Drug-drug Interaction of Empagliflozin (BI 10773) and Microgynon

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01328184
• Collaborator: (none)
• Enrollment: 18
• Location: 1
• Arms: 2

Study Details

Study Description

Brief Summary

The objective of this study is to investigate the possible effect of multiple oral doses of 25 mg BI 10773 on the steady state pharmacokinetics of ethinylestradiol (EE) and levonogestrel (LNG) (Microgynon®).

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: levonorgestrel; Drug: levonorgestrel; Drug: Ethinylestradiol; Drug: Microgynon + BI 10773; Drug: Ethinylestradiol	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Two-period, Fixed-sequence Trial to Evaluate the Effect of Multiple Doses of BI 10773 on the Multiple-dose Pharmacokinetics of a Combination of Ethinylestradiol and Levonorgestrel in Healthy Premenopausal Female Volunteers
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Reference multiple doses of Microgynon	Drug: levonorgestrel; multiple doses; Drug: Ethinylestradiol; multiple doses
Active Comparator: Test multiple doses of Microgynon + BI 10773	Drug: levonorgestrel; multiple doses; Drug: Ethinylestradiol; multiple doses; Drug: Microgynon + BI 10773; multiple doses BI 10773

Outcome Measures

Primary Outcome Measures

1. Ethinylestradiol: Area Under the Curve at Steady State Over the Uniform Dosing Interval τ (AUCτ,ss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Area under the concentration-time curve of ethinylestradiol in plasma at steady state over the uniform dosing interval τ.

2. Levonorgestrel: Area Under the Curve at Steady State Over the Uniform Dosing Interval τ (AUCτ,ss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Area under the concentration-time curve of levonorgestrel in plasma at steady state over the uniform dosing interval τ.

3. Ethinylestradiol: Maximum Measured Concentration (Cmax,ss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Maximum measured concentration of ethinylestradiol in plasma at steady state over the uniform dosing interval τ.

4. Levonorgestrel: Maximum Measured Concentration (Cmax,ss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Maximum measured concentration of levonorgestrel in plasma at steady state over the uniform dosing interval τ.

Secondary Outcome Measures

1. Ethinylestradiol: Time From Last Dosing to Maximum Measured Concentration (Tmax,ss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Time from last dosing to the maximum measured concentration of ethinylestradiol in plasma at steady state

2. Levonorgestrel: Time From Last Dosing to Maximum Measured Concentration (Tmax,ss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Time from last dosing to the maximum measured concentration of levonorgestrel in plasma at steady state

3. Ethinylestradiol: Apparent Clearance at Steady State (CL/Fss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Apparent clearance of ethinylestradiol in the plasma at steady state after oral administration

4. Levonorgestrel: Apparent Clearance at Steady State (CL/Fss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Apparent clearance of levonorgestrel in the plasma at steady state after oral administration

5. Ethinylestradiol: Apparent Volume of Distribution During the Terminal Phase at Steady State (Vz/Fss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Apparent volume of distribution during the terminal phase at steady state after oral administration

6. Levonorgestrel: Apparent Volume of Distribution During the Terminal Phase at Steady State (Vz/Fss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Apparent volume of distribution during the terminal phase at steady state after oral administration

7. Ethinylestradiol: Terminal Half-life at Steady State (t1/2,ss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Terminal half-life of ethinylestradiol in plasma at steady state

8. Levonorgestrel: Terminal Half-life at Steady State (t1/2,ss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Terminal half-life of levonorgestrel in plasma at steady state

9. Ethinylestradiol: Terminal Rate Constant at Steady State (λz,ss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

   Terminal rate constant of ethinylestradiol in plasma at steady state

10. Levonorgestrel: Terminal Rate Constant at Steady State (λz,ss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

    Terminal rate constant of levonorgestrel in plasma at steady state

11. Ethinylestradiol: Mean Residence Time at Steady State (MRTpo,ss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

    Mean residence time of ethinylestradiol in the body at steady state after oral administration

12. Levonorgestrel: Mean Residence Time at Steady State (MRTpo,ss) [Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.]

    Mean residence time of levonorgestrel in the body at steady state after oral administration

13. Number of Participants With Clinically Relevant Abnormalities in Physical Examination, Vital Signs, ECG and Clinical Laboratory Tests. [Day 1 to day 17]

    Number of participants with clinically relevant abnormalities in physical examination, vital signs and clinical laboratory tests. Relevant findings or worsenings of baseline conditions were reported as adverse events.

