Conditions: Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6103
Healthy volunteers: no

Brief summary:
The aim of the study is to investigate the longterm impact on cardiovascular morbidity and mortality, relevant efficacy parameters (e.g., glycaemic parameters) and safety (e.g., weight and hypoglycaemia) of treatment with linagliptin in patients with type 2 diabetes at elevated cardiovascular risk receiving usual care, and compare outcome against glimepiride.

Detailed description:

Arms:
arm 1: patient to receive linagliptin or glimepiride placebo over encapsulated tablet Quaque die (QD) arm 2: patient to receive glimepiride 1-4 mg or linagliptin placebo tablet Quaque die (QD)

Interventions: intervention 1: linagliptin intervention 2: glimepiride intervention 3: linagliptin placebo intervention 4: glimepiride placebo
Intervention descriptions: intervention 1: linagliptin tablets 5mg QD intervention 2: glimepiride over-encapsulated tablet 1-4 mg QD intervention 3: linagliptin placebo intervention 4: glimepiride placebo

Protocol document:
Prot_000.pdf: 
 
 
 
Clinical Trial Protocol 
 
Doc. No.: c01618200-19 
EudraCT No.: 
 
BI Trial No.: 
2009-013157-15 
 
1218.74 
 
BI Investigational 
Product(s): 
Linagliptin 
Title: 
A multicentre, international, randomised, parallel group, double 
blind study to evaluate Cardiovascular safety of linagliptin 
versus glimepiride in patients with type 2 diabetes mellitus at 
high cardiovascular risk.  
The CAROLINA Trial. 
Clinical Phase: 
III 
 
Trial Clinical Monitor:  
 
                                          
 
                                          
 
                                          Phone: 
 Fax: 
 
 
Co-ordinating 
Investigators: 
 
phone: 
         
fax:     
 
 
 
phone: 
        
fax:     
 
Status:  
Version and Date:  
Final Protocol  
Version 7, 20 April 2016 
 
 
Page 1 of 173 
 
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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. 
TITLE PAGE


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Doc No.: c01618200-19                              Protocol Revision 6 
         Page 2 of 173 
 
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CLINICAL TRIAL PROTOCOL SYNOPSIS 
Name of company: 
Tabulated 
Trial Protocol 
 
Boehringer Ingelheim 
 
Name of finished product 
Not applicable  
Name of active ingredient: 
 
Linagliptin 
 
Protocol date: 
Trial number: 
 
Revision date: 
20 April 2016 
17 August 2010 
1218.74 
Title of trial: 
A multicentre, international, randomised, parallel group, double blind study to 
evaluate Cardiovascular safety of linagliptin versus glimepiride in patients with type 
2 diabetes mellitus at high cardiovascular risk. The CAROLINA Trial. 
Co-ordinating 
Investigators: 
 
 
 
 
and: 
 
  
 
 
Trial sites: 
Approximately 700 study centres, on average 8 to 10 patients per site 
Clinical phase: 
III 
Objectives: 
The primary objective is to demonstrate non-inferiority (by means of comparing the 
upper limit of a two-sided (1-2*alpha)*100% confidence interval with the non-
inferiority margin of 1.3) of treatment with linagliptin in comparison to glimepiride 
(as monotherapy or as add-on therapy) with respect to time to first occurrence of any 
of the adjudicated components of the primary composite endpoint (i.e. cardiovascular  
[CV] death, non-fatal stroke or non-fatal myocardial infarction [MI] (excluding silent 
MI) in patients with  type 2 diabetes mellitus [T2DM]. If the non-inferiority 
hypothesis with margin 1.3 has revealed a significant result, then secondly, the 
primary composite endpoint will be tested with a superiority hypothesis. If the 
superiority test has revealed a significant result, then thirdly the first key secondary 
endpoint will be tested hierarchically with a superiority hypothesis. If the test of the 
first key secondary hypothesis has revealed a significant result, then fourthly the 
second key secondary endpoint will be tested hierarchically. If the test of the second 
key secondary hypothesis has revealed a significant result, then fifthly the third key 
secondary endpoint will be tested hierarchically. 
Other objectives are to compare HbA1c change from baseline, the incidence of 
hypoglycaemia, weight change, treatment sustainability [defined as the proportion of 
patients that are on study treatment at study end without need for rescue medication, 
that at Final Visit maintain glycaemic control (HbA1c ≤ 7.0%)].  


Boehringer Ingelheim    
 
 
 
 
 
                       20 April 2016 
BI Trial No.: 1218.74 
Doc No.: c01618200-19                              Protocol Revision 6 
         Page 3 of 173 
 
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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 
Not applicable  
Name of active ingredient: 
 
Linagliptin 
 
Protocol date: 
Trial number: 
 
Revision date: 
20 April 2016 
17 August 2010 
1218.74 
Methodology: 
This is a multicentre, multinational, randomised, double blind, parallel group, 
comparator-controlled study of linagliptin versus glimepiride as monotherapy or as 
add-on therapy. 
No. of patients:  
total entered: 
An estimated number of 6000 randomised patients to obtain a minimum of 631 
primary endpoints. 
each treatment: An estimated number of 3000 randomised patients per treatment group. 
Diagnosis : 
T2DM 
Inclusion criteria: 
Documented diagnosis of T2DM and concurrently insufficient glycaemic control and 
a high risk of CV events prior to informed consent: 
 
Insufficient glycaemic control (at Visit 1a) defined as: 
a) HbA1c 6.5 - 8.5% (48 - 69 mmol/mol) while patient is treatment naïve (if 
intolerant or contra-indicated to first line anti-diabetic treatment) or treated 
with: 
 
- metformin monotherapy, or 
 
 
- alpha-glucosidase inhibitor monotherapy (e.g. acarbose, voglibose), or 
- metformin + alpha-glucosidase inhibitor, or 
 
 
 
 
 
b) HbA1c 6.5 - 7.5% (48 - 58 mmol/mol) while patient is treated with 
- sulphonylurea (SU) monotherapy, or  
 
       
 
 
- glinide monotherapy (e.g. repaglinide, nateglinide), or 
- metformin + SU (combination maximal up to 5 years), or  
- metformin + glinide (combination maximal up to 5 years), or 
- alpha-glucosidase inhibitor + SU (combination maximal up to 5 years), 
  or 
             - alpha-glucosidase inhibitor + glinide (combination maximal up to 5 years) 


Boehringer Ingelheim    
 
 
 
 
 
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BI Trial No.: 1218.74 
Doc No.: c01618200-19                              Protocol Revision 6 
         Page 4 of 173 
 
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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 
Not applicable  
Name of active ingredient: 
 
Linagliptin 
 
Protocol date: 
Trial number: 
 
Revision date: 
20 April 2016 
17 August 2010 
1218.74 
Inclusion criteria: 
 
High risk of CV events defined as any one (or more) of A), B), C) or D): 
       A) Previous Vascular Disease: 
-  
Myocardial infarction (> 6 weeks prior to informed consent)  
- 
Documented coronary artery disease (≥ 50% luminal diameter narrowing 
of left main coronary artery or  ≥50% in at least two major coronary 
arteries in angiogram) 
- 
Percutaneous Coronary Intervention (PCI)  > 6 weeks prior informed 
consent 
- 
Coronary Artery By-pass Grafting (CABG) > 4 years prior to informed 
consent or with recurrent angina pectoris following surgery  
- 
Ischemic or hemorrhagic stroke (> 3 months prior to informed consent)  
- 
Peripheral occlusive arterial disease (previous limb bypass surgery, 
stenting or percutaneous transluminal angioplasty; previous limb or foot 
amputation due to circulatory insufficiency, angiographic or ultrasound 
detected significant vessel stenosis (≥ 50%) of major limb arteries 
(common iliac-, internal iliac-, external iliac-, femoral- and/or popliteal 
artery), history of intermittent claudication with uni- or bilateral ankle: 
arm blood pressure ratio < 0.90). 
 
B) Evidence of vascular related end-organ damage: 
 
-     Moderately impaired renal function (as defined by modified diet of   
            renal disease (MDRD) formula) with estimated glomerular filtration   
             rate [eGFR]) 30-59 mL/min/1.73 m2  
 
-     Random spot urinary albumin creatinine ratio ≥ 30 μg/mg (≥ 3.4   
            mg/mmol) in two of three unrelated specimens in previous 12  
      
             months prior Visit 1a 
 
-     Proliferative retinopathy defined as retinal neovascularisation or      
             previous retinal laser coagulation therapy.  
C) Age ≥ 70 years (at Visit 1a) 
D) At least two of the following CV risk factors:  
 
-     Type 2 diabetes mellitus duration > 10 years at Visit 1a. 
 
-     Current* systolic blood pressure (SBP) > 140 mmHg (or on at least  
             one blood pressure lowering treatment at Visit 1a) 
 
-     Current daily cigarette smoking 
 
-     Current* LDL cholesterol ≥ 135 mg/dL (3.5 mmol/l) (or specific current  
             treatment for this lipid abnormality at Visit 1a) 


Boehringer Ingelheim    
 
 
 
 
 
                       20 April 2016 
BI Trial No.: 1218.74 
Doc No.: c01618200-19                              Protocol Revision 6 
         Page 5 of 173 
 
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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 
Not applicable  
Name of active ingredient: 
 
Linagliptin 
 
Protocol date: 
Trial number: 
 
Revision date: 
20 April 2016 
17 August 2010 
1218.74 
Inclusion criteria: 
* Current  = Blood pressure or LDL cholesterol measurement < 6 months 
   prior V1a. 
 
Body Mass Index (BMI) ≤ 45 kg/m2 at Visit 1b 
 
Age ≥ 40 and ≤ 85 years at Visit 1a 
 
Signed and dated written informed consent at the latest by the date of Visit 
1a,  in accordance with GCP and local legislation 
 
Stable anti-diabetic background medication (unchanged daily dose) for at 
least 8 weeks prior V1a and without short term use of insulin. Background 
medication should be stable during screening/run-in phase to allow 
randomisation 
 
Treatment compliance in the placebo run-in should be between 80% and 120% to be 
eligible for randomisation.  
Note: To ensure appropriate representation of patients from the different 
cardiovascular risk categories (A-D), the trial team will monitor the proportion of 
patients being recruited into these categories (trial level, and by region and/or 
country). In consultation with the steering committee, 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.  
In consultation with the Steering Committee, enrolment of patients currently at least 
on SU or glinide may be limited. 


Boehringer Ingelheim    
 
 
 
 
 
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BI Trial No.: 1218.74 
Doc No.: c01618200-19                              Protocol Revision 6 
         Page 6 of 173 
 
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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 
Not applicable  
Name of active ingredient: 
 
Linagliptin 
 
Protocol date: 
Trial number: 
 
Revision date: 
20 April 2016 
17 August 2010 
1218.74 
Criteria for exclusion: 
 
Type 1 diabetes mellitus 
 
Any history and/or current treatment with other antidiabetic drugs (e.g. 
rosiglitazone, pioglitazone, GLP-1 analogue/agonists, DPP-IV inhibitors or 
any insulin) prior to informed consent. Note 1: This also includes clinical 
trials where these antidiabetic drugs have been provided to the patient. Note 
2: Previous short term use of insulin (up to two consecutive weeks) is 
allowed (e.g. during hospitalisation) if taken at least 8 weeks prior informed 
consent 
 
Treatment with anti-obesity drugs within 3 months prior to informed consent 
 
Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (>13.3 
mmol/L) after an overnight fast during placebo run-in and confirmed by a 
second measurement (not on the same day) 
 
Any previous (or planned within next 12 months) bariatric surgery (open or 
laparascopic) or intervention (gastric sleeve)  
 
Current treatment with systemic corticosteroids at time of informed consent 
or pre-planned initiation of such therapy. Note: inhaled use of steroids (e.g. 
for asthma/COPD) is no exclusion criterion, as this does not cause systemic 
steroid action 
 
Change in dose of thyroid hormones within 6 weeks prior informed consent  
 
Active liver disease or impaired hepatic function, defined by serum levels of 
either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper 
limit of normal (ULN) as determined at visit 1a 
 
Pre-planned coronary artery re-vascularisation (PCI, CABG) within next 6 
months after V1a or any previous PCI and/or CABG ≤ 6 weeks prior 
informed consent  
 
Known hypersensitivity or allergy to the investigational product or its 
excipients, or glimepiride (or the SU class) 
 
Inappropriateness of glimepiride treatment for renal safety issues or other 
issues (e.g. allergy) according to local prescribing information 
 
Congestive heart failure of NYHA class III or IV 
 
Acute or chronic metabolic acidosis (present condition in patient history) 
 
Hereditary galactose intolerance  
 
Alcohol or drug abuse within the 3 months prior to informed consent that 
would interfere with trial participation 
 
Participation in another trial with an investigational drug given within 2 
months prior to informed consent 
 


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BI Trial No.: 1218.74 
Doc No.: c01618200-19                              Protocol Revision 6 
         Page 7 of 173 
 
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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 
Not applicable  
Name of active ingredient: 
 
Linagliptin 
 
Protocol date: 
Trial number: 
 
Revision date: 
20 April 2016 
17 August 2010 
1218.74 
 
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.  
 
Patients considered unreliable by the investigator concerning the 
requirements for follow-up during the study and/or compliance with study 
drug administration, has a life expectancy less than 5 years for non-CV 
causes, or has cancer other than non-melanoma 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 
 
Acute coronary syndrome ≤ 6 weeks prior to informed consent 
 
Stroke or TIA ≤ 3 months prior to informed consent 
Test product: 
Linagliptin 
dose: 
5 mg once daily 
mode of admin. : Tablets per os 
Comparator product: 
Glimepiride 
dose: 
1-4 mg once daily 
mode of admin. : Tablets (overencapsulated) per os 
Duration of treatment: 2 up to 4 weeks placebo run-in phase followed by up to an estimated  432 weeks 
treatment period and 30 days follow-up after study drug termination. 


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Name of company: 
Tabulated 
Trial Protocol 
 
Boehringer Ingelheim 
 
Name of finished product 
Not applicable  
Name of active ingredient: 
 
Linagliptin 
 
Protocol date: 
Trial number: 
 
Revision date: 
20 April 2016 
17 August 2010 
1218.74 
Criteria for efficacy:  
1) Primary endpoint: time to first occurrence of any of the following adjudicated 
components of the primary composite endpoint: CV death (including fatal stroke 
and fatal MI), non-fatal stroke or non-fatal MI (excluding silent MI)  
2) First key secondary endpoint: time to first occurrence of any of the following 
adjudicated components of the composite endpoint: CV death (including fatal 
stroke and fatal MI), non-fatal stroke, non-fatal MI (excluding silent MI) or 
hospitalisation for unstable angina pectoris. 
3) Second key secondary endpoint: composite endpoint of (treatment sustainability 
defined as the proportion of patients that are on study treatment at study end, that 
at Final Visit maintain glycaemic control (HbA1c ≤ 7.0%) without need for 
rescue medication (between end of titration [Visit 6] and Final Visit) and patients 
without any moderate/severe hypoglycaemic episodes (between Visit 6 and Final 
Visit) and without > 2% weight gain at Final Visit (between Visit 6 and Final 
Visit)).  
4) Third key secondary endpoint: composite endpoint of (treatment sustainability 
defined as the proportion of patients that are on study treatment at study end, that 
at Final Visit maintain glycaemic control (HbA1c ≤ 7.0%) without need for 
rescue medication (between Visit 6 and Final Visit) and patients without > 2% 
weight gain at Final Visit (between Visit 6 and Final Visit)) 
Criteria for safety: 
1) The occurrence of and time to each of the following adjudicated events: CV death 
(including fatal stroke and fatal MI), (non)- fatal MI, (non)- fatal stroke, 
hospitalisation for unstable angina pectoris, TIA, hospitalisation for congestive 
heart failure, hospitalisation for coronary revascularization procedures (CABG, 
PCI); and the occurrence of and time to silent myocardial infarction 
2) Incidence and intensity of adverse events, physical examination, vital signs, ECG, 
change from baseline in laboratory parameters 
3) Proportion of patients with serious and non-serious hypoglycaemic episodes 
4) Change from baseline in weight and proportion of patients with ≤ 2% or > 2% 
weight gain (with or without rescue medication during maintenance phase) at 
Final Visit  
Refer to section 5.2 for a comprehensive list of safety criteria.  
Statistical methods: 
For the primary analysis a cox proportional hazards regression model of time to the 
first event with factor treatment will be conducted. The primary analysis will be 
performed on the full analysis set. The non-inferiority margin will be 1.3 and the 
hypotheses will be one-sided with an overall significance level of alpha=0.025.  
The first key secondary endpoint will be analysed with a cox proportional hazards 
regression model of time to the first event with factor treatment. The second and third 
key secondary endpoints will be analysed with Chi-Square test. 


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         Page 9 of 173 
 
 
 
 
 
FLOW CHART 
 
Trial Period 
Screening 
Placebo 
run-in 
Treatment phase (titration) 
Visit 
1a 
1bA 
2 
3 
4 
5 
Study week 
 
-4 / -2 
0 
4 
8 
12 
Days from randomisation 
-35/ -15 
  -28 /  -14 
0  
28  
56 
84  
Time window (days)J 
 
 
 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
In-/exclusion criteria 
X 
X 
XC 
 
 
 
Medical History/ 
Concomitant diagnoses 
X 
 
 
 
 
 
Demographicso 
X 
X 
 
 
 
 
Physical examination 
 
XM 
 
 
 
 
Vital signs 
 
XM 
X 
X 
X 
X 
Height 
 
XI 
 
 
 
 
Weight 
 
XI 
X 
 
 
 
Waist circumference 
 
X 
X 
 
 
 
12-lead-ECG 
 
 
XM 
 
 
 
Diet and exercise 
counselling 
X 
 
X 
X 
X 
X 
Pregnancy TestF 
X 
 
X 
 
 
 
Fasted Home Blood 
Glucose Monitoring 
(HBGM)G 
 
X 
XL 
X 
X 
X 
Safety lab Tests (Urine and 
Blood)H 
X 
 
X 
 
 
 
Glomerular filtration rateK 
X 
 
X 
 
 
 


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                       20 April 2016 
BI Trial No.: 1218.74 
Doc No.: c01618200-19                              Protocol Revision 6 
         Page 10 of 173 
 
 
 
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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. 
 
Trial Period 
Screening 
Placebo 
run-in 
Treatment phase (titration) 
Visit 
1a 
1bA 
2 
3 
4 
5 
Study week 
 
-4 / -2 
0 
4 
8 
12 
Days from randomisation 
-35/ -15 
  -28 /  -14 
0  
28  
56 
84  
Time window (days)J 
 
 
 
±7 
±7 
±7 
Fasting Plasma GlucoseB  
 
X 
X 
X 
X 
X 
HbA1c 
X 
 
XC 
 
 
 
                  
              
              
 
 
 
 
 
 
 
PG sampling E 
 
 
X 
 
 
 
Lipid profile 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
Concomitant Therapy 
X 
X 
X 
X 
X 
X 
Dispense placebo run-in 
medication (via IXRS) 
 
X 
 
 
 
 
Randomisation (via IXRS) 
 
 
X 
 
 
 
Dispense double-blind 
medication 
 
 
X 
X 
X 
X 
Medication compliance 
check 
 
 
X 
X 
X 
X 
Flow Chart (continued) 


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         Page 11 of 173 
 
 
 
 
 
Trial Period 
Treatment phase (maintenance) 
Visit 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Study week 
16 
32 
48 
64 
80 
96 
112 
128 
144 
160 
176 
192 
208 
Days from 
randomisation 
112 
224 
336 
448 
560 
672 
784 
896 
1008 
1120 
1232 
1344 
1456 
Time window 
(days) 
±7  
±14 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
Physical 
examination 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Waist 
circumference 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
12-lead-ECG 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Diet and 
exercise 
counselling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy TestF 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasted Home 
Blood Glucose 
Monitoring 
(HBGM)G 
 
 
 
 
 
 
 
 
 
XL 
 
 
 
Safety lab Tests 
(Urine and 
Blood) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Glomerular 
filtration rateK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting Plasma 
GlucoseB  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flow Chart (continued) 


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Doc No.: c01618200-19                              Protocol Revision 6 
         Page 12 of 173 
 
 
 
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Lipid profile 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense 
double-blind 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication 
compliance 
check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Flow Chart (continued) 


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Trial Period 
 
 
Treatment phase (maintenance) 
F’ 
up 
Visit 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
EOTN 
33 
Study week 
224 
240 
256 
272 
288 
304 
320 
336 
352 
368 
384 
400 
416 
432 
436 
Days from 
randomisation 
 
1568 
 
1680 
 
1792 
 
1904 
 
2016 
 
2128 
 
2240 
 
2352 
 
2464 
 
2576 
 
2688 
 
2800 
 
2912 
 
3024 
 
3054 
Time window 
(days) 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
+7 
Physical 
examination 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Waist 
circumference 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
12-lead-ECG 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
Diet and 
exercise 
counselling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy 
TestF 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fasted Home 
Blood Glucose 
Monitoring 
(HBGM)G 
 
 
 
 
 
 
 
 
 
 
 
 
 
XL 
 
Safety lab 
Tests (Urine 
and Blood) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Glomerular 
filtration rateK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting Plasma 
GlucoseB  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Flow Chart (continued) 


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         Page 14 of 173 
 
 
 
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Trial Period 
 
 
Treatment phase (maintenance) 
F’ 
up 
Visit 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
EOTN 
33 
Study week 
224 
240 
256 
272 
288 
304 
320 
336 
352 
368 
384 
400 
416 
432 
436 
Days from 
randomisation 
 
1568 
 
1680 
 
1792 
 
1904 
 
2016 
 
2128 
 
2240 
 
2352 
 
2464 
 
2576 
 
2688 
 
2800 
 
2912 
 
3024 
 
3054 
Time window 
(days) 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
±14 
 
+7 
        
 
          
           
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid profile 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense 
double-blind 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Medication 
compliance 
check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Flow Chart (continued) 


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         Page 15 of 173 
 
 
 
 
A 
Visit 1b to be performed within 1 week from Visit 1a 
 
B 
Overnight fasting (10 hours no food and only water) 
 
C 
HbA1c measured at Visit 1a will be used for inclusion 
 
  
 
 
 
 
 
 
 
 
 
F 
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. 
 
G 
Home blood glucose monitoring (HBGM) device provided at Visit 1b. The patient should be instructed to bring 
 their HBGM device to the clinic at least at the specified visits for an additional measurement of fasted glucose.  
 
H 
Visit 1a safety laboratory only includes ALT (SGPT), AST (SGOT), alkaline phosphatase, serum creatinine, urine 
analysis and urine albumin and creatinine, in addition to HbA1c and does not need to be collected in fasted state.  
 
I 
Body Mass Index will be calculated automatically.  
 
J 
Maximal time window between two visits during titration phase is 5 weeks and during maintenance phase 18 
weeks. 
 
K 
Calculated based on MDRD formula (see Section 5.2.3.4). This formula considers the race as an adjustment factor, 
therefore, the race must be known (and will be collected) for accurate estimation.  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
M 
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 event. If such abnormalities already 
pre-exist prior study inclusion they should be considered as baseline conditions. 
 
 
N 
The End of Treatment Visit (EOT) activities will be performed when a patient discontinues study medication 
treatment permanently. A follow-up visit will take place 30 days after the EOT visit. Patients who discontinue 
study drug prematurely should be observed until study end as if they were still receiving blinded study treatment, 
but no (safety) laboratory sampling (including pregnancy test), ECG or vital signs will be required. 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 and a telephone call at study end  (through the patient or alternative person 
designated by the patient) will be asked for, to document the occurrence of outcome events and vital status. If 
possible, also other AE’s and concomitant therapy changes since last visit should be recorded.  
 
 


 
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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. In case the patient is re-instituted on study treatment, the preferred dosage for 
glimepiride/glimepiride placebo is the dose used before stopping treatment (unless hypoglycaemia was the reason 
to temporarily stop treatment, see section 4.1.4).  In case there is a need for further adjustments after this re-
institution the guidance for treatment initiation should be followed.   
 
O 
Race of patients will be collected because T2DM treatment results maybe race sensitive. Furthermore, the renal 
function will be assessed using the MDRD formula. This formula considers the race as an adjustment factor, 
therefore, the race must be known for accurate estimation.  


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TABLE OF CONTENTS 
TITLE PAGE .................................................................................. 1 
CLINICAL TRIAL PROTOCOL SYNOPSIS ............................ 2 
FLOW CHART ............................................................................... 9 
TABLE OF CONTENTS ............................................................. 17 
ABBREVIATIONS ....................................................................... 20 
1. 
INTRODUCTION ............................................................. 23 
1.1 
MEDICAL BACKGROUND ..................................................... 23 
1.2 
DRUG PROFILE ........................................................................ 25 
2. 
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT .................................................................. 27 
2.1 
RATIONALE FOR PERFORMING THE TRIAL ................. 27 
2.2 
TRIAL OBJECTIVES ................................................................ 28 
2.3 
BENEFIT - RISK ASSESSMENT ............................................. 28 
3. 
DESCRIPTION OF DESIGN AND TRIAL 
POPULATION .................................................................. 31 
3.1 
OVERALL TRIAL DESIGN AND PLAN ................................ 31 
3.1.1 
 Administrative structure of the trial .................................. 32 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE 
CHOICE OF CONTROL GROUP............................................ 33 
3.3 
SELECTION OF TRIAL POPULATION ................................ 33 
3.3.1 
Main diagnosis for study entry............................................. 35 
3.3.2 
Inclusion criteria .................................................................... 35 
3.3.3 
Exclusion criteria ................................................................... 38 
3.3.4 
Removal of patients from therapy or assessments ............. 39 
3.3.4.1 
Removal of individual patients .......................................... 39 
3.3.4.2  
Discontinuation of the trial by the sponsor ....................... 41 
4. 
TREATMENTS ................................................................. 42 
4.1 
TREATMENTS TO BE ADMINISTERED ............................. 42 
4.1.1 
Identity of investigational product(s) .................................. 42 
4.1.2 
Method of assigning patients to treatment groups ............. 43 
4.1.3 
Selection of doses in the trial ................................................ 43 
4.1.4 
Drug assignment and administration of doses for each 
patient ..................................................................................... 43 
4.1.5 
Blinding and procedures for unblinding ............................. 46 
4.1.5.1 
Blinding ............................................................................. 46 
4.1.5.2 
Procedures for emergency unblinding ............................... 46 
4.1.6 
Packaging, labelling, and re-supply ..................................... 47 
4.1.7 
Storage conditions ................................................................. 47 
4.1.8 
Drug accountability ............................................................... 47 
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND 
RESCUE TREATMENT ............................................................ 48 
4.2.1 
Rescue medication, emergency procedures, and additional 
treatment(s) ............................................................................ 48 
4.2.2 
Restrictions ............................................................................. 50 


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4.2.2.1 
Restrictions regarding concomitant treatment ................... 50 
4.2.2.2  
Restrictions on diet and life style ...................................... 50 
4.3 
TREATMENT COMPLIANCE ................................................ 50 
5. 
VARIABLES AND THEIR ASSESSMENT .................. 52 
5.1 
EFFICACY .................................................................................. 52 
5.1.1 
Endpoint(s) of efficacy .......................................................... 52 
5.1.2 
Assessment of efficacy ........................................................... 52 
5.2 
SAFETY ....................................................................................... 53 
5.2.1 
Endpoint(s) of safety ............................................................. 53 
5.2.1.1    Reporting waiver for cardiovascular outcome events ......... 53 
5.2.2 
Assessment of adverse events ............................................... 54 
5.2.2.1 
Definitions of adverse events ............................................ 54 
5.2.2.2 
Adverse event and serious adverse event reporting .......... 57 
5.2.2.3 Oncological adverse events.................................................... 59 
5.2.3 
Assessment of safety laboratory parameters ...................... 60 
5.2.3.1 
Haematology ..................................................................... 60 
5.2.3.2 
Clinical chemistry .............................................................. 60 
5.2.3.3 
Urinalysis ........................................................................... 61 
5.2.3.4 
Renal function impairment ................................................ 61 
5.2.4 
Electrocardiogram (ECG) .................................................... 62 
5.2.5 
Assessment of other safety parameters ............................... 62 
 
 
  
 
  
 
 
 
 
 
 
5.4 
APPROPRIATENESS OF MEASUREMENTS ...................... 65 
 
 
 
 
 
  
 
 
 
6. 
INVESTIGATIONAL PLAN ........................................... 67 
6.1 
VISIT SCHEDULE ..................................................................... 67 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED 
VISITS .......................................................................................... 67 
6.2.1 
Screening and Placebo run-in period .................................. 67 
6.2.2 
Treatment phase .................................................................... 68 
6.2.3 
End of trial and Follow-up period ....................................... 68 
7. 
STATISTICAL METHODS AND DETERMINATION 
OF SAMPLE SIZE ........................................................... 70 
7.1 
STATISTICAL DESIGN - MODEL ......................................... 70 
7.2 
NULL AND ALTERNATIVE HYPOTHESES ........................ 74 
7.3 
PLANNED ANALYSES ............................................................. 75 
7.3.1 
Primary analyses ................................................................... 77 
7.3.2 
Secondary analyses ................................................................ 78 


