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

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ClinicalTrials.gov Identifier: NCT01284621
Recruitment Status : Completed
First Posted : January 27, 2011
Results First Posted : July 22, 2014
Last Update Posted : July 22, 2014
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Healthy
Interventions Drug: BI 10773
Drug: Ramipril
Enrollment 23
Recruitment Details  
Pre-assignment Details This was a randomised, open-label, three period, crossover study. Each treatment period was 8 days, with drug administration on days 1 to 5, and they were separated by a washout period of at least 7 days between drug administrations of 2 subsequent treatments.
Arm/Group Title Empa Alone / Empa + Ramipril / Ramipril Alone Empa Alone / Ramipril Alone / Empa + Ramipril Ramipril Alone / Empa Alone / Empa + Ramipril Ramipril Alone / Empa + Ramipril / Empa Alone Empa + Ramipril / Empa Alone / Ramipril Alone Empa + Ramipril / Ramipril Alone / Empa Alone
Hide Arm/Group Description

Patients were administered three treatments in the following order:

  • Empagliflozin alone
  • Empagliflozin plus Ramipril
  • Ramipril

Patients were administered three treatments in the following order:

  • Empagliflozin alone
  • Ramipril
  • Empagliflozin plus Ramipril

Patients were administered three treatments in the following order:

  • Ramipril
  • Empagliflozin alone
  • Empagliflozin plus Ramipril

Patients were administered three treatments in the following order:

  • Ramipril
  • Empagliflozin plus Ramipril
  • Empagliflozin alone

Patients were administered three treatments in the following order:

  • Empagliflozin plus Ramipril
  • Empagliflozin alone
  • Ramipril

Patients were administered three treatments in the following order:

  • Empagliflozin plus Ramipril
  • Ramipril
  • Empagliflozin alone
Period Title: First Intervention (8 Days)
Started 3 4 4 4 4 4
Completed 3 4 4 4 4 4
Not Completed 0 0 0 0 0 0
Period Title: Washout Period 1 (7 Days)
Started 3 4 4 4 4 4
Completed 3 4 4 4 3 4
Not Completed 0 0 0 0 1 0
Reason Not Completed
Required unexpected medical treatment             0             0             0             0             1             0
Period Title: Second Intervention (8 Days)
Started 3 4 4 4 3 4
Completed 3 4 4 4 3 4
Not Completed 0 0 0 0 0 0
Period Title: Washout Period 2 (7 Days)
Started 3 4 4 4 3 4
Completed 3 4 4 4 3 4
Not Completed 0 0 0 0 0 0
Period Title: Third Intervention (8 Days)
Started 3 4 4 4 3 4
Completed 3 4 4 4 3 4
Not Completed 0 0 0 0 0 0
Arm/Group Title Study Overall
Hide Arm/Group Description

A randomised, open-label, three period, crossover study. The three treatments administered were

  • Empagliflozin alone
  • Ramipril
  • Empagliflozin plus Ramipril

Each treatment period was 8 days, with drug administration on days 1 to 5, and they were separated by a washout period of at least 7 days between drug administrations of 2 subsequent treatments.

