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
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

Clinical Trial Protocol
Doc. No.: c02204602-03
EudraCT No.:
BI Trial No.:
2014-000904-88
1218.149
BI Investigational
Product(s):
Tradjenta®, Trajenta®, Trayenta®, Trazenta®, linagliptin
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
Clinical Phase:
IV
Trial Clinical 
Monitor:
, 
 
Phone: 
Fax: 
Co-ordinating 
Investigator:
Phone:
Fax: 
Status:
Final Protocol (Revised Protocol based on global amendment 1)
Version and Date:
Version: 2.0
Date:  15 May 2014 Original Protocol
16 October 2015        Revised Protocol
Page 1 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
TITLE PAGE

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 2 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim(BI)
Name of finished product:
Tradjenta®, Trajenta®, Trayenta®, Trazenta®
Name of active ingredient:
linagliptin
Protocol date:
Trial number:
Revision date:
16 October 2015
15 May 2014
1218.149
Title of trial:
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
Co-ordinating 
Investigator:
Trial sites:
A multi-centre trial to be conducted in multiple countries
Clinical phase:
Phase IV
Objectives:
To investigate the efficacy, safety, and tolerability of linagliptin 5 milligrams (mg) 
once a day (q.d.) compared to placebo as add-on therapy for 24 weeks to stable basal 
insulin treatment in elderly (≥60 years old) patients with Type 2 Diabetes Mellitus 
(T2DM) with insufficient glycaemic control
Methodology:
Randomised, double-blind, multi-national, placebo-controlled, parallel design 
comparison as add-on therapy to a stable background of basal insulin, metformin 
(optional), and/or alpha-glucosidase inhibitors (optional) over 24 weeks.
No. of patients: 
total entered:
Entered (into the double-blind treatment period): approximately 300
each treatment:
1:1 allocation ratio per treatment arm [i.e., 150 patients assigned to linagliptin 5mg 
q.d. and 150 patients assigned to placebo matching linagliptin 5 mg q.d.]
Diagnosis:
Elderly (≥60 years old) T2DM patients with glycated (or glycosylated) haemoglobin 
(HbA1c) levels of 7.0% to 10.0% at Screen who are on a stable background 
antidiabetic therapy of basal insulin, metformin (optional), and/or alpha-glucosidase 
inhibitor (optional).
Main criteria
for inclusion:
T2DM patients who are 60 years of age or older: 

with HbA1c levels of 7.0% to 10.0% at Screen

taking stable doses of basal insulin at least 4 weeks prior to randomisation,
and metformin (optional) and/or alpha-glucosidase inhibitor (optional) at 
least 12 weeks prior to randomization

with a Body Mass Index (BMI) of less than or equal to 45 kilograms per 
meters squared (≤ 45 kg/m2 )

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 3 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim(BI)
Name of finished product:
Tradjenta®, Trajenta®, Trayenta®, Trazenta®
Name of active ingredient:
linagliptin
Protocol date:
Trial number:
Revision date:
16 October 2015
15 May 2014
1218.149
Test product(s):
linagliptin tablet 
dose:
5 mg (tablet strength)
mode of admin.:
by mouth (p.o.) each morning
Comparator products:
placebo tablet (matching linagliptin)
dose:
Not Applicable (N/A)
mode of admin.:
p.o.
Duration of treatment: A one week Screen period with no study medication, leading into a one week placebo 
Run-In period, followed by a double-blind treatment period for 24 weeks, and a one 
week post-treatment period with no study medication.
Criteria for efficacy:
The primary endpoint is the change from baseline in HbA1c after 24 weeks of 
treatment.  
Secondary endpoints are the following:

Proportion of patients experiencing at least one confirmed hypoglycaemic 
event during 24 weeks of treatment.

Proportion of patients with HbA1c on treatment <8.0% after 24 weeks of 
treatment

Proportion of patients with HbA1c on treatment <7.0% after 24 weeks of 
treatment

Proportion of patients with HbA1c lowering by at least 0.5% after 24 weeks of 
treatment

Change from baseline in Fasting Plasma Glucose (FPG) after 24 weeks of 
treatment
Criteria for safety:
Adverse events (including relevant new or worsening pre-existing conditions) and 
hypoglycaemic events
Statistical methods:
Restricted maximum likelihood estimation based on mixed-effect model for repeated
measures analysis will be used to obtain adjusted means for the treatment effects.
This model will include treatment, baseline insulin dose, and week as discrete fixed 
effects, baseline HbA1c as a continuous fixed effect, interaction between week and 
treatment, and interaction between week and baseline HbA1c. The primary treatment 
comparisons will be the contrast between treatments at Week 24.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 4 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
FLOW CHART
Screen
Run-In
Treatment
Post-Treatment
Visit
1
2
3
4
5
6
98
99
Week
-2
-1
1
6
12
18
24
25
Day 
-14
-7
1
43
85
127
169
176
Visit Duration to Next Visit (days)
7
7
42
42
42
42
7
N/A
Maximum Visit Window (in days) A
-7
-7
0
+/-7
+/-7
+/-7
+/-7
N/A
Informed Consent A
X
Patient Health Questionnaire (9 item) B
X
Mental Status Examination B
X
Medical History B
X
Demographics B
X
Inclusion/Exclusion Criteria Checks B
X
X
X
Blood Pressure and Pulse B
X
X
X
X
X
X
X
X
Height and BMI A
X
Weight A
X
X
X
Physical Examination B
X
X
12-Lead ECG C 
X
X
X
FPG D 
X
X
X
X
X
HbA1c
X
X
X
X
X
X
Laboratory Tests (urine and blood) B, F
X
X
X
X
X
X
X
X
Lipid Panel
X
X
HBGM and eDiary
X
X
X
X
X
X
X
X
Diet / Exercise Counseling I
X
X
X
X
X
X
X
Adverse Events B, J
X
X
X
X
X
X
X
X
Concomitant Therapy B
X
X
X
X
X
X
X
X
Interactive Response Technology Use K
X
X
X
X
X
X
X
X
Dispense Study Medication L
X
X
X
X
X
Randomisation 
X
Study Medication Compliance Check
X
X
X
X
X
Conclusion of Patient Participation M
X
A
The duration of the Screen Visit or Run-In Visit (each visit) must be 7 days in duration but no fewer provided that all 
evaluations, including laboratory and ECG results as well as any applicable medical information are available at the trial 
site, and the patient meets the inclusion and exclusion criteria.  The allowed visit window for the Screen Visit or Run-In 
Visit (each visit) includes an additional 1 to 7 days.  Therefore, the maximum duration of the Screen Visit or Run-In 
Visit (each visit) is a total of 14 days.  
If a visit window (+/- 7 days: i.e., 1 day to 7 days) is used after randomisation, the patient should be returned to the 
original trial schedule by the next visit (i.e., the number of visit window days used must be subtracted from the 
upcoming visit).  This procedure ensures that all patients complete: the treatment period at approximately Day 169 and 
the Post-Treatment Visit at approximately Day 176.  The visit window between Visits 98 and 99 will not be allowed 
once trial enrolment has been achieved (sufficient patients screened to randomise 300 with 100 from Japan); the 
Clinical Monitor Local (CML) will inform trial sites when trial enrolment is complete.
B
Functional reviews (Patient Health Questionnaire and Saint Louis University Mental Status Examination) will be 
completed first to assess the functional ability, mental health, and cognitive ability of potential patients.  
For the Screen Visit: the screening evaluations (except for the Patient Health Questionnaire, Saint Louis University 
Mental Status Examination, and HbA1c which must be completed in this order immediately after informed consent) may 
be completed on separate days as long as the results are obtained within the allowed days for the visit.  
C
In the event of any cardiac symptoms (i.e., suspicion of heart rhythm disorders or cardiac ischemia) at Visit 1, Visit 3 
and/or Visit 98, an additional follow-up ECG will be collected and recorded after that particular visit.
D
Fasting blood samples (no food and/or drink except for water 10 hours prior to visit) via central lab.  Starting at Visit 3,
if hyperglycaemia is noted, repeat FPG via central lab.
 
 
F
Exception: For the Screen Visit only, patients do not have to be fasting.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 5 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
H
Instruction on how to use the Home Blood Glucose Monitoring (HBGM) device will be conducted at Visit 1 and the 
device will be given to the patient.  The patient should be instructed to monitor their blood glucose 4 times daily (before 
breakfast after overnight fasting, before lunch, before dinner, and before bedtime) using the HBGM device beginning 
that day with the closest monitoring time point.  The patient will also answer meal, exercise, and symptom questions on 
the eDiary and upload their glucose values to the eDiary daily.  The patient will be instructed to monitor their blood 
glucose once or twice weekly during sleeping hours if the patient gets up.  During the trial participation, additional 
HBGM monitoring should be completed if the patient has hypo- or hyperglycaemia-related symptoms.
I
Diet and exercise counseling by a diet specialist or trained staff member.  Counseling should be based on local diet 
recommendations.  At all other visits, patients should be reminded about the importance of following the recommended 
diet and exercise plan.
J
The only adverse events that are required to be reported for patients who screen fail before Visit 2 are serious adverse 
events (SAEs).
 
 
M The criteria for discontinuing patients from the trial participation are included in Section 3.3.4.1.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 6 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.............................................................................................9
1.
INTRODUCTION.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILE...............................................................................................16
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 18
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................18
2.2
TRIAL OBJECTIVES.......................................................................................18
2.3
BENEFIT - RISK ASSESSMENT ...................................................................18
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 21
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................21
3.1.1
Administrative structure of the trial...................................................22
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................23
3.3
SELECTION OF TRIAL POPULATION ......................................................24
3.3.1
Main diagnosis for study entry............................................................24
3.3.2
Inclusion criteria...................................................................................25
3.3.3
Exclusion criteria ..................................................................................25
3.3.4
Removal of patients from therapy or assessments.............................28
4.
TREATMENTS........................................................................................ 30
4.1
TREATMENTS TO BE ADMINISTERED....................................................30
4.1.1
Identity of BI investigational product and comparator product......30
4.1.2
Method of assigning patients to treatment groups ............................30
4.1.3
Selection of doses in the trial................................................................31
4.1.4
Drug assignment and administration of doses for each patient .......31
4.1.5
Blinding and procedures for unblinding ............................................32
4.1.6
Packaging, labelling, and re-supply ....................................................33
4.1.7
Storage conditions.................................................................................33
4.1.8
Drug accountability ..............................................................................33

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 7 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................35
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................35
4.2.2
Restrictions............................................................................................37
4.3
TREATMENT COMPLIANCE.......................................................................38
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 39
5.1
EFFICACY - PHARMACODYNAMICS........................................................39
5.1.1
Endpoints of efficacy.............................................................................39
5.1.2
Assessment of efficacy...........................................................................40
5.2
SAFETY..............................................................................................................41
5.2.1
Endpoints of safety................................................................................41
5.2.2
Assessment of adverse events...............................................................42
5.2.3
Assessment of safety laboratory parameters......................................46
5.2.4
Electrocardiogram................................................................................48
5.2.5
Assessment of other safety parameters...............................................48
5.3
OTHER...............................................................................................................49
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................51
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................51
5.7
PHARMACODYNAMICS................................................................................52
6.
INVESTIGATIONAL PLAN.................................................................. 53
6.1
VISIT SCHEDULE............................................................................................53
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................53
6.2.1
Screen and Run-In Periods ..................................................................53
6.2.2
Treatment period ..................................................................................54
6.2.3
End of trial and follow-up period........................................................55
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 56
7.1
STATISTICAL DESIGN - MODEL................................................................56
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................56
7.3
PLANNED ANALYSES....................................................................................56
7.3.1
Primary analyses...................................................................................57

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 8 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
7.3.2
Secondary analyses ...............................................................................58
7.3.3
Safety analyses.......................................................................................59
7.3.4
Interim analyses ....................................................................................60
7.3.5
Pharmacokinetic analyses ....................................................................60
7.3.6
Pharmacodynamic analyses.................................................................60
7.4
HANDLING OF MISSING DATA ..................................................................60
7.4.1
Efficacy endpoints.................................................................................60
7.4.2
Safety and other endpoints...................................................................61
7.5
RANDOMISATION ..........................................................................................61
7.6
DETERMINATION OF SAMPLE SIZE ........................................................61
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 63
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................63
8.2
DATA QUALITY ASSURANCE .....................................................................65
8.3
RECORDS..........................................................................................................66
8.3.1
Source documents .................................................................................66
8.3.2
Direct access to source data and documents.......................................66
8.3.3
Storage of records .................................................................................66
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................67
8.4.1
Listedness...............................................................................................67
8.4.2
Expedited reporting to health authorities and IECs/IRBs................67
8.5
STATEMENT OF CONFIDENTIALITY.......................................................67
8.6
COMPLETION OF TRIAL..............................................................................67
8.7
PROTOCOL VIOLATIONS ............................................................................68
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT 
OF TRIAL RELATED INJURY......................................................................68
9.
REFERENCES......................................................................................... 69
9.1
PUBLISHED REFERENCES...........................................................................69
10. APPENDICES .......................................................................................... 75
10.1
INCLUSION OF ILLITERATE PATIENTS .................................................75
10.1.1 Home Blood Glucose Monitoring and eDiary ....................................75
10.1.2 Patient information and informed consent (including 
pharmacogenomics)..............................................................................75
11. DESCRIPTION OF GLOBAL AMENDMENT................................... 77

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 9 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT
Alanine aminotransferase (or SGPT)
a.m.
ante meridiem
AST
Aspartate aminotransferase (or SGOT)
BI
Boehringer Ingelheim
BMI
Body Mass Index
CA
Competent Authority
CEC
Clinical Event Committee
CI
Confidence Interval
CK
Creatine kinase
CML
Clinical Monitor Local
CRA
Clinical Research Associate
CTP
Clinical Trial Protocol
DPP-4
Dipeptidyl-Peptidase IV
 
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
e.g.
exempli gratia (for example)
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDA
Food and Drug Administration
FPG
Fasting Plasma Glucose
-GT
gamma-glutamyl-transferase
GCP
Good Clinical Practice
GIP
Glucose-dependent insulinotropic peptide
GLP-1
Glucagon-like Peptide
GmbH&Co. KG Gesellschaft mit beschränkter Haftung &Company Kommanditgesellschaft
HbA1c
Glycated or glycosylated Haemoglobin

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 10 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
HBGM
Home Blood Glucose Monitoring
HDL
High Density Lipoprotein
ICH
International Conference on Harmonisation
i.e.
id est (that is)
IEC
Independent Ethics Committee
Inc.
Incorporated
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITT
intention to treat
kg/m2
kilograms per meters squared
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
milligrams
mg/dL
milligrams per deciliter
mmol/L
millimoles per Liter
mmol/mol
millimoles per mole
MMRM
Mixed Model Repeated Measures
N/A
not applicable
NCF
Non-completer’s considered failures
NGSP
National Glycohaemoglobin Standardisation Program
OC
Observed Cases
OPU
Operating Unit
p.o.
per os (oral)
PPS
Per Protocol Set
q.d.
quaque die (once a day)
RDC
Remote Data Capture

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 11 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
REP
residual effect period
SAE
Serious Adverse Event
SGLT2
sodium glucose co-transporter 2
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOP
Standard Operating Procedure
STEMI
ST Elevation Myocardial Infarction
SUSAR
Serious Unexpected Suspected Adverse Reaction
T2DM
Type 2 Diabetes Mellitus
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
TMF
Trial Master File
TS
treated set
TSAP
Trial Statistical Analysis Plan
ULN
upper limit of normal