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7.3.3 
Safety analyses ....................................................................... 78 
7.3.4 
Interim analyses ..................................................................... 79 
7.4 
HANDLING OF MISSING DATA ............................................ 80 
7.5 
RANDOMISATION .................................................................... 80 
7.6 
DETERMINATION OF SAMPLE SIZE.................................. 81 
8. 
INFORMED CONSENT, DATA PROTECTION, 
TRIAL RECORDS ............................................................ 82 
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND 
INFORMED CONSENT ............................................................ 82 
8.2 
DATA QUALITY ASSURANCE............................................... 83 
8.3 
RECORDS ................................................................................... 83 
8.3.1 
Source documents .................................................................. 83 
8.3.2 
Direct access to source data and documents ....................... 83 
8.3.3 
Storage of records .................................................................. 84 
8.4 
LISTEDNESS AND EXPEDITED REPORTING OF 
ADVERSE EVENTS ................................................................... 84 
8.4.1 
Listedness ............................................................................... 84 
8.4.2 
Expedited reporting to health authorities and IECs/IRBs 84 
8.5 
STATEMENT OF CONFIDENTIALITY ................................ 85 
8.6 
COMPLETION OF TRIAL ....................................................... 85 
8.7 
PROTOCOL VIOLATIONS...................................................... 85 
8.8 
COMPENSATION AVAILABLE TO THE PATIENT IN THE 
EVENT OF TRIAL RELATED INJURY ................................. 85 
9. 
REFERENCES .................................................................. 86 
9.1 
PUBLISHED REFERENCES .................................................... 86 
9.2 
UNPUBLISHED REFERENCES .............................................. 91 
10. 
APPENDICES ................................................................... 92 
10.1 
INCLUSION OF ILLITERATE PATIENTS ........................... 92 
10.1.1 
Home blood glucose monitoring ........................................... 92 
10.1.2 
Patient information and informed consent 
 
 ................................................................. 92 
10.2 
DEFINITIONS OF ENDPOINT EVENTS ............................... 93 
10.3 
BLOOD PRESSURE MEASUREMENT PROCEDURE AND 
TREATMENT RECOMMENDATIONS ................................. 93 
10.4 
TREATMENT RECOMMENDATIONS FOR 
DYSLIPIDAEMIA ...................................................................... 94 
10.5 
 SILENT MYOCARDIAL INFARCTION ............................... 95 
10.6  
CLINICAL EVALUATION OF LIVER INJURY ................... 95 
10.6.1  Introduction ........................................................................... 95 
10.6.2  Procedures .............................................................................. 95 
10.6.3  Decision to Stop Drug Administration ................................ 97 
11. 
SUMMARY OF CLINICAL TRIAL PROTOCOL  
MODIFICATIONS ........................................................... 98 


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ABBREVIATIONS 
ACE 
Angiotensin Converting Enzyme 
ADA 
American Diabetes Association 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alaline transaminase (SGPT) 
ANCOVA 
Analysis of covariance 
AST 
Aspartate transaminase (SGOT) 
AT-II  
Angiotensin II 
BI 
Boehringer Ingelheim 
BMI 
Body Mass Index (weight divided by height squared) 
BP 
Blood Pressure 
CA 
Competent Authority 
CABG 
Coronary Artery Bypass Graft 
CEC 
Clinical Event Committee 
 
 
CI 
Confidence Interval 
CK 
Creatinine Kinase 
CK-MB 
Creatinine Kinase isoenzyme 
CML 
Clinical Monitor Local 
COPD 
Chronic Obstructive Pulmonary Disease 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Clinical Research Organisation 
CT 
Computerized Tomography 
CTMF 
Clinical Trial Master File 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
CTSU 
Clinical Trial Supply Unit 
CV 
Cardiovascular 
DBP 
Diastolic Blood Pressure 
DILI 
Drug Induced Liver Injury 
DMC 
Data Monitoring Committee 
DPP-IV 
Dipeptidyl-peptidase IV 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EASD 
European Association for the Study of Diabetes 
EOS 
End Of Study 
EOT 
End Of Treatment 
eGFR 
Estimated Glomerular filtration Rate 
EudraCT 
European Clinical Trials Database 
EU SmPc 
European Summary of Product characteristics 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 


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γ-GT 
Gamma-glutamyl-transferase (GGT) 
GI 
GastroIntestinal  
GIP 
Glucose-dependent Insulinotropic Peptide 
GLP-1 
Glucagon-like peptide 1 
HAs 
Health Authorities  
HbA1c 
Glycosylated haemoglobin 
HBGM 
Home Blood Glucose Monitoring 
HDL-C 
High Density Lipoprotein - Cholesterol 
HR 
Hazard Ratio 
ICH 
International Conference of Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intent To Treat 
IUD 
IntraUterine Device 
IUS 
IntraUterine System 
IXRS 
Interactive Voice and Web-based Response System 
LADA 
Latent autoimmune diabetes of adults 
LDL-C 
Low Density Lipoprotein - Cholesterol 
LOCF 
Last Observational Carried Forward 
LTFU 
Lost To Follow Up 
MACE 
Major Adverse Cardiovascular Event 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
 
 
MI 
Myocardial infarction 
MRI 
Magnet Resonance Imaging  
NGSP 
National Glycohemoglobin Standardization Program  
NPH 
Neutral Protamine Hagedorn (insulin) 
NYHA 
New York Heart Association 
OAD 
Oral Antidiabetic Drug 
OPU 
Operative Unit 
PCI 
Percutaneous Coronary Intervention 
PG 
PharmaGenetic 
p.o. 
per os (oral) 
PPS 
Per Protocol Set 
PR 
Pulse rate 
RDC 
Remote Data Capture 
REML 
Restricted Maximum Likelihood 
REP 
Residual Effect Period 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SC 
Steering Committee 
SU 
 
Sulfonylurea 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 


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SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TCM 
Trial Clinical Monitor 
T2DM 
Type 2 diabetes mellitus 
TDMAP 
Trial Data Management and Analysis Plan 
TG 
Triglyceride 
TIA 
Transient Ischemic Attack 
TMT 
Trail Making Test 
TSAP 
Trial Statistical Analysis Plan 
UAP 
Unstable Angina Pectoris 
UKPDS 
United Kingdom Prospective Diabetes Study 
ULN 
Upper Limit of Normal 
 
 


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1. 
INTRODUCTION 
Linagliptin is an orally available inhibitor of the enzyme dipeptidyl-peptidase IV 
(DPP-IV) facilitating a decrease of blood glucose levels in 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. The latter is primarily related to increased 
athero-thrombosis that leads to increased morbidity and premature mortality from 
cardiovascular (CV) disease [R10-0116, P08-06509]. Studies suggest that 70-75% of 
all deaths in people with diabetes can be attributed to CV complications [R10-0117]. 
Since hyperglycaemia in itself probably plays a causal role in this, strategies aiming at 
improving glycaemic control, could contribute in reducing complications and thereby 
also societies cost.  
 
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 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 its cautions against use in patients with impaired kidney 
function [P96-4362] where current product information documents include a ‘boxed 
warning’ or contraindication for metformin use if estimated glomerular filtration rate 
(eGFR) is below 60 mL/min/1.73 m2 [R10-4375]. Besides this also acute diabetic 
ketoacidosis, acute conditions with the potential to alter renal function acute or 
chronic disease which may cause tissue hypoxia, hepatic insufficiency, acute alcohol 
intoxication and alcoholism, are contraindications against its use. In a UK population 
study (published in Diabetic Medicine 2001;18:483-488), Emslie-Smith et al found 
that 6.4% of all patients with T2DM had some of these contraindications against using 


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this drug. Further limitations of metformin is gastrointestinal (GI) side effects [R10-
4375] that e.g. in the A Diabetes Outcome Prevention Trial (ADOPT) affected more 
than 1/3 of the participants [R09-6400]. However, despite these limitations, this 
compound is the most widely used and has a good safety profile and also has some 
degree of support for being cardio protective [R09-6405, R09-6409], or at least 
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 
T2DM, traditional insulin secretagogues such as the sulfonylureas (SUs) that 
stimulate to insulin secretion in a non-glucose-dependent manner is widely used; in 
fact it is the most used second line therapy. However, this treatment carries an 
increased risk for hypoglycaemia and weight gain [R09-6400] and, as for metformin, 
is also associated with a lack of sustainable effect [R09-6400]. Therefore, 
international treatment guidelines have opened for the 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 these drugs have also some side effects that limit 
their use, e.g. hypoglycaemia, weight gain, GI side effects and peripheral oedema. 
This could even also have prognostic implications since hypoglycaemia and weight 
gain was recently postulated as contributors to the adverse outcomes in the “Action to 
Control Cardiovascular Risk in Diabetes” (ACCORD) [R09-6407] and in the 
Veterans Affairs Diabetes trial (VADT) serious hypoglycaemia was the 2nd strongest 
predictor for developing a new myocardial infarction (MI) [R09-6408].  
Since CV caveats with drugs to treat T2DM, historically also have been found to arise 
at relatively late stage; just before, or even after, the compound reached the market, 
regulating authorities such as the US Food and Drugs Administration (FDA) has 
issued some guidance to industry in order to rule out potential excessive morbidity 
and mortality potentially associated with all new drugs for the treatment of T2DM 
[R09-2151]. Such an assessment could involve dedicated trials.  Having seen the 
potential limitations of drugs that are associated with weight gain and hypoglycaemia 
it is therefore of interest to explore novel treatment options that offer glycaemic 
reduction without associated such side effects.   
Emerging treatment for T2DM; DPP- IV inhibitors                                                                
The incretin effect is a phenomenon where the glucose-dependent insulin secretion is 
augmented by intestinally derived peptides (i.e. incretins), which 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. Glucagon like peptide 1 (GLP-1) is an 
important member of the incretin hormone family and accounts, together with 
glucose-dependent insulinotropic peptide (GIP), for more than 50% of the incretin 
effect in humans [R09-6409]. These hormones are almost instantaneously inactivated 
by the enzyme DPP-IV. DPP-IV 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-IV inhibition has been proven as a 
therapy. Besides its stimulatory effects on insulin secretion, that depend on the actual 
glucose concentration [R09-6409], resulting in a reduction of HbA1c, GLP-1 has also 


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been shown to inhibit glucagon secretion, to delay gastric emptying, to induce satiety, 
and, in animal models, to maintain long-term ß-cell function. Especially the 
maintenance of ß-cell function is of interest, that, if also would be the case in humans, 
would represent the first modulating therapy of the T2DM. However, no long term 
studies in human have actually confirmed this yet. An added interesting feature of this 
therapeutic option is that it seems to be associated with no weight gain and no 
hypoglycaemia (at least in monotherapy).  
Study proposal                                                                                                                              
In this large-scale intervention trial we will test the impact of treatment with the DPP-
IV inhibitor linagliptin head-to-head versus a SU (glimepiride) on CV safety and 
efficacy. The study will be given the acronym CAROLINA (Cardiovascular safety 
of linagliptin). 
1.2 
DRUG PROFILE 
The DPP-IV inhibitor compound linagliptin was discovered by Boehringer Ingelheim 
[BI] Pharma GmBH & Co. KG, Biberach, 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]. 
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 


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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 and relevant efficacy parameters (HbA1c, fasting plasma glucose, 
treatment sustainability) of treatment with linagliptin in a relevant population of 
patients with T2DM and compare outcome against one compound of the second most 
used OAD class, i.e., SU (glimepiride). To date this has not been tested in a long-term 
trial; as also is the case for other DPP-IV inhibitors. However, there are currently no 
safety signals that indicate that linagliptin should be inferior to glimepiride in this 
respect. A recent meta-analysis of the marketed DPP-IV inhibitors on the contrary 
indicates a potential beneficial CV effect of DPP-IV inhibitors as a class; although 
this meta-analysis mainly included trials of shorter duration where trial participants 
were not at a particular high CV risk, leaving the findings as hypothesis generating 
[R09-6410]. 
Since most guidelines state that metformin should be first line treatment, this study 
will in principal be conducted as add-on to metformin background. Since a relatively 
large proportion of patients with T2DM have some degree of contraindications or 
intolerance to metformin, or local guidelines may indicate other treatments as first 
line therapy, the study is also open for inclusion of patients being treatment naïve or 
on other antidiabetic treatments as specified in Section 3.3.2. In brief, the patients 
included might be OAD naïve (due to contraindications or intolerant to first line 
treatment), previously receiving monotherapy with metformin, any SU, any glinide or 
any alpha-glucosidase inhibitor or previously on dual therapy with metformin + SU, 
metformin + glinide, metformin + alpha-glucosidase inhibitor, SU + alpha-
glucosidase inhibitor or glinide + alpha-glucosidase inhibitor. 
Hence, the study has two study arms: linagliptin or glimepiride as monotherapy or as 
add-on to other allowed treatments. The study design is described in more detail in 
Section 3.1. 
Allowing this will generate a trial population with a short to moderate diabetes 
duration with a high CV risk (e.g., due to renal impairment, chronic cardiac disease or 
a recent MI, advanced age) to participate, thereby it will assess the CV safety profile 
of the drug as compared to one of the most widely used oral antidiabetic drug (OAD) 
globally (i.e. glimepiride) in a broad and relevant population of patients with T2DM. 
This study design therefore also concurs with the recent FDA guidelines for target 
population whom to in particular address CV risk of novel OADs in T2DM [R09-
2151] and will also be an integral part of the ongoing CV safety assessment for 
linagliptin and data will also be used to support regulatory submission.  
 
 
 
 


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2.2 
TRIAL OBJECTIVES 
The primary objective is to demonstrate non-inferiority (by means of comparing the 
upper limit of a two-sided (1-2*alpha)*100% confidence interval with the non-
inferiority margin of 1.3) of treatment with linagliptin in comparison to glimepiride 
(as monotherapy or as add-on therapy) with respect to time to first occurrence of any 
of the adjudicated components of the primary composite endpoint (i.e. cardiovascular  
death, non-fatal stroke or non-fatal myocardial infarction (excluding silent MI) in 
patients with type 2 diabetes mellitus. If the non-inferiority hypothesis with margin 
1.3 has revealed a significant result, then secondly, the primary composite endpoint 
will be tested with a superiority hypothesis. If the superiority test has revealed a 
significant result, then thirdly the first key secondary endpoint of time to first 
occurrence of any of the adjudicated components of cardiovascular death, non-fatal 
stroke, non-fatal myocardial infarction (excluding silent MI) or hospitalisation for 
unstable angina pectoris will be tested hierarchically with a superiority hypothesis. If 
the test of the first key secondary hypothesis has revealed a significant result, then 
fourthly the second key secondary endpoint will be tested hierarchically. If the test of 
the second key secondary hypothesis has revealed a significant result, then fifthly the 
third key secondary endpoint will be tested hierarchically. 
Other objectives are to compare HbA1c change from baseline, the incidence of 
hypoglycaemia, weight gain and treatment sustainability defined as the proportion of 
patients that are on study treatment at study end without need for rescue medication, 
that at Final Visit maintain glycaemic control (HbA1c ≤ 7.0%). 
For a description of the endpoints chosen and statistical analyses to assess these 
objectives, please refer to Section 5 and 7. 
2.3 
BENEFIT - RISK ASSESSMENT 
Potential general benefits for study participants in this trial (irrespective of 
investigational drug received, i.e. linagliptin or glimepiride) 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 during the study. 
Further, the participants can contribute to generate a potential future benefit for larger 
groups of patients with T2DM by participating in this clinical trial if linagliptin fulfils 
much of its promises as a future treatment of T2DM. 
General risk associated with participating is related to trial specific procedures such as 
blood sampling that can be associated with bruising and pain. The amount of blood 
taken during the whole course of the trial is not believed to be associated with any 
discomfort for the patients.  
 


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Investigational drug specific risk  
Glimepiride is a drug that has been on the market for a long time, is widely used and 
therefore is believed to be well characterized in term of risk profile. Patients 
randomised to glimepiride can nevertheless experience hypoglycaemia as a 
consequence of its mode of action. However, in a cohort of patients with T2DM of 
short-to-moderate duration this risk is relatively small as was seen in the UKPDS 
where yearly rate of severe hypoglycaemia was 1.0% for chlorpropamide (a first 
generation SU) and 1.4% with glibenclamide (a second generation SU) [R04-2173]. 
Also, there is a certain risk for patients to gain weight with this treatment; however 
not all trials with glimepiride has shown a weight increase [R09-6394].  
Linagliptin from its clinical phase III testing has shown a “placebo-like” safety 
profile. It carries a low risk for inducing hypoglycaemia and weight gain. However, 
linagliptin has by far not the same cumulative exposure compared to glimepiride. 
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, the very good 
tolerability seen 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 when compared to the potential benefits of a 
successful clinical development of linagliptin for patients with T2DM. 
Pioglitazone, metformin, alpha-glucosidase inhibitor or basal insulin could be used in 
this trial as rescue therapy (see Section 4.2.1). Pioglitazone has been extensively 
tested and has been associated with CV benefits [R09-6395]. However, some side 
effects might occur with this drug; i.e. weight gain, peripheral oedema, osteopenia and 
heart failure. The latter is however relatively infrequent and occurs in those 
susceptible to this. In combination with SU also hypoglycaemia risk is increased. 
Metformin might be used as rescue therapy; however BI expects that the proportion of 
patients that would be eligible for this would be low due to our inclusion criteria. 
However, metformin is associated with side effects as gastrointestinal discomfort, 
nausea and increases also the risk of hypoglycaemia.  
An alpha-glucosidase inhibitor may also be used as rescue therapy to maintain 
glycaemic control; however BI expects that the proportion of patients that would 
accept this treatment predominantly would be in the Asian study population due to the 
higher usage of this drug in this region. Side-effect of alpha-glucosidase inhibitors 
includes gastrointestinal discomfort, diarrea, nausea and increases also the risk of 
hypoglycaemia, in particular if combined with SU.  
Insulin might, as per all international guidelines, be expected required to certain 
patients as other OADs fail to control blood glucose levels adequately. Basal insulin 
(i.e. intermediate or long-acting insulin) is all widely used. Side effects of these are 
weight gain and hypoglycaemia. Some insulins also require need for re-suspension (at 
least NPH insulin) and they all need to be subcutaneously injected.  


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Pregnancy 
Metformin, alpha-glucosidase inhibitors, glimepiride, pioglitazone, most of the long 
acting insulin analogues and linagliptin are not approved for use in pregnancy. In the 
embryofoetal and fertility studies in rats and rabbits with linagliptin, no effects on 
early embryonic development, mating, male and female fertility, and bearing live 
young were observed up to and including the high dose group given 240 mg/kg. 
Therefore, women who are of child-bearing potential will be included in this study 
provided that they are using adequate contraceptive methods. 
Induced liver injury 
Based on principal considerations, there is always the possibility that so fare unknown 
safety issues are upcoming. One of those issues is drug induced liver injury. Albeit 
there was no risk identified so far, this study will follow a careful protocol to follow-
up laboratory alterations of liver parameters in order to safeguard patients' safety and 
to stay in compliance with international regulatory requirements. Although rare, drug 
induced liver injury is under constant surveillance by sponsors and regulators.  This 
study requires follow-up and expedited reporting of laboratory alterations of selected 
liver laboratory parameters to ensure patient safety and to remain compliant with 
international regulations. 
 


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3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION 
3.1 
OVERALL TRIAL DESIGN AND PLAN 
This multicentre, multinational, randomised, double-blind, parallel group, comparator 
-controlled study compares treatment with linagliptin (5 mg once daily) to treatment 
with glimepiride (1-4 mg) as monotherapy or as add-on therapy to metformin and/or 
other antidiabetic treatment as specified in Section 3.3.2. 
The trial is event driven and will run with an estimated number of 6000 patients for an 
estimated treatment time of  432 weeks, beginning with the randomisation of the first 
patient. In the case the number of events is not or may not be reached within this 
period the trial duration and/or the number of patients enrolled will be increased until 
the defined number of adjudicated primary events is reached. 
Patients will enter an open-label placebo (add-on) run-in period of 2 up to 4 weeks 
before randomisation. Patients who successfully complete at least two weeks of the 
placebo-run (should have a treatment compliance between 80% to 120%) and who 
still meet the inclusion/exclusion criteria will be randomised to receive either 
linagliptin or glimepiride. Patients who do not successfully complete at least two 
weeks of the placebo run-in, may continue the placebo run-in phase up to four weeks 
to meet the compliance criterion as specified above. Any SU or glinide will be 
discontinued at randomisation Visit 2 (SU/glinide should not be taken in the morning 
of Visit 2).  
The randomised treatment will be double-blind within the dose groups of linagliptin 
and glimepiride (i.e. each patient will receive one active treatment and placebo 
matching the alternative active treatment in a double-dummy design).  
 
 
 
 
 
 
Figure 3.1: 1 Treatment periods and treatment groups in the trial design 
For all patients, contacts are scheduled at regular time intervals (see flow chart). The 
estimated treatment duration for the first randomised patient is 432 weeks. The End of 
Treatment Visit (EOT) activities will be performed when a patient discontinues study 
medication permanently. Patients who discontinue study drug prematurely should be 
observed until study end as if they were still receiving blinded study treatment, but no 
(safety) laboratory sampling (including pregnancy test), ECG or vital signs will be 
required. If a patient who prematurely discontinued study drug is not willing to return 
Placebo (add-
on) Run-in  
2-4 weeks 
R
16 weeks titration 
phase of glimepiride 
up to 4 mg/day 
Estimated 416 weeks 
maintenance phase  
 
linagliptin 5mg  
glimepiride 1 to 4 mg  
16 weeks  
432 weeks  


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at the pre-defined regular visit schedule at minimum a yearly telephone call and a 
telephone call at study end will be asked for (through the patient or alternative person 
designated by the patient), to document the occurrence of outcome events and vital 
status. If possible, also other AE’s and concomitant therapy changes since last visit 
should be recorded.  
 
All patients will have a follow up visit 30 days following completion of the treatment 
period. The follow-up visit may be performed as a phone visit for patients who 
completed the planned treatment period and who do not have any abnormalities at the 
EOT visit (only adverse events/outcome events and changes in concomitant therapy to 
be obtained). 
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 631, 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 proposed time schedule, communicated via an investigator 
letter. A follow-up visit will take place 30 days after the EOT visit. 
In case early study termination is to be performed (e.g. based on recommendation by 
the 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. The following committees will 
participate in the conduct of the trial, their specific functions are summarised below: 
 
Steering Committee 
A Steering Committee (SC) will have a scientific and clinical advisory function in the 
study. The Steering Committee is composed by university and sponsor based 
scientists with clinical and methodological expertise.  
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will review safety and efficacy 
data and make recommendations whether to continue the study, continue the study 
with modifications, or terminate the study. The DMC analyses and operations will be 
formally separated from the sponsor, the investigators and the steering committee.  
Clinical Event Committees  
The study is set up with prospective adjudication of all cardio/cerebrovascular 
pancreatic 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 


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procedures and interactions are provided in a separate CEC Charter. Additionally, a 
separate independent, blinded, external committee will be set up for adjudication of 
pancreatic events. The adjudication process for these events will be clarified in a 
separate CEC charter.  
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP 
According to current guidelines of the ADA/EASD, metformin should be initiated 
concurrently with lifestyle intervention at diagnosis in patients newly diagnosed with 
T2DM when HbA1c > 7.0% and be titrated to a maximum tolerated dose (up to 2x 
1000 mg/day or total 2500 mg/day) [R09-1164]. Therefore, patients enrolling on 
metformin monotherapy represent an important proportion of patients with T2DM. 
However, contraindications or intolerance to metformin due to e.g. congestive heart 
failure or severe renal impairment also constitutes a significant amount of people with 
T2DM. Further, local guidelines may indicate other first line treatment. Therefore this 
trial also allows for patients that are treatment naïve or are on other antidiabetic 
treatments as specified in Section 3.3.2.  
Treatment with linagliptin is compared against glimepiride, a drug from the second 
most widely used antidiabetic class after metformin (i.e. SUs). Treatment goal for 
HbA1c is in this trial, according to most international guidelines, ≤ 7.0%. During the 
trial additional therapy (“rescue therapy”) is allowed, and encouraged, if HbA1c  > 
7.5% during maintenance phase. This is considered important as to ensure that an 
optimal level of standard of care is reached. However, the decision to initiate rescue 
medication remains with the investigator and the appropriate local treatment 
guidelines. 
 
The protocol also encourages the investigators to treat all other CV risk factors (lipid 
levels, blood pressure, micro/macroalbuminuria, unhealthy lifestyle, smoking) 
according to an optimal level of standard of care. In a high CV risk population this 
usually implies liberal use (if tolerated or not contraindicated) of statins, ACE-
inhibitors, AT-II receptor blockers, aspirin, beta-blockers, calcium channel blockers, 
etc.). This should be conducted in the context of local or regional guidance for 
primary or secondary CV prevention.  
The treatment period is planned for up to an estimated 432 weeks. The treatment 
period will be followed by a follow-up period of 30 days.  
3.3 
SELECTION OF TRIAL POPULATION 
Approximately 10000 patients will be screened for the trial in about 45 countries. 
Approximately 700 trial centres will be participating to randomise the estimated 
number of 6000 patients.  
 
 
 
 


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Participating sites are expected to randomise a least 8 patients. Investigators who fail 
to randomise 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 
recruited. 
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 has been randomised to trial 
treatment. Investigators will be notified when the appropriate number of patients has 
been screened and screening is complete, and will not be allowed to recruit additional 
patients for this study. Patients who have completed Visit 1a procedures prior to 
notification of the termination of recruitment will be allowed to continue in the study, 
if they meet all entry criteria. 
The check for 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. 
Conditions under therapy are always clinically relevant. 
A log of all patients included into the study (i.e. having given informed consent) will 
be maintained in the ISF at the investigational site irrespective of whether they have 
been treated with investigational drug or not. 
Re-screening and/or re-testing (of assessments) is permitted under certain 
circumstances. Whilst the information provided below is not an exhaustive list, it 
provides some guidance as to when such re-screening and/or re-testing would be 
considered appropriate. If a site is in any doubt as to whether re-screening and/or re-
testing is appropriate in their particular situation, then clarification should be sought 
with the CML. 
 
Re-testing: 
Re-testing is only to be performed for a lab result which is obviously received beyond 
stability at the central laboratory or thought to be a spurious result. It is not permitted 
to perform re-testing (in any time window after V1a sampling) for HbA1c when it 
does not meet the study criteria only.  
 
Re-screening: 
- 
Re-screening of the same patient is only allowed once. 
- 
The patient should be declared a screening failure in the eCRF/RDC with their 
original patient number. 
- 
Upon re-screening, the next available (= new) patient number should be 
selected from RDC. 
- 
The patient must be re-consented using the current approved version of the 
information sheet and consent form. 
- 
There is no time limit for re-screening – as long as the patient fits the 
eligibility criteria they could be re-screened whenever the investigator feels 
they may become eligible. 


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3.3.1 
Main diagnosis for study entry  
Patients with documented diagnosis of T2DM with insufficient glycaemic control and 
at high risk of CV events prior to informed consent can be enrolled in the study. Any 
antidiabetic background medication at Visit 1a should be on a stable (unchanged) 
daily dose for at least 8 weeks. There is no short term use of insulin within 8 weeks 
prior informed consent. Background medication should be stable during 
screening/run-in phase to allow randomisation.  
As local guidelines for management of T2DM will be followed, treatment naive 
T2DM patients should be offered first line anti-diabetic treatment (e.g. metformin) 
before allowing them for study inclusion, unless they have specific contra-indications 
or intolerances to its use (see also Section 2.1). 
Prior SU or glinide treatment will be discontinued at Visit 2, whereas if medications 
such as metformin and alpha-glucosidase inhibitor are being used, these should be 
continued. 
3.3.2 
Inclusion criteria 
1) Documented diagnosis of T2DM and concurrently 2) insufficient glycaemic 
control and a high risk of CV events  3) prior to informed consent.  
 
2) Insufficient glycaemic control (at Visit 1a) defined as: 
 
a) HbA1c 6.5 - 8.5% (48 - 69 mmol/mol) while patient is treatment naïve (if 
intolerant or contra-indicated to first line anti-diabetic treatment) or treated 
with:  
- metformin monotherapy, or  
 
- alpha-glucosidase inhibitor monotherapy (e.g. acarbose, voglibose), or  
- metformin + alpha-glucosidase inhibitor (e.g. acarbose, voglibose), or  
 
 
b) HbA1c 6.5 - 7.5% (48 - 58 mmol/mol) while patient is treated with 
- sulphonylurea (SU) monotherapy, or  
 
       
 
 
- glinide monotherapy (e.g. repaglinide, nateglinide), or 
- metformin + SU (combination maximal up to 5 years), or  
- metformin + glinide (combination maximal up to 5 years), or 
- sulphonylurea + alpha-glucosidase inhibitor (combination maximal up to 5 
 
  years), or 
- glinide + alpha-glucosidase inhibitor (combination maximal up to 5 years) 
 
 
 
3) High risk of CV events defined as any one (or more) of A), B), C) or D): 
 
       A) Previous Vascular Disease: 
-  Myocardial infarction (> 6 weeks prior to informed consent)  


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- 
Documented coronary artery disease (≥ 50% luminal diameter 
narrowing of left main coronary artery or ≥ 50% in at least two major 
coronary arteries in angiogram) Note: CT or MRI detection of this will not 
suffice for inclusion; only invasive angiography. The left main coronary artery is 
often abbreviated to LCA or LCMA. As this is a very important artery that is 
branched to other major arteries it suffices to have a  ≥ 50% stenosis in this artery 
(any segment) for inclusion. If there are no stenosis in this artery patient could be 
included if patient has a  ≥ 50% stenosis in two, or more, of the other major coronary 
arteries (any segment): LAD (Left Anterior Descending; also called AIB = Anterior 
interventricular branch), CX (= art. Circumflex, also called CB=Circumflex branch) 
or RCA (right coronary artery).  
- 
Percutaneous Coronary Intervention (PCI) > 6 weeks prior informed 
consent 
- 
Coronary Artery By-pass Grafting (CABG) > 4 years prior to informed 
consent or with recurrent angina following surgery  
- 
Ischemic or hemorrhagic stroke (> 3 months prior to informed consent)  
- 
Peripheral occlusive arterial disease (previous limb bypass surgery, 
stenting or percutaneous transluminal angioplasty; previous limb or 
foot amputation due to circulatory insufficiency, angiographic or 
ultrasound detected significant vessel stenosis (> 50%) of major limb 
arteries (common iliac artery, internal iliac artery, external iliac artery, 
femoral artery, popliteal artery), history of intermittent claudication, 
with an ankle: arm blood pressure ratio < 0.90 on at least one side). 
 
