Safety and Efficacy of the Combination of Empagliflozin and Linagliptin Compared to Linagliptin Alone Over 24 Weeks in Patients With Type 2 Diabetes

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01734785
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 607
• Locations: 90
• Arms: 3
• Duration (Months): 25.9
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This trial compare the use of two different doses of Empagliflozin to placebo, in T2DM patients on 16 wks linagliptin treatment and metformin background therapy.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Linagliptin; Drug: Empagliflozin + Linagliptin; Drug: Empagliflozin + Linagliptin; Drug: Empagliflozin + Linagliptin; Drug: Empaglifozin placebo + Linagliptin placebo; Drug: Empagliflozin + Linagliptin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 607 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomised, Double-blind, Parallel Group, 24 Week Study to Evaluate Efficacy and Safety of Once Daily Empagliflozin 10 mg and 25 mg Compared to Placebo, All Administered as Oral Fixed Dose Combinations With Linagliptin 5 mg, in Patients With Type 2 Diabetes Mellitus and Insufficient Glycaemic Control After 16 Weeks Treatment With Linagliptin 5 mg Once Daily on Metformin Background Therapy.
• Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Linagliptin 5 mg once daily	Drug: Linagliptin; tablet; Drug: Empaglifozin placebo + Linagliptin placebo; Matching Empaglifozin + Linagliptin low dose
Experimental: Empaglifozin + Linagliptin low dose 1 tablet once daily	Drug: Empagliflozin + Linagliptin; Fixed dose combination.; Drug: Empagliflozin + Linagliptin; Fixed dose combination
Experimental: Empagliflozin + Linagliptin high dose 1 tablet once daily	Drug: Empagliflozin + Linagliptin; Fixed dose combination; Drug: Empagliflozin + Linagliptin; Fixed dose combination.

Outcome Measures

Primary Outcome Measures

1. HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment [Baseline and 24 weeks]

   Change from baseline in Glycated haemoglobin (HbA1c) [%] after 24 weeks of treatment with double-blind trial medication. Baseline was defined as the last observation before the first intake of any double-blind randomised trial medication. The term 'baseline' was not used to refer to measurements before the administration of open-label medication.

Secondary Outcome Measures

1. Fasting Plasma Glucose (FPG) Change From Baseline After 24 Weeks of Double-blind Treatment. [Baseline and 24 weeks]

   Change from baseline FPG (mmol/L) after 24 weeks of treatment with double-blind trial medication.

2. Body Weight Change From Baseline After 24 Weeks of Double-blind Treatment [Baseline and 24 weeks]

   Change from baseline Body weight after 24 weeks of treatment with double-blind trial medication.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Diagnosis of type 2 diabetes mellitus.

2. Male and female patients on diet and exercise regimen, pre-treated with immediate release metformin for at least 12 weeks, and patients should be on a dose higher or equal to 1500 mg/day of metformin, or maximum tolerated dose, or maximum dose as per local label.

3. HbA1c higher or equal to 8.0% and lower or equal to 10.5% at screening visit.

4. Age 18 years or more at screening.

5. Body Mass Index lower or equal to 45 kg/m2 at screening visit.

6. Signed and dated written informed consent.

Exclusion criteria:

1. Uncontrolled hyperglycemia with glucose level above 270 mg/dl (above 15 mmol/dl) after an overnight fast.

2. Use of any other antidiabetic drug (except metformin background therapy).

3. Acute coronary syndrome, stroke or TIA within 3 months prior to informed consent.

4. Indication of liver disease.

5. Impaired renal function.

6. Gastrointestinal surgery.

7. Treatment with anti-obesity drugs within 3 months prior to screening, or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight.