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 12 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
T2DM accounts for 90% to 95% of all cases of diabetes and is an increasingly prevalent 
disease with over 300 million people estimated to be affected worldwide (R09-4240). The 
rate of obesity is increasing, with a parallel increase in the rate of T2DM (R14-0447).  The 
high frequency of complications leads to a significant reduction of life expectancy
(R09-4241). Because of hyperglycaemia induced microvascular complications, diabetes is 
currently the most frequent cause of adult-onset loss of vision, renal failure, and amputation 
in the Industrialised World and is additionally associated with a two to five fold increase in 
cardiovascular disease risk.
Emerging treatment for T2DM
With the chronic progression of T2DM in many patients, a declining glycaemic control over 
time can become evident despite adequate diet, exercise, and therapies with oral 
antihyperglycaemic agents.  Within a few years, treatment intensification is required because 
of a progressive loss of beta cells and the diminishing secretory capacity of the remaining 
cells, resulting in secondary drug failure and the necessity to institute insulin therapy in many 
patients.  In most cases, insulin resistance cannot be compensated by an adequately increased 
insulin secretion, ultimately leading to increased fasting and postprandial glucose 
concentrations.  Currently available antidiabetic agents are not sufficient to maintain long 
term glycaemic control.  Management of diabetes in the elderly population is complicated by 
these age-related changes (P13-00432).  
Traditional insulin secretagogues, such as the sulphonylurea drugs, increase insulin secretion 
in a non-glucose-dependent manner and carry an increased risk for hypoglycaemia.  
Additionally, it is unclear whether such a glucose independent stimulation of insulin secretion 
accelerates the loss in beta cell function.
An improved understanding of the interaction between gut related hormones and the 
endocrine system has led to the incretin concept and, based on this concept, to the 
development of a new class of antidiabetic agents.  The incretin effect is a phenomenon 
where the glucose-stimulated insulin secretion is augmented by intestinally derived peptides, 
which are released in the presence of glucose or nutrients in the gut.  Glucagon-like peptide-1 
(GLP-1) is an important member of the incretin hormone family.  Importantly, the actions of 
GLP-1 depend on the actual glucose concentration. GLP-1’s stimulation of insulin secretion 
ceases when glucose concentrations fall below 55 milligrams per deciLiter (mg/dL).  
Therefore, elevation of GLP-1 levels bears little to no risk of hypoglycaemia. 
GLP-1 is almost instantaneously inactivated by the enzyme dipeptidyl-peptidase IV (DPP-4) 
explaining its short half-life of only a few minutes.  Postprandial GLP-1 secretion has been 
reported to be attenuated in T2DM which may partially explain the increased postprandial 
glucose excursions.  Therefore, a prolongation of the half-life of GLP-1 may be seen as a 
therapy which restores the lack of GLP-secretion.  Besides its stimulatory effects on insulin 
secretion, GLP-1 has been shown to inhibit glucagon secretion, to delay gastric emptying, to 
induce satiety, and, in animal models, to maintain long-term beta cell function.  Especially 
the maintenance of beta cell function is of interest, because loss of beta cell function has been 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 13 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
identified as a major contributor to the deterioration of long term glycaemic control in 
T2DM.
DPP-4 is an enzyme widely expressed in many tissues including kidney, liver, intestine, 
lymphocytes and vascular endothelial cells.  In addition, a significant level of DPP-4 activity 
is also observed in plasma, which likely originates from multiple tissues that express the 
enzyme.  DPP-4 is thought to play an important role in the degradation of a number of 
peptides, thus regulating their half-life.  However, physiological evidence for the role of 
DPP-4 in this process is only available for a few DPP-4 substrates, e.g., GLP-1 and glucose-
dependent insulinotropic peptide (GIP), both of which exert glucose-dependent insulinotropic 
actions and thereby contribute to the maintenance of post-meal glycaemic control.  DPP-4 
knock out rodents exhibit improved glycaemic control and are resistant to diet induced 
obesity, indicating a physiological role of this enzyme in glucose homeostasis and body 
weight regulation. 
A newer class of antihyperglycaemic agent, DPP-4 inhibitors, acting on the GLP-1 axis, 
targets pancreative islet dysfunction, in particular gut-derived incretin hormones.  DPP-4 
inhibitors have some characteristics which may be of particular value in older patients.  
DPP-4 inhibitors can be taken orally, are weight neutral, well tolerated and have a lower risk 
of hypoglycaemia compared with insulin and sulphonylureas (P12-06615).  Indeed, the 
American Diabetes Association and European Association for the Study of Diabetes position 
statement specifically describe the advantage of DPP-4 inhibitors as rarely having severe side 
effects as opposed to the other treatment options (P12-05315).  In a recent observational trial 
evaluating the tolerability and safety of DPP-4 inhibitors for the treatment of older people has 
shown that patients prescribed DPP-4 inhibitors had evidence of improved glycaemic control 
in addition to a lower rate of documented hypoglycaemia (3% vs. 8%) than the non-DPP4 
inhibitor treated group (R14-0340).
A strong scientific rationale suggests that DPP-4 inhibitors can prevent or counteract 
hypoglycaemia.  This is especially important for the management of insulin-treated patients 
since the limiting factor in this population is iatrogenic hypoglycaemia.  The insulinotropic 
effects of incretins are glucose-dependent and decline as postprandial serum glucose levels 
return to normal ranges.  The incretin GIP increases glucagon levels during fasting and 
hypoglycaemic conditions, while potentiating glucose-induce insulin secretion during 
hyperglycaemia (P13-14398).  The DPP-4 inhibitors have been studied in large clinical trials, 
as add-ons to insulin.  For vildagliptin, sitagliptin and saxagliptin, an improved glycaemic 
control was shown when added to ongoing insulin therapy.  All three DPP-4 inhibitors were 
generally well tolerated in patients with T2DM (R14-0340).  The results of these trials 
suggest that concomitant treatment with DPP-4 and insulin is effective for achieving better 
glycaemic control in patients with T2DM while improving the safety and tolerability of the 
antihyperglycaemic treatment.
Management of elderly T2DM patients
T2DM is up to five times more prevalent in elderly patients (65 years of age and older) 
compared to patients who are younger (R14-0340).  Additionally, up to one in five elderly 
patients have T2DM while a similar proportion may have undiagnosed T2DM (R14-0183).  

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 14 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Furthermore, diabetes in the elderly is metabolically distinct from diabetes in middle aged 
patients (R04-1263, R09-5797).  
Glucose-lowering treatment of elderly patients with T2DM is generally deemed necessary to 
alleviate symptoms associated with hyperglycaemia and risk reduction of the long-term 
complications.  Although the general goal for patients with T2DM of a HbA1c level of 7.0% 
or less may be reasonable for some elderly patients, recent guidelines stress individualizing 
this target to balance potential benefit and risk of treatment for elderly patients at high risk of 
hypoglycaemia or complications from hypoglycaemia, as long as acutely symptomatic 
hyperglycaemia is avoided (R14-0344).  
Higher glucose levels may contribute to an increase risk of dementia through several 
potential mechanisms, including acute and chronic hyperglycaemia, insulin resistance, and 
increased microvascular disease of the central nervous system (R12-1338, R14-0250, 
R14-0436, R14-0435, R14-0434, R14-0437).  This link of hyperglycaemia to an increase risk 
of dementia may speak against generally higher targets for HbA1c in the elderly population.  
Moreover, the general concern about stricter HbA1c control is largely based on trials that used 
glucose-lowering drugs with relatively high risk of hypoglycaemia.  Thus, hypoglycaemia 
has been shown to increase the risk for dementia and is associated with increased
cardiovascular risk in patients with T2DM.  This illustrates the dilemma of poor health 
outcomes with either hyperglycaemia or hypoglycaemia in older adults with T2DM.  This 
burden may be alleviated by using pharmacotherapies that could achieve relevant 
improvements in glycaemic control with low risk of hypoglycaemia or other adverse effects.
Elderly patients with T2DM generally have a reduced ability to tolerate the adverse effects of 
medication, compared with younger patients (R09-6092).  Over time, most patients with 
T2DM experience progressive beta cell dysfunction and will require insulin therapy, usually 
in combination with oral agents, for satisfactory glycaemic control (P13-14398).  Insulin 
treatment can improve and maintain glycaemic control, preventing long-term complications 
in T2DM.  Basal insulin is becoming an important option when initiating insulin therapy in 
T2DM patients who require insulin (R14-0360).  Many elderly patients are prescribed insulin 
along with other antidiabetic medications for glycaemic control, which increases the risk of 
hypoglycaemia (P13-00432).  
Many glucose-lowering drugs have potential disadvantages for elderly patients, particularly a 
risk for hypoglycaemia (sulfonylureas, insulin), fractures (thiazolidinediones), 
contraindication, or dose adjustments for renal impairment for most oral and injectable agents 
(P13-00432).  Additionally, efficacy of glucose lowering can be affected by disease duration, 
because of deterioration over time in pancreatic beta cell function.  Therefore, safety is an 
important consideration for treatment, especially avoidance of iatrogenic hypoglycaemia, 
which occurs frequently in elderly patients and can have severe consequences. Renal 
impairment is also very common in elderly with T2DM, increasing their risk for 
hypoglycaemia and complicating treatment strategies (P13-00432, R14-0183).
Of particular importance is that hypoglycaemia had the third highest incidence of nonfatal 
complications in 70 year old and older T2DM patients, with the highest rates in patients who 
had T2DM for 10 years or more (R14-0002).  Eventually, the initiation of insulin therapy is 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 15 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
necessary in order to maintain glycaemic control.   Insulin accounts for a significant number 
of hypoglycaemic events in the elderly American population each year and SAEs, reported to 
the United States Food and Drug Administration (FDA), related to its use have been steadily 
rising in recent years (P07-11112, P11-14211).  Additionally, sulfonylureas, insulin, and 
metformin (possibly used in combination with each other or other antidiabetic medications) 
trigger a large proportion of drug-related emergency room visits and hospitalizations in the 
United States (R14-0002).  
There is a significant variation in T2DM prevalence and associated mortality rates between 
different geographic areas (P08-11948).  There is a disproportionate burden of this disease 
among some racial and ethnic populations, especially those at the low end of the 
socioeconomic spectrum and/or residing in developing countries.
Clinical trials contribute toward reducing health disparities through improved knowledge 
about treatment among diverse populations.  Minorities are significantly underrepresented in 
clinical trials, with non-participation frequently related to recruitment barriers.  The limited 
generalisability of trial results led the National Institutes of Health to develop guidelines 
ensuring that funded clinical research would generate information about the effects of the 
study intervention on both genders and diverse racial (and ethnic) groups (R13-2759).  Even 
with such guidelines in place, literature suggests significant barriers to successful recruitment 
of minority patients into clinical trials, including cultural beliefs regarding illness and disease, 
mistrust of the health care system, and differences in health beliefs and practices.  Solutions 
lie in exploring new venues to reach minority populations and to create strategies aimed at 
recruiting and retaining these patients.  Greater diversity in clinical trial samples allows for 
broader generalization of trial results, increased minority access to trials, improved standards 
of care, decreased disparities in disease treatment and outcomes, and improved external 
validity supported by a more representative sample (R13-2759).
Despite assuming a disproportional burden of disease and consumption of prescription drugs 
as well as therapies, these older patients have been vastly underrepresented in clinical trials, 
thereby restricting treatments’ generalizability, efficacy and safety (R14-0182).  A recent 
analysis has shown that only 0.6% of interventional trials in T2DM specifically targeted this 
age group, 31% excluded patients older than 65 years, and almost all excluded those older 
than 75 years (R14-0345).  In addition, elderly patients, defined as 65 years of age and older, 
by the American Geriatric Society, have frequently been excluded from those major clinical 
trials used to develop practice guidelines due to age-related complications (R10-5452).  
Based on patients’ health status and risk factors, these complications include but are not 
limited to comorbid conditions, polypharmacy, renal insufficiency, increase fall risk, visual 
impairment, and cognitive impairment and age-related decrease in pancreatic-islet function 
(P14-00552).  As noted, although there are numerous evidence-based guidelines, few 
guidelines are specifically targeted toward the needs of these patients.  
As a result of the extreme difficulty with recruiting this population, the global protocol 
amendment 1 expanded the definition of elderly population beginning at age 60 and 
reduced the lower limit of HbA1c to match the trials that were used for this trial’s 
hypothesis. 
 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 16 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
1.2
DRUG PROFILE
 
 
 
 
 
 
 
Linagliptin is a potent inhibitor of DPP-4 and prolongs the half-life of endogenous GLP-1.  
Unlike the other DPP-4 inhibitors, linagliptin, given in a once-daily, single-dose 5 mg 
regimen is excreted mainly by non-renal pathways and dose adjustment is not needed for 
renal impairment or any other factor (P12-05699).  Linagliptin also has minimal drug 
interactions (P12-05699). 
 
  
Treatment with 5 mg linagliptin, once daily, has been shown to be well-tolerated and results 
in clinically meaningful and statistically significant reductions in HbA1c, FPG, and 
postprandial glucose
  There was a consistent pattern in the 
improvement in HbA1c when linagliptin was used in patients with different background 
therapies.  Linagliptin 5 mg has also been shown to give sustained efficacy over 52 weeks in 
T2DM patients with severe renal impairment.  Additionally, linagliptin 5 mg has 
demonstrated clinically relevant efficacy for elderly and African American T2DM patients 
(P10-14001, P11-02847, P11-06845, P11-09378, P11-12477, P13-09565, 
 
 
 
 
 
  
 
  To date, 
in Phase III trials in patients with T2DM, linagliptin elicited meaningful glucose-lowering 
effects and was well tolerated with little intrinsic risk for hypoglycaemia (P10-14001, 
P11-02847, P11-06845, P11-09378, P11-12477).  
 
 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 17 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
  Overall, it has 
been shown that linagliptin is an effective and safe add-on therapy to insulin in patients with 
T2DM.  This combination therapy was also shown to be safe and effective in vulnerable, 
elderly T2DM patients and in T2DM patients with renal impairment (P13-14398).  
Recently, in a randomised, placebo-controlled clinical trial that included 241 patients, who 
were 70 years of age and older, with inadequate glycaemic control on stable backgrounds of 
metformin and/or sulphonylurea and/or basal insulin, linagliptin was shown to be safe and 
effective in this patient population (P13-09565).  A subset from a pooled analysis of two 
Phase III trials consisting of 247 patients, 70 years of age and older, who received linagliptin 
or placebo showed adding linagliptin to basal insulin appeared to decrease the risk of 
hypoglycaemia despite significant reduction in HbA1c and no relevant reductions in insulin 
dose (P13-07824).  In summary, linagliptin has been shown to be effective and safe as an 
add-on therapy that can help patients on basal insulin to improve their blood sugar control 
without weight gain or additional risk of hypoglycaemia.
Symptoms that could be attributed to hypoglycaemia as well as plasma glucose levels will be 
closely monitored in this current trial.  Glycaemic goals in elderly patients and interventions 
to achieve such goals must take into account the clinical status of individual patients, in 
particular, avoidance of hypoglycaemia which can have a profound impact on health and 
quality of life in elderly patients.  

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 18 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
The rationale for conducting this trial in an elderly population on a stable background therapy 
of basal insulin is:

to further establish the adverse event profile of linagliptin,

to achieve improved glycaemic control without increasing adverse events, 

to assess the occurrence of hypoglycaemia, and

to collect additional data in this population.
2.2
TRIAL OBJECTIVES
The objective of this trial is to investigate the efficacy, safety, and tolerability of linagliptin 
5 mg given orally once daily compared to placebo as add-on therapy for 24 weeks to stable
basal insulin treatment in elderly patients, 60 years of age and older, with T2DM with 
insufficient glycaemic control (i.e., HbA1c of 7.0% to 10%).  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 HbA1c, a well-accepted
measurement of chronic glycaemic control.  
For a description of the endpoints chosen and statistical analyses to assess these objectives, 
refer to Section 5 and 7.
2.3
BENEFIT - RISK ASSESSMENT
Potential general benefits for patients in this trial irrespective of the investigational 
medication received are: improvements in glycaemic control, regular diet and exercise 
counseling, as well as general medical benefit from careful and close monitoring by medical 
personnel, and HBGM during the trial.  
General risk associated with participating is related to trial specific procedures such as blood 
sampling that can be associated with bruising and pain.  The amount of blood taken during 
the whole course of the trial is not believed to be excessive and is associated with the 
standard of care for the patients.
One week Run-In Period Risk
Trial designs with a one-week placebo Run-In Period are well-established for T2DM trials.  
The patients will be maintained on stable antidiabetic therapy during the one-week Run-In 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 19 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Period and continue regular monitoring of blood glucose with a HBGM device. Thus, the 
risk of the one-week placebo treatment in this trial is considered to be minimal. 
Background Therapy and Study Medication Specific Risk
Basal insulin is the stable background therapy in this trial.  Patients are administered basal 
insulin and not short-acting insulin because there are fewer injections, lower risk of 
hypoglycaemia, and basal insulin covers postprandial peaks.  Weight gain, hypoglycaemia, 
allergic reactions, injection site reaction, lipodystrophy, pruritus, and rash are the most 
common side effects noted with basal insulin.  All patients will have received basal insulin 
and these events mainly occur shortly after insulin initiation (at least allergic reactions).  For 
safety reasons, the basal insulin dose can always be modified by investigators.
Metformin, a typical background medication, is a drug that has been on the market for a long 
time, is widely used as a first line therapy, and therefore believed to be well characterized in 
terms of risk profile.  Metformin can however cause lactic acidosis to develop, which is 
relatively infrequent and more likely to occur in patients who have kidney or liver disease, 
excessive alcohol use, X-ray or scanning procedures that require an injectable iodinated 
contrast drug, surgery, or a serious infection (R10-5341, R10-5537).  Patients may be taking
metformin as part of their stable background therapy.  With all these conditions being 
excluded and the monitoring throughout the trial, this risk will be minimal for patients taking 
linagliptin and metformin. 
Alpha-glucosidase inhibitors (such as acarbose) may be used as background medication and 
decrease the absorption of carbohydrates from the digestive tract, thereby lowering the 
post-meal glucose levels.  Alpha-glucosidase inhibitors are used to establish greater 
glycaemic control over hyperglycaemia in T2DM, particularly with regard to postprandial 
hyperglycaemia.  Alpha-glucosidase inhibitors may be used as monotherapy in conjunction 
with an appropriate diabetic diet and exercise, or they may be used in conjunction with other 
anti-diabetic drugs.  Alpha-glucosidase inhibitors commonly are associated with 
gastrointestinal side effects such as flatulence, bloating, nausea, vomiting, and diarrhoea.
Angioedema, urticaria and rash are listed as side effects for linagliptin (with any background, 
R11-2588).  For the fixed dose combination of linagliptin plus metformin, the identified side 
effects correspond to the observed side effects of metformin (i.e., decreased appetite, 
diarrhoea, nausea, vomiting, and pruritus) plus the events for linagliptin on all backgrounds 
(nasopharyngitis, cough, hypersensitivity and pancreatitis as well as angioedema, urticaria, 
and rash).  Furthermore, longer term safety data have not shown any further safety trends to 
date. 
 
