Linagliptin as Add on to Basal Insulin in the Elderly

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02240680
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 302
• Locations: 145
• Arms: 2
• Actual Duration (Months): 31
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To investigate the efficacy, safety, and tolerability of linagliptin 5 milligrams once a day compared to placebo as as add-on therapy for 24 weeks to stable basal insulin treatment in elderly patients, 60 years of age and older, with Type 2 Diabetes Mellitus and insufficient glycaemic control.Stable background therapy of metformin and/or alpha-glucosidase inhibitors is also allowed.

In addition, this trial will assess if linagliptin reduces the risk of hypoglycaemia when added to background basal insulin therapy. The treatment duration of this trial (24 weeks) will enable assessment of the clinically relevant endpoint of a decrease in glycosylated Haemoglobin, a well-accepted measurement of chronic glycaemic control.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: placebo; Drug: linagliptin	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 302 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A 24 Week Randomized, Double-blind, Placebo-controlled, Parallel Group, Efficacy and Safety Trial of Once Daily Linagliptin, 5 Milligrams Orally, as Add on to Basal Insulin in Elderly Type 2 Diabetes Mellitus Patients With Insufficient Glycaemic Control
• Actual Study Start Date: Sep 23, 2014
• Actual Primary Completion Date: Apr 18, 2017
• Actual Study Completion Date: Apr 25, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: linagliptin 5 mg patient to receive a tablet of linagliptin 5 mg each day	Drug: linagliptin; 5 mg once a day
Placebo Comparator: placebo patient to receive a tablet of placebo matching linagliptin 5 mg	Drug: placebo; placebo matching linagliptin 5 mg

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Hemoglobin A1c (HbA1c) After 24 Weeks of Treatment. [Baseline and Week 24]

   This outcome has measured difference between HbA1c values from baseline to 24 weeks post treatment. The term 'baseline' refers to the last observation prior to the administration of any randomised study medication. HbA1c is a form of hemoglobin, a blood pigment that carries oxygen, which is bound to glucose. The term HbA1c also refers to glycated hemoglobin. High levels of HbA1c (Normal range is less than 6%) indicate poorer control of diabetes than level in normal range.

Secondary Outcome Measures

1. Percentage of Patients Experiencing at Least One Hypoglycaemia Accompanied by a Prespecified Glucose Value. [24 weeks]

   Hypoglycaemia accompanied by a prespecified glucose value is defined as any investigator reported hypoglycaemia (event or AE) with a reported blood glucose level of less than 54 milligram/deciLitre (3.0 millimole/Litre) or any investigator reported symptomatic hypoglycaemic AE with a reported blood glucose level of less or equal 70 milligram/deciLitre (3.9millimole/Litre) or any severe hypoglycaemic AE. Severe hypoglycaemia is an event that requires the assistance of another person to actively administer carbohydrates or glucagon because the patient is unable to take the substance on his or her own. The confidence intervals mentioned in measure of dispersion are exact 95% confidence interval by Clopper and Pearson. The percentage of patients with at least one hypoglycaemia accompanied by a glucose value less than 54mg/dL alone has also represented separately according American Diabetes Association definition of clinically significant hypoglycaemia.

2. Percentage of Patients With HbA1c<8.0% [24 weeks]

   This is the percentage of patients with HbA1c on treatment <8.0% after 24 weeks of treatment. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson.

3. Percentage of Patients With HbA1c on Treatment <7.0% [24 weeks]

   This is the percentage of patients with HbA1c on treatment <7.0% after 24 weeks of treatment. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson.

4. Percentage of Patients With HbA1c Lowering by at Least 0.5%. [24 weeks]

   The percentage of patients who attained lowering of HbA1c by ≥0.5% from baseline after 24 weeks of treatment were analysed. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson.

5. Change From Baseline in Fasting Plasma Glucose (FPG) [Baseline and Week 24]

   This outcome has measured difference between FPG values from baseline to 24 weeks post treatment. The term 'baseline' refers to the last observation prior to the administration of any randomised study medication

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Patients must sign and date an Informed Consent consistent with International Conference on Harmonisation and Good Clinical Practice guidelines and local regulations prior to any evaluation and participation in the trial.

• Male and female patients with a clinical diagnosis of Type 2 Diabetes Mellitus, at the time of Informed Consent, who are:

• 60 years of age or older at informed consent or Screen Visit,

• taking stable doses of basal or biosimilar basal insulin [strictly inclusive of: insulin neutral protamine Hagedorn and isophane insulin; Humalog Basal (a suspension of insulin lispro protamine); insulin degludec; insulin detemir; and insulin glargine] for at least 4 weeks prior to randomisation (Visit 3) with dose adjustments up to a maximum of plus or minus 20% of baseline being allowed,

• may or may not be taking metformin immediate release or extended release [if the patient is taking metformin, stable dose must be maintained for at least twelve weeks without dose adjustments prior to randomisation (Visit 3)], and

• may or may not be taking alpha-glucosidase inhibitors [acarbose, miglitol, and voglibose; if the patient is taking alpha-glucosidase inhibitors, stable dose must be maintained for at least twelve weeks without dose adjustments prior to randomisation (Visit 3)].

