Efficacy and Safety of BI 1356 in Combination With Metformin in Patients With Type 2 Diabetes

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00622284
• Collaborator: (none)
• Enrollment: 1,560
• Locations: 221
• Arms: 2
• Patients Per Site: 7.1

Study Details

Study Description

Brief Summary

The objective of the current study is to investigate the efficacy, safety and tolerability of BI 1356 (5.0 mg daily) compared to glimepiride given for 104 weeks as add-on therapy to preferably > 1500 mg metformin in patients with type 2 diabetes mellitus with insufficient glycaemic control

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Placebo identical to BI 1356 5mg; Drug: Placebo identical to Glimepiride 1mg or 2mg or 3mg or 4 mg; Drug: BI 1356; Drug: Glimepiride	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1560 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Randomised Double-blind, Active-controlled Parallel Group Efficacy and Safety Study of BI 1356 ( 5.0 mg, Administered Orally Once Daily) Compared to Glimepiride Over Two Years in Type 2 Diabetic Patients With Insufficient Glycaemic Control Despite Metformin Therapy
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 1356 5mg, once daily patient to receive a tablet containing 5mg BI 1356 plus one (two in US) inactive placebo capsule matching Glimepiride	Drug: Placebo identical to Glimepiride 1mg or 2mg or 3mg or 4 mg; Placebo tablets once daily; Drug: BI 1356; 5mg, once daily in the morning for 104 weeks
Active Comparator: Glimepiride patient to receive 1mg or 2mg or 3mg (not in US) or 4mg Glimepiride capsule plus one inactive placebo tablet matching BI 1356 (plus one inactive placebo capsule in US)	Drug: Placebo identical to BI 1356 5mg; Placebo tablet once daily; Drug: Glimepiride; 1mg or 2mg or 3mg or 4mg in the morning for 104 weeks

Outcome Measures

Primary Outcome Measures

1. HbA1c Change From Baseline at Week 52 [Baseline and week 52]

   This co-primary endpoint, change from baseline, reflects the Week 52 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and the number of previous anti-diabetic medications.

2. HbA1c Change From Baseline at Week 104 [Baseline and week 104]

   This co-primary endpoint, change from baseline, reflects the Week 104 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and the number of previous anti-diabetic medications.

Secondary Outcome Measures

1. Body Weight Change From Baseline at Week 52 [Baseline and week 52]

   This key secondary endpoint, change from baseline, reflects the Week 52 body weight minus the baseline body weight. Means are treatment adjusted for baseline HbA1c, baseline weight and the number of previous antidiabetic-medications.

2. Body Weight Change From Baseline at Week 104 [Baseline and week 104]

   This key secondary endpoint, change from baseline, reflects the Week 104 body weight minus the baseline body weight. Means are treatment adjusted for baseline HbA1c, baseline weight and the number of previous antidiabetic-medications.

3. Incidence of Hypoglycaemic Events up to 52 Weeks [Week 52]

   A hypoglycaemic event is defined as patient showing clinical signs suggestive of low blood glucose confirmed by a home blood glucose monitoring (HBGM) of below 55 mg/dl (3.1 mmol/L)

4. Incidence of Hypoglycaemic Events up to 104 Weeks [Week 104]

   A hypoglycaemic event is defined as patient showing clinical signs suggestive of low blood glucose confirmed by a HBGM of below 55 mg/dl (3.1 mmol/L)

5. Fasting Plasma Glucose (FPG) Change From Baseline at Week 52 [Baseline and week 52]

   This change from baseline reflects the Week 52 FPG minus the Baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and the number of previous anti-diabetic medications.

6. Fasting Plasma Glucose (FPG) Change From Baseline at Week 104 [Baseline and week 104]

   This change from baseline reflects the Week 104 FPG minus the Baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and number of previous anti-diabetic medications.

7. Percentage of Patients With HbA1c <7.0% at Week 52 [Week 52]

   The percentage of patients with an HbA1c value below 7.0% at week 52, based upon patients with baseline HbA1c >= 7%. If a patient did not have an HbA1c value at week 52 they were considered a failure, so HbA1c >= 7.0%. The logistic regression is treatment adjusted for baseline HbA1c and number of previous anti-diabetic medications.

8. Percentage of Patients With HbA1c <7.0% at Week 104 [Week 104]

   The percentage of patients with an HbA1c value below 7.0% at week 104, based upon patients with baseline HbA1c >= 7%. If a patient did not have an HbA1c value at week 104 they were considered a failure, so HbA1c >= 7.0%. The logistic regression is treatment adjusted for baseline HbA1c and number of previous anti-diabetic medications.

9. Percentage of Patients With HbA1c <6.5% at Week 52 [Week 52]

   The percentage of patients with an HbA1c value below 6.5% at week 52, based upon patients with baseline HbA1c >= 6.5%. If a patient did not have an HbA1c value at week 52 they were considered a failure, so HbA1c >= 6.5%. The logistic regression is treatment adjusted for baseline HbA1c and number of previous anti-diabetic medications.

10. Percentage of Patients With HbA1c <6.5% at Week 104 [Week 104]

    The percentage of patients with an HbA1c value below 6.5% at week 104, based upon patients with baseline HbA1c >= 6.5%. If a patient did not have an HbA1c value at week 104 they were considered a failure, so HbA1c >= 6.5%. The logistic regression is treatment adjusted for baseline HbA1c and number of previous anti-diabetic medications.

11. Percentage of Patients With HbA1c Lowering by 0.5% at Week 104 [Week 104]

    Occurrence of relative efficacy response, defined as a lowering of 0.5% HbA1c at week 104

12. 2 hr Postprandial Glucose (PPG) Change From Baseline at Week 104 [Baseline and week 104]

    This change from baseline reflects the Week 104 2 hr PPG minus the Baseline 2hr PPG. Means are treatment adjusted for baseline HbA1c, baseline 2hr PPG and number of previous anti-diabetic medications.

13. HbA1c Change at Week 4 [Baseline and week 4]

    Difference of base percent value [Week x(%) - baseline (%)]

14. HbA1c Change at Week 8 [Baseline and week 8]

15. HbA1c Change at Week 12 [Baseline and week 12]

16. HbA1c Change at Week 16 [Baseline and week 16]

17. HbA1c Change at Week 28 [Baseline and week 28]

18. HbA1c Change at Week 40 [Baseline and week 40]

19. HbA1c Change at Week 52 [Baseline and week 52]

20. HbA1c Change at Week 65 [Baseline and week 65]

21. HbA1c Change at Week 78 [Baseline and week 78]

22. HbA1c Change at Week 91 [Baseline and week 91]

23. HbA1c Change at Week 104 [Baseline and week 104]

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

24. Change in Baseline Lipid Parameter Cholesterol at Week 104 [Baseline and week 104]

25. Change in Baseline Lipid Parameter HDL at Week 104 [Baseline and week 104]

26. Change in Baseline Lipid Parameter Low Density Lipoprotein (LDL) at Week 104 [Baseline and week 104]

27. Change in Baseline Lipid Parameter Triglyceride at Week 104 [Baseline and week 104]

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 one other oral antidiabetic drug

2. Glycosylated haemoglobin (HbA1c) 6.0 - 9.0% at screening for patients treated with metformin and one other oral antidiabetic drug

3. HbA1c 6.5 - 10.0% at screening for patients treated with metformin alone

4. HbA1c 6.5 - 10.0% at beginning of the placebo run-in phase

Exclusion criteria:

