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Efficacy and Safety of Empagliflozin (BI 10773) in Type 2 Diabetes Patients on a Background of Pioglitazone Alone or With Metformin

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ClinicalTrials.gov Identifier: NCT01210001
Recruitment Status : Completed
First Posted : September 28, 2010
Results First Posted : June 17, 2014
Last Update Posted : June 17, 2014
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double;   Primary Purpose: Treatment
Condition Diabetes Mellitus, Type 2
Interventions Drug: Placebo
Drug: BI 10773
Enrollment 499
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo Empa 10mg Empa 25mg
Hide Arm/Group Description A placebo tablet, matching the empagliflozin 10mg and 25mg tablets, taken once daily for 24 weeks Single oral dose of empagliflozin (empa) 10mg taken once daily for 24 weeks Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks
Period Title: Overall Study
Started 166 165 168
Completed 147 154 156
Not Completed 19 11 12
Reason Not Completed
Not treated             1             0             0
Adverse Event             4             2             5
Non compliant with protocol             2             2             3
Lost to Follow-up             4             3             2
Patient refusal to continue,not due toAE             6             2             1
Other reason not defined above             2             2             1
Arm/Group Title Placebo Empa 10mg Empa 25mg Total
Hide Arm/Group Description A placebo tablet, matching the empagliflozin 10mg and 25mg tablets, taken once daily for 24 weeks Single oral dose of empagliflozin (empa) 10mg taken once daily for 24 weeks Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks Total of all reporting groups
Overall Number of Baseline Participants 165 165 168 498
Hide Baseline Analysis Population Description
Treated set (TS): all patients treated with at least one dose of randomised study medication
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 165 participants 165 participants 168 participants 498 participants
54.6  (10.5) 54.7  (9.9) 54.2  (8.9) 54.5  (9.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 165 participants 165 participants 168 participants 498 participants
Female
92
  55.8%
82
  49.7%
83
  49.4%
257
  51.6%
Male
73
  44.2%
83
  50.3%
85
  50.6%
241
  48.4%
1.Primary Outcome
Title HbA1c Change From Baseline
Hide Description

Change From Baseline in HbA1c after 24 weeks.

Note that adjusted means are provided.

Time Frame Baseline and 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) which included all randomised and treated patients who had a baseline HbA1c value. Values after start of antidiabetic rescue therapy were set to missing and last observation carried forward (LOCF) was used for imputation of missing values.
Arm/Group Title Placebo Empa 10mg Empa 25mg
Hide Arm/Group Description:
A placebo tablet, matching the empagliflozin 10mg and 25mg tablets, taken once daily for 24 weeks
Single oral dose of empagliflozin (empa) 10mg taken once daily for 24 weeks
Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks
Overall Number of Participants Analyzed 165 165 168
Mean (Standard Error)
Unit of Measure: percentage of HbA1c
-0.11  (0.07) -0.59  (0.07) -0.72  (0.07)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Empa 10mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical testing to adjust for multiple comparisons within each dose level, alpha split equally between the doses (2.5%). Empa versus placebo change from baseline in HbA1c was the first step in each hierarchical sequence.
Method ANCOVA
Comments Based on ANCOVA with terms for treatment, background antidiabetic medication, renal function at baseline and baseline HbA1c.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.48
Confidence Interval (2-Sided) 97.5%
-0.69 to -0.27
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.09
Estimation Comments Difference calculated as empa 10mg minus placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Empa 25mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical testing to adjust for multiple comparisons within each dose level, alpha split equally between the doses (2.5%). Empa versus placebo change from baseline in HbA1c was the first step in each hierarchical sequence.
Method ANCOVA
Comments Based on ANCOVA with terms for treatment, background antidiabetic medication, renal function at baseline and baseline HbA1c.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.61
Confidence Interval (2-Sided) 97.5%
-0.82 to -0.40
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.09
Estimation Comments Difference calculated as empa 25mg minus placebo
2.Primary Outcome
Title HbA1c Change From Baseline for Pio and Met Background Medication Patients
Hide Description

Change From Baseline in HbA1c after 24 weeks for patients with pioglitazone (pio) and metformin (met) background medication only.

