Trial Outcomes & Findings for DDI Between BI Empagliflozin (10773) and Verapamil (NCT NCT01276301)

NCT ID: NCT01276301

Last Updated: 2014-06-17

Results Overview

Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 extrapolated to infinity.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 16 participants
• Primary outcome timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration
• Results posted on: 2014-06-17

Participant Flow

Participant milestones

Measure	Empa / Empa Plus Verapamil A single dose of empagliflozin (empa) 25 mg, followed by a washout period of at least 7 days, followed by a single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.	Empa Plus Verapamil / Empa A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil, followed by a washout period of at least 7 days, followed by a single dose of empagliflozin (empa) 25 mg.
First Intervention STARTED	8	8
First Intervention COMPLETED	8	8
First Intervention NOT COMPLETED	0	0
Washout Period of 7 Days STARTED	8	8
Washout Period of 7 Days COMPLETED	8	8
Washout Period of 7 Days NOT COMPLETED	0	0
Second Intervention STARTED	8	8
Second Intervention COMPLETED	8	8
Second Intervention NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

DDI Between BI Empagliflozin (10773) and Verapamil

Baseline characteristics by cohort

Measure	Entire Study Population n=16 Participants An open label, randomised, two-period crossover trial. The two treatments administered were * A single dose of empagliflozin (empa) 25 mg * A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil The two treatment periods were separated by a washout period of at least 7 days.
Age, Continuous	34.3 years STANDARD_DEVIATION 10.3 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants

PRIMARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration

Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 extrapolated to infinity.

Outcome measures

Measure	Empa n=16 Participants A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil n=16 Participants A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Area Under the Curve 0 to Infinity (AUC0-∞)	5190 nmol*h/L Geometric Coefficient of Variation 25.0	5340 nmol*h/L Geometric Coefficient of Variation 25.5

PRIMARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration

Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Maximum measured concentration of empagliflozin (empa) in plasma.

Outcome measures

Measure	Empa n=16 Participants A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil n=16 Participants A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Maximum Measured Concentration (Cmax)	785 nmol Geometric Coefficient of Variation 31.5	725 nmol Geometric Coefficient of Variation 29.1

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration

Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 to time of last quantifiable data point.

Outcome measures

Measure	Empa n=16 Participants A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil n=16 Participants A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Area Under the Curve 0 to Time of Last Quantifiable Data Point (AUC0-tz)	5140 nmol*h/L Geometric Coefficient of Variation 25.0	5280 nmol*h/L Geometric Coefficient of Variation 25.7

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration

Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Time from last dosing to the maximum plasma concentration

Outcome measures

Measure	Empa n=16 Participants A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil n=16 Participants A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Time From 0 to Maximum Plasma Concentration (Tmax)	1.50 h Interval 1.0 to 2.5	1.75 h Interval 0.68 to 3.0

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration

Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Terminal elimination rate constant in plasma.

Note: The numbers provide below for standard deviation are of Coefficient of Variation.

Outcome measures

Measure	Empa n=16 Participants A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil n=16 Participants A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Terminal Elimination Rate Constant (λz)	0.0573 1/h Geometric Coefficient of Variation 29.2	0.0531 1/h Geometric Coefficient of Variation 30.2

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration

Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Terminal half-life of empagliflozin in plasma.

Note: The numbers provide below for standard deviation are of Coefficient of Variation.

Outcome measures

Measure	Empa n=16 Participants A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil n=16 Participants A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Terminal Half-life in Plasma (t1/2)	12.1 h Geometric Coefficient of Variation 29.2	13.1 h Geometric Coefficient of Variation 30.2

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration

Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Mean residence time of empagliflozin (empa) in the body after oral administration.

Note: The numbers provide below for standard deviation are of Coefficient of Variation.

Outcome measures

Measure	Empa n=16 Participants A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil n=16 Participants A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Mean Residence Time in the Body After Administration (MRTpo)	9.47 h Geometric Coefficient of Variation 12.0	9.95 h Geometric Coefficient of Variation 13.8

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration

Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.

Apparent clearance of empagliflozin (empa) in plasma after extravascular administration.

Note: The numbers provide below for standard deviation are of Coefficient of Variation.

Outcome measures

Measure	Empa n=16 Participants A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil n=16 Participants A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Apparent Clearance in Plasma After Extravascular Administration (CL/F)	178 mL/min Geometric Coefficient of Variation 25.0	173 mL/min Geometric Coefficient of Variation 25.5

SECONDARY outcome

Timeframe: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration

Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation

Apparent volume of distribution during the terminal phase following an extravascular dose.

