Trial Outcomes & Findings for Bioequivalence of Empagliflozin and Metformin Given as a Fixed Dose Combination Compared to Single Tablets (NCT NCT01844531)

NCT ID: NCT01844531

Last Updated: 2015-07-27

Results Overview

AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 24 participants
• Primary outcome timeframe: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake
• Results posted on: 2015-07-27

Participant Flow

Participant milestones

Measure	FDC Empa12.5/ Empa12.5+Met500/ FDC Empa5/ Empa5+Met500 Participants first received Treatment T1 (12.5 mg empagliflozin/500 mg metformin Fixed Dose Combination (FDC)). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). Oral administration.	Empa12.5+Met500/ FDC Empa12.5/ Empa5+Met500/ FDC Empa5 Participants first received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). Oral administration.	FDC Empa5/ Empa5+Met500/ FDC Empa12.5/ Empa12.5+Met500 Participants first received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets)Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). Oral administration.	Empa5+Met500/ FDC Empa5/ Empa12.5+Met500/ FDC Empa12.5 Participants first received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). Oral administration.
Overall Study STARTED	6	6	6	6
Overall Study COMPLETED	6	5	6	6
Overall Study NOT COMPLETED	0	1	0	0

Reasons for withdrawal

Measure	FDC Empa12.5/ Empa12.5+Met500/ FDC Empa5/ Empa5+Met500 Participants first received Treatment T1 (12.5 mg empagliflozin/500 mg metformin Fixed Dose Combination (FDC)). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). Oral administration.	Empa12.5+Met500/ FDC Empa12.5/ Empa5+Met500/ FDC Empa5 Participants first received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). Oral administration.	FDC Empa5/ Empa5+Met500/ FDC Empa12.5/ Empa12.5+Met500 Participants first received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets)Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). Oral administration.	Empa5+Met500/ FDC Empa5/ Empa12.5+Met500/ FDC Empa12.5 Participants first received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). Oral administration.
Overall Study Withdrawal by Subject	0	1	0	0

Baseline Characteristics

Bioequivalence of Empagliflozin and Metformin Given as a Fixed Dose Combination Compared to Single Tablets

Baseline characteristics by cohort

Measure	FDC Empa12.5/ Empa12.5+Met500/ FDC Empa5/ Empa5+Met500 n=6 Participants Participants first received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). Oral administration.	Empa12.5+Met500/ FDC Empa12.5/ Empa5+Met500/ FDC Empa5 n=6 Participants Participants first received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). Oral administration.	FDC Empa5/ Empa5+Met500/ FDC Empa12.5/ Empa12.5+Met500 n=6 Participants Participants first received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets)Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). Oral administration.	Empa5+Met500/ FDC Empa5/ Empa12.5+Met500/ FDC Empa12.5 n=6 Participants Participants first received Treatment R2 (5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T2 (5 mg empagliflozin/500 mg metformin FDC). After a washout phase of at least 5 days, they then received Treatment R1 (12.5 mg empagliflozin and 500 mg metformin, single tablets). After a washout phase of at least 5 days, they then received Treatment T1 (12.5 mg empagliflozin/500 mg metformin FDC). Oral administration.	Total n=24 Participants Total of all reporting groups
Age, Continuous	38.2 years STANDARD_DEVIATION 8.6 • n=5 Participants	30.8 years STANDARD_DEVIATION 7.6 • n=7 Participants	35.8 years STANDARD_DEVIATION 10.5 • n=5 Participants	37.5 years STANDARD_DEVIATION 9.0 • n=4 Participants	35.6 years STANDARD_DEVIATION 8.9 • n=21 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	4 Participants n=4 Participants	15 Participants n=21 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants	9 Participants n=21 Participants

PRIMARY outcome

Timeframe: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake

Population: Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax

AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin

Outcome measures

Measure	12.5 mg Empagliflozin and 500 mg Metformin as FDC n=21 Participants 12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=23 Participants 12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg Empagliflozin and 500 mg Metformin as FDC n=23 Participants 5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=20 Participants 5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
AUC0-∞ for Empagliflozin	2780 nmol*h/L Geometric Coefficient of Variation 16.1	2870 nmol*h/L Geometric Coefficient of Variation 17.3	1110 nmol*h/L Geometric Coefficient of Variation 15.7	1070 nmol*h/L Geometric Coefficient of Variation 19.2

PRIMARY outcome

Timeframe: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake

Population: Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax

AUC0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Metformin

Outcome measures

Measure	12.5 mg Empagliflozin and 500 mg Metformin as FDC n=21 Participants 12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=23 Participants 12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg Empagliflozin and 500 mg Metformin as FDC n=23 Participants 5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=20 Participants 5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
AUC0-∞ for Metformin	5590 ng*h/mL Geometric Coefficient of Variation 19.0	5820 ng*h/mL Geometric Coefficient of Variation 21.8	5960 ng*h/mL Geometric Coefficient of Variation 18.0	6190 ng*h/mL Geometric Coefficient of Variation 19.5

