Efficacy and Safety of B I1356 (Linagliptin) vs. Placebo Added to Metformin Background Therapy in Patients With Type 2 Diabetes

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00601250
• Collaborator: (none)
• Enrollment: 701
• Locations: 82
• Arms: 2
• Patients Per Site: 8.5

Study Details

Study Description

Brief Summary

The objective of the current study is to investigate the efficacy, safety and tolerability of BI 1356 (5 mg once daily) compared to placebo given for 24 weeks as add-on therapy to metformin in patients with type 2 diabetes mellitus with insufficient glycaemic control

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: linagliptin; Drug: linagliptin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 701 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Randomised, Double-blind, Placebo-controlled Parallel Group Efficacy and Safety Study of BI 1356 (One Dose, e.g. 5 mg), Administered Orally Once Daily Over 24 Weeks, With an Open Label Extension to 80 Weeks (Placebo Patients Switched to BI 1356), in Type 2 Diabetic Patients With Insufficient Glycaemic Control Despite Metformin Therapy
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: May 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Linagliptin Patients receive linagliptin 5 mg tablets once daily	Drug: linagliptin; Patients receive linagliptin 5 mg tablets once daily
Placebo Comparator: Placebo Patients receive placebo tablets matching linagliptin 5 mg tablets once daily	Drug: linagliptin; Patients receive linagliptin 5 mg tablets once daily

Outcome Measures

Primary Outcome Measures

1. HbA1c Change From Baseline at Week 24 [Baseline and week 24]

   HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.

Secondary Outcome Measures

1. HbA1c Change From Baseline at Week 6 [Baseline and week 6]

   HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 6 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.

2. HbA1c Change From Baseline at Week 12 [Baseline and week 12]

   HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 12 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.

3. HbA1c Change From Baseline at Week 18 [Baseline and week 18]

   HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.

4. FPG Change From Baseline at Week 24 [Baseline and week 24]

   This change from baseline reflects the Week 24 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.

5. FPG Change From Baseline at Week 6 [Baseline and week 6]

   This change from baseline reflects the Week 6 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.

6. FPG Change From Baseline at Week 12 [Baseline and week 12]

   This change from baseline reflects the Week 12 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.

7. FPG Change From Baseline at Week 18 [Baseline and week 18]

   This change from baseline reflects the Week 18 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.

8. Percentage of Patients With HbA1c <7.0% at Week 24. [Baseline and week 24]

   The percentage of patients with an HbA1c value below 7.0% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c >= 7.0%. Only patients with baseline HbA1c >= 7%

9. Percentage of Patients With HbA1c < 7.0% at Week 24 [Baseline and week 24]

   The percentage of patients with an HbA1c value below 7.0% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c >= 7.0%.

10. Percentage of Patients With HbA1c <6.5% at Week 24 [Baseline and week 24]

    The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c >= 6.5%. Only patients with baseline HbA1c >= 6.5%

11. Percentage of Patients With HbA1c<6.5% at Week 24 [Baseline and week 24]

    The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c >= 6.5%.

12. Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24 [Baseline and week 24]

    The percentage of patients with an HbA1c reduction from baseline >= 0.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c reduction less than 0.5%.

13. Adjusted Means for 2h Post Prandial Blood Glucose (PPG) Change From Baseline at Week 24 [Baseline and week 24]

    This change from baseline reflects the Week 24 2h PPG minus the baseline 2h PPG. Means are treatment adjusted for baseline HbA1c, baseline PPG and previous anti-diabetic medication.

14. 2 Hour Post-Prandial Glucose (PPG) Increment Over Fasting Plasma Glucose (FPG) at Week 24 [Baseline and week 24]

    This change from baseline reflects the Week 24 (2h PPG - FPG) minus the baseline (2h PPG - FPG). Means are treatment adjusted for baseline HbA1c, baseline 2h PPG increment over FPG and previous anti-diabetic medication.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Male and female patients with a diagnosis of type 2 diabetes mellitus and previously treated with metformin alone, or with metformin and not more than one other oral antidiabetic drug

2. Diagnosis of type 2 diabetes prior to informed consent

3. Glycosylated haemoglobin A1 (HbA1c)at screening:

For patients undergoing wash out of previous medication: HbA1c 6.5 - 9.0% For patients not undergoing wash-out of previous medication: HbA1c 7.0 - 10.0%

