Linagliptin as Add on Therapy to Empagliflozin 10 mg or 25 mg With Background Metformin in Patient With Type 2 Diabetes

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01778049
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 708
• Locations: 114
• Arms: 8
• Duration (Months): 25.9
• Patients Per Site: 6.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The objective of the study is to investigate the efficacy, safety and tolerability of linagliptin 5 mg qd compared to placebo given for 24 weeks in inadequately controlled T2DM patients on empagliflozin 10 mg or 25 mg and maximum tolerated dose of metformin. The primary objective of efficacy evaluation is planned after 24 weeks of treatment. The study is designed to show superiority of the combination of empagliflozin and linagliptin over empagliflozin alone.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: BI 10773; Drug: BI 10773 Placebo; Drug: BI 10773 / BI 1356; Drug: BI 10773; Drug: BI 10773 / BI 1356; Drug: BI 10773 / BI 1356 Placebo; Drug: BI 10773; Drug: BI 10773; Drug: BI 10773; Drug: BI 10773 / BI 1356 Placebo; Drug: BI 10773 Placebo; Drug: BI 10773 / BI 1356 Placebo; Drug: BI 10773; Drug: BI 10773 / BI 1356 Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 708 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-blind, Parallel Group Study to Evaluate the Efficacy and Safety of Linagliptin 5 mg Compared to Placebo, Administered as Oral Fixed Dose Combination With Empagliflozin 10 mg or 25 mg for 24 Weeks, in Patients With Type 2 Diabetes Mellitus and Insufficient Glycaemic Control After 16 Weeks of Treatment With Empagliflozin 10 mg or 25 mg 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
Experimental: Empagliflozin 10 mg dose Empagliflozin open label treatment period	Drug: BI 10773; Empagliflozin active
Experimental: Placebo add on 10 mg dose Empagliflozin / Linagliptin 10/5 mg Dose FDC placebo add on run-in	Drug: BI 10773 / BI 1356 Placebo; Empagliflozin / Linagliptin 10/5 mg Dose placebo FDC; Drug: BI 10773; Empagliflozin active
Experimental: Empagliflozin/Linagliptin 25/5 mg Dose Empagliflozin / Linagliptin 25/5 mg Dose FDC active	Drug: BI 10773 / BI 1356; Empagliflozin / Linagliptin 25/5 mg Dose FDC active; Drug: BI 10773 Placebo; Empagliflozin placebo
Experimental: Empagliflozin/Linagliptin 10/5 mg Dose. Empagliflozin / Linagliptin 10/5 mg Dose FDC placebo	Drug: BI 10773 / BI 1356 Placebo; Empagliflozin / Linagliptin 10/5 mg Dose FDC placebo; Drug: BI 10773; Empagliflozin active
Experimental: Empagliflozin/Linagliptin 10/5 mg Dose Empagliflozin / Linagliptin 10/5 mg Dose FDC active	Drug: BI 10773 Placebo; Empagliflozin placebo; Drug: BI 10773 / BI 1356; Empagliflozin / Linagliptin 10/5 mg Dose FDC active
Experimental: Empagliflozin 25 mg dose Empagliflozin open label treatment period	Drug: BI 10773; Empagliflozin active
Experimental: Empagliflozin/Linagliptin 25/5 mg Dose. Empagliflozin / Linagliptin 25/5 mg Dose FDC placebo	Drug: BI 10773; Empagliflozin active; Drug: BI 10773 / BI 1356 Placebo; Empagliflozin / Linagliptin 25/5 mg Dose FDC placebo
Experimental: Placebo add on 25 mg dose Empagliflozin / Linagliptin 25/5 mg Dose FDC placebo add on run-in	Drug: BI 10773; Empagliflozin active; Drug: BI 10773 / BI 1356 Placebo; Empagliflozin / Linagliptin 25/5 mg Dose FDC placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline of HbA1c After 24 Weeks of Treatment. [Baseline and 24 weeks]

   Change from baseline in Glycated haemoglobin (HbA1c) [%] after 24 weeks of treatment with double-blind trial medication, i.e. HbA1c change from baseline at Week 24. The term "baseline" was not used to refer to measurements prior to the administration of open-label medication. Such measurements were referred to as "pre-treatment". Analyses of change from pre-treatment used the last value before first administration of open-label medication as point of reference. Observed Case (OC): This method analyse only available data that were observed while patients were on treatment, i.e., excluding the missing data. All values measured after rescue medication taken were set to missing. Full Analysis Set (FAS): Includes all patients in the Treated set who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment during the double-blind part of the trial.