8. Current treatment with systemic steroids at time of informed consent or uncontrolled endocrine disorder except type 2 diabetes mellitus.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1275.9.01013 Boehringer Ingelheim Investigational Site	Gulf Shores	Alabama	United States
2	1275.9.01009 Boehringer Ingelheim Investigational Site	Norwalk	California	United States
3	1275.9.01015 Boehringer Ingelheim Investigational Site	San Diego	California	United States
4	1275.9.01017 Boehringer Ingelheim Investigational Site	San Diego	California	United States
5	1275.9.01011 Boehringer Ingelheim Investigational Site	Northglenn	Colorado	United States
6	1275.9.01010 Boehringer Ingelheim Investigational Site	Coral Gables	Florida	United States
7	1275.9.01004 Boehringer Ingelheim Investigational Site	Miami	Florida	United States
8	1275.9.01006 Boehringer Ingelheim Investigational Site	Oldsmar	Florida	United States
9	1275.9.01001 Boehringer Ingelheim Investigational Site	Palm Coast	Florida	United States
10	1275.9.01027 Boehringer Ingelheim Investigational Site	Port Orange	Florida	United States
11	1275.9.01029 Boehringer Ingelheim Investigational Site	Blue Ridge	Georgia	United States
12	1275.9.01003 Boehringer Ingelheim Investigational Site	Marietta	Georgia	United States
13	1275.9.01022 Boehringer Ingelheim Investigational Site	Savannah	Georgia	United States
14	1275.9.01031 Boehringer Ingelheim Investigational Site	Chicago	Illinois	United States
15	1275.9.01019 Boehringer Ingelheim Investigational Site	Methuen	Massachusetts	United States
16	1275.9.01024 Boehringer Ingelheim Investigational Site	Troy	Michigan	United States
17	1275.9.01023 Boehringer Ingelheim Investigational Site	St. Louis	Missouri	United States
18	1275.9.01002 Boehringer Ingelheim Investigational Site	Omaha	Nebraska	United States
19	1275.9.01007 Boehringer Ingelheim Investigational Site	Newington	New Hampshire	United States
20	1275.9.01016 Boehringer Ingelheim Investigational Site	Asheboro	North Carolina	United States
21	1275.9.01025 Boehringer Ingelheim Investigational Site	Burlington	North Carolina	United States
22	1275.9.01014 Boehringer Ingelheim Investigational Site	Shelby	North Carolina	United States
23	1275.9.01028 Boehringer Ingelheim Investigational Site	Winston-Salem	North Carolina	United States
24	1275.9.01018 Boehringer Ingelheim Investigational Site	Dayton	Ohio	United States
25	1275.9.01005 Boehringer Ingelheim Investigational Site	Corvallis	Oregon	United States
26	1275.9.01032 Boehringer Ingelheim Investigational Site	Corpus Christi	Texas	United States
27	1275.9.01030 Boehringer Ingelheim Investigational Site	Houston	Texas	United States
28	1275.9.01021 Boehringer Ingelheim Investigational Site	San Antonio	Texas	United States
29	1275.9.61009 Boehringer Ingelheim Investigational Site	Liverpool	New South Wales	Australia
30	1275.9.61001 Boehringer Ingelheim Investigational Site	St Leonards	New South Wales	Australia
31	1275.9.61003 Boehringer Ingelheim Investigational Site	Carina Heights	Queensland	Australia
32	1275.9.61002 Boehringer Ingelheim Investigational Site	Herston	Queensland	Australia
33	1275.9.61006 Boehringer Ingelheim Investigational Site	Malvern	Victoria	Australia
34	1275.9.61007 Boehringer Ingelheim Investigational Site	Nedlands	Western Australia	Australia
35	1275.9.55002 Boehringer Ingelheim Investigational Site	Brasilia		Brazil
36	1275.9.55005 Boehringer Ingelheim Investigational Site	Goiania		Brazil
37	1275.9.55001 Boehringer Ingelheim Investigational Site	Sao Paulo		Brazil
38	1275.9.55003 Boehringer Ingelheim Investigational Site	Sao Paulo		Brazil
39	1275.9.55004 Boehringer Ingelheim Investigational Site	Sao Paulo		Brazil
40	1275.9.01101 Boehringer Ingelheim Investigational Site	Burnaby	British Columbia	Canada
41	1275.9.01103 Boehringer Ingelheim Investigational Site	Victoria	British Columbia	Canada