PRIMARY outcome

Timeframe: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake

Population: Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax

Cmax (maximum measured concentration of the analyte in plasma) for Empagliflozin

Outcome measures

Measure	12.5 mg Empagliflozin and 500 mg Metformin as FDC n=21 Participants 12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=23 Participants 12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg Empagliflozin and 500 mg Metformin as FDC n=23 Participants 5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=20 Participants 5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Cmax for Empagliflozin	294 nmol/L Geometric Coefficient of Variation 23.7	282 nmol/L Geometric Coefficient of Variation 27.4	109 nmol/L Geometric Coefficient of Variation 22.8	106 nmol/L Geometric Coefficient of Variation 22.5

PRIMARY outcome

Timeframe: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake

Population: Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax

Cmax (maximum measured concentration of the analyte in plasma) for Metformin

Outcome measures

Measure	12.5 mg Empagliflozin and 500 mg Metformin as FDC n=21 Participants 12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=23 Participants 12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg Empagliflozin and 500 mg Metformin as FDC n=23 Participants 5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=20 Participants 5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Cmax for Metformin	686 ng/mL Geometric Coefficient of Variation 14.1	718 ng/mL Geometric Coefficient of Variation 19.7	693 ng/mL Geometric Coefficient of Variation 12.8	743 ng/mL Geometric Coefficient of Variation 19.6

SECONDARY outcome

Timeframe: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake

Population: Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) for Empagliflozin

Outcome measures

Measure	12.5 mg Empagliflozin and 500 mg Metformin as FDC n=21 Participants 12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=23 Participants 12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg Empagliflozin and 500 mg Metformin as FDC n=23 Participants 5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=20 Participants 5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
AUC0-tz for Empagliflozin	2740 nmol*h/L Geometric Coefficient of Variation 16.3	2830 nmol*h/L Geometric Coefficient of Variation 17.3	1080 nmol*h/L Geometric Coefficient of Variation 15.7	1040 nmol*h/L Geometric Coefficient of Variation 19.1

SECONDARY outcome

Timeframe: 1hour (h) before drug intake and 20minutes (min),40min,1h,1h 30min,2h,2h 30min, 3h, 3h 30min, 4h, 5h, 6h, 8h,10h,12h,24h,34h,48h,72h after drug intake

Population: Pharmacokinetics set (PKS) included all treated subjects with at least 1 evaluable observation for at least 1 primary pharmacokinetic endpoint without important protocol violations relevant to the statistical evaluation of pharmacokinetics who had not taken any restricted medication and had not experienced emesis before or at 2 times median tmax

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) for Metformin

Outcome measures

Measure	12.5 mg Empagliflozin and 500 mg Metformin as FDC n=21 Participants 12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=23 Participants 12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg Empagliflozin and 500 mg Metformin as FDC n=23 Participants 5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=20 Participants 5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
AUC0-tz for Metformin	5480 ng*h/mL Geometric Coefficient of Variation 18.9	5720 ng*h/mL Geometric Coefficient of Variation 21.2	5820 ng*h/mL Geometric Coefficient of Variation 17.7	6110 ng*h/mL Geometric Coefficient of Variation 19.2

Adverse Events

12.5 mg Empagliflozin and 500 mg Metformin as FDC

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

5 mg Empagliflozin and 500 mg Metformin as FDC

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

5 mg Empagliflozin and 500 mg Metformin as Single Tablets

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	12.5 mg Empagliflozin and 500 mg Metformin as FDC n=21 participants at risk 12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=23 participants at risk 12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration	5 mg Empagliflozin and 500 mg Metformin as FDC n=23 participants at risk 5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration	5 mg Empagliflozin and 500 mg Metformin as Single Tablets n=20 participants at risk 5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Gastrointestinal disorders Diarrhoea	4.8% 1/21 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)	8.7% 2/23 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)	8.7% 2/23 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)	10.0% 2/20 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)
Gastrointestinal disorders Nausea	0.00% 0/21 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)	8.7% 2/23 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)	4.3% 1/23 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)	0.00% 0/20 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)
Gastrointestinal disorders Vomiting	0.00% 0/21 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)	8.7% 2/23 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)	0.00% 0/23 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)	0.00% 0/20 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)
Nervous system disorders Headache	9.5% 2/21 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)	13.0% 3/23 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)	8.7% 2/23 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)	0.00% 0/20 • From study drug administration of 1 treatment period until study drug administration in the next treatment period or date of trial completion plus 1 day, up to 8 days (and up to 16 days for one subject only)

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim

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