Secondary Outcome Measures

1. Fasting Plasma Glucose (FPG) Change From Baseline at 24 Weeks. [Baseline and 24 weeks]

   Change from baseline FPG (mmol/L) after 24 weeks of treatment with double-blind trial medication, i.e. FPG change from baseline at Week 24.

Eligibility Criteria

Criteria

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

Inclusion criteria:

1. Signed and dated ICF (Informed Consent Form)

2. Male or female on diet and exercise regime and on stable background metformin > or equal to 1500 mg or maximun dose according to local label

3. HBA1c (Glicoslated Hemoglobin) > or equal to 8% and < or equal to 10.5 % at Visit 1

4. HbA1c > or equal to 7 and < or equal to 10.5 at Visit 4

5. Age > or equal to 18 years

6. BMI (Body Mass Index) < or equal to 45

Exclusion criteria:

1. Uncontrolled hyperglycemia during open label period and placebo add on "run-in" period

2. Use of any other antidiabetic

3. Renal function below 60 ml/min/1.73 m2

4. Antiobesity drugs or aggresive diets

5. Gastorintestinal surgeries

6. Current systemic steroids or uncontrolled endocrine disorders other than Diabetes Type 2

7. Acute coronary syndrome and stroke within 3 months of informed consent

8. Known allergies to DPP-IV (Dypeptidil Peptidase IV) or SGLT-2 (Sodium Glucose Transporter 2) inhibitors

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1275.10.01019 Boehringer Ingelheim Investigational Site	Chino	California	United States
2	1275.10.01008 Boehringer Ingelheim Investigational Site	Huntington Beach	California	United States
3	1275.10.01003 Boehringer Ingelheim Investigational Site	San Diego	California	United States
4	1275.10.01024 Boehringer Ingelheim Investigational Site	San Diego	California	United States
5	1275.10.01002 Boehringer Ingelheim Investigational Site	Sylmar	California	United States
6	1275.10.01011 Boehringer Ingelheim Investigational Site	Miami	Florida	United States
7	1275.10.01009 Boehringer Ingelheim Investigational Site	Orlando	Florida	United States
8	1275.10.01023 Boehringer Ingelheim Investigational Site	Oviedo	Florida	United States
9	1275.10.01006 Boehringer Ingelheim Investigational Site	Tamarac	Florida	United States
10	1275.10.01017 Boehringer Ingelheim Investigational Site	Conyers	Georgia	United States
11	1275.10.01016 Boehringer Ingelheim Investigational Site	Snellville	Georgia	United States
12	1275.10.01012 Boehringer Ingelheim Investigational Site	Avon	Indiana	United States
13	1275.10.01013 Boehringer Ingelheim Investigational Site	Muncie	Indiana	United States
14	1275.10.01010 Boehringer Ingelheim Investigational Site	Elkton	Maryland	United States
15	1275.10.01001 Boehringer Ingelheim Investigational Site	Stevensville	Michigan	United States
16	1275.10.01007 Boehringer Ingelheim Investigational Site	Salisbury	North Carolina	United States
17	1275.10.01005 Boehringer Ingelheim Investigational Site	Bismarck	North Dakota	United States
18	1275.10.01020 Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma	United States
19	1275.10.01022 Boehringer Ingelheim Investigational Site	Pittsburgh	Pennsylvania	United States
20	1275.10.01021 Boehringer Ingelheim Investigational Site	Union	South Carolina	United States
21	1275.10.01014 Boehringer Ingelheim Investigational Site	North Richland Hills	Texas	United States
22	1275.10.01018 Boehringer Ingelheim Investigational Site	Draper	Utah	United States
23	1275.10.01015 Boehringer Ingelheim Investigational Site	Richmond	Virginia	United States
24	1275.10.01025 Boehringer Ingelheim Investigational Site	Virginia Beach	Virginia	United States
25	1275.10.54005 Boehringer Ingelheim Investigational Site	Caba		Argentina