1. Myocardial infarction, stroke or transient ischemic attack (TIA)

2. Impaired hepatic function

3. Renal failure or renal impairment

4. Treatment with rosiglitazone or pioglitazone within 6 months prior to screening

5. Treatment with insulin or glucagon-like peptide 1 (GLP-1) analogue/antagonists within 3 months prior to screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1218.20.10033 Boehringer Ingelheim Investigational Site	Tempe	Arizona	United States
2	1218.20.10003 Boehringer Ingelheim Investigational Site	Chula Vista	California	United States
3	1218.20.10020 Boehringer Ingelheim Investigational Site	Los Angeles	California	United States
4	1218.20.10035 Boehringer Ingelheim Investigational Site	Los Angeles	California	United States
5	1218.20.10037 Boehringer Ingelheim Investigational Site	Los Gatos	California	United States
6	1218.20.10034 Boehringer Ingelheim Investigational Site	West Palm Beach	Florida	United States
7	1218.20.10023 Boehringer Ingelheim Investigational Site	Indianapolis	Indiana	United States
8	1218.20.10030 Boehringer Ingelheim Investigational Site	Topeka	Kansas	United States
9	1218.20.10028 Boehringer Ingelheim Investigational Site	St. Louis	Missouri	United States
10	1218.20.10006 Boehringer Ingelheim Investigational Site	Omaha	Nebraska	United States
11	1218.20.10022 Boehringer Ingelheim Investigational Site	Endwell	New York	United States
12	1218.20.10032 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio	United States
13	1218.20.10031 Boehringer Ingelheim Investigational Site	Columbus	Ohio	United States
14	1218.20.10013 Boehringer Ingelheim Investigational Site	Mentor	Ohio	United States
15	1218.20.10045 Boehringer Ingelheim Investigational Site	Perrysburg	Ohio	United States
16	1218.20.10042 Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma	United States
17	1218.20.10024 Boehringer Ingelheim Investigational Site	Philadelphia	Pennsylvania	United States
18	1218.20.10002 Boehringer Ingelheim Investigational Site	Greer	South Carolina	United States
19	1218.20.10007 Boehringer Ingelheim Investigational Site	San Antonio	Texas	United States
20	1218.20.10036 Boehringer Ingelheim Investigational Site	Murray	Utah	United States
21	1218.20.10029 Boehringer Ingelheim Investigational Site	Salt Lake City	Utah	United States
22	1218.20.10009 Boehringer Ingelheim Investigational Site	Federal Way	Washington	United States
23	1218.20.10026 Boehringer Ingelheim Investigational Site	Renton	Washington	United States
24	1218.20.35201 Boehringer Ingelheim Investigational Site	Sofia		Bulgaria
25	1218.20.35202 Boehringer Ingelheim Investigational Site	Sofia		Bulgaria
26	1218.20.35203 Boehringer Ingelheim Investigational Site	Sofia		Bulgaria
27	1218.20.35207 Boehringer Ingelheim Investigational Site	Sofia		Bulgaria
28	1218.20.35204 Boehringer Ingelheim Investigational Site	Stara Zagora		Bulgaria
29	1218.20.45006 Boehringer Ingelheim Investigational Site	Aalborg		Denmark
30	1218.20.45001 Boehringer Ingelheim Investigational Site	Aarhus C		Denmark
31	1218.20.45011 Boehringer Ingelheim Investigational Site	Aarhus C		Denmark
32	1218.20.45013 Boehringer Ingelheim Investigational Site	Aarhus C		Denmark
33	1218.20.45002 Boehringer Ingelheim Investigational Site	Hvidovre		Denmark
34	1218.20.45003 Boehringer Ingelheim Investigational Site	København NV		Denmark
35	1218.20.45007 Boehringer Ingelheim Investigational Site	Odense		Denmark
36	1218.20.3307A Boehringer Ingelheim Investigational Site	Joué les Tours Cedex		France
37	1218.20.3307B Boehringer Ingelheim Investigational Site	Joué les Tours cedex		France
38	1218.20.3307C Boehringer Ingelheim Investigational Site	Joué les Tours cedex		France
39	1218.20.3307D Boehringer Ingelheim Investigational Site	Joué les Tours cedex		France
40	1218.20.3307E Boehringer Ingelheim Investigational Site	Joué les Tours cedex		France
41	1218.20.3307F Boehringer Ingelheim Investigational Site	Joué les Tours cedex		France
42	1218.20.3307G Boehringer Ingelheim Investigational Site	Joué les Tours cedex		France
43	1218.20.3307H Boehringer Ingelheim Investigational Site	Joué les Tours cedex		France
44	1218.20.3307I Boehringer Ingelheim Investigational Site	Joué les Tours cedex		France
45	1218.20.3310A Boehringer Ingelheim Investigational Site	Joué les Tours Cedex		France
46	1218.20.3310B Boehringer Ingelheim Investigational Site	Joué les Tours Cedex		France
47	1218.20.3310C Boehringer Ingelheim Investigational Site	Joué les Tours Cedex		France
48	1218.20.3310D Boehringer Ingelheim Investigational Site	Joué les Tours Cedex		France
49	1218.20.3310E Boehringer Ingelheim Investigational Site	Joué les Tours Cedex		France
50	1218.20.3312A Boehringer Ingelheim Investigational Site	Joué les Tours Cedex		France
51	1218.20.3312B Boehringer Ingelheim Investigational Site	Joué les Tours Cedex		France
52	1218.20.3312C Boehringer Ingelheim Investigational Site	Joué les Tours Cedex		France
53	1218.20.3312D Boehringer Ingelheim Investigational Site	Joué les Tours Cedex		France
54	1218.20.3308A Boehringer Ingelheim Investigational Site	Joué les Tours		France
55	1218.20.3308C Boehringer Ingelheim Investigational Site	Joué les Tours		France
56	1218.20.3308D Boehringer Ingelheim Investigational Site	Joué les Tours		France
57	1218.20.3308E Boehringer Ingelheim Investigational Site	Joué les Tours		France
58	1218.20.3308F Boehringer Ingelheim Investigational Site	Joué les Tours		France
59	1218.20.3309A Boehringer Ingelheim Investigational Site	Joué les Tours		France
60	1218.20.3309B Boehringer Ingelheim Investigational Site	Joué les Tours		France
61	1218.20.3309C Boehringer Ingelheim Investigational Site	Joué les Tours		France
62	1218.20.3309D Boehringer Ingelheim Investigational Site	Joué les Tours		France
63	1218.20.3309E Boehringer Ingelheim Investigational Site	Joué les Tours		France
64	1218.20.3311A Boehringer Ingelheim Investigational Site	Joué les Tours		France
65	1218.20.3311B Boehringer Ingelheim Investigational Site	Joué les Tours		France
66	1218.20.3311C Boehringer Ingelheim Investigational Site	Joué les Tours		France
67	1218.20.3313A Boehringer Ingelheim Investigational Site	Joué les Tours		France
68	1218.20.3313B Boehringer Ingelheim Investigational Site	Joué les Tours		France
69	1218.20.3313C Boehringer Ingelheim Investigational Site	Joué les Tours		France
70	1218.20.3313D Boehringer Ingelheim Investigational Site	Joué les Tours		France
71	1218.20.3314A Boehringer Ingelheim Investigational Site	Joué les Tours		France
72	1218.20.3314B Boehringer Ingelheim Investigational Site	Joué les Tours		France
73	1218.20.3314C Boehringer Ingelheim Investigational Site	Joué les Tours		France
74	1218.20.3314D Boehringer Ingelheim Investigational Site	Joué les Tours		France
75	1218.20.3314E Boehringer Ingelheim Investigational Site	Joué les Tours		France
76	1218.20.3314F Boehringer Ingelheim Investigational Site	Joué les Tours		France
77	1218.20.3301A Boehringer Ingelheim Investigational Site	Nantes Cedex 1		France
78	1218.20.3302A Boehringer Ingelheim Investigational Site	Nantes		France
79	1218.20.3302C Boehringer Ingelheim Investigational Site	Nantes		France
80	1218.20.3302D Boehringer Ingelheim Investigational Site	Nantes		France
81	1218.20.3302E Boehringer Ingelheim Investigational Site	Nantes		France
82	1218.20.3302G Boehringer Ingelheim Investigational Site	Nantes		France
83	1218.20.3302H Boehringer Ingelheim Investigational Site	Nantes		France
84	1218.20.3302I Boehringer Ingelheim Investigational Site	Nantes		France
85	1218.20.3303A Boehringer Ingelheim Investigational Site	Nantes		France
86	1218.20.3303B Boehringer Ingelheim Investigational Site	Nantes		France
87	1218.20.3303C Boehringer Ingelheim Investigational Site	Nantes		France
88	1218.20.3303D Boehringer Ingelheim Investigational Site	Nantes		France
89	1218.20.3303E Boehringer Ingelheim Investigational Site	Nantes		France
90	1218.20.3303G Boehringer Ingelheim Investigational Site	Nantes		France
91	1218.20.3303H Boehringer Ingelheim Investigational Site	Nantes		France
92	1218.20.3303I Boehringer Ingelheim Investigational Site	Nantes		France
93	1218.20.3304A Boehringer Ingelheim Investigational Site	Nantes		France
94	1218.20.3304B Boehringer Ingelheim Investigational Site	Nantes		France
95	1218.20.3304C Boehringer Ingelheim Investigational Site	Nantes		France
96	1218.20.3304D Boehringer Ingelheim Investigational Site	Nantes		France
97	1218.20.3304F Boehringer Ingelheim Investigational Site	Nantes		France
98	1218.20.3304H Boehringer Ingelheim Investigational Site	Nantes		France
99	1218.20.3305A Boehringer Ingelheim Investigational Site	Nantes		France
100	1218.20.3305B Boehringer Ingelheim Investigational Site	Nantes		France
101	1218.20.3305H Boehringer Ingelheim Investigational Site	Nantes		France
102	1218.20.3306A Boehringer Ingelheim Investigational Site	Nantes		France
103	1218.20.3306B Boehringer Ingelheim Investigational Site	Nantes		France
104	1218.20.3306D Boehringer Ingelheim Investigational Site	Nantes		France
105	1218.20.3306F Boehringer Ingelheim Investigational Site	Nantes		France
106	1218.20.3306G Boehringer Ingelheim Investigational Site	Nantes		France
107	1218.20.3306H Boehringer Ingelheim Investigational Site	Nantes		France