• Patients must have an glycosylated Haemoglobin of 7.0% (53 millimoles per mole) to 10.0% (86 millimoles per mole) at the first visit (Screen).

• Patients must have a Body Mass Index of 45 kilogram/meter squared or less at the Screen Visit.

• In the investigator's opinion, patients must be reliable, compliant, and agree to cooperate with all planned future trial evaluations as explained in detail during the informed consent process and to be able to perform them.

Exclusion criteria:

• Impaired cognitive ability as supported by the Saint Louis University Mental Status Examination, additional assessment if necessary, and verified by the investigator at the Screen Visit.

• Depressed mood as supported by a score of 10 or more on the Patient Health Questionnaire at the Screen Visit.

• Type 1 Diabetes Mellitus as determined by past medical records and history.

• Acute coronary syndrome (non-ST Elevation Myocardial Infarction, ST Elevation Myocardial Infarction, and/or unstable angina pectoris), stroke or transient ischemic attack within 3 months prior to Screen Visit.

• Indication of liver disease determined during Screen and/or Run-In Period, defined by a serum level above 3 times the upper limit of normal in any of the following: alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase.

• Bariatric, gastric bypass, and other gastrointestinal procedures or surgeries (including all types of gastric banding, restriction, and/or LapBand) with the objective of promoting weight loss within the past two years at Screen Visit.

