Clinical trial NCT01897532
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim
Start date: 2013-07-10; Completion date: 2018-01-18
Enrollment: 6991 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of the study is to investigate the longterm impact on cardiovascular morbidity, mortality and renal function of treatment with linagliptin in a selected population of patients with Type 2 diabetes mellitus (T2DM) and to compare outcomes against placebo, on a background of standard of care.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Placebo intervention 2: Linagliptin
Intervention descriptions: intervention 1: placebo matching tablets intervention 2: None

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: 
c02155180-06
EudraCT No.:
BI Trial No.:
2011-004148-23
1218.22
BI Investigational
Product(s):
Linagliptin (BI 1356)
Title:
A multicenter, international, randomized, parallel group, double-blind, 
placebo-controlled CArdiovascular Safety & Renal Microvascular
outcomE study with LINAgliptin, 5 mg once daily in patients with type 
2 diabetes mellitus at high vascular risk. CARMELINA
Clinical Phase:
IV
Trial Clinical 
Monitor:
Phone  
Fax    
Phone: 
   
Fax: 
Co-ordinating 
Investigators:
Phone: 
     Fax:     
Phone: 
    Fax: 
Phone:
     Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date:
Version: 3.0
Date: 22 November 2016
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Trajenta®
Name of active ingredient:
Linagliptin (BI 1356)
Protocol date:
Trial number:
Revision date:
22 November 2016
5 February 2013
1218.22
Title of trial:
A multicenter, international, randomized, parallel group, double-blind, placebo-
controlled CArdiovascular Safety & Renal Microvascular outcomE study with 
LINAgliptin, 5 mg once daily in patients with type 2 diabetes mellitus at high 
vascular risk. CARMELINA
Co-ordinating     
Investigators
Phone: 
    Fax:
Phone:
    Fax: 
 
Phone: 
    Fax: 
Trial site(s):
Approximately 600
Clinical phase:
IV
Objective(s):
The primary objective is to demonstrate non-inferiority (by means of comparing the 
upper limit of a two-sided 95% confidence interval with the non-inferiority margin of 
1.3) of treatment with linagliptin in comparison to placebo (as add-on therapy on top    
of standard of care) with respect to time to first occurrence of any of the adjudicated 
components of the primary composite endpoint (i.e. cardiovascular (CV) death
[including fatal stroke, fatal MI and sudden death], non-fatal stroke or non-fatal 
myocardial infarction (MI) (excluding silent MI) and hospitalisation for unstable 
angina pectoris) in patients with type 2 diabetes mellitus (T2DM).
If non-inferiority has been demonstrated, then the primary composite endpoint will be 
tested for superiority and the other objective, to assess the impact of treatment with 
respect to the composite renal endpoint (i.e. renal death, sustained end-stage renal 
disease (ESRD), sustained decrease in estimated global glomerular filtration rate 
(eGFR) ≥50 40% from baseline), will be investigated separately with a test on 
superiority.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Trajenta®
Name of active ingredient:
Linagliptin (BI 1356)
Protocol date:
Trial number:
Revision date:
22 November 2016
5 February 2013
1218.22
Methodology:
This randomized, double-blind, placebo controlled, parallel group study compares 
treatment with linagliptin (5 mg once daily) to treatment with placebo (matching  
tablets once daily) as add-on therapy to standard of care.
No. of patients: 
total entered:
An estimated 8300 7000 randomized patients to obtain a minimum of 625 611 primary 
endpoint events.
each treatment:
An estimated 4150 3500 randomized patients per treatment group.
Diagnosis :
T2DM
Criteria
for inclusion:
1. Documented diagnosis of T2DM before visit 1(screening). 
2. Male or female patients who are drug-naïve or pre-treated with any antidiabetic 
background medication, excluding treatment with GLP-1 receptor agonists, DPP-4 
inhibitors or SGLT-2 inhibitors if  ≥ consecutive 7 days.
3. Stable antidiabetic background medication (unchanged daily dose) for at least 8 
weeks prior to randomization. If insulin is part of the background therapy, the average 
daily insulin dose should not have changed by more than 10% within the 8 weeks prior 
to randomization compared with the daily insulin dose at randomization.
4. HbA1c of ≥6.5% and ≤10.0% at visit 1 (screening) 
5. Age ≥ 18 years at visit 1(screening). For Japan only: Age ≥20 years at visit 1
6. Body Mass Index (BMI) 45 kg/m2 at visit 1 (screening)
7. Signed and dated written informed consent by date of visit 1(screening) in 
accordance with Good Clinical Practice (GCP) and local legislation prior to any study 
related procedure
8.High risk of CV events defined by:

Albuminuria (micro or macro) and previous macrovascular disease: defined 
according to section 3.3.2 and/or

Impaired renal function with predefined UACR: for criteria see section 3.3.2
Refer to section 3.3.3 for exclusion criteria.
Test product(s):
Linagliptin
dose:
5 mg
mode of admin.:
Tablets per os
Comparator product:
Placebo
dose:
NA
mode of admin.:
Tablets per os
Duration of treatment: Estimated 48 54 months treatment period from first patient randomized, depending on 
observed number of primary endpoint events.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Trajenta®
Name of active ingredient:
Linagliptin (BI 1356)
Protocol date:
Trial number:
Revision date:
22 November 2016
5 February 2013
1218.22
Criteria for efficacy:
The primary endpoint in this trial is time to the first occurrence of any of the 
following by adjudicationed confirmed components of the primary composite 
endpoint (4 3-point MACE): CV death (including fatal stroke, fatal MI and sudden 
death), non-fatal MI (excluding silent MI) or non-fatal stroke and hospitalisation for 
unstable angina pectoris.
The key secondary endpoints are is time to the first occurrence of any of the 
following by adjudication confirmed components:

CV death (including fatal stroke, fatal MI and sudden death), non-fatal MI
(excluding silent MI), non-fatal stroke (3-point MACE)

Composite renal endpoint (renal death, sustained ESRD, sustained decrease 
of 50 40% or more in eGFR)
The primary endpoint (4 3-point MACE) will be tested for non-inferiority. Thereafter, 
if non-inferiority has been demonstrated, the 4 3-point MACE and the combined 
composite renal endpoint will be tested separately (= in parallel) for superiority. In 
case the 4-point MACE and/or the composite renal endpoint is significantly superior, 
the 3-point MACE will be tested for superiority.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Trajenta®
Name of active ingredient:
Linagliptin (BI 1356)
Protocol date:
Trial number:
Revision date:
22 November 2016
5 February 2013
1218.22


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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
Name of finished product:
Trajenta®
Name of active ingredient:
Linagliptin (BI 1356)
Protocol date:
Trial number:
Revision date:
22 November 2016
5 February 2013
1218.22
Criteria for safety:
Secondary and tertiary CV and renal endpoints are described above and in Section 7.
In addition, incidence and intensity of adverse events, physical examination, vital 
signs, electrocardiogram (ECG) and change from baseline in laboratory parameters 
will be assessed.
Statistical methods:
For the primary analyses a Cox proportional hazards regression model of time to first 
event with factor treatment and geographical region will be conducted. The primary 
analyses will be performed on the full analysis set Treated Set following the intent-
to-treat principle. The first null hypothesis states that linagliptin is inferior to placebo 
by a hazard ratio of at least 1.3 regarding the primary composite endpoint. 
The study is powered to reject that hypothesis.
If the non-inferiority test with margin 1.3 has revealed a significant result, then two 
separate hypothesis tests for
a)
the primary composite endpoint
b)
the composite renal endpoint (i.e. renal death, sustained ESRD, 
sustained decrease in estimated GFR ≥50 40% from baseline)
will be tested for superiority in parallel, each with the Cox proportional hazards 
regression model for time to first event. To adjust for multiplicity a sequentially 


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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
Name of finished product:
Trajenta®
Name of active ingredient:
Linagliptin (BI 1356)
Protocol date:
Trial number:
Revision date:
22 November 2016
5 February 2013
1218.22
rejective multiple test procedure will be applied.


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FLOW CHART
Trial period
Screening
Treatment period
FU
Visit
1
2
3
4
5
6 to N
EOTC
FUD
Week
-2
0
12
36
60
84 to NB
-
-
Days from randomization 
-14A    
0
84
252 
420 
588 to NB
-
EOT 
+ 30
Time window (days)O
+13 A
±7
±14
±14  
±14
±14
+7
Informed consent
X
In-/exclusion criteria
X
X
Medical history/ concomitant diagnoses
X
Demographics
X
Physical examinationF
X
X
X
X
XD
Vital signs
X
X
X
X
X
X
X
XD
Height
XE
Weight
XE
X
X
X
X
Waist circumference
X
X
X
X
X
12-lead-ECGH
X
X
X
X
X
XD
Pregnancy TestI
X
X
X
X
X
Fasted home blood glucose monitoringJ
X
X
X
X
X
X
Safety laboratoryK
X
X
X
X
X
X
X
XD
UACRQ
X
XA
X
XK
X
XD
HbA1c
X
X
X
X
X
X
X
Lipid panel
X
X
XK
X
XD
eGFRL
X
X
X
X
X
X
X
XD
Pharmacogenetic samplingP
X
Adverse events/outcome events M
X
X
X
X
X
X
X
X
Concomitant therapy 
X
X
X
X
X
X
X
X
Randomization (IRT)N
X
Dispense study medication (IRT)N
X
X
X
X
X
Return study medication/ medication 
compliance check
X
X
X
X
X


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Flow Chart (continued)
A
Randomization may be done as soon as the visit 1 (safety) laboratory results and eGFR are known and 
all other eligibility criteria are met. If the UACR result at visit 2 is required to fulfil inclusion criterion 
8, randomization may be postponed until the laboratory results are known. It’s not required to repeat 
visit 2 assessments if the patient returns to the clinic for randomization. 
B
A clinic visit will be scheduled every 24 weeks until study end.
C 
The study is event driven. The number of confirmed adjudicated primary endpoint events will be 
continuously monitored during the trial. Based on the available number of events the projected number 
of expected future events will be calculated. As soon as the projection reliably suggests that the total 
number of patients with a by adjudication confirmed primary endpoint event will reach 625 611 within 
the next 24 weeks, the trial team will perform respective actions to stop the trial. From this time point 
on, all patients are expected to perform their last visit (EOT visit) within the regular proposed time 
schedule, which means within the next 24 weeks communicated via an investigator letter. A follow-
up visit will take place one week 30 days after the end of treatment (EOT visit).
Patients who discontinue study drug prematurely should continue study visits until study end. Study 
assessments may be omitted if a patient is willing to return to the pre-defined study visits, with 
exception 
, collection of adverse events, outcome events, concomitant 
therapy and laboratory testing of creatinine for the calculation of the eGFR. 
If a patient who prematurely discontinued study drug is not willing to return to the pre-defined study 
visits, at minimum a yearly telephone call (preferably every 6 months) and a telephone call at study end 
will be required, to document the occurrence of outcome events and vital status. If possible, other 
adverse events and concomitant therapy changes since last visit might should be recorded (refer to 
section 3.3.4). 
D
All patients will have a follow up visit one week 30 days following regular or premature completion of 
the treatment period. The follow-up visit may be performed as a phone visit for patients who did not 
prematurely discontinue study medication and who do not have abnormalities at the EOT visit (only 
adverse events/outcome events and changes in concomitant therapy to be obtained).
E
Body Mass Index will be calculated automatically.
F
A complete, head-to-toe physical examination (e.g. evaluation of the body and its functions using 
inspection, palpation, percussion, and auscultation) will be done.
G
 
 
 
 
 
H
In addition to the visits indicated, electrocardiogram (ECG) should be recorded in case of respective 
cardiac symptoms (indicating rhythm disorders or cardiac ischemia).
I
For female patients (local urine pregnancy test in women of child bearing potential). More frequent 
testing can be done if required by local regulations/authorities. 
J
Distribution of glucometer and testing supplies with instructions at randomization (visit 2). During the 
treatment period, weekly finger stick glucose measurements are recommended (fasted). During the 
whole trial participation, additional measurements should be done if necessary and in case of hypo- or 
hyperglycaemia related symptoms. The patient should be instructed to bring their HBGM device and 
diary to the clinic for an additional measurement (fasted).


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K
At visit 1 safety laboratory includes ALT, AST, alkaline phosphatase and creatinine to check for 
eligibility in addition to lipase, urine albumin, urine creatinine and HbA1c as specified in the flow chart. 
At randomization (visit 2) baseline laboratory will be obtained. See section 5.2.3 for to be obtained 
laboratory parameters. As of visit 6: yearly (every other visit) lipid profile (Total cholesterol, HDL 
cholesterol, LDL cholesterol and triglycerides), urine albumin and urine creatinine.
L 
Estimated creatinine clearance glomerular filtration rate (eGFR) will be calculated using the MDRD
formula. This formula considers the race as an adjustment factor, therefore, the race must be known 
(and will be collected) for accurate estimation. In case of an eGFR decrease of  ≥ 40% since baseline 
(visit 2) and again in case of an eGFR decrease of  ≥50% since baseline (visit 2) an additional visit 4-8
weeks after detection should be scheduled to collect a blood sample for repeat analysis of creatinine 
(eGFR). An additional sample of creatinine should also be taken between the visits if a signal of 
increasing creatinine is reported to the study site by others (e.g., GPs from local labs). 
M
In case of a stroke the reported value from the modified Rankin Scale will be collected approximately 
one week after stroke onset and 3 months after stroke onset. This might require an additional contact.
N
Interactive Response Technology (IRT) will allocate medication kit numbers at all study visits from 
visit 2 till study end. At visit 2 patients will receive one treatment box sufficient for 12 weeks treatment 
(plus one week reserve). As of visit 3 patients will receive two medication boxes sufficient for 24 
weeks treatment (plus two weeks reserve). 
O
The protocol allows a time window of +/- 7 days for visit 3 and +/- 14 days for all scheduled visits in 
the treatment period after visit 3. To ensure sufficient medication, visits after visit 3 should be 
scheduled within 182 days and visit 3 should take place no later than 91 days after visit 2. 
P
To allow possible retrospective pharmacogenetic analyses, all patients eligible for randomization will 
be asked for a blood sample with a separate informed consent. The pharmacogenetic sample should 
preferably be taken at visit 2, but could also be taken at any later visit, depending on availability of the 
respective informed consent. Pharmacogenetic sampling is voluntary and is not a prerequisite for 
participation in the study.
Q         Urine Albumin Creatinine Ratio (UACR) will be calculated at the central lab, and should be measured 
on a first morning void specimen wherever possible.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................8
TABLE OF CONTENTS ................................................................................ 11
ABBREVIATIONS.......................................................................................... 15
1.
INTRODUCTION.................................................................................... 17
1.1
MEDICAL BACKGROUND............................................................................17
1.2
DRUG PROFILE...............................................................................................19
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 22
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................22
2.2
TRIAL OBJECTIVES.......................................................................................23
2.3
BENEFIT - RISK ASSESSMENT ...................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 25
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................25
3.1.1
Administrative structure of the trial...................................................26
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................27
3.3
SELECTION OF TRIAL POPULATION ......................................................28
3.3.1
Main diagnosis for study entry............................................................29
3.3.2
Inclusion criteria...................................................................................29
3.3.3
Exclusion criteria ..................................................................................31
3.3.4
Removal of patients from therapy or assessments.............................32
3.3.4.1
Removal of individual patients................................................32
3.3.4.2
Discontinuation of the trial by the sponsor..............................34
4.
TREATMENTS........................................................................................ 35
4.1
TREATMENTS TO BE ADMINISTERED....................................................35
4.1.1
Identity of BI investigational product and comparator 
product(s)...............................................................................................35
4.1.2
Method of assigning patients to treatment groups ............................35
4.1.3
Selection of doses in the trial................................................................35
4.1.4
Drug assignment and administration of doses for each patient .......35
4.1.5
Blinding and procedures for unblinding ............................................36
4.1.5.1
Blinding....................................................................................36
4.1.5.2
Procedures for emergency unblinding .....................................37
4.1.6
Packaging, labelling, and re-supply ....................................................37
4.1.7
Storage conditions.................................................................................37
4.1.8
Drug accountability ..............................................................................38


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................39
4.2.1
Glycaemic control, emergency procedures, and additional 
treatment(s) ...........................................................................................39
4.2.2
Restrictions............................................................................................40
4.2.2.1
Restrictions regarding concomitant treatment .........................40
4.3
TREATMENT COMPLIANCE.......................................................................40
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 41
5.1
EFFICACY.........................................................................................................41
5.1.1
Endpoint(s) of efficacy..........................................................................41
5.1.2
Assessment of efficacy...........................................................................43
5.2
SAFETY..............................................................................................................43
5.2.1
Endpoint(s) of safety.............................................................................43
5.2.1.1 Reporting waiver for cardiovascular outcome events..............44
5.2.2
Assessment of adverse events...............................................................44
5.2.2.1
Definitions of adverse events...................................................44
5.2.2.2
Adverse event and serious adverse event reporting.................48
5.2.2.3 Oncological adverse events........................................................49
5.2.3
Assessment of safety laboratory parameters......................................50
5.2.3.1
Renal function..........................................................................51
5.2.4
Electrocardiogram................................................................................51
5.2.5
Assessment of other safety parameters...............................................52
5.3
OTHER...............................................................................................................53
5.3.2 Post stroke functional assessment........................................................54
5.3.3     Pharmacogenomic evaluation.............................................................54
5.3.3.1
Methods and timing of Pharmacogenetics sample collection..54
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................54
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................54
5.6
BIOMARKER(S) ...............................................................................................55
5.7
PHARMACODYNAMICS................................................................................55
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....55
6.
INVESTIGATIONAL PLAN.................................................................. 56
6.1
VISIT SCHEDULE............................................................................................56
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................56
6.2.1
Screening period....................................................................................56
6.2.2
Treatment period ..................................................................................56
6.2.3
End of treatment and follow-up period ..............................................57
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 59


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7.1
STATISTICAL DESIGN - MODEL................................................................59
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................59
7.3
PLANNED ANALYSES....................................................................................62
7.3.1
Primary analyses...................................................................................63
7.3.2
Secondary analyses ...............................................................................64
7.3.3
Safety analyses.......................................................................................66
7.3.4
Interim analyses ....................................................................................66
7.3.5
Pharmacokinetic analyses ....................................................................67
7.3.6
Pharmacodynamic analyses.................................................................67
7.3.7
Pharmacogenomic analyses..................................................................67
7.4
HANDLING OF MISSING DATA ..................................................................67
7.5
RANDOMIZATION..........................................................................................68
7.6
DETERMINATION OF SAMPLE SIZE ........................................................68
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 71
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................71
8.2
DATA QUALITY ASSURANCE .....................................................................72
8.3
RECORDS..........................................................................................................72
8.3.1
Source documents .................................................................................73
8.3.2
Direct access to source data and documents.......................................73
8.3.3
Storage of records ................................................................................73
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................73
8.4.1
Listedness...............................................................................................73
8.4.2
Expedited reporting to health authorities and IECs/IRBs................74
8.5
STATEMENT OF CONFIDENTIALITY.......................................................74
8.6
COMPLETION OF TRIAL..............................................................................74
8.7 
PROTOCOL VIOLATIONS ............................................................................74
8.8 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT 
OF TRIAL RELATED INJURY......................................................................74
9.
REFERENCES......................................................................................... 75
9.1
PUBLISHED REFERENCES...........................................................................75
9.2
UNPUBLISHED REFERENCES.....................................................................78
10. APPENDICES .......................................................................................... 79
10.1
INCLUSION OF ILLITERATE PATIENTS .................................................79
10.1.1 Home blood glucose monitoring ..........................................................79
10.1.2 Patient information and informed consent.........................................79
10.2
DEFINITIONS OF ENDPOINT EVENTS .....................................................80
10.3
BLOOD PRESSURE MEASUREMENT PROCEDURE..............................80
10.4
SILENT MYOCARDIAL INFARCTION......................................................81


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11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 82


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ABBREVIATIONS
ACEi
AE
AESI
ALD
Angiotensin Converting Enzyme inhibitor
Adverse Event
Adverse Event of Special Interest
Approximate Lethal Dose
ALT
Alanine Transaminase (SGPT)
AP
Alkaline Phosphatase
ARB
Angiotensin Receptor Blocker
AST
Aspartate transaminase (SGOT)
BI
Boehringer Ingelheim
BMI
BP
Body Mass Index (weight in kg divided by height in meters squared)
Blood Pressure
CA
Competent Authority
CABG
Coronary Artery Bypass Graft
CCDS
Company Core Data Sheet
CEC
Clinical Event Committee
CES-D
Center for Epidemiologic Studies Depression scale
CHF
Congestive Heart Failure
CKD
Chronic Kidney Disease
CRA
CRO
Clinical Research Associate
Contract Research Organisation
CRF
Case Report Form
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTSU
Clinical Trial Supply Unit
CV
DBP
Cardiovascular
Diastolic Blood Pressure
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DPP-4
Dipeptidyl-peptidase 4
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular filtration Rate
EOT
End of Treatment
ESRD
End Stage Renal Disease
EudraCT
European Clinical Trials Database
FAS
FDA
Full Analysis Set
Food and Drug Administration
FPG
Fasting Plasma Glucose
GCP
Good Clinical Practice
γ-GT
GI
Gamma-glutamyl-transferase (GGT)
GastroIntestinal
GIP
Glucose-dependent Insulinotropic Peptide
GLP-1
Glucagon-like Peptide 1
HbA1c
Glycosylated Haemoglobin


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HBGM
βHCG
Home Blood Glucose Monitoring
beta Human Chorionic Gonadotropin
HDL
High Density Lipoprotein 
HR
Hazard Ratio
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
ISF
ITT
IUDs/IUSs
Interactive Response Technology
Investigator Site File
Intention To Treat
Intra Uterine Devices/Systems
LDL
Low Density Lipoprotein
LDH
Lactate Dehydrogenase
MACE
Major Adverse Cardiovascular Events
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Drug Regulatory Activities
MI
MMSE
NGSP
Myocardial infarction
Mini-Mental State Examination
National Glycohemoglobin Standardization Program
NI
Non-Inferiority 
OAD
Oral antidiabetic drug
OS
On-treatment Set
PCI
Percutaneous Coronary Intervention
p.o.
per os (oral)
PPS
Per Protocol Set
PR
Pulse Rate
PV
Protocol Violation
SAE
Serious Adverse Event
SC
SGLT-2
SOP
Steering Committee
Sodium Glucose Linked Transporter
Standard Operating Procedure
SU
SUSAR
Sulfonylurea
Suspected Unexpected Serious Adverse Reactions
T2DM
Type 2 diabetes mellitus
TIA
Transient Ischemic Attack
TMT
Trial Making Test
TS
Treated Set
TSAP
UACR
Trial Statistical Analysis Plan
Urine Albumin Creatinine Ratio
ULN
Upper Limit of Normal
VEGF
Vascular endothelial growth factor
VFT
Verbal Fluency Test


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1.
INTRODUCTION
Linagliptin is an orally available inhibitor of the enzyme dipeptidyl-peptidase IV (DPP-4) 
facilitating a decrease of blood glucose levels in patients with type 2 diabetes mellitus 
(T2DM).
1.1
MEDICAL BACKGROUND
T2DM is a chronic metabolic disease defined by elevated glucose levels that is associated 
with an increased risk for acute and/or late complications related to the micro- and 
macrovascular circulation. For instance, T2DM is the leading cause for end stage renal 
disease (ESRD) worldwide and a major cause of new cases of blindness and visual 
impairment. The elevated risk for macrovascular disease is primarily related to increased risk 
for athero-thrombosis that leads to increased morbidity and premature mortality from 
cardiovascular (CV) disease [R10-0116, P08-06509] and an important predictor for CV 
diseases is chronic kidney disease (CKD) which often co-exist. Studies suggest that 70-75% 
of all deaths in people with diabetes can be attributed to CV complications [R10-0117]. 
Strategies for glycaemic management of T2DM; guidelines and limitations                             
Patients with T2DM are usually treated by combinations of lifestyle and pharmacological 
interventions and several international guidelines for the treatment of T2DM have been 
issued [R07-1076, P10-00533, R09-1164, R09-6397, R08-1310, R10-4077, P08-01788]. Most 
guidelines suggest that the therapeutic goal for glycosylated haemoglobin (HbA1c) should be 
6.5-7.0%, which by the use of available tools seem hard to obtain after more than 5-10 years 
of diabetes duration. A survey in the US (National Health and Nutrition Examination Survey 
[NHANES] 2003-2004) found that only 57% of participants had HbA1c < 7.0% [R10-0133].
Poor control was also noted among the 7000 individuals with T2DM in the Cost of Diabetes 
in Europe – Type 2 study where only 31% achieved the < 6.5% HbA1c goal for HbA1c [R10-
0134]. Reasons for this are, amongst other factors, related to a progressive failure of the 
pancreatic ß-cells to compensate for an endogenous insulin resistance by an adequately 
increased insulin secretion, and the lack of treatment with sustainable effects. Ample 
evidence tells that lifestyle modification alone, or oral monotherapy, are not sufficient to 
maintain target levels of glycaemic control in most patients over time. In guidance for the 
clinician on which pharmacological compounds to use to achieve glycaemic goals amongst 
patients with T2DM the international guidelines differs slightly [R07-1076, P10-00533, R09-
1164, R09-6397, R08-1310, R10-4077, P08-01788]. In general however, all bodies 
recommend that metformin should be first line treatment. Despite some limitations, this 
compound is the most widely used with a good safety profile, with some evidence suggesting
cardio protective properties [R09-6405, R09-6406], and without associated cardiotoxicity. 
Most other drugs on the market lack such documentation. 
As a second line treatment, because of the progressive loss of ß-cell function in patients with 
T2DM, traditional insulin secretagogues such as the sulfonylurea’s (SUs) that stimulate 
insulin secretion in a non-glucose-dependent manner are widely used; in fact, they are the 
most commonly used second line therapy. However, treatment with SUs carries an increased 
risk for hypoglycaemia and weight gain [R09-6400], and as is the case for metformin, are


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also associated with a lack of sustainable effect [R09-6400]. Therefore, international 
treatment guidelines have endorsed use of other drugs, e.g. insulins, glitazones, glinides and 
alpha-glucosidase inhibitors, to be used as 2nd line or 3rd line in certain settings. However, 
most of these drugs also have side effects that limit their use, such as hypoglycaemia, weight 
gain, gastrointestinal (GI) side effects and peripheral oedema. In addition to morbidity 
associated with each of these side effects, they could also have adverse CV implications.
Hypoglycaemia and weight gain were recently postulated as contributors to the adverse 
mortality outcomes in the “Action to Control Cardiovascular Risk in Diabetes” (ACCORD) 
trial [R09-6407]. In addition, serious hypoglycaemia was the 2nd strongest predictor for 
incident myocardial infarction (MI) in the Veterans Affairs Diabetes trial (VADT)[R09-
6408]. 
Since CV risk signals with drugs to treat T2DM have historically been observed at relatively 
late stages, just before or even after the drugs have reached the market, regulatory authorities 
such as the US Food and Drugs Administration (FDA) have issued a guidance to industry in 
order to rule out potential excessive CV morbidity and mortality associated with all new 
drugs for the treatment of T2DM [R09-2151]. Such an assessment could involve dedicated 
trials. It is therefore of interest to explore novel treatment options that offer glycaemic 
reduction without an associated increased CV risk. 
Of note is that data from recent years indicates a decrease in the age-specific mortality rates 
due to CV diseases (although the increased relative CV risk between subjects with T2DM and 
without still is high and increased 2-4 fold), a reduction in renal complications seems not to 
occur. Establishing treatment options for T2DM that potentially not only reduce overall 
glycaemic burden, but also potentially could address current unmet medical need in 
prevention and/or treatment of macro-/microvascular complications could therefore have 
huge implications for T2DM patient care as there currently are insufficient and low-quality 
evidence on the effectiveness of individual oral antidiabetic drugs (OADs) on the 
development or progression of CV complications and nephropathy, as underscored also in the 
recent systematic review on the ‘Comparative Effectiveness and Safety of Oral Diabetes
Medications for Adults with Type 2 Diabetes’, sponsored by the Agency for Healthcare 
Research and Quality [R11-4860].
Emerging treatment for T2DM; DPP- 4 inhibitors                                                               
The incretin effect is a phenomenon where glucose-dependent insulin secretion is augmented 
by intestinally derived peptides (i.e. incretins) that are released in the presence of glucose or 
nutrients in the gut and thereby contribute to the maintenance of long term and post-meal 
glycaemic control in a glucose-dependent manner. Glucagon-like peptide 1 (GLP-1) is an 
important member of the incretin hormone family, and together with glucose-dependent 
insulinotropic peptide (GIP), accounts for more than 50% of the incretin effect in humans 
[R09-6409]. These hormones are almost instantaneously inactivated by the enzyme DPP-4.
DPP-4 is widely expressed in many tissues including kidney, liver, intestine, lymphocytes 
and vascular endothelial cells. Since postprandial GLP-1 secretion has been reported to be 
attenuated in T2DM [R09-6409], a prolongation of the half life of GLP-1 by DPP-4
inhibition has been proven as a therapeutic target to improve glycaemic control in patients 
with T2DM. Besides its stimulatory effects on insulin secretion dependent on the actual 