108	1218.20.3306I Boehringer Ingelheim Investigational Site	Nantes		France
109	1218.20.3311D Boehringer Ingelheim Investigational Site	Potigny		France
110	1218.20.49004 Boehringer Ingelheim Investigational Site	Aschaffenburg		Germany
111	1218.20.49028 Boehringer Ingelheim Investigational Site	Bad Mergentheim		Germany
112	1218.20.49022 Boehringer Ingelheim Investigational Site	Berlin		Germany
113	1218.20.49024 Boehringer Ingelheim Investigational Site	Bosenheim		Germany
114	1218.20.49020 Boehringer Ingelheim Investigational Site	Dresden		Germany
115	1218.20.49018 Boehringer Ingelheim Investigational Site	Flörsheim		Germany
116	1218.20.49015 Boehringer Ingelheim Investigational Site	Frankfurt/Main		Germany
117	1218.20.49006 Boehringer Ingelheim Investigational Site	Großheirath		Germany
118	1218.20.49025 Boehringer Ingelheim Investigational Site	Haag		Germany
119	1218.20.49016 Boehringer Ingelheim Investigational Site	Hamburg		Germany
120	1218.20.49029 Boehringer Ingelheim Investigational Site	Hannover		Germany
121	1218.20.49021 Boehringer Ingelheim Investigational Site	Hatten		Germany
122	1218.20.49017 Boehringer Ingelheim Investigational Site	Kelkheim		Germany
123	1218.20.49012 Boehringer Ingelheim Investigational Site	Köln		Germany
124	1218.20.49005 Boehringer Ingelheim Investigational Site	Künzing		Germany
125	1218.20.49010 Boehringer Ingelheim Investigational Site	Leipzig		Germany
126	1218.20.49003 Boehringer Ingelheim Investigational Site	Neuwied		Germany
127	1218.20.49007 Boehringer Ingelheim Investigational Site	Nürnberg		Germany
128	1218.20.49008 Boehringer Ingelheim Investigational Site	Rednitzhembach		Germany
129	1218.20.49027 Boehringer Ingelheim Investigational Site	Saaldorf-Surheim		Germany
130	1218.20.49014 Boehringer Ingelheim Investigational Site	Saarbrücken		Germany
131	1218.20.49030 Boehringer Ingelheim Investigational Site	Speyer		Germany
132	1218.20.49019 Boehringer Ingelheim Investigational Site	St. Ingbert/Oberwürzbach		Germany
133	1218.20.49002 Boehringer Ingelheim Investigational Site	Sulzbach-Rosenberg		Germany
134	1218.20.49009 Boehringer Ingelheim Investigational Site	Unterschneidheim		Germany
135	1218.20.49026 Boehringer Ingelheim Investigational Site	Wangen		Germany
136	1218.20.49011 Boehringer Ingelheim Investigational Site	Westerkappeln		Germany
137	1218.20.49013 Boehringer Ingelheim Investigational Site	Würzburg		Germany
138	1218.20.85201 Boehringer Ingelheim Investigational Site	Hong Kong		Hong Kong
139	1218.20.85202 Boehringer Ingelheim Investigational Site	Hong Kong		Hong Kong
140	1218.20.85204 Boehringer Ingelheim Investigational Site	Hong Kong		Hong Kong
141	1218.20.36208 Boehringer Ingelheim Investigational Site	Ajka		Hungary
142	1218.20.36205 Boehringer Ingelheim Investigational Site	Baja		Hungary
143	1218.20.36204 Boehringer Ingelheim Investigational Site	Békéscsaba		Hungary
144	1218.20.36206 Boehringer Ingelheim Investigational Site	Hódmezövásárhely		Hungary
145	1218.20.36202 Boehringer Ingelheim Investigational Site	Makó		Hungary
146	1218.20.36201 Boehringer Ingelheim Investigational Site	Miskolc		Hungary
147	1218.20.36207 Boehringer Ingelheim Investigational Site	Mosonmagyarovar		Hungary
148	1218.20.36203 Boehringer Ingelheim Investigational Site	Szentes		Hungary
149	1218.20.91022 Boehringer Ingelheim Investigational Site	Chennai		India
150	1218.20.91024 Boehringer Ingelheim Investigational Site	Coimbatore		India
151	1218.20.91025 Boehringer Ingelheim Investigational Site	Gujarat		India
152	1218.20.91023 Boehringer Ingelheim Investigational Site	Hyderabad		India
153	1218.20.91021 Boehringer Ingelheim Investigational Site	Kochi		India
154	1218.20.91020 Boehringer Ingelheim Investigational Site	Mumbai		India
155	1218.20.91027 Boehringer Ingelheim Investigational Site	Patna		India
156	1218.20.91026 Boehringer Ingelheim Investigational Site	Tamilnadu		India
157	1218.20.35307 Boehringer Ingelheim Investigational Site	Co. Cork		Ireland
158	1218.20.35304 Boehringer Ingelheim Investigational Site	Co. Wexford		Ireland
159	1218.20.35306 Boehringer Ingelheim Investigational Site	Co. Wexford		Ireland
160	1218.20.35310 Boehringer Ingelheim Investigational Site	Co. Wexford		Ireland
161	1218.20.35308 Boehringer Ingelheim Investigational Site	Dublin		Ireland
162	1218.20.35303 Boehringer Ingelheim Investigational Site	Waterford		Ireland
163	1218.20.39034 Boehringer Ingelheim Investigational Site	Catania		Italy
164	1218.20.39027 Boehringer Ingelheim Investigational Site	Chieti		Italy
165	1218.20.39029 Boehringer Ingelheim Investigational Site	Codogno (lo)		Italy
166	1218.20.39021 Boehringer Ingelheim Investigational Site	Genova		Italy
167	1218.20.39033 Boehringer Ingelheim Investigational Site	Perugia		Italy
168	1218.20.39022 Boehringer Ingelheim Investigational Site	Pordenone		Italy
169	1218.20.39028 Boehringer Ingelheim Investigational Site	Ravenna		Italy
170	1218.20.39030 Boehringer Ingelheim Investigational Site	Roma		Italy
171	1218.20.39032 Boehringer Ingelheim Investigational Site	Roma		Italy
172	1218.20.39020 Boehringer Ingelheim Investigational Site	Siena		Italy
173	1218.20.31023 Boehringer Ingelheim Investigational Site	's Hertogenbosch		Netherlands
174	1218.20.31014 Boehringer Ingelheim Investigational Site	Almere		Netherlands
175	1218.20.31016 Boehringer Ingelheim Investigational Site	Beek en Donk		Netherlands
176	1218.20.31011 Boehringer Ingelheim Investigational Site	Ewijk		Netherlands
177	1218.20.31018 Boehringer Ingelheim Investigational Site	Hoogwoud		Netherlands
178	1218.20.31012 Boehringer Ingelheim Investigational Site	Oude Pekela		Netherlands
179	1218.20.31022 Boehringer Ingelheim Investigational Site	Rilland		Netherlands
180	1218.20.31019 Boehringer Ingelheim Investigational Site	Roelofarendsveen		Netherlands
181	1218.20.31013 Boehringer Ingelheim Investigational Site	Wildervank		Netherlands
182	1218.20.47005 Boehringer Ingelheim Investigational Site	Fevik		Norway
183	1218.20.47004 Boehringer Ingelheim Investigational Site	Fornebu		Norway
184	1218.20.47002 Boehringer Ingelheim Investigational Site	Hamar		Norway
185	1218.20.47001 Boehringer Ingelheim Investigational Site	RUD		Norway
186	1218.20.47003 Boehringer Ingelheim Investigational Site	Sandvika		Norway
187	1218.20.48210 Boehringer Ingelheim Investigational Site	Bialystok		Poland
188	1218.20.48208 Boehringer Ingelheim Investigational Site	Gdynia		Poland
189	1218.20.48207 Boehringer Ingelheim Investigational Site	Krakow		Poland
190	1218.20.48201 Boehringer Ingelheim Investigational Site	Lodz		Poland
191	1218.20.48202 Boehringer Ingelheim Investigational Site	Lodz		Poland
192	1218.20.48203 Boehringer Ingelheim Investigational Site	Olsztyn		Poland
193	1218.20.48206 Boehringer Ingelheim Investigational Site	Torun		Poland
194	1218.20.48205 Boehringer Ingelheim Investigational Site	Warsaw		Poland
195	1218.20.48209 Boehringer Ingelheim Investigational Site	Warsaw		Poland
196	1218.20.27007 Boehringer Ingelheim Investigational Site	Bellville		South Africa
197	1218.20.27002 Boehringer Ingelheim Investigational Site	Cape Town		South Africa
198	1218.20.27006 Boehringer Ingelheim Investigational Site	Durban		South Africa
199	1218.20.27004 Boehringer Ingelheim Investigational Site	Lenasia		South Africa
200	1218.20.27005 Boehringer Ingelheim Investigational Site	Lenasia		South Africa
201	1218.20.27003 Boehringer Ingelheim Investigational Site	Pretoria		South Africa
202	1218.20.46003 Boehringer Ingelheim Investigational Site	Göteborg		Sweden
203	1218.20.46001 Boehringer Ingelheim Investigational Site	Malmö		Sweden
204	1218.20.46002 Boehringer Ingelheim Investigational Site	Malmö		Sweden
205	1218.20.46004 Boehringer Ingelheim Investigational Site	Uppsala		Sweden
206	1218.20.44108 Boehringer Ingelheim Investigational Site	Baillieston, Glasgow		United Kingdom
207	1218.20.44115 Boehringer Ingelheim Investigational Site	Blackpool		United Kingdom
208	1218.20.44110 Boehringer Ingelheim Investigational Site	Bradford on Avon		United Kingdom
209	1218.20.44102 Boehringer Ingelheim Investigational Site	Buckshaw Village, Chorley		United Kingdom
210	1218.20.44114 Boehringer Ingelheim Investigational Site	Cheadle		United Kingdom
211	1218.20.44116 Boehringer Ingelheim Investigational Site	Chestfield, Whitstable		United Kingdom
212	1218.20.44109 Boehringer Ingelheim Investigational Site	Chippenham		United Kingdom
213	1218.20.44113 Boehringer Ingelheim Investigational Site	Dundee		United Kingdom
214	1218.20.44105 Boehringer Ingelheim Investigational Site	Edgbaston, Birmingham		United Kingdom
215	1218.20.44112 Boehringer Ingelheim Investigational Site	Ely		United Kingdom
216	1218.20.44101 Boehringer Ingelheim Investigational Site	Guildford		United Kingdom
217	1218.20.44103 Boehringer Ingelheim Investigational Site	Manchester		United Kingdom
218	1218.20.44106 Boehringer Ingelheim Investigational Site	Trowbridge		United Kingdom
219	1218.20.44104 Boehringer Ingelheim Investigational Site	Waterloo, Liverpool		United Kingdom
220	1218.20.44111 Boehringer Ingelheim Investigational Site	Westbury		United Kingdom
221	1218.20.44107 Boehringer Ingelheim Investigational Site	Whitstable		United Kingdom