1. Glycosylated haemoglobin A1 (HbA1c) 7.0 - 10.0% at the beginning of Placebo Run-in

2. Age 18 -80 years

3. BMI (Body Mass Index) less than 40 kg/m2

4. Signed and dated written informed consent by date of Visit 1a in accordance with GCP and local legislation

Exclusion criteria:

1. Myocardial infarction, stroke or transient ischemic attack (TIA) within 6 months prior to informed consent

2. Impaired hepatic function

3. Known hypersensitivity or allergy to the investigational product or its excipients or metformin or placebo

4. Treatment with rosiglitazone or pioglitazone within 3 months prior to informed consent

5. Treatment with an injectable GLP-1 analogue (e.g. exenatide) within 3 months prior to informed consent

6. Treatment with insulin within 3 months prior to informed consent

7. Treatment with anti-obesity drugs (e.g. sibutramine, orlistat, rimonabant) within 3 months prior to informed consent

8. Alcohol abuse within the 3 months prior to informed consent that would interfere with trial participation or drug abuse

9. Participation in another trial with an investigational drug within 2 months prior to informed consent

10. Pre-menopausal women who:

• are nursing or pregnant,

• or 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 study and do not agree to submit to periodic pregnancy testing during participation in the trial.

1. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent.

2. Renal failure or renal impairment

3. Unstable or acute congestive heart failure

4. Acute or chronic metabolic acidosis (present in patient history)

5. Hereditary galactose intolerance

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1218.17.10003 Boehringer Ingelheim Investigational Site	Chula Vista	California	United States
2	1218.17.10014 Boehringer Ingelheim Investigational Site	Spring Valley	California	United States
3	1218.17.10001 Boehringer Ingelheim Investigational Site	Walnut Creek	California	United States
4	1218.17.10021 Boehringer Ingelheim Investigational Site	Northglenn	Colorado	United States
5	1218.17.10010 Boehringer Ingelheim Investigational Site	Hollywood	Florida	United States
6	1218.17.10011 Boehringer Ingelheim Investigational Site	Miami	Florida	United States
7	1218.17.10008 Boehringer Ingelheim Investigational Site	Pembroke Pines	Florida	United States
8	1218.17.10017 Boehringer Ingelheim Investigational Site	Gurnee	Illinois	United States
9	1218.17.10006 Boehringer Ingelheim Investigational Site	Omaha	Nebraska	United States
10	1218.17.10012 Boehringer Ingelheim Investigational Site	Charlotte	North Carolina	United States
11	1218.17.10013 Boehringer Ingelheim Investigational Site	Mentor	Ohio	United States
12	1218.17.10015 Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma	United States
13	1218.17.10016 Boehringer Ingelheim Investigational Site	Eugene	Oregon	United States
14	1218.17.10002 Boehringer Ingelheim Investigational Site	Greer	South Carolina	United States
15	1218.17.10004 Boehringer Ingelheim Investigational Site	Simpsonville	South Carolina	United States
16	1218.17.10005 Boehringer Ingelheim Investigational Site	Dallas	Texas	United States
17	1218.17.10018 Boehringer Ingelheim Investigational Site	Houston	Texas	United States
18	1218.17.10007 Boehringer Ingelheim Investigational Site	San Antonio	Texas	United States
19	1218.17.10009 Boehringer Ingelheim Investigational Site	Federal Way	Washington	United States
20	1218.17.42006 Boehringer Ingelheim Investigational Site	Breclav		Czech Republic
21	1218.17.42001 Boehringer Ingelheim Investigational Site	Brno		Czech Republic
22	1218.17.42004 Boehringer Ingelheim Investigational Site	Brno		Czech Republic
23	1218.17.42007 Boehringer Ingelheim Investigational Site	Brno		Czech Republic
24	1218.17.42009 Boehringer Ingelheim Investigational Site	Brno		Czech Republic
25	1218.17.42008 Boehringer Ingelheim Investigational Site	Hodonin		Czech Republic
26	1218.17.42003 Boehringer Ingelheim Investigational Site	Olomouc		Czech Republic
27	1218.17.35806 Boehringer Ingelheim Investigational Site	Helsinki		Finland
28	1218.17.35804 Boehringer Ingelheim Investigational Site	Jyväskylä		Finland
29	1218.17.35801 Boehringer Ingelheim Investigational Site	Kuopio		Finland