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plasma glucose concentration [R09-6409], resulting in a reduction of HbA1c, GLP-1 has also 
been shown to inhibit glucagon secretion, to delay gastric emptying, to induce satiety, to 
affect weight loss, and, in animal models, to maintain long-term ß-cell function. The potential 
benefit of maintenance of ß-cell function is of particular interest, that if also the case in 
humans, would represent an important clinical finding. However, no long term studies in 
humans have confirmed this. An added interesting feature of this therapeutic option is that it 
seems to be associated with no weight gain and a very low risk of hypoglycaemia.
Study proposal                                                                                                                             
In this large-scale intervention trial we will test the impact of treatment with the DPP-4
inhibitor linagliptin head-to-head versus placebo on long-term CV safety as well as the 
potential preventive impact on CV and renal complications. The study will be given the 
acronym CARMELINA (CArdiovascular Safety & Renal Microvascular outcomE with 
LINAgliptin in patients with type 2 diabetes mellitus at high vascular risk).
1.2
DRUG PROFILE
The DPP-4 inhibitor compound linagliptin was discovered by Boehringer Ingelheim Pharma 
GmbH & Co. KG, Germany.
Linagliptin is a potent inhibitor of DPP-4 activity and prolongs the half-life of GLP-1. This 
has been shown in vitro, in various animal models, and in clinical trials. Linagliptin is an 
orally available compound with a low risk for hypoglycaemic episodes [U04-1767].
In general pharmacological tests, linagliptin exhibited good tolerability in a variety of 
physiological systems. No genotoxic effect was observed in any of the tests performed with 
linagliptin or with its major metabolite CD 1790. The single dose (acute) toxicity of 
linagliptin after oral administration was low as indicated by an Approximate Lethal Dose 
(ALD50) between 1000 and 2000 mg/kg. In repeat dose toxicity studies, a wide margin of
safety was demonstrated. This was also true with respect to exposure to the major metabolite 
CD 1750.
Linagliptin shows nonlinear pharmacokinetics, both after oral and intravenous administration 
in the therapeutic dose range, with a less than dose-proportional increase in plasma 
concentrations. After oral administration of a 5 mg dose, linagliptin is rapidly absorbed, with 
peak plasma concentrations (median Tmax) occurring approximately 1.5 hours post dose.
Clearance, volume of distribution, and amount excreted unchanged in urine increase with 
increasing doses, which may be a result of nonlinear protein binding in the therapeutic 
plasma concentration range. Linagliptin is predominantly excreted unchanged in faeces. 
Renal excretion is considered to be a minor elimination pathway of linagliptin at therapeutic 
dose levels.
The long terminal half-life of >100 hours does not reflect the effective half-life, as steady 
state is reached within 2-7 days. Time to steady state decreases dose-dependently from 4-7 


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days to 2 days for once daily dosing of 1-10 mg linagliptin. The accumulation factors of Cmax
and AUC range from 1.2-2 upon multiple dosing.
No adjustment of linagliptin dosage based on the intrinsic factors age, BMI, weight, gender
or race is considered necessary. Linagliptin showed no clinically relevant interaction with 
either the CYP 3A4 substrate simvastatin, with metformin, pioglitazone, glyburide, or 
empagliflozin (BI 10773). After strong inhibition of P-gp and CYP 3A4 by ritonavir 
linagliptin AUC and Cmax increased approximately twofold and threefold, respectively. 
Since linagliptin has a large safety window and no obvious change in the safety profile was 
seen under concomitant administration of P-gp and/or CYP3A4 inhibitors in phase II and III, 
these changes are considered to be not clinically relevant.
There is no effect of food on the extent of absorption. Only the rate of absorption was slightly
reduced (median Tmax increased from 1.02 to 2.99 hours and Cmax reduced by about 15%)
when linagliptin was given with food, which was considered to be of no clinical relevance.
No dose adjustment of linagliptin in patients with any degree of hepatic or renal impairment
is suggested as the pharmacokinetics of linagliptin did not relevantly change with decreasing
hepatic function and the exposure changes seen at steady state in patients decreased renal
function are considered as not clinically relevant.
In all trials to date in patients with T2DM, more than 5955 patients have received linagliptin 
5 mg. Inhibition of DPP-4 activity by linagliptin also translated into an increase in plasma 
GLP-1 levels. In addition, linagliptin exhibited excellent tolerability at all dose levels in 
phase II studies with an absence of a dose dependent increase in adverse events. 
In phase II and III clinical trials in patients with T2DM, the overall incidence of adverse 
events (AEs) with linagliptin 5 mg was comparable to placebo (linagliptin 5 mg: 52.5%, 
placebo: 51.6%). In addition, the number of patients with AEs leading to discontinuation of 
trial drug (linagliptin 5 mg: 2.3%, placebo: 2.8%) and with investigator defined drug-related 
AEs (linagliptin 5 mg: 8.3%, placebo: 9.1%) did not differ significantly between linagliptin 
and placebo. 
The most frequently reported adverse events (≥ 5%) in both treatment groups were 
nasopharyngitis (4.7% placebo, 5.9% linagliptin 5 mg), hyperglycaemia (10.6% placebo, 
5.1% linagliptin 5 mg) and hypoglycaemia (5.1% placebo and 7.8% linagliptin 5 mg)
The increased incidence of hypoglycaemia observed in the phase II and III studies nearly 
exclusively came from trial 1218.18 where linagliptin was added to a background therapy of 
metformin and SU where hypoglycemia rates after 24 weeks were observed to be 14.8% for 
placebo, and 22.8% for linagliptin 5 mg. When linagliptin was administered as monotherapy 
there was no difference between the placebo group and linagliptin with regard to the 
occurrence of ‘hypoglycaemia’. Also the addition of linagliptin to a metformin background 
did not appear to increase the frequency of hypoglycaemia.
The incidence of serious adverse events (SAEs) in the phase II and III studies was 3.1% in 
patients treated with linagliptin 5 mg and 3.8% in patients treated with placebo. 
Consistency of efficacy of linagliptin 5 mg has been shown in a number of phase III double 


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blind placebo-controlled efficacy trials, in reduction of HbA1c, fasting plasma glucose
(FPG), postprandial plasma glucose etc. These trials have tested linagliptin as monotherapy, 
on a background of metformin, and as add-on therapy to metformin plus SU and initial 
combination with metformin in the factorial design trial. 
For further information about the drug profile of linagliptin, please refer to EU SPC or US-PI, 
or another regulatory label document.
Clinical Pharmacokinetics
In earlier PK trials, linagliptin showed nonlinear PK in the therapeutic dose range, with 
a less than dose proportional increase in plasma concentrations. Clearance, volume of 
distribution, and amount excreted unchanged in urine increased with increasing doses, 
possibly due to nonlinear protein binding. Linagliptin was predominantly excreted 
unchanged in faeces. Renal excretion was considered to be a minor elimination 
pathway. No dose adjustment of linagliptin based on hepatic impairment, renal 
impairment, age, body mass index (BMI), weight, gender, or race is considered 
necessary. Linagliptin showed no clinically relevant interaction with metformin, 
pioglitazone, glyburide or empagliflozin.
Clinical efficacy and safety
Treatment with 5 mg linagliptin once daily has resulted in clinically meaningful and 
statistically significant reductions in HbA1c, FPG, and postprandial glucose. There is a 
consistent pattern in the improvement in HbA1c levels when linagliptin was used in 
patients with different background therapies. These findings demonstrate efficacy for 
up to 18 to 24 weeks duration for different background therapies and are further 
supported by trials of longer duration up to 104 weeks.
Overall, in phase III studies the overall incidence of adverse events (AEs), drug related 
AEs, AEs of severe intensity, AEs leading to discontinuation, and serious AEs (Serious 
Adverse Event, SAEs) were very similar across studies, with linagliptin being mostly 
comparable with placebo. For description of side effects of linagliptin refer to the 
current Investigator’s Brochure [U04-1767] and the local prescribing information for 
linagliptin.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
The aim of the present study is to investigate the long–term impact on CV morbidity and 
mortality of treatment with linagliptin in a selected population of patients with T2DM and 
compare outcomes against placebo, on a background of standard of care. To date, this has not 
been tested in long-term trials of linagliptin. Since this is the case for other DPP-4 inhibitors
approved for the treatment of T2DM, several long-term studies are presently ongoing. There 
are currently no safety signals that indicate that linagliptin should be inferior to placebo with 
respect to CV safety [P12-00933]. A recent meta-analysis of the marketed DPP-4 inhibitors,
on the contrary, indicates actually a potential beneficial CV effect of DPP-4 inhibitors as a 
class, although this meta-analysis mainly included trials of shorter duration with patients who 
were not at a particular high CV risk, limiting the findings to hypothesis generation [R09-
6410]; thus this requires further studies.
The rationale to assess microvascular outcomes, in particular renal safety with the aim of 
demonstrating renal benefits, is derived from the hypothesis based on pre-clinical and limited 
clinical data, that GLP-1 based therapies, and in particular linagliptin, may have a direct 
impact on the integrity of the endothelium and podocytes of the glomerula and the proximal 
tubular cells as well as endothelial function and last, that linagliptin has a relatively high 
tissue distribution, including in the kidney, albeit all these features currently remains to be 
demonstrated.
As the study population of this trial are patients with high CV risk, all with various degrees of 
end-organ damage (i.e., renal impairment) it is conceivable that the study will include 
patients at all stages of T2DM duration since in fact many patients are being diagnosed with 
T2DM for the first time at the occasion of a CV event [R12-1135]. Therefore, antidiabetic 
treatment naïve, as well as patients with all kind of approved background antidiabetic 
treatment (including insulins) are eligible. The only exceptions are patients on DPP-4 
inhibitors and/or GLP-1 receptor agonists and/or sodium glucose linked transporter (SGLT-2)
inhibitors. Taking into consideration linagliptins mode of action, there is not an option in this 
trial to combine study drug (i.e., placebo or linagliptin) with a GLP-1 receptor analogue as 
the DPP4 inhibitor and GLP1 receptor analogue combination is not approved or indicated 
(per label of all GLP-1 products and DPP4 inhibitors). Also concomitant use of an SGLT-2 
inhibitor is not allowed since this is a new class of drug that is and hithereto undescribed in 
terms of CV benefit-risk ratio in order to reduce complexity of interpretation of study 
outcome. Further, as this trial would like to address the impact on CV outcomes of linagliptin 
compared to placebo in a high CV risk population, some with high degree of renal 
impairment, where most likely the use of SGLT-2 inhibitors will be restricted, SGLT-2 
inhibitors would only be an applicable therapy for a subset of the study cohort.
The study has two arms: linagliptin or placebo as add-on to antidiabetic treatment naive 
patients or other allowed antidiabetic treatments. The study design is described in more detail 
in Section 3.1.


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The planned eligibility criteria will hence target a trial population with a short to long T2DM 
duration with a high CV risk (e.g., due to previous macrovascular disease and albuminuria 
(micro or macro) and/or renal impairment and predefined urine albumin creatinine ratio 
[UACR]). Thereby, it will assess the CV safety profile of linagliptin as compared with 
placebo in a broad (> 50% of patients with T2DM and CV complications are assumed to have 
some degree of renal impairment and some others > 20% have renal impairment alone) and 
relevant population of patients with T2DM. This study design therefore concurs with the 
recent FDA guidance for target populations in whom to specifically assess CV safety of novel 
OADs for the treatment of T2DM [R09-2151]. This study will also be an integral part of the 
ongoing CV safety assessment for linagliptin and data will be used to support regulatory 
submission.
 
Functional assessment of post-stroke 
recovery outcome of linagliptin versus placebo when provided on top of standard of care will 
also be evaluated using a simple one-tick box questionnaire (Rankin modified test scale), 
which could further advance our understanding of important issues in the management of 
patients with T2DM (Section 5.3.2). 
2.2
TRIAL OBJECTIVES
The primary objective is to demonstrate non-inferiority (by means of comparing the upper 
limit of a two-sided 95% confidence interval with the non-inferiority margin of 1.3) of 
treatment with linagliptin in comparison with placebo (as add-on therapy on top of standard 
of care) with respect to time to first occurrence of any of the adjudicated components of the 
primary composite endpoint (i.e. CV death [including fatal stroke, fatal MI and sudden 
death], non-fatal stroke or non-fatal MI (excluding silent MI) and hospitalisation for unstable 
angina pectoris) in patients with T2DM. 
If non-inferiority has been demonstrated, then the primary composite endpoint will be tested 
for superiority and the other objective, to assess the impact of treatment with respect to the 
first occurrence of any of the adjudicated components of the composite renal endpoint
(i.e. renal death, sustained ESRD, sustained loss in estimated glomerular filtration rate 
(eGFR) ≥50 40% from baseline), will be investigated with a test on superiority.
The CV and renal superiority tests will be performed separately, with no an upfront 
imbalance regarding the assigned alpha-levels.
If linagliptin is superior with regard to the primary endpoint and/or the composite renal 
endpoint, a further test will evaluate the superiority of linagliptin with regard to the 3-
component Major Adverse Cardiovascular Events (MACE) endpoint (CV death [including 
fatal stroke, fatal MI and sudden death], non-fatal stroke, non-fatal MI [excluding silent MI]).
For a description of the endpoints chosen and statistical analyses to assess these objectives, 
please refer to Section 5 and Section 7.


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2.3
BENEFIT - RISK ASSESSMENT
Potential general benefits for study participants in this trial irrespective of investigational 
drug received are 1) improvements in glycaemic control, 2) improvements of other CV risk 
factors and 3) general medical benefit from careful and close monitoring by medical 
personnel and home blood glucose monitoring during the study. 
General risks associated with participating are 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 associated with any discomfort for 
the patients. 
Investigational drug specific risk 
Linagliptin from its clinical phase III testing has shown a safety profile similar to placebo. It 
carries a low risk for inducing hypoglycaemia and is generally weight neutral. Safety will be 
ensured by monitoring the patients for 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. Given the large safety margin derived from the toxicology studies, the wide 
therapeutic window of linagliptin (120-fold recommended clinical dose), the high tolerability 
observed in previous trials in subjects with T2DM, and the monitoring throughout the trial 
the sponsor is of the opinion that the risks for the participating patients are minimal and 
justified.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This randomized, double-blind, and placebo controlled study compares treatment with 
linagliptin (5 mg once daily) with placebo treatment (matching tablets once daily) as add-on 
therapy to standard of care background antidiabetic treatment as specified in Section 3.3.2.
The trial is event driven and will run until 625 611 patients with a by adjudication confirmed 
primary endpoint event are observed (Section 7.6), with an estimated 8300 7000 randomized 
patients to be observed for an estimated study duration of 48 54 months, beginning with the 
randomization of the first patient. The anticipated recruitment period is 36 months. In case
the number of primary endpoint events is not or may not be reached within this period the 
trial duration and/or the number of patients will be increased until the defined number of 
adjudicated primary endpoint events is reached.
Figure 3.1: 1 Treatment periods and treatment groups in the trial design
For all patients, site visits are scheduled at regular time intervals (see flow chart). The 
estimated treatment duration for the first randomized patient is 48 54 months. The number of 
confirmed adjudicated primary endpoint events will be continuously monitored during the 
trial. Based on the available number of events the projected number of expected future events 
will be calculated. As soon as the projection reliably suggests that the total number of patients 
with a by adjudication confirmed primary endpoint event will reach 625 611 within the next 
24 weeks, the trial team will perform respective actions to stop the trial. From this time point 
on, all patients are expected to perform their last visit (EOT visit) within the regular
proposed time schedule, which means within the next 24 weeks communicated via an 
investigator letter.
The End of Treatment visit (EOT) activities will be performed when a patient discontinues 
study medication treatment permanently. The EOT activities are not required for temporary 
interruptions of study drug. All patients will have a follow up visit one week 30 days
following discontinuation of study drug, irrespective whether they complete the treatment 
period or pre-maturely discontinue study treatment. Patients who discontinue study drug 
prematurely should continue study visits until study end. Study assessments may be omitted 
Screening
R
Estimated 48 54 months treatment phase (until 
625 611 patients with a by adjudication 
confirmed primary CV endpoint event)
Matching placebo
Linagliptin 5 mg 
+ 30 days FU


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if a patient is willing to return to the pre-defined study visits, with exception of 
 
 collection of adverse events, outcome events, concomitant therapy and 
laboratory testing of creatinine for the calculation of the eGFR.
If a patient who prematurely discontinued study drug is not willing to return to the pre-
defined study visits, at minimum a yearly telephone call (preferably every 6 months) and a 
telephone call at study end will be required, to document the occurrence of outcome events 
and vital status. If possible, other AE’s and concomitant therapy changes since last visit 
might be recorded. Every attempt will be made by the investigator to ensure patients continue 
participating in the study during study drug interruptions and after discontinuation of study 
drug. The ITT analysis requires that all study patients be followed until study end even if the 
study drug was temporarily interrupted or discontinued.
Patients will have a follow up visit one week 30 days following regular or premature 
completion of the treatment period. The follow-up visit may be performed as a phone visit for
patients who did not prematurely discontinue study medication and who do not have 
abnormalities at the EOT visit (only AEs/outcome events and changes in concomitant therapy 
to be obtained).
In case early study termination is to be performed (e.g. based on recommendation by the Data 
Monitoring Committee [DMC]), a reasonable timeframe to stop the trial (perform last patient 
visits) will be defined and communicated to the investigators. 
3.1.1
Administrative structure of the trial
The study is sponsored by Boehringer Ingelheim (BI). 
Co-ordinating Investigators who will (co) chair the Steering Committee (SC) will be 
nominated. 
Documents on principal investigators and other important participants at each site, especially 
their curricula vitae, will be filed in the Clinical Trial Master File (CTMF). 
CRO’s will be assigned for central laboratory, interactive response technology (IRT), ECG 
analyses and conduct of the trial.
The following committees will participate in the conduct of the trial, their specific functions 
are summarised below:
Steering Committee
A SC will have a scientific and clinical advisory function in the study. The SC is comprised 
of university- and sponsor-based scientists with clinical and methodological expertise. Details 
on the composition of the committee, its procedures and interactions are provided in a 
separate SC Charter.


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Data Monitoring Committee
An independent DMC will review safety and efficacy data and will make recommendations 
whether to continue or terminate the study. The DMC analyses and operations will be 
formally separated from the sponsor, the investigators, and the SC. Details on the 
composition of the committee, its procedures and interactions are provided in a separate 
DMC Charter.
Clinical Event Committee 
The study is set up with prospective centralized blinded adjudication of all 
cardio/cerebrovascular trigger events. The prospectively defined adjudication process will 
assess cardiac and neurological vascular events through an independent, blinded, external 
Clinical Event Committee (CEC). Details on the composition of the committee, its 
procedures and interactions are provided in a separate CEC charter.
Additionally, separate independent, blinded, external committees will be set up for 
adjudication of renal events and pancreatic events. The adjudication process for renal events
and pancreatic events will be clarified in a separate the CEC charter.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A wide variety of antidiabetic medications are available for the treatment of T2DM, but it is 
unclear how these drugs compare with respect to long term CV risk and microvascular 
outcomes [R11-4860]. The aim of this study is to have patients with T2DM on various 
antidiabetic background therapies represented to evaluate the long term CV and 
microvascular safety of linagliptin in a real life clinical setting.
The placebo-controlled design is considered ethically acceptable on the basis of appropriate 
criteria for patient discontinuation, ability to change background treatment to maintain, or 
obtain, sufficient level of glycaemic control as defined in relevant local and regional 
guidelines for optimized standard of care. 
The treatment period is planned until the necessary number of by adjudication confirmed 
primary endpoint events is observed, to demonstrate non-inferiority of linagliptin compared 
to placebo when added on to standard of care.
Treatment with linagliptin will be compared against placebo. The treatment goal for HbA1c  
in this trial, according to most international guidelines, will be a target of ≤ 7.0%, using open-
label titration and addition of non-study therapies in both arms to achieve this goal 
throughout the trial. During the trial, additional therapy will be allowed, and encouraged, if 
HbA1c  > 7.5 % during the trial treatment phase in accordance with guidelines. This is 
considered important to ensure that an optimal level of standard of care is reached in both 
arms of the trial. However, the decision to titrate or initiate medication to optimize glycaemic 
control will remain with the investigator and the patients’ health care providers in accordance
with appropriate local treatment guidelines.


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The protocol also encourages the investigators and the patients’ health care providers to treat 
all other CV risk factors (e.g. lipid levels, blood pressure, albuminuria, unhealthy lifestyle, 
smoking) according to an optimal level of local/regional standard of care. In a high CV risk 
population with renal impairment (i.e., albuminuria or eGFR [modification of diet in renal 
disease (MDRD) formula] 15-75 mL/min/1.73 m2), this usually implies liberal use (if 
tolerated or not contraindicated) of statins, beta-blockers, calcium channel blockers, platelet 
inhibitors etc. This should be conducted in the context of local or regional guidance for 
primary or secondary CV risk prevention. 
As in management of any patient with diabetic nephropathy and hypertension, the 
investigator may consider referral to a physician experienced in the care of kidney disease 
and hypertension for uncertainty about treatment. In particular it is expected that the patients 
at least are treated with either an angiotensin converting enzyme inhibitor (ACEi) or 
angiotensin receptor blocker (ARB) therapy (if one class is not tolerated, the other should be 
substituted) and that the target blood pressure (BP) goal is < 130/80 mmHg. When ACE 
inhibitors, ARBs, or diuretics are used, additional monitoring apart from the 24 week
assessments in the protocol of serum creatinine, is at the investigators discretion. 
The background medication will not be provided as part of the clinical trial supplies, unless 
required by local laws and regulations. The investigator can adjust the antihypertensive 
therapy, or other needed therapy, according to local and international recommendations, if 
better BP control is warranted during the course of the trial.
3.3
SELECTION OF TRIAL POPULATION
An appropriate number of patients will be screened (synonym enrolled) for the trial in 
approximately 600 study centres in up to 35 countries to ensure that an estimated 8300 7000
patients are randomized (4150 3500 to each treatment group) and evaluable. Investigators 
who fail to randomize at least one study subject in the first 12 weeks of the trial may be 
excluded from further participation. If enrolment is delayed, additional centres may be 
initiated.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
centres when a sufficient number of patients have been randomized to trial treatment. 
Investigators will be notified when screening is complete and will not be allowed to recruit 
additional patients thereafter. Patients who have completed visit 1 procedures prior to 
notification of the termination of recruitment will be allowed to be randomized in the study, if 
they meet all eligibility criteria. Subject eligibility will be based upon a complete medical 
history including a physical examination and clinical laboratory tests. Judgement of the 
clinical relevance of a concomitant disease is at the discretion of the investigator. 
Re-screening and/or re-testing (of assessments) is permitted once.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the investigator site file (ISF) at the investigational site irrespective of whether 
they have been treated with investigational drug or not.


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3.3.1
Main diagnosis for study entry 
Patients with documented diagnosis of T2DM at high risk of CV events and meeting all other 
eligibility criteria can be enrolled in the study. 
3.3.2
Inclusion criteria
1) Documented diagnosis of T2DM before visit 1 (screening).
2) Male or female patients who are drug-naïve or pre-treated with any antidiabetic 
background therapy, excluding treatment with GLP-1 receptor agonists, DPP-4 inhibitors 
or SGLT-2 inhibitors if ≥ 7 consecutive days. 
3) Stable antidiabetic background medication (unchanged daily dose) for at least 8 weeks 
prior to randomization.  If insulin is part of the background therapy, the average daily 
insulin dose should not have been changed by more than 10% within the 8 weeks prior to 
randomization compared with the daily insulin dose at randomization.
4) HbA1c of ≥6.5% and ≤10.0% at visit 1 (screening).
5) Age ≥18 years at visit 1 (screening). For Japan only: Age ≥20 years at Visit 1.
6) Body Mass Index (BMI) 45 kg/m2 at visit 1 (screening).
7) Signed and dated written informed consent by date of visit 1 (screening) in accordance 
with GCP and local legislation prior to any study related procedure.
8) High risk of CV events (I and/or II):
I.
Albuminuria (UACR ≥ 30 mg/g creatinine or ≥ 30 µg/min [microgram albumin per 
minute] or ≥ 30 mg/24 h [milligram albumin per 24 hours] in two out of three 
unrelated spot urine or timed samples in the last 24 months prior to randomization)* 
AND previous macrovascular disease, defined as either one or more:
a
Confirmed history of MI (> 2 months prior to Visit 1) 
b
Advanced coronary artery disease, defined by any one of the following:

≥ 50% narrowing of the luminal diameter in 2 or more major coronary arteries by 
coronary angiography, MRI angiography or CT angiography;
Definition of major coronary arteries: LAD (Left Anterior Descending). CX 
(Circumflex) or RCA (right coronary artery) 

Left main stem coronary artery with ≥ 50% narrowing of the luminal diameter by 
coronary angiography, MRI angiography or CT angiography;

Prior percutaneous or surgical revascularization of 2 major coronary arteries at 
least 2 months prior to Visit 1 (screening);

The combination of prior percutaneous or surgical revascularization of 1 major 
coronary artery at least 2 months prior to visit 1 (screening), and ≥ 50% narrowing 
of the luminal diameter by coronary angiography, MRI angiography or CT 
angiography of at least 1 additional major coronary artery.


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c
High-risk single-vessel coronary artery disease, defined as the presence of 50% 
narrowing of the luminal diameter of one major coronary artery by coronary angiography,
MRI angiography or CT angiography in patients not revascularised:
AND at least one of the following: 

A positive non invasive stress test, confirmed by either:
o
a positive ECG exercise tolerance test in patients without left bundle 
branch block, Wolff-Parkinson-White syndrome, left ventricular 
hypertrophy with repolarization abnormality, or paced ventricular rhythm, 
atrial fibrillation in case of abnormal ST-T segments; 
o
a positive stress echocardiogram showing induced regional systolic wall 
motion abnormalities;
o
a positive nuclear myocardial perfusion imaging stress test showing stress-
induced reversible perfusion abnormality; 
o
a positive cardiac stress perfusion MRI showing a stress induced perfusion 
defect;

Patient discharged from hospital with a documented diagnosis of unstable angina 
pectoris between 2 and 12 months prior to visit 1 (screening).
d
History of ischemic or haemorrhagic stroke (>3 months prior to visit 1)
e
Presence of carotid artery disease (symptomatic or not) documented by either:
o
imaging techniques with at least one lesion estimated to be ≥50% 
narrowing of the luminal diameter;
o
prior percutaneous or surgical carotid revascularization.
f
Presence of peripheral artery disease documented by either:
o
previous limb angioplasty, stenting or bypass surgery; 
o
previous limb or foot amputation due to macrocirculatory insufficiency; 
o
angiographic evidence of peripheral artery stenosis 50% narrowing of the 
luminal diameter in at least one limb (definition of peripheral artery: 
common iliac artery, internal iliac artery, external iliac artery, femoral 
artery, popliteal artery).
II.
Evidence of impaired renal function with predefined UACR, with or without CV co-
morbidities, defined as follows (and/or criteria):

Impaired renal function (as defined by MDRD formula) with an eGFR:15- <45 
mL/min/1.73 m2 at visit 1 (screening) with any UACR. 

Impaired renal function (as defined by MDRD formula) with an eGFR ≥45-75 
mL/min/1.73 m2 at visit 1 (screening) with an UACR > 200 mg/g creatinine or 
> 200 µg/min (microgram albumin per minute) or > 200 mg/24 h [milligram 
albumin per 24 hours] demonstrated in two out of three unrelated spot urine or 
timed samples in the last 24 months prior to randomization*.


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*If the UACR result at Visit 2 is required to fulfil inclusion criterion 8, randomization may be 
postponed until the laboratory results are known.
Note: To ensure appropriate representation of patients from the different CV risk categories, 
the trial team will monitor the proportion of patients being recruited into these categories 
(trial level, and by region and/or country if appropriate). In consultation with the SC, 
limitation of recruitment of a particular category may be arranged (trial level, or per region 
and/or country level). This process will be implemented to ensure a proper distribution of CV 
risk categories worldwide. 
3.3.3
Exclusion criteria
1) Type 1 diabetes mellitus.
2) Treatment (≥ 7 consecutive days) with GLP-1 receptor agonists, other DPP-4 inhibitors or 
SGLT-2 inhibitors prior to informed consent. Note: This also includes clinical trials 
where these antidiabetic drugs have been provided to the patient. 
3) Active liver disease or impaired hepatic function, defined by serum levels of either ALT 
(SGPT), AST (SGOT), or alkaline phosphatase (AP) ≥3 x upper limit of normal (ULN) as 
determined at Visit 1.
4) eGFR <15 ml/min/1.73 m2 (severe renal impairment or ESRD, MDRD formula), as 
determined during screening at Visit 1 and/or the need for maintenance dialysis.
5) Any previous (or planned within next 12 months) bariatric surgery (open or laparoscopic) 
or intervention (gastric sleeve).
6) Pre-planned coronary artery re-vascularisation (PCI, CABG) or any previous PCI and/or 
CABG ≤ 2 months prior informed consent
7) Known hypersensitivity or allergy to the investigational products or its excipients.
8) Any previous or current alcohol or drug abuse that would interfere with trial participation
in the opinion of the investigator.
9) Participation in another trial with an investigational drug ongoing or within 2 months 
prior to visit 1 (screening)*.
10) Pre-menopausal women (last menstruation 1 year prior to informed consent) who:
- are nursing or pregnant,
- or are of child-bearing potential and are not practicing an acceptable method of birth 
control (acceptable methods of birth control include tubal ligation, transdermal patch, 
intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, 
sexual abstinence (if allowed by local authorities), double barrier method and
vasectomised partner) or do not plan to continue using acceptable method of birth control
throughout the study and do not agree to submit to periodic pregnancy testing during 
participation in the trial.
11) Patients considered unreliable by the investigator concerning the requirements for follow-
up during the study and/or compliance with study drug administration, have a life 
expectancy less than 5 years for non-CV causes, or have cancer other than non-melanoma 


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skin cancer within last 3 years, or has any other condition than mentioned which in the 
opinion of the investigator, would not allow safe participation in the study.
12) Acute coronary syndrome (ACS), diagnosed ≤ 2 months prior to visit 1 (screening).
13) Stroke or TIA ≤ 3 months prior to visit 1 (screening).
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
This is a long-term safety outcome study and every effort should be made by the site staff 
to encourage patients to remain in the study and on study drug if medically safe.
Patients who discontinue study drug prematurely should be observed until study end as if 
they were still receiving blinded study treatment. Patients who prematurely discontinue study 
drug should remain in the study. Study assessments may be omitted if a patient is willing to 
return to the pre-defined study visits, with exception of
, collection of 
adverse events, outcome events, concomitant therapy and laboratory testing of creatinine for 
the calculation of the eGFR. 
If a patient who prematurely discontinued study drug is not willing to return at the pre-
defined regular visit schedule, at minimum a yearly telephone call (preferably every 6 
months) and a telephone call at study end will be asked for required, to document the 
occurrence of outcome events and vital status. If possible, also other AE’s and concomitant 
therapy changes since last visit might should be recorded. Every attempt will be made by the 
investigator to ensure patients continue participating in the study during study drug 
interruptions and after discontinuation of study drug.
Patients who prematurely discontinue study medication during the treatment phase are 
allowed to restart the study medication at any time if appropriate in the opinion of the 
investigator and if not contraindicated. In this study, patients are allowed to have multiple 
study drug interruptions. There is no limit on either the number of study drug interruptions or 
the maximum length of any study drug interruption. Investigators should routinely 
consider re-starting study drug at every visit following study drug discontinuation.
A patient should be instructed to stop the study drug only after discussion between 
sponsor representative and investigator, if eligibility criteria are being violated, or if the 
patient fails to comply with the protocol (e.g. non-attendance at study assessments).
Early discontinuation of study medication is not a criterion for withdrawal of consent 
for participating in the study.
If a patient becomes pregnant during the trial, the study treatment will be stopped, the patient 
will be followed up during the study and until birth or termination of the pregnancy (see 
further details in Section 5.2.2.2).
If pancreatitis is suspected, the study treatment should be stopped.  
An individual patient is to be withdrawn from the study and follow up assessments only if the 
patient actively withdraws consent, without the need to justify the decision.


