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

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ClinicalTrials.gov Identifier: NCT01844531
Recruitment Status : Completed
First Posted : May 1, 2013
Results First Posted : July 27, 2015
Last Update Posted : July 27, 2015
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Healthy
Interventions Drug: empagliflozin
Drug: metformin (Glucophage®)
Drug: empagliflozin and metformin
Enrollment 24
Recruitment Details  
Pre-assignment Details  
Arm/Group Title FDC Empa12.5/ Empa12.5+Met500/ FDC Empa5/ Empa5+Met500 Empa12.5+Met500/ FDC Empa12.5/ Empa5+Met500/ FDC Empa5 FDC Empa5/ Empa5+Met500/ FDC Empa12.5/ Empa12.5+Met500 Empa5+Met500/ FDC Empa5/ Empa12.5+Met500/ FDC Empa12.5
Hide Arm/Group Description 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. 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. 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. 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.
Period Title: Overall Study
Started 6 6 6 6
Completed 6 5 6 6
Not Completed 0 1 0 0
Reason Not Completed
Withdrawal by Subject             0             1             0             0
Arm/Group Title FDC Empa12.5/ Empa12.5+Met500/ FDC Empa5/ Empa5+Met500 Empa12.5+Met500/ FDC Empa12.5/ Empa5+Met500/ FDC Empa5 FDC Empa5/ Empa5+Met500/ FDC Empa12.5/ Empa12.5+Met500 Empa5+Met500/ FDC Empa5/ Empa12.5+Met500/ FDC Empa12.5 Total
Hide Arm/Group Description

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.

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.

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. 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 of all reporting groups
Overall Number of Baseline Participants 6 6 6 6 24
Hide Baseline Analysis Population Description
Treated set, included all subjects that entered the study and had taken at least 1 dose of trial medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants 6 participants 6 participants 6 participants 24 participants
38.2  (8.6) 30.8  (7.6) 35.8  (10.5) 37.5  (9.0) 35.6  (8.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 6 participants 6 participants 6 participants 24 participants
Female
5
  83.3%
2
  33.3%
4
  66.7%
4
  66.7%
15
  62.5%
Male
1
  16.7%
4
  66.7%
2
  33.3%
2
  33.3%
9
  37.5%
1.Primary Outcome
Title AUC0−∞ for Empagliflozin
Hide Description AUC0−∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title 12.5 mg Empagliflozin and 500 mg Metformin as FDC 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets 5 mg Empagliflozin and 500 mg Metformin as FDC 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Hide Arm/Group Description:
12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration
12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration
5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Overall Number of Participants Analyzed 21 23 23 20
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
2780
(16.1%)
2870
(17.3%)
1110
(15.7%)
1070
(19.2%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUCinfpred [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA). The statistical model used was an analysis of variance (ANOVA) model on the logarithmic scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0000
Comments Model included effects:sequence;subjects within sequences;period and treatment with subjects within sequences as random effect.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 97.92
Confidence Interval (2-Sided) 90%
93.529 to 102.520
Parameter Dispersion
Type: Standard Error of the mean
Value: 8.4
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability − analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUCinfpred [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA). The statistical model used was an analysis of variance (ANOVA) model on the logarithmic scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments Model included effects:sequence;subjects within sequences;period and treatment with all effects as fixed.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 98.00
Confidence Interval (2-Sided) 90%
93.57 to 102.65
Parameter Dispersion
Type: Standard Error of the mean
Value: 8.3
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500 , PK set AUCinfpred [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA). The statistical model used was an analysis of variance (ANOVA) model on the logarithmic scale.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0000
Comments Model included effects:sequence;subjects within sequences;period and treatment with subjects within sequences as random effect.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 102.79
Confidence Interval (2-Sided) 90%
99.077 to 106.633
Parameter Dispersion
Type: Standard Error of the mean
Value: 6.7
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection 5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability − analysis with fixed effects for all terms comparison FDC Empa5 (T2) : Empa5 + Met500 (R2), PK set AUCinfpred [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 102.50
Confidence Interval (2-Sided) 90%
98.78 to 106.36
Parameter Dispersion
Type: Standard Error of the mean
Value: 6.7
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
2.Primary Outcome
Title AUC0−∞ for Metformin
Hide Description AUC0-infinity (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Metformin
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title 12.5 mg Empagliflozin and 500 mg Metformin as FDC 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets 5 mg Empagliflozin and 500 mg Metformin as FDC 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Hide Arm/Group Description:
12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration
12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration
5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Overall Number of Participants Analyzed 21 23 23 20
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
5590
(19.0%)
5820
(21.8%)
5960
(18.0%)
6190
(19.5%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUCinfpred [ng*h/mL] for METFORMIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0006
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 96.25
Confidence Interval (2-Sided) 90%
