Empagliflozin Add on to Linagliptin Study in Japanese Patient With Type 2 Diabetes Mellitus

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02453555
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 275
• Locations: 40
• Arms: 6
• Actual Duration (Months): 22.4
• Patients Per Site: 6.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This trial will compare the use of fixed dose combination of empagliflozin and linagliptin to linagliptin alone in patient with type 2 diabetes mellitus

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Linagliptin; Drug: Empagliflozin placebo + linagliptin placebo low dose; Drug: Empagliflozin + linagliptin low dose; Drug: Linagliptin placebo; Drug: Empagliflozin + linagliptin high dose; Drug: Empa + lina highdose placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 275 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomised, Double-blind, Parallel Group, 52 Week Study to Evaluate Efficacy and Safety of Once Daily Empagliflozin and Linagliptin Fixed Dose Combination Compared With Linagliptin Plus Placebo in Japanese Type 2 Diabetes Mellitus Patients With Insufficient Glycaemic Control After 16 Weeks Treatment With Once Daily Linagliptin 5 mg.
• Actual Study Start Date: May 14, 2015
• Actual Primary Completion Date: Aug 26, 2016
• Actual Study Completion Date: Mar 27, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Linagliptin patient to receive 5 mg linagliptin once daily	Drug: Linagliptin; Other Names: tablet ; Drug: Empagliflozin placebo + linagliptin placebo low dose; Matching placebo empagliflozin + linagliptin; Drug: Empa + lina highdose placebo
Experimental: Empagliflozin + linagliptin low dose patient to receive one tablet once daily	Drug: Empagliflozin + linagliptin low dose; tablet; Drug: Linagliptin placebo; Matching placebo linagliptin
Experimental: Empagliflozin + linagliptin high dose patient to receive one tablet once daily	Drug: Linagliptin placebo; Matching placebo linagliptin; Drug: Empagliflozin + linagliptin high dose; tablet
Placebo Comparator: Linagliptin placebo	Drug: Empagliflozin + linagliptin low dose; tablet; Drug: Linagliptin placebo; Matching placebo linagliptin; Drug: Empagliflozin + linagliptin high dose; tablet
Placebo Comparator: Empagliflozin + linagliptin high dose placebo	Drug: Linagliptin; Other Names: tablet ; Drug: Empa + lina highdose placebo
Placebo Comparator: Empagliflozin + linagliptin low dose placebo	Drug: Linagliptin; Other Names: tablet ; Drug: Empagliflozin placebo + linagliptin placebo low dose; Matching placebo empagliflozin + linagliptin

Outcome Measures

Primary Outcome Measures

1. Change of Glycosylated Haemoglobin A1c (Glycosylated Haemoglobin A1c After 24 Weeks of Double-blind Treatment From Baseline) [Baseline and 24 week]

   Change from baseline in Glycosylated haemoglobin A1c (HbA1c) at Week 24 was calculated as: HbA1c at Week 24 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.

Secondary Outcome Measures

1. Change in HbA1c From Week 28 at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Only) [28 Week (pre up-titration) and 52 Week]

   Change from Week 28 in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at Week 28. Week 28 (pre up-titration) is referred to the last observed measurement prior to the first administration of any double-blind randomized trial medication in the up-titration period. Adjusted mean (Least square mean) and its standard error (SE) is presented. This endpoint was based on 1 group of the Full analysis set with up-titration (FASUT-II) whose dose was up-titrated to Empagliflozin 25 mg/Linagliptin 5 mg fixed dose combination thus there is no comparison group. Hence, no comparison is made. A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline eGFR, prior use of antidiabetic drug, visit as fixed effect(s). The covariance used to fit the model was unstructured.

2. Change in HbA1c From Baseline at Week 52 (All Empagliflozin Versus All Placebo) [Baseline and 52 week]

   Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.

3. Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus Linagliptin 5 mg + Placebo 25 mg) [Baseline and 52 week]

   Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.

4. Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus All Placebo) [Baseline and 52 week]

   Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Diagnosis of Type-2 Diabetes Mellitus (T2DM) prior to informed consent

2. Male and female patients on diet and exercise regimen for at least 12 weeks prior to informed consent who are:

• 1 drug-naïve, defined as no antidiabetic drugs for at least 12 weeks prior to informed consent, or

• 2 pre-treated with one oral antidiabetic drug (for sulfonylurea, with up to half of the maximum approved dose) on stable dosage for at least 12 weeks prior to informed consent (for thiazolidinedione, therapy has to be unchanged for at least 18 weeks prior to the informed consent, for linagliptin 5 mg at least 16 weeks prior to Visit 1). Individual antidiabetic drug (except linagliptin) will have to be discontinued at Visit 1.

1. HbA1c at Visit 1

• 1 HbA1c =8.0% and =10.5% for patients who are drug-naïve, or

• 2 HbA1c =7.5% and =10.5% for patients with one oral antidiabetic drug (except linagliptin), or

• 3 HbA1c =7.5% and =10.0% for patients with linagliptin 5 mg

1. HbA1c =7.5% and =10.0% at Visit 4 for randomisation into the double-blind treatment period. Patient who are pre-treated with linagliptin 5 mg for 16 weeks or more prior to Visit 1 and meet the criteria of HbA1c can directly move on to the run-in (Visit 4).

2. Age =20 years at informed consent

3. BMI =40.0 kg/m2 at Visit 1 (screening)

4. Signed and dated written informed consent by date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation

Exclusion criteria:

1. Uncontrolled hyperglycemia with a glucose level >270 mg/dL (>15.0 mmol/L) after an overnight fast during the open-label stabilisation period (from Visit 2 to Visit 4) and run-in period (from Visit 4 to Visit 5) , confirmed by a second measurement (not on the same day and done either at the central or at local laboratory).

2. Acute coronary syndrome (ST-elevation myocardial infarction [STEMI], non-STEMI, and unstable angina pectoris), stroke or transient ischemic attack within 12 weeks prior to informed consent

3. Indication of liver disease, defined by serum levels of either alanine aminotransferase (ALT Serum glutamic pyruvate transaminase [SGPT]), aspartate aminotransferase (AST, Serum glutamic oxaloacetic transaminase [SGOT]), or alkaline phosphatase (ALP) above 3 x upper limit of normal (ULN) as determined during screening, open-label stabilisation period and/or run-in period

4. Impaired renal function, defined as estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 (MDRD formula) as determined during screening, open-label stabilisation period and/or run-in period

5. Known hereditary galactose intolerance

6. Known contraindications to linagliptin and empagliflozin according to the Japanese label

7. Any previous (within 2 years prior to informed consent) or planned bariatric surgery (or any other weight loss surgery) or other gastrointestinal surgery that induce chronic malabsorption

8. Medical history of cancer (except for resected non-invasive basal cell or squamous carcinoma) and/or treatment for cancer within the last 5 years

9. Known blood dyscrasias or any disorders causing haemolysis or unstable red blood cell (RBC) count (e.g. malaria, babesiosis, haemolytic anaemia).

10. Treatment with insulin, Glucagon-like peptide-1 agonists, within 12 weeks prior to informed consent

11. Treatment with anti-obesity drugs within 12 weeks prior to informed consent or any other treatment at the time of screening (i.e., surgery, aggressive diet regimen, etc.) leading to unstable body weight

12. Current treatment with systemic steroids (other than inhaled or topical steroids) at informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except T2DM

13. Pre-menopausal women (last menstruation =1 year prior to informed consent) who:

• 1 are nursing or pregnant or

• 2 are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the trial and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, intra uterine devices/systems, oral contraceptives, complete sexual abstinence, double barrier method and vasectomised partner