B) Evidence of vascular related end-organ damage: 
       -  Moderately impaired renal function (as defined by modified diet of 
renal disease (MDRD) formula) with estimated glomerular filtration 
rate [eGFRF]) 30-59 mL/min/1.73 m2  
-  Random spot urinary albumin: creatinine ratio ≥ 30 μg/mg (≥ 3.4 
mg/mmol) in two of three unrelated specimens in previous 12 months 
prior Visit 1a 
- 
Proliferative retinopathy defined as retinal neovascularisation or 
previous retinal laser coagulation therapy.  
 
C) Age ≥ 70 years (at Visit 1a) 
 
D) At least two of the following CV risk factors:  
 
- 
Type 2 diabetes mellitus duration > 10 years at Visit 1a. 
 
- 
Current* systolic blood pressure (SBP) > 140 mmHg (or on at least one 
 
blood pressure lowering treatment at Visit 1a) 
 
- 
Current daily cigarette smoking 
- 
Current* LDL cholesterol ≥ 135 mg/dL (3.5 mmol/L) (or specific 
current treatment for this lipid abnormality at Visit 1a). 
* Current = Blood pressure or LDL cholesterol measurement < 6 months 
prior V1a.  
 


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Note: To ensure appropriate representation of patients from the different 
cardiovascular risk categories (A-D), the trial team will monitor the proportion of 
patients being recruited into these categories (trial level, and by region and/or 
country). In consultation with the steering committee, 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.  
If a patient fulfils more than one CV risk category all CV risk categories will be 
indicated in the CRF. For CV risk distribution the patient will be allocated to highest 
CV risk category. CV risk category A is relatively highest category, followed by B, C, 
D.  
 
Examples: if patient is at age of 71 years and has T2DM > 10 years and is currently 
smoking, this patient will be allocated to category C.  
A patient with vascular end-organ damage and previous stroke will be allocated to 
category A.  
Patients may be included if any criterion A – D is fulfilled as long as it is not in 
conflict with any other exclusion criteria. Example: a patient at age 73 years may be 
included [fulfils criterion C] in case CABG was conducted two years ago. 
If a patient fulfils CV risk category A, C and/or D and has only one albumin 
creatinine ratio ≥ 30 μg/mg in previous 12 months prior Visit 1a, and an albumin 
creatinine ratio ≥ 30 μg/mg at V1a, such patient will also be identified as Cat. B 
patient in the CRF. The patient will be allocated to highest CV risk group for (A or 
B).  
 
In consultation with the Steering Committee, enrolment of patients currently at least 
on SU or glinide may be limited. 
 
4) Body Mass Index (BMI) ≤ 45 kg/m2 at Visit 1b. 
 
5) Age ≥ 40 and ≤ 85 years at Visit 1a 
 
6) Signed and dated written informed consent at the latest by the date of Visit 1a, in 
accordance with GCP and local legislation 
 
7) Stable anti-diabetic background medication (unchanged daily dose) for at least 8 
weeks prior V1a and without short term use of insulin. Background medication 
should be stable during screening/run-in phase to allow randomisation. 
 
 
 
 
 


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3.3.3 
Exclusion criteria 
1) Type 1 diabetes mellitus 
 
2) Any history and/or current treatment with other antidiabetic drugs (e.g. 
rosiglitazone, pioglitazone, GLP-1 analogue/agonists, DPP-IV inhibitors or any 
insulin) prior to informed consent.  
Note 1: This also includes clinical trials where these antidiabetic drugs have been provided to the 
patient. Note 2: Previous short term use of any insulin (up to two consecutive weeks) is allowed 
(e.g. during hospitalisation) if taken at least 8 weeks prior informed consent 
 
3) Treatment with anti-obesity drugs 3 months prior to informed consent 
 
4) Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (>13.3 mmol/L) 
after an overnight fast during placebo run-in and confirmed by a second 
measurement (not on the same day). 
 
5) Active liver disease or impaired hepatic function, defined by serum levels of 
either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit 
of normal (ULN) as determined at Visit 1a. 
 
6) Any previous (or planned within next 12 months) bariatric surgery (open or 
laparascopic) or intervention (gastric sleeve)  
 
7) Pre-planned coronary artery re-vascularisation (PCI, CABG) within next 6 months 
after V1a or any previous PCI and/or CABG ≤ 6 weeks prior informed consent  
 
8) Known hypersensitivity or allergy to the investigational product or its excipients, 
or glimepiride (or the SU class). 
 
9) Inappropriateness of glimepiride treatment for renal safety issues or other issues 
(e.g. allergy) according to local prescribing information 
 
10)  Congestive heart failure of NYHA class III or IV 
 
11)  Acute or chronic metabolic acidosis (present condition in patient history) 
 
12)  Hereditary galactose intolerance  
 
13)  Alcohol or drug abuse within the 3 months prior to informed consent that would 
interfere with trial participation 
 
14)  Current treatment with systemic corticosteroids at time of informed consent or 
pre-planned initiation of such therapy. Note: inhaled use of steroids (e.g. for 


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asthma/COPD) is no exclusion criterion, as this does not cause systemic steroid 
action.  
 
15)  Change in dose of thyroid hormones within 6 weeks prior informed consent 
 
16)  Participation in another trial with an investigational drug given within 2 months 
prior to informed consent 
 
17)  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.  
18) Patients considered unreliable by the investigator concerning the requirements for 
follow-up during the study and/or compliance with study drug administration, has 
a life expectancy less than 5 years for non-CV causes, or has cancer other than 
non-melanoma 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 
19) Acute coronary syndrome ≤ 6 weeks prior to informed consent 
20) Stroke or TIA ≤ 3 months prior to informed consent 
 
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 prematurely discontinue study drug should remain in the study and 
should be observed until study end, preferably at the study time points as pointed out 
in the Flow Chart. 
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 (through the patient or alternative 
person designated by the patient) will be required, to document the occurrence of 
outcome events and vital status. If possible, also 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. 


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Patients who prematurely discontinue study medication 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 could 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 determined by investigator as necessary for patient safety, new antidiabetic 
medication regimen can be started immediately after discontinuation of study 
treatment and must be recorded in the eCRF (see further details in Section 4.2). 
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 otherwise termination of 
the pregnancy (see further details in Section 5.2.2.2) 
If pancreatitis is suspected, the study treatment should be stopped. 
Patients who drop out during the screening/run-in phase prior to randomisation (Visit 
2) will be considered a screening failure. They have to be recorded as screening 
failure in eCRFs and no further follow-up is required.  
Patients who withdraw or discontinue from the study after randomisation will not be 
replaced. 
If a patient needs to take concomitant drugs that interfere with the investigational 
product (or other study medications) or in the occurrence of hypoglycaemia that may 
put the patient at risk with continued participation (e.g. repeated hypoglycaemic 
episodes) the trial medication can be discontinued temporarily, or if needed 
permanently. Since this is an outcome study, the primary analysis will be performed 
based on all randomised patients who were treated with at least one dose of study 
drug. Therefore investigators are encouraged to re-administer study medication to a 
randomised patient if there are no further safety concerns. 
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 must be involved in the discussions 
with the patient regarding a withdrawal of consent. 
If the patient withdrew informed consent the patient should stop taking study 
medication and should be asked to complete the study ending tests and procedures as 
described in the Flow Chart for End of Treatment Visit and Visit 33 (Follow up visit). 
Completing these procedures is strongly recommended for the patient’s safety. The 


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reason for discontinuing treatment will be recorded in the eCRF. The data will be 
included in the trial database and will be reported.  
For patients that have withdrawn informed consent, the patient will be asked to resign 
an informed consent form, which will allow to enquire at least about the patient’s vital 
status and occurred outcome events through contacts to relatives, acquaintances, 
family physicians, hospital records, etc.  
If patients who discontinue from treatment after randomisation could not be followed-
up until the end of study (i.e. at least the vital status could not be collected) those 
patients will be indicated as Lost To Follow Up (LTFU). The number of LTFU 
patients should be limited. 
The End of Treatment Visit (EOT) activities will be performed when a patient 
discontinues study treatment permanently.  
A follow-up visit will take place 30 days after the EOT visit. Patients who discontinue 
study drug prematurely should be observed until study end as if they were still 
receiving blinded study treatment, but no (safety) laboratory sampling (including 
pregnancy test), ECG or vital signs will be required. 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 and a telephone call at study end will be 
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 be recorded. 
Patients should keep their antidiabetic medication stable for the course of the trial 
(except prior SU or glinide treatment which should be stopped at V2. SU/glinide 
should not be taken in the morning of Visit 2). 
3.3.4.2  Discontinuation of the trial by the sponsor 
Boehringer Ingelheim 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 GCP, the 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 investigational product(s) 
The characteristics of the test product are below. 
 
Substance: 
Linagliptin (BI linagliptin) 
Pharmaceutical form: 
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: 
tablet 
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit Strength: 
- 
Route of administration: 
p.o., once daily 
The characteristics of the reference product are below. 
 
Substance: 
glimepiride 1 mg (Amaryl® 1 mg) 
Pharmaceutical form: 
tablet (overencapsulated) 
Source: 
Sanofi-Aventis 
Unit Strength: 
1 mg 
Route of administration: 
p.o., once daily 
Substance: 
glimepiride 2 mg (Amaryl® 2 mg) 
Pharmaceutical form: 
tablet (overencapsulated) 
Source: 
Sanofi-Aventis 
Unit Strength: 
2 mg 
Route of administration: 
p.o., once daily 
Substance: 
glimepiride 3 mg (Amaryl® 3 mg) 
Pharmaceutical form: 
tablet (overencapsulated) 
Source: 
Sanofi-Aventis 
Unit Strength: 
3 mg 
Route of administration: 
p.o., once daily 
Substance: 
glimepiride 4 mg (Amaryl® 4 mg) 
Pharmaceutical form: 
tablet (overencapsulated) 
Source: 
Sanofi-Aventis 
Unit Strength: 
4 mg 
Route of administration: 
p.o., once daily 


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Substance: 
Placebo matching glimepiride (Amaryl® 1-4 mg) 
Pharmaceutical form: 
tablet (overencapsulated) 
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 
Patients who meet the trial entry criteria at the end of the 2-4 weeks placebo run-in 
phase will be randomly assigned to linagliptin 5 mg or glimepiride in a balanced ratio 
(see Section 7.5). Patient assignment to the treatment groups will be determined by a 
computer generated random sequence using an interactive voice and web-based 
response system (IXRS). To facilitate the use of IXRS, each study site will receive an 
information manual describing the steps to randomise a patient, to obtain a medication 
kit assignment and to acknowledge receipt of study medication.  
The assigned medication number will be entered in the eCRF, and the corresponding 
medication kit should be given to the patient. Using this procedure, the investigator 
will not know to which treatment group the next patient will belong. 
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 (please refer to the actual version of the Investigator's Brochure [U04-
1767]) and represents the marketed dose for linagliptin. 
4.1.4 
Drug assignment and administration of doses for each patient 
Following the screening period and the placebo run-in period, patients who qualify 
will be randomised (Visit 2) to one of the dosage and treatment schedules outlined in 
Table 4.1.4: 1 below. Medication will be dispensed in a double-blind and double-
dummy manner as either 5 mg linagliptin (plus glimepiride placebo) or an initial dose 
of 1 mg /day of glimepiride (plus linagliptin placebo). IXRS will allocate medication 
kit numbers at each scheduled in-clinic visit (V2 – 31). At visits 2-5 patients will 
receive one treatment box, sufficient for 4 weeks treatment (plus 1 week reserve). At 
visits 6- 31 patients will receive one treatment box, sufficient for 16 weeks (plus two 
weeks reserve) of treatment. 
After the starting dose of 1 mg/day, glimepiride/ glimepiride placebo has to be 
uptitrated in 4 week intervals during the first 16 weeks of treatment to the next dose to 
a potential maximum dose of 4 mg/day, if the fasted HBGM values are > 110 mg/dl 
(6.1 mmol/l) at the day of visit 3, 4 and 5 (in-clinic HBGM measurement at the day of 
the visit), unless the investigator considers that it would place the patient at an 
increased risk for hypoglycaemia. The average HBGM value of previous recent 
fasting HBGM measurements prior to the day of visit (from the patient’s HBGM 
diary) could also be used to guide uptitration at the discretion of the investigator, if 
there is a meaningful discrepancy between the single fasted HBGM value at the day 
of the visit in the clinic and this average HBGM value.  
 


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Patients on previous glimepiride may continue on their previous glimepiride dose up 
to Visit 2 (SU/glinide should not be taken in the morning of Visit 2). These patients 
will start the glimepiride/glimepiride placebo at their pre-trial glimepiride dose. If 
prior glimepiride dose was ≥ 4 mg/day, the patient will start the glimepiride/ 
glimepiride placebo in the randomisation phase at a dose of 4 mg/day combined with 
5 mg /day linagliptin/ linagliptin placebo. Patients on a previous SU, that is not 
glimepiride, or glinide should start glimepiride /glimepiride placebo at Visit 2 at a 
starting dose of 1 mg/day combined with 5 mg/day linagliptin/ linagliptin placebo.  
The patients will be instructed to bring their HBGM devices to a visit for an 
additional measurement of fasted glucose during the titration phase, and if required, 
during maintenance phase (see flow chart).  
HBGM measurements at visits during Titration Phase are mandatory to efficaciously 
uptitrate dosing of the glimepiride/glimepiride placebo. 
 
Uptitration of glimepiride/glimepiride placebo may occur at (un)scheduled visits 
during the maintenance phase in case of deterioration of glucose control to the next 
dose to a potential maximum of 4 mg/day (glimepiride or placebo) combined with 5 
mg/day linagliptin/ linagliptin placebo (with at least a dose interval of 4 weeks), 
provided fasted and confirmed HBGM values are > 110 mg/dl (6.1 mmol/L). 
 
At any time during the study, the glimepiride/glimepiride placebo can be down 
titrated to prevent recurrent hypoglycaemic events.  
Glimepiride/glimepiride placebo may be uptitrated again to the next dose (in case it 
was down titrated due to hypoglycaemia) to the potential maximum dose of 4 mg/day 
with 5 mg/day linagliptin/ linagliptin placebo.  


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Table 4.1.4: 1 
Linagliptin and glimepiride oral administration per dose group 
and day  
Dose group 
Tablet 
 
Capsule 
(overencapsulated 
tablet) 
 (For run-in phase only) 
Placebo 
 
Placebo tablet matching to  
linagliptin 
Placebo capsule 
matching to glimepiride 
(For treatment phase only) 
linagliptin 
5 mg 
 
 
5 mg tablet 
 
Placebo capsule 
matching to glimepiride 
 
glimepiride 
1 mg 
Placebo matching to  
linagliptin 5 mg tablet 
1 mg capsule 
 
glimepiride  
2 mg 
 
Placebo matching to  
linagliptin 5 mg tablet 
 
2 mg capsule 
 
 
glimepiride  
3 mg 
 
Placebo matching to  
linagliptin 5 mg tablet 
 
3 mg capsule 
 
 
glimepiride  
4 mg 
 
Placebo matching to  
linagliptin 5 mg tablet 
 
4 mg capsule 
 
 
If applicable, patients will continue with their standard metformin therapy (preferably 
> 1500 mg daily) 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 
discontinued according to local guidelines (see also Section 4.2.2.1). The above 
principle also applies for patients being included on a background of alpha-
glucosidase inhibitor. 
During the maintenance phase it is investigator’s judgement to change the 
glimepiride/glimepiride placebo and/or background medication dose. Rescue 
medication could also be initiated provided protocol criteria are met (see section 
4.2.1) 
Administration of the study medication is once daily. Patients should be instructed to 
take their trial medication once daily with 150 mL of 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 should be taken shortly before or during a meal. 
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 


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in the opinion of the investigator and if not contraindicated. In case the patient is re-
instituted on study treatment, the preferred dosage for glimepiride/glimepiride placebo 
is the dose used before stopping treatment (unless hypoglycaemia was the reason to 
temporarily stop treatment).  In case there is a need for further adjustments after this 
re-institution the guidance for treatment initiation should be followed.  
Patients should be instructed 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, ideally on the following day. Background 
and/or rescue medication will be taken as prescribed including visit days. 
Patient visits should be routinely scheduled in the morning (preferably between 7:00 
AM and 11:00 AM), 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. 
4.1.5 Blinding and procedures for unblinding 
4.1.5.1 Blinding 
After randomisation at Visit 2, neither the patients nor the investigators or sponsor 
will be aware of the treatment allocation.  
Patients assigned to one of the double-blind treatments will take 1 tablet and 1 capsule 
daily, either: 
 One 5 mg tablet of linagliptin plus one inactive placebo capsule 
(overcapsulated tablet) matching glimepiride 
 
 One 1 mg or 2 mg or 3 mg or 4 mg glimepiride capsule (overencapsulated 
tablet) plus one inactive placebo tablet matching linagliptin. 
The placebo tablets and capsules will be identical in appearance to the respective 
active treatments.  
At any time during the study, glimepiride/glimepiride placebo can be down titrated to 
prevent recurrent hypoglycaemic events. Glimepiride/ glimepiride placebo dose 
adjustments can be done through IXRS in a blinded manner.  
4.1.5.2 Procedures for emergency unblinding 
In the event of a medical emergency which requires identification of an individual 
patient's treatment, investigators will be able to access this information via IXRS. The 
local Clinical 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. A patient could continue with 
study medication after unblinding. 


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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, Biberach, Germany. All study 
medication will be contained in medication boxes identified with the trial number and 
medication number. Each medication box will contain an appropriate amount of BI 
linagliptin tablets or glimepiride capsules, plus some reserve, for dosing until the next 
scheduled visit. 
Trial drug will be supplied on a per visit basis. Supply will be managed by an IXRS.  
Examples of the labels will be available in the Investigator's Site File (ISF) 
4.1.7 
Storage conditions 
All trial medication should be stored at room temperature (not above 25 ºC) in the 
original containers. Patients should be instructed not to remove the trial medication 
from the blisters/wallets 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 site. If the storage conditions are found to be 
outside the specified range, the CML, IXRS and the BI 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 and/or appointed CRO, must be 
kept in a secure, limited access storage area under the storage conditions defined by 
the sponsor. Throughout the trial, drug receipt, usage, and return must be documented 
by the site and verified by the CRA, any discrepancies in drug supplies will be noted 
and explained. All unused medication including blisters/wallets and patient boxes 
(empty or filled) must be returned to the sponsor. 
The investigator, pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor 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 IRB / ethics committee,  
 availability of a signed and dated clinical trial contract between the sponsor 
and the 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 
 if applicable availability of the proof of a medical licence for the principal 
investigator 
 for USA only: availability of the Form 1572 


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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 and reconcile all investigational product(s) received from 
the sponsor. At the time of return to the sponsor and/or appointed CRO, 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. 
This text is only applicable to Japan: 
The Investigator / pharmacist / investigational drug storage manager should return 
the unused and collected investigational drugs (including the empty containers) 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 container (excluding empty containers) 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 and other relevant trial staff members remain blinded to the patient’s 
name on the package (container or label) of the investigational drugs. 
Upon completion of the trial, the Investigator / pharmacist / investigational drug 
storage manager will submit to the Sponsor 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 and other relevant trial staff members remain blind to the patient’s name. 
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT 
4.2.1 
Rescue medication, emergency procedures, and additional treatment(s) 
The use of rescue medication will be permitted in this trial, and will be limited to 
pioglitazone, metformin, alpha-glucosidase inhibitor or basal insulin (i.e. intermediate 
or long-acting insulin such as insulin glargine, insulin determir, neutral protamine 
hagedorn [NPH] insulin) including during the FU period.  


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In specific situations (e.g. during hospitalisation) short-acting insulin may be given as 
rescue medication for up to two weeks in combination with the study medication.  
The dose of rescue medication will be according to local labelling at the investigator’s 
discretion. Rescue medication will not be provided as part of the clinical trial 
supplies, unless required by local laws and regulations. Particular rescue medication 
may not be available in countries (e.g. pioglitazone). 
The use of rescue medication in case of hyperglycaemia will be permitted during the 
randomised treatment period of the trial only and only if one or more of the following 
criteria have met: 
 During the titration phase (Visit 2 to Visit 6): The patient has a glucose level 
>240 mg/dl (>13.3 mmol/L) after an overnight fast. 
 During the maintenance phase (Visit 6 to Final Visit): The patient has a 
glucose level >180 mg/dl (>10.0 mmol/L) after an overnight fast  
 During the maintenance phase (Visit 6 to Final Visit): the patient has an HbA1c  
> 7.5% (58 mmol/mol)  
The above results for fasting plasma glucose, which could be obtained from the 
HBGM device, should be confirmed, meaning that there is a minimum of two 
measurements, at least one of which should be performed after an overnight fast at the 
investigational site, and on a different day to the initial measurement. 
In the case of repeated symptomatic hypoglycaemia or severe hypoglycaemia (criteria 
see Section 5.2.2.1.); appropriate adjustment of oral antidiabetic therapy like dose 
reduction of metformin, alpha-glucosidase inhibitor, rescue therapy or study 
medication should be initiated.  
The use of rescue medication 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 rescue medication than the protocol defined rescue therapy should discontinue 
study treatment when the combined use of the study treatment and this rescue 
medication is contraindicated, but will remain in the trial. 
Any additional treatment, that does not qualify as a rescue medication, and is 
considered necessary for the patient's welfare may be given at the discretion of the 
investigator. Exceptions to this are the restrictions described in Section 4.2.2.  
All concomitant (additional) and/or rescue medication will be recorded on the 
appropriate pages of the eCRF.   
There are no special emergency procedures to be followed. 


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4.2.2 
Restrictions 
4.2.2.1 Restrictions regarding concomitant treatment  
The use of other antidiabetic agents (next to background therapy and any rescue 
therapy) such as other oral agents, short-acting insulin* or injectable GLP-1 
analogue/agonists will be prohibited during the course of the study.  
*Short acting insulin may be given as rescue medication for up to two weeks (e.g. 
during hospitalisation). 
Additionally treatment with anti-obesity drugs is prohibited. 
In case metformin is used as background therapy and participants are in need for 
intravascular administration of iodine containing contrast agents: metformin is 
allowed to be discontinued according to local practice; usually before administration 
and 48 hours afterwards. 
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 dose can be 
reduced, or the study medication can be discontinued temporarily, or if needed 
permanently (see also Section 3.3.4.1). 
4.2.2.2  Restrictions on diet and life style 
No restrictions given; all patients should be provided healthy lifestyle advice at 
baseline and also have this reinforced during the trial. Available educational material 
(e.g. from national diabetes associations or national health authorities) relevant for the 
country/region could be supplied by the site.  
4.3 
TREATMENT COMPLIANCE 
Patients will be asked to bring all trial medication (with or without any remaining 
tablets/capsules) with them to each trial Visit. The tablets/capsules will be counted by 
the investigator or his/her designate and compliance will be calculated. Compliance 
will be calculated according to the formula: 
%
100
period
 
same
 
in the
 
been taken
 
have
 
should
 which 
aps.
 tablets/c
of
 
Nr.
count
 
t/capsule
last table
 
since
aken 
actually t
 
apsules
 tablets/c
of
 
Nr.
(%)
Compliance


 
Compliance during the open-label placebo run-in phase should be between 80% and 
120%. If compliance is outside this range, the patient should be carefully interviewed 
and, if necessary, re-informed about the purpose and the conduct of the trial. 
Investigator may extend the placebo-run phase up to four weeks to meet this 
compliance requirement. Unreliable patients should be withdrawn from the study 
before randomisation at the discretion of the investigator. 
Compliance during the randomised treatment phase should also be between 80% and 
120%. Severe violation of treatment compliance is defined as an important protocol 
violation and will lead to the exclusion from the per protocol set (PPS). 


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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 adjudicated components of the primary composite endpoint: CV death 
(including fatal stroke and fatal MI), non-fatal MI (excluding silent MI) or non-fatal 
stroke  
The key secondary efficacy endpoints are:  
 time to the first occurrence of any of the following adjudicated components of 
CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent 
MI), non-fatal stroke or hospitalisation for unstable angina pectoris 
 composite endpoint of (treatment sustainability defined as the proportion of 
patients that are on study treatment at study end, that at Final Visit maintain 
glycaemic control (HbA1c ≤ 7.0%) without need for rescue medication 
(between end of titration [Visit 6] and Final Visit) and patients without any 
moderate/severe hypoglycaemic episodes (between Visit 6 and Final Visit) 
and without > 2% weight gain at Final Visit (between Visit 6 and Final Visit))  
 composite endpoint of (treatment sustainability defined as the proportion of 
patients that are on study treatment at study end, that at Final Visit maintain 
glycaemic control (HbA1c ≤ 7.0%) without need for rescue medication 
(between Visit 6 and Final Visit) and patients without > 2% weight gain at 
Final Visit (between Visit 6 and Final Visit))  
Whereas moderate/severe hypoglycaemic episodes are defined as: 
 
-  Moderate hypoglycaemic event: documented symptomatic hypoglycaemia   
      with plasma glucose concentration ≤ 70 mg/dL. Event accompanied by typical 
 
symptoms of hypoglycaemia but no need for external assistance 
 
-  Severe hypoglycaemic event: documented hypoglycaemic episode requiring 
 
assistance of another person to actively administer carbohydrate, glucagon or 
 
other resuscitative actions need for external assistance 
 
Additionally secondary efficacy endpoints are the change from baseline of HbA1c, 
FPG, proportion of patients that at Final Visit maintain glycaemic control without 
need for rescue medication (between end of titration [Visit 6] and Final Visit) to 
obtain HbA1c ≤ 7.0% or that obtain HbA1c ≤ 7.0% overall (see Section 7.1). 
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 


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Standardization Program (NGSP) Level I certificate. Further details about sample 
handling, shipment, and assay procedures can be found in the Investigator’s Site File 
(Lab manual). 
FPG: 
Blood samples for the determination of FPG will be taken according to the Flow 
Chart after an overnight fast (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 at a central laboratory using validated 
assays. Further details about sample handling and shipment can be found in the 
Investigator Site File (Lab manual). 
5.2 
SAFETY 
5.2.1 
Endpoint(s) of safety 
Secondary and tertiary CV endpoints are described in Section 7. 
In addition, incidence and intensity of adverse events, physical examination, vital 
signs, ECG and change from baseline in laboratory parameters will be assessed. 
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, cardiovascular outcome events that occur after randomisation and represent a 
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.  
Cardiovascular outcome events are defined as the following components of the 
primary, secondary and tertiary cardiovascular endpoints:  
 
- cardiovascular death  
- non fatal myocardial infarction 
- silent myocardial infarction 
- non fatal stroke (ischemic/hemorrhagic/etiology unknown) 
- hospitalisation for unstable angina 
- heart failure requiring hospitalisation 
- transient ischemic attack (TIA) 
- coronary revascularisation procedures (PCI and CABG) 
 
For definitions of the cardiovascular outcome events see Appendix 10.2. 
 
The investigator must document immediately (within 24 hours or the next business 
day whichever is shorter) the outcome events on the appropriate eCRF page in the 
RDC. 


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In case of a stroke the disability or dependence in the daily activities will be collected 
with the grade of modified Rankin Scale (mRS) at day 7 or at hospital discharge (if 
duration of hospitalization is < 7 days) and 3-6 months after stroke onset. 
 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 unfavorable 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. 
  
Serious adverse event 
A serious adverse event (SAE) is defined as any AE which results in death, is 
immediately life-threatening, results in persistent or significant disability / incapacity, 
requires or prolongs patient hospitalisation, is a congenital anomaly / birth defect, or 
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgement which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. 
Life-threatening in this context refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if more severe. 
 
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) which is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe: 
Incapacitating or causing inability to work or to perform usual 
activities 
Causal relationship of adverse event 
Medical judgment should be used to determine the relationship, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or 
re-challenge, confounding factors such as concomitant medication, concomitant 
diseases and relevant history. Assessment of causal relationship should be recorded in 
the case report forms.  