88.542 to 104.628
Parameter Dispersion
Type: Standard Error of the mean
Value: 15.4
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability − analysis with fixed effects for all terms comparison FDC Empa12.5 (T1) : Empa12.5 + Met500 (R1), PK set AUCinfpred [ng*h/mL] for METFORMIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 97.21
Confidence Interval (2-Sided) 90%
89.41 to 105.68
Parameter Dispersion
Type: Standard Error of the mean
Value: 15.1
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set AUCinfpred [ng*h/mL] for METFORMIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0000
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 96.79
Confidence Interval (2-Sided) 90%
91.772 to 102.093
Parameter Dispersion
Type: Standard Error of the mean
Value: 9.8
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection 5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability − analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set AUCinfpred [ng*h/mL] for METFORMIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 96.91
Confidence Interval (2-Sided) 90%
91.79 to 102.32
Parameter Dispersion
Type: Standard Error of the mean
Value: 9.8
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
3.Primary Outcome
Title Cmax for Empagliflozin
Hide Description Cmax (maximum measured concentration of the analyte in plasma) for Empagliflozin
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title 12.5 mg Empagliflozin and 500 mg Metformin as FDC 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets 5 mg Empagliflozin and 500 mg Metformin as FDC 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Hide Arm/Group Description:
12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration
12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration
5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Overall Number of Participants Analyzed 21 23 23 20
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
294
(23.7%)
282
(27.4%)
109
(22.8%)
106
(22.5%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set Cmax [nmol/L] for EMPAGLIFLOZIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0000
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 104.61
Confidence Interval (2-Sided) 90%
99.882 to 109.555
Parameter Dispersion
Type: Standard Error of the mean
Value: 8.4
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability − analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set Cmax [nmol/L] for EMPAGLIFLOZIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 104.53
Confidence Interval (2-Sided) 90%
99.76 to 109.53
Parameter Dispersion
Type: Standard Error of the mean
Value: 8.4
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set Cmax [nmol/L] for EMPAGLIFLOZIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0000
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 102.96
Confidence Interval (2-Sided) 90%
97.917 to 108.258
Parameter Dispersion
Type: Standard Error of the mean
Value: 9.2
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection 5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability − analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set Cmax [nmol/L] for EMPAGLIFLOZIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 102.80
Confidence Interval (2-Sided) 90%
97.72 to 108.14
Parameter Dispersion
Type: Standard Error of the mean
Value: 9.2
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
4.Primary Outcome
Title Cmax for Metformin
Hide Description Cmax (maximum measured concentration of the analyte in plasma) for Metformin
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title 12.5 mg Empagliflozin and 500 mg Metformin as FDC 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets 5 mg Empagliflozin and 500 mg Metformin as FDC 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Hide Arm/Group Description:
12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration
12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration
5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Overall Number of Participants Analyzed 21 23 23 20
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
686
(14.1%)
718
(19.7%)
693
(12.8%)
743
(19.6%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set Cmax [ng/mL] for METFORMIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 94.76
Confidence Interval (2-Sided) 90%
89.056 to 100.819
Parameter Dispersion
Type: Standard Error of the mean
Value: 11.4
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability − analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set Cmax [ng/mL] for METFORMIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 94.40
Confidence Interval (2-Sided) 90%
88.64 to 100.54
Parameter Dispersion
Type: Standard Error of the mean
Value: 11.4
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set Cmax [ng/mL] for METFORMIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 93.83
Confidence Interval (2-Sided) 90%
88.006 to 100.034
Parameter Dispersion
Type: Standard Error of the mean
Value: 11.9
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection 5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability − analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set Cmax [ng/mL] for METFORMIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 93.98
Confidence Interval (2-Sided) 90%
87.94 to 100.43
Parameter Dispersion
Type: Standard Error of the mean
Value: 12.0
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
5.Secondary Outcome
Title AUC0-tz for Empagliflozin
Hide Description 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
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title 12.5 mg Empagliflozin and 500 mg Metformin as FDC 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets 5 mg Empagliflozin and 500 mg Metformin as FDC 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Hide Arm/Group Description:
12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration
12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration
5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Overall Number of Participants Analyzed 21 23 23 20
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
2740
(16.3%)
2830
(17.3%)
1080
(15.7%)
1040