1. Known or suspected allergy or hypersensitivity to trial products or related products (e.g., Dipeptidyl-peptidase-4 inhibitors or Sodium-glucose co-transporter-2 inhibitors)

2. Alcohol or drug abuse within the 12 weeks prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to trial procedures or trial drug intake, by the judgment of the investigator

3. Intake of an investigational drug in another trial within 30 days prior to Visit 1 or participation in the follow-up period of another trial (participation in observational studies is permitted)

4. Any other clinical condition that, in the opinion of the investigator, would jeopardize patient's safety while participating in this clinical trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nagoya Kyoritsu Hospital	Aichi, Nagoya		Japan	454-0933
2	Kashiwa City Hospital	Chiba, Kashiwa		Japan	277-0825
3	Otabe internal medicine clinic	Fukuoka, Fukuoka		Japan	811-1346
4	Nakamura Cardiovascular Clinic	Fukuoka, Itoshima		Japan	819-1104
5	Tanaka I.M. Clinic, Fukuoka, I.M.	Fukuoka, Kurume		Japan	830-0023
6	Seino I.M. Clinic, Fukushima, I.M.	Fukushima, Koriyama		Japan	963-8851
7	Hiraoka Naika Clinic, Hiroshima, I.M.	Hiroshima, Hiroshima		Japan	733-0011
8	Matsuda Cardiovascular Clinic	Hokkaido, Sapporo		Japan	003-0026
9	Teine Keijinkai Clinic	Hokkaido, Sapporo		Japan	006-0811
10	Mita Internal Medicine Cardiology Clinic	Hokkaido, Sapporo		Japan	006-0852
11	Miyanosawa Clinic of Internal Medicine and Cardiology	Hokkaido, Sapporo		Japan	063-0826
12	Itabashi Diabetic medicine and Dermatology Clinic	Ibaraki, Koga		Japan	306-0232
13	Nakakinen Clinic	Ibaraki, Naka		Japan	311-0113
14	Kubota Clinic	Kanagawa, Kawasaki		Japan	214-0014
15	Kitasato University Hospital	Kanagawa, Sagamihara		Japan	252-0375
16	H.E.C Science Clinic	Kanagawa, Yokohama		Japan	235-0045
17	Yoshimasa Diabetes & Endocrine Clinic	Kyoto, Kyoto		Japan	604-8151
18	Rakuwakai Otowa Hospital	Kyoto, Kyoto		Japan	607-8062
19	Medical Corporation Hayashi Katagihara Clinic	Kyoto, Kyoto		Japan	615-8125
20	Miyamoto Naika Clinic, Nagano, I.M.	Nagano, Matsumoto		Japan	390-0848
21	Gibo Hepatology Clinic, Nagano, Digestive Tract I.M.	Nagano, Matsumoto		Japan	399-0036
22	Takekawa Clinic, Osaka, I.M.	Osaka, Higashi-Osaka		Japan	577-0803
23	Medical Corporation Koseikai Fukuda Naika Clinic	Osaka, Osaka		Japan	532-0003
24	Kinugawa Cardiovascular Internal Medicine clinic	Osaka, Osaka		Japan	532-0026
25	Sato Hospital	Osaka, Osaka		Japan	536-0023
26	Nakaoka Clinic	Osaka, Osaka		Japan	555-0032
27	OCROM Clinic	Osaka, Suita		Japan	565-0853
28	Miyauchi Medical Center	Osaka, Takatsuki		Japan	569-1123
29	Medical Corporation Shinseikai Mashiba Clinic	Saitama, Hanno		Japan	357-0024
30	Asano Clinic	Saitama, Kawagoe		Japan	350-0851
31	Medical Corporation Fusa Shimizu Clinic Fusa	Saitama, Saitama		Japan	336-0963
32	Ogino Clinic	Saitama, Tokorozawa		Japan	359-1161
33	Kanda Clinic	Tokyo, Chiyoda-ku		Japan	101-0047
34	Fukuwa Clinic	Tokyo, Chuo-ku		Japan	103-0027
35	Tokyo-Eki Center-building Clinic	Tokyo, Chuo-ku		Japan	103-0027
36	Myojin Tou Clinic	Tokyo, Hachioji		Japan	192-0046
37	Sawai Medical Clinic	Tokyo, Koto-ku		Japan	136-0073
38	Mishuku Hospital	Tokyo, Meguro-ku		Japan	153-0051
39	Toshiba General Hospital	Tokyo, Shinagawa-ku		Japan	140-8522
40	ToCROM Clinic	Tokyo, Shinjuku-ku		Japan	160-0022