14. Assessment of Tolerability [Within Day 24 to Day 31]

    Tolerability will be assessed by the investigator according to the categories good, satisfactory, not satisfactory, bad and not assessable.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 39 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

1. Healthy female subjects

Exclusion criteria:

1. Any relevant deviation from healthy conditions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1245.41.1 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: NCT01328184
• Other Study ID Numbers: 1245.41; 2010-023432-16
• First Posted: Apr 4, 2011
• Last Update Posted: Jun 18, 2014
• Last Verified: May 1, 2014

• Additional relevant MeSH terms: Empagliflozin; Levonorgestrel; Ethinyl Estradiol; Ethinyl estradiol, levonorgestrel drug combination; Ethinyl Estradiol-Norgestrel Combination

Study Results

Participant Flow

Arm/Group Title	Study Overall
Arm/Group Description	A open label, two-period, fixed sequence trial. Patients received one tablet of Microgynon once daily for 14 days, immediately followed by one tablet of Microgynon once daily plus 25mg empa once daily for 7 days.
Period Title: Overall Study
STARTED	18
COMPLETED	18
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Study Overall
Arm/Group Description	A open label, two-period, fixed sequence trial. Patients received one tablet of Microgynon once daily for 14 days, immediately followed by one tablet of Microgynon once daily plus 25mg empa once daily for 7 days.
Overall Participants	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.2 (4.1)
Sex: Female, Male (Count of Participants)
Female	18 100%
Male	0 0%

Outcome Measures

1. Primary Outcome

Title	Ethinylestradiol: Area Under the Curve at Steady State Over the Uniform Dosing Interval τ (AUCτ,ss)
Description	Area under the concentration-time curve of ethinylestradiol in plasma at steady state over the uniform dosing interval τ.
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [pg*h/mL]	907 (24.4)	932 (22.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Microgynon, Microgynon Plus Empa
	Comments	No formal testing, investigation of relative bioavailability.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Ratio calculated as Microgynon plus empa divided by Microgynon
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	102.82
	Confidence Interval	(2-Sided) 90%; 97.58 to 108.35
	Parameter Dispersion	Type: Standard Deviation; Value: 9.0
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation (gCV)

2. Primary Outcome

Title	Levonorgestrel: Area Under the Curve at Steady State Over the Uniform Dosing Interval τ (AUCτ,ss)
Description	Area under the concentration-time curve of levonorgestrel in plasma at steady state over the uniform dosing interval τ.
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	94.0 (34.4)	95.9 (36.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Microgynon, Microgynon Plus Empa
	Comments	No formal testing, investigation of relative bioavailability.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Ratio calculated as Microgynon plus empa divided by Microgynon
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	101.94
	Confidence Interval	(2-Sided) 90%; 98.54 to 105.47
	Parameter Dispersion	Type: Standard Deviation; Value: 5.9
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation (gCV)

3. Primary Outcome

Title	Ethinylestradiol: Maximum Measured Concentration (Cmax,ss)
Description	Maximum measured concentration of ethinylestradiol in plasma at steady state over the uniform dosing interval τ.
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [pg/mL]	97.6 (17.6)	96.8 (21.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Microgynon, Microgynon Plus Empa
	Comments	No formal testing, investigation of relative bioavailability.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Ratio calculated as Microgynon plus empa divided by Microgynon
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	99.22
	Confidence Interval	(2-Sided) 90%; 93.40 to 105.39
	Parameter Dispersion	Type: Standard Deviation; Value: 10.4
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation (gCV).

4. Primary Outcome

Title	Levonorgestrel: Maximum Measured Concentration (Cmax,ss)
Description	Maximum measured concentration of levonorgestrel in plasma at steady state over the uniform dosing interval τ.
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	7.98 (26.1)	8.44 (25.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Microgynon, Microgynon Plus Empa
	Comments	No formal testing, investigation of relative bioavailability.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Ratio calculated as Microgynon plus empa divided by Microgynon
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	105.81
	Confidence Interval	(2-Sided) 90%; 99.47 to 112.55
	Parameter Dispersion	Type: Standard Deviation; Value: 10.7
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation (gCV)

5. Secondary Outcome

Title	Ethinylestradiol: Time From Last Dosing to Maximum Measured Concentration (Tmax,ss)
Description	Time from last dosing to the maximum measured concentration of ethinylestradiol in plasma at steady state
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Median (Full Range) [hours(h)]	1.26 (39.5)	1.50 (34.2)

6. Secondary Outcome

Title	Levonorgestrel: Time From Last Dosing to Maximum Measured Concentration (Tmax,ss)
Description	Time from last dosing to the maximum measured concentration of levonorgestrel in plasma at steady state
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Median (Full Range) [hours(h)]	1.00 (28.1)	1.00 (25.5)

7. Secondary Outcome

Title	Ethinylestradiol: Apparent Clearance at Steady State (CL/Fss)
Description	Apparent clearance of ethinylestradiol in the plasma at steady state after oral administration
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [mL/min]	552 (24.4)	536 (22.8)

8. Secondary Outcome

Title	Levonorgestrel: Apparent Clearance at Steady State (CL/Fss)
Description	Apparent clearance of levonorgestrel in the plasma at steady state after oral administration
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [mL/min]	26.6 (34.4)	26.1 (36.6)

9. Secondary Outcome

Title	Ethinylestradiol: Apparent Volume of Distribution During the Terminal Phase at Steady State (Vz/Fss)
Description	Apparent volume of distribution during the terminal phase at steady state after oral administration
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [L]	729 (35.1)	757 (30.3)