As with all drugs, the potential for hypersensitivity and allergic reactions has to be taken into 
consideration when linagliptin is administered.  Other risks to the patients are the risks 
inherent to any clinical trial such as unexpected adverse clinical or laboratory events.  Safety 
will be ensured by monitoring the patients for adverse events (AEs) both clinically and by 
laboratory testing.  If any investigator should have a clinical concern, the safety of the 
patients will be of paramount importance.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 20 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Approximately half of the patients participating in this trial may derive a direct benefit from 
being treated with an active compound and not a placebo.  Patients who are not adequately 
controlled (whether in the blinded placebo or active compound group), as evidenced by FPG
or blood glucose values (by HBGM device), will have adjustments to their background 
therapy or receive rescue therapy (according to Section 4.2.1) to ensure their safety.
Rescue therapy will be permitted in case of hyperglycaemia during the randomised treatment 
period if the defined criteria are met (refer to Section 4.2.1).  The choice of rescue medication 
and its dosage according to Section 4.2.1 will be left to the discretion of the investigator and 
rescue medication will be taken in accordance with the local prescribing information of that 
respective medication.  The use of rescue medication may be associated with relevant side 
effects, such as increase of hypoglycaemia risk, weight gain, etc.
Alternative Therapies for T2DM
There are several alternative therapies available for the treatment of T2DM (e.g., biguanides, 
sulphonylureas, thiazolidinediones, sodium glucose co-transporter 2 (SGLT2) inhibitors, 
metglitinides, alpha-glucosidase inhibitors, rapid acting or short acting insulin); however, 
these are not without side effects.  Side effects in the elderly population with 
thiazolidinediones include fluid retention, fracture risk, and heart failure risk.  Side effects in 
the elderly population with sulphonylureas and metglitinides include hypoglycaemia.  In the 
context of advanced age and diminished renal functions, cases of prolonged and severe 
hypoglycaemia with sulphonylurea treatment have been reported.  Side effects in the elderly 
population with alpha-glucosidase inhibitors include gastrointestinal side effects.  Side effects 
in the elderly population with rapid acting or short acting insulin include several injections 
and hypoglycaemia.
Thus, given the above considerations, the benefit-risk assessment for the use of linagliptin for 
the treatment of T2DM in elderly patients to improve glycaemic control is considered 
favourable for the conduct of this trial.  

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 21 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This randomised, double-blind, multi-national, placebo-controlled, parallel group trial will 
compare linagliptin 5 mg daily to placebo as add-on therapy to a stable background of basal 
insulin, metformin (optional), and/or alpha-glucosidase inhibitors (optional) over 24 weeks in 
elderly T2DM patients with insufficient glycaemic control.
In total, approximately 300 T2DM patients (100 from Japan), 60 years of age and older, 
with insufficient glycaemic control will enter (i.e., be randomised in) this trial.  The 
randomised treatment will be provided in a double-blind design within the two treatment 
arms (each patient will receive either linagliptin as active treatment or placebo matching 
linagliptin). 
Patients are enrolled into the trial once they have signed the informed consent.  The Screen 
Period is one week in length.  All patients meeting the inclusion and exclusion criteria will 
complete a one week placebo Run-In Period before randomisation.  
Patients who successfully complete the Run-In Period and still meet the inclusion and 
exclusion criteria will be randomised into the 24 week treatment period of the trial in which 
they will receive either linagliptin 5 mg or placebo.  
Run-In
(7 to 14 days duration)
Eligibility Assessment
linagliptin 5 mg
(24 weeks duration)
Post-Treatment
(7 days duration)
Screen
(7 to 14 days duration)
Eligibility Assessment
placebo
(24 weeks duration)
Randomisation
or
Figure 3.1: Trial Periods
All adverse events with an onset after the first dose of study medication up to a period of 
seven days after the last dose of study medication will be assigned to the treatment phase for 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 22 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
evaluation.  This includes adverse events that start before first study medication intake and 
deteriorate under treatment.  Other adverse events will be assigned either to the screening, 
run-in, or follow-up phase as appropriate.  All adverse events, including those persisting after 
trial completion at the Post-Treatment Visit (Visit 99), will be followed-up for up to 7 days.  
The investigative staff should confirm if continuing adverse events have resolved or have 
been sufficiently characterised.  
The end of the trial is defined as “last patient out”, i.e., last visit completed by the last patient.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim Pharma GmbH & Co. KG. 
BI will appoint a Trial Clinical Monitor (TCM), responsible for coordinating the activities 
required in order to manage the trial in accordance with applicable regulations and internal 
standard operating procedures (SOPs), directing the clinical trial team in the preparation, 
conduct, and reporting of the trial, order the materials as needed for the trial, ensures 
appropriate training and information of CML, Clinical Research Associates (CRAs), and 
investigators of participating countries.
Data Management and Statistical evaluation will be performed by BI according to BI SOPs.  
For these activities, a Trial Data Manager and a Trial Statistician will be appointed.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs.  A list of responsible persons will be given in the Trial Master 
File (TMF) document.
The organisation of the trial in the participating countries will be done by the respective local 
BI organisation [Operating Unit (OPU)] or a by a Contract Research Organisation with which 
the responsibilities and tasks will have been agreed and a written contract filed before 
initiation of the clinical trial.  In each OPU participating in this trial, a CML will be appointed 
responsible for coordinating the activities required in order to manage the trial in accordance 
with applicable regulations and internal SOPs in the countries covered by the respective BI 
OPU.
A Co-ordinating Investigator will be nominated to coordinate investigators at different trial 
sites participating in this multicentre trial.  Tasks and responsibilities for the Co-ordinating 
Investigator will be defined in a contract filed before initiation of the trial.
Documents on participating (Principal) investigators and other important participants, 
especially their curricula vitae, will be filed in the TMF. 
A BI preferred central laboratory, ECG, and IRT provider will be selected to provide services 
for laboratory sample handling and analyses, ECG interpretation, and for study medication 
logistics, respectively as required for this protocol. 
The eDiary and HBGM device will be provided by a BI preferred provider.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 23 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Details on handling of the trial supplies including responsible institutions are given in 
Section 4 of this protocol.
The Investigator Site File (ISF) will be kept in printed version at the trial sites as far as 
required by local regulation and BI SOP.  A copy of the ISF documents will be kept as an 
electronic TMF document according to BI SOPs.
Based on the known safety profile, therapeutic window, and tolerability of linagliptin, a Data 
Monitoring Committee is not required for this trial.
Clinical Event Committees:
Independent, blinded, external committees will be managed by BI’s third party preferred 
provider and set up for adjudication of pancreatic, cerebrovascular, and cardiovascular 
events.  Details on the composition of each of the committees, their respective procedures and 
interaction will be provided in separate Clinical Event Committee (CEC) charters that will be 
filed in the TMF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
Due to its mechanism of action and the low risk for hypoglycaemia induction, DPP-4 
inhibitors like linagliptin should provide additional efficacy alongside manageable 
tolerability and safety in elderly patients when added to background antidiabetic therapy 
consisting of basal insulin, metformin (optional), and/or alpha-glucosidase inhibitors
(optional).  
Elderly patients with T2DM who have insufficient glycaemic control will enter the trial and 
receive either double-blind linagliptin or placebo.  The placebo-controlled design is 
considered ethically acceptable on the basis of the benefit and risk assessment, as defined in 
Section 2.3; appropriate criteria for patient discontinuation, ability to adjust or change 
permitted antidiabetic therapy to maintain, or obtain sufficient level of glycaemic control, as 
defined in Section 4.2.1; and relevant local and regional guidelines for optimized standard of 
care. 
The randomised treatment period is planned for 24 weeks because the primary efficacy 
endpoint of HbA1c has been shown to reflect glycaemic control over the preceding 12 weeks
and this period should allow sufficient time to demonstrate changes in the incidence of 
hypoglycaemia events.  The 1-week Post-Treatment period is considered to be sufficient, as 
previous trials with linagliptin have shown that the pharmacodynamic effect of linagliptin 
only extends to about 7 days after the last dose.
The permitted background antidiabetic therapy will not be provided as part of the clinical trial 
supplies, unless required by local laws and regulations.
The rationale for dose and dose-interval selection is described in Section 4.1.3.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 24 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
3.3
SELECTION OF TRIAL POPULATION
This is an international trial in which approximately 300 patients (100 patients from Japan)
will be randomised to treatment (150 patients to each treatment group). 
It is expected that at least 4 to 8 patients should be enrolled (or screened) at each trial site.  If 
enrolment is delayed, additional trial sites may be recruited.
The IRT system will permit each trial site to randomise up to 30 patients.  The TCM may 
allow the randomisation of additional patients after a careful assessment of potential bias due 
to the patient distribution across trial sites.  Permission for a trial site to randomise more than 
30 patients must be obtained from the TCM in writing, via the Clinical Monitor Local at BI, 
in order to increase the number of patients allowed to be randomised at the trial site.
Screening of patients for this trial is competitive (i.e., when a sufficient number of patients 
have been screened and/or randomised to study medication, screening of patients for the trial 
will end at all trial sites).  It is possible that recruitment for countries may be stopped 
while recruitment in Japan continues in order to achieve the required 100 patients 
randomized in Japan.  Investigators will be notified when a sufficient number of patients 
have been screened and of the date on which screening will finish.  The date that screening 
may end could be within a 24 hour period of time depending on enrolment numbers.  
Therefore, investigators may need to contact patients in order to cancel planned screening 
visits.  The investigators will not be allowed to recruit additional patients for this trial after 
the date that screening has ended.  Patients who have completed Screen procedures prior to 
notification of the termination of recruitment will be allowed to continue in the trial if they 
meet all entry criteria and are able to follow the visit schedule specified in this protocol.
Patient eligibility will be assessed by a complete medical history, which may be obtained by 
the investigator verbally from the patient during a trial site visit but is required to be 
documented in a source document by the investigator (including past medical records of at
least 1 year), physical examination, and laboratory tests as described in this protocol.  
Judgement of the clinical relevance of a concomitant disease is at the discretion of the 
investigator.  Conditions under therapy are always clinically relevant. 
A log of all patients included into the trial (i.e., having given informed consent) will be 
maintained in the ISF at the trial site irrespective of whether they have been treated with 
study medication or not.
3.3.1
Main diagnosis for study entry
The trial will be conducted in elderly patients with T2DM on stable basal insulin, metformin 
(optional), and/or alpha-glucosidase inhibitors (optional) with insufficient glycaemic control,
who may or may not be on a diet and exercise program per standard local clinical practice,
prior to entry.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 25 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
3.3.2
Inclusion criteria
1. Patients must sign and date an Informed Consent consistent with International 
Conference on Harmonisation (ICH) / Good Clinical Practice (GCP) guidelines and 
local regulations prior to any evaluation and participation in the trial.
2. Male and female patients with a clinical diagnosis of T2DM, at the time of Informed 
Consent, who are:
a.
60 years of age or older at informed consent or Screen Visit,
b. taking stable doses of basal or biosimilar basal insulin [strictly inclusive of: 
insulin neutral protamine Hagedorn (NPH), Humalog Basal® (a suspension 
of insulin lispro protamine), and isophane insulin; 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 +/- 20% of baseline being 
allowed, 
c.
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 
12 weeks without dose adjustments prior to randomisation (Visit 3)], and
d. 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 12 weeks without dose adjustments prior to 
randomisation (Visit 3)].
3. Patients must have an HbA1c of 7.0% [53 millimoles per mole (mmol/mol)] to 10.0% 
(86 mmol/mol) at the first visit (Screen).  
4. Patients must have a BMI of 45 kg/m2 or less at the Screen Visit.
5. 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.
3.3.3
Exclusion criteria
Patients with, who are, who have, or who have had:
1. Impaired cognitive ability as supported by the Saint Louis University Mental Status 
Examination (R14-0995, R14-0977, R14-0992), additional assessment if necessary 
(as described below), and verified by the investigator at Screen. Saint Louis 
University Mental Status Examination scores of 21 to 26 for those patients with high 
school education or 20 to 24 for those patients who did not complete a high school 
education indicate that the patient probably has mild neurocognitive disorder and 
may be further evaluated as noted below.  

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 26 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
The investigator may complete an additional assessment based on typical activities of 
daily living so that mild neurocognitive disorder can be ruled out if the investigator 
believes that a patient does not have mild neurocognitive disorder as supported by 
the score on the Saint Louis University Mental Status Examination.  Patients with 
dementia scores on this assessment of 1 to 20 with a high school education 
equivalent or 1 to 19 without a high school education equivalent must not proceed 
with further evaluations in the Screen Visit.
Note:  High school or upper secondary education (completing approximately 12 grade 
levels) equivalents may include the following examinations or certificates such as 
General Certificate of Education, Leaving Certificate, Reifezeugnis or Abitur, 
Apolyterion, Baccalaureate, Matura, Swiadectwo Dojrzalosci, Maturity,
Studentereksamen, Ylioppilastutkintotodistus or Studentbetyg, Diploma de 
Maturitate, Corso de Orientacion Universitaria, Senior High School Grad, 
Gymnasium, Higher Preparatory Examination, Higher Commercial Examination,
Higher Technical Examination, Bachillerato, University Entrance Certificate, Senior 
Certificate, National Senior Certificate, Joint Matriculation Board Certificate, 
Advanced Level Exams, National Senior Certificate or Matric examination.
2. Depressed mood as supported by a score of 10 or more on the Patient Health 
Questionnaire (R13-3779) at the Screen Visit.  
3. Type 1 Diabetes Mellitus as determined by past medical records and history.
4. Acute coronary syndrome [non-ST Elevation Myocardial Infarction (STEMI), 
STEMI, and/or unstable angina pectoris], stroke or transient ischemic attack within 
3 months prior to Screen Visit.
5. 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 (ULN) in any of the following: 
alanine aminotransferase [ALT or called serum glutamic pyruvic transaminase 
(SGPT)], aspartate aminotransferase [AST or serum glutamic oxaloacetic 
transaminase (SGOT)], or alkaline phosphatase.  Gilbert-Meulengracht syndrome 
(also known as conjugated hyperbilirubinemia, constitutional hepatic dysfunction, or 
familial nonhemolytic jaundice) will be permitted.
6. 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.
7. Medical history of cancer (except for resected non-invasive basal or squamous cell 
carcinoma) and/or treatment for cancer within the last 5 years.
8. Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells (e.g., 
malaria, babesiosis, haemolytic anaemia). 
9. Treatment with GLP-1 analogues within 3 months prior to Informed Consent.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 27 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
10. Treatment with sulphonylureas, thiazolidinediones, meglitinides, bromocriptine,
SGLT2 inhibitors, or DPP-4 inhibitors within 3 months prior to randomization (Visit 
3).
11. Treatment with rapid acting or short acting insulin and/or pre-mixed insulin
containing rapid acting or short acting insulin within 3 months prior to randomization 
(Visit 3).
12. Known hypersensitivity, allergy, or any contraindication to linagliptin or its excipients 
or the patients’ background therapy (i.e., basal insulin, metformin, or 
alpha-glucosidase inhibitors) or placebo, according to local labels. 
13. Treatment with anti-obesity drugs, including over-the-counter drugs such as Alli
(orlistat), 4 weeks prior to informed consent or any other treatment at the time of 
screening (i.e., surgery, aggressive diet regimen, etc.) leading to unstable body 
weight.
14. Current treatment with any drugs known to have significant effect on glucose 
metabolism, such as systemic steroids, at time of informed consent or change in 
dosage of thyroid hormones within 6 weeks prior to informed consent or any other 
uncontrolled endocrine disorder excluding T2DM.
15. Alcohol or drug abuse within the 3 months prior to informed consent that would 
interfere with trial participation or any ongoing condition leading to decreased 
compliance to trial procedures or study medication intake in the opinion of the 
investigator.
16. Participation in another trial with an investigational drug within 2 months prior to 
informed consent.
17. Psychological, familial, sociological, or geographical factors potentially hampering 
compliance with the protocol, visits, or trial procedures or any other clinical condition 
that would jeopardize patient safety while participating in this clinical trial in the 
opinion of the investigator.
18. Inability to commit to regular overnight fasting of at least 10 hours duration and 
attendance to trial site visits between 07:00 and 11:00 ante meridiem (a.m.).
NOTE:  No protocol waivers will be granted for any reason during the trial.  Patients who do 
not meet one or more of the entry criteria or discontinue before Visit 3 will not be 
randomised and will be screen failures.  The primary reason for the screen failure will be 
recorded on the electronic case report form (eCRF). 
If a protocol violation occurred in relation to inclusion or exclusion criteria and a patient was 
mistakenly randomized, the investigator will need to contact the CML to request permission 
for the patient to continue in the trial, document the reason for this protocol violation in the 
patient's medical records, and report the protocol violation to their Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC).