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

• Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells (malaria, babesiosis, haemolytic anaemia).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Syed Research Consultants, LLC	Sheffield	Alabama	United States	35660
2	Precision Research Institute, LLC	Chula Vista	California	United States	91910
3	Aurora Care Clinic, LLC	Costa Mesa	California	United States	92627
4	Prime Care Clinical Research	Laguna Hills	California	United States	92653
5	Torrance Clinical Research Institute Inc.	Lomita	California	United States	90717
6	Internal Medicine of the Rockies	Colorado Springs	Colorado	United States	80910
7	Cohen Medical Research Associates, LLC	Delray Beach	Florida	United States	33446
8	Riverside Clinical Research	Edgewater	Florida	United States	32132
9	Clinical Research of Hollywood	Hollywood	Florida	United States	33024
10	East Coast Institute for Research LLC at NE FL Endo & Diabetes	Jacksonville	Florida	United States	32204
11	Solutions Through Advanced Research, Inc.	Jacksonville	Florida	United States	32258
12	Panax Clinical Research	Miami Lakes	Florida	United States	33014
13	Baptist Diabetes Associates, PA	Miami	Florida	United States	33156
14	International Research Associates	Miami	Florida	United States	33183
15	South Florida Research Solutions, LLC	Pembroke Pines	Florida	United States	33026
16	Georgia Clinical Research, LLC	Snellville	Georgia	United States	30078
17	Midwest Endocrinology	Crystal Lake	Illinois	United States	60012
18	American Health Network	Avon	Indiana	United States	46123
19	Accent Clinical Trials	Las Vegas	Nevada	United States	89052
20	Clinical Research of South Nevada	Las Vegas	Nevada	United States	89121
21	Manhattan Medical Research Practice PLLC	New York	New York	United States	10016
22	Family Practice Center of Wadsworth, Inc.	Wadsworth	Ohio	United States	44281
23	Clinical Research Associates of Central Pennsylvania	Altoona	Pennsylvania	United States	16602
24	Fleetwood Clinical Research	Fleetwood	Pennsylvania	United States	19522
25	Preferred Primary Care Phys	Uniontown	Pennsylvania	United States	15401
26	TLM Medical Services, LLC	Columbia	South Carolina	United States	29204
27	Advanced Research Associates	Hodges	South Carolina	United States	29653
28	Holston Medical Group	Kingsport	Tennessee	United States	37660
29	Arlington Family Research Center, Inc.	Arlington	Texas	United States	76012
30	Renaissance Clinical Research and Hypertension of Texas	Dallas	Texas	United States	75234
31	Diabetes and Thyroid Center of Fort Worth	Fort Worth	Texas	United States	76132
32	Houston Clinical Research Associates	Houston	Texas	United States	77090
33	Science Advancing Medicine Clinical Research Center	San Antonio	Texas	United States	78229
34	Office of Dr. Val R. Hansen	Bountiful	Utah	United States	84010
35	Millennium Clinical Trials LLC	Arlington	Virginia	United States	22203
36	York Clinical Research, LLC	Norfolk	Virginia	United States	23510
37	Rowan Research, Inc.	Spokane	Washington	United States	99218
38	Family Medical Clinic	Milwaukee	Wisconsin	United States	53216
39	AIM Centre	Merewether	New South Wales	Australia	2291
40	Royal Brisbane & Women's Hospital-Endocrinology	Herston	Queensland	Australia	4029
41	ECRU Maroondah	East Ringwood	Victoria	Australia	3135
42	Ham - PRAC Mortelmans	Oostham		Belgium	3945
43	CEQUIN	Armenia		Colombia	630004
44	Dexa Diabetes Servicios Médicos Ltda	Bogotá		Colombia	110221
45	CAFAM Caja de Compensación Familiar	Bogotá		Colombia	111211
46	Asociacion IPS Medicos Internistas de Caldas	Manizales		Colombia	170004
47	Hospital Pablo Tobón Uribe	Medellín		Colombia	050034
48	Aalborg Sygehus Syd	Aalborg		Denmark	9100
49	Sydvestjyst Sygehus Esbjerg, Endokrinologisk afdeling	Esbjerg		Denmark	6700
50	Frederiksberg Hospital, Endokrinologisk afd.	Frederiksberg		Denmark	2000
51	Gentofte University Hospital	Hellerup		Denmark	2900
52	Kolding Sygehus	Kolding		Denmark	6000
53	Bispebjerg Hospital	København NV		Denmark	2400
54	Køge Sygehus	Køge		Denmark	4600
55	Roskilde Sygehus	Roskilde		Denmark	4000
56	Keravan terveyskeskus	Kerava		Finland	04200
57	Terveystalo Oulu, Diapolis	Oulu		Finland	FI-90100
58	Lääkärikeskus Aava, Turku	Turku		Finland	20520
59	TYKS	Turku		Finland	FI-20520
60	Gemeinschaftspraxis, Asslar	Asslar		Germany	35614
61	ikfe - Institut für klinische Forschung und Entwicklung Berlin GmbH	Berlin		Germany	10115
62	Diabetologische Schwerpunktpraxis, Bosenheim	Bosenheim		Germany	55545
63	Dünnwaldpraxis, Köln	Koeln		Germany	51069
64	Praxis Dr. Naudts, Rodgau	Rodgau		Germany	63110
65	Praxis Dr. Braun, Unterschneidheim	Unterschneidheim		Germany	73485
66	"Korgialeneio-Benakeio" Hellenic Red Cross Hospital	Athens		Greece	115 26
67	General Hospital of Athens "G. Gennimatas"	Athens		Greece	11527
68	Univ. Gen. Hosp. of Ioannina	Ioannina		Greece	45500