30	1218.17.35803 Boehringer Ingelheim Investigational Site	Oulu		Finland
31	1218.17.35805 Boehringer Ingelheim Investigational Site	Seinäjoki		Finland
32	1218.17.35802 Boehringer Ingelheim Investigational Site	Turku		Finland
33	1218.17.30004 Boehringer Ingelheim Investigational Site	Athens		Greece
34	1218.17.30013 Boehringer Ingelheim Investigational Site	Athens		Greece
35	1218.17.30011 Boehringer Ingelheim Investigational Site	Piraeus		Greece
36	1218.17.91009 Boehringer Ingelheim Investigational Site	Andhra Pradesh		India
37	1218.17.91002 Boehringer Ingelheim Investigational Site	Bangalore		India
38	1218.17.91005 Boehringer Ingelheim Investigational Site	Bangalore		India
39	1218.17.91012 Boehringer Ingelheim Investigational Site	Chennai		India
40	1218.17.91014 Boehringer Ingelheim Investigational Site	Chennai		India
41	1218.17.91010 Boehringer Ingelheim Investigational Site	Hyderabad		India
42	1218.17.91006 Boehringer Ingelheim Investigational Site	Jaipur		India
43	1218.17.91007 Boehringer Ingelheim Investigational Site	Karnataka		India
44	1218.17.91008 Boehringer Ingelheim Investigational Site	Mangalore		India
45	1218.17.91004 Boehringer Ingelheim Investigational Site	Mumbai		India
46	1218.17.91011 Boehringer Ingelheim Investigational Site	Nagpur		India
47	1218.17.91003 Boehringer Ingelheim Investigational Site	Nasik		India
48	1218.17.91001 Boehringer Ingelheim Investigational Site	Trivandrum		India
49	1218.17.91013 Boehringer Ingelheim Investigational Site	Uttar Pradesh		India
50	1218.17.97274 Boehringer Ingelheim Investigational Site	Afula		Israel
51	1218.17.97273 Boehringer Ingelheim Investigational Site	Haifa		Israel
52	1218.17.97275 Boehringer Ingelheim Investigational Site	Holon		Israel
53	1218.17.97271 Boehringer Ingelheim Investigational Site	Jerusalem		Israel
54	1218.17.97272 Boehringer Ingelheim Investigational Site	Nahariya		Israel
55	1218.17.97276 Boehringer Ingelheim Investigational Site	Safed		Israel
56	1218.17.97278 Boehringer Ingelheim Investigational Site	Tel Aviv		Israel
57	1218.17.52007 Boehringer Ingelheim Investigational Site	Aguascalientes, Ags.		Mexico
58	1218.17.52009 Boehringer Ingelheim Investigational Site	cOL OBREGON,León, Guanajuato		Mexico
59	1218.17.52003 Boehringer Ingelheim Investigational Site	Col. Lomas de San Francisco, Monterrey		Mexico
60	1218.17.52001 Boehringer Ingelheim Investigational Site	Col. Mitras Centro, Monterrey, N.L.		Mexico
61	1218.17.52010 Boehringer Ingelheim Investigational Site	Col.Americana, Guadalajara, Jalisco		Mexico
62	1218.17.52005 Boehringer Ingelheim Investigational Site	Colonia Reforma Social		Mexico
63	1218.17.52008 Boehringer Ingelheim Investigational Site	Colonia Tlalpan, mexico		Mexico
64	1218.17.52006 Boehringer Ingelheim Investigational Site	Faccionamiento Lomas de Campestre,AGUASCAL		Mexico
65	1218.17.52002 Boehringer Ingelheim Investigational Site	Mexico		Mexico
66	1218.17.52004 Boehringer Ingelheim Investigational Site	Tlalpan-México D,F		Mexico
67	1218.17.64004 Boehringer Ingelheim Investigational Site	Christchurch		New Zealand
68	1218.17.64003 Boehringer Ingelheim Investigational Site	Dunedin		New Zealand
69	1218.17.64002 Boehringer Ingelheim Investigational Site	Otahuhu		New Zealand
70	1218.17.64001 Boehringer Ingelheim Investigational Site	Tauranga		New Zealand
71	1218.17.64005 Boehringer Ingelheim Investigational Site	Wellington		New Zealand
72	1218.17.70001 Boehringer Ingelheim Investigational Site	Moscow		Russian Federation
73	1218.17.70002 Boehringer Ingelheim Investigational Site	Moscow		Russian Federation
74	1218.17.70003 Boehringer Ingelheim Investigational Site	Moscow		Russian Federation
75	1218.17.70005 Boehringer Ingelheim Investigational Site	Novosibirsk		Russian Federation
76	1218.17.70006 Boehringer Ingelheim Investigational Site	Perm		Russian Federation
77	1218.17.70004 Boehringer Ingelheim Investigational Site	Tomsk		Russian Federation
78	1218.17.46013 Boehringer Ingelheim Investigational Site	Härnösand		Sweden
79	1218.17.46001 Boehringer Ingelheim Investigational Site	Malmö		Sweden
80	1218.17.46012 Boehringer Ingelheim Investigational Site	Uddevalla		Sweden
81	1218.17.46004 Boehringer Ingelheim Investigational Site	Uppsala		Sweden
82	1218.17.46015 Boehringer Ingelheim Investigational Site	Uppsala		Sweden