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A patient has the right to withdraw informed consent for participation at any time for 
any reason.  However, withdrawal of consent from study participation should be very 
rare and unusual.  Because of this, the investigator should be involved in the discussions 
with the patient regarding a withdrawal of consent.  Additionally, the investigator 
should discuss the withdrawal of consent with the sponsor representative prior to 
stopping study participation.
Patients that are not actively taking study drug may be less motivated to adhere to the 
study visit schedule. Investigators and site staff should work to detect early signs of 
losing interest and readily present such patients (not actively taking study drug) with 
the following options to encourage continued participation: 
Option 1
Continue to attend regularly scheduled study visits at the site until the study ends
Option 2
Conduct all remaining study visits over the phone
Option 3
Discontinue participation in remaining study activities but permit collection of 
vital status and CV outcome events at minimum at the end of the study through 
the patient or alternative person designated by the patient (e.g., family, spouse, 
partner, legal representative, or physician) even if only by telephone
Option 4
Discontinue participation in remaining study activities but permit collection of 
vital status at minimum at the end of the trial through the patient, alternative 
person designated by the patient, or through review of patient’s medical 
information from alternative sources (e.g., doctor’s notes, hospital records, etc.)
Patients will be asked to choose the most rigorous form of follow-up that they are willing to 
comply with.
Patients who refuse all four of the above are considered to have fully withdrawn 
informed consent to participate in the study. A patient should be withdrawn from the 
study and all follow up assessments only if the patient refused all four options and 
withdraws informed consent, without the need to justify the decision. Where allowed,
patients should be followed-up for vital status.
If the patient withdraws informed consent for participation in the study, the study will end for 
that patient. The patient should stop taking study medication and should be asked to complete 
the EOT and follow-up procedures as described in the Flow Chart. Completing these 
procedures is strongly recommended for the patient’s safety. A patient could be instructed to 
stop the study treatment only after discussion between sponsor representative and 
investigator, if eligibility criteria are being violated, or if the patient fails to comply with the 
protocol (e.g. non-attendance at study assessments). Patients that withdraw informed 
consent or discontinue from the study after randomization will not be replaced.
If a patient is lost, every effort should be made by the Investigator and site staff to 
contact and locate the patient before the patient is declared lost to follow-up.  
Investigators and site staff should use every possible allowable means to locate patients 


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who have missed visits. The sponsor might involve third party vendor in compliance 
with local legislation. 
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 
3) Violation of good clinical practice (GCP), the clinical trial protocol (CTP), or the contract 
by a trial site or investigator, disturbing the appropriate conduct of the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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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(s)
The characteristics of the test products are below.
Substance:
Linagliptin (BI linagliptin)
Pharmaceutical form:
film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength:
5 mg
Route of administration:
p.o., once daily
Substance:
Placebo matching linagliptin 5 mg
Pharmaceutical form:
film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength:
-
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 randomized treatment period, treatment
assignment will be by means of a third-party phone/web-based randomization on visit 2.
Patient assignment to the treatment groups will be determined by a computer generated 
random sequence using IRT. Details are described in the manual for IRT procedures, which is 
available in the ISF. Details of the process of treatment allocation can be found in Section 
7.5.
The assigned medication number(s) will be entered in the electronic case record form 
(eCRF), and the corresponding medication kit(s) should be given to the patient. 
4.1.3
Selection of doses in the trial
The dose of 5 mg linagliptin was selected based on the results from previous dose finding 
studies and represents the approved dose for linagliptin.
4.1.4
Drug assignment and administration of doses for each patient
Patients will continue with their standard background antidiabetic therapy throughout the 
entire study with an unchanged dose unless medical emergencies or other plausible reasons 
(e.g. renal impairment, lactacidosis, heart failure, dose intolerance, hypoglycaemia or 
hyperglycaemia) necessitates changes (at the discretion of the investigator). In case of 
contrast exposure for investigation of coronary artery pathology or other vessel assessment, 
metformin is allowed to be temporally held according to regional/local guidelines.


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Therefore, during the treatment phase it is investigator judgement to change the background 
medication dose, as the background medication of the trial is standard of care treatment with 
hypoglycaemic targets as defined by guidelines. Medication for optimising glycaemic control 
could also be initiated provided protocol criteria are met (see section 4.2.1).
Sulphonylureas and insulin are known to cause hypoglycaemia. Therefore, caution is advised 
when linagliptin is used in combination with a sulphonylurea and/or insulin. A dose reduction 
of the sulphonylurea or insulin may be considered.
Medication will be dispensed in a double-blind-manner as either 5 mg linagliptin or matching 
placebo. IRT will allocate medication kit numbers at all study visits from visit 2 till study 
end. At visit 2 patients will receive one treatment box sufficient for 12 weeks treatment (plus 
one week reserve). As of visit 3 (till study end) patients will receive two medication boxes 
sufficient for 24 weeks treatment (plus two weeks reserve). The protocol allows a time 
window of +/- 7 days for visit 3 and +/- 14 days for all scheduled visits in the treatment 
period after visit 3. To ensure sufficient medication, visits after visit 3 should be scheduled 
within 182 days and visit 3 should take place no later than 91 days after visit 2.
The patients will be instructed to bring their home blood glucose monitoring (HBGM)
devices to each visit for measurement of fasted glucose.
Administration of the study medication is once daily. Patients should be instructed to take 
their trial medication with water. To ensure a dose interval of about 24 hours, the medication 
should be taken at the same time every day. 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. Study medication can be taken with or without food.
In some situations, it might be necessary to interrupt study medication temporarily. Patients 
are encouraged to re-start study treatment after an interruption if appropriate in the opinion of 
the investigator and if not contraindicated.
Patients should be instructed to be fasted and not to take their trial medication in the morning 
of visit days as they will be dosed whilst in the clinic. Patients who fail to do so should have 
the visit rescheduled as soon as possible, reminding the patient about the expectations at the 
study visit. Background and/or optimizing hypoglycaemic control medication will be taken as 
prescribed including visit days.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators and everyone involved in analyzing or with an interest in this double 
blind study will remain blinded with regard to the randomized treatment assignments until 
after database lock.
The randomization code will be kept secret by Clinical Trial Support up to database lock.
Refer to Section 4.1.5.2 for rules of breaking the code for an individual or for all patients in


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emergency situations.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions
(SUSARs), it may be necessary for a representative from Boehringer Ingelheim’s
Pharmacovigilance group to access the randomization code for individual patients 
during trial conduct. The access to the code will only be given to authorized
Pharmacovigilance representatives and not be shared further.
For Japan only: in this blinded trial, an emergency code break will be available to the
Investigator via the IRT system. This code break may only be accessed in emergency
situations when the identity of the trial drug must be known to the Investigator in order 
to provide appropriate medical treatment or if required to assure the safety of trial 
participants. Each site receives a manual from the IRT provider that contains 
instructions on how to unblind the treatment of a patient via the IRT (via 24-hour 
Emergency helpline). If the code break for a patient is accessed, the sponsor must be 
informed immediately. The reason for accessing the code break, together with the date, 
must be documented on the appropriate CRF page. In case third party needs to break 
the code, however, when the Investigator cannot be reached, the code can be opened by 
calling emergency code manager.
The DMC will have access to unblinded data, refer to Section 3.1 and Section 7.3.4. 
4.1.5.2
Procedures for emergency unblinding
In the event of a medical emergency that requires identification of an individual patient's 
treatment, investigators will be able to access this information via IRT. The monitor or the 
onsite monitor/CRA should be contacted immediately (preferably before unblinding takes 
place) and the reason for unblinding the patient’s treatment should be documented in the 
medical records. The patient could continue with study medication after unblinding.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. All study medication will be 
contained in medication boxes identified with the trial number and medication number. Each 
medication box will contain sufficient BI linagliptin tablets or matching placebo tablets for 
12 weeks treatment (plus one week reserve).
Trial drug will be supplied on a per visit basis. Supply will be managed by IRT.
Examples of the labels will be available in 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. All trial medication should be stored according to 
the storage conditions as specified on the label and in the original package. Patients should be 


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instructed not to remove the trial medication from the blisters until immediately prior to the 
time of intake to protect tablets from humidity and light. Patients will be reminded to keep 
the study drug out of the sight and reach of children.
A temperature log must be maintained at sites. If storage conditions are found to be outside 
the specific range, the monitor or designee, IRT and the BI clinical trial supply unit (CTSU)
must be contacted immediately in order to clarify whether the trial medication can still be 
used. 
4.1.8
Drug accountability
Drug supplies, which will be provided by the sponsor, must be kept in a secure, limited 
access storage area under the storage conditions defined by the sponsor. 
The investigator, pharmacist and/or investigational drug storage manager will receive the 
investigational drugs when all country specific required approvals are in place and all 
required country specific essential documents are in house e.g.:

approval of the study protocol by the independent review board (IRB) / ethics 
committee,

availability of a signed and dated clinical trial contract between the sponsor 
representative and the Head of Trial Centre,

approval/notification of the regulatory authority, e.g. competent authority,

availability of the curriculum vitae of the principal investigator,

availability of a signed and dated clinical trial protocol or immediately imminent 
signing of the clinical trial protocol,

if applicable: availability of the proof of a medical licence for the principal 
investigator, 

For USA: availability of Form 1572.
The investigator, pharmacist and/or investigational drug storage manager must maintain 
records of the product’s delivery to the trial site, the inventory at the site, the use by each 
patient, and the return to the sponsor or alternative disposition of unused product(s). 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and trial patients. The 
investigator, pharmacist and/or investigational drug storage manager will maintain records 
that document adequately that the patients were provided the doses specified by the CTP, 
plus kits assigned by IRT and reconcile all investigational product(s) received from the 
sponsor. At the time of return to the sponsor, the investigator, pharmacist and/or 
investigational drug storage manager must verify that all unused or partially used drug 
supplies have been returned by the clinical trial patient and that no remaining supplies are in 
the investigator’s possession.
The following text is only applicable for Japan:
The investigator / pharmacist / investigational drug storage manager will receive the


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investigational drugs delivered by the sponsor representative after IRB / ethics committee 
approval of the study and completion of a clinical trial contract between the sponsor
representative and the Head of Trial Centre.
The investigator / pharmacist / investigational drug storage manager should return the 
unused and collected investigational drugs (including the empty boxes) to the sponsor after
unblinding the trial.
In case investigational drugs are returned before unblinding of the trial, the investigator /
pharmacist / investigational drug storage manager should seal the opened box (excluding
empty boxes) for the patient, and before returning the unused and collected investigational
drugs (including the empty boxes) to the sponsor. When returning the investigational drugs, 
the investigator / pharmacist / investigational drug 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 investigational 
drugs.
Upon completion of the trial, the investigator / pharmacist / investigational storage manager
submits to the sponsor representative a copy of the investigational drug dispensing and 
return log. When submitting the copy, the investigator / pharmacist / investigational drug 
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
Glycaemic control, emergency procedures, and additional treatment(s)
The use of medication for optimization of glycaemic control as standard of care will be 
permitted in this trial. This medication can include all types of approved antidiabetic 
medication except for DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors. The 
dose of glycaemic optimization medication will be according to local labelling at the 
investigator’s discretion and in accordance with local/international guidelines. 
The use of medication for optimizing glycaemic control in case of hyperglycaemia is advised 
when during the treatment period:

the patient has a glucose level >180 mg/dl (>10.0 mmol/L) after an overnight fast;

the patient has an HbA1c > 7.5% (58 mmol/mol).
The above results for FPG should be confirmed, meaning that there is a minimum of two 
measurements on two different days.
The use of medication optimizing glycaemic control has to be taken in accordance with the 
prescribing information and will be recorded in the eCRF. Patients who have to be treated 
with other medication than specified in the protocol should discontinue study treatment, but 
will remain in the trial.


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Any additional treatment, that does not qualify as a medication optimizing glycaemic control, 
and is considered necessary for the patient's welfare may be given at the discretion of the 
investigator. Exceptions to this are the restrictions described in Section 4.2.2.
Handling of hypoglycaemic episodes can be done according to the guidelines and standard of 
care used by the treating physicians. These episodes need to be documented on the 
appropriate pages of the eCRF.
All concomitant (additional) medications and other therapies will be recorded on the 
appropriate pages of the eCRF.
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The use of other DDP DPP4 inhibitors and/or injectable GLP-1 receptor agonists and/or 
SGLT-2 inhibitors (next to background therapy and any additional anti-diabetic therapy) will 
be prohibited during the course of the study. 
If any restricted treatments or any other concomitant drugs interfering with the study 
medication are given during the conduct of the trial, the study medication can be discontinued 
temporarily, or if needed permanently.
4.3
TREATMENT COMPLIANCE
Patients will be asked to bring all trial medication (boxes, including blisters with or without 
any remaining tablets) with them to each trial visit. The tablets will be counted by the 
investigator or his/her designate and compliance will be calculated. The compliance check 
will be based on the number of capsules tablets missing (i.e. actually taken) in relation to the 
number of capsules tablets that should have been taken. 
Compliance should be between 80% and 120%. Compliance should be emphasised with a 
goal of at least 80% compliance rate. However, randomized patients will not be discontinued 
for lack of compliance without prior discussion with the monitor or designee. 
Patients who are not compliant with their medication should again be carefully interviewed 
and again re-informed about the purpose and the conduct of the trial.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY
5.1.1
Endpoint(s) of efficacy
The primary endpoint in this trial is time to the first occurrence of any of the following by
adjudicationed confirmed components of the primary composite endpoint (4 3-point 
MACE): CV death (including fatal stroke, fatal MI and sudden death), non-fatal MI
(excluding silent MI) or non-fatal stroke and hospitalisation for unstable angina pectoris. 
The key secondary endpoints are is time to the first occurrence of any of the following by 
adjudication confirmed components:

CV death (including fatal stroke, fatal MI and sudden death), non-fatal MI (excluding 
silent MI), non-fatal stroke (3-point MACE)

Composite renal endpoint (renal death, sustained ESRD, sustained decrease of 50
40% or more in eGFR)
At the final analysis the The primary endpoint (4 3-point MACE) will be tested for non-
inferiority. Thereafter, if non-inferiority has been demonstrated, the 4 3-point MACE and
the combined composite renal endpoint will be tested separately (= in parallel) for 
superiority. In case the 4-point MACE and/or composite renal endpoint is significantly 
superior, the 3-point MACE will then be tested for superiority.
Even after occurrence of a non-fatal endpoint, the patient should be followed-up until the end 
of the study in order to document other endpoints/variables.


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* Silent MI is an investigator reported endpoint, and is a trigger term for central 
adjudication for cardiovascular events. Any investigator reported silent MI that is 
adjudicated and confirmed as being an MI by the CEC will be counted as MI.


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Albuminuria progression is defined according to change from normoalbuminuria to either 
microalbuminuria (UACR > 30 mg/g and <≤300 mg/g) or clinical proteinuria (UACR > 300 
mg/g) or from microalbuminuria (UACR > 30 mg/g and <≤300 mg/g) to clinical proteinuria 
(UACR > 300 mg/g).
5.1.2
Assessment of efficacy
HbA1c:
Blood samples for the determination of HbA1c will be taken according to the Flow Chart. The 
blood sample can be taken at any time during the visit. The samples will be analysed at a 
central laboratory or its affiliates having a National Glycohemoglobin Standardization 
Program (NGSP) Level I certificate. Further details about sample handling, shipment, and 
assay procedures can be found in the ISF (Lab manual).
FPG:
Blood samples for the determination of FPG will be taken according to the Flow Chart
after an overnight fast (at least 10 hours no food and only water). At all respective visits, the 
samples should be taken before breakfast and before trial drug administration. The samples 
will be measured with the HBGM device. 
5.2
SAFETY
5.2.1
Endpoint(s) of safety
Incidence and intensity of adverse events, physical examination, vital signs, ECG and change 
from baseline in laboratory parameters will be assessed.


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5.2.1.1 
Reporting waiver for cardiovascular outcome events
In accordance with ICH-guideline E2A and in order to maintain the integrity of this study, 
CV outcome events that occur after randomization and represent an SAE are exempted from 
expedited reporting to health authorities. The medication code will not be broken for the 
purpose of expedited reporting to regulatory authorities.
CV outcome events are defined as the following components of the primary, key secondary 
and other CV endpoints: 
- CV death 
- non fatal MI
- silent MI
- non fatal stroke (ischemic/hemorrhagic/etiology unknown)
- hospitalisation for unstable angina pectoris
- hospitalisation due to congestive for heart failure (CHF)
- transient ischemic attack (TIA)
- coronary revascularisation procedures (PCI and CABG)
- peripheral revascularization procedures
For definitions of the CV outcome events see Appendix 10.2.
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. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious 
and unintended. Response in this context means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility. Adverse 
reactions may arise from use of the product within or outside the terms of the 
marketing authorisation or from occupational exposure. Conditions of use outside the 
marketing authorization include off label use, overdose, misuse, abuse and medication 
errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE that results in death, is immediately life-
threatening, results in persistent or significant disability / incapacity, requires or prolongs 


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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 that may jeopardise the patient and may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definitions.
Medical and scientific judgement should be exercised in deciding whether other 
situations should be considered serious reactions, such as important medical events that 
might not be immediately life threatening or result in death or hospitalization but might 
jeopardize the patient or might require intervention to prevent one of the other 
outcomes listed above. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalization or development of dependency or abuse. Any suspected 
transmission via a medicinal product of an infectious agent is also considered a serious 
adverse reaction.
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 drug and the occurrence of the cancer.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that 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 case report forms. For 
Japan: The reason for the decision on causal relationship needs to be provided in the CRF.
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 an SAE is reported from a still 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 underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the (e)CRF.
Changes in vital signs, ECG, physical examination, and laboratory test results 


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Changes in vital signs, ECG*, physical examination and laboratory test results will be 
recorded as an (S)AE in the (e)CRF, if they are judged clinically relevant by the investigator.
*Changes in the ECG indicating (silent) MI should be reported as a cardiovascular outcome 
event.
Hypoglycaemic events
Hypoglycaemic events should be documented according to the following criteria:

Asymptomatic hypoglycaemia: Event not accompanied by typical symptoms of 
hypoglycaemia but with a measured plasma glucose concentration ≥54 mg/dl and ≤70 
mg/dl (≥3.0 mmol/l and ≤3.9 mmol/l):

Asymptomatic hypoglycaemia: Event not accompanied by typical symptoms of 
hypoglycaemia but with a measured plasma glucose concentration < 54 mg/dl (<3.0
mmol/l)

Documented symptomatic hypoglycaemia with glucose concentration ≥54 mg/dl and 
≤70 mg/dl (≥3.0 mmol/l and ≤3.9 mmol/l): Event accompanied by typical symptoms 
of hypoglycaemia 

Documented symptomatic hypoglycaemia with glucose concentration < 54 mg/dl 
(<3.0 mmol/l): Event accompanied by typical symptoms of hypoglycaemia but no 
need for external assistance

Severe hypoglycaemic episode: Event with any degree of documented hypoglycemia, 
requiring the assistance of another person to actively administer carbohydrate, 
glucagon or other resuscitative actions
All symptomatic hypoglycaemic events, all asymptomatic events with glucose levels less 
than 3.0 mmol/l and all asymptomatic hypoglycaemic events that are considered as adverse 
event by the investigator have to be recorded as an adverse event.
Adverse Events of Special Interest
The term AESI relates to any specific AE that has been identified at the project level as 
being of particular concern for prospective safety monitoring and safety assessment 
within this trial, e.g. the potential for AEs based on knowledge from other compounds 
in the same class. AESI’s need to be reported to the sponsor’s Pharmacovigilance 
Department within the same timeframe that applies to SAE.
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.


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
Renal adverse events such as acute renal failure

Pancreatitis (refer to the ISF)

Thyroid neoplasm (benign)

Thyroid cancer

Pancreatic cancer
A list of terms that must be documented as AESI for each topic is provided in the ISF.
The renal events and pancreatic events will be adjudicated by independent adjudication 
committees.
AESI’s, even though they might be non-serious are to be documented in the eCRF within 24 
hours of receipt and must be reported to the sponsor/CRO in an expedited manner similar to 
Serious Adverse Events. For details please see Section 5.2.2.2.  
Protocol-specified AESIs (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, even if they do not meet any of the 
SAE seriousness criteria.
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 
(SMQs), and user defined searches (BicMQs)) 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 (summarized under the so called ‘overview of protocol 
defined 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 ISF and changes will be communicated to all investigators.
Hepatic events: 
Patients showing an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation 
of total bilirubin ≥2 fold ULN measured in the same blood sample need to be followed up
locally according to the “DILI checklist” provided in ISF.
Renal events: 
Estimated creatinine clearance eGFR will be calculated using the MDRD formula. This 
formula considers the race as an adjustment factor, therefore, the race must be known (and 
will be collected) for accurate estimation.
In case of an eGFR decrease of ≥ 40% since baseline (visit 2) and again in case of an eGFR 
decrease of ≥50% since baseline (visit 2) an additional visit 4-8 weeks after detection should 


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be scheduled (unless detected at the EOT visit at study end) to collect a blood sample for 
repeat analysis of creatinine for calculation of the eGFR. An additional sample of creatinine 
should also be taken between the visits interval if a signal of increasing creatinine is reported 
to the study site by others (e.g., treating physicians from local labs).
Skin lesions:
If skin lesions occur (such as exfoliative rash, skin necrosis, or bullous dermatitis): further 
follow-up investigations should be done according to medical judgement depending on the 
clinical course until the patient is recovered and/or a diagnosis is made.
5.2.2.2
Adverse event and serious adverse event reporting
The Investigator shall maintain and keep detailed records of all AEs in their patient 
files.
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 visit) will be 
collected, documented and reported to the sponsor/CRO by the investigator on the 
appropriate CRF(s) / eCRFs / SAE reporting forms. 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 last per protocol visit, it 
should be reported by the investigator to the sponsor if considered relevant by the 
investigator. Reporting will be done according to the specific definitions and instructions 
detailed in the ‘Adverse Event Reporting’ section of the Investigator Site File.
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 must report the following events, immediately (within 24 hours of 
awareness) to the sponsor/CRO: SAEs, AESI and non-serious AEs relevant for the reported 
SAE or AESI.
The investigator must document immediately (within 24 hours of awareness) CV outcome 
events if they occur after randomization on the appropriate eCRF page. CV outcome events 
which occur prior randomization have to be reported as an (S)AE.
Clinically relevant abnormalities found at physical examination, vital signs or ECG that are 
not pre-existing prior to signing of informed consent (study inclusion) should be reported as 
adverse events. If such abnormalities already pre-exist prior to signed informed consent they 
should be considered as baseline conditions.
AEs considered “Always Serious”


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Cancers of new histology and exacerbations of existing cancer must be reported as a 
serious event regardless of the duration between discontinuation of the drug and the 
occurrence of the cancer. In accordance with the European Medicines Agency initiative 
on Important Medical Events, Boehringer Ingelheim has set up a list of further AEs, 
which by their nature, can always be considered to be “serious” even though they may 
not have met the criteria of an SAE as given above.
The latest list of “Always Serious AEs” can be found in the ISF. A copy of the latest list 
of “Always Serious AEs” will be provided to you upon request. These events should 
always be reported as SAEs as described above.
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 serious adverse events”, 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 adverse events can be found in the ISF.
For Japan: This information must be also reported immediately to the head of the trial site.
With receipt of any further information to these events, a follow-up SAE report has to be 
provided. SAEs, AESIs and non-serious AEs must include a causal relationship assessment 
made by the investigator. The SAE form is to be forwarded to the defined unique entry point 
(contact details will be provided in the Investigator Site File). 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 
Adverse Events of Special Interest becomes available. 
Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
report immediately any drug exposure during pregnancy to the sponsor/CRO. Drug exposure 
during pregnancy has to be reported immediately (within 24 hours of awareness) to the 
defined unique entry point for SAE forms (contact details will be provided in the Investigator 
Site File). The outcome of the pregnancy associated with the drug exposure during pregnancy 
must be followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for 
Clinical Trials and not the SAE form is to be completed. The ISF will contain the Pregnancy 
Monitoring Form for Clinical Trials (Part A and Part B).
5.2.2.3 Oncological adverse events
Epidemiological evidence suggests that people with diabetes are at a significantly higher risk 
of several forms of cancer compared with subjects without diabetes [R10-6495]. Currently, it 
is unclear whether the association between cancer and diabetes is indirect and largely due to 
shared risk factors (such as the modifiable risk factors: e.g. obesity, diet, physical activity, 
tobacco smoking, alcohol, or non-modifiable risk factors: e.g. age, gender, race, and 


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ethnicity), whether it is direct influence (e.g. due to hyperglycaemia), whether it is related to 
medical therapies used in the treatment of T2DM, or whether T2DM represents a condition 
with underlying biologic factors that alter cancer risk (e.g. insulin resistance and 
hyperinsulinemia) [R10-6496, R10-6498, R10-6536, R10-6497, R10-6494].
In order to assess patients with oncological adverse events (benign and malignant) in detail, 
and in addition to the AESIs thyroid neoplasm (benign), thyroid cancer, and pancreatitic 
cancer, detailed information will be requested and should be provided by the site. The main 
focus on oncological adverse events is on the following organ systems, based on [R10-6638] 
where an increased risk for cancer in the population of patients with T2DM was described:

Liver

Endometrium

Colon and rectum

Breast

Bladder

Prostate
Request for detailed information (e.g. medical history, diagnostic result, laboratory results 
staging), will be mainly focused on the above listed organ systems, however is not restricted 
to them. For details refer to the oncology committee assessment charter.
5.2.3
Assessment of safety laboratory parameters
The parameters that will be determined are listed below. Analysis will be performed by a 
central laboratory:
Visit 1 (screening):

Clinical chemistry: ALT, AST, AP, lipase and creatinine

Urine analysis: albumin and creatinine
Visit 2 (baseline):

Haematology: haematocrit, haemoglobin, erythrocyte count, platelet count and total 
and automates differential leukocyte counts (in absolute counts). 

Clinical chemistry: ALT, AST, -GT, AP, lipase, lactate dehydrogenase (LDH), total 
bilirubin, albumin, potassium, Sodium, creatinine, urea, calcium, inorganic 
phosphorous, urid acid, cholesterol (total), high density lipoprotein (HDL)
cholesterol, low density lipoprotein (LDL) cholesterol and triglycerides. 

Urine analysis: albumin, creatinine, protein, ketone and leucocytes.
Visit 3 – EOT - FU

Clinical chemistry: creatinine and lipase

Urine analysis: albumin and creatinine (visit 4, visit 6 and thereafter yearly).

Clinical chemistry: cholesterol (total), HDL cholesterol, LDL cholesterol and 
triglycerides (visit 4, visit 6 and thereafter yearly)


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HbA1c will be determined at all scheduled visits, with exception of the FU visit.
Exact date and time of blood and urine sampling should be recorded in the central laboratory 
requisition form.
UACR will be calculated at the central lab, and should be measured on a first morning void 
specimen wherever possible. UACR will be performed according to the Flow Chart.
Pregnancy testing (beta Human Chorionic Gonadotropin [βHCG method]) will be performed 
in female patients of child-bearing potential according to the Flow Chart. 
A negative pregnancy test result is required at visit 2 for all female patients of childbearing 
potential to remain eligible for entry into the treatment phase of the trial and reconfirmed at 
future visits.
5.2.3.1
Renal function 
Renal function will be assessed by the central lab based on the plasma creatinine value 
measured according to the Flow Chart. The eGFR will be calculated from serum creatinine 
using the following MDRD formula:    
eGFR = 175 x (creatinine (µmol/L)/88.4)-1.154 x age-0.203 x (0.742 if female) x (1.212 if black)
Renal impairment will be classified in the following way:
No renal impairment: eGFR 90 mL/min/1.73m2;
No renal impairment with evidence of kidney damage (eGFR 90 mL/min/1.73m2 and
UACR ≥30mg/ g creatinine);
Mild renal impairment: eGFR 60-89 mL/min/1.73m2;
Moderate renal impairment: eGFR 30-59 mL/min/1.73m2;
Severe renal impairment: eGFR 15-29 mL/min/1.73m2;
ESRD: eGFR < 15 mL/min/1.73m2.
Prevalent kidney disease will be defined in the following way:

eGFR <60mL/min/1.73m2 and/or UACR >300mg/ g creatinine
5.2.4
Electrocardiogram
12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded according to the Flow 
Chart.
The ECGs will be centrally analysed. Additional ECGs may be collected by the investigator 
for safety reasons. Clinically relevant abnormal findings will be reported as AEs, if they are 
newly discovered after inclusion in the trial.
The recordings will be checked for pathological results by the investigator. Any ECG 
abnormalities will be carefully monitored and medically treated.