26	1275.10.54012 Boehringer Ingelheim Investigational Site	Caba		Argentina
27	1275.10.54002 Boehringer Ingelheim Investigational Site	Capital Federal		Argentina
28	1275.10.54007 Boehringer Ingelheim Investigational Site	Capital Federal		Argentina
29	1275.10.54013 Boehringer Ingelheim Investigational Site	Capital Federal		Argentina
30	1275.10.54006 Boehringer Ingelheim Investigational Site	Cordoba		Argentina
31	1275.10.54008 Boehringer Ingelheim Investigational Site	Cordoba		Argentina
32	1275.10.54011 Boehringer Ingelheim Investigational Site	Córdoba		Argentina
33	1275.10.54003 Boehringer Ingelheim Investigational Site	Godoy Cruz, Mendoza		Argentina
34	1275.10.54009 Boehringer Ingelheim Investigational Site	Mar del Plata		Argentina
35	1275.10.54004 Boehringer Ingelheim Investigational Site	Salta		Argentina
36	1275.10.54001 Boehringer Ingelheim Investigational Site	San Isidro		Argentina
37	1275.10.54010 Boehringer Ingelheim Investigational Site	Zarate		Argentina
38	1275.10.61008 Boehringer Ingelheim Investigational Site	Cardiff	New South Wales	Australia
39	1275.10.61002 Boehringer Ingelheim Investigational Site	East Ringwood	Victoria	Australia
40	1275.10.61001 Boehringer Ingelheim Investigational Site	Heidelberg Heights	Victoria	Australia
41	1275.10.61009 Boehringer Ingelheim Investigational Site	Mirrabooka	Western Australia	Australia
42	1275.10.02004 Boehringer Ingelheim Investigational Site	Edmonton	Alberta	Canada
43	1275.10.02001 Boehringer Ingelheim Investigational Site	Red Deer	Alberta	Canada
44	1275.10.02003 Boehringer Ingelheim Investigational Site	Chilliwack	British Columbia	Canada
45	1275.10.02009 Boehringer Ingelheim Investigational Site	Coquitlam	British Columbia	Canada
46	1275.10.02012 Boehringer Ingelheim Investigational Site	Vancouver	British Columbia	Canada
47	1275.10.02006 Boehringer Ingelheim Investigational Site	Winnipeg	Manitoba	Canada
48	1275.10.02008 Boehringer Ingelheim Investigational Site	Winnipeg	Manitoba	Canada
49	1275.10.02005 Boehringer Ingelheim Investigational Site	Moncton	New Brunswick	Canada
50	1275.10.02013 Boehringer Ingelheim Investigational Site	Burlington	Ontario	Canada
51	1275.10.02002 Boehringer Ingelheim Investigational Site	Strathroy	Ontario	Canada
52	1275.10.02007 Boehringer Ingelheim Investigational Site	Sudbury	Ontario	Canada
53	1275.10.02011 Boehringer Ingelheim Investigational Site	Drummondville	Quebec	Canada
54	1275.10.02010 Boehringer Ingelheim Investigational Site	Montreal	Quebec	Canada
55	1275.10.34014 Boehringer Ingelheim Investigational Site	Ávila		El Salvador
56	1275.10.49007 Boehringer Ingelheim Investigational Site	Asslar		Germany
57	1275.10.49014 Boehringer Ingelheim Investigational Site	Berlin		Germany
58	1275.10.49016 Boehringer Ingelheim Investigational Site	Elsterwerda		Germany
59	1275.10.49012 Boehringer Ingelheim Investigational Site	Hamburg		Germany
60	1275.10.49005 Boehringer Ingelheim Investigational Site	Hatten		Germany
61	1275.10.49008 Boehringer Ingelheim Investigational Site	Kiel Kronshagen		Germany
62	1275.10.49004 Boehringer Ingelheim Investigational Site	Köln		Germany
63	1275.10.49010 Boehringer Ingelheim Investigational Site	Lübeck		Germany
64	1275.10.49003 Boehringer Ingelheim Investigational Site	Münster		Germany
65	1275.10.49006 Boehringer Ingelheim Investigational Site	Pirna		Germany
66	1275.10.49013 Boehringer Ingelheim Investigational Site	St. Ingbert/Oberwürzbach		Germany
67	1275.10.49001 Boehringer Ingelheim Investigational Site	Unterschneidheim		Germany
68	1275.10.49015 Boehringer Ingelheim Investigational Site	Wangen		Germany