Overall Number of Baseline Participants 23
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 23 participants
38.0  (11.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants
Female
15
  65.2%
Male
8
  34.8%
1.Primary Outcome
Title Total Empa: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss)
Hide Description Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of empagliflozin (empa).
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Empa Alone Empa + Ramipril
Hide Arm/Group Description:
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
5850
(18.1%)
5680
(16.3%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Empa Alone, Empa + Ramipril
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability. Ratio calculated as empa plus ramipril divided by empa alone
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 96.55
Confidence Interval (2-Sided) 90%
93.05 to 100.18
Parameter Dispersion
Type: Standard Deviation
Value: 7.1
Estimation Comments Standard deviation is actually the geometric coefficient of variation (gCV)
2.Primary Outcome
Title Total Empa: Maximum Measured Concentration (Cmax,ss)
Hide Description Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of empagliflozin (empa).
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Empa Alone Empa + Ramipril
Hide Arm/Group Description:
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
874
(25.9%)
911
(21.1%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Empa Alone, Empa + Ramipril
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability. Ratio calculated as empa plus ramipril divided by empa alone
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 104.47
Confidence Interval (2-Sided) 90%
97.65 to 111.77
Parameter Dispersion
Type: Standard Deviation
Value: 13.1
Estimation Comments Standard deviation is actually the gCV
3.Primary Outcome
Title Total Ramipril: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss).
Hide Description Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of ramipril.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Ramipril Alone Empa + Ramipril
Hide Arm/Group Description:
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
6.59
(37.0%)
7.27
(37.8%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ramipril Alone, Empa + Ramipril
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability. Ratio calculated as empa plus ramipril divided by ramipril alone
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 108.14
Confidence Interval (2-Sided) 90%
100.51 to 116.35
Parameter Dispersion
Type: Standard Deviation
Value: 14.0
Estimation Comments Standard deviation is actually the gCV
4.Primary Outcome
Title Total Ramipril: Maximum Measured Concentration (Cmax,ss)
Hide Description Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramipril.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Ramipril Alone Empa + Ramipril
Hide Arm/Group Description:
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
8.42
(45.6%)
8.97
(53.6%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ramipril Alone, Empa + Ramipril
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability. Ratio calculated as empa plus ramipril divided by ramipril alone.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 103.61
Confidence Interval (2-Sided) 90%
89.73 to 119.64
Parameter Dispersion
Type: Standard Deviation
Value: 28.0
Estimation Comments Standard deviation is actually the gCV
5.Primary Outcome
Title Total Ramiprilat: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss).
Hide Description 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).
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Ramipril Alone Empa + Ramipril
Hide Arm/Group Description:
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
87.2
(15.5%)
85.1
(20.1%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ramipril Alone, Empa + Ramipril
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability. Ratio calculated as empa plus ramipril divided by ramipril alone
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 98.67
Confidence Interval (2-Sided) 90%
96.00 to 101.42
Parameter Dispersion
Type: Standard Deviation
Value: 5.2
Estimation Comments Standard deviation is actually the gCV
6.Primary Outcome
Title Total Ramiprilat: Maximum Measured Concentration (Cmax,ss)
Hide Description Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramiprilat.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Ramipril Alone Empa + Ramipril
Hide Arm/Group Description:
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
11.2
(36.8%)
10.5
(46.6%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ramipril Alone, Empa + Ramipril
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability. Ratio calculated as empa plus ramipril divided by ramipril alone.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 98.29
Confidence Interval (2-Sided) 90%
92.67 to 104.25
Parameter Dispersion
Type: Standard Deviation
Value: 11.3
Estimation Comments Standard deviation is actually the gCV
7.Secondary Outcome
Title Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)
Hide Description Predose concentration of the analyte in plasma prior to administration of the Nth dose, of empagliflozin.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Empa Alone Empa + Ramipril
Hide Arm/Group Description:
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
Cpre,2
40.3
(31.0%)
38.6
(32.1%)
Cpre,3
45.8
(33.7%)
45.1
(30.6%)
Cpre,4
49.2
(29.5%)
46.4
(27.2%)
Cpre,5
47.8
(25.5%)
48.3
(27.9%)
8.Secondary Outcome
Title Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)
Hide Description

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.

Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Ramipril Alone Empa + Ramipril
Hide Arm/Group Description:
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Cpre,2
1.03
(25.5%)
1.02
(21.7%)
Cpre,3
1.33
(21.9%)
1.31
(17.4%)
Cpre,4
1.39
(20.7%)
1.37
(17.2%)
Cpre,5
1.45
(23.4%)
1.44
(16.6%)
9.Secondary Outcome
Title Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss)
Hide Description Time from last dosing to the maximum measured concentration of the analyte in plasma at steady state.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Empa Alone Ramipril Alone Empa + Ramipril
Hide Arm/Group Description:
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 22 23
Median (Full Range)
Unit of Measure: hours
Total empa
1.02
(0.667 to 3.00)
NA [1] 
(NA to NA)
1.50
(1.00 to 4.00)
Total ramipril
NA [2] 
(NA to NA)
0.333
(0.333 to 1.00)
0.333
(0.333 to 1.00)
Total ramiprilat
NA [2] 
(NA to NA)
2.00
(1.48 to 4.02)
2.00
(1.50 to 4.00)
[1]
Not applicable - no ramipril in this treatment arm
[2]
Not applicable - no empagliflozin in this treatment arm
10.Secondary Outcome
Title Terminal Rate Constant (λz,ss)
Hide Description Terminal rate constant in plasma at steady-state
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Empa Alone Ramipril Alone Empa + Ramipril
Hide Arm/Group Description:
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 1/h
Total empa
0.055
(37.9%)
NA [1] 
(NA%)
0.050
(37.7%)
Total ramipril
NA [2] 
(NA%)
0.261
(107%)
0.298
(118%)
Total ramiprilat
NA [2] 
(NA%)
0.0095
(24.1%)
0.0091
(32.2%)
[1]
Not applicable - no ramipril in this treatment arm
[2]
Not applicable - no empagliflozin in this treatment arm
11.Secondary Outcome
Title Terminal Half-life (T 1/2,ss)
Hide Description Terminal half-life of the analyte in plasma at steady-state.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Empa Alone Ramipril Alone Empa + Ramipril
Hide Arm/Group Description:
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
Total empa
12.7
(37.9%)
NA [1] 
(NA%)
13.9
(37.7%)
Total ramipril
NA [2] 
(NA%)
2.66
(107%)
2.32
(118%)
Total ramiprilat
NA [2] 
(NA%)
73.2
(24.1%)
76.2
(32.2%)
[1]
Not applicable - no ramipril in this treatment arm
[2]
Not applicable - no empagliflozin in this treatment arm
12.Secondary Outcome
Title Mean Residence Time (MRTpo,ss)
Hide Description Mean residence time of the analyte in the body after oral administration at steady-state.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Empa Alone Ramipril Alone Empa + Ramipril
Hide Arm/Group Description:
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
Total empa
9.95
(18.0%)
NA [1] 
(NA%)
9.68
(16.8%)
Total ramipril
NA [2] 
(NA%)
1.29
(54.2%)
1.42
(57.8%)
Total ramiprilat
NA [2] 
(NA%)
44.7
(29.9%)
47.1
(38.7%)
[1]
Not applicable - no ramipril in this treatment arm
[2]
Not applicable - no empagliflozin in this treatment arm
13.Secondary Outcome
Title Apparent Clearance After Extravascular Administration (CL/Fss)
Hide Description Apparent clearance of the analyte in plasma after extravascular administration at steady-state.
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Empa Alone Ramipril Alone Empa + Ramipril
Hide Arm/Group Description:
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: mL/min
Total empa
158
(18.1%)
NA [1] 
(NA%)
163
(16.3%)
Total ramipril
NA [2] 
(NA%)
12600
(37.0%)
11500
(37.8%)
Total ramiprilat
NA [2] 
(NA%)
955
(15.5%)
979
(20.1%)
[1]
Not applicable - no ramipril in this treatment arm
[2]
Not applicable - no empagliflozin in this treatment arm
14.Secondary Outcome
Title Apparent Volume of Distribution During the Terminal Phase (Vz/Fss)
Hide Description Apparent volume of distribution at steady-state during the terminal phase λz following an extravascular dose.
Time Frame 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
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Hide Analysis Population Description
Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
Arm/Group Title Empa Alone Ramipril Alone Empa + Ramipril
Hide Arm/Group Description:
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 22 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L
Total empa
174
(31.8%)
NA [1] 
(NA%)
196
(40.0%)
Total ramipril
NA [2] 
(NA%)
2910
(89.1%)
2310
(97.3%)
Total ramiprilat
NA [2] 
(NA%)
6050
(32.0%)
6460
(42.5%)
[1]
Not applicable - no ramipril in this treatment arm
[2]
Not applicable - no empagliflozin in this treatment arm
15.Secondary Outcome
Title Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Tolerability
Hide Description 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.
Time Frame From drug administration until end of washout period (36 days)
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Hide Analysis Population Description
Treated set which included all subjects who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.
Arm/Group Title Empa Alone Ramipril Alone Empa + Ramipril
Hide Arm/Group Description:
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
Overall Number of Participants Analyzed 22 22 23
Measure Type: Number
Unit of Measure: participants
0 0 0
Time Frame Treatment duration plus following washout period (36 days)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Empa Alone Ramipril Alone Empa + Ramipril
Hide Arm/Group Description Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5. Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
All-Cause Mortality
Empa Alone Ramipril Alone Empa + Ramipril
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Empa Alone Ramipril Alone Empa + Ramipril
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/22 (0.00%)   0/22 (0.00%)   0/23 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Empa Alone Ramipril Alone Empa + Ramipril
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/22 (4.55%)   3/22 (13.64%)   2/23 (8.70%) 
Gastrointestinal disorders       
Nausea  1  0/22 (0.00%)  0/22 (0.00%)  2/23 (8.70%) 
Nervous system disorders       
Headache  1  1/22 (4.55%)  3/22 (13.64%)  0/22 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 14.0
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01284621     History of Changes
Other Study ID Numbers: 1245.45
2010-022717-25 ( EudraCT Number: EudraCT )
First Submitted: January 20, 2011
First Posted: January 27, 2011
Results First Submitted: May 16, 2014
Results First Posted: July 22, 2014
Last Update Posted: July 22, 2014