42	1275.9.01105 Boehringer Ingelheim Investigational Site	Cornwall	Ontario	Canada
43	1275.9.01106 Boehringer Ingelheim Investigational Site	Hamilton	Ontario	Canada
44	1275.9.01104 Boehringer Ingelheim Investigational Site	Toronto	Ontario	Canada
45	1275.9.01102 Boehringer Ingelheim Investigational Site	Waterloo	Ontario	Canada
46	1275.9.34008 Boehringer Ingelheim Investigational Site	Barcelona		El Salvador
47	1275.9.33006 Boehringer Ingelheim Investigational Site	Bourg des Comptes		France
48	1275.9.33008 Boehringer Ingelheim Investigational Site	Dessenheim		France
49	1275.9.33003 Boehringer Ingelheim Investigational Site	La Riche		France
50	1275.9.33012 Boehringer Ingelheim Investigational Site	Paris		France
51	1275.9.33002 Boehringer Ingelheim Investigational Site	Saint Avertin		France
52	1275.9.33005 Boehringer Ingelheim Investigational Site	Savonnieres		France
53	1275.9.33004 Boehringer Ingelheim Investigational Site	Tours		France
54	1275.9.82006 Boehringer Ingelheim Investigational Site	Daejeon		Korea, Republic of
55	1275.9.82009 Boehringer Ingelheim Investigational Site	Deagu		Korea, Republic of
56	1275.9.82002 Boehringer Ingelheim Investigational Site	Goyang		Korea, Republic of
57	1275.9.82004 Boehringer Ingelheim Investigational Site	Seongnam		Korea, Republic of
58	1275.9.82001 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
59	1275.9.82005 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
60	1275.9.82007 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
61	1275.9.82008 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
62	1275.9.82010 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
63	1275.9.64005 Boehringer Ingelheim Investigational Site	Auckland, New Zealand		New Zealand
64	1275.9.64006 Boehringer Ingelheim Investigational Site	Auckland, New Zealand		New Zealand
65	1275.9.64008 Boehringer Ingelheim Investigational Site	Birkenhead Auckland		New Zealand
66	1275.9.64007 Boehringer Ingelheim Investigational Site	Christchurch Central		New Zealand
67	1275.9.64004 Boehringer Ingelheim Investigational Site	Christchurch, New Zealand		New Zealand
68	1275.9.64002 Boehringer Ingelheim Investigational Site	Otahuhu Auckland		New Zealand
69	1275.9.64001 Boehringer Ingelheim Investigational Site	Takapuna Auckland		New Zealand
70	1275.9.64003 Boehringer Ingelheim Investigational Site	Tauranga, New Zealand		New Zealand
71	1275.9.47001 Boehringer Ingelheim Investigational Site	Bergen		Norway
72	1275.9.47002 Boehringer Ingelheim Investigational Site	Oslo		Norway
73	1275.9.47003 Boehringer Ingelheim Investigational Site	Oslo		Norway
74	1275.9.47007 Boehringer Ingelheim Investigational Site	Oslo		Norway
75	1275.9.47006 Boehringer Ingelheim Investigational Site	Svelvik		Norway
76	1275.9.34011 Boehringer Ingelheim Investigational Site	A Coruña		Spain
77	1275.9.34009 Boehringer Ingelheim Investigational Site	Alicante		Spain
78	1275.9.34005 Boehringer Ingelheim Investigational Site	Badía del Vallès - Barcelona		Spain
79	1275.9.34001 Boehringer Ingelheim Investigational Site	Barcelona		Spain
80	1275.9.34003 Boehringer Ingelheim Investigational Site	Barcelona		Spain
81	1275.9.34004 Boehringer Ingelheim Investigational Site	Barcelona		Spain
82	1275.9.34002 Boehringer Ingelheim Investigational Site	Sevilla		Spain
83	1275.9.34010 Boehringer Ingelheim Investigational Site	Valencia		Spain
84	1275.9.34006 Boehringer Ingelheim Investigational Site	Vic		Spain
85	1275.9.88606 Boehringer Ingelheim Investigational Site	Kaohsiung		Taiwan
86	1275.9.88607 Boehringer Ingelheim Investigational Site	Kaohsiung		Taiwan
87	1275.9.88602 Boehringer Ingelheim Investigational Site	New Taipei		Taiwan
88	1275.9.88603 Boehringer Ingelheim Investigational Site	Taichung		Taiwan
89	1275.9.88604 Boehringer Ingelheim Investigational Site	Taichung		Taiwan
90	1275.9.88605 Boehringer Ingelheim Investigational Site	Tainan		Taiwan