69	General Hospital of Attiki "KAT-EKA"	Kifisia		Greece	14561
70	General Hospital of Nikaia	Nikaia		Greece	18454
71	General Hospital of Thessaloniki "G. Papanikolaou"	Thessaloniki		Greece	57010
72	Connolly Hospital Blanchardstown	Dublin		Ireland	Dublin 15
73	Daishinkai Medical Corporation Ookuma Hospital	Aichi, Nagoya		Japan	462-0825
74	Matsuyama Shimin Hospital	Ehime, Matsuyama		Japan	790-0067
75	Iryohojin Kikuchi Naika Clinic	Gunma, Maebashi		Japan	370-3573
76	Nakamura Digestive Organ Internal Medicine Clinic	Hokkaido, Bibai		Japan	072-0012
77	Iida Medical Clinic	Hokkaido, Hakodate		Japan	042-0942
78	Jiyugaoka Yamada Clinic	Hokkaido, Obihiro		Japan	080-0848
79	Shinkotoni family Clinic	Hokkaido, Sapporo		Japan	001-0912
80	Yoshida Memorial Hospital	Hokkaido, Sapporo		Japan	003-0026
81	Teine Keijinkai Clinic	Hokkaido, Sapporo		Japan	006-0811
82	Japan Community Health Care Organization Hokkaido Hospital	Hokkaido, Sapporo		Japan	062-8618
83	Itabashi Diabetic medicine and Dermatology Clinic	Ibaraki, Koga		Japan	306-0232
84	Nakakinen Clinic	Ibaraki, Naka		Japan	311-0113
85	Takai Naika Clinic	Kanagawa, Kamakura		Japan	247-0056
86	Kaneshiro DIAB Clinic, Kanagawa, I.M.	Kanagawa, Sagamihara		Japan	252-0302
87	Asahi Med. clinic, Kanagawa, I.M.	Kanagawa, Yokohama		Japan	221-0802
88	Ishikawa Med. Clinic, Kanagawa, I.M.	Kanagawa, Yokohama		Japan	241-0821
89	National Hospital Organization Yokohama Medical Center	Kanagawa, Yokohama		Japan	245-8575
90	Okayama Saiseikai General Hospital Outpatient Center	Okayama, Okayama		Japan	700-8511
91	AMC Nishi-umeda Clinic	Osaka, Osaka		Japan	530-0001
92	Nissay Hospital Nippon Life Saiseikai Public Interest Incorporated Foundation	Osaka, Osaka		Japan	550-0012
93	OCROM Clinic	Osaka, Suita		Japan	565-0853
94	Saga Memorial Hospital	Saga, Saga		Japan	849-0917
95	Asano Clinic	Saitama, Kawagoe		Japan	350-0851
96	Hamamatsu Rosai Hospital	Shizuoka, Hamamatsu		Japan	430-8525
97	Kuriyama Clinic	Tokyo, Adachi-ku		Japan	121-0064
98	The Institute for Adult Deseases, Asahi Life Foundation	Tokyo, Chuo-ku		Japan	103-0002
99	Tokyo-Eki Center-building Clinic	Tokyo, Chuo-ku		Japan	103-0027
100	Tokyo Center Clinic	Tokyo, Chuo-ku		Japan	103-0028
101	AGE Makita Medical Clinic	Tokyo, Chuo-ku		Japan	104-0061
102	Kobayashi Internal Medicine Clinic	Tokyo, Koto-ku		Japan	135-0011
103	Kunitachi Naika Clinic	Tokyo, Kunitachi		Japan	186-0002
104	Japanese Red Cross Medical Center	Tokyo, Shibuya-ku		Japan	150-8935
105	Investigación en Salud y Metabolismo S.C.	Chihuahua		Mexico	31217
106	Centro de At. e Inv.en Fact.de riesgo cardiovasc.Omega, S.C.	Mexico		Mexico	06400
107	CAIMED	Mexico		Mexico	06760
108	Clinstile S.A. de C.V.	México		Mexico	06700
109	CEDOPEC-Ctro Esp en Diab, Obesidad y Prev de Enf Cardiovasc	México		Mexico	C.P. 11650
110	Asociación Mexicana para la Investigacion Clínica, A.C(AMIC)	Pachuca		Mexico	42070
111	South Pacific Clinical Trials	Auckland, New Zealand		New Zealand	0610
112	Middlemore Clinical Trials	Auckland		New Zealand	2025
113	Christchurch Hospital	Christchurch		New Zealand	8011
114	Medicome Sp. z o.o.	Oswiecim		Poland	32-600
115	Omedica Centrum Medyczne	Poznan		Poland	60-111
116	NBR Polska	Warszawa		Poland	00-465
117	Nicodiab SRL, Bucharest	Bucharest		Romania	010507
118	Pelican Impex SRL, Cabinet Nr. 15	Oradea		Romania	410469
119	Mediab SRL	Tirgu Mures		Romania	540142
120	TREAD Research	Cape Town		South Africa	7500
121	Tiervlei Trial Centre	Cape Town		South Africa	7530
122	Paarl Research Centre	Cape Town		South Africa	7646
123	Soweto Clinical Trials Centre	Johannesburg		South Africa	1818
124	LCS Clinical Research Unit	Johannesburg		South Africa	2021
125	Resego Health Services	Johannesburg		South Africa	2189
126	Zinakekele Medical Centre	KwaMhlanga		South Africa	1022
127	Mzansi Ethical Research Centre	Middleburg		South Africa	1055
128	VX Pharma (Pty) Ltd Pretoria	Pretoria		South Africa	0087
129	Hospital A Coruña	A Coruña		Spain	15003
130	Instituto de Ciencias Médicas	Alicante		Spain	03004
131	Hospital Quiron. I.C.U.	Barcelona		Spain	08023
132	C.A.P. Sardenya	Barcelona		Spain	08025
133	CAP Les Corts	Barcelona		Spain	08028
134	CAP Canet de Mar	Canet de Mar		Spain	08360
135	Hospital Virgen de la Victoria	Malaga		Spain	29010
136	Hospital Nuestra Señora de Valme	Sevilla		Spain	41014
137	Hospital Clínico de Valencia	Valencia		Spain	46010
138	CAP El Remei	Vic		Spain	08500
139	The Haven Surgery	Burnhope		United Kingdom	DH7 0BD
140	South Axholme Practice	Doncaster		United Kingdom	DN9 2HY
141	Fowey Clinical Research Company Ltd	Fowey		United Kingdom	PL23 1DT
142	Oak Tree Surgery	Liskeard		United Kingdom	PL14 3XA
143	St. Mary's Hospital, Vectasearch Clinic, Newport	Newport		United Kingdom	PO309 5TG
144	Mounts Bay Medical Ltd	Penzance		United Kingdom	TR19 7HX
145	Rame Medical, Penntorr Health	Torpoint		United Kingdom	PL11 2TB