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.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT00622284
• Other Study ID Numbers: 1218.20; 2007-004585-40
• First Posted: Feb 25, 2008
• Last Update Posted: Jan 29, 2014
• Last Verified: Dec 1, 2013

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

Study Results

Participant Flow

Recruitment Details	There were in total 1560 patients randomised in the study. Of these, 1 patient was not treated. The remaining 8 patients not accounted for in the treated set were removed from all study analyses (explained in trial report) due to major good-clinical-practice violations at the site, and the inability to verify the validity of any patient level data.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Period Title: Overall Study
STARTED	776	775
COMPLETED	587	604
NOT COMPLETED	189	171

Baseline Characteristics

Arm/Group Title	Linagliptin	Glimepiride	Total
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin	Total of all reporting groups
Overall Participants	776	775	1551
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.8 (9.4)	59.8 (9.4)	59.8 (9.4)
Sex: Female, Male (Count of Participants)
Female	314 40.5%	304 39.2%	618 39.8%
Male	462 59.5%	471 60.8%	933 60.2%
Body mass index (BMI) continuous (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	30.21 (4.77)	30.31 (4.57)	30.26 (4.67)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	86.14 (17.57)	86.77 (16.69)	86.46 (17.14)
Glycosylated haemoglobin (HbA1c) (Percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent]	7.69 (0.88)	7.69 (0.86)	7.69 (0.87)
Fasting blood plasma glucose (FPG) (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	164.46 (42.83)	166.09 (42.05)	165.27 (42.43)

Outcome Measures

1. Primary Outcome

Title	HbA1c Change From Baseline at Week 52
Description	This co-primary endpoint, change from baseline, reflects the Week 52 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and the number of previous anti-diabetic medications.
Time Frame	Baseline and week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Error) [Percent]	-0.36 (0.03)	-0.57 (0.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The null hypothesis of non-inferiority is rejected if the upper bound of the two-sided 97.5% confidence interval is less than 0.35%. Superiority testing was not part of the pre-specified Week 52 confirmatory analysis.
Statistical Test of Hypothesis	p-Value	0.0005
	Comments	Due to multiple testing of the primary endpoints at weeks 52 and 104 a Bonferroni correction was applied and 97.5% confidence intervals produced. This 1-sided p-value for non-inferiority should be compared to the 1-sided threshold of 0.0125.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.22
	Confidence Interval	() 97.5%; 0.13 to 0.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.04
	Estimation Comments

2. Primary Outcome

Title	HbA1c Change From Baseline at Week 104
Description	This co-primary endpoint, change from baseline, reflects the Week 104 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and the number of previous anti-diabetic medications.
Time Frame	Baseline and week 104

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Error) [Percent]	-0.16 (0.03)	-0.36 (0.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The null hypothesis of non-inferiority is rejected if the upper bound of the two-sided 97.5% confidence interval is less than 0.35%. However, superiority testing is only applicable if the Linagliptin decrease is greater than that in Glimepiride.
Statistical Test of Hypothesis	p-Value	0.0004
	Comments	This 1-sided p-value should be compared to the 1-sided threshold of 0.0125 for non-inferiority. Due to the pre-specified hierarchial approach, further confirmatory analysis on the Week24 endpoints is only applicable if superiority is already met.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.20
	Confidence Interval	() 97.5%; 0.09 to 0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.05
	Estimation Comments

3. Secondary Outcome

Title	Body Weight Change From Baseline at Week 52
Description	This key secondary endpoint, change from baseline, reflects the Week 52 body weight minus the baseline body weight. Means are treatment adjusted for baseline HbA1c, baseline weight and the number of previous antidiabetic-medications.
Time Frame	Baseline and week 52

Outcome Measure Data

Analysis Population Description

This population includes the FAS further restricted to patients with a baseline body weight and one on-treatment body weight measurement. Last observation carried forward (LOCF) was used as imputation rule.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	733	722
Mean (Standard Error) [kg]	-1.12 (0.13)	1.38 (0.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This Week52 key secondary endpoint was only to be tested (2-sided threshold of 0.025 to allow for multiple testing within a visit) if the Week52 primary hypothesis was rejected.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.50
	Confidence Interval	() 97.5%; -2.91 to -2.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments

4. Secondary Outcome

Title	Body Weight Change From Baseline at Week 104
Description	This key secondary endpoint, change from baseline, reflects the Week 104 body weight minus the baseline body weight. Means are treatment adjusted for baseline HbA1c, baseline weight and the number of previous antidiabetic-medications.
Time Frame	Baseline and week 104

