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Trial record 77 of 187 for:    BI10773

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

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ClinicalTrials.gov Identifier: NCT01304329
Recruitment Status : Completed
First Posted : February 25, 2011
Results First Posted : July 28, 2014
Last Update Posted : July 28, 2014
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: BI 10773
Drug: simvastatin
Enrollment 18
Recruitment Details  
Pre-assignment Details This was a randomised, open label, 3 period crossover study. Treatment periods were separated by a washout period of at least 7 days.
Arm/Group Title Empa Alone / Simvastatin Alone / Empa Plus Sim Empa Alone / Empa Plus Sim / Simvastatin Alone Simvastatin Alone / Empa Alone / Empa Plus Sim Simvastatin Alone / Empa Plus Sim / Empa Alone Empa Plus Sim / Empa Alone / Simvastatin Alone Empa Plus Sim / Simvastatin Alone / Empa Alone
Hide Arm/Group Description

Patients were administered three treatments in the following order:

  • A single dose of empagliflozin 25mg
  • A single dose of simvastatin 40mg
  • A single dose of empagliflozin 25mg together with 40mg simvastatin

Patients were administered three treatments in the following order:

  • A single dose of empagliflozin 25mg
  • A single dose of empagliflozin 25mg together with 40mg simvastatin
  • A single dose of simvastatin 40mg

Patients were administered three treatments in the following order:

  • A single dose of simvastatin 40mg
  • A single dose of empagliflozin 25mg
  • A single dose of empagliflozin 25mg together with 40mg simvastatin

Patients were administered three treatments in the following order:

  • A single dose of simvastatin 40mg
  • A single dose of empagliflozin 25mg together with 40mg simvastatin
  • A single dose of empagliflozin 25mg

Patients were administered three treatments in the following order:

  • A single dose of empagliflozin 25mg together with 40mg simvastatin
  • A single dose of empagliflozin 25mg
  • A single dose of simvastatin 40mg

Patients were administered three treatments in the following order:

  • A single dose of empagliflozin 25mg together with 40mg simvastatin
  • A single dose of simvastatin 40mg
  • A single dose of empagliflozin 25mg
Period Title: First Intervention (3 Days)
Started 3 3 3 3 3 3
Completed 3 3 3 3 3 3
Not Completed 0 0 0 0 0 0
Period Title: Second Intervention (3 Days)
Started 3 3 3 3 3 3
Completed 3 3 3 3 3 3
Not Completed 0 0 0 0 0 0
Period Title: Third Intervention (3 Days)
Started 3 3 3 3 3 3
Completed 3 2 3 3 3 3
Not Completed 0 1 0 0 0 0
Reason Not Completed
Adverse Event             0             1             0             0             0             0
Arm/Group Title Study Overall
Hide Arm/Group Description This was a randomised, 3-period, crossover trial. The trial was open label. The three treatments were separated by a washout period of at least 7 days.
Overall Number of Baseline Participants 18
Hide Baseline Analysis Population Description
Treated Set: All subjects who took at least 1 dose of investigational treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 18 participants
35.9  (8.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants
Female
6
  33.3%
Male
12
  66.7%
1.Primary Outcome
Title Empa: Area Under the Curve 0 to Infinity (AUC0-∞)
Hide Description

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

The geometric mean (gMean) and geometric coefficient of variation (gCV) are adjusted values.

Time Frame 0 hours (h), 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: PK set included all evaluable subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary PK endpoint without important protocol violations relevant to the evaluation of PK.
Arm/Group Title Empa Alone Empa Plus Sim
Hide Arm/Group Description:
25mg empagliflozin (empa) alone
25 mg empagliflozin (empa) together with 40 mg simvastatin (sim)
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
5571.70
(5.4%)
5685.69
(5.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Empa Alone, Empa Plus Sim
Comments Considered characteristic is empa plus simvastatin divided by empa alone
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 102.05
Confidence Interval (2-Sided) 90%
98.90 to 105.29
Parameter Dispersion
Type: Standard Deviation
Value: 5.4
Estimation Comments Standard deviation is actually the geometric coefficient of variation (gCV)
2.Primary Outcome
Title Simvastatin: Area Under the Curve 0 to Infinity (AUC0-∞)
Hide Description

Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. Simvastatin acid is an active metabolite of simvastatin.