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5.2.5
Assessment of other safety parameters
Vital signs and height 
Systolic and diastolic blood pressure (DBP) as well as pulse rate (electronically or by 
palpation, count for 1 minute) will be measured after 5 minutes of rest in the seated position 
according to the Flow Chart. All recordings should be made using a similar type of and
validated certified blood pressure recording instrument on the same arm. See for further 
details Section 10.3. Height (metres, m) will be measured according to the Flow Chart. Body 
mass index, BMI (kg/m2) will be calculated for determination of eligibility at Visit 1.
Weight and Waist circumference
Weight measurements should always be done on a similar approved type of scale for one 
patient. In order to get comparable body weight values, it should be performed in the 
following way:

fasting (except for the screening visit), 

after the urine sampling (weight after bladder voiding), 

shoes and coat/jackets should be taken off 

pockets should be emptied of heavy objects (i.e. keys, coins etc). 
Waist circumference measurements should be made around a patient’s bare midriff, 1 cm 
above the iliac crests, after the patient exhales while standing without shoes and with both 
feet touching and arms hanging freely. The measuring tape should be made of a material that 
is not easily stretched, such as fibreglass. The tape should be placed perpendicular to the long 
axis of the body and parallel with the floor and with sufficient tension to conform to the 
measurement surface [R07-4080].
Physical examination
A head-to toe 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 Flow Chart. Documentation of, and findings from the physical examination, 
must be part of the source documents available at the site.
Home Blood Glucose Monitoring
All patients will be provided with HBGM equipment and supplies for use at home at the 
randomization visit. Weekly finger stick glucose measurements are recommended. During the 
whole trial participation, additional measurements should be done if necessary and in case of 
hypo- or hyperglycaemia related symptoms. Patients will be instructed to bring their HBGM 
device to visits for an additional measurement of fasted glucose. 
More frequent testing can be done if deemed necessary by the investigator or required by 
local authorities. The respective procedure for illiterate patients (if included) is described in 
the Appendix 10.1.1.


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Instruction on the proper use of the HBGM will be provided by the study staff. The patient 
will be asked to record the results of the HBGM test on a HBGM diary that will be included 
in the patient’s source document file. Only in the case of linked adverse events or of 
asymptomatic hypoglycaemia with a measured plasma glucose concentration ≥ 3.0 and ≤ 3.9 
mmol/l (≥54 and ≤ 70 mg/dL), the single HBGM values will be recorded in the eCRF.
If the results of a HBGM test reveal blood plasma glucose value of > 180 mg/dl (>10.0 
mmol/L) after an overnight fast or  > 400 mg/dl (22.2 mmol/L) randomly determined and 
confirmed by a second HBGM (not on the same day) the patient should contact the site for 
further advice.
During the trial, the patient should also contact the site for advice if the results of a HBGM 
test reveal blood plasma glucose value of < 70 mg/dL (3.9 mmol/L) after an overnight fast. If 
the blood glucose level is <54 mg/dL (3.0 mmol/L), the patient should be instructed to 
eat/drink some carbohydrate.  
The HBGM diary should be brought to each visit for review by investigator/trial staff. The 
HBGM diary should be collected at the visit (if completed) and a new HBGM diary should be 
given to the patient. 
5.3
OTHER


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5.3.2
Post stroke functional assessment
To assess clinical disability after stroke the reported value from the modified Rankin Scale, 
an ordinary scale that is being widely used in clinical practice to rank disability will be 
collected. It is reported as a single digit from 0-6 (covering the spectrum “no symptoms” to 
“dead”) approximately one week after stroke onset and 3 months after stroke onset. This 
might require an additional contact.
5.3.3     Pharmacogenomic evaluation
For DNA Banking an additional blood sample will be requested. The DNA sample derived 
from the original blood sample will be stored by Boehringer Ingelheim for up to 15 years 
after the end of the clinical trial. The stored DNA may be analysed at a later time for 
pharmacogenomic analyses, e.g. to identify whether there are other genetic factors that could 
contribute to a better therapeutic outcome or a higher risk of developing treatment-related 
adverse drug reactions.
5.3.3.1
Methods and timing of Pharmacogenetics sample collection
One (1) blood sample for DNA banking will be taken at visit 2 or later. A maximum of 8.5 
mL blood will be collected per PAXgene Blood DNA sampling tube for those patients who 
signed a separate informed consent concerning the sample banking part. The PAXgene Blood 
DNA tubes can be stored and shipped at room temperature within 14 days. If a longer storage 
and shipment period for PAXgene Blood DNA tubes is necessary, the blood samples should 
be stored at a temperature of -20 degrees Celsius or below. Once frozen, thawing of the 
samples should be avoided. Detailed instructions for pharmacogenomic sampling, handling 
and shipment of samples are provided in the ISF/Lab Manual.
Participation in the pharmacogenetic sampling is voluntary and not a prerequisite for 
participation in the study. 
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 see drug induced changes in vital signs, 
laboratory values, and ECG. The endpoints are standard and accepted for evaluation of 
efficacy and safety of an oral antidiabetic drug, and they are widely used in this kind of study. 
Therefore, the appropriateness of all measurements applied in this trial is given.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
The plasma concentration of linagliptin will not be determined.


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5.6
BIOMARKER(S)
No additional biomarkers will be determined in this study.
5.7
PHARMACODYNAMICS
No additional pharmacodynamic parameters will be determined in this study.
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
The relationship between linagliptin trough plasma concentrations and biomarkers will not be 
investigated.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All trial visits should take place preferably between 7:00 AM and 11:00 AM. If a patient 
mistakenly takes trial medication in the morning of a visit before attending the clinic or 
comes in non-fasted where a fasting condition is required (all visits except visit 1), 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 in a short enough time-frame so 
that the patient has sufficient trial medication available.
All patients are to adhere to the visit schedule as specified in the Flow Chart. Some flexibility 
is allowed in scheduling the visits according to visit time windows as specified in the Flow 
Chart. If any visit has to be rescheduled, subsequent visits should follow the original visit 
date schedule (calculated from randomization visit 2). 
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The Flow Chart summarizes the investigational procedures to be done at each visit. The 
procedures are further described below.
6.2.1
Screening period
After the informed consent process is complete and written informed consent is obtained, the 
patients will be assessed for study eligibility (visit 1) including central laboratory assessments
as specified in Section 5.2.3.
Screening will occur at visit 1 and will be registered in IRT.
Those patients who qualify at screening (as determined at visit 1) and meet all inclusion and 
exclusion criteria prior to randomization (see Sections 3.3.2.and 3.3.3.), will be randomized 
at visit 2. Randomization may be done as soon as the visit 1 (safety) laboratory results and
eGFR are known and all other eligibility criteria are met. No additional medication for 
optimization of glycaemic control may be initiated during the screening phase. 
6.2.2
Treatment period
Randomization will occur at visit 2 using IRT.
Patients will return to the clinic for regularly scheduled study visits after randomization as 
specified in the Flow Chart. These visits will assess the occurrence of safety and efficacy 
endpoints, study medication compliance and accountability, concomitant therapy or 
intervention. 
Patient visits should be routinely scheduled in the morning, at approximately the same time at 
each visit. The actual date/time of trial drug administration at the study visit will be recorded 
in the eCRF.


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At each visit all trial medication will be returned, compliance will be calculated and new trial 
medication kit(s) will be assigned via IRT and will be dispensed.
This is a long-term safety outcome study and every effort should be made by the site staff 
to encourage patients to remain in the study and on study drug if medically safe. All 
patients, including those who discontinue treatment must be followed up until the end of the 
study. Patients who prematurely discontinue treatment will continue to be contacted by the 
investigator at regular intervals (according to the original visit schedule or an alternative 
reduced schedule negotiated with the patient) either by clinic visits or by phone (refer to 
section 6.2.3).
Patients who prematurely discontinued study medication during the treatment phase are 
allowed to restart the study medication at any time if appropriate in the opinion of the 
investigator and if not contraindicated. Investigators should routinely consider re-starting 
study drug at every visit following study drug discontinuation.
Early discontinuation of study medication is not a criterion for withdrawal of consent 
for participating in the study.
6.2.3
End of treatment and follow-up period
Patients who discontinue study drug should continue study visits until study end. Study 
assessments may be omitted if a patient is willing to return to the pre-defined study 
visits, with exception
, collection of adverse events, outcome 
events, concomitant therapy and laboratory testing of creatinine for the calculation of 
the eGFR. 
If a patient who discontinued study drug is not willing to return to the pre-defined study 
visits, at minimum a yearly telephone call (preferably every 6 months) and a telephone 
call at study end will be required, to document the occurrence of outcome events and 
vital status. If possible, other AE’s and concomitant therapy changes since last visit 
should be recorded. Every attempt will be made by the investigator to ensure patients 
continue participating in the study during study drug interruptions and after 
discontinuation of study drug.
Patients that are not actively taking study drug may be less motivated to adhere to the 
study visit schedule. Investigators and site staff should work to detect early signs of 
losing interest and readily present such patients (not actively taking study drug) with 
options to encourage continued participation.  Refer to section 3.3.4.1 for options to 
encourage continued participation and for details regarding patients who are lost-to-
follow-up or who have withdrawn informed consent.  
If the patient withdraws informed consent for study participation, the study-participation of 
the patient will end. The patient should stop taking study medication and should be asked to 
complete the EOT and follow-up visit activities as described in the Flow Chart. Completing 
these procedures is strongly recommended for the patient’s safety.


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Patients who discontinue study drug prematurely should continue study visits until study end.
Study assessments may be omitted if a patient is willing to return to the pre-defined study 
visits, with exception of 
, collection of adverse events, outcome 
events, concomitant therapy and laboratory testing of creatinine for the calculation of the 
eGFR. 
If a patient who prematurely discontinued study drug is not willing to return to the pre-
defined study visits, at minimum a yearly telephone call (preferably every 6 months) and a 
telephone call at study end will be required, to document the occurrence of outcome events 
and vital status. If possible, other AE’s and concomitant therapy changes since last visit 
might be recorded. Every attempt will be made by the investigator to ensure patients continue 
participating in the study during study drug interruptions and after discontinuation of study 
drug.
All patients will have a follow up visit one week 30 days following regular or premature 
completion of the treatment period. The follow-up visit may be performed as a phone visit for 
patients who did not prematurely discontinue study medication and who do not have 
abnormalities at the EOT visit (only adverse events/outcome events and changes in 
concomitant therapy to be obtained).


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
Design
This is a multicentre, multinational, randomized, double blind, parallel group, placebo-
controlled safety study of linagliptin versus placebo. The trial is event driven and will run 
with an estimated number of 8300 7000 randomized patients for an estimated period of 48 54
months beginning with the randomization of the first patient. In case the number of events is 
not or may not be reached within this period the trial duration and/or the number of patients 
will be prolonged or increased respectively, to ensure that the required number of 625 611
patients with adjudicated primary endpoint events is reached. 
Objectives
The study objectives are described in Section 2.2.
For the primary objective the upper bound of the two-sided (1-2*alpha) confidence interval 
which equals the upper bound of the one-sided (1-alpha) confidence interval will be used to 
investigate non-inferiority (NI) of linagliptin versus placebo regarding the hazard ratio of the
primary endpoint. The non-inferiority margin is chosen as 1.3 (FDA Guidance for Industry -
Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat 
Type 2 Diabetes, (R09-2151). The overall one-sided significance level is 2.5%. 
Primary endpoint
The primary endpoint is time to the first occurrence of any of the following adjudicated 
components of the composite endpoint (43-point MACE): CV death (including fatal stroke, 
fatal MI, and sudden death), non-fatal MI (excluding silent MI), or non-fatal stroke, 
hospitalisation for unstable angina pectoris. 
Patients without occurrence of a specific endpoint (composite endpoint or individual 
components) will be considered censored at their last documented study visit. If any 
measurement of laboratory data or ECG is available after the last visit of a patient, the date of 
the respective measurement will be used for censoring of the CV endpoint. If any 
measurement of eGFR is available after the last visit of a patient, the date of the respective 
measurement will be used for censoring of the renal endpoint. For all endpoints including the 
component CV (renal) death, adjudicated CV (renal) death will be counted even if occurred 
thereafter.
7.2
NULL AND ALTERNATIVE HYPOTHESES
An interim analysis will be performed at the one-sided alpha-level of 1.0%, the final analysis 
at the one-sided alpha-level of 2.12%. At the interim analysis MACE endpoints will be tested 


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in a pre-specified order, at the final analysis also the composite renal endpoint will be tested 
for superiority. The experimentwise (multiple) level alpha is controlled with the following 
three step gatekeeping hierarchy within the interim and final analysis, respectively.
No confirmatory interim analysis for efficacy endpoints will be performed. For the final 
analysis, the first hypothesis (non-inferiority of the primary endpoint) will be tested at the 
one-sided alpha-level of 2.12% 2.5%. In case of significance, the null hypothesis is rejected 
in a confirmatory sense and the next set of hypotheses (two separate hypothesis tests) will be 
tested: a) test of the primary endpoint for superiority and b) test of the composite renal 
endpoint for superiority. To adjust for multiplicity the truncated Hochberg a sequentially 
rejective multiple test procedure will be applied (R16-4473) with a selected gamma of 0.5
(R12-4087). Both one-sided hypotheses H0(Sup1) and H0(Sup2) will be tested separately, at the 
initial alpha-levels of 0.2*alpha for 3-point MACE and 0.8*alpha for the composite 
renal endpoint, respectively. If both null hypotheses cannot be rejected at these initial 
alpha-levels, the procedure stops and for none of these endpoints superiority can be 
declared. After having shown superiority for one of these endpoints, the used alpha can 
be shuffled to the other test: If H0(Sup2) is rejected at the alpha-level of 0.8*alpha, then
H0(Sup1) can be tested at the full alpha-level of 2.5% (one-sided). If H0(Sup1) is rejected at 
the alpha-level of 0.2*alpha, then H0(Sup2) can be tested at the full alpha-level of 2.5% 
(one-sided). If both tests are significant at the one-sided alpha-level of 1.59% each, 
superiority of both endpoints (4-point MACE and composite renal endpoint) has been 
demonstrated. If not, superiority can only be claimed for the endpoint significant at the alpha-
level of 1.06%. If superiority of both, the 4-point MACE and the composite renal endpoint
has been demonstrated at the one-sided alpha-level of 1.59% each, then superiority of the 3-
point MACE can be tested at the alpha-level of 2.12%. If superiority of only one of these 
endpoints (4-point MACE or composite renal endpoint) has been demonstrated at the one-
sided alpha-level of 1.06%, then superiority of the 3-point MACE can be tested at the alpha-
level of 0.53%.  
At the interim analysis superiority of the composite renal endpoint will not be tested and 
therefore all tests on MACE can be performed in the pre-specified order at the alpha-level of 
1.0%. 
If a step is not significant, all subsequent steps may not be interpreted in a confirmatory 
sense.The sequence of tests is as follows:
1st step:
The primary endpoint (4 3-point MACE) is time to the first occurrence of any of the 
following adjudicated components of the composite endpoint: CV death (including fatal 
stroke, fatal MI, and sudden death), non-fatal MI, or non-fatal stroke, hospitalisation for 
unstable angina pectoris. 
H0(NI): HRlinagliptin vs. placebo ≥1.3
(Interpretation of H0(NI): Regarding the time to first occurrence of the primary endpoint, the 
risk (expressed as hazard ratio (HR)) for linagliptin relative to placebo is at least 30% higher.)


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vs.
H1(NI): HRlinagliptin vs. placebo < 1.3
(H1(NI): Regarding the time to first occurrence of the primary endpoint, the risk for linagliptin 
relative to placebo is less than 30% higher, i.e. linagliptin can be regarded as non-inferior.)
2nd step:
If the null hypothesis of non-inferiority (1st step) can be rejected, then in a second step two
confirmatory tests on superiority will be performed at the final analysis: 

time to first occurrence of the primary endpoint (4 3-point MACE)

time to first occurrence of the composite renal endpoint
At the interim analysis superiority of the composite renal endpoint (i.e. H0(Sup2)) will not be 
tested.
H0(Sup1): HRlinagliptin vs. placebo ≥1
(H0(Sup1): Regarding the time to first occurrence of the primary endpoint, the risk for
linagliptin relative to placebo is higher.)
vs.
H1(Sup1): HRlinagliptin vs. placebo < 1
(H1(Sup1): Regarding the time to first occurrence of the primary endpoint, the risk for
linagliptin relative to placebo is lower.)
H0(Sup2): HRlinagliptin vs. placebo ≥1
(H0(Sup2): Regarding the time to first occurrence of the composite renal endpoint, the risk for 
linagliptin relative to placebo is higher.)
vs.
H1(Sup2): HRlinagliptin vs. placebo < 1
(H1(Sup2): Regarding the time to first occurrence of the composite renal endpoint, the risk for 
linagliptin relative to placebo is lower.)
To adjust for multiplicity at the final analysis the truncated Hochberg a sequentially 
rejective multiple test procedure will be applied.
3rd step:
If superiority of the primary endpoint (4-point MACE) and/or the composite renal endpoint 
has been demonstrated, then as a further confirmatory test superiority is tested with respect to 
time to first occurrence of the 3-point MACE.


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H0(Sup3): HRlinagliptin vs. placebo ≥1
(H0(Sup3): Regarding the time to first occurrence of the 3-point MACE, the risk for linagliptin 
relative to placebo is higher.)
vs.
H1(Sup3): HRlinagliptin vs. placebo < 1
(H1(Sup3): Regarding the time to first occurrence of the 3-point MACE, the risk for linagliptin 
relative to placebo is lower.)
7.3
PLANNED ANALYSES
The primary analyses (including all confirmatory tests described in Section 7.2) will be 
performed on the full analysis set (FAS) Treated Set (TS). The FAS TS will consist of all 
randomized patients who were treated with at least one dose of study drug.
For the primary and key secondary endpoints a ‘classical intention to treat (ITT) analysis on 
the FAS TS’ will be done. That means that:
-
the analysis set consists of the FAS TS, 
-
the allocated study treatment at randomization will be used for the analysis (‘as 
randomized’),
-
all events which occur until study end will be taken into account. 
A per protocol set (PPS) of patients following the trial protocol in essential criteria will be 
created for sensitivity analyses. Patients included in the FAS TS who have important protocol 
violations will be excluded from the PPS. A protocol violation (PV) 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:
-
Randomized study drug: incorrect study drug taken.
-
Severe violation of treatment compliance (defined as compliance with study treatment
< 80% for more than 50% of the time between randomization and first endpoint (CV 
death, non-fatal MI, non-fatal stroke, hospitalisation for unstable angina pectoris).
-
Non-adherence to other specifications of the protocol that could bias the primary 
composite endpoint (e.g. limited life expectancy (< 5 years) at randomization due to 
various medical conditions)
Additionally a ‘30-day treatment’ ‘on-treatment’ set (OS) of patients will be created for 
sensitivity analysis. The ’30-day treatment’ OS set will include all patients with minimum 
treatment duration of 30-days.
All patients treated with at least one dose of study drug (the Treated Set) will be included in 
the safety evaluation. In case only randomized patients take study drug, this set is identical to 
the FAS; the safety analyses will be displayed ‘as randomized’.


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Data recorded on entry into the study and at randomization will be summarized and compared 
using univariate descriptive statistics.  
Additional analyses will be explored in specific subgroups, e.g. depending on characteristics 
at baseline with respect to the primary and key secondary endpoints. Examples of
Ccovariates that will be explored include: 

Region (North America, Europe, Asia etc.)

Age (<65, ≥ 65 years)

Systolic and diastolic blood pressure (<140160 and < 90100 mmHg , ≥140160 or 
≥90100 mmHg)

Gender (male, female)

Prior anti-diabetic treatment (none, monotherapy, combination therapy insulin, no
insulin)

eGFR < 60 mL/min/1.73 m2 at baseline

Prevalent kidney disease defined as eGFR < 60 mL/min/1.73 m2 at baseline 
and/or UACR > 300mg/g creatinine at baseline
Further details will be given in the trial statistical analysis plan (TSAP).
7.3.1
Primary analyses
A classical ITT-approach on the FAS TS will be performed as described above. For the 
primary analysis a Cox proportional hazards regression model of time to the first event with 
randomized treatment and geographical region as factors will be applied. Kaplan-Meier 
estimates by treatment group will be displayed. The confirmatory test approach is outlined in 
Section 7.2.
No centre effect will be included into the Cox models, as the centre size is expected to be 
small. Furthermore, due to the low event rate there would not be a sufficient number of 
events per centre for the analysis of a centre effect and a centre by treatment interaction.
For the primary and key secondary endpoints, sensitivity analyses will be done on the PPS, 
for the ’30 days treatment’ set OS and as an ‘on-treatment’ a ‘TS+30’ analysis as described 
below. These sensitivity analyses will be performed based on the corresponding patient sets 
for the time patients are on-treatment + 30 days after permanent treatment discontinuation or 
end of observation, whichever comes first. The ‘on-treatment analysis’ ‘TS+30’ analysis will 
be performed on the FAS TS (consisting of all randomized patients who were treated with at 
least one dose of study drug) with censoring at the time patients are on treatment + 30 days 
after permanent treatment discontinuation or end of observation, whichever comes first. 
For these sensitivity analyses, the randomized study treatment (‘as randomized’) will be used 
for treatment assignment.
To check the proportional hazards assumption, Schoenfeld residuals will be plotted for each 
covariate versus time; in addition, ln(-ln(S(t))) will be plotted vs. time and checked for


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parallelism. As a further assessment the interaction of covariates with time will be 
investigated. In case the proportionality assumption does not hold, a stratified log-rank test 
will be performed.
7.3.2
Secondary analyses
In addition to the primary analysis (time to first event), crude rates will be displayed for the 
primary and key secondary endpoints. The interpretation of crude rates has to take into 
account that the likelihood to observe an event increases with a longer survival and/or 
observation period; therefore a difference between the treatment groups with regard to the 
actual observation period will be explored.
The key secondary endpoints are is time to the first occurrence of any of the following by 
adjudication confirmed components:

CV death (including fatal stroke, fatal MI and sudden death), non-fatal MI (excluding  
silent MI), non-fatal stroke (3-point MACE)

Composite renal endpoint (renal death, sustained ESRD, sustained decrease of 50
40% or more in eGFR)
After non-inferiority has been established for the primary endpoint (4 3-point MACE), the 
same endpoint and the composite renal endpoint (at the final analysis) will be tested for 
superiority. In case of significant superiority of the 4-point MACE and/or the composite renal 
endpoint, the 3-point MACE will then be tested for superiority.
For the primary, and key secondary endpoints and, their individual components, and 
 
the time-to-event analyses will be based on the randomization date;
for the other endpoints time-to-AE analyses the date of first study drug intake will be used. 


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Other endpoints: 


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The key secondary endpoints and the individual components of the primary and key
secondary endpoints will be analysed as time to first occurrence. In addition, crude rates will 
be displayed. Chi-Square tests will be applied for efficacy data; these tests will be interpreted 
in an exploratory sense, two-sided p-values without alpha-adjustment will be presented. 
Wilson confidence intervals will be reported for the proportion of patients with primary and 
key secondary endpoints; in addition logistic regression models will be applied. 
7.3.3
Safety analyses
All safety data will be displayed and analysed (Treated Set, ‘as randomized’) using 
descriptive statistical methods. No formal inferential analysis is planned for safety 
comparisons. 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; in addition, all AEs after the first dose of 
study medication will be displayed by randomized treatment group. Laboratory values taken 
after the first dose of randomized 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. For hypoglycaemic events the incidences 
and the treatment-time adjusted frequencies will be displayed.
7.3.4
Interim analyses
An independent Data Monitoring Committee (DMC) will review safety and efficacy data and 
make recommendations whether to continue or terminate the study. As described in Section 
3.1.1 the DMC analyses and operations will be formally separated from the sponsor, the 
investigators and the Steering Committee. The details on its procedures and interactions are 
provided in a separate DMC Charter.
It is planned that there will be one formal interim analysis for CV efficacy after 70% of the 
expected primary CV events, i.e. after 437 patients have experienced an adjudicated primary 
CV endpoint. The interim analysis will be performed at the one-sided alpha-level of 1.0%; 


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according to Haybittle-Peto (East version 5.4), this results in a one-sided alpha of 2.12% for 
the final analysis. The first test will be on non-inferiority of the primary endpoint, in case of 
significance followed by the superiority tests for the composite CV endpoints outlined in 
Section 7.2. No confirmatory interim analysis will be performed for the composite renal 
endpoint, i.e. for the renal endpoint superiority will formally be tested only once after regular 
or premature study termination, respectively. In case non-inferiority has not yet been 
demonstrated, the study will be continued as planned unless the interim results indicate major 
safety concerns. In case of demonstrated superiority of the primary variable at the interim 
analysis, the DMC may recommend stopping the study; non-inferiority of the primary
endpoint may lead to early study termination if the DMC considers it unrealistic to achieve 
superiority. Further details will be given in the DMC Charter.
Prior to the interim final analysis, the SC will evaluate available external data with relevance 
for the superiority test strategy and consequently may suggest to the sponsor adapting the 
assumptions and study size, respectively.
In addition there will be interim analyses for safety, based on all adverse events as recorded, 
but these interim analyses may not lead to early study termination due to demonstrate non-
inferiority or superiority; therefore these interim safety analyses have no negative impact on 
the alpha-level. 
7.3.5
Pharmacokinetic analyses
Not specified in this protocol
7.3.6
Pharmacodynamic analyses
Not specified in this protocol
7.3.7
Pharmacogenomic analyses
No prespecified pharmacogenomic analyses planned.
7.4
HANDLING OF MISSING DATA
Patients with temporary or permanent study treatment termination will be followed up for CV
events. Details on how to handle missing data will be outlined in detail in the trial statistical 
analysis plan (TSAP).
CV safety and other safety endpoints (including renal safety endpoints)
It is not planned to impute missing values. 
Diabetes related endpoints
Missing efficacy data for continuous variables for patients who discontinue the study 
treatment prematurely or miss a visit will be estimated by their last observed data. Missing 


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data for binary efficacy endpoints for patients who discontinue the study treatment 
prematurely will be considered as non-responders (worst case-scenario).
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 primary endpoint will be 
decided prior to unblinding.
The impact of all methods of handling missing data will be analysed using a sensitivity 
analysis by performing an analysis of the original data (i.e. without any imputation).
7.5
RANDOMIZATION
The sponsor will arrange for the randomization 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 randomization 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 randomization will be performed in blocks. The block size will be reported in the clinical 
trial report. The allocation process will be performed on visit 2 through IRT. Stratification 
will be by geographical region. Except for the DMC, access to the code will be restricted to 
dedicated randomization personnel and any exceptional access to the code (in case of an 
emergency) will be documented according to the sponsor's standard operating procedures 
(SOPs).
The study will only be unblinded after all CRF / 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 CTMF.
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
The 1-year event rate for the initially planned primary combined endpoint (CV death, non-
fatal MI, non-fatal stroke, hospitalisation for unstable angina pectoris) is was expected to be 
3.5% in the placebo group. 
Assuming a constant hazard over time, the distribution is exponential and the proportion of 
patients with event can be derived as F(t)=1-exp(-λt). The 1-year event rate of 3.5% translates
into a λ of 0.0356 and this results in an estimated rate of 12.7% patients with primary event 
after 3.8 years.
Assuming the hazard over time in patients on linagliptin is the same as in patients on placebo 
(hazard ratio (HR): λ linagliptin/λ placebo =1), 625 611patients with events will deliver an overall
power of 90% in a test to demonstrate non-inferiority of linagliptin vs. placebo within the 


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pre-specified non-inferiority (NI) margin of 1.3 for the HR; at the overall 1-sided α-level of 
2.5% and with one interim analysis at α=1.0% after 70% of the events (calculated with East, 
version 5.4). Assuming a study duration of 3.8 years, recruitment within 3 years and a 
cumulative lost to follow-up rate of 2.0%, 4150 patients per group are required to achieve 
625 patients with a primary endpoint. The change of the primary variable from 4-point 
MACE to 3-point MACE does not affect the required number of patients with event;
the slight reduction from 625 to 611 patients is due to the elimination of the interim 
analysis. Since the event rate is higher than initially assumed the same power can be 
achieved within the originally planned timelines with a sample size of approximately 
7000 patients.
Out of these, 531 patients are expected to experience CV death, non-fatal MI or non-fatal 
stroke. 
If the event distribution is lower than expected, the impact on the study conduct should be 
carefully considered. The SC would further monitor the recruitment of the trial with regard to 
baseline data for CV complications and renal impairment. The intent is to obtain a balanced 
mix of patients with CV complications and albuminuria AND patients with renal impairment. 
As such the SC may recommend to cap specific patient populations. 
If non-inferiority has been demonstrated, then superiority with regard to the primary endpoint 
will be tested. Assuming 625 611 patients with event and a hazard rate on linagliptin at any 
time 20% less than the risk on placebo (HR: λ linagliptin/λ placebo = 0.02848/0.0356 = 0.80), then 
the resulting power to demonstrate superiority at the final analysis is 74% 79% if the for a
test can be performed at the α-level of 1.59% 2.5% (cf. Section 7.2) and 69% if the test has to 
be performed at the α-level of 1.06%. If the risk reduction is 21.3% (HR: 0.787) and the test 
can be performed at the α-level of 1.59%, the power to demonstrate superiority is 80%; the 
power is 75% if the test has to be performed at the α-level of 1.06%.
Assuming 432 patients with a composite renal endpoint, a yearly event rate of 2.5% in the 
placebo group and a hazard rate HR on linagliptin of 0.75, then the resulting power to 
demonstrate superiority at the final analysis is 80% 85% if the test can be performed at the α-
level of 1.59% and 75% if the test has to be performed at the α-level of 1.06%2.5%. If the 
HR is 0.70, 210 patients with renal event provide a power of 73%.
If superiority for the primary endpoint and/or the composite renal endpoint has been 
demonstrated, then superiority with regard to the 3-point MACE (CV death, non-fatal MI, 
non-fatal stroke) will be tested. Assuming 531 patients with event and a hazard rate on 
linagliptin at any time 20% less than the risk on placebo (HR: 0.80), then the resulting power 
to demonstrate superiority at the final analysis is 70% if the test can be performed at the full 
α-level of 2.12% (if the primary endpoint and the composite renal endpoint are significant) 
and 50% if the test has to be performed at the α-level of 0.53% (if only one of these endpoints 
is significant). If the risk reduction is 21.3% (HR: 0.787), then the resulting power to 
demonstrate superiority at the final analysis is 76% if the test can be performed at the full α-
level of 2.12% and 58% if the test has to be performed at the α-level of 0.53%.