Note that adjusted means are provided.

Time Frame Baseline and 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) which included all randomised and treated patients who had a baseline HbA1c value for patients on pioglitazone and metformin background medication. Values after start of antidiabetic rescue therapy were set to missing and last observation carried forward (LOCF) was used for imputation of missing values.
Arm/Group Title Placebo Empa 10mg Empa 25mg
Hide Arm/Group Description:
A placebo tablet, matching the empagliflozin 10mg and 25mg tablets, taken once daily for 24 weeks
Single oral dose of empagliflozin (empa) 10mg taken once daily for 24 weeks
Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks
Overall Number of Participants Analyzed 124 125 127
Mean (Standard Error)
Unit of Measure: percentage of HbA1c
-0.11  (0.08) -0.55  (0.08) -0.70  (0.07)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Empa 10mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical testing to adjust for multiple comparisons within each dose level, alpha split equally between the doses (2.5%). Empa vs placebo change from baseline in HbA1c for pio+met background only was the fourth step in each hierarchical sequence.
Method ANCOVA
Comments Based on ANCOVA with terms for treatment, background antidiabetic medication, renal function at baseline and baseline HbA1c.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.45
Confidence Interval (2-Sided) 97.5%
-0.69 to -0.21
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.11
Estimation Comments Difference calculated as empa 10mg minus placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Empa 25mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical testing to adjust for multiple comparisons within each dose level, alpha split equally between the doses (2.5%). Empa vs placebo change from baseline in HbA1c for pio+met background only was the fourth step in each hierarchical sequence.
Method ANCOVA
Comments Based on ANCOVA with terms for treatment, background antidiabetic medication, renal function at baseline and baseline HbA1c.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.60
Confidence Interval (2-Sided) 97.5%
-0.83 to -0.36
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.11
Estimation Comments Difference calculated as empa 25mg minus placebo
3.Secondary Outcome
Title Fasting Plasma Glucose (FPG) Change From Baseline
Hide Description

Change from baseline in fasting plasma glucose (FPG) after 24 weeks of treatment.

Note that adjusted means are provided.

Time Frame Baseline and 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) which included all randomised and treated patients who had a baseline HbA1c value. Values after start of antidiabetic rescue therapy were set to missing and last observation carried forward (LOCF) was used for imputation of missing values.
Arm/Group Title Placebo Empa 10mg Empa 25mg
Hide Arm/Group Description:
A placebo tablet, matching the empagliflozin 10mg and 25mg tablets, taken once daily for 24 weeks
Single oral dose of empagliflozin (empa) 10mg taken once daily for 24 weeks
Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks
Overall Number of Participants Analyzed 165 163 168
Mean (Standard Error)
Unit of Measure: mg/dL
6.47  (2.61) -17.00  (2.63) -21.99  (2.59)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Empa 10mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical testing to adjust for multiple comparisons within each dose level, alpha split equally between the doses (2.5%). Empa versus placebo change from baseline in FPG was the second step in each hierarchical sequence.
Method ANCOVA
Comments Based on ANCOVA with terms for treatment, background antidiabetic medication, renal function at baseline, baseline HbA1c and baseline FPG
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -23.48
Confidence Interval (2-Sided) 97.5%
-31.81 to -15.15
Parameter Dispersion
Type: Standard Error of the mean
Value: 3.71
Estimation Comments Difference calculated as empa 10mg minus placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Empa 25mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical testing to adjust for multiple comparisons within each dose level, alpha split equally between the doses (2.5%). Empa versus placebo change from baseline in FPG was the second step in each hierarchical sequence.
Method ANCOVA
Comments Based on ANCOVA with terms for treatment, background antidiabetic medication, renal function at baseline, baseline HbA1c and baseline FPG
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -28.46
Confidence Interval (2-Sided) 97.5%
-36.73 to -20.19
Parameter Dispersion
Type: Standard Error of the mean
Value: 3.68
Estimation Comments Difference calculated as empa 25mg minus placebo
4.Secondary Outcome
Title Body Weight Change From Baseline
Hide Description

Change from baseline in body weight after 24 weeks.