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 28 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
Screen failures
Patients who do not meet one or more of the entry criteria or discontinue before Visit 3 will 
not be randomized and will be screen failures.  The primary reason for the screen failure will 
be recorded on the eCRF. Patients who have screen failed in this trial are not permitted to be 
re-screened at a later time point.
Discontinuing or withdrawing patients from the trial
If a patient discontinues (drops out or withdraws) from this trial after randomization, the 
patient will not be replaced.
Patients have the right to withdraw from this trial at any time for any reason.  The patients 
will be asked by the investigator to provide the specific reason for their withdrawal from the 
trial (e.g., moving out of the state or country, unable to drive to trial site, etc.) and this reason 
will be recorded on the eCRF. 
Patients who discontinue from this trial are not allowed to re-enrol in this trial, including 
patients from other trial sites.
Patients will be discontinued from the trial for:

significant non-compliance (If the patient fails to comply with the protocol (e.g., 
non-compliance with study medication or evaluations), a patient may be discontinued 
after discussion between investigator and sponsor), 

concomitant drugs that interfere with the medications being given in this trial,

no longer being able to participate for other medical reasons (e.g., surgery, AEs, or other 
diseases),

persistent hyperglycaemia that is uncontrolled with rescue medication as described in 
Section 4.2.1 (In this case, the reason for discontinuation will be classified as “lack of 
efficacy”), and

occurrence of hypoglycaemia that may put the patient at risk with continued participation 
(e.g., repeated hypoglycaemic episodes).

If pancreatitis is suspected, the study medication should be stopped.
The investigator also has the right to withdraw patients from the trial because continuation of 
study medication or continuation of the follow up visits may not be in the best interest of the 
patient.
If necessary for patient safety, as determined by investigator, new antidiabetic medication 
regimen may be started the day after study medication discontinuation. The new antidiabetic 
medication must be recorded in eCRFs.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 29 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
It is understood by all concerned that an excessive rate of withdrawals can render the trial 
uninterpretable; therefore, unnecessary withdrawal of patients should be avoided.  Should a 
patient decide to discontinue, all efforts by the investigator will be made to complete and 
report the last treatment visit evaluations (i.e., Visit 98) as thoroughly as possible.
If a patient discontinues from this trial, the patient should have the Visit 98 (the final 
assessment that is considered to be on-treatment or shortly thereafter) evaluations completed 
as soon after stopping study medication as possible.  Additionally, the patient should have the 
Post-Treatment Visit (Visit 99) evaluations completed one week after Visit 98.  The 
investigator or a staff member should contact the patient (or a responsible relative or 
designee) either by telephone to determine the primary reason for withdrawal from the trial if 
the patient refuses to return to the trial site.  The primary reason for the withdrawal from the 
trial will be recorded on the Termination of Trial Medication eCRF.  If the patient is dropped 
due to an adverse event, the Termination of Trial Medication form must agree with the 
adverse event eCRF.  The reason for discontinuation will be included in the trial database and 
reported.
3.3.4.2
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information that could significantly affect 
continuation of the trial and/or invalidate the earlier positive benefit-risk-assessment
3. Violation of GCP, this protocol, or the contract by a trial site or investigator, 
disturbing the appropriate conduct of the trial.
The investigator and/or the trial site will be reimbursed for reasonable expenses incurred in 
case of trial termination (except in case of the third reason).

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 30 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The study medication will be provided by Boehringer Ingelheim Pharma GmbH & Co. KG.
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test products are below.
Substance: 
linagliptin film-coated tablet 5 mg
Pharmaceutical form: 
tablet
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength: 
5 mg
Route of administration: 
p.o., once daily
Substance: 
placebo for linagliptin film-coated tablet 5 mg
Pharmaceutical form: 
tablet
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength: 
N/A
Route of administration: 
p.o., once daily
4.1.2
Method of assigning patients to treatment groups
When a patient is qualified for entry into the randomised, double-blind treatment period, 
treatment assignment will be by means of a third-party phone/web-based randomisation at 
Visit 3.  
Patients will be randomly assigned to linagliptin film-coated tablet 5 mg or placebo for 
linagliptin film-coated tablet 5 mg in a 1:1 ratio.  The randomisation will be stratified by 
HbA1c (< 8.5% vs. ≥ 8.5%) as determined from the blood sample taken at Visit 1 and insulin 
dose (< 40 international units total daily dose vs. ≥ 40 international units total daily dose) as 
determined at the beginning of the placebo run-in period (Visit 2).  To ensure appropriate 
representation of patients with insulin doses of < 40 international units total daily dose as 
well as ≥ 40 international units total daily dose, the trial team will monitor the proportion of 
patients being recruited into these categories.  The limitation of recruitment of a particular 
category may be arranged (on trial level and/or country level).  For further details, refer to 
Section 7.5.
Patient assignment to the treatment groups will be determined by a computer generated 
random sequence. IRT will be used to assign study medication.  IRT handling details are 
described in the manual for IRT procedures, which is available in the ISF.  Access to the 
randomisation code will be controlled and documented, for further details refer to Sections 
4.1.5.1 and 4.1.5.2.  
The assigned medication numbers will be entered in the eCRF, and the corresponding study 
medication bottle should be given to the patient.  Using this procedure, relevant parties will 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 31 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
be blinded to the treatment group assignment.  
4.1.3
Selection of doses in the trial
The dose of 5 mg linagliptin was selected based on the results from previous dose ranging 
studies (refer to Investigator's Brochure, U04-1767, current version) and represents the final 
marketed dose for linagliptin.
4.1.4
Drug assignment and administration of doses for each patient
Patients will continue with the permitted antidiabetic therapy throughout the duration of the 
trial unless a medical emergency or another plausible reason (e.g., renal impairment, lactic 
acidosis, dose intolerance, hypoglycaemia, or hyperglycaemia) necessitate changes (at the 
discretion of the investigator).  If a patient is taking antidiabetic therapy that includes 
metformin and is expected to be exposed to an iodine-containing contrast agent for a 
diagnostic or surgical procedure, metformin should be temporarily stopped before and after 
the administration of iodine-containing contrast agent according to the metformin prescribing 
information and regional or local guidelines.
Patients who qualify for double-blind treatment will be randomized to one of the dosage and 
treatment schedules described in Table 4.1.4: 1.  The study medication for this trial will be 
dispensed in a double-blind manner.  Each patient will receive a Run-In bottle at Visit 2 and 
be instructed to take placebo medication daily for one week.  At Visit 3, patients who qualify 
based on inclusion and exclusion criteria will be randomised to one of the two dosage 
regimens, either linagliptin 5 mg daily or placebo matching linagliptin daily.  
Dispensing of bottles for the double-blind treatment period will begin at Visit 3.  Dispensing 
will occur on 4 occasions over a period of 24 weeks.  For further details regarding packaging 
(e.g., number of tablets per bottle), refer to Section 4.1.6.  
Table 4.1.4: 1
Treatment group dosing schedule
Group 1: linagliptin 5 mg treatment group
Visit 
Day 
Treatment arm
Morning
Note
2
-7
placebo
〇
Run-In Period
3 to 98 1 to 169 linagliptin 5 mg 
●
Treatment Period: The last dose of study 
medication will be taken by the patient on 
the morning before Visit 98.
●: linagliptin 5 mg tablet; 〇: placebo for linagliptin 5 mg tablet
Group 2: placebo for linagliptin 5 mg tablet treatment group
Visit 
Day 
Treatment arm
Morning
Note
2
-7
placebo
〇
Run-In Period
3 to 98 1 to 169 placebo for 
linagliptin 5 mg
〇
Treatment Period: The last dose of study 
medication will be taken by the patient on 
the morning before Visit 98.
〇: placebo for linagliptin 5 mg tablet

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 32 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Administration of the study medication is once daily. Study medication can be taken with or 
without food.  At Visit 2 and each subsequent clinic visit, the investigator will open the study 
medication bottle and administer the first dose of study medication to the patient after the 
safety laboratory tests and ECG, if applicable, have been completed.
At the beginning of the placebo Run-In Period (Visit 2), patients should be instructed to take 
1 tablet with water in the morning.  To ensure a dose interval of about 24 hours, the 
medication should be taken at the same time every morning.  If a dose is missed by more than 
12 hours, that dose should be skipped and the next dose should be taken as scheduled. No 
double doses should be taken and dose reductions are not permitted.
Patients should be instructed not to take their study medication and remain fasting on the 
morning of clinic visits.  After the laboratory tests and ECG (if applicable at that particular 
visit) have been completed, the investigator will open the study medication bottle and 
administer the first dose of study medication to the patient.  Patients who fail to follow this 
procedure should have the visit rescheduled as soon as possible, ideally on the following day.  
Visits will be routinely scheduled in the morning from 07:00 a.m. to 11:00 a.m., at 
approximately the same time of day for each visit.  The actual date and time of administration 
of the study medication at the clinic visit will be recorded in the eCRF.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is a double-blind, placebo-controlled trial.  After randomisation at Visit 3, all patients, 
members of the investigative staff, sponsor’s Clinical Trial Team, and anyone involved in 
analysing or with an interest in this trial are to remain blinded to the randomisation treatment 
assignments until after the database is locked.  The randomisation treatment assignments 
(code) will be kept secret by Clinical Trial Support until database lock.
During the trial conduct, a Clinical Safety Officer or representative from BI’s Global 
Pharmacovigilance group will have access to the randomisation code for individual patients 
and would be able to unblind Serious Unexpected Suspected Adverse Reactions (SUSARs) 
for regulatory requirements to report these events.  In such cases, access to the randomisation 
treatment assignments will only be provided to authorised Clinical Safety Officers or 
representatives of Global Pharmacovigilance.  
Please refer to Section 4.1.5.2 for the procedure regarding unblinding the randomisation code 
for an individual patient in an emergency situation.
4.1.5.2
Procedures for emergency unblinding
An emergency unblinding process will allow the investigator to access an individual patient's 
treatment via IRT.  This emergency unblinding process may only be initiated in emergency 
situations when the identity of the study medication must be known to the investigator in 
order to provide appropriate medical treatment or if required to assure safety of trial 
participants.  The investigator will contact the sponsor to discuss the emergency situation as 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 33 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
soon as possible.  The reason for obtaining the emergency unblinding must be documented in 
the appropriate eCRF along with the date and the reason for unblinding the study medication.  
4.1.6
Packaging, labelling, and re-supply
Study medication will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. 
The study medication will consist of bottles labeled with the trial identification and 
medication number.  After randomisation, each bottle will contain an appropriate number of 
linagliptin or placebo matching linagliptin tablets with two weeks reserve, for dosing until the 
next scheduled visit. 
Study medication will be supplied on a per visit basis.  Supply and re-supply will be managed 
by IRT.  
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
The study medication must be kept in its original packaging under the recommended storage 
conditions indicated on the label.  
Trial sites must maintain a temperature log in the location that the study medication is being 
stored. The temperature must be recorded daily with temperature range (minimum and 
maximum temperatures) being collected for the week (i.e., thermometers must record and 
retain temperatures for 7 days so that temperatures can be retrieved and recorded for holidays 
and weekends).  If the storage conditions are found to be outside the specified range, 
immediately contact the CRA and CML, as provided in the list of contacts in the ISF, in 
writing.
Following completion of the trial, all unused medication as well as bottles and containers 
must be returned to the Sponsor.  Please refer to the detailed instructions on how to return the 
study medication in Section 4 of the ISF.  Receipt, usage, and return must be documented on 
the appropriate forms.  An account must be provided for all discrepancies.
4.1.8
Drug accountability
Study medication, which will be provided by the Sponsor and/or an IRT vendor appointed by 
the Sponsor, must be kept in a secure, limited access storage area under the storage 
conditions defined by the sponsor.  A temperature log must be maintained to make certain 
that the study medication is stored at the correct temperature.
The investigator, pharmacist, or study medication storage manager will receive the study 
medications delivered by the sponsor when the following requirements are fulfilled:
•
approval of the trial protocol by the IRB or ethics committee,

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 34 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
•
availability of a signed and dated clinical trial contract between the sponsor and the 
principal investigator or trial site,
•
approval/notification of the regulatory authority, e.g., competent authority (CA),
•
availability of the curriculum vitae of the principal investigator,
•
availability of a signed and dated clinical trial protocol (CTP) or immediately 
imminent signing of the CTP (in exceptional cases, medication could already be 
sent to the trial site, before its activation via IRT)
•
availability of the proof of a medical licence for the principal investigator, and
•
for the United States, availability of the FDA Form 1572.
The investigator, pharmacist, or study medication storage manager must maintain records of 
the study medication’s delivery to the trial site, the inventory at the trial site, the use by each 
patient, and the return to the sponsor or alternative disposition of unused study medication.  
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the study medication and patients in the trial.  The 
investigator, pharmacist, or study medication storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all study medication received from the Sponsor.  At the time of return to the 
Sponsor or appointed IRT vendor, the investigator, pharmacist, or study medication manager 
must verify that all unused or partially used study medication has been returned by the 
patients in the trial and that no remaining study medication is in the investigator’s possession.
The following text is only applicable for Japan:
The investigator, pharmacist, or study medication storage manager will receive the study 
medication delivered by the sponsor representative after IRB or ethics committee approval of 
the trial and completion of a clinical trial contract between the sponsor representative and 
the Head of Trial Site.
The investigator, pharmacist, or study medication storage manager should return the unused 
and collected study medication (including the empty boxes) to the sponsor after unblinding 
the trial.
In case study medication is returned before unblinding of the trial, the investigator, 
pharmacist, or study medication storage manager should seal the opened box (excluding 
empty boxes) for the patient, and before returning the unused and collected study medication 
(including the empty boxes) to the sponsor. When returning the study medication, the 
investigator, pharmacist, or study medication storage manager should exercise utmost 
caution to assure that the sponsor representative and other relevant trial staff members 
remain blinded to the patient’s name on the package (box or label) of the study medication.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 35 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Upon completion of the trial, the investigator, pharmacist, or study medication storage 
manager submits to the sponsor representative a copy of the study medication dispensing and 
return log. When submitting the copy, the investigator, pharmacist, or study medication 
storage manager should exercise caution to assure that the sponsor representative and other 
relevant trial staff members remain blind to the patient’s name.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
Patients should only take study medication and the permitted antidiabetic therapy of basal 
insulin, metformin (optional) and/or alpha-glucosidase inhibitor (optional) after 
randomisation (i.e., from Visit 3 to Visit 98) for the treatment of T2DM.
The patient’s permitted antidiabetic therapy should not be increased or decreased by > 20% 
from stable baseline during the 7 day period from the Run-In Visit to randomisation (Visit 3).
After randomisation, investigators should review the patient’s HBGM results electronically 
for hyperglycaemia and should follow the permitted antidiabetic therapy criteria noted 
below to achieve improved patient glycaemic control before taking any additional action
with rescue therapy.  Additionally, investigators should review the patient’s HBGM and 
eDiary results electronically for hypoglycaemia and should adjust or decrease the patient’s 
permitted antidiabetic therapy by electronic contact with the patient via the eDiary or 
recommend other medical advice (e.g., encouraging the patient not to skip meals, increasing 
carbohydrate intake if increasing exercise, etc.) to achieve improved or individualised patient 
glycaemic control before taking any additional action.
Criteria for Increasing, Adjusting, or Decreasing Permitted Antidiabetic Therapy 
If the following FPG criteria are met and if further supported by HBGM results during the 
same time period, investigators may increase or adjust the patient’s permitted antidiabetic 
therapy (i.e., the patient’s background therapy of stable basal insulin prior to or after 
informed consent, and if applicable metformin and/or alpha-glucosidase inhibitor) for the 
treatment of hyperglycaemia (R08-2669):
Visit 3 to Visit 5
The patient has a FPG level > 270 mg/dL [>15.0 millimoles per Liter (mmol/L)]
drawn by the study staff for the central lab after an overnight fast 
Visit 5 to Visit 98
The patient has a FPG level >240 mg/dL (>13.3 mmol/L) drawn by the study staff 
for the central lab after an overnight fast
If the above criteria are met, the investigator should increase or adjust (e.g., by changing the 
timing of administration, etc.) the patient’s permitted antidiabetic therapy to improve 
glycaemic control according to investigator’s discretion and the changes should be 
documented in the eCRF.  
If the patient is experiencing hypoglycaemia, the investigator should review the eDiary 
responses to diet and physical activity as well as the HBGM results to determine the 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 36 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
appropriate approach to reduce occurrences of hypoglycaemia (e.g., encouraging the patient 
not to skip meals, increasing carbohydrate intake if increasing exercise, decreasing or 
adjusting the patient’s permitted antidiabetic therapy).
The following permitted antidiabetic therapy will be considered to be rescue therapy:

For patients with a baseline daily insulin dose ≤10 units, any increase of basal 
insulin >50% from baseline for > 7 days duration

For patients with a baseline daily insulin dose >10 and ≤20 units, any increase of 
basal insulin >30% from baseline for > 7 days duration

For patients with a baseline daily insulin dose > 20 units, any increase of basal 
insulin >20% from baseline for > 7 days duration

Any increase in metformin and/or alpha-glucosidase inhibitors (AGI) for ≥ 1 day

Any introduction of a new antidiabetic therapy for ≥ 1 day.
Due to the elderly population and the inclusion of patients on very low daily insulin 
doses at baseline, this allows short term increases that may be required for reasons not 
associated with glycaemic control, e.g., medical procedures.
Initiating Rescue Medication (i.e., additional medications)
Rescue medication cannot be initiated during the Run-In Period and would prohibit the 
randomisation of the patient.
If increasing or adjusting the patient’s permitted antidiabetic therapy, as noted above, is 
unsuccessful in reducing the patient’s FPG to 270 mg/dL or lower (≤ 15.0 mmol/L) after an 
overnight fast following a dosage adjustment period of 6 weeks (i.e., occurring no earlier than 
Visit 4), the initiation of rescue medication is at the investigator’s discretion, based on the 
patient’s current clinical condition (e.g., ongoing illness, etc.).  
Before the initiation of rescue therapy, a sample for FPG and HbA1c will be taken using the 
central laboratory.  The HbA1c sample is not required if the HbA1c has been completed by the 
central laboratory within the last 4 weeks.
The choice of rescue medication and its dosage will be left to the discretion of the 
investigator.  However, DPP-4 inhibitors and/or a GLP-1 agonist/analogue are not allowed to 
be used as rescue medication.  
Rescue medication will not be provided as part of the clinical trial supplies, unless required 
by local laws and regulations.  The rescue medication should be taken in accordance with the 
local prescribing information of that respective medication, taking into account potential 
contraindications. 
If no further effect from the rescue medication is anticipated, in the investigator’s clinical 
opinion, and/or the patient’s hyper- or hypoglycaemia cannot be controlled, the patient should 
be discontinued from the trial as specified in Section 3.3.4.  
All concomitant (additional) and/or rescue medication will be recorded in the source 
documents and on the appropriate pages of the eCRF.  
Any additional treatment, that does not qualify as a rescue medication, and is considered 
necessary for the patient's welfare may be given at the discretion of the investigator. 
Restrictions to additional treatment are described in Section 4.2.2.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 37 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The use of the following classes of antidiabetic medications will be prohibited during the 
course of the trial: sulphonylureas, thiazolidinediones, SGLT2 inhibitors, meglitinides, 
bromocriptine, GLP-1 analogues or DPP-4 inhibitors.  The use of rescue medication for 
elevated FPG levels is noted in Section 4.2.1.  
Short-term use of rapid-acting insulin (e.g., in the event of hospitalisation) will be permitted 
based on clinical judgement of the investigator or treating physician.  Prolongation of 
rapid-acting insulin treatment over more than 2 weeks vs. treatment discontinuation should be 
discussed on a case-by-case basis between the investigator and the CML or TCM.  Refer to 
Section 3.3.3 regarding the permitted use of antidiabetic agents.
Additionally, treatment with anti-obesity drugs [including over the counter preparations such 
as Alli(orlistat)] or systemic steroids will be prohibited due to their influence on glucose 
metabolism.  However, one off or short-term use (i.e., ≤1 week duration) of systemic steroids 
will be permitted as well as therapy with non-systemic steroids such as inhaled or local 
steroids.  Furthermore, for patients taking thyroid hormones, any change in the dose should 
be avoided.  If dose changes do occur, then they should be recorded in the source documents 
and in the eCRF.  
No special contraindication for concomitant use with linagliptin is known based on the data 
from drug development to date (refer to Section 1.2). 
For patients who are taking metformin as background therapy: If vascular administration of 
an iodine-containing contrast agent is required, patients should be informed to discontinue 
metformin 48 hours before the contrast agent is given and not to resume metformin 
administration until 48 hours after the vascular administration.
4.2.2.2
Restrictions on diet and life style
At the first visit, patients will receive diet and exercise counseling by a diet specialist, trained 
staff member, physician, or investigator.  This diet and exercise counseling will be reviewed 
at each subsequent visit.  Documentation of diet and exercise counseling training of the 
applicable investigative staff is required to be maintained at the trial site.  The counseling will 
be based on local diet recommendations.  The patients will be reminded to follow the agreed 
diet and exercise plan at every visit.  Patients may be provided with diet and exercise 
educational material (e.g., from national diabetes associations or national health authorities) 
relevant for the country/region by the trial site. 
Patients also should not take part in another clinical trial involving an investigational 
medicinal product within the 2 months prior to Informed Consent and throughout this trial.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 38 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
4.3
TREATMENT COMPLIANCE
Patients will be asked to bring all study medication containers (with or without any remaining 
tablets) with them to each trial visit.  The tablets will be counted by the investigator or study 
coordinator and compliance will be calculated according to the formula:
%
100
period
same
in the
been taken
have
should
 which 
 tablets
of
Number 
count
t 
last table
since
aken 
actually t
 tablets
of
Number 
(%)
Compliance


During the Run-In Period, patients must have taken 80% to 120% of their prescribed study 
medication to be considered compliant.  If a patient is non-compliant during the Run-In 
Period, the investigative staff will review the patient’s correct daily dosage and counsel the 
patient on the importance of proper compliance.  Extremely non-compliant (less than or equal 
to 50% compliant) patients should not be randomised at the discretion of the investigator.
At each visit, the investigative staff will assess medication compliance by counting the tablets 
remaining.  Patients must have taken 80% to 120% of their prescribed study medication to be 
considered compliant.  If a patient is non-compliant at any visit, the investigative staff should 
determine what the cause of the non-compliance is, will review the patient’s correct daily 
dosage, and counsel the patient on the importance of proper compliance. 
Patients who do not take any study medication for 10 consecutive days should not begin 
taking study medication at the next visit or re-start study medication and should be 
discontinued from the trial.  The investigative staff should determine what the cause of the 
non-compliance is and bring the patient in for Visit 98 (last assessment considered to be 
on-treatment) as soon as possible.  The patient should return one week later to complete 
Visit 99 (Post-Treatment Visit).  Alternate antidiabetic therapy may be prescribed to patients 
being discontinued as necessary and any alternate antidiabetic therapy should be documented 
in the eCRFs.
If a patient has been non-compliant for two consecutive visits, the investigative staff should 
determine what the cause of the non-compliance is and contact the CML to discuss the 
patient’s participation in the trial.  
Patients who are extremely non-compliant (< 50% compliant) for two consecutive visits 
should be discontinued from study medication and the trial.  The investigative staff should 
determine what the cause of the non-compliance is and bring the patient in for Visit 98 (last 
assessment considered to be on treatment) as soon as possible.  The patient should return one 
week later to complete Visit 99 (Post Treatment Visit).  Alternate antidiabetic therapy may be 
prescribed to patients being discontinued as necessary and any alternate antidiabetic therapy 
should be documented in the eCRFs.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 39 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - PHARMACODYNAMICS
Refer to the Flow Chart for a schedule of each efficacy observation in the trial.
5.1.1
Endpoints of efficacy
The primary endpoint in this trial is the change from baseline in HbA1c after 24 weeks of 
treatment.  Throughout the trial protocol, the term "baseline" refers to the last observation 
prior to the administration of any randomised study medication.
Secondary endpoints are the following:

Proportion of patients experiencing at least one confirmed hypoglycaemic event 
during 24 weeks of treatment.  A confirmed hypoglycaemic event is defined as 
any symptomatic or asymptomatic event less than 54 mg/dL (< 3.0 mmol/L) as 
measured by the central laboratory (FPG) or HBGM device, any symptomatic 
event less than or equal to 70 mg/dL (3.9 mmol/L), and all events classified as 
“severe hypoglycaemia”.  
Severe hypoglycaemic episode:  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.
Note:  If another person hands the carbohydrate or glucagon to the patient without 
having to actively administer the substance because the patient is able to take the 
substance on his or her own, the hypoglycaemic episode does not qualify as 
severe.

Proportion of patients with HbA1c on treatment <8.0% after 24 weeks of treatment

Proportion of patients with HbA1c on treatment <7.0% after 24 weeks of treatment

Proportion of patients with HbA1c lowering by at least 0.5% after 24 weeks of 
treatment

Change from baseline in FPG after 24 weeks of treatment
 

 
 
 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 40 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

 
 
 
 
 
 
5.1.2
Assessment of efficacy
HbA1c:
Blood samples for the determination of HbA1c will be taken at the trial site and processed by 
the central laboratory.  At Screen Visit, the blood sample can be taken at any time during the 
visit.  At all other visits, the blood samples should be drawn before breakfast and before study 
medication administration.  The samples will be analysed at a central laboratory or its 
affiliates having a National Glycohaemoglobin Standardisation Program (NGSP) Level I 
certificate.  Further details about sample handling, shipment, and assay procedures will be 
located in the ISF (laboratory manual).

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 41 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
FPG:
Blood samples for the determination of FPG will be taken after an overnight fast (at least 
10 hours after the last meal) at the trial site and processed by central laboratory.  The samples 
should be taken before breakfast and before study medication administration.  The samples 
will be measured using validated assays by a central laboratory.  Further details about sample 
handling and shipment will be located in the ISF (laboratory manual).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2
SAFETY
5.2.1
Endpoints of safety

Incidence and intensity of Adverse Events (AEs)

Withdrawal due to AEs

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 42 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

Incidence of hypoglycaemic events:
All investigator–reported hypoglycaemic events (with or without symptoms, 
with or without measured glucose)
Severe or symptomatic hypoglycaemic events
o Severe or symptomatic events with measured glucose ≤70 mg/dL
(3.9 mmol/L)
o Severe or symptomatic events with measured glucose < 54 mg/dL
(< 3.0 mmol/L)
Severe hypoglycaemic event or hypoglycaemic events (with or without 
symptoms) with measured glucose of ≤70 mg/dL (3.9 mmol/L)
Severe hypoglycaemic event or hypoglycaemic events (with or without 
symptoms) with measured glucose of < 54 mg/dL (< 3.0 mmol/L)
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A SAE is defined as any AE which results in death, is immediately life-threatening, results in 
persistent or significant disability / incapacity, requires or prolongs patient hospitalisation, is 
a congenital anomaly / birth defect, or is to be deemed serious for any other reason if it is an 
important medical event when based upon appropriate medical judgement which may 
jeopardise the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definitions.
For Japan: An AE which possibly leads to disability will be reported as an SAE. Every new 
occurrence of cancer will be reported as a SAE regardless of the duration between 
discontinuation of the study medication and the occurrence of the cancer.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 43 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the eCRF. 
For Japan: The reason for the decision on causal relationship needs to be provided in the 
eCRF.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
If a SAE is reported from a blinded trial, the causal relationship must be provided by the 
investigator for all potential trial drugs, i.e. the BI trial drug and for all other trial drugs (i.e.,
any active comparator or placebo according to the trial design).
Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
AE or SAE (if SAE criteria are met) in the eCRF.
Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an AE or SAE (if SAE criteria are met) in the eCRF, if they are judged clinically 
relevant by the investigator.
Criteria for hypoglycaemic events
Every episode of FPG or blood glucose (by HBGM device) below or equal to 70 mg/dL 
(3.9 mmol/L) should be documented as a hypoglycaemic event in the eCRF with the 
respective time and date of occurrence.  
Symptomatic, severe, and hypoglycaemias with FPG or blood glucose values < 54 mg/dL 
(< 3.0 mmol/L) should be documented as an AE of "hypoglycaemic event".  Data related to 
these hypoglycaemic events [i.e., symptomatic, severe, and hypoglycaemias with FPG or 
blood glucose values < 54 mg/dL (< 3.0 mmol/L)] will be collected on a specific eCRF and 
included in the clinical trial report.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 44 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
In the case of hypoglycaemia that may put a patient at risk (for example, repeated 
symptomatic hypoglycaemia, or severe hypoglycaemia), appropriate adjustment of 
background therapy such as a dose reduction or time change should be initiated.  Patients 
should be instructed to contact the trial site if they experience symptomatic hypoglycaemia.
Adverse Events of Special Interest
The following events are considered as Adverse Events of Special Interest (AESI):

Hypersensitivity reactions such as angioedema, angioedema-like events, and 
anaphylaxis

Skin lesions such as exfoliative rash, skin necrosis, or bullous dermatitis

Hepatic events such as ≥3 fold ULN of AST and/or ALT in combination with an 
elevation of total bilirubin >2 fold ULN measured in the same blood draw 
sample, hepatitis, hepatic injury, jaundice and potential Hy’s Law cases

Renal adverse events such as acute renal failure

Pancreatitis (refer to the ISF)

Pancreatic cancer
Protocol-specified AESI (as identified by the investigator based on the above definitions 
for Adverse Events of Special Interest) can be classified as serious or non-serious but all 
these AESIs once identified by the investigator must be reported on an SAE form in an 
expedited manner similar to SAEs (within 24 hours of awareness), even if they do not 
meet any of the SAE seriousness criteria (refer to Section 5.2.2.1 for details).  Beyond of 
this, and for the purposes of ongoing pharmacovigilance activities by the sponsor, 
adverse events based on additional searches for coded preferred terms of adverse events 
captured in the trial database (such as Special MedDRA Queries and user defined 
searches) will be queried to verify with the investigator if the adverse event reported 
represent a suspected or diagnosed protocol-specified AESI.  AESIs once identified by 
the investigator must be reported on an SAE form in an expedited manner similar to 
SAEs, even if they do not meet any of the SAE seriousness criteria. 
These additional searches (summarised under the so called ‘overview of protocol-
specified AESIs and safety topics of interest ’) may change according to active 
pharmacovigilance of linagliptin.  The most up to date list of these searches will be 
included in the Remote Data Capture (RDC) system and changes will be communicated 
to all investigators. 
5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the last per protocol contact) will be 
collected, documented and reported to the sponsor by the investigator on the appropriate 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 45 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
eCRFs / SAE reporting forms. Reporting will be done according to the specific definitions 
and instructions detailed in the ‘Adverse Event Reporting’ section of the ISF. 
The residual effect period (REP), defined as the period of time after the last dose of 
medication when measureable drug levels or pharmacodynamic effects are still likely to be 
present, for linagliptin is 7 days.  Therefore all events reported within 7 days of the last trial 
medication will be considered on-treatment.  The follow-up period, defined as the period 
between the last medication and the last per protocol visit, is 7 days.
Reporting will be done according to the specific definitions and instructions detailed in the 
‘Adverse Event Reporting’ section of the ISF.
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
Section 5.2.2.1. 
The investigator does not need to actively monitor patients for adverse events once the 
clinical trial has ended. However, if the investigator becomes aware of an SAE(s) that 
occurred after the patient has completed the clinical trial (including any protocol required 
REP and / or follow-up period), it should be reported by the investigator to the sponsor if 
considered relevant by the investigator.
All AEs and/or SAEs, including those persisting after trial completion, must be followed up 
until they have resolved, have been sufficiently characterized, or no further information can 
be obtained.
If not stipulated differently in the ISF, the investigator must report the following events 
immediately (within 24 hours of awareness) to the sponsor: SAEs, AESIs, and non-serious 
AEs relevant to the reported SAE or AESI.
SAEs occurring in patients after having discontinued in the study due to screening failure and 
who did not receive any study medication, should only be reported if the investigator 
considers the SAE to be related to the screening procedure.
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always SAEs”, if a non-serious AE is identified 
to be serious per BI definition, a query will be raised. The investigator must verify the 
description and seriousness of the event.  If the event description is correct, the item “serious” 
needs to be ticked and an SAE has to be reported in expedited fashion following the same 
procedure as above.
The list of these always SAEs can be found in the RDC system.
With receipt of any further information to these events, a follow-up SAE report has to be 
provided. SAEs and non-serious AEs must include a causal relationship assessment made by 
the investigator.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 46 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
For Japan: This information must be also reported immediately to the head of the trial site. 
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the ISF). This immediate report is 
required irrespective of whether the investigational product has been administered or not and 
irrespective of causal relationship. It also applies if new information to existing SAEs or 
AESIs becomes available. 
5.2.3
Assessment of safety laboratory parameters
The blood sample at the Screen Visit may be taken with the patient in a fasted or non-fasted 
state.  However, after the Screen Visit, all laboratory samples must be collected after a full 
overnight fast (nothing to eat or drink except water for at least 10 hours) and before study 
medication is administered to the patient as described in the Flow Chart and Section 6.  
All laboratory tests that will be performed during the trial are listed in Tables 5.2.3: 1 and 
5.2.3: 2.  The analysis of all laboratory tests will be performed by a central laboratory.  The 
respective reference range and details regarding sample handling and shipment will be 
provided in the ISF (Laboratory Manual).
Laboratory tests and urinalysis will be performed for the visits as noted in the Flow Chart 
with the following exceptions:

For the Screen Visit, only liver transaminases, alkaline phosphatase, serum creatinine, 
and urinalysis will be performed.