Sponsors and Collaborators

• Boehringer Ingelheim
• Eli Lilly and Company

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Study Protocol - Oct 16, 2015
• Statistical Analysis Plan - Nov 9, 2016

More Information

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02240680
• Other Study ID Numbers: 1218.149; 2014-000904-88
• First Posted: Sep 16, 2014
• Last Update Posted: Jul 3, 2018
• Last Verified: May 1, 2018

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

Study Results

Participant Flow

Recruitment Details	This was randomised, double blinded, placebo controlled, parallel study. Total 525 patients with type 2 diabetes mellitus (T2DM) and insufficient glycaemic control were screened. 302 patients were randomised into two groups. The trial was extended to 52 weeks for Japanese patients. 102 patients were identified and observed for the extended period.
Pre-assignment Detail	All patients were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subject) met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

Arm/Group Title	Placebo (Up to 24 Weeks)	Linagliptin 5 Milligram (Up to 24 Weeks)	Placebo (Up to 52 Weeks)	Linagliptin 5 Milligram (Up to 52 Weeks)
Arm/Group Description	Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks	Patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 24 weeks.	Only Japanese patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 52 weeks	Only Japanese patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 52 weeks
Period Title: Overall Study (Up to 24 Weeks)
STARTED	151	151	0	0
COMPLETED	136	143	0	0
NOT COMPLETED	15	8	0	0
Period Title: Overall Study (Up to 24 Weeks)
STARTED	0	0	50	52
COMPLETED	0	0	42	45
NOT COMPLETED	0	0	8	7

Baseline Characteristics

Arm/Group Title	Placebo (Up to 24 Weeks)	Linagliptin 5 Milligram (Up to 24 Weeks)	Total
Arm/Group Description	Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks	Patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 24 weeks.	Total of all reporting groups
Overall Participants	151	151	302
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	72.5 (5.6)	72.3 (5.1)	72.4 (5.4)
Sex: Female, Male (Count of Participants)
Female	60 39.7%	59 39.1%	119 39.4%
Male	91 60.3%	92 60.9%	183 60.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	19 12.6%	15 9.9%	34 11.3%
Not Hispanic or Latino	132 87.4%	136 90.1%	268 88.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	7 4.6%	4 2.6%	11 3.6%
Asian	52 34.4%	52 34.4%	104 34.4%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.7%	1 0.3%
Black or African American	10 6.6%	8 5.3%	18 6%
White	81 53.6%	84 55.6%	165 54.6%
More than one race	1 0.7%	2 1.3%	3 1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Hemoglobin A1c (HbA1c) at baseline (Percentage of HbA1c (%)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of HbA1c (%)]	8.1 (0.7)	8.2 (0.8)	8.2 (0.8)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Hemoglobin A1c (HbA1c) After 24 Weeks of Treatment.
Description	This outcome has measured difference between HbA1c values from baseline to 24 weeks post treatment. The term 'baseline' refers to the last observation prior to the administration of any randomised study medication. HbA1c is a form of hemoglobin, a blood pigment that carries oxygen, which is bound to glucose. The term HbA1c also refers to glycated hemoglobin. High levels of HbA1c (Normal range is less than 6%) indicate poorer control of diabetes than level in normal range.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set observed cases (FAS (OC)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. These analyses used available data as observed while patients were on treatment. All values collected after a patient started rescue medication were excluded from the analysis.

Arm/Group Title	Placebo (Up to 24 Weeks)	Linagliptin 5 Milligram (Up to 24 Weeks)
Arm/Group Description	Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks	Patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 24 weeks.
Measure Participants	147	149
Least Squares Mean (Standard Error) [Percentage (%) of HbA1c]	-0.38 (0.07)	-1.01 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Up to 24 Weeks), Linagliptin 5 Milligram (Up to 24 Weeks)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed model repeated measures(MMRM) included treatment, week and interaction as fixed effects, baseline HbA1c, daily basal insulin dose as covariates
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.63
	Confidence Interval	(2-Sided) 95%; -0.81 to -0.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments	Adjusted mean of all differences between HbA1c at baseline and after 24 weeks. It is based on all patients in the model (not only patients with a baseline and week 24 measurement).
Other Statistical Analysis		MMRM including fixed effects treatment , week and treatment by week interaction linear covariates baseline HbA1c , baseline daily basal insulin and baseline HbA1c by week interaction and random effect for patient. Within-patient errors are modelled by unstructured covariance matrix. Adjusted mean is based on all patients in the model (not only patients with a baseline and week 24 measurement).