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All calculations are based on an allocation ratio between treatment groups of 1:1 and were 
derived using ADDPLAN (version 6.0.4), East (version 5.4) and nQuery Advisor (version 
6.0.1).


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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 
Good Clinical Practice (GCP), relevant SOPs of the clinical CRO 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/CRO 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> 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.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File).
The certificate of insurance cover is made available to the Investigator and the patients, and 
is stored 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 / Independent Ethics Committee (IEC) and competent 
authority (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 BI 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 or Clinical Quality Assurance auditors appointed by Boehringer Ingelheim, by 
appropriate IRB / IEC members, and by inspectors from regulatory authorities.


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The following text is only applicable 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 institutional review board 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 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
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/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.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor/CRO, via remote data capture. 
See Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.


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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 site.
Data reported 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. All possible attempts should be 
made to collect source documents for events that trigger adjudication.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/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 clinical trial monitor, 
auditor and inspection by health authorities (e.g. FDA). The Clinical Research Associate 
(CRA) / on site monitor and auditor may review all CRFs/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:  “Storage period of records
Trial site(s):The trial site(s) must retain the source documents and essential documents for a 
period defined by the Japanese GCP regulation and the sponsor’s or designated CRO SOP.
Sponsor: The sponsor/CRO must retain the essential documents according to the sponsor’s 
or designated CRO SOPs. When it is no longer necessary for the trial site to retain the source 
documents and essential documents, the sponsor representative 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 or CRO
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 linagliptin this is the current version of the Company Core Data Sheet (CCDS). 
No AEs are classified as listed for matching placebo, study design, or invasive procedures. 


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8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
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 / IEC and the regulatory authorities For EU, i.e. 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 the sponsor representative of the completion in writing.
For EU member states: The EC/competent authority in each participating EU member state 
needs to be notified about the end of the trial (last patient out, unless specified differently in 
Section 6.2.3 of the CTP) or early termination of the trial. 
8.7 
PROTOCOL VIOLATIONS
For Japan: The investigator or sub-investigator should record all CTP violations. The 
investigator should provide and submit the sponsor representative 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 representative 
is responsible for compensation based on the contract signed by the trial site.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R07-1076
International Diabetes Federation, Clinical Guidelines Task Force. Global 
guideline for type 2 diabetes. Brussels: International Diabetes Federation 
(2005)
R07-4080
Klein S, Allison DB, Heymsfield SB, Kelley DE, Leibel RL et al. Waist 
circumference and cardiometabolic risk: a consensus statement from Shaping 
America’s Health: Association for Weight Management and Obesity 
Prevention; NAASO, The Obesity Society; the American Society for 
Nutrition; and the American Diabetes Association.  Am J Clin Nutr 
2007;85:1197-202.
R08-1310
AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American 
association of clinical endocrinologists medical guidelines for clinical practice 
for the management of diabetes mellitus.
Endocr Pract 13 (Suppl 1), 3 - 68 (2007)
R09-1164
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, 
Zinman B; American Diabetes Association; European Association for Study 
of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a 
consensus algorithm for the initiation and adjustment of therapy: a consensus 
statement of the American Diabetes Association and the European Association 
for the Study of Diabetes. Diabetes Care. 2009;32:193-203.
R09-2151
Guidance for industry: diabetes mellitus - evaluating cardiovascular risk in
new antidiabetic therapies to treat type 2 diabetes (December 2008). Silver
Spring: U.S.Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2008
R09-6397
Asian-Pacific Type 2 Diabetes Policy Group. Type 2 diabetes: practical targets 
and treatments. 4th ed. Melbourne, Singapore: International Diabetes Institute, 
In Vivo Communications (Asia) (2005)
R09-6400
Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, 
Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G; ADOPT Study 
Group. Glycemic durability of rosiglitazone, metformin, or glyburide 
monotherapy. N Engl J Med. 2006;355:2427-43
R09-6405
Effect of intensive blood-glucose control with metformin on complications in 
overweight patients with type 2 diabetes (UKPDS 34). UK Prospective 
Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65


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R09-6406
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up 
of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-
89
R09-6407
Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of 
Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med 2008; 358(24): 
2545-2559
R09-6408
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve 
FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, 
Vitek ME, Henderson WG, Huang GD; VADT Investigators. Glucose control 
and vascular complications in veterans with type 2 diabetes. N Engl J Med. 
2009 Jan 8;360(2):129-139
R09-6409
Meier JJ, Nauck MA. Glucagon-like peptide 1 (GLP-1) in biology and 
pathology. Diabetes Metab Res Rev 2005;21:91–117 
R09-6410
Monami M, Iacomelli I, Marchionni N, Mannucci E. Dipeptydil peptidase-4 
inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. 
Nutrition, Metabolism and Cardiovascular Diseases, article in press, doi: 
10.1016/j.numecd.2009.03.015 Nutr Metab Cardiovasc Dis 2009
R10-0116
Vaccaro O, Eberly LE, Neaton JD, Yang L, Riccardi G, Stamler J, Multiple 
Risk Factor Intervention Trial (MRFIT) Research Group. Impact of diabetes 
and previous myocardial infarction on long-term survival: 25-year mortality 
follow-up of primary screenees of the Multiple Risk Factor Intervention Trial. 
Arch Intern Med 164, 1438 - 1443 (2004)
R10-0117
Gu K, Cowie CC, Harris MI. Mortality in adults with and without diabetes in a 
national cohort of the U.S. population, 1971 - 1993. Diabetes Care 21 (7), 
1138 – 1145 (1998)
R10-0133
Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving 
in U.S. adults? Diabetes Care 2008;31:81-86
R10-0134
Liebl A, Mata M, Eschwege E, Advisory Board. Evaluation of risk factors for 
development of complications in Type II diabetes in Europe. Diabetologia 
2002;45:S23-8 
R10-4077
National Institute for Health and Clinical Excellence. Type 2 diabetes: newer 
agents for blood glucose control in type 2 diabetes (this short clinical guideline 
partially updates NICE clinical guideline 66. The recommendations have been 
combined with unchanged recommendations from CG66 in NICE clinical 
guideline 87 (NICE short clinical guideline 87, issue date: May 2009). 
weblink: nice.org.uk ; London: National Institute for Health and Clinical 
Excellence (2009)


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R10-4342
Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The Prevalence of 
Comorbid Depression in Adults With Diabetes, a meta-analysis. Diabetes Care 
2001;6(24): 1069-1078.
R10-6494
Vigneri P, FF, Sciacca L, PG, Vigneri R. Diabetes and cancer. Endocr Relat 
Cancer 2009;16:1103-1123.
R10-6495
Hemminki K, Li X, Sundquist J, Sundquist K. Risk of cancer following 
hospitalisation for type 2 diabetes. Oncologist 2010;15:548-555.
R10-6496
Giovannucci E, Michaud D. The role of obesity and related metabolic 
disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology 
2007;132(6):2208-2225.
R10-6497
Smith U, Gale EAM. Does diabetes therapy influence the risk of cancer? 
Diabetologia 2009;52:1699-1708.
R10-6498
Xue F, Michels KB. Diabetes, metabolic syndrome, and breast cancer: a 
review of the current evidence. Am J Clin Nutr 2007;86(Suppl):823S 835S. 
R10-6536
Hjartaker A, Langseth H, Weiderpass E. Obesity and diabetes epidemics: 
cancer repercussions. In: Berstein LM, Santen RJ, editors.Innovative 
endocrinology of cancer.Austin: Landes Bioscience 2008:72-93.
R10-6638
Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel 
LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus 
report. Diabetes Care 33 (7), 1674 - 1685 (2010)
R11-4860 
   Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, 
   Marinopoulos SS, Puhan MA, Ranasinghe P, Block L, Nicholson WK, 
   Hutfless S, Bass EB, Bolen S. Comparative effectiveness and safety of 
   medications for type 2 diabetes: an update including new drugs and 2-drug 
   combinations. Ann Intern Med 2011;154(9):602-613. 
R12-1135 
R12-4087
   Bartnik M, Ryden L, Ferrari R, Malmberg K, Pyorala K, Simoons M, Standl E, 
   Soler-Soler J, Ohrvik J, Euro Heart Survey Investigators. The prevalence of 
   abnormal glucose regulation in patients with coronary artery disease across 
   Europe: the Euro Heart Survey on diabetes and the heart. Eur Heart J 
   2004;25:1880-1890
   Dmitrienko A, Tamhane AC, Wiens BL.General multistage gatekeeping 
   procedures. Biometr J 50 (5), 667 - 677 (2008)
P08-01788
Ryden L, Standl E, Bartnik M, Berghe G van den, Betteridge J, Boer MJ de, 
Cosentino F, Jonsson B, Laakso M, Malmberg K, Priori S, Ostergren J, 
Tuomilehto J, Thrainsdottir I. Guidelines on diabetes, pre-diabetes, and 
cardiovascular diseases: full text: the Task Force on Diabetes and 


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Cardiovascular Diseases of the European Society of Cardiology (ESC) and of 
the European Association for the Study of Diabetes (EASD).Eur Heart J 9 
(Suppl C), C3 - C74 (2007)
P08-06509
Johansen OE. Cardiovascular disease and type 2 diabetes mellitus: a 
multifaceted symbiosis. Scand J Clin Lab Invest 2007;67(8):786-800. 
P10-00533
Canadian Diabetes Association Clinical Practice Guidelines Expert 
Committee. Canadian Diabetes Association 2008 clinical practice guidelines 
for the prevention and management of diabetes in Canada. Can J Diabetes 
32(suppl 1), S1-S201. 2008
P12-00933
Johansen OE, Neubacher D, Eynatten M von, Patel S, Woerle HJ
Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: 
a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 
programme. Cardiovasc Diabetol 11, 3 (2012)
R16-4473
Bretz F, Maurer W, Brannath W, Posch M (2009) A graphical approach to 
sequentially rejective multiple test procedures. Statist Med; 28:586-604
9.2
UNPUBLISHED REFERENCES
U04-1767
 Linagliptin Investigator's Brochure. Current Version.


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10.
APPENDICES
10.1
INCLUSION OF ILLITERATE PATIENTS
10.1.1
Home blood glucose monitoring
In the event of recruiting an illiterate patient, the following process should be followed with 
respect to HBGM and documenting the results:
-
at visit 1(screening), 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 site staff should confirm that this individual will be present with the patient, whenever 
he/she is likely to need to perform HBGM
-
the 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 
control solution(s).  Furthermore, if whole blood referenced test strips are standard in the 
country(ies) where illiterate patients are being recruited, the 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 site staff should also train both the patient and the above-mentioned individual with 
respect to the completion of the HBGM diary.  As for all other patients, the results of all 
per-protocol HBGM that is performed by/on illiterate patients should be documented on a 
HBGM diary that will be included in the patients source document file.  In the event of 
hyper or hypoglycaemia, the person assisting the patient should record symptoms on the 
HBGM diary in accordance with the patients’ description  
HGBM tests can be performed either by the patient him/herself, or by the person assisting the 
patient with this aspect of the trial. 
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 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 


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-
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 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 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 site personnel also signs and personally dates the informed consent form
10.2
DEFINITIONS OF ENDPOINT EVENTS
Definitions of the adjudicated endpoint events and the principles of standardised data 
collection in the centralised CEC adjudication process are outlined in the CEC charters and 
process guidelines. 
10.3
BLOOD PRESSURE MEASUREMENT PROCEDURE 
Initially, blood pressure should be taken three times in both arms. The arm with the higher 
pressure (either systolic –if needed to decide- or diastolic) should be used for subsequent 
measurements.
Blood pressure measurements can be performed with either a standard mercury 
sphygmomanometer or a fully automated blood pressure device, depending on the standard 
practice at each study site - Note: BI will not provide electronic devices to sites that use the 
standard manual sphygmomanometers. The fully automated blood pressure devices should be 
validated by website: dableducational.org. Other devices are not acceptable.


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Blood pressure measurements should be performed on the same arm and, if possible, by the 
same person. The same method must be used throughout the trial, for a given patient, i.e. if a 
patient receives the first blood pressure measurement for example with an electronic device, 
the same method and a similar type of device should be used throughout the study for this 
patient (without switching to manual blood pressure measurement).  On the other hand, inter-
patients variability is acceptable, i.e. a study site is allowed to consistently use an electronic 
device to measure the blood pressure in a given patient throughout the study and a manual 
technique in another patient.
After patients have rested quietly, in the seated position for five minutes, three blood pressure 
measurements will be taken approximately two minutes apart.  The seated pulse rate will be 
taken during the two-minute interval between the second and third blood pressure reading. If 
an electronic blood pressure device is used the pulse rate at time of the second blood pressure
reading may should be used.
Blood pressure measurements should be recorded to the nearest 0 or 5 mmHg only when 
measured with a manual sphygmomanometer; when digital devices are used the value from 
the device should be rounded to the nearest 1 mmHg. For calculation of mean values, 
decimal places should be rounded to integers (e.g. a DBP of 94.5 would be rounded to 95 
mmHg and a DBP of 109.4 would be rounded to 109 mmHg or 110 mmHg in case of a 
manual sphygmomanometer). The mean value should be recorded in the eCRF.
10.4
SILENT MYOCARDIAL INFARCTION
Incidence and impact of silent MI will be assessed in this study. Its definition is based on the 
global MI guidelines currently described as the presence in the ECG of: 
Definition of relevant ECG abnormalities related to silent MI is the presence of:

Any Q-wave in leads V2-V3 ≥ 0.02 seconds or QS complex in leads V2 and V3

Q-wave ≥ 0.03 seconds and ≥ 0.1 mV deep or QS complex in leads I, II, aVL, aVF, or 
V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V6; V4-V6; II, III, and 
aVF)

R-wave ≥ 0.04 seconds in V1-V2 and R/S ≥ 1 with a concordant positive T-wave in 
the absence of a conduction defect
An MI will only be classified as silent if 1) the ECG criteria’s are fulfilled, 2) the ECG 
changes were absent from baseline or previous ECGs and 3) no preceding clinical history of 
MI (including stent thrombosis and other coronary events) during study follow-up 
occurred and 4) investigator reporting of silent MI.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of CTP modification
1
Date of CTP modification
24 October 2013
EudraCT number
2011-004148-23
BI Trial number
1218.22
BI Investigational Product(s)
Linagliptin (BI 1356)
Title of protocol
A multicenter, international, randomized, 
parallel group, double-blind, placebo-controlled 
CArdiovascular Safety & Renal Microvascular 
outcomE study with LINAgliptin, 5 mg once 
daily in patients with type 2 diabetes mellitus at 
high vascular risk. CARMELINA
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Clinical trial protocol synopsis (objectives)
Description of change
....sustained loss in estimated global filtration rate (eGFR) 
≥ 50% from baseline… 
Was changed into:
....sustained decrease in estimated global filtration rate 
(eGFR) ≥ 50% from baseline …
Rationale for change
To use consistent terminology
Section to be changed
Clinical trial protocol synopsis (criteria for efficacy)
Description of change
Change 1:
  
   


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Description of change
  
   
 
   
  
   
 
   
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
Change 2:
For clarification.
Change 3:
To use consistent terminology.
Change 4:
To clarify that endpoint event definitions are outlined in 
the CEC charters.
Section to be changed
Clinical trial protocol synopsis (statistical methods)
Description of change
b) the composite renal endpoint (i.e. renal death, 
sustained ESRD, sustained loss in estimated GFR ≥ 50% 
from baseline) 
was changed into:


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b) the composite renal endpoint (i.e. renal death, 
sustained ESRD, sustained decrease in estimated GFR ≥ 
50% from baseline 
Rationale for change
To use consistent terminology.
Section to be changed
Flowchart
Description of change
Change 1:
Adding pharmacogenetic sampling.
Change 2:
Footnote C: …end of trial (EOT visit) was changed into: 
end of treatment (EOT visit).
Change 3:
Footnote  C: Patients who discontinue study drug 
prematurely should continue study visits until study end, 
but no physical examination, vital signs, (safety) 
laboratory sampling (including pregnancy test, lipid panel 
HbA1c , UACR and eGFR) or ECG will be required.
Was changed into:
Footnote C: Patients who discontinue study drug 
prematurely should continue study visits until study end. 
Study assessments may be omitted if a patient is willing 
to return to the pre-defined study visits, with exception of 
, collection of adverse events, 
outcome events, concomitant therapy and laboratory 
testing of creatinine for the calculation of the eGFR. 
Change 4:
The following text under footnote G was deleted:
 
 
 
 
 
 
 
 
 


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Change 5:
Footnote K:
At visit 1 safety laboratory includes ALT, AST, alkaline 
phosphatase and creatinine to check for eligibility in 
addition to urine albumin, urine creatinine and HbA1c as 
specified in the flow chart. 
Was changed into:
At visit 1 safety laboratory includes ALT, AST, alkaline 
phosphatase and creatinine to check for eligibility in 
addition to lipase, urine albumin, urine creatinine and 
HbA1c as specified in the flow chart. 
Change 6:
Footnote L: …In case of an eGFR loss of ≥50% since 
baseline (visit 2) an additional visit 4 weeks after 
detection should be scheduled to collect a blood sample 
for repeat analysis of creatinine (eGFR)….
Was changed into:
…In case of an eGFR decrease of ≥ 40%  since baseline 
(visit 2) and again in case of an eGFR decrease of ≥50% 
since baseline (visit 2) an additional visit 4 weeks after 
detection should be scheduled to collect a blood sample 
for repeat analysis of creatinine (eGFR)….
Change 7:
Footnote N: ….. (plus 2 week reserve) was changed into:
…(2 weeks reserve).
Change 8:
Footnote O: Returned study medication may be re-
dispensed if the time window around the patient visit 
schedule requires this.  
Was changed into:
Footnote O: The protocol allows a time window of +/- 7 
days for visit 3 and +/- 14 days for all scheduled visits in 
the treatment period after visit 3. To ensure sufficient 
medication, visits after visit 3 should be scheduled within 
182 days and visit 3 should take place no later 
than 91 days after visit 2. 
Change 9:
Footnote P was added: To allow possible retrospective 
pharmacogenetic analyses, all patients eligible for 
randomization will be asked for a blood sample with a 
separate informed consent. The pharmacogenetic sample 
should preferably be taken at visit 2, but could also be 
taken at any later visit, depending on availability of the 
respective informed consent. Pharmacogenetic sampling 
is voluntary and is not a prerequisite for participation in
the study. 


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Change 10:
Footnote Q was added: Urine Albumin Creatinine
Ratio (UACR) will be calculated at the central lab, and 
should be measured on a first morning void specimen 
wherever possible.
Rationale for change
Change 1:
To allow possible retrospective pharmacogenetic 
analyses.
Change 2:
For clarification.
Change 3:
For clarification and to add creatinine for calculation of 
eGFR to the assessments for patients who pre-maturely 
discontinue study medication, but are willing to return to 
the pre-defined study visits (ITT principle, primary renal 
endpoint).
 
Change 5:
To add lipase to the laboratory assessment schedule.
 
 
Change 7:
Correction of typographical error. 
Change 8:
To clarify the allowed time window between study visits 
in relation to the available study medication dispensed.
Change 9:
To add an explanatory footnote for the pharmacogenetic 
sampling added to the flowchart.
Change 10: 
For clarification in line with section 5.2.3 of the clinical 
trial protocol.
Section to be changed
Abbreviations
Description of change
The following abbreviation was added:
DNA – Deoxyribonucleic Acid
In addition:
EOT - End of Trial was changed into: EOT – End of 
Treatment.
Rationale for change
Change 1:
Abbreviation added.


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Change 2:
For clarification.
Section to be changed
1.1 Medical background
Description of change
In this large-scale intervention trial we will test the 
impact of treatment with the DPP-4 inhibitor linagliptin 
head-to-head versus placebo on long-term CV safety. 
Was changed into:
In this large-scale intervention trial we will test the 
impact of treatment with the DPP-4 inhibitor linagliptin 
head-to-head versus placebo on long-term CV safety as 
well as the potential preventive impact on CV and renal 
complications.
Rationale for change
To underscore the importance of the renal aspects in the 
study.
Section to be changed
2.1 Rationale for performing the trial
Description of change
Paragraph 5: 
…predefined urin albumin …was changed into 
….predefined urine albumin. 
Rationale for change
Correction of typographical error. 
Section to be changed
3.1 Overall trial design and plan
Description of change
Change 1:
End of Trial….. was changed into: End of Treatment….
Change 2:
….Patients who discontinue study drug prematurely 
should continue study visits until study end, but no 
physical examination, vital signs, (safety) laboratory 
sampling (including pregnancy test, lipid panel HbA1c ,
UACR and eGFR) or ECG will be required.
Was changed into:
Patients who discontinue study drug prematurely should 
continue study visits until study end. Study assessments 
may be omitted if a patient is willing to return to the pre-
defined study visits, with exception of 
 
collection of adverse events, outcome events, 
concomitant therapy and laboratory testing of creatinine 
for the calculation of the eGFR.
Rationale for change
Change 1:
For clarification.
Change 2:
For clarification and to add creatinine for calculation of 
eGFR to the assessments for patients who pre-maturely 
discontinue study medication, but are willing to return to 
the pre-defined study visits (ITT principle, primary renal 
endpoint).


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Section to be changed
3.1.1 Administrative structure of the trial
Description of change
Additionally, a separate independent, blinded, external 
committee will be set up for adjudication of renal events. 
The adjudication process for renal events will be clarified 
separately in a CEC charter.
Was changed into:
Additionally, separate independent, blinded, external 
committees will be set up for adjudication of renal events 
and pancreatic events. The adjudication process for renal 
events and pancreatic events will be clarified in a 
separate CEC charter.
Rationale for change
To add independent adjudication of pancreatic events. 
Section to be changed
3.3.2 inclusion criteria
Description of change
Change 1:
Inclusion criterion number 8: the definition of  
albuminuria  ≥ 30 mg/l (milligram albumin per litre of 
urine) was removed.
Change 2:
Inclusion criterion number 8: Impaired renal function (as 
defined by MDRD formula) with an eGFR: 15- 45 
mL/min/1.73 m2 at Visit 1 (screening) with any UACR.
Was changed into:
Impaired renal function (as defined by MDRD formula) 
with an eGFR: 15- <45 mL/min/1.73 m2 at Visit 1 
(screening) with any UACR.
Change 3:
Inclusion criterion number 8: the definition of UACR      
≥ 200 mg/l (milligram albumin per litre of urine) was 
removed.
Change 4: 
Inclusion criterion number 8: MRI angiography was 
added as clinical test and clinical tests were added to the 
second bullet under inclusion criterion 8b and 8c.
Rationale for change
Change 1:
To reflect the definition KDIGO Clinical Practice 
Guideline for the Evaluation and Management of Chronic 
Kidney Disease.
Change 2:
For clarification.
Change 3:
To reflect the definition KDIGO Clinical Practice 
Guideline for the Evaluation and Management of Chronic 
Kidney Disease.
Change 4:
To add MRI angiography as clinical test and to clarify 


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allowed clinical testing for inclusion criterion 8b and 8c. 
Section to be changed
3.3.3 exclusion criteria
Description of change
Exclusion criterion number 5: ..(open or laparascopic) 
..was changed into… (open or laparoscopic)…
Rationale for change
Correction of typographical error.
Section to be changed
3.3.4.1 Removal of individual patient
Description of change
….Patients who discontinue study drug prematurely 
should continue study visits until study end, but no 
physical examination, vital signs, (safety) laboratory 
sampling (including pregnancy test, lipid panel HbA1c ,
UACR and eGFR) or ECG will be required.
Was changed into:
Patients who discontinue study drug prematurely should 
continue study visits until study end. Study assessments 
may be omitted if a patient is willing to return to the pre-
defined study visits, with exception of 
 
, collection of adverse events, outcome events, 
concomitant therapy and laboratory testing of creatinine 
for the calculation of the eGFR.
Rationale for change
For clarification and to add creatinine for calculation of 
eGFR to the assessments for patients who pre-maturely 
discontinue study medication, but are willing to return to 
the pre-defined study visits (ITT principle, primary renal 
endpoint).
Section to be changed
4.1.4 Drug assignment and administration of doses for
each patient
Description of change
Change 1:
Paragraph 4: …..Returned study medication may be re-
dispensed if the time window around the patient visit 
schedule requires this. 
Was changed into:
The protocol allows a time window of +/- 7 days for visit 
3 and +/- 14 days for all scheduled visits in the treatment 
period after visit 3. To ensure sufficient medication, visits 
after visit 3 should be scheduled within 182 days and visit 
3 should take place no later than 91 days after visit 2.
Change 2:
Paragraph 4….. (plus 2 week reserve) was changed into:
…(2 weeks reserve).
Rationale for change
Change 1:
To clarify the allowed time window between study visits 
in relation to the available study medication dispensed.
Change 2:
To correct a typographical error


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Section to be changed
5.1.1 Endpoint(s) of efficacy
Description of change
  
   
  
    
 
    
 
    
 
    
 
    
Change 2: 
Albuminuria change over time was changed into: UACR 
change over time.
Change 3:
Sustained loss of 50% or more in eGFR was changed 
into: Sustained decrease of 50% or more in eGFR.
In addition:
Composite microvascular outcome (50% loss of eGFR, 
albuminuria progression, requirement for renal 
replacement therapy or death due to renal failure, use of 
retinal photocoagulation or intravitreal injections of an 
anti-VEGF therapy for diabetic retinopathy).
was changed into:
Composite microvascular outcome (50% decrease or 
more in eGFR, albuminuria progression, requirement for 
renal replacement therapy or death due to renal failure, 
use of retinal photocoagulation or intravitreal injections 
of an anti-VEGF therapy for diabetic retinopathy).
Change 4:
The following text was added: Definitions of the 
adjudicated endpoint events are outlined in the CEC 
charters.
Rationale for change
Change 2:
For clarification.
Change 3:
To use consistent terminology.
Change 4:
To clarify that endpoint event definitions are outlined in 
the CEC charters.


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Section to be changed
5.2.2.1 Definitions of adverse events
Description of change
Change 1:
A list of terms that must be documented as AESI for each 
topic is provided in the ISF.  Renal events will be 
adjudicated by an independent adjudication committee.
Was changed into:
A list of terms that must be documented as AESI for each 
topic is provided in the ISF.  Renal events and pancreatic 
events will be adjudicated by independent adjudication 
committees.
Change 2:
Patients showing an elevation of AST and/or ALT ≥ 3 
fold ULN combined with an elevation of total bilirubin ≥ 
2 fold ULN measured in the same blood sample need to 
be followed up locally.
Was changed into:
Patients showing an elevation of AST and/or ALT ≥ 3 
fold ULN combined with an elevation of total bilirubin ≥ 
2 fold ULN measured in the same blood sample need to 
be followed up locally according to the “DILI checklist” 
provided in ISF.
Change 3:
In case of an eGFR loss of  ≥ 50% since baseline (Visit 2) 
an additional visit 4 weeks after detection should be 
scheduled (unless detected at the EOT visit at study end) 
to collect a blood sample for repeat analysis of creatinine 
for calculation of the eGFR.
Was changed into:
In case of an eGFR decrease of ≥ 40%  since baseline 
(visit 2) and again in case of an eGFR decrease of  ≥ 50% 
since baseline (visit 2) an additional visit 4 weeks after 
detection should be scheduled (unless detected at the 
EOT visit at study end) to collect a blood sample for 
repeat analysis of creatinine for calculation of the eGFR.
Rationale for change
Change  1:
Adjudication of pancreatic events added.
Change 2:
To provide additional guidance for follow-up of patient 
showing an elevation of AST and/or ALT ≥ 3 fold ULN 
combined with an elevation of total bilirubin ≥ 2 fold 
ULN.
Change 3:
To add an additional trigger for repeat analysis of eGFR 
in line with the newly added tertiary endpoints. 