Note that adjusted means are provided.

Time Frame Baseline and 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) which included all randomised and treated patients who had a baseline HbA1c value. Values after start of antidiabetic rescue therapy were set to missing and last observation carried forward (LOCF) was used for imputation of missing values.
Arm/Group Title Placebo Empa 10mg Empa 25mg
Hide Arm/Group Description:
A placebo tablet, matching the empagliflozin 10mg and 25mg tablets, taken once daily for 24 weeks
Single oral dose of empagliflozin (empa) 10mg taken once daily for 24 weeks
Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks
Overall Number of Participants Analyzed 165 165 168
Mean (Standard Error)
Unit of Measure: kg
0.34  (0.21) -1.62  (0.21) -1.47  (0.21)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Empa 10mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical testing to adjust for multiple comparisons within each dose level, alpha split equally between the doses (2.5%). Empa versus placebo change from baseline in body weight was the third step in each hierarchical sequence.
Method ANCOVA
Comments Based on ANCOVA with terms for treatment, background antidiabetic medication, renal function at baseline, baseline HbA1c and baseline weight
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.95
Confidence Interval (2-Sided) 97.5%
-2.64 to -1.27
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.30
Estimation Comments Difference calculated as empa 10mg minus placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Empa 25mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Hierarchical testing to adjust for multiple comparisons within each dose level, alpha split equally between the doses (2.5%). Empa versus placebo change from baseline in body weight was the third step in each hierarchical sequence.
Method ANCOVA
Comments Based on ANCOVA with terms for treatment, background antidiabetic medication, renal function at baseline, baseline HbA1c and baseline weight
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.81
Confidence Interval (2-Sided) 97.5%
-2.49 to -1.13
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.30
Estimation Comments Difference calculated as empa 25mg minus placebo
5.Other Pre-specified Outcome
Title Hypoglycaemic Events
Hide Description Number of patients with hypoglycaemic events, as reported as adverse events.
Time Frame From first drug administration until 7 days after last intake of study drug, up to 256 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Treated set which included all patients treated with at least one dose of randomised study medication
Arm/Group Title Placebo Empa 10mg Empa 25mg
Hide Arm/Group Description:
A placebo tablet, matching the empagliflozin 10mg and 25mg tablets, taken once daily for 24 weeks
Single oral dose of empagliflozin (empa) 10mg taken once daily for 24 weeks
Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks
Overall Number of Participants Analyzed 165 165 168
Measure Type: Number
Unit of Measure: percentage of participants
1.8 1.2 2.4
Time Frame From first dose of randomised study medication until 7 days after the last dose, up to 256 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Empa 10mg Empa 25mg
Hide Arm/Group Description A placebo tablet, matching the empagliflozin 10mg and 25mg tablets, taken once daily for 24 weeks Single oral dose of empagliflozin (empa) 10mg taken once daily for 24 weeks Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks
All-Cause Mortality