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00601250
• Other Study ID Numbers: 1218.17; 2007-002457-24
• First Posted: Jan 28, 2008
• Last Update Posted: Jan 28, 2014
• Last Verified: Dec 1, 2013

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

Study Results

Participant Flow

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Period Title: Overall Study
STARTED	177	523
COMPLETED	163	484
NOT COMPLETED	14	39

Baseline Characteristics

Arm/Group Title	Placebo	Linagliptin	Total
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg	Total of all reporting groups
Overall Participants	177	523	700
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	56.6 (10.9)	56.5 (10.1)	56.5 (10.3)
Sex: Female, Male (Count of Participants)
Female	76 42.9%	245 46.8%	321 45.9%
Male	101 57.1%	278 53.2%	379 54.1%
Body Mass Index (BMI) continuous (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	30.05 (5.01)	29.85 (4.84)	29.90 (4.88)
Glycosylated haemoglobin A1 (HbA1C) (Percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent]	8.02 (0.88)	8.09 (0.86)	8.08 (0.87)
Fasting blood plasma glucose (FPG) (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	166.42 (41.89)	169.62 (43.51)	168.81 (43.10)

Outcome Measures

1. Primary Outcome

Title	HbA1c Change From Baseline at Week 24
Description	HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time Frame	Baseline and week 24

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all treated and randomised patients with a baseline and at least one on-treatment HbA1c measurement available. Last observation carried forward (LOCF) was used as the imputation rule.

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	175	513
Mean (Standard Error) [Percent]	0.15 (0.06)	-0.49 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.64
	Confidence Interval	(2-Sided) 95%; -0.78 to -0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments

2. Secondary Outcome

Title	HbA1c Change From Baseline at Week 6
Description	HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 6 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time Frame	Baseline and week 6

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all treated and randomised patients with a baseline and at least one on-treatment HbA1c measurement available. Last observation carried forward (LOCF) was used as the imputation rule.

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	175	513
Mean (Standard Error) [Percent]	0.069 (0.044)	-0.363 (0.027)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.431
	Confidence Interval	(2-Sided) 95%; -0.530 to -0.333
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.050
	Estimation Comments

3. Secondary Outcome

Title	HbA1c Change From Baseline at Week 12
Description	HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 12 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time Frame	Baseline and week 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all treated and randomised patients with a baseline and at least one on-treatment HbA1c measurement available. Last observation carried forward (LOCF) was used as the imputation rule.

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	175	513
Mean (Standard Error) [Percent]	0.096 (0.056)	-0.499 (0.034)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.596
	Confidence Interval	() 95%; -0.721 to -0.471
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.064
	Estimation Comments

4. Secondary Outcome

Title	HbA1c Change From Baseline at Week 18
Description	HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time Frame	Baseline and week 18

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all treated and randomised patients with a baseline and at least one on-treatment HbA1c measurement available. Last observation carried forward (LOCF) was used as the imputation rule.