69	1275.10.39005 Boehringer Ingelheim Investigational Site	Ancona		Italy
70	1275.10.39006 Boehringer Ingelheim Investigational Site	Catania		Italy
71	1275.10.39009 Boehringer Ingelheim Investigational Site	Catania		Italy
72	1275.10.39014 Boehringer Ingelheim Investigational Site	Catania		Italy
73	1275.10.39007 Boehringer Ingelheim Investigational Site	Latina		Italy
74	1275.10.39012 Boehringer Ingelheim Investigational Site	Milano		Italy
75	1275.10.39013 Boehringer Ingelheim Investigational Site	Milano		Italy
76	1275.10.39015 Boehringer Ingelheim Investigational Site	Olbia (OT)		Italy
77	1275.10.39016 Boehringer Ingelheim Investigational Site	Orbassano (TO)		Italy
78	1275.10.39004 Boehringer Ingelheim Investigational Site	Palermo		Italy
79	1275.10.39003 Boehringer Ingelheim Investigational Site	Pistoia		Italy
80	1275.10.39008 Boehringer Ingelheim Investigational Site	Roma		Italy
81	1275.10.39001 Boehringer Ingelheim Investigational Site	Sesto San Giovanni (MI)		Italy
82	1275.10.39010 Boehringer Ingelheim Investigational Site	Siena		Italy
83	1275.10.39011 Boehringer Ingelheim Investigational Site	Terni		Italy
84	1275.10.35104 Boehringer Ingelheim Investigational Site	Cantanhede		Portugal
85	1275.10.35112 Boehringer Ingelheim Investigational Site	Porto		Portugal
86	1275.10.35103 Boehringer Ingelheim Investigational Site	Sandim		Portugal
87	1275.10.35105 Boehringer Ingelheim Investigational Site	Tornada		Portugal
88	1275.10.35108 Boehringer Ingelheim Investigational Site	Valadares		Portugal
89	1275.10.35101 Boehringer Ingelheim Investigational Site	Vila Nova de Gaia		Portugal
90	1275.10.07004 Boehringer Ingelheim Investigational Site	Chelyabinsk		Russian Federation
91	1275.10.07006 Boehringer Ingelheim Investigational Site	Saint-Petersburg		Russian Federation
92	1275.10.07001 Boehringer Ingelheim Investigational Site	Saratov		Russian Federation
93	1275.10.07005 Boehringer Ingelheim Investigational Site	Saratov		Russian Federation
94	1275.10.07003 Boehringer Ingelheim Investigational Site	St. Petersburg		Russian Federation
95	1275.10.07002 Boehringer Ingelheim Investigational Site	Yaroslavl		Russian Federation
96	1275.10.34003 Boehringer Ingelheim Investigational Site	Barcelona		Spain
97	1275.10.34004 Boehringer Ingelheim Investigational Site	Canet de Mar		Spain
98	1275.10.34008 Boehringer Ingelheim Investigational Site	Centelles		Spain
99	1275.10.34009 Boehringer Ingelheim Investigational Site	L'Hospitalet de Llobregat (Barcelona)		Spain
100	1275.10.34012 Boehringer Ingelheim Investigational Site	La Roca del Vallès		Spain
101	1275.10.34006 Boehringer Ingelheim Investigational Site	Madrid		Spain
102	1275.10.34010 Boehringer Ingelheim Investigational Site	Malaga		Spain
103	1275.10.34011 Boehringer Ingelheim Investigational Site	Mataró		Spain
104	1275.10.34001 Boehringer Ingelheim Investigational Site	Málaga		Spain
105	1275.10.34013 Boehringer Ingelheim Investigational Site	Pineda de Mar		Spain
106	1275.10.34002 Boehringer Ingelheim Investigational Site	Sabadell		Spain
107	1275.10.34005 Boehringer Ingelheim Investigational Site	Tarragona		Spain
108	1275.10.38006 Boehringer Ingelheim Investigational Site	Chernivtsi		Ukraine
109	1275.10.38007 Boehringer Ingelheim Investigational Site	Dnipropetrovs'k		Ukraine
110	1275.10.38002 Boehringer Ingelheim Investigational Site	Kiev		Ukraine
111	1275.10.38003 Boehringer Ingelheim Investigational Site	Kiev		Ukraine
112	1275.10.38004 Boehringer Ingelheim Investigational Site	Lviv		Ukraine
113	1275.10.38001 Boehringer Ingelheim Investigational Site	Vinnitsa		Ukraine
114	1275.10.38005 Boehringer Ingelheim Investigational Site	Zhytomyr		Ukraine