2. Secondary Outcome

Title	Percentage of Patients Experiencing at Least One Hypoglycaemia Accompanied by a Prespecified Glucose Value.
Description	Hypoglycaemia accompanied by a prespecified glucose value is defined as any investigator reported hypoglycaemia (event or AE) with a reported blood glucose level of less than 54 milligram/deciLitre (3.0 millimole/Litre) or any investigator reported symptomatic hypoglycaemic AE with a reported blood glucose level of less or equal 70 milligram/deciLitre (3.9millimole/Litre) or any severe hypoglycaemic AE. Severe hypoglycaemia is an event that requires the assistance of another person to actively administer carbohydrates or glucagon because the patient is unable to take the substance on his or her own. The confidence intervals mentioned in measure of dispersion are exact 95% confidence interval by Clopper and Pearson. The percentage of patients with at least one hypoglycaemia accompanied by a glucose value less than 54mg/dL alone has also represented separately according American Diabetes Association definition of clinically significant hypoglycaemia.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set observed cases (FAS (OC)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. These analyses used available data as observed while patients were on treatment. All values collected after a patient started rescue medication were excluded from the analysis.

Arm/Group Title	Placebo (Up to 24 Weeks)	Linagliptin 5 Milligram (Up to 24 Weeks)
Arm/Group Description	Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks	Patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 24 weeks.
Measure Participants	147	149
Prespecified glucose value	23.8	30.9
Glucose value <54 mg/dL	15.0	16.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Up to 24 Weeks), Linagliptin 5 Milligram (Up to 24 Weeks)
	Comments	For any hypoglycemia event accompanied by prespecified glucose value
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1594
	Comments
	Method	Regression, Logistic
	Comments	A logistic regression model with treatment as fixed effect and baseline HbA1c and baseline daily basal insulin dose as linear covariates was applied.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.464
	Confidence Interval	(2-Sided) 95%; 0.861 to 2.491
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.397
	Estimation Comments	The dispersion value standard error of the mean is actually standard error for odds ratio.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo (Up to 24 Weeks), Linagliptin 5 Milligram (Up to 24 Weeks)
	Comments	For glucose value < 54mg/dL according American Diabetes Association definition of clinically significant hypoglycaemia
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6720
	Comments
	Method	Regression, Logistic
	Comments	A logistic regression model with treatment as fixed effect and baseline HbA1c and baseline daily basal insulin dose as linear covariates was applied.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.149
	Confidence Interval	(2-Sided) 95%; 0.604 to 2.188
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.377
	Estimation Comments	The dispersion value standard error of the mean is actually standard error for odds ratio.

3. Secondary Outcome

Title	Percentage of Patients With HbA1c<8.0%
Description	This is the percentage of patients with HbA1c on treatment <8.0% after 24 weeks of treatment. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (Non-completers considered failure)(FAS (NCF)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. This analyses regarded missing values for binary efficacy endpoints as failure.

Arm/Group Title	Placebo (Up to 24 Weeks)	Linagliptin 5 Milligram (Up to 24 Weeks)
Arm/Group Description	Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks	Patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 24 weeks.
Measure Participants	147	149
Number (95% Confidence Interval) [Percentage of patients (%)]	40.2	70.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Up to 24 Weeks), Linagliptin 5 Milligram (Up to 24 Weeks)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Regression, Logistic
	Comments	A logistic regression model with treatment as fixed effect and baseline HbA1c and baseline daily basal insulin dose as linear covariates was applied.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.018
	Confidence Interval	(2-Sided) 95%; 2.468 to 10.206
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.818
	Estimation Comments	The dispersion value standard error of the mean is actually standard error of odds ratio

4. Secondary Outcome

Title	Percentage of Patients With HbA1c on Treatment <7.0%
Description	This is the percentage of patients with HbA1c on treatment <7.0% after 24 weeks of treatment. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set non-completers considered failure (FAS (NCF)): Includes all patients randomised in the treated set who had a baseline and at least one on-treatment HbA1c value. This analyses regarded missing values for binary efficacy endpoints as failure.

Arm/Group Title	Placebo (Up to 24 Weeks)	Linagliptin 5 Milligram (Up to 24 Weeks)
Arm/Group Description	Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks	Patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 24 weeks.
Measure Participants	147	149
Number (95% Confidence Interval) [Percentage of Patients (%)]	14.6	37.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Up to 24 Weeks), Linagliptin 5 Milligram (Up to 24 Weeks)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Regression, Logistic
	Comments	A logistic regression model with treatment as fixed effect and baseline HbA1c and baseline daily basal insulin dose as linear covariates was applied.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.689
	Confidence Interval	(2-Sided) 95%; 2.485 to 8.848
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.519
	Estimation Comments	The dispersion value standard error of the mean is actually standard error of odds ratio

5. Secondary Outcome

Title	Percentage of Patients With HbA1c Lowering by at Least 0.5%.
Description	The percentage of patients who attained lowering of HbA1c by ≥0.5% from baseline after 24 weeks of treatment were analysed. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set non-completers considered failure (FAS (NCF)): Includes all patients randomised in the treated set who had a baseline and at least one on-treatment HbA1c value. This analyses regarded missing values for binary efficacy endpoints as failure.