The lipid panel will be performed for only Visit 3 and Visit 98
Table 5.2.3: 1
Haematology laboratory tests
Haematology
Haematocrit
Haemoglobin - Reticulocyte Count (reflex test if Haemoglobin outside normal range)
Red Blood Cells/Erythrocytes
White Blood Cells/Leukocytes
Platelet Count/Thrombocytes
Differential Automatic (relative and absolute count): 
Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 47 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Table 5.2.3: 1 (Cont.) Chemistry laboratory tests 
Lipase
aspartate aminotransferase (AST, SGOT)
alanine aminotransferase (ALT, SGPT)
gamma-glutamyl-transferase (-GT)
Alkaline phosphatase
Lactic dehydrogenase (LDH)
Total bilirubin
Total Protein 
Direct bilirubin, if total bilirubin is 
elevated
Albumin 
Creatine kinase (CK)
Troponin T (reflex only for CK)
Potassium
activated partial thromboplastin time 
(aPTT)
fibrinogen

Sodium

Creatinine 

Urea (i.e., blood urea nitrogen)

Calcium

Chloride

Magnesium

Inorganic phosphorous

Uric acid

Cholesterol (total) *

High-Density Lipoprotein (HDL) 
cholesterol*

Low-Density Lipoprotein (LDL) 
cholesterol (calculated)*

Plasma triglycerides*

Glucose
* Visits 3 and 98 only
If AST and/or ALT are increased ≥3 times ULN, follow-up laboratory tests of ALT, AST, 
total bilirubin (with differentiation of bilirubin in direct and indirect), with the addition of 
alkaline phosphate, creatine kinase (CK, CK isoenzyme MB if CK is elevated), amylase, 
lipase, and International Normalized Ratio (INR) blood samples must be collected as soon as 
possible (ideally within 48 to 72 hours of the pathologic test result).  Further follow-up 
investigations shall be initiated depending on the patient's clinical course until the patient is 
recovered and/or a diagnosis was established.  
Table 5.2.3: 2
Urinalysis
Albumin, Creatinine 
(spot urine: quantitative measurement)
Protein
Glucose

Ketone

Leucocytes

Erythrocytes
Albumin/creatinine ratio will be calculated at the central laboratory.  Urine sediment will 
only be performed if there is a positive finding on the urinalysis.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 48 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
5.2.4
Electrocardiogram
Twelve-lead ECGs will be recorded according to the Flow Chart.
The 12-lead ECGs will be centrally analysed with interpretation by a cardiologist and 
assessed for pre-existing abnormalities.  Patients with any pre-existing ECG abnormalities
determined at the Screen Visit may be referred to a cardiologist and medically treated, as well 
as should be carefully monitored throughout the trial, as necessary.  ECG abnormalities
determined at the Screen Visit should be recorded on the baseline condition eCRF.  After the 
12-lead ECG is performed at the Screen Visit, any clinically relevant abnormal changes 
should be reported as AEs according to Section 5.2.2.1.
Additional ECGs may be collected by the investigator for safety reasons.  
5.2.5
Assessment of other safety parameters
Physical examination
A physical examination (e.g., evaluation of the body and its functions using inspection, 
palpation, percussion, and auscultation) will be performed by the investigator according to
the Flow Chart.  Documentation of and findings from the physical examination must be part 
of the source documents available at the trial site.
Home Blood Glucose Monitoring
All patients will receive HBGM supplies at the Screen Visit to monitor their glucose levels at 
home each day.  Instruction on the proper use of the glucometer will be provided by the study 
staff.  
Each day:  The patient should be instructed to complete 4 finger stick glucose measurements:
1. in a fasting state in the morning before breakfast (e.g., before 7 or 8 a.m.)
2. before lunch (e.g., 12 p.m.)
3. before dinner (e.g., 6 p.m.)
4. before bedtime (e.g., 8 or 9 p.m.)
It is not recommended that patients’ skip meals but approximate times of glucose measuring 
have been provided above as general guidance.
Once or twice a week during typical hours of sleep (i.e., 10 p.m. to 5 a.m.):
The patient should be instructed to complete a finger stick glucose measurement when getting 
up to use the bathroom or any other reason for being awake during typical hours of sleep.
The patient should be instructed to also contact the trial site for advice if the results of a 
HBGM test reveal blood glucose value of ≤70 mg/dL (3.9 mmol/L) after an overnight fast.  

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 49 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
If the blood glucose level is <54 mg/dL (3.0 mmol/L), the patient should be instructed to eat 
and/or drink some carbohydrate containing food.  
Additional HBGM measurements should be performed in case of hypo- or hyperglycaemia 
related symptoms and if deemed necessary by the investigator or required by local 
authorities. Patients will be instructed to bring their HBGM device to visits for an additional 
measurement of fasted glucose levels. 
HBGM test results will be processed and collected by a glucometer that will transmit the 
results electronically to a small personal handheld electronic device (eDiary) each day.  The 
investigator will be able to view the patient’s HBGM data within the vendor’s database and 
should review the patient’s blood glucose results in order to determine if treatment 
adjustments need to be instituted.
The respective HBGM and eDiary procedure for illiterate patients is described in the
Appendix 10.1.1.
Assessment of meals, physical activity, and hypoglycaemic symptoms and events by eDiary
A small personal handheld electronic device will be used by the patients to record 
information regarding their blood glucose monitoring, meals, and their symptoms daily 
(eDiary).  Patients will be instructed to complete the eDiary four times every day (while 
fasting before breakfast, before lunch, before dinner, and before bedtime).  When completing 
an eDiary entry, patients will answer questions regarding their blood glucose monitoring, 
meals, physical activity or exercise, and their symptoms since their last eDiary entry.  If 
patients miss or are late with their eDiary entry, they may enter information covering a 
maximum time period of 12 hours in the past.  In addition, the patient’s HBGM values will 
be uploaded electronically to the eDiary daily.  The investigator should review the patient’s 
blood glucose and eDiary results in order to determine if treatment adjustments need to be 
instituted.
The eDiary data will be transferred to the vendor server on a daily basis.  The data will be 
transferred to the sponsor on a periodic, batch basis.  Patients will be instructed to contact the 
trial site staff if they have any problems using the eDiary.  
 
 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 50 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 51 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
 
 
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor efficacy and safety aspects in an appropriate way.
The scheduled measurements are appropriate to determine relevant drug-induced changes in 
blood pressure, pulse, standard laboratory values, and ECG specific to the efficacy of 
treatment of T2DM.  The primary and secondary endpoints are standard, are widely used, and 
accepted for evaluation of safety and tolerability of oral antidiabetic drugs in respective 
pivotal Phase III trials. 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
The plasma concentration and pharmacokinetic analysis of linagliptin will not be performed 
in this trial.
 
 
 
 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 52 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
5.7
PHARMACODYNAMICS
No additional pharmacodynamic parameters will be determined in this trial.
 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 53 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All trial visits should be routinely scheduled in the morning, at approximately the same time 
of day (07:00 AM to 11:00 AM). If a patient mistakenly takes study medication on the 
morning of a visit before attending the clinic (excluding visits starting before randomisation) 
or comes in non-fasted where a fasting condition is required (all visits except Screen), the 
visit should be rescheduled for another day as soon as possible reminding the patient about 
the expected conditions.  The rescheduled visit must take place within the allowed visit
window (i.e., in less than 7 days) so that the patient has sufficient study medication.
All patients are to adhere to the visit schedule as specified in the Flow Chart.  If any visit has 
to be rescheduled, subsequent visits should follow the original visit date schedule.  The study 
medication bottles contain sufficient medication to allow for these time windows.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screen and Run-In Periods
Screen
No trial procedures should begin until the patient has signed the informed consent for the 
trial.
Patients who have been on stable background therapy [i.e., basal insulin, metformin 
(optional), and/or alpha-glucosidase inhibitor (optional)] will have the Screen Visit 
performed.
The Screen Visit does not need to be performed fasting.
After a patient has signed the informed consent, the patient is enrolled in the trial and has 
begun screening.  The patient should be recorded on the enrolment log and be registered in 
IRT as a screened patient.
Patients who are not eligible due to inclusion and exclusion criteria should be entered as a 
screen failure in IRT.  
Run-In
Patients should be fasting (no food or drinks for at least 10 hours, only water is allowed).
Patients will be assigned and receive a placebo kit number through the IRT at this visit.
Patients who fail the Run-In Period following the Visit 2 evaluations should be entered as a 
screen failure in the IRT.  

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 54 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
6.2.2
Treatment period
Patients should not take study medication at home on the morning of trial visits during the 
treatment period.
The treatment period is from Visit 3 to Visit 98.  Study medication will be dispensed to 
patients at each of these visits (except for Visit 98).  Patients will be assigned a new 
medication number through IRT at each visit.  Study medication will be administered by the 
investigator from a new bottle with the IRT-assigned medication number on the day of the 
visit.
Treatment Period (Visits 3, 4, 5, 6, 98) 
Visits should be performed fasting and as indicated in the Flow Chart, and Table 4.1.4: 1 and 
the respective protocol sections.
For Visit 98, patients will be entered in IRT as completing or discontinuing treatment.  
Premature discontinuation from the trial (between Visits 3 and 98)
If a patient prematurely discontinues from the 24-week treatment period, the patient must 
return to the trial site for both Visit 98 and Visit 99 (7 days after Visit 98), which will be 
performed. 
The investigator may initiate any additional antidiabetic therapy based on his or her 
discretion no sooner than one day after discontinuing study medication.
The scheduled Visit 98 evaluations should be performed for patients who prematurely 
discontinued from the trial including the following:
•
Blood pressure and pulse
•
Weight 
•
Physical examination
•
12-lead ECG
•
Collection of blood and urine samples for safety laboratory evaluation
•
eDiary
•
Diet and exercise counseling

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 55 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
•
Study medication compliance
•
Documentation of any adverse events
•
Documentation of concomitant therapies
In addition, the patient will be instructed to return in one week for Visit 99 evaluations.
6.2.3
End of trial and follow-up period
Visits should be performed as indicated in the Flow Chart and in Table 4.1.4: 1 and the 
respective protocol sections.
For Visit 99, patients will be entered in IRT as completing or discontinuing the trial.  
Post-Treatment Period
Patients that complete the trial will take the last dose of study medication the day before 
Visit 98.  The investigator may initiate any additional antidiabetic therapy based on his or her 
discretion no sooner than one day after Visit 98.
The following Visit 99 evaluations should be performed for all patients returning for this visit 
including those patients who prematurely discontinued from the trial:

Blood pressure and pulse

Collection of blood and urine samples for safety laboratory evaluation

Return of the HBGM device for assessment of blood glucose levels

Return of the eDiary 

Documentation of any adverse events

Documentation of concomitant therapies
The end of the trial is defined as "last patient out", i.e., last visit completed by the last patient.
Premature discontinuation from the trial (between Visits 98 and 99)
If a patient discontinues after the 24-week treatment period, the patient should return to the 
trial site for Visit 99 (the Post-Treatment Visit that occurs 7 days after Visit 98), which will 
be performed as a trial visit.  
The investigator may initiate any additional antidiabetic therapy based on his or her 
discretion no sooner than one day after discontinuing study medication.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 56 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
The objective of the current trial is to investigate the efficacy, safety and tolerability of 
linagliptin compared to placebo given for 24 weeks as add-on therapy to a stable background 
of basal insulin, metformin (optional), and/or alpha-glucosidase inhibitors (optional) in 
elderly patients (≥60 years of age) with T2DM and insufficient glycaemic control (i.e., 
HbA1c of 7.0% to 10%).  It is planned to show superiority of linagliptin to placebo for the 
primary endpoint, the change from baseline in HbA1c (HbA1c after 24 weeks of treatment 
minus HbA1c at baseline), followed by a decrease in the proportion of patients experiencing at 
least one confirmed hypoglycaemic event during 24 weeks of treatment, in a hierarchical 
manner.
HbA1c will be measured in the unit of percent (%) at all clinical visits.  A mixed model for 
repeated measures (MMRM) will be used to compare the change from baseline in HbA1c
after 24 weeks of the treatments.  The model will include treatment, baseline HbA1c, baseline 
insulin dose, week, week by baseline HbA1c interaction, and week by treatment interaction.
With regard to efficacy and safety endpoints, the term “baseline” refers to the last observed 
measurement prior to administration of any randomised study medication.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The superiority of treatment with linagliptin to placebo will be tested for HbA1c change from 
baseline to Week 24 at the level of α=0.05 (two-sided).
The primary hypothesis can be written as follows:
H0, 1: Mean change from baseline in HbA1c after 24 weeks of treatment with linagliptin
      = Mean change from baseline in HbA1c after 24 weeks of treatment with placebo
H1, 1: Mean change from baseline in HbA1c after 24 weeks of treatment with linagliptin
      ≠ Mean change from baseline in HbA1c after 24 weeks of treatment with placebo
This will be performed on the full analysis set (FAS).  
7.3
PLANNED ANALYSES
The primary analysis will be performed on the FAS.  The FAS will consist of all randomised 
patients who were treated with at least one dose of study medication, had a baseline and at 
least one on-treatment HbA1c measurement.
The FAS-completers set of patients is defined as all patients in the FAS who complete 24 
weeks of treatment and have an HbA1c measurement after 24 weeks of treatment.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 57 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
  A protocol violation will be considered important 
if it can be expected to have a distorting influence on the assessment of the primary endpoint.
Important protocol violations include:

Randomised study medication: incorrect study medication taken

Severe violation of treatment compliance

Severe violation of inclusion criteria 

Non-adherence to other specifications of the protocol that could bias the primary 
endpoint
Further details will be given in the Trial Statistical Analysis Plan (TSAP).
All patients treated with at least one dose of study medication (the Treated Set) will be 
included in the safety evaluation.
7.3.1
Primary analyses
The primary analysis will be performed on the FAS [observed cases (OC)]. Mean changes 
from baseline in HbA1c after 24 weeks of treatments will be analysed using a restricted 
maximum likelihood-based repeated measures approach. Analyses will include the fixed, 
categorical effects of baseline insulin dose, treatment, week, and treatment by week
interaction, as well as the continuous, fixed covariates of baseline HbA1c and baseline HbA1c
by week interaction. An unstructured (co)variance structure will be used to model the within 
patient measurements.
If this analysis fails to converge, the following covariance structures will be tested: Toeplitz, 
AR (1), and compound symmetry.  The (co)variance structure converging to the best fit, as 
determined by Akaike’s information criterion, will be used as the primary analysis. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
Significance tests will be based on least-squares means using a two-sided α = 0.05 
[two-sided 95% confidence intervals (CI)]. The residuals are assumed to have a 
multivariate normal distribution with zero means and covariance matrix as mentioned 
above. All analyses will be implemented using SAS®. The primary treatment comparisons 
will be the contrast between treatments at Week 24.  
The statistical model will be:
HbA1c change from baseline = overall mean + baseline HbA1c + baseline insulin dose 
+ treatment + week + week by baseline HbA1c interaction
+ week by treatment interaction + random error

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 58 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
The primary analysis will be performed on the FAS; patients will be assigned to the treatment 
they were randomised to.
7.3.2
Secondary analyses
 
 
 
 
 
 
 
 
The additional secondary efficacy endpoints 
 will be 
analysed as follows:

Continuous endpoints (except for basal insulin dose change) with the parameter 
measured at least twice on-treatment will be analysed using a MMRM model similar 
to the primary endpoint analysis.  Descriptive summary statistics will be presented for 
each endpoint, and at each week if appropriate.

 

Binary endpoints will be tabulated (with the frequency and proportion in each 
treatment group, by week if appropriate).  Logistic regression will be applied for 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 59 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
secondary and certain other endpoints (to be specified in TSAP) to obtain the odds 
ratio between treatment groups and its 95% CI and 2-sided p-value.