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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 a 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 linagliptin, active 
comparator glimepiride and placebo. 
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  
Changes in vital signs including blood pressure, pulse rate, ECG*, physical 
examination, and laboratory tests results will be recorded as (S)AEs in the eCRF if 
they are judged clinically relevant by the investigator.  
* Changes in the ECG indicating silent MI should be reported as cardiovascular 
outcome event (see also Section 10.5). 
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 study 
inclusion they should be considered as baseline conditions. 
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 
≤ 70 mg/dl (3.9 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 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 (or less than 54 mg/dL) and all asymptomatic hypoglycaemic 


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events that are considered as adverse events by the investigator have to be recorded as 
an adverse event. 
Adverse Events of Special Interest (AESI) 
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 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. 
 Renal adverse events such as acute renal failure,  
 Pancreatitis (refer to ISF) 
 Pancreatic cancer 
 
Hepatic injury is defined by the following alterations of liver parameters: for patients 
with normal liver function at baseline: 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 draw sample. Patients showing these lab abnormalities need to be followed up 
according to Section 10.6 of this clinical trial protocol and the “DILI checklist” 
provided in ISF.  
Hepatic events:  
If AST and/or ALT are increased  ≥ 3 x ULN, follow-up laboratory tests of ALT, 
AST, total bilirubin (with differentiation of bilirubin in direct and indirect if total 
bilirubin is elevated) and additionally alkaline phosphates (ALP), CK (CK-MB if CK 
is elevated), amylase, lipase and INR must be initiated as soon as possible (ideally 
within 48 to 72 hours of the pathologic test result). Further follow-up investigations 
shall be initiated depending on the clinical course until the patient is recovered and/or 
a diagnosis was made. See for further details Section 10.6.2. 
 
Laboratory Criteria for “Potential Hy’s Law case”: 
 
1. AST and/or ALT > 3 x ULN and 
2. Total bilirubin > 2 x ULN and 
3. ALP < 2 x ULN 
 
 
 
 


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Renal events:  
If creatinine shows a ≥ 2-fold increase from baseline, the investigator should make 
arrangements for follow-up blood samples(s) to be collected for repeat analysis of 
creatinine.  
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. 
Skin lesions: 
If skin lesions (such as exfoliative rash, skin necrosis, or bullous dermatitis - see 
further detailed list in ISF): 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. 
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 such a suspected or diagnosed 
protocol specific AESI. AESIs once identified by the investigator must be reported on 
a SAE form in an expedited manner similar to SAEs, even if they do not meet any of 
the SAE seriousness criteria.  
These additional searches (summarised under the so called ‘overview of protocol 
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/Remote Data Capture (RDC) system and changes will be 
communicated to all investigators. 
5.2.2.2 Adverse event and serious adverse event reporting 
Reporting will be done according to the specific definitions and instructions detailed 
in the ‘Adverse Event Reporting’ section of the Investigator Site File (ISF).  
All adverse events, serious and non-serious and all AESIs, occurring during the 
course of the clinical trial (i.e., from signing the informed consent onwards through 
the residual effect period (REP) until the individual patient’s end of trial) will be 
collected, documented and reported to the sponsor by the investigator on the 
appropriate eCRFs pages.  
 


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The REP (timeframe after last dose of study medication when measurable drug levels 
or pharmacodynamic effects are still likely to be present) is defined as 7 days after the 
last trial medication application. All AEs which occurred through the treatment phase 
and throughout the REP will be considered as on treatment please see section 7.3.3. 
Events which occurred after the REP will be considered as post treatment events. 
 
After the individual patient’s end of trial the investigator does not need to actively 
monitor the patient for AEs but should only report relevant SAEs and relevant AESIs 
of which the investigator may become aware of. 
 
However, if in an individual patient only vital status information is collected after 
premature discontinuation, from then on and until the individual patient’s end of trial, 
the investigator does not need to actively monitor the patient for AEs but should only 
report fatal AEs, relevant SAEs and relevant AESIs of which the investigator may 
become aware of. 
 
Immediate documentation of events:  
The investigator must report immediately (within 24 hours of awareness the following 
events on the SAE form to the sponsor’s unique entry point as specified in the ISF: 
 All SAEs  
 All serious and non-serious AESIs 
 Non-serious AEs relevant for a reported SAE(s) and/or AESI(s) 
 Potential Hy’s Law cases (see Section 5.2.2.1) 
 Cardiovascular outcome events if they represent a SAE and occur during the 
screening/run-in phase 
 
The same timeline applies if follow-up information becomes available. In specific 
occasions the Investigator could inform the Sponsor upfront via telephone. This does 
not replace the requirement to complete and fax the BI SAE form. 
 
AEs considered “Always Serious” 
In accordance with the European Medicines Agency initiative on Important Medical 
Events, Boehringer Ingelheim has set up a list of 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. 
BI has established 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 a SAE has to 
be reported in expedited fashion following the same procedure as above. 
The list of these adverse events can be found via the RDC-system. 
For Japan: This information must be also reported immediately to the head of the 
trial site.  


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Information required 
For each AE, the Investigator should provide the information requested on the 
appropriate (e)CRF pages and the BI SAE form, e.g. onset, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational 
drug(s). The Investigator should determine the causal relationship to the trial 
medication, and any possible interactions between the investigational drug(s) and a 
Non-Investigational Medicinal Product (NIMP). 
 
All (S)AEs, including those persisting after individual patient’s end of trial must be 
followed up until they have resolved, have been sufficiently characterized, or no 
further information can be obtained. 
 
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 protocol-specified AESIs 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. Drug 
exposure during pregnancy has to be reported immediately (within 24 hours of 
awareness to the defined unique entry point for SAE forms of the respective BI OPU 
(country-specific 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 ethnicity), whether it is direct influence (e.g. due to 
hyperglycaemia), or whether diabetes is a marker of 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, detailed information will be requested and should be provided. 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 
 Pancreas  
 Endometrium 


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 Colon and rectum 
 Breast 
 Bladder 
 Thyroid 
 Prostate 
 
Request for detailed information (e.g. medical history, diagnostic result, laboratory 
results staging, genetics), will be mainly focused on the above listed organ systems, 
however is not restricted to them. For details refer to the oncology 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: 
5.2.3.1 Haematology 
 Haematocrit 
 Haemoglobin 
 Erythrocyte count 
 Platelet count 
 Total and automates differential 
leukocyte counts (Neutrophils, 
Eosinophils, Basophils, 
Lymphocytes, Monocytes) in 
absolute counts 
5.2.3.2 Clinical chemistry 
 Amylase 
 Lipase  
 AST** (aspartate 
transaminase, SGOT) 
 ALT** (alanine 
transaminase, SGPT) 
 -GT (gamma-glutamyl-
transferase) 
 Alkaline phosphatase 
 Lactic dehydrogenase (LDH) 
 Total bilirubin** 
 Direct and indirect bilirubin 
if total bilirubin is elevated 
 Total Protein  
 Albumin  
 Creatine kinase (CK) 
 CK-MB, if CK is elevated 
 
 Potassium 
 Sodium 
 Creatinine 
 Urea  
 Calcium 
 Inorganic phosphorous 
 Urid acid 
 Cholesterol (total)*** 
 HDL cholesterol*** 
 LDL cholesterol*** 
 Triglycerides*** 
 Troponin 
 
 
 
 
 
 
 
**AST, ALT and Total bilirubin are combined in any lab assessment, with exception of Visit 1a.  
*** Lipid profile, only obtained at Visits 2, 6, 9, 12, 15, 18, 21, 24, 27, and 30 and 32. 


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5.2.3.3 Urinalysis 
 Albumin, Creatinine (spot 
urine – quantitative 
measurement) 
 Protein 
 Ketone 
 Leucocytes 
Visit 1a safety laboratory only includes ALT (SGPT), AST (SGOT), alkaline 
phosphatase, serum creatinine, urine analysis and urine albumin and creatinine, in 
addition to HbA1c and does not need to be collected in fasted state.  
Exact date and time of blood sampling should be recorded on the central laboratory 
requisition form. 
Albumin/creatinine ratio will be calculated at the central lab. 
Pregnancy testing (urine dipstick method) will be performed in female patients of 
child-bearing potential according to the Flow Chart. Testing will be performed 
locally, using pregnancy test kits provided by the central laboratory. 
Immediately after the result of a pregnancy test is known, the pregnancy test kit will 
be discarded at the site.  The result of the test must therefore be documented in the 
source documents available at site for future verification by the on-site monitor. 
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. 
5.2.3.4 Renal function impairment 
Renal function impairment will be assessed by the central lab based on the plasma 
creatinine value measured according to the Flow Chart.  
Estimated Creatinine clearance will be calculated from serum creatinine using the 
following MDRD formula as specified in the Statistical Analysis Plan. 
This formula considers the race as an adjustment factor, therefore, the race must be 
known (and will be collected) for accurate estimation. 
Renal impairment will be classified in the following way: 
 No renal function impairment: eGFR  90 mL/min/1.73m2; 
 Mild renal function impairment: eGFR 60-89 mL/min/1.73m2; 
 Moderate renal function impairment: eGFR 30-59 mL/min/1.73m2; 
 Severe renal function impairment: eGFR 15-29 mL/min/1.73m2; 
 Kidney failure: eGFR < 15 mL/min/1.73m2. 
 


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5.2.4 
Electrocardiogram (ECG) 
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 and stored by third party. Investigators will 
receive evaluated ECGs within 3 working days by third party, unless there are 
unresolved discrepancies. 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, if necessary, the patient will be 
removed from the trial and medically treated. 
5.2.5 Assessment of other safety parameters 
Vital signs and height  
Systolic and diastolic blood pressure 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 blood pressure recording instrument (i.e., approved sphygmomanometer or an 
approved blood pressure meter utilizing liquid mercury) 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 1a.   
Weight and Waist circumference 
Weight measurements (kilogram, kg) should always be done using 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, 
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 horizontal to the floor and applied with sufficient tension to 
conform to the measurement surface [R07-4080].   
Waist circumference should be determined by measuring the midpoint between the 
lowest rib and the iliac crest [R07-4080]. 


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Physical examination 
A complete physical examination 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 Home Blood Glucose Monitoring (HBGM) 
equipment and supplies for use at home during the 2 up to 4 week run-in phase. 
HBGM testing should be performed at least once a week after an overnight fast during 
the placebo run-in phase of the trial and when patient experiences signs/symptoms of 
hypo- or hyperglycaemia. Once the patient is randomised, weekly testing is no longer 
required for study purposes and may be discontinued, however the patients will be 
instructed to bring their HBGM devices to a visit for an additional measurement of 
fasted glucose if required (see flow chart). HBGM measurements at visits during the 
titration phase are mandatory to efficaciously uptitrate dosing of the glimepiride/ 
glimepiride placebo arm. 
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. 
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 Testing Log 
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 <=3.9mmol/L (>=54 and <=70 mg/dL), if not considered as 
adverse event, the single HBGM values will be recorded in the CRF. 
If the results of a HBGM test reveal blood plasma glucose value of > 240 mg/dL 
(>13.3 mmol/L) after an overnight fast during the titration phase or > 180 mg/dL 
(>10.0 mmol/L) after an overnight fast during the maintenance phase 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 (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 something containing carbohydrate.   
HBGM (i.e. fasting glucose) will be measured in the morning of the visit prior the 
cognitive function testing (see Flow Chart). 
The HBGM diary should be brought to each visit for review by investigator/trial staff. 
Patient HBGM diary should be collected at the visit (if completed) and a new HBGM 
diary should be given to the patient.  


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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, standard 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. 


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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 on the morning of a visit before attending the 
clinic (excluding visits starting before randomisation) or comes in non-fasted where a 
fasting condition is required (all visits except Visit 1a), 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 randomisation Visit 2). 
The trial medication packs contain sufficient medication to allow for these time 
windows. 
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 and Placebo run-in period 
After informed consent process is complete and written informed consent is obtained, 
the patients will be assessed for study eligibility (Visit 1a) including central laboratory 
assessments: ALT (SGPT), AST (SGOT), alkaline phosphatase, serum creatinine, 
urinalysis and urine albumin and creatinine, in addition to HbA1c. Visit 1b should 
occur within one week after Visit 1a once it has been confirmed that the patient is 
eligible to continue to Visit 1b. 
Those patients who qualify at screening (as determined at Visit 1a and Visit 1b), will 
undergo a 2 up to 4 week placebo run-in phase (Visit 1b to Visit 2). During the run-in 
phase the patients will continue receiving their background therapy and they will be 
given a Home Blood Glucose Monitor and all the necessary supplies to use it. The 
HBGM will be used according to Section 5.2.5. Patients requiring rescue therapy 
during the screening and/or placebo run-in phase will not be eligible.  
Patients must satisfy all inclusion and exclusion criteria prior to randomisation (see 
Sections 3.3.2 and 3.3.3). In addition, if during the run-in phase there is any indication 
that the patient is not stable enough, in terms of their type 2 diabetes, to complete the 
study or that the patient will be non-compliant with the study medication or 
restrictions, then these patients should not be randomised. The placebo-run phase 
could be extended up to 4 weeks to satisfy patients’ successful completion of run-in 
phase. 


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6.2.2 Treatment phase 
Randomisation will occur at Visit 2 using IXRS.  
The patients will return to the clinic for regularly scheduled visits 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. 
Between Visit 2 and Visit 6 glimepiride/glimepiride placebo will be uptitrated up to 
maximal 4 mg/day (refer to section 4.1.4). 
At each visit trial medication compliance will be calculated and new supplies from a 
new medication kit assigned via IXRS will be dispensed.  
This is an outcome study. 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). 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 (through the patient or 
alternative person designated by the patient) will be required, to document the 
occurrence of outcome events and vital status. If possible, also 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 who prematurely discontinued study medication during the Maintenance 
Phase are allowed to restart the study medication at any time. Every attempt should be 
made by the investigator to have the patient restart study medication, even if the dose 
must be down titrated. 
6.2.3 
End of trial and Follow-up period 
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 must be involved in the discussions 
with the patient regarding a withdrawal of consent. 
If the patient withdrew informed consent the patient should stop taking study 
medication and should be asked to complete the study ending tests and procedures as 
described in the Flow Chart for End of Treatment Visit and Visit 33 (Follow up visit). 
Completing these procedures is strongly recommended for the patient’s safety. 
For patients that have withdrawn informed consent, the patient will be asked to resign 
an informed consent form, which will allow to enquire at least about the patient’s 
vital status and occurred outcome events through contacts to relatives, acquaintances, 
family physicians, hospital records, etc. 
 


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End of Treatment Visit (EOT) activities will be performed when a patient 
discontinues study medication treatment permanently. A follow-up visit will take 
place 30 days after the EOT visit.  
 
The follow-up visit may be performed as a phone visit for patients who completed the 
planned treatment period (only adverse events/outcome events and changes in 
concomitant therapy, details on trial completion and vital status 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, randomised, double blind, parallel group, 
comparator-controlled safety study of linagliptin versus glimepiride. The trial is event 
driven and will run with an estimated number of 6000 patients for approximately 432 
weeks beginning with the randomisation of the first patient. In the case the numbers 
of events is not or may not be reached within this period the trial duration and/or the 
number of patients enrolled will be increased until the defined number of adjudicated 
primary events is reached. We plan a 2 to 4 weeks run-in phase. 
Objectives 
The study objectives are described in Section 2.2. 
For the primary objective the upper bound of the two-sided (1-2*alpha)*100% 
confidence interval which equals the upper bound of the one-sided (1-alpha)*100% 
confidence interval will be used to investigate non- inferiority of linagliptin versus 
glimepiride regarding 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 
significance level is 2.5%. The alpha for each analysis depends on the alpha-spending 
function and the schedule of interim analyses. 
Primary endpoint 
The primary endpoint used in the primary analysis is time to the first occurrence of 
any of the following adjudicated components of the primary composite endpoint: CV 
death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI) or non-
fatal stroke.  
If patients do not experience a primary endpoint event, they will be considered 
censored at their last documented study visit. If a patient died and has no primary 
outcome event, the patient will be censored at the date of death. 
 
Key Secondary endpoints  
As key secondary endpoints will be analysed: 
1) time to the first occurrence of any of the following adjudicated components of 
the composite endpoint: CV death (including fatal stroke and fatal MI), non-
fatal MI (excluding silent MI), non-fatal stroke or hospitalisation for unstable 
angina pectoris. 


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2) composite endpoint of (treatment sustainability defined as the proportion of 
patients that are on study treatment at study end, that at Final Visit maintain 
glycaemic control (HbA1c ≤ 7.0%) without need for rescue medication* 
(between end of titration [Visit 6] and Final Visit) and patients without any 
moderate/severe hypoglycaemic episodes (between Visit 6 and Final Visit) 
and without > 2% weight gain at Final Visit (between Visit 6 and Final Visit)).  
3) composite endpoint of (treatment sustainability defined as the proportion of 
patients that are on study treatment at study end, that at Final Visit maintain 
glycaemic control (HbA1c ≤ 7.0%) without need for rescue medication* 
(between Visit 6 and Final Visit) and patients without > 2% weight gain at 
Final Visit (between Visit 6 and Final Visit))  
* Any dose increase of anti-diabetic background medication or introduction of 
new anti-diabetic treatment during study medication treatment will be counted as 
rescue medication. Short term use of any insulin- up to two weeks - (e.g. during 
hospitalisation) won’t count as rescue medication in the definition of treatment 
sustainability. 
 
Secondary cardiovascular endpoints 
In additional analyses the occurrence of the primary and first key secondary endpoint 
will be evaluated, resulting in the number of patients with at least one of the events 
above and the relative frequency with respect to the number of patients in the full 
analysis set (FAS). 
Further secondary CV-endpoints are the occurrence of and time to: 
 Composite endpoint of all CEC confirmed adjudicated events (see tertiary 
cardiovascular endpoints) 
 
 


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Secondary diabetes related endpoints 
Secondary diabetes related endpoints include change from baseline to Final Visit in 
the following laboratory parameters: 
 HbA1c 
 fasting plasma glucose 
 Total cholesterol 
 LDL cholesterol 
 HDL cholesterol 
 Triglycerides 
 Creatinine 
 eGFR (MDRD formula) 
 Urinary albumin 
 
In addition any transition in albuminuria classes will be investigated. 
 


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7.2 
NULL AND ALTERNATIVE HYPOTHESES 
For the primary objective, first a non-inferiority hypothesis is tested with respect to 
time to first occurrence of any of the adjudicated components of the primary 
composite endpoint. 
H0(NonInf): HRlinagliptin vs. glimepiride ≥ δ 
(H0(NonInf): Linagliptin is inferior to glimepiride  by at least δ regarding the risk of the 
primary composite endpoint of cardiovascular events.)  
vs. 
 
 
    
H1(NonInf): HRLinagliptin vs. glimepiride < δ 
(H1(NonInf): Linagliptin is non-inferior to glimepiride by the margin δ regarding the risk 
of the primary composite endpoint of cardiovascular events.) 
The non-inferiority margin δ is chosen to be 1.3 [R09-2151] 
If the non-inferiority hypothesis with margin 1.3 has revealed a significant result, then 
secondly, a superiority hypothesis is tested with respect to time to first occurrence of 
any of the adjudicated components of the primary composite endpoint. 
H0(Superiority): HRlinagliptin vs. glimepiride ≥ 1      vs.  
(H0(Superiority): Linagliptin is inferior to glimepiride regarding the risk of the composite 
primary endpoint of cardiovascular events.) 
vs. 
H1(Superiority): HRlinagliptin vs. glimepiride < 1 
 (H1(Superiority): Linagliptin is superior to glimepiride regarding the risk of the composite 
primary endpoint of cardiovascular events.) 
If the superiority hypothesis has revealed a significant result, then thirdly, a 
superiority hypothesis is tested with respect to the first key secondary endpoint 
H0(Superiority): HRlinagliptin vs. glimepiride ≥ 1      vs.  
(H0(Superiority): Linagliptin is inferior to glimepiride regarding the risk of the first key 
secondary endpoint.) 
vs. 
H1(Superiority): HRlinagliptin vs. glimepiride < 1 
 (H1(Superiority): Linagliptin is superior to glimepiride regarding the risk of the first key 
secondary endpoint.) 


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If the superiority hypothesis has revealed a significant result, then fourthly the second 
key secondary endpoint will be analysed hierarchically. The second key secondary 
endpoint (see Section 7.1) will be tested regarding the following hypothesis (p: 
probability for composite endpoint) 
H0(key secondary 2): plinagliptin - pglimepiride  = 0      vs.  
(H0(key secondary2 ): Linagliptin is equal to glimepiride regarding the occurrence of the 
second key secondary endpoint.) 
H1(key secondary 2): plinagliptin - pglimepiride  0      
(H1(key secondary 2): Linagliptin is unequal to glimepiride regarding the occurrence of the 
second key secondary endpoint.) 
If this hypothesis has revealed a significant result, then fifthly the third key secondary 
endpoint will be tested hierarchically regarding the following hypothesis: 
H0(key secondary 3: plinagliptin - pglimepiride  = 0      vs.  
(H0(key secondary 3: Linagliptin is equal to glimepiride regarding the occurrence of the 
third key secondary endpoint.) 
H1(key secondary 3: plinagliptin - pglimepiride   0      
(H1(key secondary 3: Linagliptin is unequal to glimepiride regarding the occurrence of the 
third key secondary endpoint.) 
Any confirmatory hypothesis test will be performed on the full analysis set. 
7.3 
PLANNED ANALYSES 
The primary analysis will be performed on the full analysis set (FAS). The FAS will 
consist of all randomised 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’ will be done. That means that: 
 
- 
the patient set consists of the FAS,  
- 
the allocated study treatment at randomisation will be used for the FAS of   
      patients for analysis (‘as randomised’)  
- 
all events which occurs 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 who have 
important protocol violations will be excluded from the PPS. A protocol violation will 
be considered important if it can be expected to have a distorting influence on the 
assessment of the primary endpoint and/or first key secondary endpoints. 
 
Important protocol violations include: 


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- 
Randomised study drug: incorrect active study drug taken. 
- 
Severe violation of treatment compliance (defined as less than 50% of visits   
      from Visit 3 on (excluding placebo run-in phase) with treatment compliance        
      outside 80-120% range. 
- 
Non-adherence to other specifications of the protocol that could bias the  
      primary endpoint 
Additionally 30-days-treatment set of patients will be created for sensitivity analysis. 
The 30-days-treatment set will include all randomised patients with a 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.  


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7.3.1 
Primary analyses 
The one-sided overall significance level will be alpha=2.5%. For the primary analysis 
a ‘classical ITT-analysis on the FAS will be performed as described above. 
For the primary analysis a cox proportional hazards regression model of time to the 
first event with factor treatment will be conducted. The non-inferiority margin will be 
1.3.  
As described in Section 7.3.4 the DMC will perform formal interim analyses. The 
overall significance level of 2.5% will be allocated to the DMC-interim analyses and 
the final analysis according to the O’Brien & Fleming alpha-spending function.  
The O’Brien & Fleming alpha-spending function defined the significance level for the 
first interim analysis on 4P-MACE. 
 
Due to the change of the primary endpoint after the first DMC interim analysis a 
Bonferroni adjustment will be applied in addition, to control the overall alpha-level. 
That means, the alpha spent at the first DMC interim analysis (performed for 4P-
MACE and based on the O’Brien & Fleming alpha-spending function) is subtracted 
from the initial overall alpha. The O’Brien & Fleming alpha-spending function based 
on the new overall alpha (after additional Bonferroni adjustment) defines the 
allocation of the still available overall significance level for the second interim 
analysis and the final analysis. 
 
The significance levels for the analyses are denoted by i, i=1,…,3. The total number 
of analyses is three, including 2 interim analyses.  
In the i-th analysis, i=1,…,3, the upper limit of the two sided (1-2*i)*100%- 
confidence interval of the hazard ratio will be compared with the non-inferiority 
margin. Also the one-sided p-value of the non-inferiority test based on the Wald chi-
squared statistic will be given. If the non-inferiority test satisfies the non-inferiority 
margin, a superiority test (Wald chi-squared statistic) will be performed. If the 
superiority test has revealed a significant result, a superiority test on the first key 
secondary endpoint will be performed on the same significance level as for the 
primary endpoint. If the superiority test has revealed a significant result, the second 
and third key secondary endpoints will be tested hierarchically (see Section 7.2.). The 
second and third key secondary endpoints will be analysed with Chi-Square test on 
the same significance level (2*i)*100% as the primary endpoint. 
 
No centre effect is included into the model, 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 endpoint sensitivity analyses will be done on the PPS, the 30-days-
treatment set and as an ‘on-treatment analysis’ as described below. For the first key 
secondary endpoint sensitivity analyses will be done on the PPS and as an ‘on-
treatment 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.  


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The ‘on-treatment analysis’ will be performed on the FAS (consisting of all 
randomised 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 all these sensitivity analyses the allocated study treatment at randomisation will 
be used for treatment assignment. 
 
For the second and third key secondary endpoints sensitivity analyses will be done on 
the PPS and the 30-days-treatment set. For the sensitivity analysis on the 30-days-
treatment set patients who prematurely discontinue study treatment will not be 
counted as non-responders as in the primary analysis for the second and third key 
secondary endpoints. The measurement of Final Visit will be used. For the sensitivity 
analysis on the PPS patients who prematurely discontinue study treatment will be 
counted as non-responders as in the primary analysis. For both sensitivity analyses the 
allocated study treatment at randomisation will be used for treatment assignment. 
 
7.3.2 
Secondary analyses 
All other secondary analyses are of exploratory nature, no correction for multiple 
hypotheses testing will be made. All statistical tests and confidence intervals are two-
sided with a significance level of alpha=0.05 and will include the factor treatment, 
unless stated otherwise. 
For all cardiovascular endpoints that include time-to-event data the same models and 
testing procedures as the primary analysis will be applied to compare the two 
treatment groups.  
For continuous secondary diabetes related endpoints with several on-treatment 
measurements change from baseline will be evaluated with a restricted maximum 
likelihood (REML) based mixed model repeated measures (MMRM) approach with 
fixed, categorical effects of treatment, week, treatment-by-week interaction, with the 
continuous covariates of baseline and baseline-by-week interaction. For those 
continuous secondary diabetes related endpoints with only one measurement on 
treatment an analysis of covariance (ANCOVA) model with the factor treatment and 
the baseline value of the respective variable as covariate will be performed. For 
qualitative secondary diabetes related endpoints, a Chi-Square test is used to compare 
the two treatment groups. 
7.3.3 
Safety analyses 
All safety data will be displayed and analysed using descriptive statistical methods. 
No formal inferential analysis is planned for safety comparison. AEs will be coded 
using the 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. Other AEs will be assigned 
either to the screening or follow-up phase as appropriate. Laboratory values taken 
after the first dose of randomised treatment up to a period of seven days after the last 


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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. 
7.3.4 
Interim analyses 
An independent Data Monitoring Committee (DMC) will review safety and efficacy 
data and make recommendations whether to continue the study, continue the study 
with modifications, 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 DMC will perform formal interim analyses of the primary endpoint for non-
inferiority and superiority. The trial team and Steering Committee stay blinded for 
these interim analyses. The sponsor will perform the final analysis. To prevent an 
inflation of the significance level a group sequential design according to the alpha-
spending approach [R97-0643] is chosen. The O’Brien & Fleming alpha-spending 
function defines the allocation of the overall significance level to the analyses.  
 
The O’Brien & Fleming alpha-spending function defined the significance level for the 
first interim analysis on 4P-MACE. Due to the change of the primary endpoint after 
the first DMC interim analysis a Bonferroni adjustment will be applied in addition, to 
control the overall alpha-level. That means, the alpha spent at the first DMC interim 
analysis (performed for 4P-MACE and based on the O’Brien & Fleming alpha-
spending function) is subtracted from the initial overall alpha. The O’Brien & 
Fleming alpha-spending function based on the new overall alpha (after additional 
Bonferroni adjustment) defines the allocation of the still available overall significance 
level for the second interim analysis and the final analysis. 
 
The second interim analysis will be performed based on approximately 411 primary 
endpoint events. The final analysis will take place after the observation of a minimum 
of 631 primary endpoint events.  
 
The trial will be terminated after a formal DMC-interim analysis, if superiority for 
linagliptin can be shown with respect to cardiovascular safety, with particular 
emphasis on CV mortality. The trial should be terminated after DMC interim analysis 
for futility, if superiority of glimepiride with respect to the primary endpoint can be 
shown prematurely or if a futility assessment shows that the 1.3 non-inferiority 
margin likely will not be met.  
The criteria for stopping the trial after a DMC-interim analysis in favour for the 
alternative hypothesis are given by the alpha-spending function according to O’Brien 
and Fleming and an additional Bonferroni adjustment applied after the first DMC 
interim analysis for 4P-MACE and the following analyses regarding 3P-MACE to 
control the overall alpha-level, with the possibility to stop the trial in favour for the 
alternative. The bounds of the group sequential design (i, i=1,..3) result from an 
overall =2.5%, number of events for final analysis= 631 and the chosen alpha-


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spending function [R10-2517] and the additional Bonferroni adjustment for the 
second interim and final analysis.  
 
The first formal DMC-interim analysis of the primary endpoint should be based on a 
minimum number of 80 adjudicated primary outcome events and a minimum duration 
of 1.5 years after the randomisation of the first patient. The Power of such an interim 
analysis would be > 80%, if the true HR is extraordinary low. 
 
The DMC will perform periodic safety reviews with an emphasis on cardiovascular 
and neurological events and CV mortality. The frequency of these reviews is detailed 
in the DMC charter, but additional looks may be scheduled as needed by the DMC. In 
addition, the Steering Committee may also request the DMC to meet for a safety 
review. 
 
7.4 
HANDLING OF MISSING DATA 
Patients with temporary or permanent study treatment termination will be followed up 
for cardiovascular events. 
Cardiovascular safety and other safety endpoints 
With respect to safety evaluations, it is not planned to impute missing values.  
Diabetes related endpoints 
The REML based MMRM analysis will handle missing data for continuous diabetes 
related endpoints for patients who discontinue the study treatment prematurely or 
miss a visit. This approach is valid, if missing observations are missing at random. 
Missing 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 last observation carried forward (LOCF) approach will be performed in a 
sensitivity analysis on diabetes related endpoints. 
 
