Relative Bioavailability of Empagliflozin (BI 10773) and Ramipril Administered Together Compared to Empagliflozin (BI 10773) and Ramipril Alone in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
Primary objective:To investigate if BI 10773 affects the pharmacokinetics of ramipril and if ramipril affects the pharmacokinetics of BI 10773.

Official Title
-----------------
Relative Bioavailability of Multiple Oral Doses of BI 10773 (25 mg) and Ramipril (5 mg) Administered Together Compared to Multiple Oral Doses of BI 10773 (25 mg) Alone and Ramipril (5 mg) Alone in Healthy Male and Female Volunteers (an Open Label, Randomised, Three Way Crossover, Clinical Phase I Study)

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: BI 10773
* Drug: Ramipril
* Drug: BI 10773
* Drug: Ramipril
* Drug: Ramipril
* Drug: Ramipril


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: 1. healthy male and female subjects Exclusion criteria: 1. Any relevant deviation from healthy conditions.

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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 10773<br>1 tablet per days for 5 days, oral administration with 240 mL water for each treatment | Drug: BI 10773<br>* medium dose oral administration<br>|
| Other: Ramipril<br>1 tablet on day 1 and 2 tablets per day on day 2-5, oral administration with 240 mL water for each treatment | Drug: Ramipril<br>* Low dose oral administration on day 1<br>Drug: Ramipril<br>* Medium dose oral administration on day 2-5<br>|
| Other: BI 10773 + Ramipril<br>1 tablet BI 10773 and 1 tablet on day 1 and 2 tablets ramipril per day on day 2-5, oral administration with 240 mL water for each treatment | Drug: BI 10773<br>* medium dose, oral administration<br>Drug: Ramipril<br>* Medium dose oral administration on day 2-5<br>Drug: Ramipril<br>* Low dose oral administration on day 1<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Empa: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss) | Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of empagliflozin (empa). | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Total Empa: Maximum Measured Concentration (Cmax,ss) | Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of empagliflozin (empa). | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Total Ramipril: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss). | Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of ramipril. | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Total Ramipril: Maximum Measured Concentration (Cmax,ss) | Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramipril. | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Total Ramiprilat: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss). | Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of ramiprilat (active metabolite of ramipril). | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Total Ramiprilat: Maximum Measured Concentration (Cmax,ss) | Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramiprilat. | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Predose concentration of the analyte in plasma prior to administration of the Nth dose, of empagliflozin. | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Predose concentration of the analyte in plasma prior to administration of the Nth dose, of ramiprilat. Note, predose concentrations for ramipril were all below the limit of quantification (BLQ) and therefore the predose concentration of the analyte in plasma prior to administration of the Nth dose, of ramipril was not analysed. | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss) | Time from last dosing to the maximum measured concentration of the analyte in plasma at steady state. | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Terminal Rate Constant (λz,ss) | Terminal rate constant in plasma at steady-state | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Terminal Half-life (T 1/2,ss) | Terminal half-life of the analyte in plasma at steady-state. | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Mean Residence Time (MRTpo,ss) | Mean residence time of the analyte in the body after oral administration at steady-state. | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Apparent Clearance After Extravascular Administration (CL/Fss) | Apparent clearance of the analyte in plasma after extravascular administration at steady-state. | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Apparent Volume of Distribution During the Terminal Phase (Vz/Fss) | Apparent volume of distribution at steady-state during the terminal phase λz following an extravascular dose. | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | 
| Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Tolerability | Clinically relevant abnormalities for physical examination, vital signs, ECG, blood chemistry and assessment tolerability by the investigator. New abnormal findings or worsening of baseline conditions were reported as adverse events. | From drug administration until end of washout period (36 days) |