10. Secondary Outcome

Title	Levonorgestrel: Apparent Volume of Distribution During the Terminal Phase at Steady State (Vz/Fss)
Description	Apparent volume of distribution during the terminal phase at steady state after oral administration
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [L]	84.6 (41.1)	85.0 (38.8)

11. Secondary Outcome

Title	Ethinylestradiol: Terminal Half-life at Steady State (t1/2,ss)
Description	Terminal half-life of ethinylestradiol in plasma at steady state
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [hours(h)]	15.3 (28.8)	16.3 (21.8)

12. Secondary Outcome

Title	Levonorgestrel: Terminal Half-life at Steady State (t1/2,ss)
Description	Terminal half-life of levonorgestrel in plasma at steady state
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [hours(h)]	36.7 (32.4)	37.6 (40.7)

13. Secondary Outcome

Title	Ethinylestradiol: Terminal Rate Constant at Steady State (λz,ss)
Description	Terminal rate constant of ethinylestradiol in plasma at steady state
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [1/h]	0.0454 (28.8)	0.0425 (21.8)

14. Secondary Outcome

Title	Levonorgestrel: Terminal Rate Constant at Steady State (λz,ss)
Description	Terminal rate constant of levonorgestrel in plasma at steady state
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [1/h]	0.0189 (32.4)	0.0184 (40.7)

15. Secondary Outcome

Title	Ethinylestradiol: Mean Residence Time at Steady State (MRTpo,ss)
Description	Mean residence time of ethinylestradiol in the body at steady state after oral administration
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [hours(h)]	18.6 (28.1)	19.5 (20.5)

16. Secondary Outcome

Title	Levonorgestrel: Mean Residence Time at Steady State (MRTpo,ss)
Description	Mean residence time of levonorgestrel in the body at steady state after oral administration
Time Frame	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set: Included all subjects who took at least one dose of study medication, who provided evaluable data for at least one primary PK endpoint without important protocol violations.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [hours(h)]	48.8 (33.1)	49.6 (41.2)

17. Secondary Outcome

Title	Number of Participants With Clinically Relevant Abnormalities in Physical Examination, Vital Signs, ECG and Clinical Laboratory Tests.
Description	Number of participants with clinically relevant abnormalities in physical examination, vital signs and clinical laboratory tests. Relevant findings or worsenings of baseline conditions were reported as adverse events.
Time Frame	Day 1 to day 17

Outcome Measure Data

Analysis Population Description

Treated set (TS) included all subjects who took at least one dose of study medication.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Number [participants]	0 0%	0 NaN

18. Secondary Outcome

Title	Assessment of Tolerability
Description	Tolerability will be assessed by the investigator according to the categories good, satisfactory, not satisfactory, bad and not assessable.
Time Frame	Within Day 24 to Day 31

Outcome Measure Data

Analysis Population Description

Treated set (TS) included all subjects who took at least one dose of study medication.

Arm/Group Title	Microgynon	Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.	One tablet of Microgynon once daily plus empa 25mg once daily for seven days
Measure Participants	18	18
Good	94.4 524.4%	94.4 NaN
Satisfactory	5.6 31.1%	5.6 NaN
Not satisfactory	0.0 0%	0.0 NaN
Bad	0.0 0%	0.0 NaN
Not assessable	0.0 0%	0.0 NaN

Adverse Events

Time Frame	day1 to day17
Arm/Group Title	Microgynon		Microgynon Plus Empa
Arm/Group Description	One tablet of Microgynon once daily for 14 days.		One tablet of Microgynon once daily plus empa 25mg once daily for seven days
All Cause Mortality
	Microgynon		Microgynon Plus Empa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Microgynon		Microgynon Plus Empa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Microgynon		Microgynon Plus Empa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/18 (55.6%)		10/18 (55.6%)
Gastrointestinal disorders
Abdominal discomfort	0/18 (0%)		1/18 (5.6%)
Diarrhoea	0/18 (0%)		1/18 (5.6%)
Nausea	1/18 (5.6%)		1/18 (5.6%)
General disorders
Fatigue	0/18 (0%)		1/18 (5.6%)
Thirst	0/18 (0%)		1/18 (5.6%)
Infections and infestations
Rhinitis	0/18 (0%)		1/18 (5.6%)
Injury, poisoning and procedural complications
Arthropod bite	0/18 (0%)		1/18 (5.6%)
Contusion	0/18 (0%)		1/18 (5.6%)
Sunburn	1/18 (5.6%)		0/18 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/18 (0%)		1/18 (5.6%)
Myalgia	2/18 (11.1%)		0/18 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus	1/18 (5.6%)		0/18 (0%)
Nervous system disorders
Dizziness	2/18 (11.1%)		1/18 (5.6%)
Headache	3/18 (16.7%)		1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/18 (0%)		2/18 (11.1%)
Vascular disorders
Haematoma	0/18 (0%)		1/18 (5.6%)

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.