Sponsors and Collaborators

• Boehringer Ingelheim
• Eli Lilly and Company

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01734785
• Other Study ID Numbers: 1275.9; 2012-002270-31
• First Posted: Nov 28, 2012
• Last Update Posted: Jul 11, 2016
• Last Verified: Jun 1, 2016

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Empagliflozin; Linagliptin

Study Results

Participant Flow

Pre-assignment Detail	16-week open-label (OL) lina 5 period followed by a 1-week OL period with additional placebo administration preceded randomisation to double-blind treatment. Patients were randomised to double blind treatment only when they had not met glycaemic control criteria after the 16-week OL period. All treatments were administered in addition to metformin.

Arm/Group Title	Empagliflozin 25 mg	Empagliflozin 10 mg	Placebo	Linagliptin 5 mg
Arm/Group Description	Patients received 1 fixed dose combination (FDC) Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 5mg dose of Linagliptin (lina 5), administered orally, once daily for 16 weeks during the OL treatment period, thereafter patients received 1 matching placebo tablet to FDC empa 25/lina 5, and 1 matching placebo tablet to FDC empa 10/lina 5 per day in addition to lina 5 OL, for 1 week during the open-label placebo add-on treatment period.
Period Title: Open-Label Period
STARTED	0	0	0	606
COMPLETED	0	0	0	333
NOT COMPLETED	0	0	0	273
Period Title: Open-Label Period
STARTED	111	112	110	0
COMPLETED	106	103	105	0
NOT COMPLETED	5	9	5	0

Baseline Characteristics

Arm/Group Title	Empagliflozin 25 mg	Empagliflozin 10 mg	Placebo	Total
Arm/Group Description	Patients received 1 FDC Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Total of all reporting groups
Overall Participants	110	112	110	332
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55.4 (9.9)	54.3 (9.5)	55.9 (9.6)	55.2 (9.7)
Sex: Female, Male (Count of Participants)
Female	39 35.5%	46 41.1%	49 44.5%	134 40.4%
Male	71 64.5%	66 58.9%	61 55.5%	198 59.6%

Outcome Measures

1. Primary Outcome

Title	HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment
Description	Change from baseline in Glycated haemoglobin (HbA1c) [%] after 24 weeks of treatment with double-blind trial medication. Baseline was defined as the last observation before the first intake of any double-blind randomised trial medication. The term 'baseline' was not used to refer to measurements before the administration of open-label medication.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) consisted of all patients in the treated set (TS) who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment during the double-blind part of the trial. Observed Case (OC): In the OC analysis, values after the use of rescue medication were set to missing.

