout between visits. | Drug: Racecadotril<br>* Marketed Film-coated Tablet<br>* Other names: Tiorfanor®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration | Maximum Observed Plasma Concentration (Cmax), which is the maximum (peak) concentration (amount of drug) measurable in blood plasma after a dose is administered, measured in nanograms/milliliter (ng/mL) | Pre-dose and 0.25, 0.5, 0.75, 1, 1.25 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours post drug administration | 
| AUC(0-t) | AUC(0-t) is the area under the plasma concentration verses time curve from start of drug administration until the time of the last measurable plasma concentration, calculated as hour*nanograms (ng) per milliliter (mL). | Pre-dose and 0.25, 0.5, 0.75, 1, 1.25 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours post drug administration | 
| AUC(0-∞) | AUC (0-∞) is the area under the plasma concentration-vs.-time curve from start of drug administration until infinity. | Pre-dose and 0.25, 0.5, 0.75, 1, 1.25 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours post drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time of Maximum Concentration | The time at which maximum concentration is reached (Tmax) | During 12 hours post-dose | 
| Terminal Elimination Rate Constant | The Terminal Elimination Rate Constant (Lamda z) is the time required to eliminate half the administered dose | During 12 hours post-dose | 
| Terminal Phase Plasma Half-Life | Terminal phase plasma half-life (t ½) is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, rather than the time required to eliminate half the administered dose. | During 12 hours post-dose | 
| Lag Time | The time delay between drug administration and the quantification of absorption | During 12 hours post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Antidiarrheals