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

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01284621
• Collaborator: (none)
• Enrollment: 23
• Location: 1
• Arms: 3

Study Details

Study Description

Brief Summary

Primary objective:To investigate if BI 10773 affects the pharmacokinetics of ramipril and if ramipril affects the pharmacokinetics of BI 10773.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: BI 10773; Drug: Ramipril; Drug: BI 10773; Drug: Ramipril; Drug: Ramipril; Drug: Ramipril	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 10773 1 tablet per days for 5 days, oral administration with 240 mL water for each treatment	Drug: BI 10773; medium dose oral administration
Other: Ramipril 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; Low dose oral administration on day 1; Drug: Ramipril; Medium dose oral administration on day 2-5
Other: BI 10773 + Ramipril 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; medium dose, oral administration; Drug: Ramipril; Medium dose oral administration on day 2-5; Drug: Ramipril; Low dose oral administration on day 1

Outcome Measures

Primary Outcome Measures

1. Total Empa: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss) [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]

   Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of empagliflozin (empa).

2. Total Empa: Maximum Measured Concentration (Cmax,ss) [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]

   Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of empagliflozin (empa).

3. Total Ramipril: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss). [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]

   Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of ramipril.

4. Total Ramipril: Maximum Measured Concentration (Cmax,ss) [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]

   Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramipril.

5. Total Ramiprilat: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss). [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]

   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).

6. Total Ramiprilat: Maximum Measured Concentration (Cmax,ss) [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]

   Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramiprilat.

Secondary Outcome Measures

1. Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) [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]

   Predose concentration of the analyte in plasma prior to administration of the Nth dose, of empagliflozin.

2. Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) [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]

   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.

3. Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss) [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 of the analyte in plasma at steady state.

4. Terminal Rate Constant (λz,ss) [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 in plasma at steady-state

5. Terminal Half-life (T 1/2,ss) [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 of the analyte in plasma at steady-state.

6. Mean Residence Time (MRTpo,ss) [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 of the analyte in the body after oral administration at steady-state.

7. Apparent Clearance After Extravascular Administration (CL/Fss) [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 of the analyte in plasma after extravascular administration at steady-state.

8. Apparent Volume of Distribution During the Terminal Phase (Vz/Fss) [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 at steady-state during the terminal phase λz following an extravascular dose.

9. Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Tolerability [From drug administration until end of washout period (36 days)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

1. healthy male and female subjects

Exclusion criteria:

1. Any relevant deviation from healthy conditions.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1245.45.1 Boehringer Ingelheim Investigational Site	Biberach		Germany

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01284621
• Other Study ID Numbers: 1245.45; 2010-022717-25
• First Posted: Jan 27, 2011
• Last Update Posted: Jul 22, 2014
• Last Verified: Jun 1, 2014

• Additional relevant MeSH terms: Empagliflozin; Ramipril

Study Results

Participant Flow

Pre-assignment Detail	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
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: First Intervention (8 Days)
STARTED	3	4	4	4	4	4
COMPLETED	3	4	4	4	3	4
NOT COMPLETED	0	0	0	0	1	0
Period Title: First 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: First 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: First 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

Baseline Characteristics

Arm/Group Title	Study Overall
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 Participants	23
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.0 (11.3)
Sex: Female, Male (Count of Participants)
Female	15 65.2%
Male	8 34.8%

Outcome Measures

1. Primary Outcome

Title	Total Empa: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss)
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

Outcome Measure Data

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
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.
Measure Participants	22	23
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	5850 (18.1)	5680 (16.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empa Alone, Empa + Ramipril
	Comments
	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
	Comments
	Method
	Comments
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)
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

Outcome Measure Data

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
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.
Measure Participants	22	23
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	874 (25.9)	911 (21.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empa Alone, Empa + Ramipril
	Comments
	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
	Comments
	Method
	Comments
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).
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

Outcome Measure Data

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
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.
Measure Participants	22	23
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	6.59 (37.0)	7.27 (37.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empa Alone, Empa + Ramipril
	Comments
	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
	Comments
	Method
	Comments
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)
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