Outcome Measure Data

Analysis Population Description

This population includes the FAS further restricted to patients with a baseline body weight and one on-treatment body weight measurement. Last observation carried forward (LOCF) was used as imputation rule.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	733	722
Mean (Standard Error) [kg]	-1.39 (0.16)	1.29 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Due to testing of multiple endpoints within a visit a sequential testing strategy (at 2-sided threshold of 0.025) was applied to the key secondary endpoints.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.68
	Confidence Interval	() 97.5%; -3.17 to -2.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.22
	Estimation Comments

5. Secondary Outcome

Title	Incidence of Hypoglycaemic Events up to 52 Weeks
Description	A hypoglycaemic event is defined as patient showing clinical signs suggestive of low blood glucose confirmed by a home blood glucose monitoring (HBGM) of below 55 mg/dl (3.1 mmol/L)
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

The treated set consisted of all patients treated with at least one dose of study drug

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	776	775
Number [Patients]	41	249

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This key secondary endpoint was only to be tested (comparing to a 2-sided threshold of 0.025) if the Week52 body weight change from baseline was confirmatory.
	Method	Cochran-Mantel-Haenszel
	Comments

6. Secondary Outcome

Title	Incidence of Hypoglycaemic Events up to 104 Weeks
Description	A hypoglycaemic event is defined as patient showing clinical signs suggestive of low blood glucose confirmed by a HBGM of below 55 mg/dl (3.1 mmol/L)
Time Frame	Week 104

Outcome Measure Data

Analysis Population Description

The treated set consisted of all patients treated with at least one dose of study drug

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	776	775
Number [Patients]	58	280

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Due to testing of multiple endpoints within a visit a sequential testing strategy (at 2-sided threshold of 0.025) was applied to the key secondary endpoints.
	Method	Cochran-Mantel-Haenszel
	Comments

7. Secondary Outcome

Title	Fasting Plasma Glucose (FPG) Change From Baseline at Week 52
Description	This change from baseline reflects the Week 52 FPG minus the Baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and the number of previous anti-diabetic medications.
Time Frame	Baseline and week 52

Outcome Measure Data

Analysis Population Description

This population includes the FAS further restricted to patients with a baseline FPG and one on-treatment FPG measurement. Last observation carried forward (LOCF) was used as imputation rule.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	733	725
Mean (Standard Error) [mg/dL]	-8.40 (1.25)	-15.24 (1.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	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	6.84
	Confidence Interval	() 95%; 3.51 to 10.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.70
	Estimation Comments

8. Secondary Outcome

Title	Fasting Plasma Glucose (FPG) Change From Baseline at Week 104
Description	This change from baseline reflects the Week 104 FPG minus the Baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and number of previous anti-diabetic medications.
Time Frame	Baseline and week 104

Outcome Measure Data

Analysis Population Description

This population includes the FAS further restricted to patients with a baseline FPG and one on-treatment FPG measurement. Last observation carried forward (LOCF) was used as imputation rule.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	733	725
Mean (Standard Error) [mg/dL]	-2.34 (1.46)	-8.72 (1.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	6.38
	Confidence Interval	() 95%; 2.51 to 10.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.97
	Estimation Comments

9. Secondary Outcome

Title	Percentage of Patients With HbA1c <7.0% at Week 52
Description	The percentage of patients with an HbA1c value below 7.0% at week 52, based upon patients with baseline HbA1c >= 7%. If a patient did not have an HbA1c value at week 52 they were considered a failure, so HbA1c >= 7.0%. The logistic regression is treatment adjusted for baseline HbA1c and number of previous anti-diabetic medications.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) patients with non-completers considered as failures (i.e., non-responders) (NCF) and with baseline HbA1c >=7.0%.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	592	599
Number [Percentage of patients]	29.6	38.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Regression, Logistic
	Comments	The odds ratio is treatment adjusted for baseline HbA1c and the number of previous anti-diabetic medications.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.625
	Confidence Interval	() 95%; 0.482 to 0.811
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Percentage of Patients With HbA1c <7.0% at Week 104
Description	The percentage of patients with an HbA1c value below 7.0% at week 104, based upon patients with baseline HbA1c >= 7%. If a patient did not have an HbA1c value at week 104 they were considered a failure, so HbA1c >= 7.0%. The logistic regression is treatment adjusted for baseline HbA1c and number of previous anti-diabetic medications.
Time Frame	Week 104

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) patients with non-completers considered as failures (i.e., non-responders) (NCF) and with baseline HbA1c >=7.0%.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	591	593
Number [Percentage of patients]	21.0	28.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0030
	Comments
	Method	Regression, Logistic
	Comments	The odds ratio is treatment adjusted for baseline HbA1c and the number of previous anti-diabetic medications.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.654
	Confidence Interval	() 95%; 0.494 to 0.866
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Percentage of Patients With HbA1c <6.5% at Week 52
Description	The percentage of patients with an HbA1c value below 6.5% at week 52, based upon patients with baseline HbA1c >= 6.5%. If a patient did not have an HbA1c value at week 52 they were considered a failure, so HbA1c >= 6.5%. The logistic regression is treatment adjusted for baseline HbA1c and number of previous anti-diabetic medications.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) patients with non-completers considered as failures (i.e., non-responders) (NCF) and with baseline HbA1c >=6.5%.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	738	740
Number [Percentage of patients]	16.9	22.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0025
	Comments
	Method	Regression, Logistic
	Comments	The odds ratio is treatment adjusted for baseline HbA1c and the number of previous anti-diabetic medications.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.648
	Confidence Interval	() 95%; 0.489 to 0.859
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Percentage of Patients With HbA1c <6.5% at Week 104
Description	The percentage of patients with an HbA1c value below 6.5% at week 104, based upon patients with baseline HbA1c >= 6.5%. If a patient did not have an HbA1c value at week 104 they were considered a failure, so HbA1c >= 6.5%. The logistic regression is treatment adjusted for baseline HbA1c and number of previous anti-diabetic medications.
Time Frame	Week 104

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) patients with non-completers considered as failures (i.e., non-responders) (NCF) and with baseline HbA1c >=6.5%.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	736	734
Number [Percentage of patients]	10.9	14.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0240
	Comments
	Method	Regression, Logistic
	Comments	The odds ratio is treatment adjusted for baseline HbA1c and the number of previous anti-diabetic medications.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.689
	Confidence Interval	() 95%; 0.498 to 0.952
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Percentage of Patients With HbA1c Lowering by 0.5% at Week 104
Description	Occurrence of relative efficacy response, defined as a lowering of 0.5% HbA1c at week 104
Time Frame	Week 104

Outcome Measure Data

Analysis Population Description

FAS (NCF)

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Number [Percentage of patients]	26.2	33.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments
	Method	Regression, Logistic
	Comments	The odds ratio is treatment adjusted for baseline HbA1c and the number of previous anti-diabetic medications.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.700
	Confidence Interval	() 95%; 0.560 to 0.875
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	2 hr Postprandial Glucose (PPG) Change From Baseline at Week 104
Description	This change from baseline reflects the Week 104 2 hr PPG minus the Baseline 2hr PPG. Means are treatment adjusted for baseline HbA1c, baseline 2hr PPG and number of previous anti-diabetic medications.
Time Frame	Baseline and week 104

Outcome Measure Data

Analysis Population Description

Patients in the FAS with a valid meal tolerance test (MTT) at baseline and at least one valid on-treatment MTT (MTT104).