7.5 
RANDOMISATION 
The sponsor will arrange for the randomisation as well as packaging and labelling of 
study medication. Eligible patients will be randomly assigned to one of the two 
treatment groups, with equal allocation of treatments  The randomisation list will be 
generated using a validated system, which involves a pseudo-random number 
generator so that the resulting treatment sequence will be both reproducible and non-
predictable. 


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The randomisation will be performed in blocks. The block size will be reported in the 
CTR. Stratification by centre will be achieved by allocating complete blocks for each 
site. The allocation process will be performed on Visit 2 through an interactive voice 
and web-based response system (IXRS). 
Except for the DMC, access to the code will be restricted to dedicated randomisation 
personnel and any exceptional access to the code (in case of an emergency) will be 
documented according to the sponsor's SOPs. 
The 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 
A group sequential design with according to the alpha-spending approach [R97-0643] 
was chosen. The critical values and the test characteristics of the group sequential test 
design are calculated according to the O’Brien & Fleming alpha-spending function 
with an additional Bonferroni adjustment applied after the first DMC interim analysis 
for 4P-MACE and the following analyses based on 3P-MACE. 
The overall Power depends on the number and time points of interim analyses. 
Therefore the overall Power cannot be calculated explicitly. Therefore the Power will 
be given for a one-stage design without any interim analyses.  
In a one-stage trial, for specified = 2.5%, and assuming equal risk between the two 
treatments (HR = 1.0) the Power for showing non inferiority (non-inferiority 
margin=1.3) will be 90.9% if the log rank test is performed at 631 number of 
accumulated events. 
The computation assumes an allocation ratio of 1:1. 
Assuming 1-year event rates of 0.018 for the glimepiride group and 0.018 for the 
linagliptin group and an accrual time of 2 years and a follow-up time of   
5.4 years and a 1-year loss to follow-up rate of 1.5% a total of 6000 patients is 
expected to yield the necessary number of events.  
 
In a one-stage trial, with 1-year event rates of  0.018 for the glimepiride group and  
0.0144 for the linagliptin group (HR = 0.8) the Power for showing superiority will be 
80% if the log rank test is performed at 631 number of accumulated events. 
Assuming an accrual time of 2 years and a follow-up time of 6.2 years and a 1-year 
loss to follow-up rate of 1.5% a total of 6000 patients is expected to yield the 
necessary number of events.  
 
The sample size calculations were calculated with Addplan 4.0.3 [R10-2517]. 


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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) and relevant BI Standard Operating 
Procedures (SOPs). Standard medical care (prophylactic, diagnostic and therapeutic 
procedures) remains in the responsibility of the treating physician of the patient. 
The investigator should inform the sponsor immediately of any urgent safety 
measures taken to protect the study patients 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 (for Japan: trial site) and of the sponsor with regard to 
publication of the results of this trial are described in the investigator contract (for 
Japan: trial site). 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). 
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 Institutional Review Board (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. 
For Japan: The investigator must give a full explanation to trial patients by using 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 respective procedure for illiterate patients is described in the Appendix 10.1. 


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The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient. 
The patient must be informed that his / her medical records may be examined by 
authorised monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by 
Boehringer Ingelheim, by appropriate IRB / IEC members, and by inspectors from 
regulatory authorities. 
8.2 
DATA QUALITY ASSURANCE 
In order to achieve a high level of standardised processes, data collection of efficacy 
and safety endpoints is coordinated centrally: 
 
Central lab analysis of efficacy endpoints and safety lab 
 
Central ECG collection 
 
Central IXRS for randomisation and kit allocation at each visit 
 
Central Outcome event adjudication process 
The data management procedures to ensure the quality of the data are described in 
detail in the trial data management and analysis plan (TDMAP) available in CTMF. 
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 
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, 
either on paper or 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. 
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. 
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 


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copies of laboratory and medical test results must be available at all times for review 
by the sponsor’s clinical trial monitor, auditor and inspection by health authorities 
(e.g. FDA). The 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 SOP. 
Sponsor: 
The sponsor must retain the essential documents according to the Sponsor’s SOP.  
When it is no longer necessary for the trial site to retain source documents and 
essential documents, the sponsor must notify the head of the trial site. 
8.4 
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS 
8.4.1 
Listedness 
To fulfil the regulatory requirements for expedited safety reporting, the sponsor 
evaluates whether a particular adverse event is "listed", i.e. is a known side effect of 
the drug or not. Therefore a unique reference document for the evaluation of 
listedness needs to be provided. For linagliptin this is the current version of the 
Investigator’s Brochure [U04-1767]. For glimepiride this is the EU SPC (Amaryl). 
The current versions of these reference documents are to be provided in the ISF. No 
AEs are classified as listed for matching placebo, study design, or invasive 
procedures.  
8.4.2 
Expedited reporting to health authorities and IECs/IRBs 
Expedited reporting of 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. Cardiovascular outcome events that occur 
after randomisation and represent a SAE, are exempted from expedited reporting to 
health authorities. Further details regarding this reporting procedure are provided in 
the Investigator Site File. 


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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 sponsor 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/patient out, unless 
specified differently in Section 6.2.3 of the CTP) or early termination of the trial.  
 
8.7 
PROTOCOL VIOLATIONS 
The investigator should document any deviations from the protocol regardless of their 
reasons. Only when the protocol was not followed in order to avoid an immediate 
hazard to trial subjects or for other medically compelling reason, the principal 
investigator should prepare and submit the records explaining the reasons thereof to 
the sponsor, and retain a copy of the records. 
For Japan: The investigator or sub-investigator should record all CTP violations. The 
investigator should provide and submit the sponsor and the head of the trial site the 
records of violations infringing the Japanese GCP or violations to eliminate an 
immediate hazard to trial patients and for other medically inevitable reasons. 
 
8.8 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT 
OF TRIAL RELATED INJURY 
For Japan only: In the event of health injury associated with this trial, the sponsor is 
responsible for compensation based on the contract signed by the trial site. 


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9. 
REFERENCES  
9.1 
PUBLISHED REFERENCES 
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 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) 
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) 
 
R07-1076 
International Diabetes Federation, Clinical Guidelines Task Force. 
Global guideline for type 2 diabetes. Brussels: International Diabetes 
Federation (2005) 
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) 
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) 
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)
 
 
P08-06509 
Johansen OE. Cardiovascular disease and type 2 diabetes mellitus: a 
multifaceted symbiosis. Scand J Clin Lab Invest 2007;67(8):786-800.  


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R10-2212 
Williams R, Van Gaal L, Lucioni C, Advisory Board. Assessing the 
impact of complications on the costs of Type II diabetes. Diabetologia 
2002;45:S13-7 
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 
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. 
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   
R10-0657 
Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with 
diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes 
mellitus: progressive requirement for multiple therapies (UKPDS 49). 
UK Prospective Diabetes Study (UKPDS) Group. JAMA. 
1999;281:2005-12. 
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 
R09-6409 
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 


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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 
R10-2210 
Nissen SE, Wolski K, Topol EJ.Effect of muraglitazar on death and 
major adverse cardiovascular events in patients with type 2 diabetes 
mellitus. JAMA. 2005;294:2581-6. 
R10-2211 
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial 
infarction and death from cardiovascular causes. N Engl J Med. 
2007;356:2457-71 
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  
R09-6409 
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 
R04-2173 
Turner RC, Holman RR, Cull CA, Stratton IM, Matthews DR, Frighi 
V, Manley SE, Neil A, McElroy H, Wright D, Kohner E, Fox C, 
Hadden D, UK Prospective Diabetes Study Group. Intensive blood-
glucose control with sulphonylureas or insulin compared with 
conventional treatment and risk of complications in patients with type 
2 diabetes (UKPDS 33). Lancet 1998;352:837-853. 
R09-6394 
Bell DSH. Practical considerations and guidelines for dosing 
sulfonylureas as monotherapy or combination therapy. Clin Ther 
2004;26(11):1714-1727.  
 
R09-6395 
Dormandy JA, et al, PROactive Investigators. Secondary prevention of 
macrovascular events in patients with type 2 diabetes in the PROactive 
Study (PROspective pioglitAzone Clinical Trial In macroVascular 
Events): a randomised controlled trial. Lancet 2005;366:1279-1289. 
R09-6396 
American Diabetes Association Workgroup on Hypoglycemia. 
Defining and reporting hypoglycaemia in diabetes: a report from the 
American Diabetes Association Workgroup on Hypoglycemia. 
Diabetes Care 2005;28(5):1245-1249.    


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R10-2517 
ADDPLAN, 2007. Software for Adaptive Designs and Analyses: 
Release 4. ADDPLAN GmbH, Cologne, Germany. 
R97-0643 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical 
trials. Biometrika 1983;70(3):659-663. 
P96-4362 
Harrower ADB. Pharmacokinetics of oral antihyperglycaemic agents in 
patients with renal insufficiency. Clin Pharmacokinet 31 (2), 111 - 119 
(1996) 
R10-4375 
Glucophage (metformin hydrochloride tablets), Glucophage XR 
(metformin hydrochloride extended-release tablets) (Bristol-Myers 
Squibb Company) (NDA 20-357/S-031, NDA 21-202/S-016, version: 
08/27/2008). 
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. 
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 
hospitalization 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. 


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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). 
P15-02848 
Marx N, Rosenstock J, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, 
Espeland MA, Bluhmki E, Mattheus M, Ryckaert B, Patel S, Johansen 
OE, Woerle HJ Design and baseline characteristics of the 
CARdiovascular Outcome Trial of LINAgliptin versus glimepiride in 
type 2 diabetes (CAROLINA). Diabetes Vasc Dis Res 12 (3), 164-174 
(2015). 
 
P13-02826  
Rosenstock J, Marx N, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, 
Bluhmki E, Patel S, Johansen OE, Woerle HJ Cardiovascular outcome 
trials in type 2 diabetes and the sulphonylurea controversy: rationale 
for the active-comparator CAROLINA trial. Diabetes Vasc Dis Res 10 
(4), 289-301 (2013). 
 
P16-04169      Pocock SJ. Design of major randomized trials: part 3 of a 4-part series 
on statistics for clinical trials. J Am Coll Cardiol 2015. 66(24):2757. 
 
R13-3903       Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg 
B, Ohman P, Frederich R, WiviottSD, Hoffman EB, Cavender MA, 
Udell JA, Desai NR, Mozenson O, McGuire DK, Ray KK, Leiter LA, 
Raz I, SAVOR-TIMI 53 Steering Committee and Investigators. 
Saxagliptin and cardiovascular outcomes in patients with type 2 
diabetes mellitus.N Engl J Med 369, 1317 - 1326 (2013). 
 
R13-3902       White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris 
GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman 
WC, Zannad F, EXAMINE Investigators. Alogliptin after acute 
coronary syndrome in patients with type 2 diabetes.N Engl J Med 369 
(14), 1327 - 1335 (2013). 
 
R16-1123       Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober LV, 
Lawson FC, Ping L, Wei X, Lewis EF, Maggioni AP, McMurray JJV, 
Probstfield JL, Riddle MC, Solomon SD, Tardif JC, ELIXA 
Investigators. Lixisenatide in patients with type 2 diabetes and acute 
coronary syndrome.N Engl J Med 373 (23), 2247 - 2257 (2015). 
 
R15-3017        Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, 
Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, 
Pencina MJ, Standl E, Stein PP, Suryawanshi S, Werf F van de, 
Peterson ED, Holman RR, TECOS Study Group. Effect of sitagliptin 
on cardiovascular outcomes in type 2 diabetes.N Engl J Med, (2015) 
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, 


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Food and Drug Administration, Center for Drug Evaluation and 
Research (CDER) (2008) 
 
R12-3960         European Medicines Agency (EMA) Committee for Medicinal 
Products For Human Use (CHMP): guideline on clinical investigation 
of medicinal products in the treatment or prevention of diabetes 
mellitus (14 May 2012,CPMP/EWP/ 1080/00 Rev. 1). 
                         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 1b, 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 testing log.  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 testing log 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 testing log 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 endpoints events and the principles of standardised data 
collection in the centralised CEC adjudication process are outlined in the current CEC 
Charter and process guideline. 
 
10.3 
BLOOD PRESSURE MEASUREMENT PROCEDURE AND 
TREATMENT RECOMMENDATIONS    
  
Initially, blood pressure should be taken three times in both arms. The arm with the 
mean higher pressure (either systolic - if needed to decide- or diastolic) should be 
used for subsequent measurements. 


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Blood pressure measurements can be performed with either a standard mercury 
sphygmomanometer or an electronic device, i.e. either electronic or manual 
measurements of blood pressure are acceptable, depending on the standard practice at 
each study site - Note: Boehringer Ingelheim will not provide electronic devices to 
sites that use the standard manual sphygmomanometers. 
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 or third blood pressure reading may be used. 
Blood pressure measurements should be recorded to the nearest 2 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). 
It has been clearly established that the co-existence of hypertension and diabetes 
increases the risk of developing renal and other organ damage, leading to a much 
greater incidence of stroke, coronary heart disease, congestive heart failure, peripheral 
artery disease and cardiovascular mortality. Reduction of high blood pressure could 
decrease the risk of stroke, heart disease and reduce the likelihood of dementia, heart 
failure, and death.                                                                                                                                            
Treatment recommendations of hypertension in diabetic patients are described in 
several guidelines, e.g. the current “Guidelines on Diabetes, pre-diabetes, and 
cardiovascular diseases of the European Society of Cardiology (ESC) and the 
European Association for the Study of Diabetes” [P08-01788], also accessible at 
weblink: escardio.org.   
10.4 
TREATMENT RECOMMENDATIONS FOR DYSLIPIDAEMIA 
Increased cardiovascular risk in T2DM patients is independently associated with their 
hyperglycemia together with high blood pressure (BP) and dyslipidaemia, the last 
typically the high-density lipoprotein cholesterol (HDL-C) and raised triglyceride 
(TG) levels found as components of the metabolic syndrome. Although low-density 
lipoprotein cholesterol (LDL-C) levels are not particularly higher in T2DM patients, 


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the opportunity to reduce cardiovascular risk is currently greatest through lipid 
lowering management by reducing LDL-C. There is almost a linear relationship 
between the absolute risk reduction in LDL-C and the proportional reductions in the 
incidence of cardiovascular events.  
Treatment recommendations of dyslipidaemia in diabetic patients are described in 
several guidelines, e.g. the current “Guidelines on Diabetes, pre-diabetes, and 
cardiovascular diseases of the European Society of Cardiology (ESC) and the 
European Association for the Study of Diabetes” [P08-01788], also accessible at 
weblink: escardio.org.  
10.5 
 SILENT MYOCARDIAL INFARCTION 
Incidence and impact of silent MI will be assessed in this study.  
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.  
10.6  
CLINICAL EVALUATION OF LIVER INJURY 
10.6.1  Introduction 
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (protocol 
specific adverse events of special interest) are to be further evaluated using the 
following procedures:  
10.6.2  Procedures 
Repeat the following lab tests: ALT, AST, total bilirubin (with differentiation of 
bilirubin in direct and indirect) and additionally alkaline phosphates (ALP), CK (CK-
MB, if CK is elevated), amylase, lipase, INR - within 48 to 72 hours and provide 
additional blood sample to the central laboratory for automatic reflex testing of the 
below listed laboratory parameters. Only in case whereby the central laboratory is not 
immediately available (e.g. if the logistics are such that the patient´s repeat specimen 
would not reach the central laboratory in a reasonable timeframe), ALT, AST, total 
bilirubin (with differentiation of bilirubin in direct and indirect) and additionally 
alkaline phosphates (ALP), CK (CK-MB, if CK is elevated), amylase, lipase, INR 
will be evaluated by local laboratory and results are made available to the investigator 


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and to BI as soon as possible. If in such a case ALT and/or AST ≥  3 fold ULN 
combined with an elevation of total bilirubin ≥  2 fold ULN are confirmed, results of 
the laboratory parameters described below must be made available to the investigator 
and to BI as soon as possible. 
In addition, 
 
 
initiate close observation of subjects by repeat testing of ALT, AST, alkaline 
phosphates (ALP), CK (CK-MB, if CK is elevated), total bilirubin (with 
differentiation of bilirubin in direct and indirect), amylase, lipase, INR with 
repeated testing of these parameters at least weekly until ALT and or AST 
abnormalities stabilize or return to normal, then according to the protocol. 
Depending on further laboratory changes, additional parameters identified e.g. by 
reflex testing will be followed up based on medical judgement and Good Clinical 
Practices (GCP).  
 
initiate examination for alternative reasons for elevation of liver parameters: 
o obtain a detailed history of current symptoms and concurrent diagnoses 
and medical history according to the “DILI checklist” provided in the 
ISF 
 
o obtain history of concomitant drug use (including non-prescription 
medications and herbal and dietary supplement preparations), alcohol 
use, recreational drug use, and special diets according to the “DILI 
checklist” provided in the ISF 
 
o obtain a history of exposure to environmental chemical agents 
(consider home and work place exposure) according to the “DILI 
checklist” provided in the ISF 
 
and report these via the CRF. 
 
o obtain further lab tests to evaluate for alternative causes (need to be 
done once): 
 
Hepatitis-Serology:  
- Anti-HAV-IgM,  
- HBsAg, HBcAg, anti-HBs (for documentation of  
     probably non-acute infection) (if any are positive then   
     HBV DNA by  
PCR),  
- Anti-HCV (if positive then HCV RNA by PCR);  
- Anti-HDV IgM;  
- Anti-HEV (if positive then Anti-HEV IgM or HEV-  
      RNA by PCR); 
- Epstein-Barr-Virus: VCA-IgG, VCA-IgM, or early  
     antigen 
- Cytomegalovirus (anti CMV-IgG and anti CMV-IgM) 
-    Herpes Simples virus  (IgG, IgM) 


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-    Parvovirus (IgG, IgM) 
-    Toxoplasmosis (IgG, IgM) 
 
Screen for autoimmune hepatitis (ANA, SMA, AMA, anti- 
            LKM) 
 
Metabolic screen (glucose, cholesterol, triglycerides) 
 
Coeruloplasmin, alpha-a antitrypsin,  
 
obtain further information on medical history and additional data as far as 
possible, use the ‘DILI’ checklist in the ISF for collecting the information. 
 
Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic 
pathology, e.g. bile duct stones or neoplasm.  
10.6.3  Decision to Stop Drug Administration 
Based on the potential risk for a patient, it can be necessary to discontinue study drug 
treatment. This decision should be made in close cooperation between the investigator 
and Boehringer Ingelheim.  


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11. 
SUMMARY OF CLINICAL TRIAL PROTOCOL 
 
MODIFICATIONS  
Summary of Clinical Trial Protocol Modifications Sheet (SOMS) 
 
Number of CTP modification  
1 
Date of CTP modification 
 
21 July 2011 
EudraCT number 
 
2009-013157-15 
 
BI Trial number 
 
1218.74 
BI Investigational Product(s) 
 
Linaglitin 
Title of protocol 
 
A multicentre, international, randomised, 
parallel group, double blind study to 
evaluate Cardiovascular safety of linagliptin 
versus glimepiride in patients with type 2 
diabetes mellitus at high cardiovascular risk. 
The CAROLINA Trial. 
 
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 
 
Protocol synopsis (objectives) 
Description of change 
 
Description of treatment sustainability 
Rationale for change 
 
To correct definition of treatment 
sustainability 
Section to be changed 
 
Protocol synopsis (inclusion criteria) 
 


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Description of change 
 
Change 1:  
Inclusion of patients with background 
medication of  
- sulphonylurea + alpha-glucosidase 
inhibitor or 
- glinide + alpha-glucosidase inhibitor 
 
Change 2:  
Documented coronary artery disease (≥50% 
luminal diameter narrowing of left main 
coronary artery or ≥ 50% in at least two 
major coronary arteries in angiogram).  
 
Change 3:  
Peripheral occlusive arterial disease will 
include stenting as inclusion criterion. 
 
Change 4:  
Since blood pressure and LDL are not 
measured at V1a, these values should be 
known prior study enrolment if used for 
inclusion (values < 6 months old prior V1a). 
 
Change 5: 
BMI ≤ 45 kg/m2 at Visit 1b 
 
Change 6:  
Addition of inclusion criterion: stable anti-
diabetic background medication (unchanged 
daily dose) for at least 8 weeks prior V1a 
and without short term use of insulin. 
Background medication should be stable 
during screening/run-in phase to allow 
randomisation 
 
Change 7:  
Limitation of recruitment of patients of 
Category C and D. 
Rationale for change 
 
Change 1:  
Combination therapy of 
sulphonylurea/glinide + alpha-glucosidase 
inhibitor is a suitable combination therapy 
for the protocol target population 
 
Change 2:  
To clarify that ≥ 50% luminal diameter 
narrowing is documented in at least two 


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major coronary arteries. Including note for 
further clarification. 
 
Change 3:  
To allow stenting cardiovascular risk 
 
Change 4 :(inclusion criterion 3) 
To clarify current blood pressure and LDL 
measurements if used for inclusion. 
 
Change 5:  
BMI will be measured at V1b 
 
Change 6: 
Medication should be stable 8 weeks prior 
V1a to allow enrolment) and during 
screening/run-in phase (to allow 
randomisation) 
 
Change 7:  
Since the cardiovascular risk is relatively 
lower for patients of category C and D 
compared to category A and B, recruitment 
of patients of category C will be limited to 
approximately 25% and recruitment of 
patients of category D will be limited to 
approximately 25% of total amount of 
randomised patients. This will be arranged 
on regional/country level. 
Section to be changed 
 
Protocol synopsis (duration of treatment) 
Description of change 
 
Observational study duration is clarified 
Rationale for change 
 
To clarify observational study duration 
Section to be changed 
 
Protocol synopsis (Criteria for efficacy) 
Description of change 
 
Description of primary efficacy endpoint 
Rationale for change 
 
To be in line with section 5.1.1. 
Section to be changed 
 
Protocol synopsis (main exclusion 
criteria) 
Description of change 
 
Change 1:  
Treatment with other diabetic drugs (as 
specified in inclusion criteria) prior 
informed consent is excluded. This included 
also clinical trials where these antidiabetic 
drugs have been provided to patients. 
 
Change 2:  
Sibutramine and orlistat were removed as 
specifically named anti-obesity drugs 
 


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Change 3:  
Pre-planned coronary artery re-
vascularisation (PCI, CABG) within next 6 
months after V1a or any previous PCI ≤ 6 
months prior informed consent or any 
previous CABG < 3 months prior informed 
consent 
 
Change 4: (new exclusion criterion)  
Exclusion of acute coronary syndrome ≤ 6 
weeks prior to informed consent 
 
Change 5: (new exclusion criterion) 
Exclusion of stroke or TIA ≤ 3 months prior 
to informed consent 
 
Rationale for change 
 
Change 1:  
To ensure other antidiabetic drugs are also 
excluded if prescribed in another clinical 
trial. 
 
Change 2:  
To remove specific anti-obesity medication 
and prevent need for future revisions when 
available products of this class may chance. 
 
Change 3:  
To exclude recent PCI and CABG 
 
Change 4: (new exclusion criterion)  
To ensure that patients with acute coronary 
syndrome ≤ 6 weeks prior to informed 
consent are not included. 
 
Change 5: (new exclusion criterion) 
To ensure that patients with stroke or TIA ≤ 
3 months prior to informed consent are not 
included. 
Section to be changed 
 
Flow Chart 
Description of change 
 
Change 1: 
Interactive Voice and Web-based Response 
System will be used, so called IXRS 
 
Change 2:  
At Visit 15 and Visit 30 (EOT/EOS) 
cognition testing will be performed. As a 


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result at these visit also HBGM will be done 
prior testing. 
 
Change 3: (footnote L)  
The FPG range is more specified for 
cognitive testing. 
 
Change 4: (footnote J)  
Between V1a and V1b AEs should also be 
collected in screen failures prior V1b. 
 
Change 5: (new footnote J)  
Maximal time window between visits is 
specified. 
 
Change 6: (footnote M)  
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. 
 
Change 7: (footnote O)  
 
  
Rationale for change 
 
Change 1: 
To clarify that Interactive Voice and Web-
based Response System will be used, so 
called IXRS 
 
Change 2:  
To ensure FPG levels are within range to 
measure cognition data. 
 
Change 3: (footnote L)  
The HBGM results at certain FPG 
concentrations may allow repeated HBGM 
after at least one hour. 
 
Change 4: (footnote J)  
To ensure all AEs will be captured, also in 
screen failures prior V1b. 
 
Change 5: (new footnote J)  
To ensure patient will not run-out of study 
medication 
 
Change 6: (footnote M)  


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To ensure that clinically relevant 
abnormalities will be reported as adverse 
events if not pre-existing prior signing of 
informed consent. 
 
 
Change 7: (footnote O)  
 
 
Section to be changed 
 
2.1 
Description of change 
 
Inclusion of patients with background 
medication of  
- sulphonylurea + alpha-glucosidase 
inhibitor or 
- glinide + alpha-glucosidase inhibitor 
Rationale for change 
 
Combination therapy of 
sulphonylurea/glinide + alpha-glucosidase 
inhibitor is a suitable combination therapy 
for the protocol target population 
Section to be changed 
 
2.2 
Description of change 
 
Change 1: 
Description of primary objectives 
 
Change 2: 
Description of treatment sustainability 
Rationale for change 
 
Change 1: 
Description of primary objectives was 
missing in this Section 
 
Change 2: 
To correct the definition of treatment 
sustainability. 
Section to be changed 
 
2.3 
Description of change 
 
Reference to linagliptin’s phase III program. 
Rationale for change 
 
Linagliptin’s phase III program has been 
completed for registration. 
Section to be changed 
 
3.1.1 
Description of change 
 
Change 1: 
Steering Committee (SC) and Data 
Monitoring (DMC) Charters won’t be 
provided in ISF  
 
Change 2: 
Description of inclusion of treatment naïve 
T2DM patients. 
Rationale for change 
 
Change 1: 
SC and DMC procedures are not required 
for sites. If required, the Charter(s) will be 


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submitted to IEC/IRB or Health Authority 
for notification. 
 
 
 
Change 2: 
To clarify that treatment naive T2DM 
patients should be offered first line therapy 
(e.g. metformin) before allowing them for 
study inclusion, unless they have specific 
contra-indications to its use. 
Section to be changed 
 
3.2 
Description of change 
 
Treatment goal for HbA1c is <7% and 
rescue medication is encouraged if HbA1c 
is >7.5%. However, the decision to initiate 
rescue medication remains with the 
investigator and the appropriate local 
treatment guidelines. 
Rationale for change 
 
To provide clarification of treatment goal 
and use of rescue medication to be in line 
with section 4.2.1 
Section to be changed 
 
3.3 
Description of change 
 
Permission to randomise more than 30 
patients will only be allowed after a careful 
review of enrolment status, resources and 
data quality of the site. 
Rationale for change 
 
Site should have sufficient resources and 
data quality to allow randomisation of more 
than 30 patients. 
Section to be changed 
 
3.3.1 
Description of change 
 
Change 1: 
Background medication should also be 
stable during screening/run-phase to allow 
randomisation.  
 
Change 2: 
Deletion of sentence.  
Rationale for change 
 
Change 1: 
To clarify that background medication 
should also be stable during screening/run-
in phase to allow randomisation. 
 
Change 2: 
Background medication is already 
highlighted in section 4.1.4. 
Section to be changed 
 
3.3.2  
Description of change 
 
Change 1:  


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Order of inclusion criteria has changed, i.e. 
T2DM is now a specific inclusion criterion 
number 1. 
 
Change 2: (inclusion criterion 2) 
Inclusion of patients with background 
medication of  
- sulphonylurea + alpha-glucosidase 
inhibitor or 
- glinide + alpha-glucosidase inhibitor 
 
Change 3: (inclusion criterion 2) 
Documented coronary artery disease (≥50% 
luminal diameter narrowing of left main 
coronary artery or ≥ 50% in at least two 
major coronary arteries in angiogram).  
 
Change 4: (inclusion criterion 3) 
Peripheral occlusive arterial disease will 
include stenting as inclusion criterion. 
 
Change 5:  
Since blood pressure and LDL are not 
measured at V1a, these values should be 
known prior study enrolment if used for 
inclusion (values < 6 months old prior V1a). 
 
Change 6: (inclusion criterion 5) 
BMI ≤ 45 kg/m2 at Visit 1b 
 
Change 7: (new inclusion criterion 7) 
Stable anti-diabetic background medication 
(unchanged daily dose) for at least 8 weeks 
prior V1a and without short term use of 
insulin. Background medication should be 
stable during screening/run-in phase to 
allow randomisation 
 
Change 8:  
Limitation of recruitment of patients of 
Category C and D. 
Rationale for change 
 
Change 1: To clearly identify T2DM as 
inclusion criterion and to be in line with 
CRF. 
 
Change 2: (inclusion criterion 2) 
Combination therapy of 
sulphonylurea/glinide + alpha-glucosidase 


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inhibitor is a suitable combination therapy 
for the protocol target population 
 
Change 3: (inclusion criterion 3) 
To clarify that ≥ 50% luminal diameter 
narrowing is documented in at least two 
major coronary arteries. Including note for 
further clarification. 
 