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:

• Synopsis Link

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02453555
• Other Study ID Numbers: 1275.19
• First Posted: May 25, 2015
• Last Update Posted: Feb 15, 2019
• Last Verified: Sep 1, 2018

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

Study Results

Participant Flow

Arm/Group Title	Empagliflozin 10 Milligram (mg)/Linagliptin 5 Milligram (mg)	Linagliptin 5 mg + Placebo 10 mg	Empagliflozin 25 mg/Linagliptin 5 mg (Extension Period)	Empagliflozin 10 mg/Linagliptin 5 mg (Extension Period)	Linagliptin 5 mg + Placebo 25 mg (Extension Period)	Linagliptin 5 mg + Placebo 10 mg (Extension Period)
Arm/Group Description	Patients were administered a fixed dose combination (FDC) of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with matching placebo of Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period.	Patients were administered a matching placebo of FDC of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period.	Patients with insufficient response based on Glycosylated haemoglobin A1c (HbA1c) after 24-week of double-blind treatment period were up-titrated to a FDC of 25 mg Empagliflozin and 5 mg Linagliptin tablet along with matching placebo of Linagliptin 5 mg orally once daily for 24 weeks of up-titration period (from Week 28 to Week 52).	Patients with sufficient response based on HbA1c after 24-week of double-blind treatment period were continued on a FDC of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with matching placebo of Linagliptin 5 mg orally once daily for subsequent 28 weeks of extension period.	Patients with insufficient response based on HbA1c after 24-week of double-blind treatment period were up-titrated to receive a matching placebo of FDC of 25 mg Empagliflozin and 5 mg Linagliptin tablet along with Linagliptin 5 mg orally once daily for 24 weeks of up-titration period (from Week 28 to Week 52).	Patients with sufficient response based on HbA1c after 24-week of double-blind treatment period were continued on a matching placebo of FDC of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with Linagliptin 5 mg orally once daily for subsequent 28 weeks of extension period.
Period Title: 24-week Double-blind Treatment Period
STARTED	182	93	0	0	0	0
COMPLETED	177	86	0	0	0	0
NOT COMPLETED	5	7	0	0	0	0
Period Title: 24-week Double-blind Treatment Period
STARTED	0	0	126	51	80	6
COMPLETED	0	0	123	49	79	5
NOT COMPLETED	0	0	3	2	1	1

Baseline Characteristics

Arm/Group Title	Empagliflozin 10 mg/Linagliptin 5 mg	Linagliptin 5 mg + Placebo 10 mg	Total
Arm/Group Description	Patients were administered a fixed dose combination (FDC) of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with matching placebo of Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period.	Patients were administered a matching placebo of FDC of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period.	Total of all reporting groups
Overall Participants	182	93	275
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.0 (9.9)	59.8 (10.8)	59.9 (10.2)
Sex: Female, Male (Count of Participants)
Female	40 22%	21 22.6%	61 22.2%
Male	142 78%	72 77.4%	214 77.8%

Outcome Measures

1. Primary Outcome

Title	Change of Glycosylated Haemoglobin A1c (Glycosylated Haemoglobin A1c After 24 Weeks of Double-blind Treatment From Baseline)
Description	Change from baseline in Glycosylated haemoglobin A1c (HbA1c) at Week 24 was calculated as: HbA1c at Week 24 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.
Time Frame	Baseline and 24 week

Outcome Measure Data

Analysis Population Description

The primary analysis was performed on the FAS (observed case [OC]) with treatment assignment as randomised.