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: NCT01778049
• Other Study ID Numbers: 1275.10; 2012-002271-34
• First Posted: Jan 29, 2013
• Last Update Posted: Apr 4, 2016
• Last Verified: Mar 1, 2016

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

Study Results

Participant Flow

Recruitment Details	Subjects randomised to 16 week(wk) open-label (OL) treatment with either empagliflozin (empa) 25 or empa 10 treatment, thereafter subjects entered to 1 wk open label placebo (Plc) add-on period in order to complete further eligibility evaluations before being randomised into 1 of the 24 wk double-blind treatment groups.
Pre-assignment Detail	This was a randomised, double-blind, multi-national, parallel group trial. In this trial the treatment effects of linagliptin (lina) 5 compared with Plc were analysed as add-on to either empa 25 or empa 10. All trial treatments were administered in addition to metformin background treatment.

Arm/Group Title	Empa 10 mg OL	Empa 25 mg OL	Lina5 (E10)	Plc (E10)	Lina5 (E25)	Plc (E25)
Arm/Group Description	Subjects were orally administered once daily empa 10 mg film-coated tablet for 16 wk during OL treatment period, thereafter patients received once daily fixed dose combination (FDC) placebo tablet matching to FDC empa 10 mg/lina 5 mg in addition to empa 10 mg for 1 week during open label placebo add-on treatment period.	Subjects were orally administered once daily empa 25 mg film-coated tablet for 16 week during OL treatment period, thereafter patients received once daily FDC Plc tablet matching to FDC empa 25 mg/lina 5 mg in addition to empa 25 mg for 1 wk during open label placebo add-on treatment period.	Subjects were orally administered FDC empa 10 mg/lina 5 mg and placebo matching to empa 10 mg for 24 wk during the double-blind treatment period.	Subjects were orally administered empa 10 mg and matching placebo to FDC empa 10 mg/lina 5 mg for 24 wk during the double-blind treatment period.	Subjects were orally administered FDC empa 25 mg/lina 5 mg and placebo matching to empa 25 mg for 24 wk during the double-blind treatment period.	Subjects were orally administered empa 25 mg and matching placebo to FDC empa 25 mg/lina 5 mg for 24 wk during the double-blind treatment period.
Period Title: Open Label Treatment Period
STARTED	354	355	0	0	0	0
COMPLETED	256	226	0	0	0	0
NOT COMPLETED	98	129	0	0	0	0
Period Title: Open Label Treatment Period
STARTED	0	0	126	130	114	112
COMPLETED	0	0	111	118	102	105
NOT COMPLETED	0	0	15	12	12	7