Outcome Measure Data

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
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.
Measure Participants	22	23
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	8.42 (45.6)	8.97 (53.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empa Alone, Empa + Ramipril
	Comments
	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
	Comments
	Method
	Comments
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).
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

Outcome Measure Data

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
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.
Measure Participants	22	23
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	87.2 (15.5)	85.1 (20.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empa Alone, Empa + Ramipril
	Comments
	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
	Comments
	Method
	Comments
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)
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

Outcome Measure Data

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
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.
Measure Participants	22	23
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	11.2 (36.8)	10.5 (46.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empa Alone, Empa + Ramipril
	Comments
	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
	Comments
	Method
	Comments
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)
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

Outcome Measure Data

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
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.
Measure Participants	22	23
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)
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

Outcome Measure Data

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
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.
Measure Participants	22	23
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)
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

Outcome Measure Data

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
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.
Measure Participants	22	22	23
Total empa	1.02 (42.6)	NA (NA)	1.50 (44.7)
Total ramipril	NA (NA)	0.333 (36.4)	0.333 (39.1)
Total ramiprilat	NA (NA)	2.00 (23.8)	2.00 (29.4)

10. Secondary Outcome

Title	Terminal Rate Constant (λz,ss)
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

Outcome Measure Data

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
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.
Measure Participants	22	22	23
Total empa	0.055 (37.9)	NA (NA)	0.050 (37.7)
Total ramipril	NA (NA)	0.261 (107)	0.298 (118)
Total ramiprilat	NA (NA)	0.0095 (24.1)	0.0091 (32.2)

11. Secondary Outcome

Title	Terminal Half-life (T 1/2,ss)
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

Outcome Measure Data

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
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.
Measure Participants	22	22	23
Total empa	12.7 (37.9)	NA (NA)	13.9 (37.7)
Total ramipril	NA (NA)	2.66 (107)	2.32 (118)
Total ramiprilat	NA (NA)	73.2 (24.1)	76.2 (32.2)

12. Secondary Outcome

Title	Mean Residence Time (MRTpo,ss)
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

Outcome Measure Data

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
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.
Measure Participants	22	22	23
Total empa	9.95 (18.0)	NA (NA)	9.68 (16.8)
Total ramipril	NA (NA)	1.29 (54.2)	1.42 (57.8)
Total ramiprilat	NA (NA)	44.7 (29.9)	47.1 (38.7)

13. Secondary Outcome

Title	Apparent Clearance After Extravascular Administration (CL/Fss)
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

Outcome Measure Data

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
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.
Measure Participants	22	22	23
Total empa	158 (18.1)	NA (NA)	163 (16.3)
Total ramipril	NA (NA)	12600 (37.0)	11500 (37.8)
Total ramiprilat	NA (NA)	955 (15.5)	979 (20.1)

14. Secondary Outcome

Title	Apparent Volume of Distribution During the Terminal Phase (Vz/Fss)
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

Outcome Measure Data

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
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.
Measure Participants	22	22	23
Total empa	174 (31.8)	NA (NA)	196 (40.0)
Total ramipril	NA (NA)	2910 (89.1)	2310 (97.3)
Total ramiprilat	NA (NA)	6050 (32.0)	6460 (42.5)

15. Secondary Outcome

Title	Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Tolerability
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)

Outcome Measure Data

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
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.
Measure Participants	22	22	23
Number [participants]	0 0%	0 NaN	0 NaN

Adverse Events

Time Frame	Treatment duration plus following washout period (36 days)
Arm/Group Title	Empa Alone		Ramipril Alone		Empa + Ramipril
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Empa Alone		Ramipril Alone		Empa + Ramipril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/22 (0%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	Empa Alone		Ramipril Alone		Empa + Ramipril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/22 (4.5%)		3/22 (13.6%)		2/23 (8.7%)
Gastrointestinal disorders
Nausea	0/22 (0%)		0/22 (0%)		2/23 (8.7%)
Nervous system disorders
Headache	1/22 (4.5%)		3/22 (13.6%)		0/22 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.