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	175	513
Mean (Standard Error) [Percent]	0.147 (0.061)	-0.502 (0.037)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.648
	Confidence Interval	() 95%; -0.785 to -0.512
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.069
	Estimation Comments

5. Secondary Outcome

Title	FPG Change From Baseline at Week 24
Description	This change from baseline reflects the Week 24 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.
Time Frame	Baseline and week 24

Outcome Measure Data

Analysis Population Description

This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	159	495
Mean (Standard Error) [mg/dL]	10.46 (2.80)	-10.68 (1.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-21.13
	Confidence Interval	() 95%; -27.3 to -14.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.14
	Estimation Comments

6. Secondary Outcome

Title	FPG Change From Baseline at Week 6
Description	This change from baseline reflects the Week 6 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.
Time Frame	Baseline and week 6

Outcome Measure Data

Analysis Population Description

This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	159	495
Mean (Standard Error) [mg/dL]	4.58 (2.38)	-11.94 (1.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-16.52
	Confidence Interval	() 95%; -21.76 to -11.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.67
	Estimation Comments

7. Secondary Outcome

Title	FPG Change From Baseline at Week 12
Description	This change from baseline reflects the Week 12 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.
Time Frame	Baseline and week 12

Outcome Measure Data

Analysis Population Description

This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	159	495
Mean (Standard Error) [mg/dL]	3.86 (2.60)	-12.86 (1.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-16.73
	Confidence Interval	() 95%; -22.44 to -11.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.91
	Estimation Comments

8. Secondary Outcome

Title	FPG Change From Baseline at Week 18
Description	This change from baseline reflects the Week 18 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.
Time Frame	Baseline and week 18

Outcome Measure Data

Analysis Population Description

This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	159	495
Mean (Standard Error) [mg/dL]	10.32 (2.72)	-10.51 (1.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-20.83
	Confidence Interval	() 95%; -26.81 to -14.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.05
	Estimation Comments

9. Secondary Outcome

Title	Percentage of Patients With HbA1c <7.0% at Week 24.
Description	The percentage of patients with an HbA1c value below 7.0% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c >= 7.0%. Only patients with baseline HbA1c >= 7%
Time Frame	Baseline and week 24

Outcome Measure Data

Analysis Population Description

This population includes the FAS with baseline HbA1c >= 7.0%. Non-completers were considered as failure imputation (NCF).

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	163	485
Number [percentage of patients]	9.2 (0.00)	26.2 (0.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo The odds-ratio is based on a logistic regression model including baseline HbA1c and previous antidiabetic medication.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.395
	Confidence Interval	() 95%; 2.410 to 8.013
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Percentage of Patients With HbA1c < 7.0% at Week 24
Description	The percentage of patients with an HbA1c value below 7.0% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c >= 7.0%.
Time Frame	Baseline and week 24

Outcome Measure Data

Analysis Population Description

This population includes the Full Analysis Set (FAS). Non-completers were considered as failure imputation (NCF).

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	175	513
Number [percentage of patients]	11.4	28.3

11. Secondary Outcome

Title	Percentage of Patients With HbA1c <6.5% at Week 24
Description	The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c >= 6.5%. Only patients with baseline HbA1c >= 6.5%
Time Frame	Baseline and week 24

Outcome Measure Data

Analysis Population Description

This population includes the FAS with baseline HbA1c >= 6.5%. Non-completers were considered as failure imputation (NCF).

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	171	511
Number [percentage of patients]	2.3 (0.00)	10.4 (0.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo The odds-ratio is based on a logistic regression model including baseline HbA1c and previous antidiabetic medication.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0016
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.456
	Confidence Interval	() 95%; 1.907 to 15.614
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Percentage of Patients With HbA1c<6.5% at Week 24
Description	The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c >= 6.5%.
Time Frame	Baseline and week 24

Outcome Measure Data

Analysis Population Description

This population includes the Full Analysis Set (FAS). Non-completers were considered as failure imputation (NCF).

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	175	513
Number [percentage of patients]	3.4	10.7

13. Secondary Outcome

Title	Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24
Description	The percentage of patients with an HbA1c reduction from baseline >= 0.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c reduction less than 0.5%.
Time Frame	Baseline and week 24

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all patients with a baseline and at least one on treatment HbA1c measurement available. Non-completers were considered as failure imputation (NCF).