Note: The numbers provide below for standard deviation are of Coefficient of Variation.

Outcome measures

Measure	Empa n=16 Participants A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil n=16 Participants A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Apparent Volume of Distribution Following an Extravascular Dose (Vz/F)	186 L Geometric Coefficient of Variation 31.8	195 L Geometric Coefficient of Variation 28.8

SECONDARY outcome

Timeframe: Day1 to Day 11

Population: Treated set (TS) included all subjects who had taken at least one dose of trial medication.

Clinically relevant abnormalities for physical examination, vital signs , blood chemistry and Electrocardiogram (ECG). New or abnormal findings were reported as adverse events.

Outcome measures

Measure	Empa n=16 Participants A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil n=16 Participants A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Clinically Relevant Abnormalities for Physical Examination, Vital Signs, Blood Chemistry and Electrocardiogram (ECG).	0 participants	0 participants

SECONDARY outcome

Timeframe: Within Day 15 to Day 25

Population: Treated set

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

Outcome measures

Measure	Empa n=16 Participants A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil n=16 Participants A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Assessment of Tolerability by Investigator Not assessable	0.0 percentage of participants	0.0 percentage of participants
Assessment of Tolerability by Investigator Good	100.0 percentage of participants	87.5 percentage of participants
Assessment of Tolerability by Investigator Satisfactory	0.0 percentage of participants	6.3 percentage of participants
Assessment of Tolerability by Investigator Not Satisfactory	0.0 percentage of participants	6.3 percentage of participants
Assessment of Tolerability by Investigator Bad	0.0 percentage of participants	0.0 percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Predose and 1 hour (h), 25h, 49h and 73h after verapamil administration

Population: Treated set (TS) included all subjects who had taken at least one dose of trial medication.

Verapamil plasma concentration were measured in order to confirm exposure.

Note: No descriptive statistics was calculated for predose, 49.0 (h) and 73.0 (h), as most of the values were below the limit of quantification (BLQ).

Outcome measures

Measure	Empa n=16 Participants A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Verapamil Plasma Concentration Planned time: 1.0 (h)	94.5 ng/mL Geometric Coefficient of Variation 76.3	—
Verapamil Plasma Concentration Planned time: 25.0(h) (included 11 participants)	2.69 ng/mL Geometric Coefficient of Variation 82.2	—

Adverse Events

Empa

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Empa Plus Verapamil

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Empa n=16 participants at risk A single dose of empagliflozin (empa) 25 mg.	Empa Plus Verapamil n=16 participants at risk A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil.
Gastrointestinal disorders Constipation	0.00% 0/16 • Day1 to Day 11	6.2% 1/16 • Day1 to Day 11
Gastrointestinal disorders Diarrhoea	0.00% 0/16 • Day1 to Day 11	6.2% 1/16 • Day1 to Day 11
Gastrointestinal disorders Nausea	0.00% 0/16 • Day1 to Day 11	6.2% 1/16 • Day1 to Day 11
General disorders Induration	6.2% 1/16 • Day1 to Day 11	0.00% 0/16 • Day1 to Day 11
Infections and infestations Oral herpes	6.2% 1/16 • Day1 to Day 11	12.5% 2/16 • Day1 to Day 11
Injury, poisoning and procedural complications Arthropod bite	0.00% 0/16 • Day1 to Day 11	6.2% 1/16 • Day1 to Day 11
Injury, poisoning and procedural complications Skeletal injury	6.2% 1/16 • Day1 to Day 11	0.00% 0/16 • Day1 to Day 11
Musculoskeletal and connective tissue disorders Back pain	6.2% 1/16 • Day1 to Day 11	0.00% 0/16 • Day1 to Day 11
Musculoskeletal and connective tissue disorders Pain in extremity	6.2% 1/16 • Day1 to Day 11	6.2% 1/16 • Day1 to Day 11
Nervous system disorders Dizziness	0.00% 0/16 • Day1 to Day 11	6.2% 1/16 • Day1 to Day 11
Nervous system disorders Headache	18.8% 3/16 • Day1 to Day 11	25.0% 4/16 • Day1 to Day 11
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	6.2% 1/16 • Day1 to Day 11	0.00% 0/16 • Day1 to Day 11
Skin and subcutaneous tissue disorders Rash	6.2% 1/16 • Day1 to Day 11	0.00% 0/16 • Day1 to Day 11

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place