Baseline Characteristics

Arm/Group Title	Empa 10 mg OL	Empa 25 mg OL	Total
Arm/Group Description	Subjects were orally administered once daily empa 10 mg film-coated tablet for 16 wk during OL treatment period, thereafter patients received once daily fixed dose combination (FDC) placebo tablet matching to FDC empa 10 mg/lina 5 mg in addition to empa 10 mg for 1 week during open label placebo add-on treatment period.	Subjects were orally administered once daily empa 25 mg film-coated tablet for 16 week during OL treatment period, thereafter patients received once daily FDC Plc tablet matching to FDC empa 25 mg/lina 5 mg in addition to empa 25 mg for 1 wk during open label placebo add-on treatment period.	Total of all reporting groups
Overall Participants	352	354	706
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	57.0 (9.6)	56.7 (9.9)	56.8 (9.8)
Sex: Female, Male (Count of Participants)
Female	145 41.2%	161 45.5%	306 43.3%
Male	207 58.8%	193 54.5%	400 56.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline of HbA1c After 24 Weeks of Treatment.
Description	Change from baseline in Glycated haemoglobin (HbA1c) [%] after 24 weeks of treatment with double-blind trial medication, i.e. HbA1c change from baseline at Week 24. The term "baseline" was not used to refer to measurements prior to the administration of open-label medication. Such measurements were referred to as "pre-treatment". Analyses of change from pre-treatment used the last value before first administration of open-label medication as point of reference. Observed Case (OC): This method analyse only available data that were observed while patients were on treatment, i.e., excluding the missing data. All values measured after rescue medication taken were set to missing. Full Analysis Set (FAS): Includes all patients in the Treated set who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment during the double-blind part of the trial.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

FAS (OC)

Arm/Group Title	Lina5 (E10)	Plc (E10)	Lina5 (E25)	Plc (E25)
Arm/Group Description	Subjects were orally administered FDC empa 10 mg/lina 5 mg and placebo matching to empa 10 mg for 24 wk during the double-blind treatment period.	Subjects were orally administered empa 10 mg and matching placebo to FDC empa 10 mg/lina 5 mg for 24 wk during the double-blind treatment period.	Subjects were orally administered FDC empa 25 mg/lina 5 mg and placebo matching to empa 25 mg for 24 wk during the double-blind treatment period.	Subjects were orally administered empa 25 mg and matching placebo to FDC empa 25 mg/lina 5 mg for 24 wk during the double-blind treatment period.
Measure Participants	111	110	98	98
Least Squares Mean (Standard Error) [Percentage of HbA1c]	-0.53 (0.07)	-0.21 (0.07)	-0.58 (0.07)	-0.10 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lina5 (E10), Plc (E10)
	Comments	Superiority of lina5 (E10) vs. Plc (E10): change in HbA1c using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c as linear covariates & baseline estimated glomerula filtration rate (eGFR), geographical region, treatment, visit, visit by treatment interaction as fixed effects.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0013
	Comments
	Method	Mixed Model Repeated Measure (MMRM)
	Comments	The unstructured covariance structure has been used to fit the mixed model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.32
	Confidence Interval	() 95%; -0.52 to -0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments	Mean Difference (Final Values) is actually the adjusted mean difference calculated as lina5 (E10) minus Plc (E10) value.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lina5 (E25), Plc (E25)
	Comments	Superiority of lina5 (E25) vs. Plc (E25): change in HbA1c using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c as linear covariates & baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effects.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	MMRM
	Comments	The unstructured covariance structure has been used to fit the mixed model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.47
	Confidence Interval	() 95%; -0.66 to -0.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments	Mean Difference (Final Values) is actually the adjusted mean difference value calculated as lina5 (E25) minus Plc (E25).

2. Secondary Outcome

Title	Fasting Plasma Glucose (FPG) Change From Baseline at 24 Weeks.
Description	Change from baseline FPG (mmol/L) after 24 weeks of treatment with double-blind trial medication, i.e. FPG change from baseline at Week 24.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

FAS (OC)