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	212	222
Mean (Standard Error) [mg/dL]	-28.47 (4.32)	-18.72 (4.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Linagliptin, Glimepiride
	Comments	Linagliptin versus Glimepiride
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0918
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-9.47
	Confidence Interval	() 95%; -21.07 to 1.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.77
	Estimation Comments

15. Secondary Outcome

Title	HbA1c Change at Week 4
Description	Difference of base percent value [Week x(%) - baseline (%)]
Time Frame	Baseline and week 4

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Deviation) [Percent]	-0.26 (0.41)	-0.33 (0.46)

16. Secondary Outcome

Title	HbA1c Change at Week 8
Time Frame	Baseline and week 8

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Deviation) [Percent]	-0.37 (0.59)	-0.58 (0.62)

17. Secondary Outcome

Title	HbA1c Change at Week 12
Time Frame	Baseline and week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Deviation) [Percent]	-0.43 (0.64)	-0.75 (0.69)

18. Secondary Outcome

Title	HbA1c Change at Week 16
Time Frame	Baseline and week 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Deviation) [Percent]	-0.45 (0.66)	-0.78 (0.73)

19. Secondary Outcome

Title	HbA1c Change at Week 28
Time Frame	Baseline and week 28

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Deviation) [Percent]	-0.43 (0.73)	-0.74 (0.81)

20. Secondary Outcome

Title	HbA1c Change at Week 40
Time Frame	Baseline and week 40

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Deviation) [Percent]	-0.42 (0.77)	-0.69 (0.83)

21. Secondary Outcome

Title	HbA1c Change at Week 52
Time Frame	Baseline and week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Deviation) [Percent]	-0.41 (0.82)	-0.63 (0.85)

22. Secondary Outcome

Title	HbA1c Change at Week 65
Time Frame	Baseline and week 65

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Deviation) [Percent]	-0.32 (0.91)	-0.53 (0.87)

23. Secondary Outcome

Title	HbA1c Change at Week 78
Time Frame	Baseline and week 78

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Deviation) [Percent]	-0.22 (0.92)	-0.43 (0.90)

24. Secondary Outcome

Title	HbA1c Change at Week 91
Time Frame	Baseline and week 91

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Deviation) [Percent]	-0.21 (0.94)	-0.43 (0.90)

25. Secondary Outcome

Title	HbA1c Change at Week 104
Description	The Full Analysis Set (FAS) included all treated and randomized patients with a baseline and at least one on-treatment HbA1c measurement available during the first phase of the study. Last observation carried forward (LOCF) was used as imputation rule.
Time Frame	Baseline and week 104

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	764	755
Mean (Standard Deviation) [Percent]	-0.21 (0.95)	-0.41 (0.93)

26. Secondary Outcome

Title	Change in Baseline Lipid Parameter Cholesterol at Week 104
Time Frame	Baseline and week 104

Outcome Measure Data

Analysis Population Description

This population includes the treated set (all patients treated with at least one dose of study drug), and non-missing laboratory data.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	741	726
Mean (Standard Deviation) [mg/dL]	0 (14)	1 (14)

27. Secondary Outcome

Title	Change in Baseline Lipid Parameter HDL at Week 104
Time Frame	Baseline and week 104

Outcome Measure Data

Analysis Population Description

This population includes the treated set (all patients treated with at least one dose of study drug), and non-missing laboratory data.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	740	725
Mean (Standard Deviation) [mg/dl]	1 (9)	0 (9)

28. Secondary Outcome

Title	Change in Baseline Lipid Parameter Low Density Lipoprotein (LDL) at Week 104
Time Frame	Baseline and week 104

Outcome Measure Data

Analysis Population Description

This population includes the treated set (all patients treated with at least one dose of study drug), and non-missing laboratory data.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	734	720
Mean (Standard Deviation) [mg/dL]	1 (23)	3 (25)

29. Secondary Outcome

Title	Change in Baseline Lipid Parameter Triglyceride at Week 104
Time Frame	Baseline and week 104

Outcome Measure Data

Analysis Population Description

This population includes the treated set (all patients treated with at least one dose of study drug), and non-missing laboratory data.

Arm/Group Title	Linagliptin	Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin	Patients randomized to receive Glimepiride 1-4mg and metformin
Measure Participants	740	725
Mean (Standard Deviation) [mg/dL]	-11 (153)	-7 (148)