(19.1%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUClast [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0000
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 98.00
Confidence Interval (2-Sided) 90%
93.530 to 102.686
Parameter Dispersion
Type: Standard Error of the mean
Value: 8.5
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability − analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUClast [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 98.07
Confidence Interval (2-Sided) 90%
93.55 to 102.81
Parameter Dispersion
Type: Standard Error of the mean
Value: 8.5
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set AUClast [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0000
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 102.77
Confidence Interval (2-Sided) 90%
99.146 to 106.522
Parameter Dispersion
Type: Standard Error of the mean
Value: 6.5
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection 5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability − analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set AUClast [nmol*h/L] for EMPAGLIFLOZIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 102.49
Confidence Interval (2-Sided) 90%
98.85 to 106.25
Parameter Dispersion
Type: Standard Error of the mean
Value: 6.5
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
6.Secondary Outcome
Title AUC0-tz for Metformin
Hide Description 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
Time Frame 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title 12.5 mg Empagliflozin and 500 mg Metformin as FDC 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets 5 mg Empagliflozin and 500 mg Metformin as FDC 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Hide Arm/Group Description:
12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration
12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration
5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
Overall Number of Participants Analyzed 21 23 23 20
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
5480
(18.9%)
5720
(21.2%)
5820
(17.7%)
6110
(19.2%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUClast [ng*h/mL] for METFORMIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0008
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 95.78
Confidence Interval (2-Sided) 90%
88.000 to 104.256
Parameter Dispersion
Type: Standard Error of the mean
Value: 15.7
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 12.5 mg Empagliflozin and 500 mg Metformin as FDC, 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability − analysis with fixed effects for all terms comparison FDC Empa12.5 : Empa12.5 + Met500, PK set AUClast [ng*h/mL] for METFORMIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0006
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 96.74
Confidence Interval (2-Sided) 90%
88.78 to 105.41
Parameter Dispersion
Type: Standard Error of the mean
Value: 15.5
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability comparison FDC Empa5 : Empa5 + Met500, PK set AUClast [ng*h/mL] for METFORMIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0000
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 95.94
Confidence Interval (2-Sided) 90%
91.199 to 100.934
Parameter Dispersion
Type: Standard Error of the mean
Value: 9.3
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection 5 mg Empagliflozin and 500 mg Metformin as FDC, 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Comments Adjusted by−treatment geometric means and relative bioavailability − analysis with fixed effects for all terms comparison FDC Empa5 : Empa5 + Met500, PK set AUClast [ng*h/mL] for METFORMIN (PLASMA EDTA)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted gMean ratio FDC/single tablets
Estimated Value 96.10
Confidence Interval (2-Sided) 90%
91.28 to 101.19
Parameter Dispersion
Type: Standard Error of the mean
Value: 9.3
Estimation Comments *Results reported as Standard Error of the mean are Intra-individual geometric coefficient of variation [%].
Time Frame 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)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title 12.5 mg Empagliflozin and 500 mg Metformin as FDC 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets 5 mg Empagliflozin and 500 mg Metformin as FDC 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Hide Arm/Group Description 12.5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration 12.5 mg empagliflozin and 500 mg metformin as single tablets, oral administration 5 mg empagliflozin/500 mg metformin as Fixed Dose Combination, oral administration 5 mg empagliflozin and 500 mg metformin as single tablets, oral administration
All-Cause Mortality
12.5 mg Empagliflozin and 500 mg Metformin as FDC 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets 5 mg Empagliflozin and 500 mg Metformin as FDC 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
12.5 mg Empagliflozin and 500 mg Metformin as FDC 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets 5 mg Empagliflozin and 500 mg Metformin as FDC 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/21 (0.00%)   0/23 (0.00%)   0/23 (0.00%)   0/20 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
12.5 mg Empagliflozin and 500 mg Metformin as FDC 12.5 mg Empagliflozin and 500 mg Metformin as Single Tablets 5 mg Empagliflozin and 500 mg Metformin as FDC 5 mg Empagliflozin and 500 mg Metformin as Single Tablets
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/21 (14.29%)   6/23 (26.09%)   3/23 (13.04%)   2/20 (10.00%) 
Gastrointestinal disorders         
Diarrhoea  1  1/21 (4.76%)  2/23 (8.70%)  2/23 (8.70%)  2/20 (10.00%) 
Nausea  1  0/21 (0.00%)  2/23 (8.70%)  1/23 (4.35%)  0/20 (0.00%) 
Vomiting  1  0/21 (0.00%)  2/23 (8.70%)  0/23 (0.00%)  0/20 (0.00%) 
Nervous system disorders         
Headache  1  2/21 (9.52%)  3/23 (13.04%)  2/23 (8.70%)  0/20 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.1
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01844531     History of Changes
Other Study ID Numbers: 1276.6
2012-000082-20 ( EudraCT Number: EudraCT )
First Submitted: April 29, 2013
First Posted: May 1, 2013
Results First Submitted: June 26, 2015
Results First Posted: July 27, 2015
Last Update Posted: July 27, 2015