Arm/Group Title	Empagliflozin 10 mg/Linagliptin 5 mg	Linagliptin 5 mg + Placebo 10 mg
Arm/Group Description	Patients were administered a fixed dose combination (FDC) of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with matching placebo of Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period.	Patients were administered a matching placebo of FDC of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period.
Measure Participants	182	93
Least Squares Mean (Standard Error) [Percentage (%)]	-0.93 (0.06)	0.21 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin 10 mg/Linagliptin 5 mg, Linagliptin 5 mg + Placebo 10 mg
	Comments	A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline estimated glomerular filtration rate (eGFR) (Modification of Diet in Renal Disease [MDRD] formula), prior use of antidiabetic drug, treatment, visit, visit by Treatment interaction as fixed effect(s). The covariance used to fit the model was unstructured.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference (Net)
	Estimated Value	-1.14
	Confidence Interval	(2-Sided) 95%; -1.36 to -0.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments	Adjusted Mean Difference was calculated as: (adjusted mean change from baseline in HbA1c at Week 24 in Empagliflozin 10 mg/linagliptin 5 mg group) - (adjusted mean change from baseline in HbA1c at Week 24 in Linagliptin 5 mg + Placebo 10 mg group)

2. Secondary Outcome

Title	Change in HbA1c From Week 28 at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Only)
Description	Change from Week 28 in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at Week 28. Week 28 (pre up-titration) is referred to the last observed measurement prior to the first administration of any double-blind randomized trial medication in the up-titration period. Adjusted mean (Least square mean) and its standard error (SE) is presented. This endpoint was based on 1 group of the Full analysis set with up-titration (FASUT-II) whose dose was up-titrated to Empagliflozin 25 mg/Linagliptin 5 mg fixed dose combination thus there is no comparison group. Hence, no comparison is made. A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline eGFR, prior use of antidiabetic drug, visit as fixed effect(s). The covariance used to fit the model was unstructured.
Time Frame	28 Week (pre up-titration) and 52 Week

Outcome Measure Data

Analysis Population Description

The full analysis set with up-titration-I (FASUT-I) consisted of all patients who were up-titrated and were treated with at least 1 dose of Empagliflozin 25 mg/linagliptin 5 mg or Linagliptin 5 mg + Placebo 25 mg after dose up-titration and who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment after dose up-titration.

Arm/Group Title	Empagliflozin 25 mg/Linagliptin 5 mg
Arm/Group Description	Patients with insufficient response based on HbA1c after 24-week of double-blind treatment period were up-titrated to a FDC of 25 mg Empagliflozin and 5 mg Linagliptin tablet along with matching placebo of Linagliptin 5 mg orally once daily for 24 weeks of up-titration period (from Week 28 to Week 52).
Measure Participants	124
Least Squares Mean (Standard Error) [Percentage (%)]	-0.21 (0.03)

3. Secondary Outcome

Title	Change in HbA1c From Baseline at Week 52 (All Empagliflozin Versus All Placebo)
Description	Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.
Time Frame	Baseline and 52 week

Outcome Measure Data

Analysis Population Description

The analysis was performed on the FAS (observed case [OC]) with treatment assignment as randomised.