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Section to be changed
5.2.2.2 Adverse event and serious adverse event 
reporting
Description of change
Change 1:
All adverse events, serious and non-serious, occurring 
during the course of the clinical trial (i.e., from signing 
the informed consent onwards through 1 week residual 
effect period) will be collected, documented and reported 
to the sponsor/CRO by the investigator on the appropriate 
CRF(s) / eCRFs/ SAE reporting forms. The investigator 
should report any SAEs which occurred to a subject after 
the residual effect period/follow-up period.
Was changed into:
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 visit) will be collected, documented and reported 
to the sponsor/CRO by the investigator on the appropriate 
CRF(s) / eCRFs/ SAE reporting forms. 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 last per protocol visit, it should be reported by 
the investigator to the sponsor if considered relevant by 
the investigator.
Change 2:
If not stipulated differently in the ISF, the investigator 
must report the following events, using the CRO 
electronic submission process immediately (within 24 
hours or the next business day whichever is shorter) to 
the sponsor/CRO: SAEs, AESI and non-serious AEs 
relevant for the reported SAE or AESI.
The investigator must document immediately (within 24 
hours or the next business day whichever is 
shorter)……….
Was changed into:
The investigator must report the following events, 
immediately (within 24 hours of awareness) to the 
sponsor/CRO: SAEs, AESI and non-serious AEs relevant 
for the reported SAE or AESI.
The investigator must document immediately (within 24 
hours of awareness)….
Change 3:
….. or by using the electronic submission process was 
deleted. 
Change 4:
Drug exposure during pregnancy has to be reported 
immediately (within 24 hours or next business day 
whichever is shorter)…


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Was changed into:
Drug exposure during pregnancy has to be reported 
immediately (within 24 hours of awareness)….
Rationale for change
Change 1: 
To clarify that AEs are collected even after the residual 
effect period for patients who pre-maturely discontinue 
study medication and to clarify that SAEs which occurred 
to a subject after the last per protocol should be reported
if considered relevant by the investigator.
Change 2:
To reflect the paper based reporting process and to update 
the definition of immediately. 
Change 3:
To reflect the paper based reporting process and to update 
the definition of immediately. 
Change 4:
To update the definition of immediately. 
Section to be changed
5.2.3 Assessment of safety laboratory parameters
Description of change
Lipase added to visit 1 and visit 2
In addition:
Visit 3 – EOT 

Clinical chemistry: creatinine

Urine analysis: albumin and creatinine (Visit 4, Visit 
6 and thereafter yearly).

Clinical chemistry: cholesterol (total), HDL 
cholesterol, LDL cholesterol and triglycerides (Visit 
4, Visit 6 and thereafter yearly)
HbA1c will be determined at all scheduled visits.
Was changed into:
Visit 3 – EOT - FU

Clinical chemistry: creatinine and lipase

Urine analysis: albumin and creatinine (Visit 4, Visit 
6 and thereafter yearly).

Clinical chemistry: cholesterol (total), HDL 
cholesterol, LDL cholesterol and triglycerides (Visit 
4, Visit 6 and thereafter yearly)
HbA1c will be determined at all scheduled visits, with 
exception of the FU visit.
Rationale for change
For clarification and to add lipase to the laboratory 
assessment schedule.


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Section to be changed
5.2.5 Assessment of other safety parameters
Description of change
……If not stipulated differently in the ISF, patient … 
was deleted.
Rationale for change
Following confirmation that a paper diary is used.
Section to be changed
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale for change
Change 1: To reflect recruitment planning per country 
following completion of feasibility. 
Change 2: For clarification.
 
Section to be changed
5.3.3 Pharmacogenomic evaluation
Description of change
Section 5.3.3 was added.
Rationale for change
To allow possible retrospective pharmacogenetic 
analyses.


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Section to be changed
6.2.3 End of trial and follow-up period
Description of change
Sub header was changed into end of treatment and 
follow-up.
In addition:
Patients who discontinue study drug prematurely should 
continue study visits until study end, but no physical 
examination, vital signs, (safety) laboratory sampling 
(including pregnancy test, lipid panel HbA1c , UACR and 
eGFR) or ECG will be required.
Was changed into:
Patients who discontinue study drug prematurely should 
continue study visits until study end. Study assessments 
may be omitted if a patient is willing to return to the pre-
defined study visits, with exception of 
 
 collection of adverse events, outcome events, 
concomitant therapy and laboratory testing of creatinine 
for the calculation of the eGFR.
Rationale for change
For clarification and to add creatinine for calculation of 
eGFR to the assessments for patients who pre-maturely 
discontinue study medication, but are willing to return to
the pre-defined study visits (ITT principles, primary renal 
endpoint).
Section to be changed
7.1 Statistical design –model
Description of change
If a patient dies without a primary outcome event, the 
patient will be censored at the date of death. 
Was changed into:
If any measurement of laboratory data or ECG is 
available after the last visit of a patient, the date of the 
respective measurement will be used for censoring of the 
CV endpoint. If any measurement of eGFR is available 
after the last visit of a patient, the date of the respective 
measurement will be used for censoring of the renal 
endpoint. For all endpoints including the component CV 
(renal) death, adjudicated CV (renal) death will be 
counted even if occurred thereafter.
Rationale for change
To add more specific information regarding censoring of 
the CV and renal endpoint, respectively.
Section to be changed
7.3 Planned analyses
Description of change
Additional analyses will be explored in specific 
subgroups, e.g. depending on characteristics at baseline 
with respect to the primary and secondary endpoints. 
Covariates that will be explored include:

Region (North America, Europe, Asia etc.)

Age (<65, ≥ 65 years)

Systolic and diastolic blood pressure (≤ 
160/100 mmHg , > 160/100 mmHg, other)

Gender (male, female)


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
Prior anti-diabetic treatment (none, 
monotherapy, combination therapy)
was changed to:
Additional analyses will be explored in specific 
subgroups, e.g. depending on characteristics at baseline 
with respect to the primary and key secondary endpoints. 
Covariates that will be explored include:

Region (North America, Europe, Asia etc.)

Age (<65, ≥ 65 years)

Systolic and diastolic blood pressure (≤ 160 
and ≤ 100 mmHg , > 160 or > 100 mmHg)

Gender (male, female)

Prior anti-diabetic treatment (none, 
monotherapy, combination therapy)

eGFR < 60 mL/min/1.73 m2 at baseline
Rational for change
To reflect definitions regarding systolic and diastolic 
blood pressure subgroups in other outcome studies and to 
add a subgroup analysis reflecting the renal status.
Section to be changed
7.3.2 Secondary analyses
Description of change
Change 1:
Composite renal endpoint (i.e. renal death, sustained 
ESRD, sustained loss of 50% or more in eGFR) 
was changed into:
Composite renal endpoint (i.e. renal death, sustained 
ESRD, sustained decrease of  50% or more in eGFR)
  
   
 
    
 
    
   
    
 
    
Change 3: 
Albuminuria change over time was changed into: UACR 
change over time.
Change 4:
Sustained loss of 50% or more in eGFR was changed 
into: Sustained decrease of 50% or more in eGFR.
In addition:
Composite microvascular outcome (50% loss of  eGFR, 
albuminuria progression, requirement for renal 
replacement therapy or death due to renal failure, use of 
retinal photocoagulation or intravitreal injections of an 
anti-VEGF therapy for diabetic retinopathy).


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was changed into:
Composite microvascular outcome (50% decrease or 
more in eGFR, albuminuria progression, requirement for 
renal replacement therapy or death due to renal failure, 
use of retinal photocoagulation or intravitreal injections 
of an anti-VEGF therapy for diabetic retinopathy).
Change 5: 
Clopper and Pearson confidence intervals  was changed 
into: Wilson confidence intervals.
Change 6: 
The following text was deleted:
Patients without occurrence of a specific endpoint will be 
considered censored at the end of study or lost to follow-
up, whichever comes first.
Change 7:
Last paragraph: secondary was changed into: key 
secondary.
Rationale for change
Change 1:
To use consistent terminology.
 
Change 3:
For clarification.
Change 4:
To use consistent terminology.
Change 5: 
Wilson confidence intervals are less conservative.
Change 6: 
Censoring has been addressed more specifically in 
section 7.1.
Change7:
For clarification/consistency
Section to be changed
7.3.7 Pharmacogenomic analyses
Description of change
Not specified in this protocol was changed into: No pre-
specified pharmacogenomics analyses planned. 
Rationale for change
To allow possible retrospective pharmacogenetic 
analyses.
Section to be changed
8.3.1 Source documents
Description of change
The following text was added: All possible attempts 
should be made to collect source documents for events 
that trigger adjudication.
Rationale for change
To emphasise the importance of source documents for 
adjudication of events. 


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Number of CTP modification
2
Date of CTP modification
22 November 2016
EudraCT number
2011-004148-23
BI Trial number
1218.22
BI Investigational Product(s)
Linagliptin (BI 1356)
Title of protocol
A multicenter, international, randomized, 
parallel group, double-blind, placebo-controlled 
CArdiovascular Safety & Renal Microvascular 
outcomE study with LINAgliptin, 5 mg once 
daily in patients with type 2 diabetes mellitus at 
high vascular risk. CARMELINA
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Title page
Description of change
 added as TCM
Rationale for change
 added as TCM
Section to be changed
Clinical trial protocol synopsis
Description of change
Change 1:
The primary endpoint changed from 4-point MACE to 3-
point MACE. 
The key secondary endpoints were changed from 3-point 
MACE and composite renal endpoint (renal death, 
sustained ESRD, sustained decrease of 50% or more in 
eGFR) to composite renal endpoint (renal death, 
sustained ESRD, sustained decrease of 40% or more in 
eGFR).
Change 2:
If non-inferiority has been demonstrated, then the 
primary composite endpoint will be tested for superiority 
and the other objective, to assess the impact of treatment 
with respect to the composite renal endpoint (i.e. renal 


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death, sustained end-stage renal disease (ESRD), 
sustained decrease in estimated global filtration rate 
(eGFR) ≥ 50% from baseline), will be investigated 
separately with a test on superiority.
Was changed into:
If non-inferiority has been demonstrated, then the 
primary composite endpoint will be tested for superiority 
and the other objective, to assess the impact of treatment 
with respect to the composite renal endpoint (i.e. renal 
death, sustained end-stage renal disease (ESRD), 
sustained decrease in estimated glomerular filtration rate 
(eGFR) ≥ 40% from baseline), will be investigated 
separately with a test on superiority
Change 3:
Number of randomized patients decreased from 8300 to 
7000 and number of patients per treatment group 
decreased from 4150 to 3500.
Change 4:
Number of patients with primary endpoint events 
decreased from 625 to 611 and estimated treatment 
period increased from 48 to 54 months.
Change 5:
The primary endpoint (4-point MACE) will be tested for 
non-inferiority. Thereafter the 4-point MACE and the 
combined composite renal endpoint will be tested 
separately (= in parallel) for superiority. In case the 4-
point MACE and/or the composite renal endpoint is 
significantly superior, the 3-point MACE will be tested 
for superiority. 
Was changed into:
The primary endpoint (3-point MACE) will be tested for 
non-inferiority. Thereafter if non-inferiority has been 
demonstrated the 3-point MACE and the combined 
composite renal endpoint will be tested separately for 
superiority.
 
  
 
 


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Change 8:
Statistical methods: The primary analyses will be 
performed on the full analysis set…
Was changed into:
The primary analyses will be performed on the Treated 
Set…
Change 9:
Statistical methods: … then two separate hypothesis tests 
for 

the primary composite endpoint 

the composite renal endpoint (i.e. renal death, 
sustained ESRD, sustained decrease in estimated 
GFR ≥ 50% from baseline)
will be tested for superiority in parallel, each with the 
Cox proportional hazards regression model for time to 
first event.
Was changed into:
Statistical methods: … then two separate hypothesis tests
for

the primary composite endpoint

the composite renal endpoint (i.e. renal death, 
sustained ESRD, sustained decrease in estimated 
GFR ≥ 40% from baseline)
will be tested for superiority, each with the Cox 
proportional hazards regression model for time to first 
event.
And the following text was added:
To adjust for multiplicity a sequentially rejective multiple 
test procedure will be applied.
Rationale for change
Change 1:
Based on review of recently published cardiovascular 
outcome trials, changing the protocol definitions of the 
primary and secondary endpoints, essentially substituting 
4-Point MACE (Cardiovascular (CV) Death, Non-Fatal 
Stoke, Non-fatal Myocardial Infarction and
Hospitalization for Unstable Angina) with 3-Point MACE 
(CV Death, Non-Fatal Stoke, Non-fatal Myocardial 
Infarction).
Change 2:
eGFR cut off changed in response to the NIH/FDA 
scientific workshop on GFR decline as an endpoint for 


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clinical trials in CKD and the current clinical landscape 
on decline in estimated glomerular filtration rate and 
subsequent risk of end stage renal disease and mortality.
Change 3:
Overall MACE event rates are higher than initially 
expected and this allows reducing the sample size without 
major impact on study duration.
Change 4:
Since the interim analysis for efficacy was deleted, the
required number of patients with primary endpoint to 
achieve a power of 90% for non-inferiority is reduced
from 625 to 611. The estimated trial duration increased 
slightly due to the change of the primary endpoint while 
ensuring a sufficiently long drug exposure for the last 
recruited patients.
Change 5: 
Since the primary endpoint was changed to 3-point 
MACE it is no longer listed as key secondary endpoint. 
 
 
 
 
Change 8:
For clarification
Change 9:
For clarification
Section to be changed
Flow chart
Description of change
Change 1:
Change in follow-up period from 7 to 30 days
Change 2:
Guidance revised on the timing of the EOT visit after 
study stop announcement after 611 endpoint events are 
reached
In addition

...changes since last visit might be recorded
Was changed into

...changes since last visit should be recorded


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Change 3:
Footnote L: estimated creatinine clearance
Was changed into:
Estimated glomerular filtration rate
Rationale for change
Change 1:
To allow for outcome event data collection up to 30 days 
after EOT
Change 2:
To clarify the respective actions to stop the trial when 
611 endpoint events are reached
Change 3: 
For clarification 
Section to be changed
Abbreviations
Description of change
CHC – Congestive Heart Failure and 
VEGF - Vascular endothelial growth factor deleted
OS - On-treatment Set and
TS – Treated Set were added
Rationale for change
Due to change in the text.
Section to be changed
1.2 Drug profile
Description of change
Drug profile section updated
Rationale for change
For clarification per current version of the investigator 
brochure.
Section to be changed
2.2 trial objectives
Description of change
Change 1: 
The primary endpoint changed from 4-point MACE to 3-
point MACE. 
The key secondary endpoints were changed from 3-point 
MACE and composite renal endpoint (renal death, 
sustained ESRD, sustained decrease of 50% or more in 
eGFR) to composite renal endpoint (renal death, 
sustained ESRD, sustained decrease of 40% or more in 
eGFR).
Change 2:
If non-inferiority has been demonstrated, then the 
primary composite endpoint will be tested for superiority 
and the other objective, to assess the impact of treatment 
with respect to the composite renal endpoint (i.e. renal 
death, sustained ESRD, sustained loss in estimated 
glomerular filtration rate (eGFR) ≥ 50% from baseline), 
will be investigated with a test on superiority.
The CV and renal superiority tests will be performed 
separately, with no upfront imbalance regarding the 
assigned alpha-levels. 
If linagliptin is superior with regard to the primary 
endpoint and/or the composite renal endpoint, a further 


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test will evaluate the superiority of linagliptin with regard 
to the 3-component Major Adverse Cardiovascular 
Events (MACE) endpoint (CV death [including fatal 
stroke, fatal MI and sudden death], non-fatal stroke, non-
fatal MI [excluding silent MI]).
Was changed into:
If non-inferiority has been demonstrated, then the 
primary composite endpoint will be tested for superiority 
and the other objective, to assess the impact of treatment 
with respect to the composite renal endpoint (i.e. renal 
death, sustained ESRD, sustained loss in estimated 
glomerular filtration rate (eGFR) ≥ 40% from baseline), 
will be investigated with a test on superiority.
The CV and renal superiority tests will be performed 
separately, with an upfront imbalance regarding the 
assigned alpha-levels.
Rationale for change
Change 1: 
Based on review of recently published cardiovascular 
outcome trials, changing the protocol definitions of the 
primary and secondary endpoints, essentially substituting 
4-point MACE (Cardiovascular (CV) Death, Non-Fatal 
Stoke, Non-fatal Myocardial Infarction and
Hospitalization for Unstable Angina) with 3-point MACE 
(CV Death, Non-Fatal Stoke, Non-fatal Myocardial 
Infarction).
eGFR cut off changed in response to the NIH/FDA 
scientific workshop on GFR decline as an endpoint for 
clinical trials in CKD and the current clinical landscape 
on decline in estimated glomerular filtration rate and 
subsequent risk of end stage renal disease and mortality.
Change 2:
A higher alpha-level will be assigned to the composite 
renal endpoint, the endpoint with the expected higher 
power for superiority. Nevertheless, this strategy allows 
testing both, 3-point MACE and the renal endpoint for 
superiority, independently of each other.
Section to be changed
3.1 Overall trial design and plan
Description of change
Change 1:
Number of randomized patients decreased from 8300 to 
7000 and number of patients per treatment group 
decreased from 4150 to 3500.
Change 2:
Number of endpoint events decreased from 625 to 611 
and estimated treatment period increased from 48 to 54 
months.
Change 3:
Guidance revised on the timing of the EOT visit after 


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study stop announcement after 611 endpoint events are 
reached.
Change 4:
Change in follow-up period from 7 to 30 days
Change 5:
…in a separate CEC charter
Was changed into:
…in the CEC charter
Rationale for change
Change 1:
Overall MACE event rates are higher than initially 
expected and this allows reducing the sample size without 
major impact on study duration.
Change 2:
Since the interim analysis for efficacy was deleted, the
required number of patients with primary endpoint to 
achieve a power of 90% for non-inferiority is reduced 
from 625 to 611. The estimated trial duration increased 
slightly due to the change of the primary endpoint while 
ensuring a sufficiently long drug exposure for the last 
recruited patients.
Change 3:
To clarify the respective actions to stop the trial when 
611 endpoint events are reached.
Change 4:
To allow for outcome event data collection up to 30 days 
after EOT 
Change 5:
For clarification
Section to be changed
3.3 Selection of trial population
Description of change
Number of randomized patients decreased from 8300 to 
7000 and number of patients per treatment group 
decreased from 4150 to 3500.
Rationale for change
Overall MACE event rates are higher than initially 
expected and this allows reducing the sample size without 
major impact on study duration
Section to be changed
3.3.3 Exclusion criteria
Description of change
Exclusion criterion 4: corrections of eGFR unit.
Rationale for change
For clarification 
Section to be changed
3.3.4.1 Removal of individual patients
Description of change
Patient retention language revised
Rationale for change
To optimize retention language
Section to be changed
4.1.1 identity of BI investigational product and 
comparator product(s)
Description of change
Film-coated added to tablets under pharmaceutical form 


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and sponsor entity omitted. 
Rationale for change
For clarification 
Section to be changed
4.1.5.1.
Description of change
Change 1:
Text related to code breaking in case of SUSARs added.
Change 2:
Text related to code breaking added for Japan
Rationale for  change
Change 1 and change 2:
For clarification
Section to be changed
4.1.7 storage condition 
Description of change
All trial medication should be stored according to the 
storage conditions as specified on the label and in the 
original package.
Was changed into:
The study medication must be kept in its original 
packaging under the recommended storage
conditions indicated on the label.
Rationale for change
For clarification
Section to be changed
4.2.2.
Description of change
DDP4 was changed to DPP4.
Rational for change
Correction of typographical error
Section to be changed
4.3 treatment compliance
Description of change
Capsules were changed into tablets
Rationale for change
Correction of error
Section to be changed
5.1.1 endpoints of efficacy
Description of change
Change 1:
The primary endpoint changed from 4-point MACE to 3-
point MACE. 
The key secondary endpoints were changed from 3-point 
MACE and composite renal endpoint (renal death, 
sustained ESRD, sustained decrease of 50% or more in 
eGFR) to composite renal endpoint (renal death, 
sustained ESRD, sustained decrease of 40% or more in 
eGFR).
In addition:
The primary endpoint in this trial is time to the first 
occurrence of any of the following adjudicated 
components of the primary composite endpoint…
Was changed into
The primary endpoint in this trial is time to the first 
occurrence of any of the following by adjudication 
confirmed components of the primary composite 
endpoint…..
Change 2:
At the final analysis the primary endpoint (4-point 
MACE) will be tested for non-inferiority. Thereafter the 


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4-point MACE and the combined composite renal 
endpoint will be tested separately (= in parallel) for 
superiority. In case the 4-point MACE and/or composite 
renal endpoint is significantly superior, the 3-point 
MACE will then be tested for superiority.
Was changed into:
The primary endpoint (3-point MACE) will be tested for 
non-inferiority. Thereafter, if non-inferiority has been 
demonstrated, the 3-point MACE and the combined 
composite renal endpoint will be tested separately for 
superiority. 
 
 
  
       
 
 
 
 
 
 
 
 
 


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In addition:
Definition of MI added.
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Change 5:
Definition of albuminuria progression updated.
Rationale for change
Change 1: Based on review of recently published 
cardiovascular outcome trials, changing the protocol 
definitions of the primary and secondary endpoints, 
essentially substituting 4-Point MACE (Cardiovascular 
(CV) Death, Non-Fatal Stoke, Non-fatal Myocardial 
Infarction and
Hospitalization for Unstable Angina) with 3-Point MACE 
(CV Death, Non-Fatal Stoke, Non-fatal Myocardial 
Infarction).
eGFR cut off changed in response to the NIH/FDA 
scientific workshop on GFR decline as an endpoint for 
clinical trials in CKD and the current clinical landscape 
on decline in estimated glomerular filtration rate and 
subsequent risk of end stage renal disease and mortality.
 
 
 
 
Change 4: 
For clarification
Change 5:
For clarification/correction of error. 
Section to be changed
5.2.1.1 reporting waiver for cardiovascular-outcome 
events
Description of change
….. secondary was changed into key secondary…
Rationale for change
For clarification
Section to be changed
5.2.2.1 definition of adverse events
Description of change
Change 1:
The definition of AEs was updated and AESI language 
was revised reflecting the newly released process by drug 
safety for reporting of AESIs. 


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Change 2:
Estimated creatinine clearance 
Was changed into:
Estimated glomerular filtration rate
Rationale for change
Change 1:
To reflect the current standard  AEs text and revised 
AESI process
Change 2:
For clarification 
Section to be changed
5.2.2.2 Adverse event and serious adverse event 
reporting
Description of change
Section was updated
Rationale of change
For clarification per current standard text.
Section to be changed
5.2.2.3 Oncological adverse events
Description of change
Added a reference to the oncology committee assessment 
charter
Rationale for change
For clarification
Section to be changed
5.2.3.1
Description of change
No renal impairment with evidence of kidney damage 
(UACR ≥30mg/ g creatinine)
Was changed into:
No renal impairment with evidence of kidney damage 
(eGFR 90 mL/min/1.73m2 and UACR ≥30mg/ g 
creatinine)
In addition definition of prevalent kidney disease added.
Rationale for change
For clarification
Section to be changed
6.2.2 treatment period & 6.2.3 end of treatment and 
follow-up
Description of change
Change 1:
Patient retention language revised
Change 2:
Change in follow-up period from 7 to 30 days
Rationale for change
Change 1:
To optimize retention language
Change 2: 
To allow for outcome event data collection up to 30 days 
after EOT 
Section to be changed
7.1 Statistical design - model
Description of change
Change 1:
Number of randomized patients decreased from 8300 to 
7000 and number of patients per treatment group 
decreased from 4150 to 3500.


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Change 2:
Number of endpoint events decreased from 625 to 611.
Change 3:
The primary endpoint was changed from 4-point MACE 
to 3-point MACE
Rationale for change
Change 1:
Overall MACE event rates are higher than initially 
expected and this allows reducing the sample size without 
major impact on study duration. The required number of 
patients with event is not affected by the lower number of 
randomised patients in this event-driven study
Change 2:
Since the planned interim analysis for efficacy will not be 
performed, a slightly lower number of patients with event 
is required for the same power (90% for non-inferiority)
Change 3:
Based on review of recently published cardiovascular 
outcome trials, changing the protocol definitions of the 
primary and secondary endpoints, essentially substituting 
4-Point MACE (Cardiovascular (CV) Death, Non-Fatal 
Stoke, Non-fatal Myocardial Infarction and
Hospitalization for Unstable Angina) with 3-Point MACE 
(CV Death, Non-Fatal Stoke, Non-fatal Myocardial 
Infarction).
Section to be changed
7.2 Null and alternative hypothesis
Description of change
Relevant changes are summarised as follows:
Change 1:
An interim analysis will be performed at the one-sided 
alpha-level of 1.0%, the final analysis at the one-sided 
alpha-level of 2.12%. At the interim analysis MACE 
endpoints will be tested in a pre-specified order, at the 
final analysis also the composite renal endpoint will be 
tested for superiority
Was changed into:
No confirmatory interim analysis for efficacy endpoints 
will be performed
Change 2:
The experimentwise (multiple) level alpha is controlled 
with the following three step gatekeeping hierarchy 
within the interim and final analysis, respectively.
For the final analysis, the first hypothesis (non-inferiority 
of the primary endpoint) will be tested at the one-sided 
alpha-level of 2.12%. In case of significance, the null 
hypothesis is rejected in a confirmatory sense and the 
next set of hypotheses (two separate hypothesis tests)
will be tested: a) test of the primary endpoint for 
superiority and b) test of the composite renal


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endpoint for superiority. To adjust for multiplicity the 
truncated Hochberg multiple test procedure will be 
applied with a selected gamma of 0.5. Both one-sided
hypotheses H0(Sup1) and H0(Sup2) will be tested 
separately. If both tests are significant at the one-sided 
alpha-level of 1.59% each, superiority of both endpoints 
(4-point MACE and composite renal endpoint) has been 
demonstrated. If not, superiority can only be claimed for
the endpoint significant at the alpha-level of 1.06%. If 
superiority of both, the 4-point MACE and the composite 
renal endpoint has been demonstrated at the one-sided 
alpha-level of 1.59% each, then superiority of the 3-point 
MACE can be tested at the alpha-level of 2.12%.
If superiority of only one of these endpoints (4-point 
MACE or composite renal endpoint) has been 
demonstrated at the one-sided alpha-level of 1.06%, then 
superiority of the 3-point MACE can be tested at the 
alpha-level of 0.53%.
Was changed into:
For the final analysis, the first hypothesis (non-inferiority 
of the primary endpoint) will be tested at the one-sided 
alpha-level of 2.5%. In case of significance, the null 
hypothesis is rejected in a confirmatory sense and the 
next set of hypotheses (two separate hypothesis tests) will 
be tested: a) test of the primary endpoint for superiority 
and b) test of the composite renal endpoint for 
superiority. To adjust for multiplicity a sequentially 
rejective multiple test procedure will be applied. Both 
one-sided hypotheses H0(Sup1) and H0(Sup2) will be 
tested separately, at the initial alpha-levels of 0.2*alpha 
for 3-point MACE and 0.8*alpha for the composite renal 
endpoint, respectively. If both null hypotheses cannot be 
rejected at these initial alpha-levels, the procedure stops 
and for none of these endpoints superiority can be 
declared. After having shown superiority for one of these 
endpoints, the used alpha can be shuffled to the other test: 
If H0(Sup2) is rejected at the alpha-level of 0.8*alpha, 
then H0(Sup1) can be tested at the full alpha-level of 
2.5% (one-sided). If H0(Sup1) is rejected at the alpha-
level of 0.2*alpha, then H0(Sup1) can be tested at the full 
alpha-level of 2.5% (one-sided).
Rationale for change
A higher alpha-level will be assigned to the composite 
renal endpoint, the endpoint with the expected higher 
power for superiority. Nevertheless, this strategy allows 
testing both, 3-point MACE and the renal endpoint for 
superiority, independently of each other.
Section to be changed
7.3 planned analysis
Description of change
Change 1:
Hospitalisation for unstable angina pectoris deleted from 
Important protocol violations.


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Change 2:
Systolic and diastolic blood pressure (≤160 and ≤100 
mmHg , > 160 or > 100 mmHg)
Was changed into:
Systolic and diastolic blood pressure (<140 and < 90 
mmHg , ≥ 140 or ≥ 90 mmHg)
Change 3:
Prior anti-diabetic treatment (none, monotherapy, 
combination therapy )
Was changed into:
Prior anti-diabetic treatment (insulin, no insulin)
Change 4:
The following subgroup has been added:
Prevalent kidney disease defined as eGFR < 60 
mL/min/1.73 m2 at baseline and/or UACR > 300mg/g 
creatinine at baseline
Change 5: 
‘In case only randomized patients take study drug, this set 
is identical to the FAS…’ was deleted
Change 6:
Analysis sets have been redefined in 7.3 and 7.3.1 as 
follows:
The full analysis set (FAS) consisting of all randomized 
patients who were treated with at least one dose of study 
drug
Was changed into:
The Treated Set consisting of all patients who were 
treated with at least one dose of study drug
In addition:
The ‘30-day treatment’ set of patients including all 
patients with minimum treatment duration of 30-days
Was changed into:
The ‘on-treatment’ set (OS) including all patients with 
minimum treatment duration of 30-days
In addition:


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The ‘on-treatment analysis’ on the FAS (consisting of all 
randomized patients who were treated with at least one 
dose of study drug) with censoring at the time patients are 
on treatment + 30 days after permanent treatment 
discontinuation or end of observation
Was changed into:
The ‘TS+30 analysis’ on the TS (consisting of all patients 
who were treated with at least one dose of study drug) 
with censoring at the time patients are on treatment + 30 
days after permanent treatment discontinuation or end of 
observation
Rationale for change
Change 1:
Deleted due to the change of the primary endpoint.
Change 2:
BP limit changed to 140/90 mmHg, to reflect BP 
treatment standards for the CARMELINA population.
Change 3:
Insulin treatment (with or without oral anti-diabetics) is 
considered the most important differentiator of anti-
diabetic treatment, while e.g. combination therapy of 
anti-diabetic drugs per se is not associated with a 
different risk for outcome events as compared to 
monotherapy (including insulin).
Change 4:
To investigate the potential impact of impaired renal 
function on outcome events and renal endpoints
Change 5:
Only randomized patients took study drug and therefore 
this statement is no longer required
Change 6:
Since only randomized patients took study drug, the TS is 
identical to the FAS and thus there is no impact on 
derived analysis sets. Labels were changed in order to 
align with recently published outcome studies and 
notations used by FDA.
Section to be changed
7.3.2 Secondary analyses
Description of change
Change 1:
The key secondary endpoints were changed from 3-point 
MACE and composite renal endpoint (renal death, 
sustained ESRD, sustained decrease of 50% or more in 
eGFR) to composite renal endpoint (renal death, 
sustained ESRD, sustained decrease of 40% or more in 
eGFR).
In addition:
After non-inferiority has been established for the primary 


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endpoint (4-point MACE), the same endpoint and the 
composite renal endpoint (at the final analysis) will be 
tested for superiority. In case of significant superiority of 
the 4-point MACE and/or the composite renal endpoint, 
the 3-point MACE will then be tested for superiority. 
Was changed into:
After non-inferiority has been established for the primary 
endpoint (3-point MACE), the same endpoint and the 
composite renal endpoint will be tested for superiority. 
 