Arm/Group Title	Empagliflozin 25 mg	Empagliflozin 10 mg	Placebo
Arm/Group Description	Patients received 1 FDC Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.
Measure Participants	110	109	106
Least Squares Mean (Standard Error) [Percentage of HbA1c]	-0.56 (0.08)	-0.65 (0.08)	0.14 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin 25 mg, Placebo
	Comments	Superiority of Empagliflozin 25 mg vs. placebo: change in HbA1c using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c as linear covariate(s) & baseline Estimated glomerula filtration rate (eGFR), geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	The unstructured covariance structure has been used to fit the mixed model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.70
	Confidence Interval	() 95%; -0.93 to -0.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Empagliflozin 25 mg minus Placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin 10 mg, Placebo
	Comments	Superiority of Empagliflozin 10 mg vs. placebo: change in HbA1c using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c as linear covariate(s) & baseline Estimated glomerula filtration rate (eGFR), geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	The unstructured covariance structure has been used to fit the mixed model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.79
	Confidence Interval	() 95%; -1.02 to -0.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Empagliflozin 10 mg minus Placebo.

2. Secondary Outcome

Title	Fasting Plasma Glucose (FPG) Change From Baseline After 24 Weeks of Double-blind Treatment.
Description	Change from baseline FPG (mmol/L) after 24 weeks of treatment with double-blind trial medication.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

FAS (OC)

Arm/Group Title	Empagliflozin 25 mg	Empagliflozin 10 mg	Placebo
Arm/Group Description	Patients received 1 FDC Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.
Measure Participants	109	109	106
Least Squares Mean (Standard Error) [mmol/L]	-1.75 (0.18)	-1.46 (0.18)	0.34 (0.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin 25 mg, Placebo
	Comments	Superiority of Empagliflozin 25 mg vs. placebo: change in FPG using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline FPG, baseline HbA1c as linear covariate(s) & baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	The unstructured covariance structure has been used to fit the mixed model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.09
	Confidence Interval	() 95%; -2.61 to -1.57
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.26
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Empagliflozin 25 mg minus Placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin 10 mg, Placebo
	Comments	Superiority of Empagliflozin 10 mg vs. placebo: change in FPG using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline FPG, baseline HbA1c as linear covariate(s) & baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	The unstructured covariance structure has been used to fit the mixed model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.80
	Confidence Interval	() 95%; -2.31 to -1.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.26
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Empagliflozin 10 mg minus Placebo.

3. Secondary Outcome

Title	Body Weight Change From Baseline After 24 Weeks of Double-blind Treatment
Description	Change from baseline Body weight after 24 weeks of treatment with double-blind trial medication.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

FAS (OC)

Arm/Group Title	Empagliflozin 25 mg	Empagliflozin 10 mg	Placebo
Arm/Group Description	Patients received 1 FDC Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.
Measure Participants	110	109	106
Least Squares Mean (Standard Error) [kg]	-2.52 (0.25)	-3.06 (0.25)	-0.30 (0.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin 25 mg, Placebo
	Comments	Superiority of Empagliflozin 25 mg vs. placebo: change in body weight using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline weight, baseline HbA1c as linear covariate(s) & baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	The unstructured covariance structure has been used to fit the mixed model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.22
	Confidence Interval	() 95%; -2.92 to -1.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.36
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Empagliflozin 25 mg minus Placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin 10 mg, Placebo
	Comments	Superiority of Empagliflozin 10 mg vs. placebo:change in body weight using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline weight, baseline HbA1c as linear covariate(s) & baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	The unstructured covariance structure has been used to fit the mixed model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.77
	Confidence Interval	() 95%; -3.47 to -2.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.36
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Empagliflozin 10 mg minus Placebo.