Arm/Group Title	All Empagliflozin	All Placebo
Arm/Group Description	Patients were administered a FDC of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with matching placebo of Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period. In the up-titration period (from Week 28 to Week 52), patients with insufficient response measured after 24 weeks of double-blind treatment got up-titrated to FDC of 25 mg Empagliflozin and 5 mg Linagliptin while the other patients kept the same dose.	Patients were administered a matching placebo of FDC of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period. In the up-titration period (from Week 28 to Week 52), patients with insufficient response measured after 24 weeks of double-blind treatment got up-titrated to matching placebo of FDC of 25 mg Empagliflozin and 5 mg Linagliptin while the other patients kept the same dose.
Measure Participants	182	93
Least Squares Mean (Standard Error) [Percentage (%)]	-1.16 (0.06)	0.06 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin 10 mg/Linagliptin 5 mg, Linagliptin 5 mg + Placebo 10 mg
	Comments	A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline estimated glomerular filtration rate (eGFR) (Modification of Diet in Renal Disease [MDRD] formula), prior use of antidiabetic drug, treatment, visit, visit by Treatment interaction as fixed effect(s). The covariance used to fit the model was unstructured.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference (Net)
	Estimated Value	-1.22
	Confidence Interval	(2-Sided) 95%; -1.45 to -0.99
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments	Adjusted Mean Difference was calculated as: (adjusted mean change from baseline in HbA1c at Week 52 in All Empagliflozin group) - (adjusted mean change from baseline in HbA1c at Week 52 in All Placebo group)

4. Secondary Outcome

Title	Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus Linagliptin 5 mg + Placebo 25 mg)
Description	Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.
Time Frame	Baseline and 52 week

Outcome Measure Data

Analysis Population Description

FASUT-I

Arm/Group Title	Empagliflozin 25 mg/Linagliptin 5 mg	Linagliptin 5 mg + Placebo 25 mg
Arm/Group Description	Patients with insufficient response based on HbA1c after 24-week of double-blind treatment period were up-titrated to a FDC of 25 mg Empagliflozin and 5 mg Linagliptin tablet along with matching placebo of Linagliptin 5 mg orally once daily for 24 weeks of up-titration period (from Week 28 to Week 52).	Patients with insufficient response based on HbA1c after 24-week of double-blind treatment period were up-titrated to receive a matching placebo of FDC of 25 mg Empagliflozin and 5 mg Linagliptin tablet along with Linagliptin 5 mg orally once daily for 24 weeks of up-titration period (from Week 28 to Week 52).
Measure Participants	126	80
Least Squares Mean (Standard Error) [Percentage (%)]	-1.10 (0.07)	0.11 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin 10 mg/Linagliptin 5 mg, Linagliptin 5 mg + Placebo 10 mg
	Comments	A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline estimated glomerular filtration rate (eGFR) (Modification of Diet in Renal Disease [MDRD] formula), prior use of antidiabetic drug, treatment, visit, visit by Treatment interaction as fixed effect(s). The covariance used to fit the model was unstructured.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference (Net)
	Estimated Value	-1.21
	Confidence Interval	(2-Sided) 95%; -1.45 to -0.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments	Adjusted Mean Difference was calculated as: (adjusted mean change from baseline in HbA1c at Week 52 in Empagliflozin 25 mg/linagliptin 5 mg group) - (adjusted mean change from baseline in HbA1c at Week 52 in Linagliptin 5 mg + Placebo 25 mg group)

5. Secondary Outcome

Title	Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus All Placebo)
Description	Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.
Time Frame	Baseline and 52 week

Outcome Measure Data

Analysis Population Description

Full analysis set with up-titration-II consisted patients who were up-titrated to Empagliflozin 25/linagliptin 5 and were treated with at least 1 dose after dose up-titration and who were randomized to receive Linagliptin 5 + Placebo 10 or Linagliptin 5 + Placebo 25 and who had HbA1c assessment at baseline and at least once after dose up-titration.