Change 4: (inclusion criterion 3) 
To allow stenting cardiovascular risk 
 
Change 5 :(inclusion criterion 3) 
To clarify current blood pressure and LDL 
measurements if used for inclusion. 
 
Change 6: (inclusion criterion 5) 
BMI will be measured at V1b 
 
Change 7: (new inclusion criterion) 
Medication should be stable 8 weeks prior 
V1a to allow enrolment) and during 
screening/run-in phase (to allow 
randomisation) 
 
Change 8:  
Since the cardiovascular risk is relatively 
lower for patients of category C and D 
compared to category A and B, recruitment 
of patients of category C will be limited to 
approximately 25% and recruitment of 
patients of category D will be limited to 
approximately 25% of total amount of 
randomised patients. This will be arranged 
on regional/country level. 
Section to be changed 
 
3.3.3 
Description of change 
 
Change 1: (exclusion criterion 2) 
Treatment with other diabetic drugs (as 
specified in inclusion criteria) prior 
informed consent is excluded. This included 
also clinical trials where these antidiabetic 
drugs have been provided to patients. 
 
Change 2: (exclusion criterion 3) 
Sibutramine and orlistat were removed as 
specifically named anti-obesity drugs 
 
Change 3: (exclusion criterion 7) 


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Pre-planned coronary artery re-
vascularisation (PCI, CABG) within next 6 
months after V1a or any previous PCI ≤ 6 
months prior informed consent or any 
previous CABG < 3 months prior informed 
consent 
 
Change 4: (exclusion criterion 17) 
Sexual abstinence (if allowed by local 
authorities) and double barrier added to list 
of acceptable method of birth control 
 
Change 5: (new exclusion criterion 19)  
Exclusion of acute coronary syndrome ≤ 6 
weeks prior to informed consent 
 
Change 6: (new exclusion criterion 20) 
Exclusion of stroke or TIA ≤ 3 months prior 
to informed consent 
 
Rationale for change 
 
Change 1: (exclusion criterion 2) 
To ensure other antidiabetic drugs are also 
excluded if prescribed in another clinical 
trial. 
 
Change 2: (exclusion criterion 3) 
To remove specific anti-obesity medication 
and prevent need for future revisions when 
available products of this class may chance. 
 
Change 3: (exclusion criterion 7) 
To exclude recent PCI and CABG 
 
Change 4: (exclusion criterion 17) 
In certain countries sexual abstinence is 
allowed by local authorities as acceptable 
method of birth control. Double barrier is an 
acceptable method of birth control. 
 
Change 5: (new exclusion criterion 19)  
To ensure that patients with acute coronary 
syndrome ≤ 6 weeks prior to informed 
consent are not included. 
 
Change 6: (new exclusion criterion 20) 


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To ensure that patients with stroke or TIA ≤ 
3 months prior to informed consent are not 
included. 
Section to be changed 
 
3.3.4.1 
Description of change 
 
Change 1: 
Updated procedures for patients who 
withdraw informed consent. 
 
Change 2: Indicating that all study 
procedures, e.g.  lab measurements should 
be done in patients who discontinued study 
medication prematurely. 
 
Change 3:  
Addition of minimal requirements for 
patients who discontinued study treatment. 
 
Change 4: 
Background medication should be kept 
stable for the course of the trial unless 
medical emergencies, or other plausible 
reasons (e.g. hyper -or hypoglycaemia) 
necessitate changes at the discretion of the 
investigator 
Rationale for change 
 
Change 1: 
To clarify procedures for patients who 
withdraw informed consent 
 
Change 2:  
To clarify that study procedures should be 
done as much as possible in patients who 
discontinued study medication prematurely. 
 
Change 3: 
To capture minimal data (i.e. primary 
endpoint events and vital status) of patients 
who discontinued study treatment. 
 
Change 4: 
To allow treatment flexibility for 
background medication in this long term 
trial, as you may expect that diabetes will 
progress over time. 
Section to be changed 
 
4.1.3 
Description of change 
 
Linagliptin marketed dose is  5mg 
Rationale for change 
 
Linagliptin 5mg is marketed in countries  
Section to be changed 
 
4.1.4 


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Description of change 
 
Change 1: 
Background medication should be kept 
stable for the course of the trial unless 
medical emergencies, or other plausible 
reasons (e.g. hyper -or hypoglycaemia) 
necessitate changes at the discretion of the 
investigator. 
 
Change 2: 
Rephrase of uptitration. 
 
Change 3: 
Patients on previous glimepiride will start 
the randomisation phase at same 
glimepiride dose. 
 
Change 4:  
Uptitration of glimepiride becomes more 
flexible and will be allowed at (un) 
scheduled visits during maintenance phase. 
 
Change 5: 
During the maintenance phase it is 
investigator judgement to change the study 
and/or background medication dose. Rescue 
medication could also be initiated provided 
protocol criteria are met. 
Change 6: 
Study medication should be taken shortly 
before or during a meal (except on visit 
days) 
 
Change 7: 
Background and/or rescue medication will 
be taken as prescribed including visit days. 
Rationale for change 
 
Change 1: 
To allow treatment flexibility for 
background medication in this long term 
trial, as you may expect that diabetes will 
progress over time. 
 
Change 2: 
To clarify that during titration phase 
uptitration is mandatory at certain FPG 
levels, provided there is no risk for 
hypoglycaemia (investigator’s judgement). 
 


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Change 3: 
To clarify those patients on previous 
glimepiride will start study medication on 
same glimepiride dose. 
 
Change 4: 
To increase flexibility of study medication. 
Instructions for uptitration of glimepiride 
are indicated. 
 
Change 5: 
To clarify that it is investigator judgement 
to change study and/or background 
medication dose or to initiate rescue 
medication. 
 
Change 6: 
According to prescription guidelines 
glimepiride should be taken shortly before 
or during a meal. 
 
Change 7: 
To clarify that background and/or rescue 
medication will be taken as usual on visit 
days. 
Section to be changed 
 
4.1.5.2 
Description of change 
 
A patient could continue with study 
medication after site or global unblinding. 
Rationale for change 
 
To clarify that patient could continue on 
study medication after site or global 
unblinding. 
Section to be changed 
 
4.2.1 
Description of change 
 
Change 1: 
Alpha-glucosidase inhibitors will be 
allowed as rescue medication 
 
Change 2:  
Adding sentence regarding rescue 
medication 
Rationale for change 
 
Change 1: 
To increase potential rescue medication in 
countries where alpha-glucosidase 
inhibitors are prescribed. 
 
Change 2: 
Particular rescue medication may not be 
available in countries (e.g. pioglitazone). 


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Section to be changed 
 
4.2.2.1 
Description of change 
 
If any restricted medication are given to the 
patient, the study medication can be 
discontinued temporarily, or if needed 
permanently. 
Rationale for change 
 
Discontinuation of study medication is 
medical judgement by investigator. To 
ensure this paragraph is in line with section 
3.3.4.1 
 
Section to be changed 
 
4.2.2.2 
Description of change 
 
All patients should be provided with healthy 
advice and relevant educational material to 
be used for this purpose will be supplied 
Rationale for change 
 
To ensure patients will receive advice and 
educational material regarding healthy 
advice. 
Section to be changed 
 
5.2.1.1 
Description of change 
 
Exemption of cardiovascular outcome 
events (heartfailure requiring 
hospitalisation, TIA. PCI and CABG) from 
expedited and unblinded SUSAR reporting. 
Rationale for change 
 
To avoid unblinding of these cardiovascular 
outcome events to maintain the integrity of 
the trial. 
Section to be changed 
 
5.2.2.1 (hepatic events) 
Description of change 
 
Section has been updated regarding 
procedures for follow-up of lab parameters. 
Rationale for change 
 
To be in line with section 10.6.2. 
Section to be changed 
 
5.2.2.2 
Description of change 
 
Change 1: 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. 
 
Change 2: 
Cardiovascular outcome events if they 
represent an SAE should be reported as 
SAE if occurred during screening/run-in 
phase. 
 
Change 3: 
Cardiovascular outcome events should be 
reported as outcome event if occurred after 
randomisation. 


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Rationale for change 
 
Change 1: To ensure that clinically relevant 
abnormalities will be reported as adverse 
events if not pre-existing prior signing of 
informed consent. 
 
Change 2: 
To ensure prior randomisation 
cardiovascular outcome events will be 
reported as SAE. 
 
Change 3: 
To ensure the integrity of the trial, 
cardiovascular outcome events should be 
reported as outcome event if occurred after 
randomisation, i.e. no unblinding will occur. 
Section to be changed 
 
5.2.2.3 
Description of change 
 
New paragraph regarding oncology adverse 
events is added 
Rationale for change 
 
In order to assess patients with oncology 
adverse events in detail, detailed 
information will be requested and has to be 
provided. 
Section to be changed 
 
5.2.3.2 
Description of change 
 
Change 1: 
 
 
Change 2: 
AST, ALT and Total bilirubin are combined 
in any lab assessment 
Rationale for change 
 
Change 1: 
 
 
 
Change 2: 
To fulfil the FDA Drug Induce Liver Injury 
guideline 
Section to be changed 
 
5.2.5 
Description of change 
 
Change 1: 
Section vital signs and height has been 
updated. Reference to section 10.3 
 
Change 2:  
Weight should be measured on same type of 
scale 
 
Change 3: 
Further instructions for use of HBGM diary. 


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Rationale for change 
 
Change 1: 
To be in line with Flow Chart and to 
highlight section 10.3 
 
Change 2: 
To allow flexibility for weight 
measurements. 
 
Change 3: 
To clarify instructions of HBGM diary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section to be changed 
 
6.2.2 
Description of change 
 
Addition of minimal requirements for 
patients who discontinued study treatment. 
Rationale for change 
 
To capture minimal data (i.e. primary 
endpoint events and vital status) of patients 
who discontinued study treatment. 
Section to be changed 
 
6.2.3 
Description of change 
 
Deletion of sentence regarding discontinued 
patients. 
Rationale for change 
 
Information is already indicated in section 
3.3.4.1 and 6.2.2 
Section to be changed 
 
7.1 (tertiary diabetes related endpoints) 
Description of change 
 
Change 1: 
Change of endpoint: proportion of patients 
with moderate/severe hypoglycaemic 
episodes. 
 
Change 2: 
Change of endpoint: Proportion of patients 
with treatment sustainability (defined as the 
proportion of patients that are on study 
treatment at study end without rescue 
medication) with  ≤ 2% weight gain at Final 
Visit (with or without rescue medication 
during maintenance phase) (between Visit 6 
and Final Visit)) 
 
Change 3:  
Short term use of basal insulin- up to two 
weeks - (e.g. during hospitalisation) won’t 
count as rescue medication in the definition 
of treatment sustainability. 
Rationale for change 
 
Change 1:  
Definitions of hypoglycaemic episodes in 
line with section 5.1.1. 
 
Change 2: 
To ensure weight endpoint will be based on 
population with treatment sustainability 
 
Change 3: 
Short term use of basal insulin is a common 
treatment option when dual oral therapy 
failed. Per definition it will be seen as (new) 


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rescue treatment if given more than two 
weeks. 
Section to be changed 
 
7.1 (other endpoints) 
Description of change 
 
Incidence of particular adverse events will 
be analysed as “other endpoint”. 
Rationale for change 
 
To fulfil safety requirements of health 
authorities. 
Section to be changed 
 
7.3.4. 
Description of change 
 
Change 1: 
The DMC will perform formal interim 
analyses of the primary endpoint for non-
inferiority and superiority 
 
Change 2: 
Sentence deleted, regarding stopping rule 
for futility. 
Rationale for change 
 
Change 1: 
To clarify formal interim analyses by DMC. 
 
Change 2: 
 
Stopping rules for futility are already 
indicated in same paragraph. 
Section to be changed 
 
8.4.2 
Description of change 
 
Cardiovascular outcome events should be 
reported as outcome event if occurred after 
randomisation 
Rationale for change 
 
To ensure the integrity of the trial. 
Section to be changed 
 
9.1 
Description of change 
 
References added 
Rationale for change 
 
References added regarding oncology 
adverse events and new standardised 
definitions for endpoint events in 
cardiovascular trials (October 2010) 
Section to be changed 
 
10.2 (and sub-sections) 
Description of change 
 
Sub-sections in 10.2 are updated according 
to new standardised definitions for endpoint 


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events in cardiovascular trials (October 
2010) 
Rationale for change 
 
To provide the definitions of the 
cardiovascular outcome events based on the 
current “Standardised Definitions for 
endpoint events in cardiovascular trials, 
Final recommendations (2010). 
Section to be changed 
 
10.3 
Description of change 
 
Clarification on blood pressure 
measurements 
Rationale for change 
 
Clarification on blood pressure 
measurements 
Section to be changed 
 
Several sections throughout the protocol 
Description/rational of 
change 
 
Typo’s, minor errors has been corrected 
throughout the protocol 
Section to be changed 
 
10.6.3 
Description of change 
 
No check-list will be provided in the ISF 
supporting the collecting of further 
information. 
Rationale for change 
 
Patients who discontinued study medication 
should be followed as much as possible. 
 
 
 


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Number of CTP modification  
2 
Date of CTP modification 
 
6 March 2012 
EudraCT number 
 
2009-013157-15 
 
BI Trial number 
 
1218.74 
BI Investigational Product(s) 
 
Linaglitin 
Title of protocol 
 
A multicentre, international, randomised, 
parallel group, double blind study to 
evaluate Cardiovascular safety of linagliptin 
versus glimepiride in patients with type 2 
diabetes mellitus at high cardiovascular 
risk. The CAROLINA Trial. 
 
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 
 
 
 
Section to be changed 
 
Protocol synopsis (objectives) 
Description of change 
 
Change 1: 
Exclusion of silent MI from primary 
endpoint 
 
Change 2: 
Correction of confidence interval 
Rationale for change 
 
Change 1: 
Silent MI will be reported as tertiary 
cardiovascular endpoint  
 
Change 2: 
Confidence interval is determined based on 
the alpha from the alpha-spending function. 
Section to be changed 
 
Protocol synopsis (criteria for safety) 
Description of change 
 
Change 1: 
Summarization of non-fatal and fatal MI, as 
well as non-fatal and fatal stroke for 
evaluation of time to and occurrence of 
adjudicated events. 
 
Change 2: 


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Deletion of stable angina pectoris as study 
endpoint. 
Rationale for change 
 
Change 1: 
To allow for an analysis of single 
components with inclusion of death 
resulting from such a component. 
 
Change 2: 
Stable angina pectoris will not be 
adjudicated as tertiary cardiovascular 
endpoint. 
Section to be changed 
 
Protocol synopsis (inclusion criteria) 
Description of change 
 
Change 1: 
Addition of the statement in the inclusion 
criteria that anti-diabetic treatment naïve 
patients are only eligible for study 
enrolment if they are intolerant or contra-
indicated to first line anti-diabetic 
treatment. 
 
Change 2: 
In consultation with the Steering 
Committee, enrolment of patients currently 
at least on SU or glinide may be limited. 
Rationale for change 
 
Change 1: 
To clarify this criterion for naïve patients in 
the inclusion criteria as stated in protocol 
section 3.3.1. 
 
Change 2: 
To ensure an early/moderate disease 
population with short to moderate diabetes 
duration. To allow assessment of the CV 
safety profile of linagliptin versus 
glimepiride. 
Section to be changed 
 
Protocol synopsis (main criteria for 
exclusion) 
Description of change 
 
Change 1: 
The wording any history and/or current 
treatment with other antidiabetic drugs 
added to inclusion criteria 
 
Change 2: 
Current treatment with systemic 
corticosteroids will exclude a patient of 
study enrolment 
 
Change 3: 


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Inappropriateness of glimepiride treatment 
for other issues (e.g. allergy) according to 
local prescribing information. 
 
Rationale for change 
 
 
Change 1: 
To clarify that any history and/or current 
treatment of anti-diabetic drugs as specified 
in the inclusion criteria will exclude a 
patient from study enrolment 
 
Change 2: 
Clinical relevant drug-drug interaction of 
the study medication is limited to 
corticosteroids 
 
Change 3: 
To avoid patients being enrolled with 
allergies to the SU class 
Section to be changed 
 
Flowchart 
Description of change 
 
Change 1: 
Addition of maximal/minimal days from 
randomisation for screening to be 
performed. 
 
Change 2: 
Visit time window of visit 6 is +/- 7 days 
Rationale for change 
 
Change 1: 
To clarify that maximal 42 days and 
minimal  15 days should be between 
screening and randomisation 
 
Change 2: 
Since patient received at visit 5 medication 
up to maximal 5 weeks, the time window 
for visit 6 is limited to +/- 1 week. 
Section to be changed 
 
1.1 (medical background) 
Description of change 
 
Change of reference number 
Rationale for change 
 
Incorrect reference number 
Section to be changed 
 
1.2 (drug profile) 
Description of change 
 
Updated drug profile 
Rationale for change 
 
To add new clinical trial data  
Section to be changed 
 
2.1 (rationale for performing the trial) 
Description of change 
 
Addition of the statement that anti-diabetic 
treatment naïve patients are only eligible for 
study enrolment if they are intolerant or 
contra-indicated to first line anti-diabetic 
treatment. 


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Rationale for change 
 
To clarify this criterion for naïve patients as 
stated in protocol section 3.3.1. 
Section to be changed 
 
2.2 (trial objectives) 
Description of change 
 
Correction of confidence interval  
 
Rationale for change 
 
 
Confidence interval is determined based on 
the alpha from the alpha-spending function. 
Section to be changed 
 
2.3 (benefit – Risk assessment) 
Description of change 
 
Change 1: 
Add description of alpha-glucosidase 
inhibitor as possible rescue medication (as 
indicated in section 4.2.1)  
 
Change 2: 
Updated list of anti-diabetic drugs (given as 
study medication or allowed as rescue 
medication) which are not approved for use 
in pregnancy. 
Rationale for change 
 
Change 1: 
To provide background of alpha-
glucosidase inhibitor as possible rescue 
medication 
 
Change 2: 
To update list of antidiabetic drugs (given 
as study medication or allowed as rescue 
medication) which are not approved for use 
in pregnancy. 
 
Section to be changed 
 
3.3 (selection of trial population) 
Description of change 
 
Change 1: 
 
 
 
 
 
 
 
 
Change 2: 
Addition of procedures for re-screening and 
re-testing 
Rationale for change 
 
Change 1: 
 
 
 
 
Change 2: 


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Procedures for re-screening and re-testing 
are permitted under certain circumstances 
Section to be changed 
 
3.3.1 (main diagnosis for study entry) 
Description of change 
 
Change 1: 
Change of wording “therapy” into “anti-
diabetic treatment” 
 
Change 2:  
Adding of  wording “intolerances”  
 
Change 3:  
Adding wording “whereas if medications 
such as metformin and alpha-glucosidase 
inhibitor are being used, these should be 
continued”. 
 
Rationale for change 
 
Change 1: 
To clarify that treatment naïve T2DM 
patients should be offered first line anti-
diabetic treatment before patients are 
eligible for study inclusion 
 
Change 2: 
To clarify that anti-diabetic treatment naïve 
patients are only eligible for study 
enrolment if they are intolerant or contra-
indicated to first line anti-diabetic 
treatment. 
 
Change 3: 
To clarify that background anti-diabetic 
medication such as metformin and alpha-
glucosidase inhibitor should be continued at 
Visit 2. 
Section to be changed 
 
3.3.2 (inclusion criteria) 
Description of change 
 
Change 1:  
Addition of the statement in the inclusion 
criteria that anti-diabetic treatment naïve 
patients are only eligible for study 
enrolment if they are intolerant or contra-
indicated to first line anti-diabetic 
treatment. 
 
Change 2: 
In consultation with the Steering 
Committee, enrolment of patients currently 
at least on SU or glinide may be limited. 
Rationale for change 
 
Change 1: 


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To clarify this criterion for naïve patients in 
the inclusion criteria as stated in protocol 
section 3.3.1. 
 
Change 2: 
To ensure an early/moderate disease 
population with short to moderate diabetes 
duration. To allow assessment of the CV 
safety profile of linagliptin versus 
glimepiride. 
Section to be changed 
 
3.3.3 (exclusion criteria) 
Description of change 
 
Change 1: 
The wording any history and/or current 
treatment with other antidiabetic drugs 
added to exclusion criteria 
 
Change 2: 
Adding wording “any” insulin. 
 
Change 3: 
Clinical relevant drug-drug interaction of 
the study medication is limited to 
corticosteroids 
 
Change 4: 
Add wording “SU class “to exclusion 
criterion 8. 
Rationale for change 
 
Change 1: 
To clarify that any history and/or current 
treatment of anti-diabetic drugs as specified 
in the exclusion criteria will exclude a 
patient from study enrolment 
 
Change 2: 
To clarify that short term us of any insulin 
(up to two weeks) is allowed. 
 
Change 3: 
Clinical relevant drug-drug interaction of 
the study medication is limited to 
corticosteroids 
 
Change 4: 
To clarify that also known allergy to SU 
treatment will exclude the patient for study 
enrolment. 
Section to be changed 
 
3.3.4 (removal of patients from therapy 
or assessments) 


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Description of change 
 
Change 1: 
Addition of the definition of Lost-To-
Follow-Up  
 
Change 2: 
Study medication can be discontinued 
temporarily. Investigators are encouraged to 
re-administer study medication to a 
randomised patient if there are no further 
safety concerns. 
Rationale for change 
 
Change 1: 
Clarification which patients are considered 
Lost-To-Follow-Up 
 
Change 2: 
Since this is an outcome study, the primary 
analysis will be performed based on all 
randomised patients who were treated with 
at least one dose of study drug. Therefore 
investigators are encouraged to re-
administer study medication to a 
randomised patient if there are no further 
safety concerns. 
Section to be changed 
 
4.1.4 (drug assignment and 
administration of doses for each patient) 
Description of change 
 
Change 1: 
The average HBGM value of previous 
recent fasting HBGM measurements prior 
to the day of visit (from the patient’s 
HBGM diary) could also be used to guide 
uptitration at the discretion of the 
investigator, if there is a meaningful 
discrepancy between the single fasted 
HBGM value at the day of the visit in the 
clinic and this average HBGM value.  
Change 2: 
The titration process of the study 
medication has been further 
clarified/described 
 
Change 3: 
To add wording that “The above principle 
also applies for patients being included on a 
background of alpha-glucosidase inhibitor. 
Rationale for change 
 
Change 1: 


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To allow to use additional HBGM values if 
there is a meaningful discrepancy between 
the HBGM value at the day of visit in the 
clinic and the HBGM values in patient’s 
HBGM diary 
Change 2: 
To clarify the titration phase in more detail 
to ensure titration process will be followed. 
 
Change 3: 
To clarify that the principle also applies for 
patients being included on a background of 
alpha-glucosidase inhibitor. 
Section to be changed 
 
4.2.1 (rescue medication, emergency 
procedures, and additional treatment(s)) 
Description of change 
 
Change 1: 
Short-acting insulin may be given as rescue 
medication for up to two weeks in 
combination with the study medication (e.g. 
during hospitalisation).  
Change 2: 
The results for fasting plasma glucose to 
initiate rescue medication could be obtained 
from the HBGM device. 
 
Change 3: 
Add alpha-glucosidase inhibitor 
 
Change 4: 
Adding wording “the protocol defined 
rescue therapy” 
Rationale for change 
 
Change 1: 
In practice short-acting insulin is given as 
rescue medication to T2DM patients (e.g. 
during hospitalization). Such treatment may 
be given in combination with the study 
medication for up to two weeks. 
 
Change 2: 
To clarify that the results for fasting plasma 
glucose to initiate rescue medication could 
be obtained from the HBGM device. 
 
Change 3:  
To be consistent since alpha-glucosidase 
inhibitor could be described as anti-diabetic 
background medication 


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Change 4: 
To clarify that there is specific protocol 
defined rescue medication 
Section to be changed 
 
4.2.2.1 (restrictions) 
Description of change 
 
Change 1: 
Short acting insulin may be given as rescue 
medication up to two weeks (e.g. during 
hospitalisation) 
 
Change 2: 
If any restricted treatments or any other 
concomitant drugs interfering with the 
study medication, the study medication dose 
can be reduced. 
Rationale for change 
 
Change 1: 
In practice short-acting insulin is given as 
rescue medication to T2DM patients (e.g. 
during hospitalization). Such treatment may 
be given in combination with the study 
medication for up to two weeks. 
 
Change 2: 
To clarify that study medication dose can be 
changed if concomitant drugs interfere with 
the study medication. 
Section to be changed 
 
5.1.1 (endpoint(s) of efficay) 
Description of change 
 
Exclusion of silent MI from primary 
endpoint 
Rationale for change 
 
To clarify that silent MI will be reported as 
tertiary cardiovascular endpoint 
Section to be changed 
 
5.2.1.1 (reporting waver for 
cardiovascular events) 
Description of change 
 
Silent MI is added to list of cardiovascular 
outcome events 
Rationale for change 
 
To avoid unblinding of patient with silent 
MI to ensure the integrity of the trial. 
Section to be changed 
 
5.2.2 (assessment of adverse events) 
Description of change 
 
Change 1: 
Change of adverse event reporting in case 
of worsening of the underlying disease or 
other pre-existing conditions 
 
Change 2: 
Change of adverse event reporting in case 
of changes in vital signs, ECG, physical 
examinations, and laboratory test results 


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Change 3: 
Updated reporting of clinical evaluation of 
hepatic injury 
Rationale for change 
 
Change 1: 
To clarify the criteria for (S)AE reporting. 
 
Change 2: 
To expand the criteria for (S)AE reporting. 
 
Change 3: 
To incorporate clinical evaluation of hepatic 
injury according to BI standards 
Section to be changed 
 
5.2.2.2 (adverse event and serious adverse 
event reporting) 
Description of change 
 
Change 1: 
The observational phase ends 30 days after 
the patient has completed the study. 
 
Change 2: 
The following paragraph has been added to 
the protocol: “BI has established 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 via the RDC-system.” 
Rationale for change 
 
Change 1: 
To clarify that the he observational phase 
ends 30 days after the patient has completed 
the study (with or without study 
medication). 
 
Change 2: 
To expand the definition of SAEs. 
Section to be changed 
 
5.2.5 (assessment of other safety 
parameters) 
Description of change 
 
To add wording “something containing” 
Rationale for change 
 
For further clarification 
 
 
 


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Description of change 
 
 
 
Rationale for change 
 
 
 
 
 
 
 
Section to be changed 
 
7.1 (objectives) 
Description of change 
 
Addition of “*100” to reflect percentage 
Rationale for change 
 
Typo correction 
Section to be changed 
 
7.1 (primary endpoint) 
Description of change 
 
Exclusion of silent MI from primary 
endpoint 
Rationale for change 
 
Silent MI will be reported as tertiary 
cardiovascular endpoint. 
Section to be changed 
 
7.1 (key secondary endpoints) 
Description of change 
 
Change 1: 
Definition of rescue medication for 
evaluation of key secondary endpoints was 
added. 
 
Change 2: 
Both short acting and basal insulin may be 
used as rescue medication. Short acting 
insulin only up to two weeks (e.g. during 
hospitalisation). Therefore the word “basal” 
was deleted. 
Rationale for change 
 
Change 1: 
To clarify definition of rescue therapy for 
evaluation of key secondary endpoints. 
 
Change 2: 
Short-acting insulin may also be used as 
rescue medication up to two weeks. Use of 
insulin up to two weeks will not count as 
rescue medication in the definition of 
treatment sustainability. 
Section to be changed 
 
7.1 (secondary cardiovascular endpoints) 
Description of change 
 
Change 1: 
Replace treated patients by patients in the 
full analysis set. 
 
Change 2: 
Exclusion of silent MI from primary 
endpoint 
Rationale for change 
 
Change 1: 


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According to Section 7.3 the primary 
analysis is performed on the patients in the 
FAS. 
 
Change 2: 
Silent MI will be reported as tertiary 
cardiovascular endpoint. 
Section to be changed 
 
7.1 (tertiary cardiovascular endpoints) 
Description of change 
 
Change 1:  
Summarization of non-fatal and fatal MI, as 
well as non-fatal and fatal stroke for 
evaluation of time to and occurrence of 
tertiary cardiovascular endpoints. 
 
Change 2: 
Refine wording of tertiary cardiovascular 
endpoint. 
 
Change 3: 
Addition of silent MI as tertiary 
cardiovascular endpoint. 
Rationale for change 
 
Change 1: 
To allow for an analysis of single 
components with inclusion of death 
resulting from such a component. 
 
Change 2: 
Improve wording 
 
Change 3: 
To clarify that silent MI will be analysed as  
tertiary cardiovascular endpoint. 
Section to be changed 
 
7.1 (secondary diabetes related 
endpoints) 
Description of change 
 
Addition of any transitions in albuminuria 
classes and change from baseline in 
albuminuria as secondary diabetes related 
endpoints. 
Rationale for change 
 
Albuminuria and change of albuminuria are 
important diabetes related endpoints, which 
results may be different between the two 
treatment arms. These endpoints are added 
to allow any publication of the results. 
Section to be changed 
 
7.1 (tertiary diabetes related endpoints) 
Description of change 
 
Change 1: 
Addition of time to rescue medication 
intake as tertiary diabetes related endpoint. 
 


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Change 2: 
Addition of proportion of patients with 
rescue therapy intake as tertiary diabetes 
related endpoint. 
 
Change 3: 
Definition of rescue medication for 
evaluation of tertiary endpoints was added. 
 