 
 
  
       
 
 
 
 
 
 
 


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
 
 
 
 
Rationale for change
Change 1:
Based on review of recently published cardiovascular 
outcome trials, changing the protocol definitions of the 
primary and secondary endpoints, essentially substituting 
4-Point MACE (Cardiovascular (CV) Death, Non-Fatal 
Stoke, Non-fatal Myocardial Infarction and
Hospitalization for Unstable Angina) with 3-Point MACE 
(CV Death, Non-Fatal Stoke, Non-fatal Myocardial 
Infarction).
eGFR cut off changed in response to the NIH/FDA 
scientific workshop on GFR decline as an endpoint for 
clinical trials in CKD and the current clinical landscape 
on decline in estimated glomerular filtration rate and 
subsequent risk of end stage renal disease and mortality.
 
 
 
 
Change 3: 
For clarification
Section to be changed
7.3.4 Interim analyses
Description of the change
Interim analyses removed
Rationale for change
Based on observed event rates, the time interval between 
interim and final analyses is estimated to be around nine 
months. This time interval is too short to make
meaningful differences to trial conduct, especially as the 
overall objective is to ensure adequate exposure to study 
drugs to characterise cardiovascular, renal and overall
safety profile
Section to be changed
7.6 Determination of sample size
Description of change
Assuming the hazard over time in patients on linagliptin 
is the same as in patients on placebo (hazard ratio (HR): λ 
linagliptin/λ placebo =1), 625 patients with events will 
deliver an overall power of 90% in a test to demonstrate 


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non-inferiority of linagliptin vs. placebo within the
pre-specified non-inferiority (NI) margin of 1.3 for the 
HR; at the overall 1-sided α-level of 2.5% and with one 
interim analysis at α=1.0% after 70% of the events 
(calculated with East, version 5.4). Assuming a study 
duration of 3.8 years, recruitment within 3 years and a
cumulative lost to follow-up rate of 2.0%, 4150 patients 
per group are required to achieve 625 patients with a 
primary endpoint
Was changed into:
Assuming the hazard over time in patients on linagliptin 
is the same as in patients on placebo (hazard ratio (HR): λ 
linagliptin/λ placebo =1), 611patients with events will 
deliver an overall power of 90% in a test to demonstrate 
non-inferiority of linagliptin vs. placebo within the pre-
specified non-inferiority (NI) margin of 1.3 for the HR; at 
the overall 1-sided α-level of 2.5%  (calculated with East, 
version 5.4)
Rationale for change
The change of the primary variable does not affect the 
required number of patients with event; the slight 
reduction from 625 to 611 patients is due to the 
elimination of the interim analysis. Since the event rate is 
higher than initially assumed the same power can be 
achieved within the originally planned timelines with a 
sample size of approximately 7000 patients.
Section to be changed
8. Informed consent, data protection, trial records
Description of change
Insurance Cover: The terms and conditions of the 
insurance cover are made available to the investigator and 
the patients via documentation in the ISF (Investigator 
Site File).
Was changed into:
The certificate of insurance cover is made available to the 
Investigator and the patients, and is stored in the ISF.
Section to be changed
9.2.Unpublished references
Decsription of change
Author of IB omitted
Rationale for change
Change in authorship
Rationale for change
For clarification 
Section to be changed
10.3 Blood pressure measurement procedure
Description of change
Change 1:
…..If an electronic blood pressure device is used the 
pulse rate at time of the second blood pressure reading 
may be used. 
Was changed into:
…..If an electronic blood pressure device is used the 
pulse rate at time of the second blood pressure reading 


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should be used.
In addition the following wording was added in the last 
paragraph: the mean value should be recorded in the 
eCRF. 
Rationale for change
Change 1:
For clarification 
Section to be changed
10.4 silent myocardial infarction
Description of change
Definition of silent MI requires no preceding clinical 
history of MI (including stent thrombosis and other 
coronary events) and investigator reporting of silent MI
Rationale for change
Clarification added


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02155180
6.0
1218-0022--protocol-revision-02
A multicenter, international, randomized, parallel group, double blind,
placebo-controlled CArdiovascular Safety & Renal Microvascular outcomE study
with LINAgliptin, 5 mg once daily in patients with type 2 diabetes mellitus at high
vascular risk. CARMELINA
Author-Trial Clinical Monitor
23 Nov 2016 13:09 CET
Approval-Therapeutic Area 
23 Nov 2016 13:24 CET
Approval-Team Member Medicine
23 Nov 2016 13:51 CET
Author-Trial Statistician
23 Nov 2016 14:14 CET
Approval-Team Member Medicine
24 Nov 2016 15:38 CET
Verification-Paper Signature
Completion
30 Nov 2016 10:40 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02155180
6.0

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TITLE PAGE 
Trial Statistical Analysis Plan 
for Final Analysis 
 
BI Trial No.: 
1218.22 
Title: 
A multicenter, international, randomized, parallel group, double-
blind, placebo-controlled CArdiovascular Safety & Renal 
Microvascular outcomE study with LINAgliptin, 5 mg once daily 
in patients with type 2 diabetes mellitus at high vascular risk.  
CARMELINA.  
Including Protocol Amendment 2 1218.22 [C02155180-06]. 
Investigational 
Product(s): 
Linagliptin (BI 1356) 
Responsible trial 
statistician(s): 
Phone: 
 
 
 
Phone: 
 
Date of statistical 
analysis plan: 
18 DEC 2017 
Version: 
Revised  
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 
 
 


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SIGNATURE PAGE 
Statistical Analysis Plan (Revised version December 18th 2017) for Protocol 1218.22. 
 
 
Name 
Signature 
Date 
Author: 
 
 
 
 
Position: 
Senior Biostatistician 
 
Company: 
 
 
Upon review of this document, the undersigned approves this version of the Statistical 
Analysis Plan, authorizing that the content is acceptable for the reporting of this study. 
Approved By: 
 
 
 
 
Position: 
Trial Statistician 
 
Company: 
 
 
Approved By: 
 
 
 
 
Position: 
Project Statistician 
 
Company: 
Boehringer Ingelheim – Ingelheim, Germany 
 
Approved By: 
 
 
 
 
Position: 
Trial Clinical Monitor  
 
Company: 
 
 
Approved By: 
 
 
 
 
Position: 
Team Member Medicine – Linagliptin 
 
Company: 
Boehringer Ingelheim – Biberach, Germany 
 


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Statistical Analysis Plan Reviewed By 
Boehringer Ingelheim 
Team Role 
Associate Therapeutic Area 
 
Team Member Medicine – Linagliptin 
Team Member Drug Safety 
Global 
 Medical Affairs Metabolism 
Project Medical Writer 
Team Member Clinical Operations 
Trial Clinical Monitor 
Project Statistician 
Trial Statistician 
Project and Trial Data Manager 
Trial Programmer 
  
Team Role 
Senior Reviewer 
 Programmer 
Statistical Team 
  
Medical Advisor 
Medical Writer 
Clinical Project Management 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................... 1 
SIGNATURE PAGE ........................................................................................... 2 
TABLE OF CONTENTS ................................................................................... 4 
LIST OF TABLES .............................................................................................. 7 
LIST OF FIGURES ............................................................................................ 8 
2. 
LIST OF ABBREVIATIONS ............................................................... 9 
3. 
INTRODUCTION ................................................................................ 12 
4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY .... 13 
5. 
ENDPOINTS ........................................................................................ 14 
5.1 
PRIMARY ENDPOINT .................................................................................... 14 
5.2 
SECONDARY ENDPOINTS ............................................................................ 14 
5.2.1 
Key secondary endpoint ................................................................................ 14 
5.2.2  
Secondary endpoint ....................................................................................... 14 
............................................................................ 14 
............................................................................ 14 
............................................................................ 21 
.................................... 22 
.................................... 22 
.................................... 22 
.................................... 22 
6. 
GENERAL ANALYSIS DEFINITIONS ........................................... 24 
6.1 
TREATMENTS .................................................................................................. 24 
6.2 
IMPORTANT PROTOCOL VIOLATIONS .................................................. 25 
6.3 
PATIENT SETS ANALYSED .......................................................................... 31 
................................................................................................... 32 
6.5 
POOLING OF CENTERS ................................................................................ 39 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS ................................... 39 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS .................. 45 
6.7.1  
Baseline ........................................................................................................... 45 
6.7.2  
Time windows for assignment to on-treatment phase ............................... 45 
  
 
6.8  
CALCULATION OF TIME TO EVENT ........................................................ 48 
6.8.1 
Start date ........................................................................................................ 49 
6.8.2 
Date of event................................................................................................... 49 
6.8.3 
Censoring ....................................................................................................... 49 
6.8.4 
Definition of lost-to follow-up for vital status ............................................. 51 
7. 
PLANNED ANALYSIS ....................................................................... 52 
 
 
 
 
  
 
 
 
 
 
7.4 
PRIMARY ENDPOINT .................................................................................... 56 
7.4.1  
Primary analysis ............................................................................................ 56 


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7.4.2  
Secondary analysis ........................................................................................ 57 
  
 
 
 
 
 
 
 
  
 
 
 
7.5 
SECONDARY ENDPOINTS ............................................................................ 60 
7.5.1 
Key secondary endpoint ................................................................................ 60 
 
 
.......... 60 
.......... 61 
.......... 62 
.......... 62 
.......... 63 
.......... 63 
 
.......... 65 
.......... 65 
 
.......... 66 
 
 
7.8 
SAFETY ANALYSIS ......................................................................................... 67 
7.8.1 
Adverse events ............................................................................................... 67 
7.8.1.1 
 Assignment of AEs to treatment ............................................................ 67 
7.8.1.2 
Intensity .................................................................................................. 68 
7.8.1.3 
Relationship to trial medication .............................................................. 68 
7.8.1.4 
Analysis of other significant AEs ........................................................... 68 
7.8.1.5 
AE summaries ......................................................................................... 69 
7.8.1.5.1  Frequency of patients with adverse events ............................................ 69 
7.8.1.5.2  Adverse event incidence rates ................................................................ 70 
7.8.1.6 
 Adverse events of special interest (AESI) ............................................. 70 
7.8.1.7 
Events qualifying for external adjudication by the Clinical Event 
Committee (CEC) ................................................................................... 71 
7.8.1.8 
Events qualifying for external adjudication by the Clinical Event 
Committee (CEC) for pancreatic events (CECP) ................................... 72 
7.8.1.9 
Events qualifying for external assessment by the Oncologic Assessment 
Committee (oncAC) ................................................................................ 72 
 
7.8.1.11 Further adverse events ............................................................................ 73 
7.8.1.12 Adverse events occurring after wrong medication intake ...................... 73 
 
 
7.8.3 
Vital signs, waist circumference, weight ..................................................... 76 
7.8.4 
ECG ................................................................................................................ 76 
 
 
8. 
REFERENCES ..................................................................................... 77 
........... 78 
.............. 78 


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 ............................................................... 79 
10. 
HISTORY TABLE ............................................................................... 80 
 


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LIST OF TABLES 
 
Table 6.1: 1 
Treatments and labels used in the analysis ...................................................... 24 
Table 6.2: 1 
Important Protocol Violations ......................................................................... 26 
Table 6.2: 1 
Important Protocol Violations (cont.) ............................................................. 27 
Table 6.3: 1 
Table specifying patient sets for analyses ....................................................... 32 
.................................................................................... 33 
.................................................................................... 34 
Table 6.6: 1 
Algorithm for missing AE end date ................................................................ 41 
Table 6.6: 2 
Algorithm for missing or partial AE onset date .............................................. 41 
Table 6.6: 3 
Algorithm for partial AE end date ................................................................... 42 
Table 6.7.2: 1 
Endpoint specific follow-up period for the assignment to treatment ...... 46 
Table 6.7.3: 1  
Time windows for parameters scheduled for each visit ......................... 47 
Table 6.7.3: 2  
Time windows for measurements until visit 6 for UACR ...................... 48 
Table 7.4.3.2: 1  
Overview of analyses on the primary endpoint ...................................... 59 
...... 64 
...... 64 
...... 64 
...... 78 
Table 10: 1 
History table .................................................................................................... 80 
 


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LIST OF FIGURES 
 
Figure 6.1: 1 Study intervals ................................................................................................. 24 


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2. 
LIST OF ABBREVIATIONS 
Include a list of all abbreviations used in the TSAP  
Term 
Definition / description 
 
  
 
 
 
 
 
 
 
  
ATC 
Anatomical-Therapeutic-Chemical 
 
  
 
 
 
  
CEC 
Clinical Event Committee 
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease 
 
  
CRA 
Clinical Research Associate  
CTMF 
Clinical Trial Master File 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
CV 
Cardiovascular  
DBL 
Data Base Lock 
DBP 
Diastolic Blood Pressure 
 
  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
 
  
EMA 
European Medicines Agency 
EOT 
End Of Treatment 
 
 


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Term 
Definition / description 
 
  
 
 
 
  
HbA1c 
Glycosylated Haemoglobin  
HR 
Hazard Ratio 
IC 
Informed Consent 
ICH 
International Conference on Harmonisation 
IQR 
Interquartile Range 
IRT 
Interactive Response Technology  
ISF 
Investigator Site File 
ITT 
Intent To Treat 
KDIGO 
Kidney Disease Improving Global Outcomes 
KM 
Kaplan-Meier 
LTFU 
Lost To Follow Up 
MACE 
Major Adverse Cardiovascular Events 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
 
 
 
 
OR 
Odds Ratio 
 
 
 
  
PPS 
Per Protocol Set 
PT 
Preferred Term 
pt-yrs 
Patient-years 
PV 
Protocol Violation 
Q1 
Lower quartile 
Q3 
Upper quartile 


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Term 
Definition / description 
RS 
Randomized Set 
REML 
Restricted Maximum Likelihood 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SCR 
Screened Set 
SD 
Standard Deviation 
SDG 
Standardized Drug Grouping 
SGLT 
Sodium Glucose Linked Transporter  
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
T2DM 
Type 2 Diabetes Mellitus  
TEAE 
Treatment Emergent Adverse Events 
TIA 
Transient Ischemic Attack  
TNM 
Tumor Node Metastasis 
TS 
Treated Set 
TSAP 
Trial Statistical Analysis Plan 
UACR 
Urine Albumin Creatinine Ratio 
ULN 
Upper Limit of Normal  
VEGF 
Vascular Endothelial Growth Factor 
WHO-DD 
World Health Organization Drug Dictionary 
 


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3. 
INTRODUCTION 
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data. 
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the trial, e.g., on trial objectives, trial design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation. 
This TSAP will be used for the final analysis only.  
CTP: The primary objective is to demonstrate non-inferiority (by means of comparing the 
upper limit of a two-sided 95% confidence interval (CI) with the non-inferiority margin of 
1.3) of treatment with linagliptin in comparison to placebo (as add-on therapy on top of 
standard of care) with respect to time to first occurrence of any of the adjudicated 
components of the primary cardiovascular (CV) composite endpoint (i.e. CV death, non-fatal 
stroke or non-fatal myocardial infarction (MI)) in patients with type 2 diabetes mellitus 
(T2DM).  
If non-inferiority has been demonstrated, then the primary CV composite endpoint will be 
tested for superiority and the other objective, to assess the impact of treatment with respect to 
the composite renal endpoint (i.e. renal death, sustained end-stage renal disease (ESRD), 
sustained decrease in estimated glomerular filtration rate (eGFR) ≥ 40% from baseline), will 
be investigated separately with a test on superiority.  
 
SAS® Version 9.4 (or later version) will be used for all analyses. 


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4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY 
The revisions of the protocol, up to including version 3.0 dated 22 November 2016 
(document number C02155180-06) were taken into account. 
Following changes as compared to the last protocol version 3.0 apply: 
 
 
 
  
 
 
 
 
 
 
 
 
 
The following changes were made based on an FDA Advice Letter dated August 14, 2017 
regarding the first signed version of this Trial Statistical Analysis (SAP) dated May 5, 2017. 
These revisions were accepted by the FDA on November 09, 2017.  
 
1. Study populations (Section 6.3) and censoring methods (Section 6.8.3) were separated 
and described separately to add clarity on the planned analyses. Sections 6.2, 7.4.3, 
7.4.4, and 7.6.1 were updated accordingly.  
 
2. The censoring rules in Section 6.8.3 were clarified and dates not expected to occur 
after the date of trial completion (e.g. laboratory sampling or ECG measurements) are 
not taken into account for censoring.  
 
 
 
In addition, the following minor changes have been made 
 to the first signed TSAP 
version. 
 
 
  
 
 
 
 
 
 


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5. 
ENDPOINTS 
The trial is set up with prospective centralized blinded adjudication of cardiovascular, 
cerebrovascular and renal trigger events. The prospectively defined adjudication process will 
assess cardiac, neurological, vascular and renal events through independent, blinded, external 
Clinical Event Committees (CEC). 
 
Additionally, two separate independent, blinded, external committees were set up for 
adjudication of pancreatic events and assessment of oncological events, respectively.  
 
Definitions of endpoints to be adjudicated and details on the composition of the committees, 
their procedures and interactions for all events (cardiovascular, cerebrovascular, renal, 
pancreatic and oncological events) are provided in the CEC charter. 
Throughout the SAP the term ‘adjudicated’ means ‘by adjudication confirmed’. The analyses 
of primary and key secondary endpoint are based on adjudicated events. 
5.1 
PRIMARY ENDPOINT 
The primary endpoint is time to the first occurrence of any of the following by adjudication 
confirmed components of the primary composite endpoint (3-point major adverse 
cardiovascular events (MACE)): CV death, non-fatal MI or non-fatal stroke.  
This endpoint will also be further referred to as time to 3-point MACE, or shortly 3P-MACE. 
5.2 
SECONDARY ENDPOINTS 
5.2.1 
Key secondary endpoint  
The key secondary endpoint is time to the first occurrence of any of the following by 
adjudication confirmed components: renal death, sustained end stage renal disease (ESRD) or 
sustained decrease of 40% or more in eGFR from baseline. This endpoint will also be further 
referred to as composite renal endpoint 1. 
5.2.2  
Secondary endpoint  
Not applicable as no secondary endpoint other than the key secondary endpoint is defined for 
this study. 


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6. 
GENERAL ANALYSIS DEFINITIONS 
6.1 
TREATMENTS 
The following treatments are investigated in this trial: 
Table 6.1: 1 
Treatments and labels used in the analysis 
Treatment 
Short label 
A 
Linagliptin 5 mg 
Lina 
B 
Placebo  
Placebo 
 
Study intervals are defined in the following figure: 
Figure 6.1: 1 Study intervals 
 
Refer to Section 6.6, in case of missing information in eCRF.  


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During the study treatment phase, patients are allowed to go off trial medication and 
subsequently re-start trial medication. This may not happen or may happen repeatedly for a 
given patient, as this trial is expected to go on for a number of years. This is reflected by the 
off-treatment phase. 
For specific safety and efficacy parameters, the duration of the on-treatment phase is given in 
Section 6.7.2 and Section 7.8.1.1. 
Patients will be analysed as randomized for all analyses (safety and efficacy). 
 
6.2 
IMPORTANT PROTOCOL VIOLATIONS 
Data discrepancies and deviations from the CTP will be identified for all patients randomized 
and/or treated.  
A protocol violation (PV) is defined as important, if it affects the rights or safety of the trial 
patients or if it can potentially influence the primary endpoint for the respective patients in a 
way that is neither negligible nor in accordance with the trial objectives.  
 
The category of important PVs, which can potentially influence the primary or key secondary 
outcome measures, forms the basis for the decision of whether a patient belongs to a patient 
analysis set. 
The following table displays the categories considered to be important protocol violations. If 
the data indicate further important PVs, this table will be supplemented accordingly, with the 
latest modification made prior to database lock. 
 
The important PVs will be described in the Clinical Trial Report (CTR). A listing of patients 
who had the medication code broken will be provided. 
 
A table showing the number of patients and frequency with violation of in- or exclusion 
criteria will be provided. 
 


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Table 6.2: 1 
Important Protocol Violations 
Category / 
Code 
Description 
Comment/Example 
Affects 
rights (R)/ 
safety (S) or 
primary/ 
key 
secondary 
outcome (E) 
Excluded 
from 
A 
 
Entrance Criteria Not Met 
 
 
 
A.1 
Inclusion criteria violated 
 
 
 
A1.1 
No type 2 diabetes 
Inclusion criterion IN1 
ticked “No“ 
E 
PPS 
 
A.2 
Exclusion criteria violated 
 
 
 
A.2.1 
Type I diabetes 
Exclusion criterion  
EX1 ticked “Yes“ 
E 
PPS 
 
A.2.2 
Severe renal 
impairment (eGFR < 15 
ml/min/1.73 m²) or 
ESRD at Visit 1 and/or 
the need for 
maintenance dialysis 
Exclusion criterion  
EX4 ticked “Yes“ 
Or  
eGFR < 15 ml/min/1.73 
m² at visit 1 
E 
PPS 
 
A.2.3 
Pre-planned coronary 
artery re-vascularisation 
(PCI, CABG) 
Exclusion criterion  
EX6 ticked “Yes“ 
 
E 
PPS 
 
A.2.4 
Specific exclusion 
criterion for 
premenopausal women 
violated 
Exclusion criterion  
EX10 ticked “Yes“ 
R/S 
None 
 


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Table 6.2: 1 
Important Protocol Violations (cont.) 
Category / 
Code 
Description 
Comment/Example 
Affects 
rights (R)/ 
safety (S) or 
primary/ 
key 
secondary 
outcome (E) 
Excluded 
from 
 
A.2.5 
Patients considered 
unreliable by the 
investigator for safe 
participation in the 
study 
Exclusion criterion  EX11 
ticked “Yes“ 
 
E 
PPS 
 
A.2.6 
Acute coronary 
syndrome (ACS), 
diagnosed ≤ 2 
months prior to Visit 
1  
Exclusion criterion  EX12 
ticked “Yes“ 
 
E 
PPS 
 
A.2.7 
Stroke or transient 
ischemic attack 
(TIA)  ≤ 3 months 
prior to Visit 1  
Exclusion criterion  EX13 
ticked “Yes“ 
 
E 
PPS 
B 
Informed Consent 
 
 
 
B1 
Informed consent not 
available 
Inclusion criterion  IN7 
ticked “No“  
Or Date of informed 
consent missing 
Or No signature on 
patient’s “Declaration of 
Informed Consent” (to be 
identified by CRA) 
R/S 
All 


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Table 6.2: 1 
Important Protocol Violations (cont.) 
Category / 
Code 
Description 
Comment/Example 
Affects 
rights (R)/ 
safety (S) or 
primary/ 
key 
secondary 
outcome (E) 
Excluded 
from 
 
B2 
Informed consent 
given too late 
Date of informed consent 
for the study not obtained 
prior to any study related 
procedure  
Minimum requirement for 
initial informed consent ≤ 
date of visit 1/date of any 
study procedure 
R/S 
None 
C 
Trial medication and randomisation 
 
 
 
C1 
Incorrect Trial Medication Taken 
 
 
 
C1.1 
No study medication 
taken 
Patient randomised, but no 
study medication taken 
E 
PPS, TS  


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Table 6.2: 1 
Important Protocol Violations (cont.) 
Category / 
Code 
Description 
Comment/Example 
Affects 
rights (R)/ 
safety (S) or 
primary/ 
key 
secondary 
outcome (E) 
Excluded 
from 
 
C1.2 
Incorrect trial 
medication taken 
Wrong medication 
(different medication than 
the patient was randomised 
to) taken for more than 
20% of the overall 
treatment duration 
(between randomisation 
and first outcome event) of 
a patient. 
This is identified by the 
medication kit number 
recorded in eCRF as well 
as the medication kit 
number as assigned by 
IRT. 
Can also be manually 
identified by investigator 
or CRA.  
Can only be finally judged 
after DBL since unblinding 
information is required. 
E 
PPS 
 
C2 
Randomisation not followed 
 
 
 
C2.1 
Treated before 
randomisation 
Date of randomisation after 
date of study medication  
intake at visit 2;  
Or 
Patient treated according to 
eCRF, but not randomised 
according to IRT. 
E 
PPS 
 
C3 
Non-compliance 
 
 


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Table 6.2: 1 
Important Protocol Violations (cont.) 
Category / 
Code 
Description 
Comment/Example 
Affects 
rights (R)/ 
safety (S) or 
primary/ 
key 
secondary 
outcome (E) 
Excluded 
from 
 
C3.1 
Non-compliance 
with criteria for 
removal from the 
trial 
A missing pregnancy test 
does not qualify as IPV. 
R/S 
None 
D 
 
Concomitant 
Medication 
Not Applicable 
 
 
E 
 
Missing data 
Not Applicable 
 
 
F 
 
Incorrect timing 
Not Applicable 
 
 
G 
 
Trial specific 
protocol violations 
 
 
 
 
G1.1 
Previous 
participation 
(randomisation) 
within this study 
 
E/S/R 
PPS 
 
G1.2 
Serious non-
compliance 
potentially affecting 
primary endpoint 
 
E/S/R 
PPS* 
Note: Missing visits, evaluations, and tests will be considered missing data, not protocol 
deviations 
*These patients might be kept out of some further patient analysis sets. The details are described in a 
separate document.  


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6.3 
PATIENT SETS ANALYSED 
 
Screened Set (SCR): 
The Screened (Enrolled) Set will include all patients who signed the informed consent. 
 
 
Randomized Set (RS): 
All screened patients who were randomized, whether treated with trial medication or not. 
 
 Treated Set (TS): 
All patients treated with at least one dose of trial medication. If no trial medication is 
taken at site during the visit, but the medication kit was dispensed to the patient and not 
all trial medication has been returned, the patient will be included in the TS. The TS is 
the basis for the primary efficacy and the safety analyses. 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
The following table defines for each planned analysis, which patient set is to be used. 


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Table 6.3: 1 
Table specifying patient sets for analyses 
 
 
Patient Sets 
Endpoint 
 
SCR 
RS 
TS 
 
 
Disposition 
 
X 
 
 
 
 
Patient analysis sets 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary/Key secondary endpoint 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other safety endpoints as per Section 5.3.2 
 
 
 
X 
 
 
Post stroke functional assessment as per 
Section 5.4.1 
 
 
 
X 
 
 
 * Sensitivity analysis 
^ Demographic analyses will be repeated on the randomised set for EudraCT purposes. 
 
Note that the number of patients with available data for an endpoint may differ. For details, 
see Section 6.6. 
 


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6.5 
POOLING OF CENTERS 
As stated in the CTP, no center effect is included into the model, as the center size is usually 
expected to be rather small. Furthermore, due to the anticipated low event rate a sufficient 
number of events per center for the analysis of a center effect and a center by treatment 
interaction are not expected. 
 
 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS 
Every effort will be made to collect data as complete as possible. The rules given below are 
the planned methods for imputation depending upon the type of the endpoint. 
 
For each time to event analysis, patients who do not have a particular outcome will be 
censored (for details, refer to Section 6.8). 
 
 
 
  
 
 
 


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Partial or missing dates and times 
Non-fatal outcome events 
In the unlikely case that only the year is documented, the day and month will be imputed as 
01 Jan unless the subsequently derived date is before randomisation; in this case the date of 
randomisation will be used as start date. If year and month is present the day will be imputed 
as first of the month unless the subsequently derived date is before randomisation; in this case 
the date of randomisation will be used. 
 
Adverse event (AE) data  
 
Beforehand the missing or partially missing date of first drug administration is imputed. 
For the handling of AE partial and missing dates the following definitions will be used: 
First possible = first possible date of an incomplete AE date 
- if only month and year are given: day is set to 1 
- if only year is given: day is set to 1 and month is set to January 
Last possible = last possible date of an incomplete AE date 
- if only month and year are given: day is set to the last possible day of the month 
- if only year is given: day is set to 31 and month is set to December  
 
The imputation must be performed in the following order: 
1) Imputation of completely missing AE end dates 
2) Imputation of missing/partial AE onset dates 
3) Imputation of partial AE end dates 
 
1) Completely missing AE end dates 
When an AE end date is missing but there is another AE occurrence with the same lowest 
level term (LLT) and onset date and with an end date, this end date will be used for the 
imputation. 
Otherwise, the imputation rules described in the Table 6.6: 1 are used. 
 