Adverse Events

Time Frame	From day of first dose until 7 days after last dose
Arm/Group Title	Linagliptin		Glimepiride
Arm/Group Description	Patients randomized to receive Linagliptin 5mg and metformin		Patients randomized to receive Glimepiride 1-4mg and metformin
All Cause Mortality
	Linagliptin		Glimepiride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Linagliptin		Glimepiride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	135/776 (17.4%)		162/775 (20.9%)
Blood and lymphatic system disorders
Anaemia	3/776 (0.4%)		1/775 (0.1%)
Iron deficiency anaemia	0/776 (0%)		1/775 (0.1%)
Lymphadenopathy	0/776 (0%)		1/775 (0.1%)
Cardiac disorders
Acute coronary syndrome	0/776 (0%)		1/775 (0.1%)
Acute myocardial infarction	1/776 (0.1%)		4/775 (0.5%)
Angina pectoris	5/776 (0.6%)		4/775 (0.5%)
Angina unstable	1/776 (0.1%)		1/775 (0.1%)
Aortic valve disease	0/776 (0%)		1/775 (0.1%)
Aortic valve stenosis	0/776 (0%)		2/775 (0.3%)
Arrhythmia	0/776 (0%)		1/775 (0.1%)
Arteriosclerosis coronary artery	3/776 (0.4%)		1/775 (0.1%)
Arteriospasm coronary	0/776 (0%)		1/775 (0.1%)
Atrial fibrillation	3/776 (0.4%)		2/775 (0.3%)
Atrial flutter	0/776 (0%)		1/775 (0.1%)
Atrioventricular block	1/776 (0.1%)		0/775 (0%)
Bradyarrhythmia	0/776 (0%)		1/775 (0.1%)
Bradycardia	2/776 (0.3%)		0/775 (0%)
Cardiac failure	3/776 (0.4%)		2/775 (0.3%)
Cardio-respiratory arrest	1/776 (0.1%)		0/775 (0%)
Congestive cardiomyopathy	0/776 (0%)		1/775 (0.1%)
Coronary artery disease	5/776 (0.6%)		6/775 (0.8%)
Coronary artery stenosis	0/776 (0%)		1/775 (0.1%)
Ischaemic cardiomyopathy	0/776 (0%)		1/775 (0.1%)
Mitral valve disease mixed	1/776 (0.1%)		0/775 (0%)
Myocardial infarction	4/776 (0.5%)		6/775 (0.8%)
Pericarditis constrictive	0/776 (0%)		1/775 (0.1%)
Sinoatrial block	1/776 (0.1%)		0/775 (0%)
Congenital, familial and genetic disorders
Central nervous system dermoid tumour	0/776 (0%)		1/775 (0.1%)
Hydrocele	1/776 (0.1%)		1/775 (0.1%)
Ear and labyrinth disorders
Hypoacusis	0/776 (0%)		1/775 (0.1%)
Vertigo	1/776 (0.1%)		2/775 (0.3%)
Endocrine disorders
Goitre	1/776 (0.1%)		2/775 (0.3%)
Hyperthyroidism	1/776 (0.1%)		0/775 (0%)
Eye disorders
Cataract	1/776 (0.1%)		1/775 (0.1%)
Glaucoma	1/776 (0.1%)		1/775 (0.1%)
Optic disc haemorrhage	0/776 (0%)		1/775 (0.1%)
Optic neuropathy	1/776 (0.1%)		0/775 (0%)
Retinal degeneration	1/776 (0.1%)		0/775 (0%)
Retinal haemorrhage	0/776 (0%)		1/775 (0.1%)
Gastrointestinal disorders
Abdominal pain upper	0/776 (0%)		1/775 (0.1%)
Anal prolapse	2/776 (0.3%)		0/775 (0%)
Colitis	1/776 (0.1%)		0/775 (0%)
Colonic polyp	0/776 (0%)		1/775 (0.1%)
Colonic stenosis	0/776 (0%)		1/775 (0.1%)
Constipation	0/776 (0%)		1/775 (0.1%)
Diarrhoea	1/776 (0.1%)		1/775 (0.1%)
Diverticulum intestinal	0/776 (0%)		1/775 (0.1%)
Duodenal ulcer haemorrhage	0/776 (0%)		1/775 (0.1%)
Gastric polyps	1/776 (0.1%)		0/775 (0%)
Gastritis	1/776 (0.1%)		1/775 (0.1%)
Gastritis erosive	1/776 (0.1%)		0/775 (0%)
Haemorrhoids	1/776 (0.1%)		0/775 (0%)
Inguinal hernia	0/776 (0%)		3/775 (0.4%)
Intestinal obstruction	1/776 (0.1%)		0/775 (0%)
Lip swelling	0/776 (0%)		1/775 (0.1%)
Oesophageal food impaction	0/776 (0%)		1/775 (0.1%)
Rectal haemorrhage	0/776 (0%)		1/775 (0.1%)
Rectal stenosis	0/776 (0%)		1/775 (0.1%)
Umbilical hernia	1/776 (0.1%)		0/775 (0%)
General disorders
Chest pain	2/776 (0.3%)		1/775 (0.1%)
Drowning	1/776 (0.1%)		0/775 (0%)
Fatigue	1/776 (0.1%)		0/775 (0%)
Mass	0/776 (0%)		1/775 (0.1%)
Medical device complication	0/776 (0%)		1/775 (0.1%)
Non-cardiac chest pain	0/776 (0%)		1/775 (0.1%)
Sudden cardiac death	1/776 (0.1%)		1/775 (0.1%)
Hepatobiliary disorders
Cholangitis	0/776 (0%)		1/775 (0.1%)
Cholecystitis	2/776 (0.3%)		2/775 (0.3%)
Cholelithiasis	3/776 (0.4%)		3/775 (0.4%)
Gallbladder polyp	1/776 (0.1%)		0/775 (0%)
Hepatic steatosis	0/776 (0%)		1/775 (0.1%)
Immune system disorders
Allergy to arthropod bite	1/776 (0.1%)		0/775 (0%)
Anaphylactic reaction	1/776 (0.1%)		0/775 (0%)
Sarcoidosis	1/776 (0.1%)		0/775 (0%)
Infections and infestations
Abdominal infection	0/776 (0%)		1/775 (0.1%)
Abscess intestinal	0/776 (0%)		1/775 (0.1%)
Abscess limb	0/776 (0%)		1/775 (0.1%)
Appendicitis	0/776 (0%)		1/775 (0.1%)
Arthritis bacterial	1/776 (0.1%)		0/775 (0%)
Arthritis infective	1/776 (0.1%)		0/775 (0%)
Balanitis candida	1/776 (0.1%)		0/775 (0%)
Bronchitis	2/776 (0.3%)		1/775 (0.1%)
Chronic sinusitis	1/776 (0.1%)		0/775 (0%)
Cystitis	1/776 (0.1%)		1/775 (0.1%)
Diverticulitis	0/776 (0%)		3/775 (0.4%)
Erysipelas	2/776 (0.3%)		2/775 (0.3%)
Escherichia sepsis	0/776 (0%)		1/775 (0.1%)
Gangrene	1/776 (0.1%)		0/775 (0%)
Gastroenteritis	0/776 (0%)		1/775 (0.1%)
Klebsiella sepsis	1/776 (0.1%)		0/775 (0%)
Localised infection	1/776 (0.1%)		0/775 (0%)
Lung infection	1/776 (0.1%)		0/775 (0%)
Malaria	1/776 (0.1%)		0/775 (0%)
Mastitis	0/776 (0%)		1/775 (0.1%)
Osteomyelitis	0/776 (0%)		1/775 (0.1%)
Otitis media chronic	1/776 (0.1%)		0/775 (0%)
Peritonsillar abscess	1/776 (0.1%)		0/775 (0%)
Pneumonia	5/776 (0.6%)		4/775 (0.5%)
Pulmonary tuberculosis	0/776 (0%)		1/775 (0.1%)
Pyelonephritis	1/776 (0.1%)		1/775 (0.1%)
Sepsis	1/776 (0.1%)		2/775 (0.3%)
Sinusitis	1/776 (0.1%)		0/775 (0%)
Skin infection	0/776 (0%)		1/775 (0.1%)
Soft tissue infection	1/776 (0.1%)		0/775 (0%)
Subcutaneous abscess	0/776 (0%)		3/775 (0.4%)
Tonsillitis	0/776 (0%)		1/775 (0.1%)
Urinary tract infection	1/776 (0.1%)		1/775 (0.1%)
Injury, poisoning and procedural complications
Accident	2/776 (0.3%)		0/775 (0%)
Ankle fracture	2/776 (0.3%)		2/775 (0.3%)
Arthropod bite	1/776 (0.1%)		0/775 (0%)
Avulsion fracture	1/776 (0.1%)		0/775 (0%)
Concussion	1/776 (0.1%)		0/775 (0%)
Contusion	1/776 (0.1%)		0/775 (0%)
Fall	3/776 (0.4%)		2/775 (0.3%)
Femoral neck fracture	1/776 (0.1%)		0/775 (0%)
Femoral nerve injury	0/776 (0%)		1/775 (0.1%)
Fibula fracture	2/776 (0.3%)		0/775 (0%)
Foot fracture	1/776 (0.1%)		0/775 (0%)
Humerus fracture	0/776 (0%)		1/775 (0.1%)
Joint sprain	3/776 (0.4%)		0/775 (0%)
Lumbar vertebral fracture	0/776 (0%)		1/775 (0.1%)
Meniscus lesion	0/776 (0%)		2/775 (0.3%)
Post procedural complication	1/776 (0.1%)		0/775 (0%)
Post procedural discharge	1/776 (0.1%)		0/775 (0%)
Post procedural haemorrhage	0/776 (0%)		1/775 (0.1%)
Road traffic accident	0/776 (0%)		1/775 (0.1%)
Suture related complication	1/776 (0.1%)		0/775 (0%)
Tendon rupture	0/776 (0%)		2/775 (0.3%)
Ulna fracture	1/776 (0.1%)		0/775 (0%)
Upper limb fracture	1/776 (0.1%)		0/775 (0%)
Investigations
Alanine aminotransferase increased	1/776 (0.1%)		0/775 (0%)
Aspartate aminotransferase increased	1/776 (0.1%)		0/775 (0%)
Blood alkaline phosphatase increased	1/776 (0.1%)		0/775 (0%)
Gamma-glutamyltransferase increased	1/776 (0.1%)		0/775 (0%)
Metabolism and nutrition disorders
Dehydration	2/776 (0.3%)		1/775 (0.1%)
Gout	1/776 (0.1%)		0/775 (0%)
Hyperglycaemia	1/776 (0.1%)		1/775 (0.1%)
Hypoglycaemia	0/776 (0%)		3/775 (0.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/776 (0.4%)		2/775 (0.3%)
Arthritis	1/776 (0.1%)		1/775 (0.1%)
Back pain	3/776 (0.4%)		0/775 (0%)
Chondropathy	0/776 (0%)		1/775 (0.1%)
Foot deformity	1/776 (0.1%)		2/775 (0.3%)
Intervertebral disc disorder	0/776 (0%)		3/775 (0.4%)
Intervertebral disc protrusion	1/776 (0.1%)		1/775 (0.1%)