Adverse Events

Time Frame	From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).
Arm/Group Title	Empagliflozin 25 mg		Empagliflozin 10 mg		Placebo		Linagliptin 5 mg
Arm/Group Description	Patients received 1 FDC Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.		Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.		Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.		Patients received 5mg dose of Linagliptin (lina 5), administered orally, once daily for 16 weeks during the OL treatment period, thereafter patients received 1 matching placebo tablet to FDC empa 25/lina 5, and 1 matching placebo tablet to FDC empa 10/lina 5 per day in addition to lina 5 OL, for 1 week during the open-label placebo add-on treatment period.
All Cause Mortality
	Empagliflozin 25 mg		Empagliflozin 10 mg		Placebo		Linagliptin 5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Empagliflozin 25 mg		Empagliflozin 10 mg		Placebo		Linagliptin 5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/110 (3.6%)		5/112 (4.5%)		10/110 (9.1%)		18/606 (3%)
Cardiac disorders
Atrial fibrillation	1/110 (0.9%)		0/112 (0%)		0/110 (0%)		0/606 (0%)
Cardiac failure congestive	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Coronary artery disease	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
Gastrointestinal disorders
Abdominal pain	1/110 (0.9%)		0/112 (0%)		0/110 (0%)		0/606 (0%)
Colitis	0/110 (0%)		1/112 (0.9%)		0/110 (0%)		0/606 (0%)
Gastritis	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Intestinal obstruction	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Umbilical hernia	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
General disorders
Oedema	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
Pyrexia	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Hepatobiliary disorders
Hepatotoxicity	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Hypertransaminasaemia	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
Immune system disorders
Hypersensitivity	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Infections and infestations
Abscess	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Diarrhoea infectious	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Erysipelas	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		1/606 (0.2%)
Gastroenteritis	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Pharyngitis bacterial	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Pneumonia	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Urosepsis	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
Wound infection	1/110 (0.9%)		0/112 (0%)		0/110 (0%)		0/606 (0%)
Injury, poisoning and procedural complications
Accidental overdose	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
Jaw fracture	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Metabolism and nutrition disorders
Dehydration	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Metabolic acidosis	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		1/606 (0.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/110 (0%)		1/112 (0.9%)		0/110 (0%)		0/606 (0%)
Intervertebral disc disorder	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
Intervertebral disc protrusion	1/110 (0.9%)		0/112 (0%)		0/110 (0%)		0/606 (0%)
Osteoarthritis	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Basal cell carcinoma	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Bladder neoplasm	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
Breast cancer	0/110 (0%)		1/112 (0.9%)		0/110 (0%)		0/606 (0%)
Nervous system disorders
Cervical radiculopathy	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
Hydrocephalus	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Psychiatric disorders
Major depression	0/110 (0%)		0/112 (0%)		0/110 (0%)		1/606 (0.2%)
Mania	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
Renal and urinary disorders
Calculus ureteric	1/110 (0.9%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
Hydronephrosis	1/110 (0.9%)		0/112 (0%)		0/110 (0%)		0/606 (0%)
Nephrolithiasis	1/110 (0.9%)		0/112 (0%)		0/110 (0%)		0/606 (0%)
Renal failure acute	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		1/606 (0.2%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/110 (0%)		0/112 (0%)		1/110 (0.9%)		0/606 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax	0/110 (0%)		1/112 (0.9%)		0/110 (0%)		1/606 (0.2%)
Surgical and medical procedures
Abortion induced	0/110 (0%)		1/112 (0.9%)		0/110 (0%)		0/606 (0%)
Other (Not Including Serious) Adverse Events
	Empagliflozin 25 mg		Empagliflozin 10 mg		Placebo		Linagliptin 5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/110 (10%)		19/112 (17%)		34/110 (30.9%)		78/606 (12.9%)
Infections and infestations
Nasopharyngitis	4/110 (3.6%)		5/112 (4.5%)		8/110 (7.3%)		25/606 (4.1%)
Urinary tract infection	3/110 (2.7%)		8/112 (7.1%)		7/110 (6.4%)		28/606 (4.6%)
Investigations
Lipase increased	3/110 (2.7%)		4/112 (3.6%)		6/110 (5.5%)		10/606 (1.7%)
Metabolism and nutrition disorders
Hyperglycaemia	1/110 (0.9%)		1/112 (0.9%)		7/110 (6.4%)		6/606 (1%)
Nervous system disorders
Headache	2/110 (1.8%)		3/112 (2.7%)		8/110 (7.3%)		14/606 (2.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.