Change 4: 
Deletion of stable angina pectoris as study 
endpoint. 
Rationale for change 
 
Change 1: 
Definition of new endpoints 
 
Change 2: 
Definition of new endpoints 
 
Change 3: 
To clarify definition of rescue therapy for 
evaluation of tertiary diabetes related 
endpoints. 
 
 
Change 4: 
Stable angina pectoris will not be 
adjudicated as tertiary cardiovascular 
endpoint. 
Section to be changed 
 
7.1 (other endpoints) 
Description of change 
 
Change 1: 
Add proportion of patients with 
hypoglycaemia and time to first 
hypoglycaemia as other endpoint. 
 
Change 2: 
Delete all-cause mortality from other 
endpoints. 
Rationale for change 
 
Change 1: 
Definition of new endpoints  
 
Change 2: 
All-cause mortality is already included in 
tertiary cardiovascular endpoints. 
Section to be changed 
 
7.2 (null and alternative hypotheses) 
Description of change 
 
Adopt hypotheses for key secondary 
endpoints. 


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Rationale for change 
 
As Fisher’s exact test will be replaced by 
Chi-Square test, the two-sided p-value will 
be reported and hence hypotheses needed to 
be changed. 
Section to be changed 
 
7.3 (planned analyses) 
Description of change 
 
Change 1:  
Definition of severe violation of treatment 
compliance refined.  
 
Change 2: 
The definition of the on-treatment set was 
refined to be more precise. 
Rationale for change 
 
Change 1: 
Refine definition of violation of compliance 
 
Change 2: 
Clarify the definition of the on-treatment set 
in detail. 
Section to be changed 
 
7.3.1 (primary analyses) 
Description of change 
 
Change 1: 
Addition of “*100” to reflect percentage 
 
Change 2: 
Change of the test for evaluation of key 
secondary endpoints to Chi-Square test, on 
the same significance level (2*i)*100% as 
the primary endpoint. 
Rationale for change 
 
Change 1: 
Typo correction. 
 
Change 2: 
Use of Chi-Square test instead of Fisher’s 
exact test as this test is more powerful. Use 
of two-sided p-values. 
Section to be changed 
 
7.3.2 (secondary analyses) 
Description of change 
 
Change 1: 
For all cardiovascular endpoints that 
include occurrence of an event, Chi-Square 
test is used to compare the two treatment 
groups. 
Change 2: 
A logistic regression with factor treatment 
is performed for cardiovascular endpoints. 


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Change 3: 
There will not be any one-sided tests (test 
for superiority of linagliptin versus 
glimepiride, alpha= 0.025) be performed for 
diabetes related endpoints. 
Change 4: 
For continuous secondary diabetes related 
endpoints with several on-treatment 
measurements change from baseline will be 
evaluated with a restricted maximum 
likelihood (REML) based mixed model 
repeated measures (MMRM) approach. For 
those continuous secondary diabetes related 
endpoints with only one measurement on 
treatment an analysis of covariance 
(ANCOVA) model with the factor 
treatment and the baseline value of the 
respective variable as covariate will be 
performed.  
Change 5: 
For qualitative secondary diabetes related 
endpoints, Chi-Square test is used to 
compare the two treatment groups. 
Rationale for change 
 
Change 1: 
Use of Chi-Square test instead of Fisher’s 
exact test as this test is more powerful. 
 
Change 2: 
The logistic regression will be performed 
additionally to report odds ratios. 
 
Change 3: 
In order to provide a consistent picture, all 
binary and continuous diabetes related 
endpoints will be investigated in the same 
way, respectively. 
 
Change 4: 
The MMRM approach will be performed to 
allow dealing with missing values and to 
account for correlations between repeated 
measurements.  
 
Change 5: 


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Use of Chi-Square test instead of Fisher’s 
exact test as this test is more powerful. 
Section to be changed 
 
7.3.4 (interim analyses) 
Description of change 
 
Deleted filing of DMC charter in ISF. 
Rationale for change 
 
The DMC charter will not be filed in the 
ISF. 
Section to be changed 
 
7.4 (handling of missing data) 
Description of change 
 
Change 1: 
The REML based MMRM analysis will 
handle missing data for continuous diabetes 
related endpoints. 
 
Change 2: 
The last observation carried forward 
(LOCF) approach will be performed in a 
sensitivity analysis on diabetes related 
endpoints. 
Rationale for change 
 
Change 1: 
This analysis will deal with missing values. 
 
Change 2: 
As the MMRM approach will be used to 
deal with missing observations of 
continuous diabetes related endpoints, 
LOCF will be performed in a sensitivity 
analysis. 
Section to be changed 
 
8 and 8.1 (study approval, patient 
information, and informed consent) 
Description of change 
 
Additional wording/paragraph for Japan 
Rationale for change 
 
To fulfil Japanese requirements 
Section to be changed 
 
8.2 (data quality assurance) 
Description of change 
 
Additional paragraph regarding data quality 
assurance 
Rationale for change 
 
To clarify data quality assurance 
Section to be changed 
 
8.4.1 (listedness and expedited reporting 
of adverse events) 
Description of change 
 
Change of required SPC references 
Rationale for change 
 
Unique reference documents for metformin 
and pioglitazone are no longer required, 
since rescue medication is not pre-specified. 
Per protocol there are several options for 
rescue medication (investigator’s 
judgement). 


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Section to be changed 
 
8.7 (protocol violations) 
Description of change 
 
Addition of paragraph regarding reporting 
of protocol violations 
Rationale for change 
 
To clarify requirement of reporting of 
protocol violations 
Section to be changed 
 
9.1 (published references) 
Description of change 
 
Deletion of reference R11-2713 
Rationale for change 
 
Reference R11-2713 is not needed 
anymore. 
Section to be changed 
 
10.2 (definitions of endpoint events) 
Description of change 
 
Definitions of the adjudicated endpoints 
events and the principles of standardised 
data collection in the centralised CEC 
adjudication process are outlined in the 
current CEC Charter and process guideline. 
The endpoint definitions are deleted from 
the protocol. 
Rationale for change 
 
To reflect that the CEC charter will be 
maintained throughout the course of current 
definitions for cardiovascular endpoints. 
Section to be changed 
 
10.3 (blood pressure measurement 
procedure and treatment 
recommendations) 
Description of change 
 
Addition of further guidance of blood 
pressure measurements 
Rationale for change 
 
To clarify blood pressure measurements 
Section to be changed 
 
Section 10.6 (clinical evaluation of liver 
injury) 
Description of change 
 
Updated paragraphs of clinical evaluation 
of liver injury  
Rationale for change 
 
To incorporate clinical evaluation of liver 
injury according to BI standards 
 
Number of CTP modification  
3 
Date of CTP modification 
 
1 August 2012 
EudraCT number 
 
2009-013157-15 
BI Trial number 
 
1218.74 
BI Investigational Product(s)  
Linagliptin 
Title of protocol 
 
A multicentre, international, randomised, 
parallel group, double blind study to 
evaluate Cardiovascular safety of linagliptin 
versus glimepiride in patients with type 2 


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diabetes mellitus at high cardiovascular risk. 
The CAROLINA Trial. 
 
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 
 
 
 
Section to be changed 
 
Title page 
Description of change 
 
Trial Clinical Monitor name and address 
details updated.   
Rationale for change 
 
New TCM assigned and address change. 
Section to be changed 
 
Protocol synopsis (Objectives) 
Description of change 
 
Inclusion of the fifth test within hierarchical 
testing procedure. 
Rationale for change 
 
As the classical MACE endpoint will be 
introduced as first key secondary endpoint, 
the testing hierarchy will include 5 
hypothesis tests. 
Section to be changed 
 
Protocol synopsis (Methodology) 
Description of change 
 
Safety was crossed out as the study’s focus 
lies on efficacy and safety. 
Rationale for change 
 
For clarification. 
Section to be changed 
 
Protocol synopsis (No. of patients) 
Description of change 
 
“At least” was changed into “An estimated 
number of”. 
Rationale for change 
 
To clarify that the study is event driven and 
that the required number of patients is an 
estimation. 
Section to be changed 
 
Protocol synopsis (inclusion criteria) 
Description of change 
 
Change 1: 
-     Myocardial infarction (≥ 6 weeks prior 
to   
      informed consent)  
- 
Percutaneous Coronary Intervention 
(PCI) ≥ 6 weeks prior informed consent 
- 
Coronary Artery By-pass Grafting 
(CABG) ≥  4 years prior to informed 


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consent or with recurrent angina pectoris 
following surgery  
- 
Ischemic or hemorrhagic stroke (≥ 3 
months prior to informed consent)  
 
Was changed to: 
 
-    Myocardial infarction (> 6 weeks prior 
to informed consent)  
-    Percutaneous Coronary Intervention 
(PCI) > 6 weeks prior informed consent 
- 
Coronary Artery By-pass Grafting 
(CABG) > 4 years prior to informed 
consent or with recurrent angina pectoris 
following surgery  
- 
Ischemic or hemorrhagic stroke (> 3 
months prior to informed consent).  
 
Change 2: 
Treatment compliance requirement in the 
placebo-run was added.  
Rationale for change 
 
To be consistent with section 3.3.2 inclusion 
criteria. 
Section to be changed 
 
Protocol synopsis (criteria for exclusion) 
Description of change 
 
Change 1:  
Duration of short term insulin (up to two 
weeks) is allowed, if taken at least 8 weeks 
prior informed consent  
 
was changed into: 
 
Duration of short term insulin (up to two 
consecutive weeks) is allowed, if taken at 
least 8 weeks prior informed consent. 
 
Change 2: 
All exclusion criteria have been added. 
Rationale for change 
 
Change 1: For clarification and 
 
Change 2: 
to be consistent with section 3.3.3 exclusion 
criteria. 
Section to be changed 
 
Protocol synopsis (duration of treatment) 
Description of change 
 
2 to 4 weeks placebo run-in phase followed 
by up to 400 weeks treatment + 1 week 
follow-up after study drug termination. 


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Observational study duration is up to 30 
days after date of patients Final Visit. 
 
Was changed into: 
2 up to 4 weeks placebo run-in phase 
followed by up to an estimated 400 weeks 
treatment period and 1 week follow-up after 
study drug termination. Observational study 
duration is up to 30 days after date of 
patients Final Visit. 
Rationale for change 
 
To clarify duration of treatment. 
Section to be changed 
 
Protocol synopsis (Criteria for efficacy) 
Description of change 
 
Inclusion of classical MACE endpoint as 
first key secondary endpoint and shift of 
previous first and second key secondary 
endpoints to second and third position. 
Rationale for change 
 
This endpoint was defined as first key 
secondary endpoint. 
Section to be changed 
 
Protocol synopsis (Criteria for safety) 
Description of change 
 
Change 1: 
non- fatal MI, non- fatal stroke, 
 
Was changed into: 
(non)- fatal MI, (non)- fatal stroke, 
 
Change 2: 
Silent myocardial infarction added as 
criteria for safety; 
 
Change 3: 
Reference to section 5.2 added.  
Rationale for change 
 
To be consistent with section 5.2.1 
endpoints and tertiary cardiovascular 
endpoints as described in section 7.1 
Section to be changed 
 
Protocol synopsis (Statistical methods) 
Description of change 
 
Inclusion of analysis methods for key 
secondary endpoints. 
Rationale for change 
 
According to Annotated clinical trial 
protocol instructions the model used for the 
analysis of key secondary endpoints should 
be mentioned. 
Section to be changed 
 
Flow chart 
Description of change 
 
 


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Change 1: 
Maximum number of days from screening 
(V1a) to randomisation changed from -42 
into -35;  
 
Change 2: 
demographics  obtained at Visits 1a and 1b, 
footnote added that the race of the patient 
will  
be collected;  
 
Change 3: 
additional footnotes added, re-ordered or 
revised; 
 
Change 4: 
added that placebo run-in medication will 
be dispensed by the IXR system; 
 
Change 5: 
 
 
 
Change 6: 
 
 
 
Change 7: 
additional laboratory parameters added to 
footnote h; 
 
Change 8: 
added that the MDRD considers race as an 
adjustment factor; 
 
Change 9: 
 
  
Change 10: 
 
 
 
 


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Change 11: 
clarification of end of trial activities and 
guidance on re-institution of 
glimepiride/glimepiride placebo added. 
Rationale for change 
 
Change 1: 
To clarify maximum number of days 
between screening and randomisation; 
 
Change 2: 
to clarify that demographic data is obtained 
at  
Visit 1a and Visit 1b and that race will be  
captured in the eCRF, because T2DM 
treatment  
results maybe race sensitive. Furthermore, 
the  
renal function will be assessed using the 
MDRD  
formula. This formula considers the race as 
an  
adjustment factor, therefore, the race must 
be  
known for accurate estimation;  
 
Change 3: 
to adapt the footnotes to the changes in the 
flowchart; 
 
Change 4: 
to clarify that placebo run-in medication is 
dispensed by IXRS; 
 
Change 5: 
 
 
 
Change 6: 
 
 
 
Change 7: 
to clarify obtained laboratory parameters at 
Visit 1a;  
Change 8: 


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to state that MDRD formula considers race 
as an adjustment factor;  
 
Change 9: 
to clarify that the number of to be obtained 
questionnaires is an approximation;  
 
Change 10: 
 
 
 
Change 11: 
to clarify end of trial activities and to add 
guidance on re-institution of trial 
medication.  
Section to be changed 
 
Abbreviations 
Description of change 
 
Several abbreviations added. 
Rationale for change 
 
To list all abbreviations used in the 
protocol. 
Section to be changed 
 
2.2 Trial Objectives 
Description of change 
 
Inclusion of classical MACE endpoint as 
first key secondary endpoint.Inclusion of 
the fifth test within hierarchical testing 
procedure. 
Rationale for change 
 
As the classical MACE endpoint will be 
introduced as first key secondary endpoint, 
the testing hierarchy will include 5 
hypothesis tests. 
Section to be changed 
 
3.1 Overall trial design and trial 
population 
Description of change 
 
Change 1: 
The first paragraph was aligned with the 
methodology section in the protocol 
synopsis; 
 
Change 2: 
the minimum number of patients of 6000 
was changed into an estimated number of 
6000 patients, in addition it was added that 
the 400 weeks treatment duration is an 
estimated treatment duration; 
 
Change 3: 


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treatment compliance criterion was added to 
the definition of successfully completed at 
least two weeks of the placebo run-in; 
 
Change 4: 
added that SU/glinide should not be taken in 
the morning of Visit 2.  
 
Change 5: 
the end of trial activities and requirements 
were clarified and 
 
Change 6: 
trial stop procedures, including timeframe to 
stop the trial and to perform last patient 
visits clarified. 
Rationale for change 
 
Change 1: 
To be consistent with the methodology 
section in the synopsis; 
 
Change 2: 
to clarify that the study is event driven and 
that the required number of patients and the 
treatment duration is an estimation; 
 
Change 3: 
to clarify that the treatment compliance 
criterion is a placebo-run requirement; 
 
Change 4: 
to clarify that no double doses should be 
taken at Visit 2; 
 
Change 5: 
to clarify end of trial activities and  
 
Change 6: 
to clarify trial stop procedures. 
Section to be changed 
 
3.1.1 Administrative structure of the trial 
Description of change 
 
Pancreatic adjudication was added. 
Rationale for change 
 
To set-up an adjudication committee for 
pancreatic events. 


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Section to be changed 
 
3.2 Discussion of trial design, including 
the choice of control group 
Description of change 
 
The treatment duration was clarified e.g. by 
adding that the 400 week treatment duration 
is estimation.  
Rationale for change 
 
To clarify treatment duration. 
Section to be changed 
 
3.3 Selection of trial population 
Description of change 
 
Change 1: 
The number of patients to be screened was 
increased from 9000 to 10.000 patients;  
 
Change 2: 
at least 6000 patients  
Was changed to:  
estimated number of 6000 patients;  
 
Change 3: 
clarification of expected number of patients 
per site and 
 
Change 4: 
Requirement to obtain approval from the 
TCM to randomise more than 30 patients 
was removed. 
Rationale for change 
 
Change 1: 
To reflect the expected number of screened 
patients based on actual data and current 
percentage of screen failures;  
 
Change 2: 
to clarify that the study is event driven and 
that the required number of patients is an 
estimation; 
 
Change 3: 
to clarify that sites could end up with less 
than 8 patients due to competitive 
recruitment and 
 
Change 4: 
approval to continue recruitment beyond 30 
patients in a certain sites is given by the 


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TCM to the CML and therefore will be 
transferred to the monitoring manual. 
Section to be changed 
 
3.3.3 Exclusion criteria 
Description of change 
 
Duration of short term insulin (up to two 
weeks) is allowed, if taken at least 8 weeks 
prior informed consent  
 
Was changed to: 
 
Duration of short term insulin (up to two 
consecutive weeks) is allowed, if taken at 
least 8 weeks prior informed consent. 
Rationale for change 
 
For clarification  
Section to be changed 
 
3.3.4.1 Removal of individual patients 
Description of change 
 
Change 1: 
End of study was changed into end of trial; 
 
Change 2: 
inappropriateness of glimepiride treatment 
for renal safety issues according to local 
prescribing information was added as a 
withdrawal criterion; 
  
Change 3: 
the end of treatment requirements and 
follow-up procedures have been updated 
and 
 
Change 4: 
added that SU/glinide should not be taken in 
the morning of Visit 2. 
Rationale for change 
 
Change 1: 
To use consistent terminology in line with 
the protocol flow chart; 
 
Change 2: 
for clarification;  
 
Change 3: 
to clarify end of treatment activities and 
follow-up requirements and 
 
Change 4: 


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to clarify that no double doses should be 
taken at Visit 2. 
Section to be changed 
 
4.1.2 Method of assigning patients to 
treatment groups 
Description of change 
 
Added that sites will receive an information 
manual describing all steps to randomise a 
patients, obtain a medication kit assignment 
and to acknowledge study drug. 
Rationale for change 
 
For clarification. 
Section to be changed 
 
4.1.4 Drug assignment and 
administration of doses for each patient 
Description of change 
 
Change 1: 
The titration requirements have been re-
written; 
 
Change 2: 
“If applicable” was added to the sentence 
that patients will continue their standard 
metformin therapy throughout the study; 
 
Change 3: 
investigator judgement to change study 
medication was changed into investigators 
judgement to change glimepirde/glimepiride 
placebo; 
 
Change 4: 
added that patients should be instructed to 
take trial medication once daily with water; 
 
Change 5: 
guidance on re-institution of glimepiride/ 
glimepiride placebo added and  
 
Change 6: 
Guidance on timing of in clinic visit added. 
Rationale for change 
 
Change 1: 
To clarify that glimepiride/glimepiride 
placebo is uptitrated and not study 
medication, which included 
linagliptin/linagliptin placebo (double 
dummy); 
 


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Change 2: 
to clarify that treatment naive patients are 
eligible if intolerant or contra-indicated to 
first line anti-diabetic treatment; 
 
Change 3 and change 4: 
for clarification;  
 
Change 5: 
to add guidance on re-institution of trial 
medication and 
 
Change 6: 
To be consistent with instruction given in 
section 6.1. 
Section to be changed 
 
4.1.7 Storage conditions 
Description of change 
 
Change 1: 
Added that in addition to wallets, blisters 
are provided; 
 
Change 2: 
added that a temperature log must be 
maintained at site and 
 
Change 3: 
medication return requirements were moved 
to the correct section in the protocol, section 
4.1.8. 
Rationale for change 
 
Change 1: 
To clarify the use of wallets and blisters; 
 
Change 2: 
to clarify temperature monitoring 
requirements for study medication and 
 
Change 3: 
to move the drug accountability 
requirements to the corresponding section in 
the protocol. 
Section to be changed 
 
4.1.8 Drug accountability 
Description of change 
 
Drug accountability requirements was 
shifted from Section 4.1.7 to this Section. 


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Rationale for change 
 
To add drug accountability requirement to 
the correct clinical trial protocol section. 
Section to be changed 
 
4.3 Treatment compliance 
Description of change 
 
Change 1: 
The requirement to use a worksheet to 
document treatment compliance was 
removed and 
 
Change 2: 
It was clarified that severe violation of 
compliance is seen as important protocol 
violation. 
Rationale for change 
 
Change 1: 
Treatment compliance should be reflected in 
the patient source documents and 
 
Change 2: 
for clarification. 
Section to be changed 
 
5.1.1 Endpoint(s) of efficacy 
Description of change 
 
Inclusion of classical MACE endpoint as 
first key secondary endpoint. 
Rationale for change 
 
This endpoint was defined as first key 
secondary endpoint. 
Section to be changed 
 
5.1.2 Assessment of efficacy 
Description of change 
 
The definition of overnight fast was made 
consistent with the definition given in the 
protocol synopsis.  
Rationale for change 
 
For consistency. 
Section to be changed 
 
5.2.1 Endpoint(s) of safety 
Description of change 
 
Change 1: 
The reporting requirements for outcome 
events was moved from section 5.2.2.2 to 
this section, describing the outcome events 
and 
 
Change 2: 
added that in case of a stroke the disability 
or dependence in daily activities will be 
collected with the modified Rankin Scale 
(mRS).  
Rationale for change 
 
Change 1: 


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To reflect the outcome reporting 
requirements in the correct section of the 
clinical trial protocol and 
Change 2: 
to clarify that the grade of mRS is collected 
in case of a stroke. 
Section to be changed 
 
5.2.2.1 Definitions of adverse events 
Description of change 
 
Change 1: 
Added that all symptomatic hypoglycaemic 
events, all asymptomatic hypoglycaemic 
events with glucose levels less than 3.0 
mmol/L and all asymptomatic 
hypoglycaemic events considered an AE by 
the investigator should be reported as 
adverse event and 
 
Change 2: 
clarification that hepatic injury is to be 
reported as SAE added. 
Rationale for change 
 
Change 1: 
To clarify reporting procedures for 
hypoglycaemic events. 
 
Change 2:  
To be in line with Boehringer Ingelheim 
standard operating procedures.  
Section to be changed 
 
5.2.2.2 Adverse event and serious adverse 
event reporting 
Description of change 
 
The reporting requirements for outcome 
events have been moved to section 5.2.1 of 
the clinical trial protocol. 
Rationale for change 
 
To reflect the reporting requirements of 
outcome events and AESI in the correct 
sections of the clinical trial protocol.  
Section to be changed 
 
5.2.3 Assessment of safety laboratory 
parameters 
Description of change 
 
Change 1: 
Added  that the lipid profile will only be 
obtained at Visits: 2, 6, 9, 12, 15, 18, 21, 24, 
27 and 30; 
 
Change 2: 


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added that bilirubin is not measured at Visit 
1a; 
 
Change 3: 
 
 
 
Change 4: 
additional laboratory parameters added to 
Visit 1a and 
 
Change 5: 
added that the MDRD considers race as an 
adjustment factor. 
Rationale for change 
 
Change 1: 
To clarify laboratory requirements; 
 
 
Change 2: 
to clarify that bilirubin is not measured a 
Visit 1a; 
 
Change 3: 
 
 
 
Change 4: 
to clarify obtained laboratory parameters at 
Visit 1a and 
 
Change 5: 
to state that MDRD formula considers race 
as an adjustment factor.  
Section to be changed 
 
5.2.4 Electrocardiogram (ECG) 
Description of change 
 
Added that in case of unresolved 
discrepancies investigators will not receive 
evaluated ECG reports from the vendor. 
Rationale for change 
 
To clarify that in case of discrepancies the 
processing timelines will be > 3 days.  
Section to be changed 
 
5.2.5 Assessment of other safety 
parameters 
Description of change 
 
Change 1: 


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The requirement to use the same blood  
pressure instrument and weight 
measurement scale throughout the study 
was changed into a similar type of blood 
pressure instrument and weight scale; 
 
Change 2: 
the procedure for HBGM devices and 
corresponding reporting and site contact 
requirements have been clarified and 
 
Change 3: 
a requirement to collect the HBGM diary at 
each visit was added. 
Rationale for change 
 
Change 1: 
Use of the same blood measure instrument 
or weight scale device is from operational 
perspective not feasible taking into account 
treatment duration. A similar type of 
instrument or scale is acceptable;  
 
Change 2: 
to clarify HBGM procedures and 
corresponding reporting and contact 
requirements and 
 
Change 3: 
to avoid potential loss of source data.  
 
 
 
 
 
 
 
  
Rationale for change 
 
 
Section to be changed 
 
 
Description of change 
 
The second paragraph was deleted. 
Rationale for change 
 
To remove duplicate text. 
Section to be changed 
 
6.2.1 Screening an placebo run-in period 
Description of change 
 
Change 1: 
Transaminases was defined as ALT (SGPT) 
and AST (SGOT) and urine albumin and 
urine creatinine was added; 
 
Change 2: 


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the placebo run-in duration was changed 
from 2 to weeks into 2 up to 4 weeks and 
 
Change 3: 
it was clarified that patient requiring rescue 
therapy during the placebo run-in are not 
eligible. 
Rationale for change 
 
Change 1: 
To clarify obtained laboratory parameters at 
Visit 1a;  
 
Change 2: 
to clarify the placebo-run in duration and  
 
Change 3: 
to clarify that rescue medication during 
placebo run-in is allowed, although the 
patient would not be eligible. 
 
Section to be changed 
 
6.2.2 Treatment phase 
Description of change 
 
It was clarified that glimepiride/ glimepiride 
placebo will be uptitrated between visits 2-6 
and all end of trial activities have been 
transferred to section 6.2.3. 
Rationale for change 
 
To clarify that glimepiride/glimepiride 
placebo is uptitrated during Visits 2-6 and to 
transfer end of trial activities to the 
corresponding section of the clinical trial 
protocol. 
Section to be changed 
 
6.2.3 End of trial and follow-up period 
Description of change 
 
Change 1: 
End of study was changed into end of trial 
and 
 
Change 2: 
the end of treatment requirements and 
follow-up procedures have been updated. 
Rationale for change 
 
Change 1: 
To use consistent terminology in line with 
the protocol flow chart and 
 
Change 2: 


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to clarify end of treatment activities and 
follow-up requirements. 
Section to be changed 
 
7.1 Design 
Description of change 
 
The minimum number of patients of 6000 
was changed into an estimated number of 
6000 patients. 
Rationale for change 
 
To clarify that the study is event driven and 
that the required number of patients is an 
estimation. 
Section to be changed 
 
7.1 Primary endpoint 
Description of change 
 
Patients without events will be considered 
censored at the end of study or at lost to 
follow-up, whichever comes first. 
Was changed to: 
If patients do not experience a primary 
endpoint event, they will be considered 
censored at their last documented study 
visit. If a patient died and has no primary 
outcome event, the patient will be censored 
at the date of death. 
Rationale for change 
 
Correction of description 
Section to be changed 
 
7.1 Key secondary endpoints 
Description of change 
 
Definition of time to the first occurrence of 
any of the adjudicated components of the 
classical MACE composite endpoint as first 
key secondary endpoint. 
 
Definition of previous first and second key 
secondary endpoints as second and third key 
secondary endpoints. 
 
Rationale for change 
 
To include the testing for superiority on the 
time to the first occurrence of any of the 
adjudicated components of the classical 
MACE composite endpoint into the testing 
hierarchy as the third test. 
 
Section to be changed 
 
7.1 Secondary cardiovascular endpoints 
Description of change 
 
Delete time to first occurrence of any of the 
adjudicated components of the classical 
MACE composite endpoint from secondary 
endpoints. 
 
Rationale for change 
 
This endpoint was defined as first key 
secondary endpoint. 


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Section to be changed 
 
7.2 Null and alternative hypotheses 
Description of change 
 
Change 1: 
Inclusion of the superiority hypothesis with 
respect to time to first occurrence of any of 
the adjudicated components of the classical 
MACE endpoint to be tested thirdly. 
The hypotheses on second and third key 
secondary endpoints will be tested fourthly 
and fifthly, respectively, if previous tests 
have revealed significant results. 
Change 2: 
Any confirmatory hypothesis test will be 
performed on the full analysis set. 
Rationale for change 
 
Change 1: 
Change of testing hierarchy to include also 
superiority testing for classical MACE 
endpoint. 
 
 
Change 2: 
According to Annotated clinical trial 
protocol instructions the patient population 
should be stated in this subsection. 
Section to be changed 
 
7.3 Planned analysis 
Description of change 
 
Change 1: 
A protocol violation will be considered 
important if it can be expected to have a 
distorting influence on the assessment of the 
primary endpoint and/or key secondary 
endpoints. 
 
Change 2: 
The name of the on-treatment set was 
changed to 30-days-treatment set. 
Rationale for change 
 
Change 1: 
Explaining the details on important protocol 
violations. 
 
Change 2: 
Ensuring the name of the patient analysis set 
reflects the definition. 


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Section to be changed 
 
7.3.1 Primary analyses 
Description of change 
 
Change 1: 
It was clarified, that the Steering 
Committee, which is blinded, will decide on 
the number and time points of the interim 
analyses. 
 
Change 2: 
Change description of testing hierarchy 
according to Section 7.2 and 
 
Change 3: 
inclusion of description of sensitivity 
analyses of first key secondary endpoint. 
Clarification of sensitivity analyses for 
second and third key secondary endpoints. 
 
Change 4: 
The name of the on-treatment set was 
changed to 30-days-treatment set. 
 
Change 5: 
In the sensitivity analyses censoring will be 
done at time patients are on-treatment + 30 
days after permanent treatment 
discontinuation or end of observation, 
whichever comes first. 
 