Arm/Group Title	Empagliflozin 25 mg/Linagliptin 5 mg	All Placebo
Arm/Group Description	Patients with insufficient response based on HbA1c after 24-week of double-blind treatment period were up-titrated to a FDC of 25 mg Empagliflozin and 5 mg Linagliptin tablet along with matching placebo of Linagliptin 5 mg orally once daily for 24 weeks of up-titration period (from Week 28 to Week 52).	Patients were administered a matching placebo of FDC of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period. In the up-titration period (from Week 28 to Week 52), patients with insufficient response measured after 24 weeks of double-blind treatment got up-titrated to matching placebo of FDC of 25 mg Empagliflozin and 5 mg Linagliptin while the other patients kept the same dose.
Measure Participants	126	86
Least Squares Mean (Standard Error) [Percentage (%)]	-1.10 (0.07)	-0.01 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Empagliflozin 10 mg/Linagliptin 5 mg, Linagliptin 5 mg + Placebo 10 mg
	Comments	A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline estimated glomerular filtration rate (eGFR) (Modification of Diet in Renal Disease [MDRD] formula), prior use of antidiabetic drug, treatment, visit, visit by Treatment interaction as fixed effect(s). The covariance used to fit the model was unstructured.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted Mean Difference (Net)
	Estimated Value	-1.09
	Confidence Interval	(2-Sided) 95%; -1.34 to -0.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments	Adjusted Mean Difference was calculated as: (adjusted mean change from baseline in HbA1c at Week 52 in Empagliflozin 25 mg/linagliptin 5 mg group) - (adjusted mean change from baseline in HbA1c at Week 52 in All Placebo group)

Adverse Events

Time Frame	From first drug administration till 52 weeks, up to 7 days after last drug administration.
Adverse Event Reporting Description	TreatedSet(TS) included of patients who were randomised and treated with at least 1Dose of trial drug. Patients were randomized into 2Groups and remained in these groups after 28Weeks treatment. Patients got dose up-titrated after treatment,but had the same medication as it was before up-titrated.Data was reported for 2Arms based on randomization.
Arm/Group Title	All Empagliflozin		All Placebo
Arm/Group Description	Patients were administered a FDC of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with matching placebo of Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period. In the up-titration period (from Week 28 to Week 52), patients with insufficient response measured after 24 weeks of double-blind treatment got up-titrated to FDC of 25 mg Empagliflozin and 5 mg Linagliptin while the other patients kept the same dose.		Patients were administered a matching placebo of FDC of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period. In the up-titration period (from Week 28 to Week 52), patients with insufficient response measured after 24 weeks of double-blind treatment got up-titrated to matching placebo of FDC of 25 mg Empagliflozin and 5 mg Linagliptin while the other patients kept the same dose.
All Cause Mortality
	All Empagliflozin		All Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	All Empagliflozin		All Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/182 (4.4%)		1/93 (1.1%)
Cardiac disorders
Prinzmetal angina	1/182 (0.5%)		0/93 (0%)
Eye disorders
Glaucoma	1/182 (0.5%)		0/93 (0%)
Hepatobiliary disorders
Cholelithiasis	1/182 (0.5%)		0/93 (0%)
Injury, poisoning and procedural complications
Patella fracture	1/182 (0.5%)		0/93 (0%)
Foot fracture	1/182 (0.5%)		0/93 (0%)
Musculoskeletal and connective tissue disorders
Lumbar spinal stenosis	0/182 (0%)		1/93 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Oesophageal carcinoma	1/182 (0.5%)		0/93 (0%)
Adrenal neoplasm	1/182 (0.5%)		0/93 (0%)
Lung neoplasm malignant	1/182 (0.5%)		0/93 (0%)
Nervous system disorders
Cerebral haemorrhage	1/182 (0.5%)		0/93 (0%)
Other (Not Including Serious) Adverse Events
	All Empagliflozin		All Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	62/182 (34.1%)		46/93 (49.5%)
Infections and infestations
Nasopharyngitis	35/182 (19.2%)		34/93 (36.6%)
Asymptomatic bacteriuria	13/182 (7.1%)		6/93 (6.5%)
Investigations
Blood ketone body increased	12/182 (6.6%)		1/93 (1.1%)
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract inflammation	14/182 (7.7%)		10/93 (10.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Other - 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.