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Table 6.6: 1 
Algorithm for missing AE end date 
Outcome of event 
Action 
Patient died 
Impute all missing AE end dates with date of death 
Patient did not die 
If follow-up performed, impute missing AE end date 
for on-going AEs with the latest follow-up date. 
Otherwise, impute missing AE end date with the date 
of the last available visit. 
2) Missing/partial AE onset date 
Step 1 
For each missing or partial AE onset date, a time-interval (O1 - O2) has to be defined as 
follows: 
If AE onset date is missing then:  
O1 = minimum between AE end date and date of informed consent 
O2 = minimum between AE end date and date of last visit 
If AE onset date is partial: 
O1 = minimum between AE end date and First Possible onset date 
O2 = minimum between AE end date and Last Possible onset date 
For the definition of this time-interval only, partial AE end date must be initially imputed as 
Last Possible end date. 
Step 2 
Then the AE onset date is imputed according to the rules described in Table 6.6: 2. 
Table 6.6: 2 
Algorithm for missing or partial AE onset date 
Condition 
Action 
Date of first drug administration > O2 
Impute onset date with O2 
O1 ≤ Date of first drug administration ≤ O2 
Impute onset date with date of first 
drug administration 
Date of first drug administration < O1 
Impute onset date with O1 
3) Partial AE end date 
Step 1 
For each partial AE end date, a time-interval (E1- E2) has to be defined as follows: 
E1 = maximum between AE onset date and First Possible end date 


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E2 = maximum between AE onset date and Last Possible end date 
Step 2 
Then the AE end date is imputed according to the rules described in Table 6.6: 3. 
Table 6.6: 3 
Algorithm for partial AE end date  
Condition 
Action 
Date of first drug administration > AE onset date and 
patient died 
Impute end date with 
minimum (E1, date of death) 
Date of first drug administration > AE onset date and 
patient did not die 
Impute end date with 
minimum (E1, last visit date 
including follow-up visits) 
Date of first drug administration ≤ AE onset date and 
patient died 
Impute end date with 
minimum (E2, date of death) 
Date of first drug administration ≤ AE onset date and 
patient did not die 
Impute end date with 
minimum (E2, last visit date 
including follow-up visits) 
Partial or missing information on the date of first administration of trial drug 
If patients have been randomised but not treated, no imputation will be done for the date of 
first administration of trial drug. Patients are considered randomised but not treated if they 
have been randomised, no administration has been done during the visits, and the number of 
kits dispensed equals the number of kits returned. 
Otherwise, if the date of first drug administration is missing but the patient was randomised 
and treated, the date of the first drug administration will be set to the date of kit dispensation. 
For partial date of first drug administration, if only the year is present and equal to the year of 
the randomisation date, the first drug administration will be set to the date of randomisation. 
If only the day is missing (month and year present), if randomisation was in the same month 
and year, then the first drug administration will be set to the date of randomisation. If 
randomisation was in the month prior to the first drug administration the missing day will be 
imputed as the first day of the month. 
 
Missing information on the time of administration of trial drug 
A missing time of first drug administration will be imputed as 12:00 o’clock noon. Missing 
administration times at on-treatment visits will be imputed by 8:00 o’clock in the morning. 
 
 


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Partial or missing information on the date of last administration of trial drug 
If this date is partial or missing, the date will be imputed by the date of the respective visit, if 
available. 
If the date is partial with only month and year and the visit date is missing, it should be the 
last day of this month. 
If a patient is lost-to-follow up and no date of last drug administration is reported, the date of 
last drug administration is set as the date of last contact. 
For a patient who dies in the treatment phase, the date of last drug administration is set as the 
date of death, assuming that the patient took the medication until the date of death. 
Rules following this are described in Section 6.1. All other cases need to be assessed by the 
trial team on an individual basis, trying to use the points above as guidance. 
 
Partial or missing information on the date of administration of trial drug (excluding first and 
last administration) 
If any such date is missing, it will be imputed by the respective visit date. 
If month and year are available and equal to the visit date, the date is imputed by the day of 
the respective visit. If month is later than the month of the visit date, the day will be imputed 
by the 1st of the month. 
 
Missing information on the birth date 
If only the year of birth is known, the day and month of birth will be imputed as 01 January. 
 
Missing information on concomitant therapy dates 
For incomplete date information always the midpoint of the possible interval will be used. 
If only the year is present the day and month will be imputed as 01 July, if year and month is 
present the day will be imputed as 15. If the year is missing, the date will be considered 
missing.  
If this leads to contradictions for the start or end date of a concomitant therapy (e.g. imputed 
end date before documented start date) a partial end date will be imputed as the end of the 
interval or a partial start date will be imputed as the start of the interval in the database to 
resolve this contradiction. 
 
Missing date of last contact  
 
If a patient dies and had not withdrawn consent, the date of last contact will be the date of 
death. If a patient did not die, the date of last contact will be the latest date of the individual 
trial completion date, last administration date and the last available measurement/procedure 
date. 
 


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6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS 
6.7.1  
Baseline 
The term "baseline" refers to the last available measurement prior to administration of any 
randomised trial medication.  
The following considerations apply for laboratory measurements, if the time of the sample is 
missing on the day of first study medication intake: 
a) For FPG: the measurement will not be considered as baseline 
b) For all other lab investigations: The last measurement on this day will still be considered 
as baseline measurement. 
 
 
 
 
 
6.7.2  
Time windows for assignment to on-treatment phase 
Measurements taken prior to the first intake of randomised trial medication will be 
considered pre-treatment values.  
The date and clock time of the first drug administration will be used to separate pre-treatment 
from on-treatment values. Measurements taken after the first intake of randomised trial 
medication will be considered on-treatment values if they have been obtained up to end of the 
parameter specific follow-up period as defined in Table 6.7.2: 1 and will be assigned to the 
randomised trial medication for analyses.  
 
Measurements taken after the end of the endpoint specific follow-up period will be 
considered post-treatment values. 
 


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6.8  
CALCULATION OF TIME TO EVENT 
This section describes the calculation of the time to event and the time that patients without 
an event were in the trial (under risk). See Section 6.8.3 on censoring rules. 
Consistent with that approach, the respective time intervals determine the start and end for 
the derivation of occurrence of a specific event. 
For patients with an event, the time to event is calculated as:  
<date of event> - < start date> + 1 
 
For patients without an event, the time at risk is calculated as: 
<date of censoring> - < start date > + 1 


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6.8.1 
Start date 
In general, the time to event will be derived from the date of randomisation, e.g. for the 
primary endpoint, the key secondary endpoint, their individual components, and the tertiary 
adjudicated endpoints.  
For the endpoints of time-to-first-hypoglycemia and time-to-AE analysis, 
 
 
 
 
 
 
 
 
 
 
 
6.8.2 
Date of event 
For composite outcomes, e.g. time to first 3P-MACE, the earliest onset date of the 
corresponding components will be used
 
 
The dates determined by the adjudication committee will be used; these can be different from 
the investigator reported dates. 
 
 
 
 
 
 
 
 
6.8.3 
Censoring 
Primary 
 endpoints
 
 
The underlying principle is that the censoring date should be the date at which the patient was 
last known to be free of an endpoint event (e.g. free of each component of the 3P-MACE). 
Patients without occurrence of a specific endpoint (composite endpoint or individual 
components) will be considered censored at the individual day of trial completion*.  


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* This is defined as the latest of the following dates as of 
- 
adverse event/outcome event start dates (if non-fatal event), 
- 
onset dates of adjudicated (by adjudication confirmed and non-confirmed) events (if 
non-fatal event), 
- 
date of trial completion (defined as latest of date of last clinic visit, last telephone 
contact, date of last contact if lost to follow-up). 
For patients who died during the study, the date until which follow-up for non-fatal outcome 
events was performed will be used for censoring.   
Censoring is considered independent from trial drug intake. 
 
 
 
 
 
 
 
 
 
Generally, the 7 days censoring definition will be used for adverse events incl. 
hypoglycaemia. 
All of the above mentioned x-day censoring rules will be handled as follows: 
Patients who did not experience the event will be censored at the earliest date between the 
individual day of trial completion (defined above) and x days after last intake of study drug. 
For this analysis events will be considered that occurred not later than x days after last intake 
of study drug, or until individual day of trial completion (defined above), whichever is 
earlier. 
 
Endpoints based only on laboratory data (by adjudication confirmed or not) 
Patients who already fulfil the respective condition at baseline are generally not considered in 
the number of patients at risk for this endpoint (
 
If a baseline laboratory measurement is not available for the parameter of interest, it is 
assumed that the patient did not experience the condition corresponding to the endpoint at 
baseline and the patient is included in the patients at risk for this endpoint. 
Patients without an event and available post-baseline laboratory measurements will be 
considered censored at the date of last laboratory sampling of the corresponding parameter. 
Patients with missing baseline laboratory required to derive a change from baseline and 
patients without laboratory data following the baseline measurement will be censored on the 
day of randomisation or date of first study drug intake, respectively. 
 


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6.8.4 
Definition of lost-to follow-up for vital status 
If a patient could not be followed up at study termination for primary endpoint information or 
respectively vital status could not be collected, this patient will be considered as Lost-To-
Follow-Up (LTFU) for 3P-MACE or respectively as LTFU for vital status. Study termination 
is defined by the start of the close-out period. The number of patients and frequency will be 
provided. 
Patients with an adjudicated event for the primary endpoint event are not regarded as LTFU 
for 3P-MACE. Patients who died are not regarded as LTFU for vital status. 
The close-out period is defined as the time period communicated to the site to schedule the 
end of trial visit (EOT). 


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7. 
PLANNED ANALYSIS 
For End-of-text and appendix tables, the set of summary statistics is: N / Mean / standard 
deviation (SD) / Min / Q1 (lower quartile) / Median / Q3 (upper quartile) / Max. 
Baseline data will be presented overall and per treatment group. 
The 1st and 99th percentiles might be substituted for minimum and maximum in tables with 
open-ended values to safeguard against implausible extremes. 
Geometric means and ranges can be added to the presentation or replace the presentation of 
mean and standard deviation for parameters which rather follow a log-normal distribution 
than a normal distribution.  
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. The category missing will be displayed only if there are actually 
missing values. In general, unless otherwise specified, percentages will be based on all 
patients in the respective patient set, irrespective of whether they have missing values or not. 
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the Global Biostatistics Standard Output Conventions (1), with exception of p-values 
presentation which will be displayed with 4 decimal places.  
A general overview on patient disposition will be provided by treatment group and in total 
and presented in the clinical trial report by frequency tabulations. This will include the 
number of patients screened, randomised, screened but not randomised, treated as well as 
those who did/ did not prematurely discontinue trial medication, did/did not prematurely 
discontinue from trial by region/country/centre. See also Table 9.1: 1 Table 9.1: 1for 
assignment of countries to region. The reason for not randomising screened patients will also 
be summarized. 
In addition, the number of patients who discontinued trial medication due to fatal and non-
fatal adverse events will be displayed for public data disclosure on European Union Drug 
Regulating Authorities Clinical Trials (EudraCT). Additionally, baseline data analyses of 
screened patients by country and by age groups will be done for EudraCT. 
The frequency of patients with important protocol violations as well as the frequency of 
patients in the different analysis sets will be presented by randomised treatment group. 
The number of patients included in each analysis set will be displayed with percentages based 
on the randomised set. 
 


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7.4 
PRIMARY ENDPOINT 
7.4.1  
Primary analysis 
The primary analysis on the primary endpoint time to first 3P-MACE (cf. Section 5.1) will be 
performed on the TS. 
 
Section 7.1 of the CTP: For the primary objective the upper bound of the two-sided (1-
2*alpha) confidence interval which equals the upper bound of the one-sided (1-alpha) 
confidence interval will be used to investigate non-inferiority (NI) of linagliptin versus 
placebo regarding the hazard ratio (HR) of the primary endpoint. The non-inferiority margin 
is chosen as 1.3. The overall one-sided significance level is 2.5%. 
 
The allocated trial treatment at randomisation will be used for analysis, and all events which 
occur until trial end will be taken into account. 
The time to the primary endpoint will be derived from the date of randomisation. The 
censoring rules are described in Section 6.8.3. 
Hypotheses tested are described in the Section 7.2 of the CTP. 
 
Statistical methods 
For the primary analysis, a Cox proportional hazard regression model will be performed to 
compare the effect of linagliptin versus placebo. The model will include randomised 
treatment and geographical region as factors. Breslow’s method will be used for dealing with 
ties. The SAS PHREG procedure will be used. 
The hypothesis of non-inferiority will be tested at the one-sided significance level of 
α1=2.5%. 
The hazard function of an event for patient j at time t is assumed to have the form: 
 
hj(t) = exp (β1x1j + β2x2j) h0(t), j=1,...,n, 
 
where  
 
o h0(t) is the non-negative baseline hazard function for a patient with a value of zero for 
the explanatory value x1j and x2j 
o β1 is the (unknown) coefficient of the explanatory variable x1 
o x1j is an indicator variable representing the treatment group for patient j=1,...,n 


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o β2 is the (unknown) coefficient of the explanatory variable x2 
o x2j is an indicator variable representing the geographical region for patient j=1,...,n 
 
The hazard ratio (HR) for the effect of treatment (linagliptin vs. placebo), adjusted for 
geographical region, will be presented with the 95% confidence interval, the  
99% confidence interval and the p-values based on the Wald Chi-Square statistic: one-sided 
p-value for the non-inferiority test (NI margin 1.3), the one-sided p-value for the superiority 
test and the two-sided p-value.  
 
Non-inferiority of the primary endpoint will be investigated by comparing the upper limit of 
the two sided 95% confidence interval of the hazard ratio with the non-inferiority margin of 
1.3: if the upper limit is less than 1.3, non-inferiority has been demonstrated. 
 
In case non-inferiority of the primary endpoint is demonstrated, then superiority of the 
primary endpoint and superiority of the key secondary endpoint will be investigated:  
For the final analysis, the first hypothesis (non-inferiority of the primary endpoint) will be 
tested at the one-sided alpha-level of 2.5%. In case of significance, the null hypothesis is 
rejected in a confirmatory sense and the next set of hypotheses (two separate hypothesis tests) 
will be tested: a) test of the primary endpoint for superiority and b) test of the composite renal 
endpoint for superiority.  
To adjust for multiplicity a sequentially rejective multiple test procedure will be applied (3). 
Both one-sided hypotheses H0(Sup1) and H0(Sup2) will be tested separately, at the initial 
alpha-levels of 0.2*alpha for 3-point MACE and 0.8*alpha for the composite renal endpoint, 
respectively. If both null hypotheses cannot be rejected at these initial alpha-levels, the 
procedure stops and for none of these endpoints superiority can be declared. After having 
shown superiority for one of these endpoints, the used alpha can be shuffled to the other test: 
If H0(Sup2) is rejected at the alpha-level of 0.8*alpha, then H0(Sup1) can be tested at the full 
alpha-level of 2.5% (one-sided). If H0(Sup1) is rejected at the alpha-level of 0.2*alpha, then 
H0(Sup2) can be tested at the full alpha-level of 2.5% (one-sided). 
 
7.4.2  
Secondary analysis 
The Kaplan-Meier (KM) estimates of failure rate per treatment group will be presented 
graphically. In addition, certain quantiles of the failure times (e.g. 2.5%, 5%, 7.5% and 10% 
quantiles) will be provided per treatment group. Kaplan-Meier estimates for failure rates at 6 
months, 1, 1.5, 2, etc years after randomisation will be presented per treatment group. 
  
The two-sided p-value resulting from the log-rank test will be presented for completeness.  
 
 
 
 
 
Descriptive statistics will display the number of patients at risk, the number of patients with 
event, the incidence (proportion of patients with event), the time at risk for event and the 
incidence rate (number of patients with event per 1000 years at risk) per treatment group. 
 


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7.5 
SECONDARY ENDPOINTS 
7.5.1 
Key secondary endpoint 
Main analysis of key secondary endpoint 
 
The key secondary endpoint will be analyzed on the TS in the same way as described in 
Section 7.4.1 and Section 7.4.2 for the primary endpoint. 
The hazard ratio (HR) for the effect of treatment (linagliptin vs. placebo), adjusted for 
geographical region, will be presented with the 95% confidence interval, the 96% confidence 
interval, and the p-values based on the Wald Chi-Square statistic: the one-sided p-value for 
the superiority test and the two-sided p-value. 
The time to first occurrence will be counted from the date of randomisation. The censoring 
rules are described in Section 6.8.3. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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7.8 
SAFETY ANALYSIS 
All safety analyses will be performed on the TS and displayed as randomised.  
Assignment of preferred terms to HLGT and SOC will be according to MedDRA “primary 
path”. 
7.8.1 
Adverse events 
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) at database lock.  
The analyses of adverse events will primarily be descriptive in nature. All analyses of AEs 
will be based on the number of patients with AEs (and not on the number of AEs). The 
general AE analysis will include all AEs (including outcome events as reported by the 
investigator). 
7.8.1.1  
Assignment of AEs to treatment 
The analysis of AEs will be based on the concept of treatment-emergent adverse events 
(TEAE). That means that all AEs occurring between first study drug intake until 7 days after 
last permanent study drug stop will be considered as on-treatment, i.e. possible treatment 
interruption phases of a patient will be part of the on-treatment phase.  
All AEs occurring prior to first study drug intake will be assigned to “screening”. All AEs 
occurring after last study drug intake + 7 days will be assigned to “post-treatment”, whereby 
the post-treatment phase according to the previous treatment will be used (post-Lina and 
post-Placebo respectively). AEs reported after the date of last contact + 1 day will be 
assigned to “post-study”. 
Patients who died before last drug intake + 7 days will have their on-treatment phase assigned 
until the date of death.  
In addition to the primary treatment emergent approach displaying the on-treatment phase 
and post-treatment phase separately, all AEs after the first dose of study medication will be 
included in an additional analysis by treatment group. 
 
Further additional approaches will be implemented for the presentation of adverse events: 


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 For cancer and pancreatic cancer in addition to the ‘TEAE approach’ on the treated 
set, all adverse events that occurred between first study drug intake up to study end 
will be presented. 
There will be additional analyses including all patients who had a minimum 
cumulative study drug exposure of 6 months (excluding treatment gaps), using 
following two approaches: 
o considering all AEs starting from the date when 6 months cumulative 
exposure was reached up to last drug stop + 7 days  
o considering all AEs starting from date when 6 months cumulative exposure 
was reached up to individual day of trial completion 
 
 For renal events, hepatic events, pancreatitis and skin lesions all adverse events that 
occurred between first study drug intake up until treatment stop + 30 days will be 
presented based on the treated set.  
 Heart failure adverse events (based on narrow SMQ cardiac failure 20000004) will be 
analyzed following the ‘TEAE approach’ (all AEs occurring between first study drug 
intake until 7 days after last permanent study drug stop will be considered as on-
treatment) and the concept where all AEs from first study drug intake up to study end 
are assigned to treatment. 
 
For the subgroup analyses of adverse events (as specified in Section 6.4), all adverse events 
occurring between first drug intake until 7 days after last permanent treatment stop will be 
considered with the following exception: for subgroup analyses of pancreatic cancer all 
adverse events that occurred between first study drug intake until study end will be 
considered based on the treated set.  
For these subgroup analyses, frequencies and incidence rates will be provided. 
 
7.8.1.2 
Intensity 
Intensity is classed as mild/moderate/severe (increasing intensity). If a patient reports an AE 
more than once within that system organ class (SOC)/ Preferred term (PT), the AE with the 
worst case intensity will be used in the corresponding intensity summaries. 
7.8.1.3 
Relationship to trial medication 
Relationship, as indicated by the Investigator, is classified as “not related” or “related”. If a 
patient reports the same AE more than once within that SOC/ PT, the AE with the worst 
case relationship to trial medication will be used in the corresponding relationship 
summaries.  
7.8.1.4 
Analysis of other significant AEs 
According to ICH E3 (4), AEs classified as ‘other significant’ will include those non-serious 
adverse events with:  


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(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or 
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator 
The identification of category (ii) will be done by medical advisor based on the eCRF data 
prior to database lock. 
7.8.1.5 
AE summaries 
7.8.1.5.1  
Frequency of patients with adverse events 
No confirmatory analysis is planned for routine safety comparisons. 
An overall summary of patients with TEAEs will be presented by treatment, including 
patients with any AE, severe AEs, investigator defined drug-related AEs, AEs leading to 
discontinuation of trial drug, serious AEs (SAEs), AEs leading to death, AEs of Special 
Interest (AESI) and other significant AEs. 
Separate tables will be provided for patients with SAEs, for patients with drug-related AEs, 
for patients with AEs leading to treatment discontinuation, for patients with fatal AEs, for 
patients with AESI, and for patients with other significant adverse events. AEs will also be 
reported by intensity. 
The frequency of patients with TEAEs will be summarized by treatment, primary SOC and 
PT. The SOCs will be sorted according to the standard sort order specified by the European 
Medicines Agency (EMA), preferred terms will be sorted by frequency (within SOC). 
Frequency tables of patients with cancer (broad BIcMQ) by treatment, High level term (HLT) 
and preferred term will be provided. 
For handling of missing or incomplete data refer to Section 6.6. 
In addition, an analysis will be done on AEs and SAEs which are assigned to the following 
phases: screening, treatment, and post-treatment for each treatment group. 
An overview of adverse events from patients screened, but not treated, will be included. 
A table showing the frequency of patients with non-serious TEAE occurring with PT 
incidences > 5% within at least one treatment group will be presented by treatment and 
preferred term for disclosure on clinicaltrial.gov website. Additionally, the following 
analyses will be reported for disclosure on EudraCT:  
 AEs per arm: This analysis includes the number of patients with serious AEs, patients 
with non-serious AEs >5%, as well as the total number of deaths (all causes), and the 
total number of deaths resulting from drug-related adverse events. 
 Number of patients with serious AEs on preferred term level (grouped by standard 
SOC terms)  


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7.8.1.5.2  
Adverse event incidence rates 
In addition to the frequency tabulations, time-adjusted adverse event analyses will be 
performed by SOC and PT, or respectively HLT and PT for TEAEs, severe TEAEs, 
investigator defined drug-related TEAEs, other significant TEAEs, TEAEs leading to 
discontinuation of trial drug, serious TEAEs, TEAE leading to death and AESI and further 
events (defined in Section 7.8.1.11). 
The time at risk in patient years is derived as follows: 
Patients with AE: 
time at risk (AE) [days] = start date of event with specified PT/SOC – treatment start date + 1 
 
Patients without AE: 
time at risk (AE) in days = end date of time at risk – study treatment start date + 1, where end 
date of time at risk is the minimum of date of last study drug intake + x days and date of 
death, if applicable. 
The standard approach will be x=7 days, but for certain AEs in addition other approaches will 
be used. 
 
Total AE-specific time at risk per treatment group is then derived as:  
 
Time at risk (AE) [years] =  
 
 
 
For ‘each row of a table’ (e.g. displaying an SOC), time at risk is calculated using start of 
first AE summarized in this row; e.g. for patient with AE in a specified SOC: 
Time at risk = start date of AE with specified PT in a SOC – treatment start date + 1. 
 
The AE incidence rate per 100 patient years can then be calculated as follows: 
 
Incidence rate [1/100 Patient years (pt-yrs)] =  
 
 
 
7.8.1.6  
Adverse events of special interest (AESI) 
According to the protocol the following events are considered as AESI: 
 Hypersensitivity reactions (defined by narrow SMQ 20000214 ‘hypersensitivity’) 
 Skin lesions (defined by narrow SMQ 20000020 ‘severe cutaneous adverse reactions’) 
 Hepatic events (defined by narrow sub-SMQ 20000010 ‘hepatitis, non-infectious’, 


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narrow sub-SMQ 20000013 ‘hepatic failure, fibrosis and cirrhosis and other liver 
damage-related conditions’, narrow sub-SMQ 20000008 ‘liver related investigations, 
signs and symptoms’, narrow sub-SMQ 20000009 ‘cholestasis and jaundice of hepatic 
origin’) 
 Renal adverse (defined by narrow SMQ 20000003 ‘acute renal failure’) 
 Pancreatitis (defined by narrow SMQ 20000022 ’acute pancreatitis’ and PT ’Pancreatitis 
chronic’ (resp. based on updated MedDRA version corresponding term for that ) 
 Thyroid neoplasm (benign) (BIcMQ Thyroid Neoplasms narrow BIcMQs, restricted to 
diagnoses (exclude symptoms) by TM DS (manual review)) 
 Thyroid cancer (presentation in table of cancer events by HLT and PT; and also under 
“Thyroid neoplasm” as defined above) 
 Pancreatic cancer (based on narrow BIcMQ) 
Patients with these AESIs will be tabulated by treatment group.  
For all AESIs, in addition frequency tables for serious adverse events (except for thyroid 
neoplasm (benign), thyroid cancer, pancreatic cancer as always-serious events) and adverse 
events leading to discontinuation from trial drug will be presented. 
The most recent version of the definitions of these AESIs at the time of the DBL will be used 
to be in line with the respective most recent AESI definition in the current MedDRA version. 
These will be stored in the CTMF.  
7.8.1.7 Events qualifying for external adjudication by the Clinical Event Committee (CEC) 
Tabulations with frequency of patients with AEs triggering CEC adjudication (based on 
specified Standardized MedDRA Queries (SMQs) according to CEC charter and manually 
identified) will be provided by treatment group and overall, by primary SOC and preferred 
term. All events will be taken into account from first study drug intake up to study end. 
This table will be provided separately for cardio/neuro, renal, pancreatic adjudication and 
oncological assessment. 
Further, outcome events captured by the investigators will be contrasted with those defined 
by the adjudication committee. 
 
For cardio- and cerebrovascular events the components as listed in Section 5.3.1 as well as 
the types of CV deaths, the types of non-fatal MIs, types of fatal and non-fatal strokes, stent 
thrombosis and all not assessable cases will be presented. The category of other 
cardiovascular causes will be presented with subcategories of “other assessable CV causes” 
and “presumed CV death”. 
 


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7.8.1.8 Events qualifying for external adjudication by the Clinical Event Committee (CEC) 
for pancreatic events (CECP) 
Based on the CECP adjudication results, the number of patients for each of the following 
events will be summarized in frequency tables (overall and by adjudication trigger i.e. lab or 
AE): 
- 
Acute pancreatitis (with organ failure) 
- 
Acute pancreatitis (without organ failure) 
- 
Chronic pancreatitis (with organ failure) 
- 
Asymptomatic pancreatic hyperenzymemia 
- 
Pancreatic malignancy 
The analysis will be performed on TS. 
The analysis will be performed using all events from study treatment start until study end and 
in addition the ‘on-treatment + 7 days’ approach. 
 
 
7.8.1.9 Events qualifying for external assessment by the Oncologic Assessment Committee 
(oncAC)  
A separate independent, blinded, external committee regularly reviews all events suspect of 
solid cancer and assesses whether the cancer case is drug related or not. Details on 
composition of the oncAC, responsibilities and clinical event definitions are provided in the 
corresponding oncAC charter. 
 
Frequency tables summarizing the relatedness will be provided. 
In addition possibly related, not related and not assessable events will be presented. 
A frequency table will be provided for trigger events that cannot be confirmed as a solid 
tumor malignancy as defined in the charter.  
The analysis will be performed on TS using all events from study treatment start until study 
end. 
 
 
 
 
 
 
 
 
  


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7.8.1.11 Further adverse events 
Patients with the following adverse events will be tabulated by treatment group:  
 
 arthralgia (defined by HLGT ‘Joint disorders’) (by HLT and PT) 
 cancer (broad BIcMQ) (by HLT and PT) 
 
For this ‘AE concept’ of arthralgia in addition frequency tables for serious adverse events 
and, adverse events leading to discontinuation from trial drug will be presented. 
The most recent version of the definitions of these AEs according to the respective most 
recent MedDRA version will be used. These will be stored in the CTMF. 
 
7.8.1.12 Adverse events occurring after wrong medication intake 
A listing of patients with on-treatment adverse events with an onset during the non-
randomised treatment will be provided. 
 
 
 
 
 
 
 


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7.8.3 
Vital signs, waist circumference, weight 
Descriptive statistics will be displayed for the summary of blood pressure (BP) (mmHg), 
pulse rate (bpm), change from baseline in BP, and change from baseline in pulse rate over 
time. The analyses will be performed on the TS.  
 
 
7.8.4 
ECG 
Clinically relevant abnormal findings will be reported as AEs or respectively as baseline 
conditions. 
AE analysis will take place as planned in Section 7.8.1. 
 
 
 
 
 
 
  


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8. 
REFERENCES 
1 
General Guideline and Template, “Global Biostatistics Standard Output 
Conventions”, current version; Output Conventions – OD BS0206. 
2 
R07-4680 Collet D (2003) Modeling Survival Data in Medical Research. Chapman 
and Hall. 
3 
Bretz F, Maurer W, Brannath W, Posch M (2009) A graphical approach to 
sequentially rejective multiple test procedures. Statist Med; 28:586-604 
4 
ICH Guideline Topic E3, “Structure and Content of Clinical Study Reports”, 
current version; Note For Guidance on Structure and Content of Clinical Study 
Reports (CPMP/ICH/137/95). 
5 
Reference Document of Corp Guideline, " Handling, Display and Analysis of 
Laboratory Data: Standard Clinical Evaluation Criteria", current version; IDEA 
for CON: 001-MCG-157_RD-02. 
 


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10. 
HISTORY TABLE 
Table 10: 1 
History table 
Version 
Date 
(DD-Mmm-YY) 
Author 
Sections 
changed 
Brief description of change 
Final 
05 May 2017 
 
 
None 
Final version 
Revised 
18-DEC-2017 
 
 
Refer to 
Section 
4 
Updated version based on FDA 
comments and minor clarifications 
(refer to Section 4)