The geometric mean (gMean) and geometric coefficient of variation (gCV) are adjusted values.

Time Frame 0 hours (h), 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: PK set included all evaluable subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary PK endpoint without important protocol violations relevant to the evaluation of PK.
Arm/Group Title Simvastatin Alone Empa Plus Sim
Hide Arm/Group Description:
40 mg simvastatin alone
25 mg empagliflozin (empa) together with 40 mg simvastatin (sim)
Overall Number of Participants Analyzed 17 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
AUC of simvastatin
33.51
(40.4%)
33.93
(40.4%)
AUC of simvastatin acid
16.83
(25.5%)
17.65
(25.5%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Simvastatin Alone, Empa Plus Sim
Comments

AUC of simvastatin

Considered characteristic is empa plus simvastatin divided by simvastatin alone

Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 101.26
Confidence Interval (2-Sided) 90%
80.06 to 128.07
Parameter Dispersion
Type: Standard Deviation
Value: 40.4
Estimation Comments Standard deviation is actually the gCV
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Simvastatin Alone, Empa Plus Sim
Comments

AUC of simvastatin acid

Considered characteristic is empa plus simvastatin divided by simvastatin alone.

Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 104.87
Confidence Interval (2-Sided) 90%
90.09 to 122.07
Parameter Dispersion
Type: Standard Deviation
Value: 25.5
Estimation Comments Standard deviation is actually the gCV
3.Primary Outcome
Title Empa: Maximum Measured Concentration (Cmax)
Hide Description

Maximum measured concentration of the analyte in plasma, per period.

The geometric mean and geometric coefficient of variation (gCV) are adjusted values

Time Frame 0 hours (h), 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: PK set included all evaluable subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary PK endpoint without important protocol violations relevant to the evaluation of PK.
Arm/Group Title Empa Alone Empa Plus Sim
Hide Arm/Group Description:
25mg empagliflozin (empa) alone
25 mg empagliflozin (empa) together with 40 mg simvastatin (sim)
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
774.06
(21.1%)
847.49
(21.1%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Empa Alone, Empa Plus Sim
Comments Considered characteristic is empa plus simvastatin divided by empa alone
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 109.49
Confidence Interval (2-Sided) 90%
96.91 to 123.69
Parameter Dispersion
Type: Standard Deviation
Value: 21.1
Estimation Comments Standard deviation is actually the gCV
4.Primary Outcome
Title Simvastatin: Maximum Measured Concentration (Cmax)
Hide Description

Maximum measured concentration of the analyte in plasma, per period.

The geometric mean and geometric coefficient of variation (gCV) are adjusted values.

Time Frame 0 hours (h), 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: PK set included all evaluable subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary PK endpoint without important protocol violations relevant to the evaluation of PK.
Arm/Group Title Simvastatin Alone Empa Plus Sim
Hide Arm/Group Description:
40 mg simvastatin alone
25 mg empagliflozin (empa) together with 40 mg simvastatin (sim)
Overall Number of Participants Analyzed 17 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Cmax of simvastatin
7.88
(41.7%)
7.65
(41.7%)
Cmax of simvastatin acid
1.51
(22.7%)
1.47
(22.7%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Simvastatin Alone, Empa Plus Sim
Comments

Cmax of simvastatin.

Considered characteristic is empa plus simvastatin divided by simvastatin alone.

Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 97.18
Confidence Interval (2-Sided) 90%
76.30 to 123.77
Parameter Dispersion
Type: Standard Deviation
Value: 41.7
Estimation Comments Standard deviation is actually the gCV
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Simvastatin Alone, Empa Plus Sim
Comments

Cmax of simvastatin acid.

Considered characteristic is empa plus simvastatin divided by simvastatin alone.

Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 97.27
Confidence Interval (2-Sided) 90%
84.90 to 111.44
Parameter Dispersion
Type: Standard Deviation
Value: 22.7
Estimation Comments Standard deviation is actually the gCV
5.Secondary Outcome
Title Empa: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)
Hide Description

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

The geometric mean and geometric coefficient of variation (gCV) are adjusted values.

