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Bioequivalence of a Fixed Dose Combination Tablet of Empagliflozin/Metformin Extended Release Compared With Mono Compound Tablets in Healthy Male and Female

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ClinicalTrials.gov Identifier: NCT02266472
Recruitment Status : Completed
First Posted : October 17, 2014
Results First Posted : March 9, 2017
Last Update Posted : March 9, 2017
Sponsor:
Collaborator:
Eli Lilly and Company
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: metformin
Drug: empagliflozin/metformin
Drug: empagliflozin
Enrollment 30
Recruitment Details  
Pre-assignment Details This was an open-label, randomised, 2-way crossover trial with 2 treatments (T and R) and 2 treatment sequences (T_R and R_T). Trial drug administrations of the 2 single dose treatments were separated by a washout period of at least 7 days.
Arm/Group Title Fed 10mg+1000mg Fixed Dose Combination (FDC)/Single (TR) Fed 10mg+1000mg Single/FDC (RT)
Hide Arm/Group Description Subjects received in period 1 a single dose of 10 mg empagliflozin/1000 mg metformin hydrochloride (HCl) extended release (XR) (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal, followed in period 2 with a single dose of 10 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal. 2 treatments separated by a wash-out period of at least 7 days. Subjects received in period 1 a single dose of 10 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal, followed in period 2 with a single dose of 10 mg empagliflozin/1000 mg metformin HCl XR (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal. 2 treatments separated by a wash-out period of at least 7 days.
Period Title: Period 1+ Washout
Started 15 15
Completed 15 15
Not Completed 0 0
Period Title: Period 2+ Washout
Started 15 15
Completed 15 15
Not Completed 0 0
Arm/Group Title Fed 10mg+1000mg FDC/Single (TR) Fed 10mg+1000mg Single/FDC (RT) Total
Hide Arm/Group Description Subjects received in period 1 a single dose of 10 mg empagliflozin/1000 mg metformin hydrochloride (HCl) extended release (XR) (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal, followed in period 2 with a single dose of 10 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal. 2 treatments separated by a wash-out period of at least 7 days. Subjects received in period 1 a single dose of 10 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal, followed in period 2 with a single dose of 10 mg empagliflozin/1000 mg metformin HCl XR (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal. 2 treatments separated by a wash-out period of at least 7 days. Total of all reporting groups
Overall Number of Baseline Participants 15 15 30
Hide Baseline Analysis Population Description
Treated set (TS): The TS was made up of all randomised subjects who were documented to have received the trial medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 15 participants 15 participants 30 participants
33.5  (8.1) 33.7  (10.1) 33.6  (9.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 15 participants 15 participants 30 participants
Female
6
  40.0%
8
  53.3%
14
  46.7%
Male
9
  60.0%
7
  46.7%
16
  53.3%
1.Primary Outcome
Title AUC0-tz of Empagliflozin in Plasma
Hide Description Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz)
Time Frame -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic set (PKS) included all treated subjects that provided at least 1 observation for at least 1 primary endpoint without important protocol violations with respect to the statistical evaluation of the pharmacokinetic endpoints.
Arm/Group Title Fed 10mg+ 1000mg FDC (T) Fed 10mg+1000mg Single (R)
Hide Arm/Group Description:
Subjects received a single dose of 10 mg empagliflozin/1000 mg metformin HCl XR (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.
Subjects received a single dose of 10 mg empagliflozin (1 tablet) together with a single dose of 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.
Overall Number of Participants Analyzed 30 30
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
2190
(18.1%)
2210
(16.3%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fed 10mg+ 1000mg FDC (T), Fed 10mg+1000mg Single (R)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The assessment of bioequivalence was based on 2-sided 90% CIs for the ratios (test to reference treatment) of the adjusted gMeans of the primary endpoints, with acceptance range of 80.00 to 125.00 %.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model on the logarithmic scale including random effects for ‘subjects within sequences’ & fixed effect for ‘sequence’, ‘period’ & ‘treatment’.
Method of Estimation Estimation Parameter ratio of the adjusted means
Estimated Value 99.11
Confidence Interval (2-Sided) 90%
96.40 to 101.89
Parameter Dispersion
Type: Standard Deviation
Value: 6.3
Estimation Comments Relative bioavailability of empagliflozin was estimated by the adjusted gMean ratio of Fed 10mg+1000mg FDC divided by Fed 10mg+1000mg Single. Standard deviation is actually intraindividual geometric coefficient variation (gCV).