 

 
 
 
 
 
 
For these analyses, patients will be assigned to the treatment they were randomised to.
The analysis of endpoints related to questionnaires will be described in the TSAP.
7.3.3
Safety analyses
All safety data will be displayed and analysed using descriptive statistical methods.  
Depending on the character of the individual safety endpoint, the most appropriate way to 
summarize the results as frequency tables for categorical data or descriptive statistics for 
continuous data will be used.  No formal inferential analysis is planned for safety 
comparison.
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA)
coding dictionary.  All events with an onset after the first dose of study medication up to a 
period of seven days after the last dose of study medication will be assigned to the treatment 
phase for evaluation.  This includes AEs that start before first study medication intake and 
deteriorate under treatment.  Other AEs will be assigned either to the screening, run-in, or 
follow-up phase as appropriate.  Safety analyses will be performed on the TS, with patients 
assigned to the treatment they were randomised to.  Additional listings based on actual 
treatment at onset of AE will be produced for patients who receive incorrect treatment at any 
point throughout the trial.
Laboratory values taken after the first dose of randomised treatment up to a period of seven 
days after the last intake of treatment will be assigned to the treatment phase for evaluation.  
Laboratory values will be compared to their reference ranges and frequency tables will be 
provided for the number of patients within and outside the reference range.
Changes from baseline in blood pressure and pulse rate will be summarised by treatment 
group.
Further details on the safety analysis will be specified in the TSAP.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 60 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
7.3.4
Interim analyses
No interim analysis is planned for this trial.
7.3.5
Pharmacokinetic analyses
No pharmacokinetic sampling is planned for this trial.
7.3.6
Pharmacodynamic analyses
No pharmacodynamic analysis is planned for this trial.
 
7.4
HANDLING OF MISSING DATA
7.4.1
Efficacy endpoints
In the primary analysis, if a patient misses a visit, the missing data will not be imputed. The 
mixed effect model will handle missing data based on a likelihood method under the "missing 
at random assumption". Following the intention-to-treat (ITT) principle, every randomised 
patient with at least baseline and one on-treatment measurement will be included in the
analysis.
 
 
 
If rescue therapy is initiated, HbA1c and FPG values after rescue will be set to missing and 
the missing data handled as above (OC or LOCF), according to the analysis strategy.
For the analysis of hypoglycaemia endpoints, the available data of all patients in the TS 
will be analysed (OC approach) and no imputation performed.
For binary endpoints including an HbA1c response criterion, non-completer’s considered 
failures (NCF) approach will be used, i.e., patients who discontinue from the trial 
prematurely and have no Week 24 HbA1c value will be considered as non-responders.
Methods to handle any other exceptional cases will be considered before unblinding the data 
and will be applied in a manner consistent with other trials of this type.  The evaluability of 
patients with deviations from the protocol likely to confound the treatment response will be 
decided prior to unblinding.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 61 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
7.4.2
Safety and other endpoints
With respect to safety evaluations, it is not planned to impute missing values.
The handling of missing 
 as patient reported outcome measures data will be 
specified in the TSAP or a separate health economics analysis plan, as appropriate.
7.5
RANDOMISATION
The sponsor will arrange for the randomisation as well as packaging and labelling of study 
medication.  Eligible patients will be randomly assigned to one of the two treatment groups, 
with equal allocation of treatments. The randomisation list will be generated using a 
validated system, which involves a pseudo-random number generator so that the resulting 
treatment sequence will be both reproducible and non-predictable.
The randomisation will be stratified by HbA1c (< 8.5% vs. ≥8.5%) as determined from the 
blood sample taken at Visit 1 and insulin dose (< 40 international units total daily dose vs. 
≥40 international units total daily dose) as determined at the beginning of the placebo run-in 
period (Visit 2).  To ensure appropriate representation of patients with insulin doses of 
< 40 international units total daily dose as well as ≥ 40 international units total daily dose, the 
trial team will monitor the proportion of patients being recruited into these categories.  The 
limitation of recruitment of a particular category may be arranged (on trial level and/or 
country level).  
The allocation process will be performed at Visit 3 through IRT.  However, the IRT
allocation and randomization will not increase the study medication bottles at each trial site
based on stratification.
Access to the code will be restricted to dedicated randomisation personnel and any 
exceptional access to the code (in case of an emergency) will be documented according to the 
sponsor's SOPs.
The trial will only be unblinded after all eCRF and electronic data have been entered into the 
trial database, after queries have been resolved, and after the database has been locked.  
Access to the codes will be controlled and documented by a signed confidentiality statement, 
which will be stored in the TMF.
Practical aspects of the treatment allocation process and methods to carry out blinding are 
detailed in Sections 4.1.2 and 4.1.5, respectively.
7.6
DETERMINATION OF SAMPLE SIZE
This trial will be powered to detect differences between linagliptin and placebo in HbA1c
change from baseline after 24 weeks.
A total of 300 patients will be randomised.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 62 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Based on pooled data from the 1218.36 and 1218.63 trials
 assuming a 
standard deviation of  1.2% in both groups in the FAS with a 0.77% difference in HbA1c 
change from baseline in treatments, a number of 150 patients in each treatment arm 
will show superiority with a power >99%. This determination of power is based on a 
Student’s t-test and a two-sided significance level of 5%.
Software package nQuery version 7.0 was used to derive the sample size.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 63 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
GCP and relevant BI SOPs. Standard medical care (prophylactic, diagnostic and therapeutic 
procedures) remains in the responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches
of the protocol/ICH GCP.
For Japan:
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol, ICH GCP, and the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997).
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. As a general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report.
For countries with insurance cover requirements:
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB or IEC and CA according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML and/or CRA) or Clinical Quality Assurance auditors appointed by Boehringer 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 64 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Ingelheim, by appropriate IRB or IEC members, and by inspectors from regulatory 
authorities.
For Japan:
The investigator must give a full explanation to trial patients including the items listed below 
in association with the use of the patient information form, which is prepared avoiding the 
use of technical terms and expressions. The patient is given sufficient time to consider 
participation in the trial. The investigator obtains written consent of the patient’s own free 
will with the informed consent form after confirming that the patient understands the 
contents. The investigator must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also 
signs (or places a seal on) and dates the informed consent.
The following items need to be included:
1. That the clinical trial is aimed at testing.
2. Objectives of the trial.
3. The name, title, and address of the investigator to contact.
4. Trial procedures.
5. Anticipated benefits of the investigational products and anticipated disadvantages to 
the patient.
6. Matters concerning other therapeutic measures.
7. Duration of participation in the clinical trial.
8. That the patient may withdraw from the trial at any time.
9. That patient’s refusal of or withdrawal from participation in the trial does not cause 
any disadvantage to him or her.
10. That the monitors, the auditors, and the IRB are given access to the relevant source 
documents on condition that confidentiality of the patient is fully secured.
11. That privacy of the patient is kept.
12. The office of the medical institution to contact in the event of trial-related injury.
13. That necessary treatment is available to the patient in the event of trial-related injury.
14. Matters concerning compensation in the event of any trial-related injury.
15. The type of the IRB which is used for the reviews and deliberations on the matters 
such as appropriateness of conducting the clinical trial, the matters to be reviewed 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 65 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
and deliberated by each IRB, and other matters concerning the IRBs involved in the 
clinical trial.
16. Other necessary matters concerning the clinical trial.
8.2
DATA QUALITY ASSURANCE
The trial will be conducted according to the principles of GCP and the company SOPs. 
The following steps will be taken to ensure accurate, consistent, complete, and reliable data:

Use of techniques to achieve standardisation (e.g., investigator meetings, etc.)

Use of techniques to achieve accuracy (e.g., global and local training sessions, etc.)

Use of centralised evaluations (e.g., central laboratory, centralised review of ECGs, 
etc.)

On-site monitoring and source data verification

Equipment validation and calibration

Auditing (in-house and on-site)

Coding (e.g., MedDRA)

Special data management procedures: The data management procedures to ensure the 
quality of the data are described in detail in the trial data management and analysis 
plan (TDMAP) available in the TMF.

Establishing CECs to evaluate specific events (refer to Section 3.1)

Taking steps to maintain the blind (refer to Section 4.1.5.1)

Inter-laboratory standardisation methods: The samples will be analysed at a central 
laboratory or its affiliates having a NGSP Level I certificate.
The data management procedures to ensure the quality of the data are described in detail in 
the TDMAP available in TMF.
A quality assurance audit/inspection of this trial may be conducted by the sponsor or
sponsor’s designees or by IRBs or IECs or by regulatory authorities. The quality assurance
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 66 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, via RDC. 
See Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s trial site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs, all data must be derived from source documents.
Additionally, the following source documents must be collected and filed at the investigator’s 
trial site:

ECG results (original or copies of printouts)

Physical examinations (original documentation)

HBGM results (printout from vendor at the end of the trial)
8.3.2
Direct access to source data and documents
The investigator and/or institution will permit trial-related monitoring, audits, IRB or IEC 
review and regulatory inspection, providing direct access to all related source data / 
documents. eCRFs and all source documents, including progress notes and copies of 
laboratory and medical test results must be available at all times for review by the sponsor’s 
clinical trial monitor, auditor and inspection by health authorities (e.g. FDA). The CRA or 
on-site monitor and auditor may review all eCRFs, and written informed consents. The 
accuracy of the data will be verified by reviewing the documents described in Section 8.3.1.
8.3.3
Storage of records
For Japan:
Trial sites:
The trial sites must retain the source documents and essential documents for a period defined 
by the Japanese GCP regulation and the sponsor’s SOP.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 67 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
When it is no longer necessary for the trial site to retain the source documents and essential 
documents, the sponsor must notify the head of trial site.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not.
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For Tradjenta®, Trajenta®, Trayenta®, and Trazenta®, this is the current version of the 
Investigator’s Brochure 
. The current version of this reference document is to be 
provided in the ISF. No AEs are classified as listed for matching placebo, study design, or 
invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of SAEs, e.g. suspected unexpected serious adverse reactions (SUSARs) 
to health authorities and IECs or IRBs, will be done according to local regulatory 
requirements. Further details regarding this reporting procedure are provided in the ISF.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB or IEC and the regulatory authorities (e.g., for EU: the CA).
8.6
COMPLETION OF TRIAL
For Japan:
When the trial is completed, the investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
sponsor of the completion in writing.
For EU member states:
The EC and CA in each participating EU member state needs to be notified about the end of 
the trial (last patient/patient out, unless specified differently in Section 6.2.3 of the CTP) or
early termination of the trial. 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 68 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
8.7
PROTOCOL VIOLATIONS
For Japan:
The investigator or sub-investigator should record all CTP violations. The investigator 
should provide and submit the sponsor and the head of the trial site the records of violations 
infringing the Japanese GCP or violations to eliminate an immediate hazard to trial subjects 
and for other medically inevitable reasons.
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
For Japan:
In the event of health injury associated with this trial, the sponsor is responsible for 
compensation based on the contract signed by the trial site.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 69 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
9.
REFERENCES
9.1
PUBLISHED REFERENCES
P07-11112
Moore TJ, Cohen MR, Furberg CD. Serious adverse drug events reported to 
the Food and Drug Administration, 1998 - 2005. Arch Intern Med 2007. 
167(16): 1752-1759.
P08-11948
Yasuda SU, Zhang L, Huang SM. The role of ethnicity in variability in 
response to drugs: focus on clinical pharmacology studies. Clin Pharmacol 
Ther 2008. 84(3): 417-423.
P10-14001
Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, 
Woerle HJ. Safety and efficacy of linagliptin as add-on therapy to metformin 
in patients with type 2 diabetes: a randomized, double-blind, placebo-
controlled study. Diabetes Obes Metab 2011. 13(1): 65-74.
P11-02847
Prato S del, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. 
Effect of linagliptin monotherapy on glycaemic control and markers of beta-
cell function in patients with inadequately controlled type 2 diabetes: a 
randomized controlled trial. Diabetes Obes Metab 2011. 13(3): 258-267.
P11-06845
Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA Efficacy and safety of 
initial combination therapy with linagliptin and pioglitazone in patients with 
inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-
controlled study. Diabetes Obes Metab 2011. 13(7): 653-661.
P11-09378
Schlosser A, Owens D, Taskinen MR, Prato S del, Gomis R, Patel S, et al. 
Long-term safety and efficacy of the DPP-4 inhibitor linagliptin: data from a 
large 2-year study in subjects with type 2 diabetes mellitus. 47th Ann Mtg of 
the European Association for the Study of Diabetes (EASD), Lisbon, 12 - 16 
Sep 2011 Diabetologia 2011. 54(1): S108 Abstr 242.
P11-12477
Gallwitz B, Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, et al. 
Efficacy and safety of linagliptin in with metformin monotherapy inadequately 
controlled type 2 diabetes. 46th Ann Mtg of the German Society of Diabetes, 
Leipzig, 1 - 4 Jun 2011 Diabetologie 2011. 6(Suppl 1): S19 Abstr FV44.
P11-14211
Budnitz DS, Lovegrove MC, Shehab N, Richards CL Emergency 
hospitalizations for adverse drug events in older Americans. N Engl J Med 
2011. 365(21): 2002-2012.
P12-05315
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et 
al. Management of hyperglycemia in type 2 diabetes: a patient-centered 
approach: position statement of the American Diabetes Association (ADA) 
and the European Association for the Study of Diabetes (EASD). Diabetes 
Care, Published online before print April 19, 2012, doi: 10.2337/dc12-0413 
Diabetes Care 2012. 35(6): 1364-1379.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 70 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
P12-05699
Graefe-Mody U, Retlich S, Friedrich C Clinical pharmacokinetics and 
pharmacodynamics of linagliptin. Clinical Pharmacokinetics, POST AUTHOR 
CORRECTIONS, 9 May 2012, doi: 10.2165/11630900-000000000-00000 
Clin Pharmacokinet 2012. 51(7): 411-427.
P12-06615
Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A Dipeptidyl 
peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical 
setting: systematic review and meta-analysis. Br Med J 2012. 344(7850):
e1369.
P13-00432
Kirkman MS, Briscoe VJ, Clark N, Florez H, Haas LB, Halter JB, et al. 
Diabetes in older adults: a consensus report. J Am Geriatr Soc 2012. 60(12):
2342-2356.
P13-07824
Inzucchi SE, Nauck M, Eynatten M von, Hehnke U, Woerle HJ, Henry R 
Lower risk of hypoglycemia in elderly type 2 diabetes patients when 
linagliptin is added to basal insulin: an exploratory analysis. 73rd Sci Sess of 
the American Diabetes Association (ADA), Chicago, 21 - 25 Jun 2013 
(Poster) 2013.
P13-09565
Barnett AH, Huisman H, Jones R, Eynatten M von, Patel S, Woerle HJ 
Linagliptin for patients aged 70 years or older with type 2 diabetes 
inadequately controlled with common antidiabetes treatments: a randomised, 
double-blind, placebo-controlled trial. Lancet, Published Online August 13, 
2013, doi: 10.1016/S0140-6736(13)61500-7 Lancet 2013. 382(9902): 1413-
1423.
P13-14398
Websky K von, Reichetzeder C, Hocher B Linagliptin as add-on therapy to 
insulin for patients with type 2 diabetes. Vasc Health Risk Manage 2013. 
9: 681-694.
P14-00552
Fravel MA, McDanel DL, Ross MB, Moores KG, Starry MJ Special 
considerations for treatment of type 2 diabetes mellitus in the elderly. Am J 
Health Syst Pharm 2011. 68: 500-509.
R04-1263
Basu R, Breda E, Oberg AL, Powell CC, Man C dalla, Basu A, et al. 
Mechanisms of the age-associated deterioration in glucose tolerance: 
contribution of alterations in insulin secretion, action, and clearance. Diabetes 
2003. 52: 1738-1748.
R08-2669
Guidance for industry: diabetes mellitus: developing drugs and therapeutic 
biologics for treatment and prevention (draft guidance, February 2008). 
Rockville: U.S.Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2008.
R09-4240
World Health Organization Diabetes. 
http://www.who.int/mediacentre/factsheets/fs312/en/ ; (WHO Fact sheet; no 
312) 2008.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 71 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
R09-4241
Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M Mortality from 
coronary heart disease in subjects with type 2 diabetes and in nondiabetic 
subjects with and without prior myocardial infarction. N Engl J Med 1998. 
339(4): 229-234.
R09-5797
Meneilly GS, Elliott T Metabolic alterations in middle-aged and elderly obese 
patients with type 2 diabetes. Diabetes Care 1999. 22(1): 112-118.
R09-6092
Abbatecola AM, Maggi S, Paolisso G New approaches to treating type 2 
diabetes mellitus in the elderly: role of incretin therapies. Drugs Aging 2008. 
25(11): 913-925.
R10-5341
Glucophage (metformin hydrochloride) tablets, Glucophage XR (metformin 
hydrochloride) extended-release tablets (Bristol-Myers Squibb), Rx only 
(product information, rev: January 2009). 2009.
R10-5452
CCalifornia Healthcare Foundation, American Geriatrics Society Panel on 
Improving Care for Elders with Diabetes Guidelines for improving the care of 
the older person with diabetes mellitus. J Am Geriatr Soc 2003. 51(5)(Suppl):
S265-S280.
R10-5537
Glucophage 500 mg and 850 mg film coated tablets (Merck Serono) 
(summary of product characteristics, date of revision of the text: 04/2010, last 
updated on the eMC: 17/08/10). http://www.medicines.org.uk 2010.
R11-2588
Tradjenta (linagliptin) tablets (Boehringer Ingelheim Pharmaceuticals) 
(prescribing information, revised: 5/2011). Tradjenta (linagliptin) tablets 
(Boehringer Ingelheim Pharmaceuticals) (prescribing information, revised: 
5/2011). 2011.
R12-1338
Ding J, Strachan WJ, Reynolds RM, Frier BM, Deary IJ, Fowkes FGR, et al. 
Diabetic retinopathy and cognitive decline in older people with type 2 
diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes 2010. 59: 2883-
2889.
R13-2759
NIH policy and guidelines on the inclusion of women and minorities as 
subjects in clinical research - amended, October, 2001. 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_200
1.htm (access date: 12 June 2013) ; Bethesda: U.S.Department of Health and 
Human Services, National Institutes of Health (NIH) 2001.
R13-3779
Sullivan MD, Katon WJ, Lovato LC, Miller ME, Murray AM, Horowitz KR, 
et al. Association of depression with accelerated cognitive decline among 
patients with type 2 diabetes in the ACCORD-MIND trial. JAMA Psychiatry, 
Published online August 14, 2013, doi:10.1001/jamapsychiatry.2013.1965 
JAMA Psychiatry 2013. 70(10): 1041-1047.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 72 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
R14-0002
Huang ES, Laiteerapong N, Liu JY, John PM, Moffet HH, Karter AJ Rates of 
complications and mortality in older patients with diabetes mellitus: the 
Diabetes and Aging study. JAMA Internal Medicine, Published online 
December 9, 2013, doi: 10.1001/jamainternmed.2013.12956 JAMA Intern 
Med 2013.
R14-0182
Herrera AP, Snipes SA, King DW, Torres-Vigil I, Goldberg DS, Weinberg 
AD Disparate inclusion of older adults in clinical trials: priorities and 
opportunities for policy and practice change. Am J Public Health 2010. 
100(Suppl 1): S105-S112.
R14-0183
Sinclair A, Morley JE, Rodriguez-Manas L, Paolisso G, Bayer T, Zeyfang A, 
et al. Diabetes mellitus in older people: position statement on behalf of the 
International Association of Gerontology and Geriatrics (IAGG), the European 
Diabetes Working Party for Older People (EDWPOP), and the International 
Task Force of Experts in Diabetes. . J Am Med Dir Assoc 2012. 13: 497-502.
R14-0250
Crane PK, Walker R, Hubbard RA, Li G, Nathan DM, Zheng H, et al. Glucose 
levels and risk of dementia. N Engl J Med 2013. 369(6): 540-548
R14-0340
Viljoen A, Meek CL, Gadsby R, Viljoen S, Langerman H, Sinclair AJ The 
tolerability and safety of DPP-4 inhibitors for the treatment of older people 
with type 2 diabetes mellitus: an observational study. Br J Diabetes Vasc Dis 
2013. 13(4): 187-191.
R14-0344
American Diabetes Association Standards of medical care in diabetes - 2014. 
Diabetes Care 2014. 37(Suppl 1): S14-S80.
R14-0345
Lakey WC, Barnard K, Batch BC, Chiswell K, Tasneem A, Green JB Are 
current clinical trials in diabetes addressing important issues in diabetes care? 
Diabetologia 2013. 56(6): 1226-1235.
R14-0360
Cryer PE Mechanisms of hypoglycemia-associated autonomic failure in 
diabetes. N Engl J Med 2013. 369(4): 362-372.
R14-0434
Nalivaeva NN, Beckett C, Belyaev ND, Turner AJ Are amyloid-degrading 
enzymes viable therapeutic targets in Alzheimer's disease? J Neurochem 2012. 
120(Suppl 1): 167-185.
R14-0435
Bartl J, Meyer A, Brendler S, Riederer P, Gruenblatt E Different effects of 
soluble and aggregated amyloid beta42 on gene/protein expression and 
enzyme activity involved in insulin and APP pathways. J Neural Transm 2013. 
120: 113-120.
R14-0436
Pandini G, Pace V, Copani A, Squatrito S, Milardi D, Vigneri R Insulin has 
multiple antiamyloidogenic effects on human neuronal cells. Endocrinology 
2013. 154(1): 375-387.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 73 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
R14-0437
Candeias E, Duarte AI, Carvalho C, Correia SC, Cardoso S, Santos RX, et al. 
The impairment of insulin signaling in Alzheimer's disease. IUBMB Life 
2012. 64(12): 951-957.
R14-0447
Lam DW, LeRoith D The worldwide diabetes epidemic. Curr Opin Endocrinol 
Diabetes Obes 2012. 19(2): 93-96.
R14-0992
Cruz-Oliver DM, MalmstromTK, Allen CM, Tumosa N, Morley JE The 
Veterans Affairs Saint Louis University Mental Status exam (SLUMS exam) 
and the Mini-Mental Status Exam as predictors of mortality and 
institutionalization. J Nutr Health Aging 2012. 16(7): 636-641.
R14-0995
Feliciano L, Horning SM, Klebe KJ, Anderson SL, Cornwell RE, Davis HP 
Utility of the SLUMS as a cognitive screening tool among a nonveteran 
sample of older adults. Am J Geriatr Psychiatry 2013. 21(7): 623-630.
R14-0977
Tariq SH, Tumosa N, Chibnall JT, Perry MH, Morley JE Comparison of the 
Saint Louis University mental status examination and the mini-mental state 
examination for detecting dementia and mild neurocognitive disorder - a pilot 
study. Am J Geriatr Psychiatry 2006. 14(11): 900-910.
 