Time Frame 0 hours (h), 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: PK set included all evaluable subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary PK endpoint without important protocol violations relevant to the evaluation of PK.
Arm/Group Title Empa Alone Empa Plus Sim
Hide Arm/Group Description:
25mg empagliflozin (empa) alone
25 mg empagliflozin (empa) together with 40 mg simvastatin (sim)
Overall Number of Participants Analyzed 18 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol*h/L
5481.31
(5.8%)
5619.60
(5.8%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Empa Alone, Empa Plus Sim
Comments Considered characteristic is empa plus simvastatin divided by empa alone.
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 102.52
Confidence Interval (2-Sided) 90%
99.10 to 106.06
Parameter Dispersion
Type: Standard Deviation
Value: 5.8
Estimation Comments Standard deviation is actually the gCV
6.Secondary Outcome
Title Simvastatin: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)
Hide Description

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

The geometric mean and geometric coefficient of variation (gCV) are adjusted values.

Time Frame 0 hours (h), 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) set: PK set included all evaluable subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary PK endpoint without important protocol violations relevant to the evaluation of PK.
Arm/Group Title Simvastatin Alone Empa Plus Sim
Hide Arm/Group Description:
40 mg simvastatin alone
25 mg empagliflozin (empa) together with 40 mg simvastatin (sim)
Overall Number of Participants Analyzed 17 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
AUC of simvastatin
31.82
(41.7%)
32.57
(41.7%)
AUC of simvastatin acid
14.86
(24.8%)
16.53
(24.8%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Simvastatin Alone, Empa Plus Sim
Comments

AUC of simvastatin.

Considered characteristic is empa plus simvastatin divided by simvastatin alone.

Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 102.34
Confidence Interval (2-Sided) 90%
80.39 to 130.29
Parameter Dispersion
Type: Standard Deviation
Value: 41.7
Estimation Comments Standard deviation is actually the gCV
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Simvastatin Alone, Empa Plus Sim
Comments

AUC of simvastatin acid.

Considered characteristic is empa plus simvastatin divided by simvastatin alone.

Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Based on ANOVA with terms for sequence, subjects within sequence, period and treatment.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 111.25
Confidence Interval (2-Sided) 90%
95.93 to 129.02
Parameter Dispersion
Type: Standard Deviation
Value: 24.8
Estimation Comments Standard deviation is actually the gCV
Time Frame First administration of trial medication until next administration of trial medication or up to post-study visit, up to 36 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Empa Alone Simvastatin Alone Empa Plus Sim
Hide Arm/Group Description 25mg empagliflozin (empa) alone 40 mg simvastatin alone 25 mg empagliflozin (empa) together with 40 mg simvastatin (sim)
All-Cause Mortality
Empa Alone Simvastatin Alone Empa Plus Sim
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Empa Alone Simvastatin Alone Empa Plus Sim
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/18 (0.00%)   0/17 (0.00%)   0/18 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Empa Alone Simvastatin Alone Empa Plus Sim
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   6/18 (33.33%)   4/17 (23.53%)   5/18 (27.78%) 
Gastrointestinal disorders       
Abdominal pain  1  0/18 (0.00%)  1/17 (5.88%)  0/18 (0.00%) 
Nausea  1  0/18 (0.00%)  0/17 (0.00%)  1/18 (5.56%) 
Infections and infestations       
Nasopharyngitis  1  2/18 (11.11%)  0/17 (0.00%)  1/18 (5.56%) 
Oral herpes  1  1/18 (5.56%)  0/17 (0.00%)  0/18 (0.00%) 
Purulence  1  0/18 (0.00%)  0/17 (0.00%)  1/18 (5.56%) 
Injury, poisoning and procedural complications       
Laceration  1  0/18 (0.00%)  1/17 (5.88%)  0/18 (0.00%) 
Nervous system disorders       
Headache  1  4/18 (22.22%)  2/17 (11.76%)  2/18 (11.11%) 
Respiratory, thoracic and mediastinal disorders       
Cough  1  0/18 (0.00%)  0/17 (0.00%)  1/18 (5.56%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 14.0
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 Pharmaceuticals
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01304329     History of Changes
Other Study ID Numbers: 1245.63
2010-023680-18 ( EudraCT Number: EudraCT )
First Submitted: February 21, 2011
First Posted: February 25, 2011
Results First Submitted: May 16, 2014
Results First Posted: July 28, 2014
Last Update Posted: July 28, 2014