2.Primary Outcome
Title AUC0-tz of Metformin in Plasma
Hide Description Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz)
Time Frame -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title Fed 10mg+ 1000mg FDC (T) Fed 10mg+1000mg Single (R)
Hide Arm/Group Description:
Subjects received a single dose of 10 mg empagliflozin/1000 mg metformin HCl XR (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.
Subjects received a single dose of 10 mg empagliflozin (1 tablet) together with a single dose of 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.
Overall Number of Participants Analyzed 29 30
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
10800
(20.1%)
10700
(22.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fed 10mg+ 1000mg FDC (T), Fed 10mg+1000mg Single (R)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The assessment of bioequivalence was based on 2-sided 90% confidence intervals (CIs) for the ratios (test to reference treatment) of the adjusted geometric means (gMeans) of the primary endpoints,using an acceptance range of 80.00 to 125.00 %.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model on the logarithmic scale including random effects for ‘subjects within sequences’ & fixed effect for ‘sequence’, ‘period’ & ‘treatment’.
Method of Estimation Estimation Parameter ratio of the adjusted means
Estimated Value 101.25
Confidence Interval (2-Sided) 90%
96.54 to 106.19
Parameter Dispersion
Type: Standard Deviation
Value: 10.7
Estimation Comments Relative bioavailability of metformin was estimated by the adjusted gMean ratio of Fed 10mg+1000mg FDC divided by Fed 10mg+1000mg Single. Standard deviation is actually intraindividual geometric coefficient variation (gCV).
3.Primary Outcome
Title Cmax of Empagliflozin in Plasma
Hide Description Maximum measured concentration of the empagliflozin in plasma
Time Frame -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title Fed 10mg+ 1000mg FDC (T) Fed 10mg+1000mg Single (R)
Hide Arm/Group Description:
Subjects received a single dose of 10 mg empagliflozin/1000 mg metformin HCl XR (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.
Subjects received a single dose of 10 mg empagliflozin (1 tablet) together with a single dose of 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.
Overall Number of Participants Analyzed 30 30
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
243
(23.1%)
245
(20.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fed 10mg+ 1000mg FDC (T), Fed 10mg+1000mg Single (R)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The assessment of bioequivalence was based on 2-sided 90% CIs for the ratios (test to reference treatment) of the adjusted gMeans of the primary endpoints, with acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model on the logarithmic scale including random effects for ‘subjects within sequences’ & fixed effect for ‘sequence’, ‘period’ & ‘treatment’.
Method of Estimation Estimation Parameter ratio of the adjusted means
Estimated Value 99.12
Confidence Interval (2-Sided) 90%
93.69 to 104.87
Parameter Dispersion
Type: Standard Deviation
Value: 12.9
Estimation Comments Relative bioavailability of empagliflozin was estimated by the adjusted gMean ratio of Fed10mg+1000mg FDC divided by Fed10mg+1000mg Single. Standard deviation is actually intraindividual geometric coefficient variation (gCV).
4.Primary Outcome
Title Cmax of Metformin in Plasma
Hide Description Maximum measured concentration of the metformin in plasma
Time Frame -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title Fed 10mg+ 1000mg FDC (T) Fed 10mg+1000mg Single (R)
Hide Arm/Group Description:
Subjects received a single dose of 10 mg empagliflozin/1000 mg metformin HCl XR (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.
Subjects received a single dose of 10 mg empagliflozin (1 tablet) together with a single dose of 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.
Overall Number of Participants Analyzed 29 30
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
1170
(25.5%)
1080
(25.2%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fed 10mg+ 1000mg FDC (T), Fed 10mg+1000mg Single (R)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The assessment of bioequivalence was based on 2-sided 90% CIs for the ratios (test to reference treatment) of the adjusted gMeans of the primary endpoints, with acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments ANOVA model on the logarithmic scale including random effects for ‘subjects within sequences’ & fixed effect for ‘sequence’, ‘period’ & ‘treatment’.
Method of Estimation Estimation Parameter ratio of the adjusted means
Estimated Value 108.58
Confidence Interval (2-Sided) 90%
104.17 to 113.17
Parameter Dispersion
Type: Standard Deviation
Value: 9.3
Estimation Comments Relative bioavailability of metformin was estimated by the adjusted gMean ratio of Fed10mg+1000mg FDC divided by Fed10mg+1000mg Single. Standard deviation is actually intraindividual geometric coefficient variation (gCV).