Arm/Group Title	Lina5 (E10)	Plc (E10)	Lina5 (E25)	Plc (E25)
Arm/Group Description	Subjects were orally administered FDC empa 10 mg/lina 5 mg and placebo matching to empa 10 mg for 24 wk during the double-blind treatment period.	Subjects were orally administered empa 10 mg and matching placebo to FDC empa 10 mg/lina 5 mg for 24 wk during the double-blind treatment period.	Subjects were orally administered FDC empa 25 mg/lina 5 mg and placebo matching to empa 25 mg for 24 wk during the double-blind treatment period.	Subjects were orally administered empa 25 mg and matching placebo to FDC empa 25 mg/lina 5 mg for 24 wk during the double-blind treatment period.
Measure Participants	108	107	93	94
Least Squares Mean (Standard Error) [mmol/L]	-0.44 (0.18)	0.21 (0.18)	-0.68 (0.15)	-0.24 (0.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lina5 (E10), Plc (E10)
	Comments	Superiority of lina5 (E10) vs. Plc (E10): change in FPG using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c & baseline eGFR as linear covariates, geographical region, treatment, visit, visit by treatment interaction as fixed effects.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0103
	Comments
	Method	MMRM
	Comments	The unstructured covariance structure has been used to fit the mixed model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.65
	Confidence Interval	() 95%; -1.15 to -0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.25
	Estimation Comments	Mean Difference (Final Values) is actually the adjusted mean difference value calculated as lina5 (E10) minus Plc (E10).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lina5 (E25), Plc (E25)
	Comments	Superiority of lina5 (E25) vs. Plc (E25): change in FPG using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c & baseline eGFR as linear covariates, geographical region, treatment, visit, visit by treatment interaction as fixed effects.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0452
	Comments
	Method	MMRM
	Comments	The unstructured covariance structure has been used to fit the mixed model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.44
	Confidence Interval	() 95%; -0.87 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.22
	Estimation Comments	Mean Difference (Final Values) is actually the adjusted mean difference value calculated as lina5 (E25) minus Plc (E25).