Musculoskeletal pain	1/776 (0.1%)		0/775 (0%)
Osteoarthritis	5/776 (0.6%)		6/775 (0.8%)
Periarthritis	0/776 (0%)		1/775 (0.1%)
Pseudarthrosis	1/776 (0.1%)		0/775 (0%)
Rotator cuff syndrome	0/776 (0%)		1/775 (0.1%)
Spinal column stenosis	1/776 (0.1%)		0/775 (0%)
Spinal disorder	1/776 (0.1%)		0/775 (0%)
Spinal osteoarthritis	0/776 (0%)		1/775 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign muscle neoplasm	1/776 (0.1%)		0/775 (0%)
Breast cancer	3/776 (0.4%)		2/775 (0.3%)
Breast cancer metastatic	0/776 (0%)		1/775 (0.1%)
Breast cancer recurrent	0/776 (0%)		1/775 (0.1%)
Bronchial carcinoma	2/776 (0.3%)		0/775 (0%)
Carcinoid tumour pulmonary	0/776 (0%)		1/775 (0.1%)
Cholesteatoma	1/776 (0.1%)		0/775 (0%)
Colon cancer	1/776 (0.1%)		2/775 (0.3%)
Endometrial cancer	1/776 (0.1%)		0/775 (0%)
Gastrointestinal carcinoma	0/776 (0%)		1/775 (0.1%)
Laryngeal cancer	0/776 (0%)		1/775 (0.1%)
Metastases to abdominal cavity	1/776 (0.1%)		0/775 (0%)
Metastases to bone	1/776 (0.1%)		1/775 (0.1%)
Metastases to central nervous system	1/776 (0.1%)		0/775 (0%)
Metastases to liver	2/776 (0.3%)		0/775 (0%)
Metastases to lung	0/776 (0%)		1/775 (0.1%)
Metastases to lymph nodes	0/776 (0%)		1/775 (0.1%)
Metastases to pleura	1/776 (0.1%)		0/775 (0%)
Metastatic bronchial carcinoma	0/776 (0%)		1/775 (0.1%)
Osteoma	1/776 (0.1%)		0/775 (0%)
Ovarian cancer recurrent	0/776 (0%)		1/775 (0.1%)
Pancreatic carcinoma	1/776 (0.1%)		1/775 (0.1%)
Pancreatic neoplasm	0/776 (0%)		1/775 (0.1%)
Prostate cancer	6/776 (0.8%)		3/775 (0.4%)
Prostatic adenoma	0/776 (0%)		1/775 (0.1%)
Rectal cancer	0/776 (0%)		1/775 (0.1%)
Renal cancer	1/776 (0.1%)		1/775 (0.1%)
Small cell lung cancer stage unspecified	1/776 (0.1%)		0/775 (0%)
Thyroid cancer	0/776 (0%)		2/775 (0.3%)
Vulval cancer	0/776 (0%)		1/775 (0.1%)
Nervous system disorders
Agnosia	1/776 (0.1%)		0/775 (0%)
Amnesia	1/776 (0.1%)		0/775 (0%)
Carotid artery stenosis	1/776 (0.1%)		0/775 (0%)
Cerebral haemorrhage	0/776 (0%)		1/775 (0.1%)
Cerebral infarction	0/776 (0%)		4/775 (0.5%)
Cerebral ischaemia	1/776 (0.1%)		0/775 (0%)
Cerebrovascular accident	2/776 (0.3%)		6/775 (0.8%)
Cubital tunnel syndrome	0/776 (0%)		1/775 (0.1%)
Diabetic neuropathy	0/776 (0%)		1/775 (0.1%)
Dizziness	0/776 (0%)		1/775 (0.1%)
Guillain-Barre syndrome	0/776 (0%)		2/775 (0.3%)
Hepatic encephalopathy	1/776 (0.1%)		0/775 (0%)
Hydrocephalus	0/776 (0%)		1/775 (0.1%)
Hypoaesthesia	1/776 (0.1%)		0/775 (0%)
Ischaemic stroke	1/776 (0.1%)		0/775 (0%)
Monoparesis	0/776 (0%)		1/775 (0.1%)
Myelopathy	0/776 (0%)		1/775 (0.1%)
Nerve compression	0/776 (0%)		1/775 (0.1%)
Parkinson's disease	1/776 (0.1%)		0/775 (0%)
Sciatica	0/776 (0%)		1/775 (0.1%)
Syncope	1/776 (0.1%)		1/775 (0.1%)
Transient global amnesia	0/776 (0%)		1/775 (0.1%)
Transient ischaemic attack	1/776 (0.1%)		5/775 (0.6%)
VIIth nerve paralysis	0/776 (0%)		1/775 (0.1%)
Psychiatric disorders
Confusional state	1/776 (0.1%)		1/775 (0.1%)
Delirium tremens	1/776 (0.1%)		0/775 (0%)
Depression	2/776 (0.3%)		2/775 (0.3%)
Paranoia	1/776 (0.1%)		0/775 (0%)
Renal and urinary disorders
Acute prerenal failure	1/776 (0.1%)		0/775 (0%)
Calculus ureteric	0/776 (0%)		1/775 (0.1%)
Calculus urinary	0/776 (0%)		1/775 (0.1%)
Haematuria	1/776 (0.1%)		1/775 (0.1%)
Hydronephrosis	1/776 (0.1%)		1/775 (0.1%)
Hypertonic bladder	1/776 (0.1%)		0/775 (0%)
Nephrolithiasis	2/776 (0.3%)		3/775 (0.4%)
Renal colic	1/776 (0.1%)		4/775 (0.5%)
Renal failure	0/776 (0%)		1/775 (0.1%)
Renal failure acute	1/776 (0.1%)		2/775 (0.3%)
Stress urinary incontinence	1/776 (0.1%)		0/775 (0%)
Ureteric stenosis	0/776 (0%)		1/775 (0.1%)
Urinary incontinence	1/776 (0.1%)		0/775 (0%)
Urinary retention	0/776 (0%)		1/775 (0.1%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/776 (0.1%)		0/775 (0%)
Cystocele	1/776 (0.1%)		0/775 (0%)
Endometrial hyperplasia	1/776 (0.1%)		1/775 (0.1%)
Endometriosis	0/776 (0%)		1/775 (0.1%)
Haemorrhagic ovarian cyst	0/776 (0%)		1/775 (0.1%)
Menorrhagia	1/776 (0.1%)		0/775 (0%)
Ovarian mass	0/776 (0%)		1/775 (0.1%)
Pelvic pain	1/776 (0.1%)		0/775 (0%)
Penile curvature	0/776 (0%)		1/775 (0.1%)
Postmenopausal haemorrhage	2/776 (0.3%)		0/775 (0%)
Prostatism	1/776 (0.1%)		0/775 (0%)
Prostatomegaly	0/776 (0%)		1/775 (0.1%)
Urogenital prolapse	0/776 (0%)		1/775 (0.1%)
Vaginal cyst	1/776 (0.1%)		0/775 (0%)
Vaginal discharge	0/776 (0%)		1/775 (0.1%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/776 (0.1%)		0/775 (0%)
Chronic obstructive pulmonary disease	3/776 (0.4%)		0/775 (0%)
Dyspnoea	0/776 (0%)		2/775 (0.3%)
Hydrothorax	0/776 (0%)		2/775 (0.3%)
Hypoxia	1/776 (0.1%)		0/775 (0%)
Lung disorder	1/776 (0.1%)		0/775 (0%)
Nasal septum deviation	1/776 (0.1%)		0/775 (0%)
Nasal turbinate hypertrophy	1/776 (0.1%)		0/775 (0%)
Pleural effusion	1/776 (0.1%)		0/775 (0%)
Pulmonary embolism	1/776 (0.1%)		0/775 (0%)
Pulmonary oedema	1/776 (0.1%)		0/775 (0%)
Sleep apnoea syndrome	1/776 (0.1%)		0/775 (0%)
Skin and subcutaneous tissue disorders
Decubitus ulcer	1/776 (0.1%)		0/775 (0%)
Diabetic ulcer	0/776 (0%)		1/775 (0.1%)
Hypertrophic scar	0/776 (0%)		1/775 (0.1%)
Pemphigoid	1/776 (0.1%)		1/775 (0.1%)
Surgical and medical procedures
Coronary artery bypass	1/776 (0.1%)		0/775 (0%)
Hip arthroplasty	1/776 (0.1%)		0/775 (0%)
Vascular disorders
Aortic aneurysm	1/776 (0.1%)		0/775 (0%)
Arterial occlusive disease	1/776 (0.1%)		0/775 (0%)
Arterial stenosis	0/776 (0%)		1/775 (0.1%)
Blood pressure inadequately controlled	0/776 (0%)		1/775 (0.1%)
Deep vein thrombosis	1/776 (0.1%)		1/775 (0.1%)
Hypertensive crisis	0/776 (0%)		1/775 (0.1%)
Hypotension	1/776 (0.1%)		0/775 (0%)
Peripheral arterial occlusive disease	2/776 (0.3%)		2/775 (0.3%)
Peripheral embolism	1/776 (0.1%)		0/775 (0%)
Peripheral vascular disorder	0/776 (0%)		1/775 (0.1%)
Other (Not Including Serious) Adverse Events
	Linagliptin		Glimepiride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	438/776 (56.4%)		526/775 (67.9%)
Gastrointestinal disorders
Diarrhoea	52/776 (6.7%)		60/775 (7.7%)
Nausea	37/776 (4.8%)		39/775 (5%)
Infections and infestations
Bronchitis	50/776 (6.4%)		60/775 (7.7%)
Nasopharyngitis	124/776 (16%)		125/775 (16.1%)
Upper respiratory tract infection	62/776 (8%)		59/775 (7.6%)
Urinary tract infection	49/776 (6.3%)		51/775 (6.6%)
Metabolism and nutrition disorders
Hyperglycaemia	39/776 (5%)		40/775 (5.2%)
Hypoglycaemia	55/776 (7.1%)		267/775 (34.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	60/776 (7.7%)		45/775 (5.8%)
Back pain	68/776 (8.8%)		65/775 (8.4%)
Pain in extremity	41/776 (5.3%)		30/775 (3.9%)
Nervous system disorders
Dizziness	26/776 (3.4%)		47/775 (6.1%)
Headache	50/776 (6.4%)		40/775 (5.2%)
Respiratory, thoracic and mediastinal disorders
Cough	47/776 (6.1%)		38/775 (4.9%)
Vascular disorders
Hypertension	48/776 (6.2%)		60/775 (7.7%)

Limitations/Caveats

With the exception of HbA1c<6.5% and HbA1c<7.0% at Week52, all other endpoints are presented in the Week52 repeated analysis within the final clinical trial report, where discrepancies between interim and final results are also explained.

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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.