 
 
 
 
 
 
 
 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 74 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 75 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
10.
APPENDICES
10.1
INCLUSION OF ILLITERATE PATIENTS
10.1.1
Home Blood Glucose Monitoring and eDiary
In the event of recruiting an illiterate patient, the following process should be followed with 
respect to HBGM as well as eDiary and documenting the results:

At Screen, the person assisting the patient with this process (e.g., the patient’s 
caregiver or relative) will attend the clinic together with the patient.

The trial site staff should confirm that this individual will be present with the patient, 
whenever he/she is likely to need to perform HBGM and answer the eDiary questions.

The trial site staff should then train both the patient and above-mentioned individual 
with respect to the correct use of the HBGM equipment during each period of the 
trial.  This will include the use of the glucose meter itself and the test strips, lancet 
device and any control solutions.  Furthermore, if whole blood referenced test strips 
are standard in the countries where illiterate patients are being recruited, the trial site
staff must ensure that both the patient and the person assisting the patient with the 
HBGM, have understood that plasma referenced test strips are used in the trial, and 
that there may be differences in the results obtained via these two methods.  A 
training letter is available to support this process.

The trial site staff should also train both the patient and the above-mentioned 
individual with respect to the completion of the eDiary questions.  
HGBM tests can be performed either by the patient him/herself, or by the person assisting the 
patient with this aspect of the trial. The person assisting the patient will need to obtain the 
answers to the eDiary questions from the patient and enter the patient’s responses into the 
eDiary.
10.1.2
Patient information and informed consent
In the event of recruiting an illiterate patient, the following process should be followed with 
respect to patient information and informed consent: 

The designated trial site personnel performing the informed consent process will read 
the trial-approved patient information sheet and informed consent form to the patient, 
and explain the details of the trial, all in the presence of an impartial witness.

This impartial witness must be literate, and can be the patient’s relative or caregiver, 
or a member of staff employed by the clinic but not part of the immediate trial team.  
In addition, if there are any further local regulations with respect to the consent of 
illiterate patients, these should also be followed.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 76 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

The requirements of the trial will be explained thoroughly and the patient will be 
given ample time to ask questions and consider his/her participation.  If he/she 
wishes, the patient can take the patient information sheet and informed consent form 
home for further consideration.

If patient agrees to take part in the trial, he/she would then return to the clinic for the 
consent process to be completed.  The trial site designated personnel responsible for 
this process will confirm that the patient has no further questions in the presence of 
the same impartial witness (if the patient returns on another day).  If a different 
impartial witness is present, the entire informed consent process must be repeated.

Participating patients will provide a thumb impression or make a mark (or signature if 
the patient is able to sign him/herself) on the signature section of the informed consent 
form.

The date of the patient’s signature will be left blank as the patient is illiterate.  
However, if the patient is able, he/she will date the mark/signature personally.

The impartial witness or the trial site designated personnel may write the name of the 
patient on the informed consent form.

The impartial witness should enter his/her name, sign and personally date the witness 
section of the informed consent form.  In countries where local data protection 
regulation permits it, the address or identification number of the impartial witness 
should also be entered.  The signature then attests that the content of the patient 
information sheet and informed consent form was accurately explained to the patient, 
who apparently understood and freely gave consent to participate in the trial.

The designated trial site personnel also signs and personally dates the informed 
consent form.

 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 77 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
11.
DESCRIPTION OF GLOBAL AMENDMENT
This is the original protocol.
Number of global amendment
1
Date of CTP revision
16 October 2015
EudraCT number
2014-000904-88
BI Trial number
1218.149
BI Investigational Product
Tradjenta®, Trajenta®, Trayenta®, Trazenta®, linagliptin
Title of protocol
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
To be implemented only after 
approval of the IRB or IEC
and/or Competent Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB or IEC and/or Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB or IEC and/or Competent 
Authority approval as changes
involve logistical or 
administrative aspects only
Section to be changed
Title Page and Synopsis
Description of change
There was a change of Coordinating Investigator
and a global amendment was added.
Rationale for change
The Coordinating Investigator discontinued from 
the trial and there was an addition of a global 
amendment due to recruitment difficulties.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 78 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Section to be changed
Synopsis
Description of change
Decrease of: 1.) age to 60 years old, and 2.) lower 
limit of HbA1c to 7.0%; and the secondary 
endpoint of < 7.5% HbA1c was changed to 
< 7.0%.
Rationale for change
This trial was based on the data of two trials 
(1218.36 and 1218.63), which used a lower limit 
in age for one trial and HbA1c in both trials.  As 
the inclusion criterion of HbA1c was decreased to 
7.0%, the secondary endpoint for < 7.5% HbA1c
was changed to < 7.0%.
Section to be changed
Synopsis and Flowchart
Description of change
Decrease sample size to 300 (150 per arm) based 
on the primary endpoint of HbA1c only, with 100 
patients randomized required in Japan. The key 
secondary endpoint was changed to a secondary 
endpoint. 
Rationale for change
Prescribing practices have changed in the past 5 
years and recruitment has proved to be too 
difficult and slow to achieve the key secondary 
endpoint sample size requirement.
Section to be changed
Section 1.1
Description of change
An additional sentence was included regarding 
the rationale for the global protocol amendment.
Rationale for change
As a result of extreme difficulty with recruiting 
this population, the global protocol amendment 
expanded the definition of elderly population 
beginning at age 60.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 79 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Section to be changed
Sections 2.2, 3.1, 3.3, and 3.3.2
Description of change
Decrease of: 1.) age to 60 years old, 2.) lower 
limit of HbA1c to 7.0% (53 mmol/mol), and 3.)
sample size to 300 (150 per arm) based on 
primary endpoint of HbA1c only, with 100 
patients randomized from Japan per regulatory 
requirements. 
Section 3.3: A time period ‘of at least 1 year’ has 
been added to the medical history documentation
requirement. 
Inclusion criterion 2b: The additions of 
‘biosimilar’ basal insulin and Humalog Basal® (a 
suspension of insulin lispro protamine) have been 
included in order to expand the permitted basal 
insulins.
Rationale for change
This trial was based on the data of two trials 
(1218.36 and 1218.63), which used a lower limit
of HbA1c of 7.0% and a lower limit in age for one 
trial.  Prescribing practices have changed in the 
past 5 years and recruitment has proved to be too 
difficult and slow to achieve the key secondary 
endpoint sample size requirement.   
Section 3.3:  Medical history documentation of at 
least 1 year is needed based on required medical 
follow up of a patient being on basal insulin.  
Inclusion criterion 2b: There are two newer basal 
insulins that can be used in this trial: ‘biosimilar’ 
basal insulin and Humalog Basal® (a suspension 
of insulin lispro protamine).

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 80 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Section to be changed
Section 3.3.3
Description of change
Exclusion criterion number 1: Saint Louis 
University Mental Status Examination scores 
were further clarified for mild neurocognitive 
disorder.  Exclusion criterion number 4: STEMI 
and/or unstable angina pectoris were added.
Exclusion criterion number 10: The addition of 
meglitinides and bromocriptine were included 
into exclusion criterion as these were missing but 
were stated in Section 4.2.2.1 from the final 
protocol,
Rationale for change
Exclusion criterion number 1: Patients with Saint 
Louis University Mental Status Examination 
scores indicating dementia must not be evaluated 
further for the trial.  Exclusion criterion number 
4: Clarified to include STEMI and unstable 
angina pectoris for complete definition of acute 
coronary syndrome.  Exclusion criterion number 
10: The exclusion criterion must be consistent 
with Section 4.2.2.1 relating to prohibited 
concomitant medications,
Section to be changed
Section 4.2.1 - Permitted antidiabetic therapy
Description of change
3rd paragraph: After randomisation, investigators 
should review the patient’s HBGM results 
electronically for hyperglycaemia and should 
follow the permitted antidiabetic therapy criteria
noted below to achieve improved patient 
glycaemic control before taking any additional 
action with rescue therapy.
Final paragraph:  Clarification of permitted 
antidiabetic therapy that will be considered to be 
rescue therapy was included.
Rationale for change
Additions were provided to further clarify: the 
procedure for permitted antidiabetic therapy 
criteria related to the HBGM data (i.e., 
glucometer) and permitted antidiabetic therapy 
that will be considered to be rescue therapy.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 81 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Section to be changed
Section 5.1.1
Description of change
The key secondary endpoint was removed and 
changed to a secondary endpoint.  As the 
inclusion criterion of HbA1c was decreased to 
7.0%, the secondary endpoint for HbA1c of 7.5% 
was changed to <7.0%.  Added the word ‘to’ 
before 70 mg/dl.
Rationale for change
Prescribing practices have changed in the past 5 
years and recruitment has proved to be too 
difficult and slow to achieve the key secondary 
endpoint sample size requirement.  As the 
inclusion criterion of HbA1c was decreased to 
7.0%, the secondary endpoint for HbA1c of 7.5% 
was changed to <7.0%.  To further clarify 
definition of hypoglycaemia as less than or equal 
to 70 mg/dl.  
Section to be changed
Sections 5.2.1, 5.2.2.1, and 5.2.5
Description of change
Symbol of ≤ added before 70 mg/dl and the AESI 
process was changed.
Rationale for change
To further clarify definition of hypoglycaemia as 
less than or equal to 70 mg/dl and the Sponsor’s 
AESI process was updated and required 
additional clarification.
Section to be changed
Section 5.2.5 - eDiary
Description of change
The patient allowed recall period for completing a 
missed entry was changed to 12 hours.
Rationale for change
The original plan was to allow for a 24 hour recall 
period but was not possible with changes required 
for the functionality of the eDiary.

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 82 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Section to be changed
Section 5.3.3 – list number 1
Description of change
The pre-specified analyses will be performed at 
the end of the trial and the data will be reported 
separately from the clinical trial report.
Rationale for change
It was subsequently determined that the pre-
specified analyses data would be reported 
separately from the clinical trial report.
Section to be changed
Section 5.3.3.1 – list numbers 1 and 2
 
 
 
 
 
 
 

Boehringer Ingelheim
16 Oct 2015
BI Trial No.: 1218.149
Doc. No.: c02204602-03
Trial Protocol
Page 83 of 83
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Section to be changed
Sections 7.1, 7.2, 7.3, 7.3.1, 7.3.7, 7.4.1, and 7.6
Description of change
Decrease of age to 60 years old and lower limit of 
HbA1c to 7.0%.  Changing the key secondary 
endpoint to a secondary endpoint and decreasing 
sample size to 300 (150 per arm) based on 
primary endpoint of HbA1c only.
 
Rationale for change
This trial was based on the data of two trials 
(1218.36 and 1218.63), which used a lower limit 
in age for one trial and HbA1c in both trials.  
Prescribing practices have changed in the past 5 
years and recruitment has proved to be too 
difficult and slow to achieve the key secondary 
endpoint sample size requirement.
 

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number:  
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02204602
3.0
clinical-trial-protocol
A randomized, double-blind, placebo-controlled, parallel group, efficacy and safety
trial of linagliptin 5 milligrams taken once daily orally with basal insulin for 24
weeks in elderly Type 2 Diabetes Mellitus patients with insufficient glycaemic
control
Author-Trial Clinical Monitor
16 Oct 2015 23:20 CEST
Author-Trial Statistician
17 Oct 2015 00:57 CEST
Author-Trial Clinical Monitor
17 Oct 2015 03:18 CEST
Approval-Team Member Medicine
17 Oct 2015 13:36 CEST
Approval-Therapeutic Area 
19 Oct 2015 17:12 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02204602
3.0