Efficacy and Safety of Empagliflozin (BI 10773) / Linagliptin (BI 1356) Fixed Dose Combination in Treatment naïve and Metformin Treated Type 2 Diabetes Patients

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double; Primary Purpose: Treatment
Condition:	Diabetes Mellitus, Type 2
Interventions:	Drug: high dose FDC; Drug: BI 10773 high dose; Drug: high dose FDC placebo; Drug: low dose FDC placebo; Drug: high dose BI 10773 placebo; Drug: low dose FDC; Drug: BI 10773 low dose; Drug: linagliptin; Drug: linagliptin placebo; Drug: BI 10773 low dose placebo; Drug: low dose BI 10773 placebo

  Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of the 1405 patients enrolled and randomized the data for 42 randomized patients were excluded from all analyses due to serious non-compliance. Therefore, 1363 patients were included in the analyses.

Reporting Groups

	Description
Metformin Background: Empagliflozin 25 mg/Linagliptin 5 mg	Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 25 mg/5 mg q.d. mode of admin: Oral
Metformin Background: Empagliflozin 10 mg/Linagliptin 5 mg	Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 10 mg/5 mg q.d. mode of admin.: Oral
Metformin Background: Empagliflozin 25 mg	Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 25 mg q.d. mode of admin.: Oral
Metformin Background: Empagliflozin 10 mg	Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 10 mg q.d. mode of admin.: Oral
Metformin Background: Linagliptin 5 mg	Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Reference therapy 2: Linagliptin tablets dose: 5 mg q.d. mode of admin.: Oral
Treatment Naive: Empagliflozin 25 mg/Linagliptin 5 mg	Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 25 mg/5 mg q.d. mode of admin.: Oral
Treament Naive: Empagliflozin 10 mg/Linagliptin 5 mg	Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 10 mg/5 mg q.d. mode of admin.: Oral
Treatment Naive: Empagliflozin 25 mg	Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 25 mg q.d. mode of admin.: Oral
Treatment Naive: Empagliflozin 10 mg	Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 10 mg q.d. mode of admin.: Oral
Treatment Naive: Linagliptin 5 mg	Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 2: Linagliptin tablets dose: 5 mg q.d. mode of admin.: Oral

Participant Flow for 2 periods

Period 1:   Week 24

	Metformin Background: Empagliflozin 25 mg/Linagliptin 5 mg	Metformin Background: Empagliflozin 10 mg/Linagliptin 5 mg	Metformin Background: Empagliflozin 25 mg	Metformin Background: Empagliflozin 10 mg	Metformin Background: Linagliptin 5 mg	Treatment Naive: Empagliflozin 25 mg/Linagliptin 5 mg	Treament Naive: Empagliflozin 10 mg/Linagliptin 5 mg	Treatment Naive: Empagliflozin 25 mg	Treatment Naive: Empagliflozin 10 mg	Treatment Naive: Linagliptin 5 mg
STARTED	137	136	141	140	132	137	136	135	134	135
COMPLETED	131	133	136	132	125	131	130	128	128	125
NOT COMPLETED	6	3	5	8	7	6	6	7	6	10
Lost to Follow-up	1	1	2	4	2	0	1	3	3	4
Consent withdrawn	5	1	3	4	5	6	5	4	3	6
Death	0	1	0	0	0	0	0	0	0	0

Period 2:   Week 52

	Metformin Background: Empagliflozin 25 mg/Linagliptin 5 mg	Metformin Background: Empagliflozin 10 mg/Linagliptin 5 mg	Metformin Background: Empagliflozin 25 mg	Metformin Background: Empagliflozin 10 mg	Metformin Background: Linagliptin 5 mg	Treatment Naive: Empagliflozin 25 mg/Linagliptin 5 mg	Treament Naive: Empagliflozin 10 mg/Linagliptin 5 mg	Treatment Naive: Empagliflozin 25 mg	Treatment Naive: Empagliflozin 10 mg	Treatment Naive: Linagliptin 5 mg
STARTED	137	136	141	140	132	137	136	135	134	135
COMPLETED	125	126	128	122	117	120	120	112	113	118
NOT COMPLETED	12	10	13	18	15	17	16	23	21	17
Lost to Follow-up	3	5	7	5	8	5	5	8	7	8
Consent withdrawn	9	4	6	12	7	12	10	12	13	9
Death	0	1	0	1	0	0	1	3	1	0

  Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS

Reporting Groups

	Description
Metformin Background: Empagliflozin 25 mg/Linagliptin 5 mg	Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation and treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. . Test product: Empagliflozin/linagliptin FDC tablets dose: 25 mg/5 mg q.d. mode of admin.: Oral
Metformin Background: Empagliflozin 10 mg/Linagliptin 5 mg	Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation and treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 10 mg/5 mg q.d. mode of admin.: Oral
Metformin Background: Empagliflozin 25 mg	Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation and treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 25 mg q.d. mode of admin.: Oral
Metformin Background: Empagliflozin 10 mg	Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation and treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 10 mg q.d. mode of admin.: Oral
Metformin Background: Linagliptin 5 mg	Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation and treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 2: Linagliptin tablets dose: 5 mg q.d. mode of admin.: Oral
Treatment Naive: Empagliflozin 25 mg/Linagliptin 5 mg	Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 25 mg/5 mg q.d. mode of admin.: Oral
Treament Naive: Empagliflozin 10 mg/Linagliptin 5 mg	Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 10 mg/5 mg q.d. mode of admin.: Oral
Treatment Naive: Empagliflozin 25 mg	Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 25 mg q.d. mode of admin.: Oral
Treatment Naive: Empagliflozin 10 mg	Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 10 mg q.d. mode of admin.: Oral
Treatment Naive: Linagliptin 5 mg	Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 2: Linagliptin tablets dose: 5 mg q.d. mode of admin.: Oral
Total	Total of all reporting groups

Baseline Measures

	Metformin Background: Empagliflozin 25 mg/Linagliptin 5 mg	Metformin Background: Empagliflozin 10 mg/Linagliptin 5 mg	Metformin Background: Empagliflozin 25 mg	Metformin Background: Empagliflozin 10 mg	Metformin Background: Linagliptin 5 mg	Treatment Naive: Empagliflozin 25 mg/Linagliptin 5 mg	Treament Naive: Empagliflozin 10 mg/Linagliptin 5 mg	Treatment Naive: Empagliflozin 25 mg	Treatment Naive: Empagliflozin 10 mg	Treatment Naive: Linagliptin 5 mg	Total
Overall Participants Analyzed; [Units: Participants]	134	135	140	137	128	134	135	133	132	133	1341
Age; [Units: Years]; Mean (Standard Deviation)	57.1 (10.2)	56.2 (10.3)	55.5 (10.0)	56.1 (10.5)	56.2 (10.0)	54.2 (10.0)	55.2 (9.8)	56.0 (9.3)	53.9 (10.5)	53.8 (11.5)	55.4 (10.2)
Gender; [Units: Participants]
Female	62	52	75	59	64	64	62	56	68	58	620
Male	72	83	65	78	64	70	73	77	64	75	721

  Outcome Measures

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1. Primary:

Change From Baseline in Glycosylated Hemoglobin (HbA1c) for Metformin Background Patients [ Time Frame: Baseline and 24 weeks ]

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2. Primary:

Change From Baseline in Glycosylated Hemoglobin (HbA1c) for Treatment Naive Patients [ Time Frame: Baseline and 24 weeks ]

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3. Secondary:

Change From Baseline in Fasting Plasma Glucose at Week 24 for Metformin Background Patients [ Time Frame: Baseline and 24 Weeks ]

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4. Secondary:

Change From Baseline in Fasting Plasma Glucose at Week 24 for Treatment Naive Patients [ Time Frame: Baseline and 24 Weeks ]

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5. Secondary:

Change From Baseline in Body Weight for Metformin Background Patients [ Time Frame: Baseline and 24 Weeks ]

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6. Secondary:

Change From Baseline in Body Weight for Treatment Naive Patients [ Time Frame: Baseline and 24 Weeks ]

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7. Secondary:

Occurrence of Treat to Target Efficacy Response for Metformin Background Patients [ Time Frame: 24 Weeks ]

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8. Secondary:

Occurrence of Treat to Target Efficacy Response for Treatment Naive Patients [ Time Frame: 24 Weeks ]

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  Serious Adverse Events

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  Other Adverse Events

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  Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information

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Certain Agreements:  

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is: The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo. The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.; Restriction Description: 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.

Results Point of Contact:  

Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim
phone: 1-800-243-0127
e-mail: clintriage.rdg@boehringer-ingelheim.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lewin A, DeFronzo RA, Patel S, Liu D, Kaste R, Woerle HJ, Broedl UC. Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care. 2015 Mar;38(3):394-402. doi: 10.2337/dc14-2365. Epub 2015 Jan 29. Erratum in: Diabetes Care. 2015 Jun;38(6):1173.

DeFronzo RA, Lewin A, Patel S, Liu D, Kaste R, Woerle HJ, Broedl UC. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015 Mar;38(3):384-93. doi: 10.2337/dc14-2364. Epub 2015 Jan 12. Erratum in: Diabetes Care. 2015 Jun;38(6):1173.

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT01422876 History of Changes
Other Study ID Numbers:	1275.1; 2011-000383-10 ( EudraCT Number: EudraCT )
First Submitted:	August 23, 2011
First Posted:	August 25, 2011
Results First Submitted:	January 15, 2015
Results First Posted:	April 2, 2015
Last Update Posted:	April 2, 2015