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	175	513
Number [percentage of patients]	21.7 (0.00)	49.7 (0.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo The odds-ratio is based on a logistic regression model including baseline HbA1c and previous antidiabetic medication.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.754
	Confidence Interval	() 95%; 2.486 to 5.669
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Adjusted Means for 2h Post Prandial Blood Glucose (PPG) Change From Baseline at Week 24
Description	This change from baseline reflects the Week 24 2h PPG minus the baseline 2h PPG. Means are treatment adjusted for baseline HbA1c, baseline PPG and previous anti-diabetic medication.
Time Frame	Baseline and week 24

Outcome Measure Data

Analysis Population Description

Meal Tolerance Test (MTT) set (treated and randomised patients with adequate MTT results available at the beginning and end of the randomised treatment period)

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	21	78
Mean (Standard Error) [mg/dL]	18.27 (12.85)	-48.86 (7.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-67.13
	Confidence Interval	(2-Sided) 95%; -94.69 to -39.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.88
	Estimation Comments

15. Secondary Outcome

Title	2 Hour Post-Prandial Glucose (PPG) Increment Over Fasting Plasma Glucose (FPG) at Week 24
Description	This change from baseline reflects the Week 24 (2h PPG - FPG) minus the baseline (2h PPG - FPG). Means are treatment adjusted for baseline HbA1c, baseline 2h PPG increment over FPG and previous anti-diabetic medication.
Time Frame	Baseline and week 24

Outcome Measure Data

Analysis Population Description

Meal Tolerance Test (MTT) set (treated and randomised patients with adequate MTT results available at the beginning and end of the randomised treatment period)

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo	Patients randomized to receive treatment with Linagliptin 5 mg
Measure Participants	21	74
Least Squares Mean (Standard Error) [mg/dL]	10.90 (9.23)	-30.90 (5.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Linagliptin vs. Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-41.80
	Confidence Interval	(2-Sided) 95%; -61.71 to -21.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.02
	Estimation Comments

Adverse Events

Time Frame	From day of first dose until 7 days after last dose
Arm/Group Title	Placebo		Linagliptin
Arm/Group Description	Patients randomized to receive treatment with matching placebo		Patients randomized to receive treatment with Linagliptin 5 mg
All Cause Mortality
	Placebo		Linagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Linagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/177 (2.3%)		18/523 (3.4%)
Cardiac disorders
Angina pectoris	0/177 (0%)		1/523 (0.2%)
Atrial fibrillation	0/177 (0%)		1/523 (0.2%)
Myocardial infarction	0/177 (0%)		1/523 (0.2%)
Myocardial ischaemia	0/177 (0%)		1/523 (0.2%)
Gastrointestinal disorders
Dyspepsia	0/177 (0%)		1/523 (0.2%)
General disorders
Non-cardiac chest pain	0/177 (0%)		1/523 (0.2%)
Infections and infestations
Blebitis	0/177 (0%)		1/523 (0.2%)
Gastroenteritis	0/177 (0%)		1/523 (0.2%)
Gastroenteritis viral	0/177 (0%)		1/523 (0.2%)
Hepatitis viral	1/177 (0.6%)		0/523 (0%)
Injury, poisoning and procedural complications
Avulsion fracture	0/177 (0%)		1/523 (0.2%)
Snake bite	0/177 (0%)		1/523 (0.2%)
Ulna fracture	0/177 (0%)		1/523 (0.2%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	1/177 (0.6%)		1/523 (0.2%)
Nervous system disorders
Cerebral ischaemia	1/177 (0.6%)		0/523 (0%)
Headache	1/177 (0.6%)		0/523 (0%)
Renal and urinary disorders
Calculus ureteric	0/177 (0%)		2/523 (0.4%)
Nephrolithiasis	0/177 (0%)		2/523 (0.4%)
Renal mass	0/177 (0%)		1/523 (0.2%)
Reproductive system and breast disorders
Rectocele	1/177 (0.6%)		0/523 (0%)
Respiratory, thoracic and mediastinal disorders
Bronchial hyperreactivity	0/177 (0%)		1/523 (0.2%)
Pulmonary embolism	0/177 (0%)		1/523 (0.2%)
Vascular disorders
Hypertension	0/177 (0%)		1/523 (0.2%)
Other (Not Including Serious) Adverse Events
	Placebo		Linagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/177 (19.2%)		54/523 (10.3%)
Infections and infestations
Nasopharyngitis	9/177 (5.1%)		27/523 (5.2%)
Metabolism and nutrition disorders
Hyperglycaemia	26/177 (14.7%)		27/523 (5.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.