Placebo Empa 10mg Empa 25mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Empa 10mg Empa 25mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   7/165 (4.24%)   7/165 (4.24%)   6/168 (3.57%) 
Cardiac disorders       
Atrial fibrillation  1  0/165 (0.00%)  0/165 (0.00%)  1/168 (0.60%) 
Atrial flutter  1  0/165 (0.00%)  0/165 (0.00%)  1/168 (0.60%) 
Cardio-respiratory arrest  1  0/165 (0.00%)  0/165 (0.00%)  1/168 (0.60%) 
Myocardial ischaemia  1  1/165 (0.61%)  0/165 (0.00%)  1/168 (0.60%) 
Eye disorders       
Diabetic retinopathy  1  0/165 (0.00%)  1/165 (0.61%)  0/168 (0.00%) 
Gastrointestinal disorders       
Anal fissure  1  1/165 (0.61%)  0/165 (0.00%)  0/168 (0.00%) 
Constipation  1  1/165 (0.61%)  0/165 (0.00%)  0/168 (0.00%) 
Oesophageal rupture  1  0/165 (0.00%)  0/165 (0.00%)  1/168 (0.60%) 
Hepatobiliary disorders       
Cholecystitis  1  0/165 (0.00%)  1/165 (0.61%)  0/168 (0.00%) 
Cholecystitis acute  1  1/165 (0.61%)  0/165 (0.00%)  0/168 (0.00%) 
Infections and infestations       
Amoebic colitis  1  0/165 (0.00%)  1/165 (0.61%)  0/168 (0.00%) 
Cellulitis  1  0/165 (0.00%)  1/165 (0.61%)  1/168 (0.60%) 
Dengue fever  1  0/165 (0.00%)  0/165 (0.00%)  1/168 (0.60%) 
Pseudomonas infection  1  0/165 (0.00%)  0/165 (0.00%)  1/168 (0.60%) 
Pyelonephritis acute  1  1/165 (0.61%)  0/165 (0.00%)  0/168 (0.00%) 
Septic shock  1  0/165 (0.00%)  0/165 (0.00%)  1/168 (0.60%) 
Urosepsis  1  0/165 (0.00%)  1/165 (0.61%)  0/168 (0.00%) 
Injury, poisoning and procedural complications       
Hand fracture  1  1/165 (0.61%)  0/165 (0.00%)  0/168 (0.00%) 
Humerus fracture  1  1/165 (0.61%)  0/165 (0.00%)  0/168 (0.00%) 
Road traffic accident  1  1/165 (0.61%)  0/165 (0.00%)  0/168 (0.00%) 
Traumatic fracture  1  1/165 (0.61%)  0/165 (0.00%)  0/168 (0.00%) 
Investigations       
Haemoglobin decreased  1  1/165 (0.61%)  0/165 (0.00%)  1/168 (0.60%) 
Musculoskeletal and connective tissue disorders       
Arthralgia  1  0/165 (0.00%)  1/165 (0.61%)  0/168 (0.00%) 
Joint swelling  1  0/165 (0.00%)  1/165 (0.61%)  0/168 (0.00%) 
Musculoskeletal chest pain  1  0/165 (0.00%)  1/165 (0.61%)  0/168 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Breast cancer  1  0/165 (0.00%)  0/165 (0.00%)  1/168 (0.60%) 
Nervous system disorders       
Brain stem infarction  1  0/165 (0.00%)  0/165 (0.00%)  1/168 (0.60%) 
Skin and subcutaneous tissue disorders       
Skin ulcer  1  1/165 (0.61%)  0/165 (0.00%)  0/168 (0.00%) 
Vascular disorders       
Haematoma  1  0/165 (0.00%)  0/165 (0.00%)  1/168 (0.60%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 15.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Empa 10mg Empa 25mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   56/165 (33.94%)   50/165 (30.30%)   34/168 (20.24%) 
Infections and infestations       
Urinary tract infection  1  18/165 (10.91%)  24/165 (14.55%)  18/168 (10.71%) 
Metabolism and nutrition disorders       
Dyslipidaemia  1  17/165 (10.30%)  18/165 (10.91%)  12/168 (7.14%) 
Hyperglycaemia  1  26/165 (15.76%)  8/165 (4.85%)  4/168 (2.38%) 
Vascular disorders       
Hypertension  1  9/165 (5.45%)  3/165 (1.82%)  2/168 (1.19%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 15.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
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: NCT01210001     History of Changes
Other Study ID Numbers: 1245.19
2009-016154-40 ( EudraCT Number: EudraCT )
First Submitted: September 27, 2010
First Posted: September 28, 2010
Results First Submitted: May 16, 2014
Results First Posted: June 17, 2014
Last Update Posted: June 17, 2014