Adverse Events

Time Frame	From first drug administration until 7 days after the last drug administration, up to 212 days (OL treatment period) and 205 days (double blind treatment period).
Arm/Group Title	Empa 10 mg OL		Empa 25 mg OL		Lina5 (E10)		Plc (E10)		Lina5 (E25)		Plc (E25)
Arm/Group Description	Subjects were orally administered once daily empa 10 mg film-coated tablet for 16 wk during OL treatment period, thereafter patients received once daily fixed dose combination (FDC) placebo tablet matching to FDC empa 10 mg/lina 5 mg in addition to empa 10 mg for 1 week during open label placebo add-on treatment period.		Subjects were orally administered once daily empa 25 mg film-coated tablet for 16 week during OL treatment period, thereafter patients received once daily FDC Plc tablet matching to FDC empa 25 mg/lina 5 mg in addition to empa 25 mg for 1 wk during open label placebo add-on treatment period.		Subjects were orally administered FDC empa 10 mg/lina 5 mg and placebo matching to empa 10 mg for 24 wk during the double-blind treatment period.		Subjects were orally administered empa 10 mg and matching placebo to FDC empa 10 mg/lina 5 mg for 24 wk during the double-blind treatment period.		Subjects were orally administered FDC empa 25 mg/lina 5 mg and placebo matching to empa 25 mg for 24 wk during the double-blind treatment period.		Subjects were orally administered empa 25 mg and matching placebo to FDC empa 25 mg/lina 5 mg for 24 wk during the double-blind treatment period.
All Cause Mortality
	Empa 10 mg OL		Empa 25 mg OL		Lina5 (E10)		Plc (E10)		Lina5 (E25)		Plc (E25)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Empa 10 mg OL		Empa 25 mg OL		Lina5 (E10)		Plc (E10)		Lina5 (E25)		Plc (E25)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/352 (3.4%)		12/354 (3.4%)		4/126 (3.2%)		5/128 (3.9%)		3/112 (2.7%)		4/112 (3.6%)
Blood and lymphatic system disorders
Pancytopenia	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Cardiac disorders
Angina unstable	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Atrial fibrillation	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Atrial flutter	0/352 (0%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		1/112 (0.9%)		0/112 (0%)
Coronary artery disease	0/352 (0%)		0/354 (0%)		0/126 (0%)		1/128 (0.8%)		0/112 (0%)		0/112 (0%)
Myocardial infarction	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		1/128 (0.8%)		0/112 (0%)		0/112 (0%)
Myocardial ischaemia	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Tachycardia	0/352 (0%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		1/112 (0.9%)		0/112 (0%)
Gastrointestinal disorders
Diverticulum intestinal	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Gastrointestinal haemorrhage	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Intestinal polyp	0/352 (0%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		1/112 (0.9%)
Pancreatitis acute	2/352 (0.6%)		0/354 (0%)		1/126 (0.8%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Upper gastrointestinal haemorrhage	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Vomiting	0/352 (0%)		0/354 (0%)		1/126 (0.8%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
General disorders
Calcinosis	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Chest pain	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Death	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
General physical health deterioration	0/352 (0%)		0/354 (0%)		1/126 (0.8%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Hepatobiliary disorders
Cholecystitis acute	2/352 (0.6%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Liver injury	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Infections and infestations
Abscess limb	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Bronchitis	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Gangrene	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Infectious colitis	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Osteomyelitis	0/352 (0%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		2/112 (1.8%)
Pneumonia	0/352 (0%)		0/354 (0%)		1/126 (0.8%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Upper respiratory tract infection	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Urinary tract infection	0/352 (0%)		0/354 (0%)		1/126 (0.8%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Injury, poisoning and procedural complications
Fall	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		1/112 (0.9%)
Skull fractured base	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Investigations
Amylase increased	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/352 (0%)		0/354 (0%)		1/126 (0.8%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Haemarthrosis	0/352 (0%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		1/112 (0.9%)
Neck pain	0/352 (0%)		0/354 (0%)		0/126 (0%)		1/128 (0.8%)		0/112 (0%)		0/112 (0%)
Rhabdomyolysis	0/352 (0%)		0/354 (0%)		1/126 (0.8%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Rotator cuff syndrome	0/352 (0%)		0/354 (0%)		0/126 (0%)		1/128 (0.8%)		0/112 (0%)		0/112 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic carcinoma metastatic	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Prostatic adenoma	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Nervous system disorders
Cerebral haematoma	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Cerebral haemorrhage	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Cerebrovascular accident	0/352 (0%)		0/354 (0%)		0/126 (0%)		1/128 (0.8%)		0/112 (0%)		0/112 (0%)
Ischaemic stroke	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Reproductive system and breast disorders
Balanoposthitis	0/352 (0%)		0/354 (0%)		0/126 (0%)		1/128 (0.8%)		0/112 (0%)		0/112 (0%)
Metrorrhagia	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Nasal septum deviation	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Nasal turbinate hypertrophy	0/352 (0%)		1/354 (0.3%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Pharyngeal lesion	0/352 (0%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		1/112 (0.9%)		0/112 (0%)
Skin and subcutaneous tissue disorders
Dermatitis bullous	0/352 (0%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		1/112 (0.9%)		0/112 (0%)
Dyshidrotic eczema	0/352 (0%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		1/112 (0.9%)		0/112 (0%)
Vascular disorders
Extremity necrosis	0/352 (0%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		1/112 (0.9%)
Subclavian vein thrombosis	1/352 (0.3%)		0/354 (0%)		0/126 (0%)		0/128 (0%)		0/112 (0%)		0/112 (0%)
Other (Not Including Serious) Adverse Events
	Empa 10 mg OL		Empa 25 mg OL		Lina5 (E10)		Plc (E10)		Lina5 (E25)		Plc (E25)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/352 (13.4%)		38/354 (10.7%)		22/126 (17.5%)		10/128 (7.8%)		18/112 (16.1%)		21/112 (18.8%)
Infections and infestations
Nasopharyngitis	17/352 (4.8%)		5/354 (1.4%)		8/126 (6.3%)		3/128 (2.3%)		2/112 (1.8%)		8/112 (7.1%)
Urinary tract infection	16/352 (4.5%)		23/354 (6.5%)		10/126 (7.9%)		6/128 (4.7%)		11/112 (9.8%)		7/112 (6.3%)
Investigations
Lipase increased	15/352 (4.3%)		10/354 (2.8%)		4/126 (3.2%)		1/128 (0.8%)		7/112 (6.3%)		7/112 (6.3%)

Limitations/Caveats

[Not Specified]

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

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