Arm/Group Title	Placebo (Up to 24 Weeks)	Linagliptin 5 Milligram (Up to 24 Weeks)
Arm/Group Description	Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks	Patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 24 weeks.
Measure Participants	147	149
Number (95% Confidence Interval) [Percentage of patients (%)]	37.4	69.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Up to 24 Weeks), Linagliptin 5 Milligram (Up to 24 Weeks)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Regression, Logistic
	Comments	A logistic regression model with treatment as fixed effect and baseline HbA1c and baseline daily basal insulin dose as linear covariates was applied.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.731
	Confidence Interval	(2-Sided) 95%; 2.302 to 6.048
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.920
	Estimation Comments	The dispersion value standard error of the mean is actually standard error of odds ratio

6. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG)
Description	This outcome has measured difference between FPG values from baseline to 24 weeks post treatment. The term 'baseline' refers to the last observation prior to the administration of any randomised study medication
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set observed cases (FAS (OC)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. These analyses used available data as observed while patients were on treatment. All values collected after a patient started rescue medication were excluded from the analysis.

Arm/Group Title	Placebo (Up to 24 Weeks)	Linagliptin 5 Milligram (Up to 24 Weeks)
Arm/Group Description	Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks	Patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 24 weeks.
Measure Participants	147	149
Least Squares Mean (Standard Error) [milligram/decilitre]	0.2 (3.6)	-11.3 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Up to 24 Weeks), Linagliptin 5 Milligram (Up to 24 Weeks)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0178
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed model repeated measures(MMRM) included treatment, week and interaction as fixed effects, baseline HbA1c, FPG, daily insulin dose as covariates
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.5
	Confidence Interval	(2-Sided) 95%; -21.0 to -2.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.8
	Estimation Comments	Adjusted mean of all differences between HbA1c at baseline and after 24 weeks. It is based on all patients in the model (not only patients with a baseline and week 24 measurement).
Other Statistical Analysis		MMRM including fixed effects treatment, week and treatment by week interaction, linear covariates baseline HbA1c, baseline daily basal insulin, baseline FPG and baseline FPG by week interaction and random effect for patient. Within-patient errors are modelled by unstructured covariance matrix. Adjusted mean is based on all patients in the model (not only patients with a baseline and week 24 measurement).