5.Secondary Outcome
Title AUC0-infinity of Empagliflozin in Plasma
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
Time Frame -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title Fed 10mg+ 1000mg FDC (T) Fed 10mg+1000mg Single (R)
Hide Arm/Group Description:
Subjects received a single dose of 10 mg empagliflozin/1000 mg metformin HCl XR (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.
Subjects received a single dose of 10 mg empagliflozin (1 tablet) together with a single dose of 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.
Overall Number of Participants Analyzed 30 30
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
2230
(18.0%)
2260
(16.3%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fed 10mg+ 1000mg FDC (T), Fed 10mg+1000mg Single (R)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The assessment of bioequivalence was based on 2-sided 90% CIs for the ratios (test to reference treatment) of the adjusted gMeans of the primary endpoints, with acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments ANOVA model on the logarithmic scale including random effects for ‘subjects within sequences’ & fixed effect for ‘sequence’, ‘period’ & ‘treatment’.
Method of Estimation Estimation Parameter ratio of the adjusted means
Estimated Value 98.89
Confidence Interval (2-Sided) 90%
96.18 to 101.67
Parameter Dispersion
Type: Standard Deviation
Value: 6.3
Estimation Comments Relative bioavailability of empagliflozin was estimated by the adjusted gMean ratio of Fed10mg+1000mg FDC divided by Fed10mg+1000mg Single. Standard deviation is actually intraindividual geometric coefficient variation (gCV).
6.Secondary Outcome
Title AUC0-infinity of Metformin in Plasma
Hide Description Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
Time Frame -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title Fed 10mg+ 1000mg FDC (T) Fed 10mg+1000mg Single (R)
Hide Arm/Group Description:
Subjects received a single dose of 10 mg empagliflozin/1000 mg metformin HCl XR (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.
Subjects received a single dose of 10 mg empagliflozin (1 tablet) together with a single dose of 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.
Overall Number of Participants Analyzed 29 30
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
11000
(20.8%)
10800
(22.7%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fed 10mg+ 1000mg FDC (T), Fed 10mg+1000mg Single (R)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The assessment of bioequivalence was based on 2-sided 90% CIs for the ratios (test to reference treatment) of the adjusted gMeans of the primary endpoints, with acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments ANOVA model on the logarithmic scale including random effects for ‘subjects within sequences’ & fixed effect for ‘sequence’, ‘period’ & ‘treatment’.
Method of Estimation Estimation Parameter ratio of the adjusted means
Estimated Value 101.37
Confidence Interval (2-Sided) 90%
96.53 to 106.45
Parameter Dispersion
Type: Standard Deviation
Value: 11.0
Estimation Comments Relative bioavailability of metformin was estimated by the adjusted gMean ratio of Fed10mg+1000mg FDC divided by Fed10mg+1000mg Single. Standard deviation is actually intraindividual geometric coefficient variation (gCV).
Time Frame From first drug administration until the end-of-trial examination (Up to 14 days)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Fed 10mg+1000mg Single (R) Fed 10mg+ 1000mg FDC (T)
Hide Arm/Group Description Subjects received a single dose of 10 mg empagliflozin (1 tablet) together with a single dose of 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal. Subjects received a single dose of 10 mg empagliflozin/1000 mg metformin HCl XR (1 tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.
All-Cause Mortality
Fed 10mg+1000mg Single (R) Fed 10mg+ 1000mg FDC (T)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Fed 10mg+1000mg Single (R) Fed 10mg+ 1000mg FDC (T)
Affected / at Risk (%) Affected / at Risk (%)
Total   0/30 (0.00%)   0/30 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Fed 10mg+1000mg Single (R) Fed 10mg+ 1000mg FDC (T)
Affected / at Risk (%) Affected / at Risk (%)
Total   9/30 (30.00%)   5/30 (16.67%) 
Gastrointestinal disorders     
Diarrhoea  1  2/30 (6.67%)  1/30 (3.33%) 
Nausea  1  2/30 (6.67%)  0/30 (0.00%) 
Nervous system disorders     
Headache  1  5/30 (16.67%)  4/30 (13.33%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, 17.1
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: 800-243-0127 ext +1
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02266472     History of Changes
Other Study ID Numbers: 1276.28
2014-002360-32 ( EudraCT Number: EudraCT )
First Submitted: October 16, 2014
First Posted: October 17, 2014
Results First Submitted: January 19, 2017
Results First Posted: March 9, 2017
Last Update Posted: March 9, 2017