Adverse Events

Time Frame	The adverse events were reported by overall population from first drug administration up to treatment period of 24 weeks, until 7 days after last drug administration. The adverse events were reported by Japanese population from first drug administration up to treatment period of 52 weeks, until 7 days after last drug administration.
Adverse Event Reporting Description	An AE was defined as any untoward medical occurrence, including an exacerbation of a preexisting condition, in a patient in a clinical investigation who received a pharmaceutical product. A treated set (TS) was used for analysis of adverse events. TS includes all patients who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.
Arm/Group Title	Placebo (Up to 24 Weeks)		Linagliptin 5 mg (Up to 24 Weeks)		Placebo (Up to 52 Weeks)		Linagliptin 5mg (Up to 52 Weeks)
Arm/Group Description	Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks		Patients were orally administered with Linagliptin 5 mg film-coated tablets once daily up to 24 weeks.		Japanese patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 52 weeks		Japanese patients were orally administered with Linagliptin 5 mg film-coated tablets once daily up to 52 weeks.
All Cause Mortality
	Placebo (Up to 24 Weeks)		Linagliptin 5 mg (Up to 24 Weeks)		Placebo (Up to 52 Weeks)		Linagliptin 5mg (Up to 52 Weeks)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/151 (0%)		2/151 (1.3%)		0/50 (0%)		0/52 (0%)
Serious Adverse Events
	Placebo (Up to 24 Weeks)		Linagliptin 5 mg (Up to 24 Weeks)		Placebo (Up to 52 Weeks)		Linagliptin 5mg (Up to 52 Weeks)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/151 (13.9%)		19/151 (12.6%)		7/50 (14%)		13/52 (25%)
Cardiac disorders
Acute myocardial infarction	0/151 (0%)		0/151 (0%)		0/50 (0%)		1/52 (1.9%)
Angina pectoris	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		1/52 (1.9%)
Angina unstable	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		1/52 (1.9%)
Arrhythmia	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Atrial fibrillation	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Bradycardia	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		0/52 (0%)
Cardiac arrest	0/151 (0%)		2/151 (1.3%)		0/50 (0%)		0/52 (0%)
Cardiac failure congestive	1/151 (0.7%)		2/151 (1.3%)		0/50 (0%)		0/52 (0%)
Coronary artery disease	2/151 (1.3%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Coronary artery stenosis	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		0/52 (0%)
Ear and labyrinth disorders
Vertigo positional	0/151 (0%)		0/151 (0%)		0/50 (0%)		1/52 (1.9%)
Eye disorders
Cataract	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		2/52 (3.8%)
Diabetic retinopathy	0/151 (0%)		2/151 (1.3%)		0/50 (0%)		2/52 (3.8%)
Glaucoma	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		1/52 (1.9%)
Gastrointestinal disorders
Ascites	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Gastrooesophageal reflux disease	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Haemorrhoids	0/151 (0%)		0/151 (0%)		0/50 (0%)		1/52 (1.9%)
Inguinal hernia	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		1/52 (1.9%)
General disorders
Chest pain	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Hepatobiliary disorders
Cholecystitis	1/151 (0.7%)		0/151 (0%)		1/50 (2%)		0/52 (0%)
Cholelithiasis	1/151 (0.7%)		0/151 (0%)		1/50 (2%)		0/52 (0%)
Infections and infestations
Bronchitis	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		0/52 (0%)
Erysipelas	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Klebsiella sepsis	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Pneumonia	1/151 (0.7%)		0/151 (0%)		1/50 (2%)		0/52 (0%)
Urinary tract infection	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		0/52 (0%)
Injury, poisoning and procedural complications
Fall	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		0/52 (0%)
Femoral neck fracture	1/151 (0.7%)		0/151 (0%)		1/50 (2%)		0/52 (0%)
Joint dislocation	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Multiple fractures	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Rib fracture	0/151 (0%)		0/151 (0%)		1/50 (2%)		0/52 (0%)
Spinal compression fracture	0/151 (0%)		0/151 (0%)		1/50 (2%)		0/52 (0%)
Investigations
Lipase increased	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	0/151 (0%)		1/151 (0.7%)		1/50 (2%)		1/52 (1.9%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/151 (0.7%)		2/151 (1.3%)		1/50 (2%)		0/52 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		0/52 (0%)
Colorectal cancer	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		1/52 (1.9%)
Enchondromatosis	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Gastric cancer	0/151 (0%)		0/151 (0%)		0/50 (0%)		1/52 (1.9%)
Lung neoplasm malignant	1/151 (0.7%)		0/151 (0%)		1/50 (2%)		0/52 (0%)
Squamous cell carcinoma of skin	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		0/52 (0%)
Nervous system disorders
Brain stem infarction	1/151 (0.7%)		1/151 (0.7%)		1/50 (2%)		1/52 (1.9%)
Cerebral arteriosclerosis	0/151 (0%)		0/151 (0%)		0/50 (0%)		1/52 (1.9%)
Cerebral infarction	0/151 (0%)		0/151 (0%)		0/50 (0%)		1/52 (1.9%)
Dizziness	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Hypoxic-ischaemic encephalopathy	0/151 (0%)		0/151 (0%)		0/50 (0%)		1/52 (1.9%)
Lumbar radiculopathy	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		0/52 (0%)
Renal and urinary disorders
Acute kidney injury	0/151 (0%)		2/151 (1.3%)		0/50 (0%)		0/52 (0%)
Haematuria	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		0/52 (0%)
Renal impairment	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		1/52 (1.9%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		0/52 (0%)
Chronic obstructive pulmonary disease	0/151 (0%)		1/151 (0.7%)		0/50 (0%)		1/52 (1.9%)
Cough	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Dyspnoea	2/151 (1.3%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Pulmonary embolism	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Vascular disorders
Deep vein thrombosis	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Intermittent claudication	1/151 (0.7%)		0/151 (0%)		0/50 (0%)		0/52 (0%)
Other (Not Including Serious) Adverse Events
	Placebo (Up to 24 Weeks)		Linagliptin 5 mg (Up to 24 Weeks)		Placebo (Up to 52 Weeks)		Linagliptin 5mg (Up to 52 Weeks)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	58/151 (38.4%)		72/151 (47.7%)		19/50 (38%)		37/52 (71.2%)
Gastrointestinal disorders
Constipation	1/151 (0.7%)		2/151 (1.3%)		0/50 (0%)		3/52 (5.8%)
Large intestine polyp	0/151 (0%)		2/151 (1.3%)		0/50 (0%)		3/52 (5.8%)
Infections and infestations
Bronchitis	4/151 (2.6%)		7/151 (4.6%)		0/50 (0%)		5/52 (9.6%)
Urinary tract infection	9/151 (6%)		10/151 (6.6%)		1/50 (2%)		1/52 (1.9%)
Viral upper respiratory tract infection	8/151 (5.3%)		11/151 (7.3%)		3/50 (6%)		11/52 (21.2%)
Metabolism and nutrition disorders
Hypoglycaemia	38/151 (25.2%)		51/151 (33.8%)		14/50 (28%)		20/52 (38.5%)
Musculoskeletal and connective tissue disorders
Back pain	6/151 (4%)		5/151 (3.3%)		3/50 (6%)		2/52 (3.8%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/151 (0.7%)		3/151 (2%)		0/50 (0%)		3/52 (5.8%)

Limitations/Caveats

For patients in Japan, a local protocol amendment was introduced, and according to it the study was extended to 52 weeks for Japanese population only.

More Information

Certain Agreements

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

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.