Change 6: 
The definition of the on-treatment analysis 
was included. 
Rationale for change 
 
Change 1: 
To ensure the decision on the number and 
time points for the formal interim analyses 
are made by the steering committee, which 
is blinded. 
 
Change 2: 
Inclusion of the superiority hypothesis with 
respect to time to first occurrence of any of 
the adjudicated components of the classical 
MACE endpoint to be tested thirdly and 
 
Change 3: 


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Clarification of sensitivity analyses of key 
secondary endpoints. 
 
Change 4: 
Ensuring the name of the patient analysis set 
reflects the definition. 
 
Change 5: 
Clarification that in the sensitivity analyses 
the censoring will be performed at the time 
patients are on-treatment + 30 days after 
permanent treatment discontinuation or end 
of observation, whichever comes first. 
 
Change 6: 
The definition of the on-treatment analysis 
was included based on FDA request. 
Section to be changed 
 
7.3.4 Interim analyses 
Description of change 
 
It was clarified, that the Steering Committee 
will decide on the number and time points 
of the interim analyses. 
 
The DMC will perform periodic safety 
reviews with a frequency as detailed in the 
DMC charter, but additional looks may be 
scheduled as needed by the DMC. In 
addition, the Steering Committee may also 
request the DMC to meet for a safety 
review. 
Rationale for change 
 
To ensure the decision on the number and 
time points for the formal interim analyses 
are made by the steering committee, which 
is blinded. 
 
It was clarified that the DMC performs 
periodic safety reviews. 
Section to be changed 
 
7.5 Randomisation 
Description of change 
 
DMC will have access to randomisation 
code. 
Rationale for change 
 
To clarify the role of the DMC. 
Section to be changed 
 
7.6 Determination of sample size 
Description of change 
 
The sentence on the decision about number 
and time points of the interim analyses was 
deleted. 


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Rationale for change 
 
These details are clarified in Section 7.3.1 
and 7.3.4. 
Section to be changed 
 
8 informed consent, data protection, trial 
records 
Description of change 
 
The version as of October 1996 of the 
declaration of Helsinki was removed. 
Rationale for change 
 
To be in line with corporate standard 
operating procedures.  
Section to be changed 
 
10.3 Blood pressure measurement 
procedure and treatment 
recommendations 
Description of change 
 
The requirement to use the same blood  
pressure instrument measurement scale 
throughout the study was changed into a 
similar type of blood pressure instrument. 
Rationale for change 
 
Use of the same blood measure instrument 
is from operational perspective not feasible 
taking into account treatment duration. A 
similar type of instrument or scale is 
acceptable. 
Section to be changed 
 
10.5 Silent myocardial infarction  
Description of change 
 
Reference to section 10.2.4 deleted. 
Rationale for change 
 
No longer a valid reference. 
Section to be changed 
 
10.6.2 procedures 
Description of change 
 
The procedures and testing requirement in 
case of clinical evaluation of liver injury 
have been aligned with the Boehringer 
Ingeheim standard operating procedure. 
 
Rationale for change 
 
To be in line with Boehringer Ingelheim 
standard operating procedures. 
 
Number of CTP modification  
4 
Date of CTP modification 
 
April 2013 
EudraCT number 
 
2009-013157-15 
BI Trial number 
 
1218.74 
BI Investigational Product(s) 
 
Linagliptin 
Title of protocol 
 
A multicentre, international, randomised, 
parallel group, double blind study to 
evaluate Cardiovascular safety of linagliptin 
versus glimepiride in patients with type 2 
diabetes mellitus at high cardiovascular 
risk. The CAROLINA Trial. 


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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 
 
 
 
Section to be changed 
 
Title page 
Description of change 
 
Trial Clinical Monitor name and address 
details updated.   
Rationale for change 
 
New TCM assigned and address change. 
Section to be changed 
 
Protocol synopsis (Duration of 
treatment) 
Description of change 
 
Introduction of the term follow-up period 
Rationale for change 
 
To be in line with current Boehringer 
Ingelheim standard operating procedures 
Section to be changed 
 
Flow chart 
Description of change 
 
 
 
Rationale for change 
 
 
Section to be changed 
 
Abbreviations 
Description of change 
 
LADA was added to the list. 
Rationale for change 
 
For clarification 
Section to be changed 
 
3.1 Overall trial design and plan 
Description of change 
 
medication treatment permanently 
Rationale for change 
 
Typo correction 
Section to be changed 
 
3.3.4.1 Removal of individual patients 
Description of change 
 
Change 1: 
The possibility of vital status and outcome 
events follow up after informed consent 
withdrawal was added. 
 
Change 2: 
End of Trial was changed into End of 
Treatment 
 


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Change  3: 
(Follow up Visit) was added after V31 
 
Change 4: 
Pancreatitis was added as a reason to stop 
the study medication. 
 
Change 5: 
“Permenantly” was added. 
Rationale for change 
 
Change 1: 
Obtain vital status and outcome events after 
withdrawal. 
 
Change 2: 
To be in line with the Flow chart 
 
Change 3: 
For clarification 
 
Change 4: 
Safety update 
 
Change 4: 
For clarification 
Section to be changed 
 
4.2.1 Rescue medication, emergency 
procedures and additional treatment(s) 
Description of change 
 
For other than the protocol defined rescue 
medication it was specified that the study 
treatment should be discontinued when this 
rescue medication is contraindicated with 
the study treatment. 
Rationale for change 
 
For clarification 
Section to be changed 
 
5.2.2.1 Definitions of adverse events 
Description of change 
 
Change 1: 
Reporting of non-serious AESIs  according 
to the SAE procedure was added. 
 
Change 2: 
(with differentiation of bilirubin in direct 
and indirect if total bilirubin is elevated) 


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was added to the hepatic event bilirubin 
testing.  
Rationale for change 
 
Change 1: 
Clarification of (S)AE and AESI reporting 
to be in line with Boehringer Ingelheim 
standard operating procedures. 
 
Change 2: 
For clarification 
Section to be changed 
 
5.2.2.2 Adverse event and serious adverse 
event reporting 
Description of change 
 
Change 1: 
Introduction of the term follow-up period. 
 
Change 2: 
The following text was added: The 
investigator should report SAEs which 
occurred in a patient after the follow-up 
period, if the investigator becomes aware of 
them. 
 
Change 3: 
Paragraph regarding the immediate 
documentation of events was updated: The 
investigator must document immediately 
(within 24 hours of awareness or the next 
business day whichever is shorter) the 
following events on the SAE case page 
form in RDC: 
 
Change 4: 
Reporting of all AESIs  according to the 
SAE procedure was added. 
Rationale for change 
 
Change 1: 
To be in line with current Boehringer 
Ingelheim standard operating procedures. 
  
Change 2: 
Clarification of (S)AE and AESI reporting 
to be in line with Boehringer Ingelheim 
standard operating procedures. 
 
Change 3: 


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Clarification of (S)AE and AESI reporting 
to be in line with Boehringer Ingelheim 
standard operating procedures. 
 
Change 4: 
Clarification of (S)AE and AESI reporting 
to be in line with Boehringer Ingelheim 
standard operating procedures. 
 
 
 
 
 
 
 
 
Rationale for change 
 
 
Section to be changed 
 
6.2.3 End of trial and Follow-up period 
Description of change 
 
Change 1: 
End of Trial was changed into End of 
Treatment 
 
Change 2: 
The possibility of vital status and outcome 
events follow up after informed consent 
withdrawal was added. 
Therefore the text about study end after ICF 
withdrawal was also removed. 
Rationale for change 
 
Change 1: 
To be in line with the Flow chart 
 
Change 2: 
Obtain vital status and outcome events after 
withdrawal. 
Section to be changed 
 
7.1 Statistical Design – Model  
Description of change 
 
Change 1:  
 
 
 
 
 
 
 
Change 2:  


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Rationale for change 
 
Change 1: 
Measurements are only performed at 
baseline. 
Change 2: 
For clarification 
Section to be changed 
 
7.3 Planned analyses 
Description of change 
 
Change 1: 
 
 
Change 2: 
 
 
 
 
 
 
 
Rationale for change 
 
Change 1: 
For clarification 
Change 2: 
 
 
 
 
 
Number of CTP modification  
5 
Date of CTP modification 
 
14 September 2015 
EudraCT number 
 
2009-013157-15 
BI Trial number 
 
1218.74 
BI Investigational Product(s) 
 
Linagliptin 
Title of protocol 
 
A multicentre, international, randomised, 
parallel group, double blind study to 
evaluate Cardiovascular safety of linagliptin 
versus glimepiride in patients with type 2 
diabetes mellitus at high cardiovascular 
risk. The CAROLINA Trial. 
 
To be implemented only after 
approval of the 
 
 


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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 
 
 
 
Section to be changed 
 
Title page 
Description of change 
 
Trial Clinical Monitor name and address 
details updated.   
Rationale for change 
 
New TCM assigned and address change. 
Section to be changed 
 
Flow chart 
Description of change 
 
Change 1: 
FU period changed from 7 to 30 days  
Change 2: 
Glomerular filtration rate and Fasting 
Plasma glucose samples to be taken at V31 
Rationale for change 
 
Change 1: 
To be in line with the project FU period 
Change 2: 
To reflect actual testing done at V31 
Section to be changed 
 
3.1 Overall trial design and plan 
Description of change 
 
Text on  Follow-up period was updated to 
reflect the 30d FU period 
Rationale for change 
 
For clarification 
Section to be changed 
 
3.2 Discussion on trial design, including 
the choice of control group 
Description of change 
 
Text on  Follow-up period was updated to 
reflect the 30d FU period 
Rationale for change 
 
For clarification 
Section to be changed 
 
3.3.4.1 Removal of individual patients 
Description of change 
 
Retention strategy language was updated + 
Follow-up period was updated to reflect the 
30d FU period 
Rationale for change 
 
For clarification 
Section to be changed 
 
4.2.1 Rescue medication, emergency 
procedures and additional treatment(s) 
Description of change 
 
‘Including during the FU period’ was added 


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Rationale for change 
 
Text on  Follow-up period was updated to 
reflect the 30d FU period 
Section to be changed 
 
5.2.2.1 Definitions of adverse events 
Description of change 
 
Change 1: 
AESI : alignment of text throughout the 
Lina project  
Change 2: 
addition of pancreatic cancer as AESI 
Change 3 : throughout this section, text was 
updated to reflect current standard text 
Rationale for change 
 
Change 1: 
For clarification 
Change 1: 
Alignment within the Lina project 
Change 3:  
AE and SAE definitions were updated to 
reflect the latest standard text 
Section to be changed 
 
5.2.2.2 Adverse event and serious adverse 
event reporting 
Description of change 
 
throughout this section, text was updated to 
reflect current standard text 
Rationale for change 
 
AE and SAE definitions were updated to 
reflect the latest standard text 
Section to be changed 
 
5.2.2.3 Oncological adverse events 
Description of change 
 
Oncological assessment was added 
Rationale for change 
 
For clarification 
Section to be changed 
 
5.2.3.4 Renal function impairment 
Description of change 
 
Formulas taken out and reference made to 
the Statistical Analysis Plan 
Rationale for change 
 
For clarification 
Section to be changed 
 
6.2.3 End of trial and Follow-up period 
Description of change 
 
Text adapted to be in line with section 
3.3.4.1 
Rationale for change 
 
For clarification 
Section to be changed 
 
7.1 Statistical design - model 
Description of change 
 
Change 1 : 
 
 
 
 
Change 2 : Secondary diabetic related 
endpoints 


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‘Urinary’ added to albumin  
Rationale for change 
 
Change 1 :  
For clarification 
Change 2 : 
For clarification 
 
Number of CTP modification  
6 
Date of CTP modification 
 
20 April 2016 
EudraCT number 
 
2009-013157-15 
BI Trial number 
 
1218.74 
BI Investigational Product(s) 
 
Linagliptin 
Title of protocol 
 
A multicentre, international, randomised, 
parallel group, double blind study to 
evaluate Cardiovascular safety of linagliptin 
versus glimepiride in patients with type 2 
diabetes mellitus at high cardiovascular 
risk. The CAROLINA Trial. 
 
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 
 
 
 
Section to be changed 
 
Title page 
Description of change 
 
Change 1: Trial Clinical Monitor name and 
address details updated.   
Rationale for change 
 
Change 1: Change in Trial Clinical Monitor 
Section to be changed 
 
Clinical Trial Protocol Synopsis 
Description of change 
 
Objectives: 
Change 1: Primary endpoint changed to 
time to the first occurrence of any of the 
following adjudicated components of the 
primary composite endpoint: CV death 
(including fatal stroke and fatal MI), non-
fatal MI (excluding silent MI) or non-fatal 
stroke. 


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Change 2:…then thirdly the first key 
secondary endpoint will be tested 
hierarchically 
Was changed into: 
…then thirdly the first key secondary 
endpoint will be tested hierarchically with a 
superiority hypothesis.  
 
Duration of treatment: 
Change 3: Estimated trial duration updated 
to 432 weeks. 
 
Criteria for efficacy: 
Change 4: Primary endpoint changed to 
time to the first occurrence of any of the 
following adjudicated components of the 
primary composite endpoint: CV death 
(including fatal stroke and fatal MI), non-
fatal MI (excluding silent MI) or non-fatal 
stroke. 
 
Change 5: First key secondary endpoint 
changed to time to the first occurrence of 
any of the following adjudicated 
components of: CV death (including fatal 
stroke and fatal MI), non-fatal MI 
(excluding silent MI), non-fatal stroke or 
hospitalisation for unstable angina pectoris. 
 
Criteria for safety 
Change 6:…silent myocardial infarction 
was changed into: … and occurrence of and 
time to silent myocardial infarction.  
Rationale for change 
 
Change 1, 4, 5: 
Testing hierarchy revised following a 
unanimous request from the trial Academic 
Steering Committee. 
 
Change 2: For clarification. 
 
Change 3: Estimated trial duration 
increased due to change of primary 
endpoint. 
 


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Change 6: Clarification added, that silent 
MI is not a by adjudication confirmed 
endpoint. 
Section to be changed 
 
Flowchart 
Description of change 
 
Change 1: Two additional visits added to 
the trial flow chart. 
 
Change 2: footnote ‘n’: …at minimum a 
yearly telephone call and a telephone call at 
study end will be asked for, to document the 
occurrence of outcome events and vital 
status. If possible, also other AE’s and 
concomitant therapy changes since last visit 
might be recorded. 
 
Was changed into: 
…at minimum a yearly telephone call and a 
telephone call at study end (through the 
patient or alternative person designated by 
the patient) will be asked for, to document 
the occurrence of outcome events and vital 
status. If possible, also other AE’s and 
concomitant therapy changes since last visit 
should be recorded. 
Rationale for change 
 
Change 1: Estimated trial duration 
increased due to change of primary 
endpoint. 
Change 2: for clarification. 
 
Section to be changed 
 
Abbreviations 
Description of change 
 
Abbreviations section updated.  
Rationale for change 
 
For clarification  
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: Primary endpoint changed to 
time to the first occurrence of any of the 
following adjudicated components of the 
primary composite endpoint: CV death 
(including fatal stroke and fatal MI), non-
fatal MI (excluding silent MI) or non-fatal 
stroke. 


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Change 2: First key secondary endpoint 
changed to time to the first occurrence of 
any of the following adjudicated 
components of: CV death (including fatal 
stroke and fatal MI), non-fatal MI 
(excluding silent MI), non-fatal stroke or 
hospitalisation for unstable angina pectoris. 
Rationale for change 
 
Change 1, 2: Testing hierarchy revised 
following a unanimous request from the 
trial Academic Steering Committee. 
Section to be changed 
 
3.1 Overall trial design and plan  
Description of change 
 
Change 1: Estimated treatment time 
updated to 432 weeks and duration of 
maintenance phase updated to an estimated 
416 weeks.  
 
Change 2: ...at minimum a yearly telephone 
call and a telephone call at study end will be 
asked for, to document the occurrence of 
outcome events and vital status. If possible, 
also other AE’s and concomitant therapy 
changes since last visit might be recorded. 
 
Was changed into: 
…at minimum a yearly telephone call and a 
telephone call at study end (through the 
patient or alternative person designated by 
the patient) will be asked for, to document 
the occurrence of outcome events and vital 
status. If possible, also other AE’s and 
concomitant therapy changes since last visit 
should be recorded. 
Change 3: Guidance revised on the timing 
of the EOT visit after study stop 
announcement after 631 endpoint events are 
reached.  
Rationale for change 
 
Change 1: Estimated trial duration 
increased due to change of primary 
endpoint. 
 
Change 2: For clarification. 
 


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Change 3: To clarify the respective actions 
to stop the trial when 631 endpoint events 
are reached.  
Section to be changed 
 
3.2 Discussion of trial design, including 
the choice of control group 
Description of change 
 
Estimated trial duration updated to 432 
weeks. 
Rationale for change 
 
Estimated trial duration increased due to 
change of primary endpoint. 
Section to be changed 
 
3.3.1 administrative structure of the trial 
Description of change 
 
Clinical Event Committee was changed in 
Clinical Event Committees. 
Rationale for change 
 
Correction of typographical error 
Section to be changed 
 
3.3.4.1 Removal of individual patients 
Description of change 
 
Change 1:...at minimum a yearly telephone 
call and a telephone call at study end will be 
asked for, to document the occurrence of 
outcome events and vital status. If possible, 
also other AE’s and concomitant therapy 
changes since last visit might be recorded. 
 
Was changed into: 
…at minimum a yearly telephone call and a 
telephone call at study end (through the 
patient or alternative person designated by 
the patient) will be asked for, to document 
the occurrence of outcome events and vital 
status. If possible, also other AE’s and 
concomitant therapy changes since last visit 
should be recorded. 
 
Change 2: See further details in section 4.2 
was added following the last sentence of 
paragraph 5. 
Change 3…Visit 31 (Follow-up) was 
changed into: Visit 33 (Follow-up). 
Rationale for change 
 
Change 1+2: For clarification  
Change 3: Two additional Visits added as 
the estimated trial duration increased due to 
change of primary endpoint. 
Section to be changed 
 
4.1.4 Drug assignment and 
administration of doses for each patient 
Description of change 
 
..IXRS will allocate medication kit numbers 
at each scheduled in-clinic visit (V2 – 


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V29)….At visits 6-29 patients will receive 
one treatment box… 
 
Was changed into: 
..IXRS will allocate medication kit numbers 
at each scheduled in-clinic visit (V2 – 
V31)….At visits 6-31 patients will receive 
one treatment box… 
Rationale for change 
 
Two additional Visits added as the 
estimated trial duration increased due to 
change of primary endpoint. 
Section to be changed 
 
5.1.1 Endpoint(s) off efficacy 
Description of change 
 
Change 1: Primary endpoint changed to 
time to the first occurrence of any of the 
following adjudicated components of the 
primary composite endpoint: CV death 
(including fatal stroke and fatal MI), non-
fatal MI (excluding silent MI) or non-fatal 
stroke. 
 
Change 2: First key secondary endpoint 
changed to time to the first occurrence of 
any of the following adjudicated 
components of: CV death (including fatal 
stroke and fatal MI), non-fatal MI 
(excluding silent MI), non-fatal stroke or 
hospitalisation for unstable angina pectoris. 
Rationale for change 
 
Change 1, 2: Testing hierarchy revised 
following a unanimous request from the 
trial Academic Steering Committee. 
Section to be changed 
 
5.2.2.1 Assessment of adverse events 
Description of change 
 
AESI: the following sentence was omitted 
Documentation should be done on the AESI 
and SAE form.  
Rationale for change 
 
Covered in section 5.2.2.2 adverse event 
and serious adverse event reporting.  
Section to be changed 
 
5.2.2.2 Adverse event and serious adverse 
event reporting 
Description of change 
 
Immediate documentations of events:…. On 
the SAE to the sponsor was changed into: 
…On the SAE form to the sponsor.  
Rationale for change 
 
For clarification  
Section to be changed 
 
5.2.3.2 Clinical chemistry 
Description of change 
 
Visit 32 added to footnote *** 


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Rationale for change 
 
Additional Visits added as the estimated 
trial duration increased due to change of 
primary endpoint. 
Section to be changed 
 
6.2.2 Treatment phase 
Description of change 
 
Change 1:…regularly scheduled 
randomization as specified.. was changed 
into: regularly scheduled Visits as 
specified… 
 
Change 2: The following text was omitted 
either by clinic visits or by phone (refer to 
section 6.2.3) and the following text was 
added: 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 (through the 
patient or alternative person designated by 
the patient) will be required, to document 
the occurrence of outcome events and vital 
status. If possible, also 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. 
 
Change 3:….even if the dose must be down 
titrated was changed into: even if the dose 
must be titrated 
Rationale for change 
 
Change 1: Correction of error. 
 
Change 2: For clarification and consistency 
with section 3. 
 
Change 3: For clarification. 
Section to be changed 
 
6.2.3 End of trial and follow-up period 
Description of change 
 
Change 1: The following text was added: 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 


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investigator must be involved in the 
discussions with the patient regarding a 
withdrawal of consent. 
Change 2: …for end of treatment visit and 
visit 31 (follow-up) was changed into: or 
end of treatment visit and visit 33(follow-
up). 
 
Change 3: Paragraph starting with patient 
who discontinue….removed 
Rationale for change 
 
Change 1: For clarification and consistency 
with section 3. 
Change 2: Two additional Visits added as 
the estimated trial duration increased due to 
change of primary endpoint. 
Change 3: Covered in section 6.2.2 and 
section 3. 
Section to be changed 
 
7.1 STATISTICAL DESIGN - MODEL 
Description of change 
 
Change 1: Estimated trial duration updated 
to 432 weeks. 
Change 2: Primary endpoint changed to 
time to the first occurrence of any of the 
following adjudicated components of the 
primary composite endpoint: CV death 
(including fatal stroke and fatal MI), non-
fatal MI (excluding silent MI) or non-fatal 
stroke. 
Change 3: First key secondary endpoint 
changed to time to the first occurrence of 
any of the following adjudicated 
components of: CV death (including fatal 
stroke and fatal MI), non-fatal MI 
(excluding silent MI), non-fatal stroke or 
hospitalisation for unstable angina pectoris. 
Change 4: List “time to silent MI” 
separately from adjudicated tertiary 
cardiovascular endpoints. 
Rationale for change 
 
Change 1: Estimated trial duration 
increased due to change of primary 
endpoint. 
Change 2,3: Testing hierarchy revised 
following an unanimous request from the 
trial Academic Steering Committee. 


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Change 4: Clarification added, that silent 
MI is not a by adjudication confirmed 
endpoint. 
Section to be changed 
 
7.2 NULL AND ALTERNATIVE 
HYPOTHESES 
Description of change 
 
First key secondary endpoint details 
removed. 
Rationale for change 
 
First key secondary endpoint was changed 
to time to the first occurrence of any of the 
following adjudicated components of: CV 
death (including fatal stroke and fatal MI), 
non-fatal MI (excluding silent MI), non-
fatal stroke or hospitalisation for unstable 
angina pectoris. 
Section to be changed 
 
7.3 PLANNED ANALYSES 
Description of change 
 
Change 1: Protocol violation is considered 
important if it can be expected to have a 
distorting influence on the assessment of the 
primary endpoint and/or first key secondary 
endpoint. 
The example of limited life expectancy (<5 
years) due to various medical conditions) as 
important protocol violations was removed. 
Change 2: 
 
 
Rationale for change 
 
Change 1: Clarification that important 
protocol violations are defined in relation to 
adjudicated outcome events as part of 
primary and first key secondary endpoint.  
The trial Statistical Analysis Plan describes 
all important protocol violations in detail. 
Change 2: 
 
 
 
Section to be changed 
 
7.3.1 Primary analyses 
Description of change 
 
A Bonferroni adjustment will be applied 
after the first DMC interim analysis for 4P-
MACE and the following analyses based on 
3P-MACE. The O’Brien & Fleming alpha-
spending function based on the new overall 
alpha (after Bonferroni adjustment) defines 
the overall significance level for the second 
DMC interim analysis and final analysis. 
Removed sentence, that the Steering 


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Committee will decide on the number of 
interim analyses. 
Rationale for change 
 
The change of the primary endpoint from 
time to first adjudicated event of the 
composite of 4P-MACE to the time to first 
adjudicated event of the composite of 3P-
MACE requires adjustment of the alpha 
level which is addressed via a Bonferroni 
adjustment. 
The number of two interim analyses and the 
number of events required for each of the 
two interim analyses were defined by the 
Steering Committee to be based on 
approximately 190 and 411 primary 
endpoint events. This decision was 
documented in the SC minutes and the 
DMC Charter.  
Section to be changed 
 
7.3.2 Secondary analyses 
Description of change 
 
Chi square test and logistic regression for 
CV endpoints removed. 
Rationale for change 
 
Cardiovascular events will be analysed by a 
Cox proportional hazards model and 
occurrence of events reported with 
frequency and incidence rates. Analyses 
that do not account for the time at risk are 
not required. 
Section to be changed 
 
7.3.4 Interim analyses 
Description of change 
 
A Bonferroni adjustment will be applied 
after the first DMC interim analysis for 4P-
MACE and the following analyses based on 
3P-MACE. The O’Brien & Fleming alpha-
spending function based on the new overall 
alpha (after Bonferroni adjustment) defines 
the allocation of the overall significance 
level for the second interim analysis and 
final analysis. 
Removed sentence, that the Steering 
Committee will decide on the number of 
interim analyses. 
Rationale for change 
 
The change of the primary endpoint from 
time to first adjudicated event of the 
composite of 4P-MACE to the time to first 
adjudicated event of the composite of 3P-
MACE requires adjustment of the alpha 
level which is addressed via a Bonferroni 
adjustment. 


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The number of two interim analyses and the 
number of events required for each of the 
two interim analyses were defined by the 
Steering Committee to be based on 
approximately 190 and 411 primary 
endpoint events. This decision was 
documented in the SC minutes and the 
DMC Charter. 
Section to be changed 
 
7.6 DETERMINATION OF SAMPLE 
SIZE 
Description of change 
 
Change 1: A Bonferroni adjustment will be 
applied between the first DMC interim 
analysis for 4P-MACE and the following 
analyses regarding 3P-MACE. The O’Brien 
& Fleming alpha-spending function based 
on the new overall alpha (after Bonferroni 
adjustment) defines the allocation of the 
overall significance level for the second 
DMC interim analysis and final analysis. 
 
Change 2: Assumed annual event rates 
updated for changed primary endpoint. 
Rationale for change 
 
Change 1: The change of the primary 
endpoint from time to first adjudicated 
event of the composite of 4P-MACE to the 
time to first adjudicated event of the 
composite of 3P-MACE requires 
adjustment of the alpha level which is 
addressed via a Bonferroni adjustment. 
 
Change 2: Lower event rates assumed for 
updated primary endpoint. 
Section to be changed 
 
9.1 Published References 
Description of change 
 
Author of IB omitted and update of 
published references 
Rationale for change 
 
Change in authorship and reflected of 
published references used for the protocol 
revision.  
Section to be changed 
 
10.5 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 


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Rationale for change 
 
Clarified that Silent MI is diagnosed on 
relevant ECG abnormalities, clinical history 
and investigator reporting.  
 

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c02152478-04
BI Trial No.:
1218.74
Title:
A multicentre, international, randomised, parallel group, double 
blind study to evaluate Cardiovascular safety of linagliptin versus 
glimepiride in patients with type 2 diabetes mellitus at high 
cardiovascular risk.
The CAROLINA Trial.
Including Global Protocol Amendments 1-6 [c01618200-19]
Investigational
Product(s):
Linagliptin
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
16 March 2018 REVISED
Version:
Revised
Page 1 of 83
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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................5
2.
LIST OF ABBREVIATIONS ...............................................................6
3.
INTRODUCTION..................................................................................9
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ....10
5.
ENDPOINTS ........................................................................................15
5.1
PRIMARY ENDPOINT ....................................................................................15
5.2
SECONDARY ENDPOINTS............................................................................15
5.2.1
Key secondary endpoints..............................................................................15
5.2.2
(Other) Secondary endpoints .......................................................................16
5.2.2.1 Secondary cardiovascular endpoints ..........................................................16
5.2.2.2 Secondary diabetes related endpoints.........................................................17
6.
GENERAL ANALYSIS DEFINITIONS...........................................25
6.1
TREATMENTS..................................................................................................25
6.1.1
Treatment regimens / study intervals..........................................................25
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................26
6.3
PATIENT SETS ANALYSED..........................................................................31
6.3.1 
Serious non-compliance potentially affecting primary endpoint..............32
6.5
POOLING OF CENTRES ................................................................................36
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................37
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................43
6.7.1 
Baseline...........................................................................................................44
6.7.2 
Time windows for assignment to on-treatment phase ...............................44
6.7.3 
Time windows for assignment to visits in the on-treatment phase...........45
6.8 
CALCULATION OF TIME TO EVENT........................................................48
6.8.1
Start date........................................................................................................48
6.8.2
Date of event...................................................................................................49
6.8.3
Censoring .......................................................................................................49
6.8.4
Definition of lost-to follow-up.......................................................................51
7.
PLANNED ANALYSIS.......................................................................52
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........52


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7.2
CONCOMITANT DISEASES AND MEDICATION ....................................53
7.3
TREATMENT COMPLIANCE .......................................................................54
7.4
PRIMARY ENDPOINT ....................................................................................54
7.4.1 
Primary analysis............................................................................................54
7.4.1.1 Statistical Methods.........................................................................................55
7.4.1.2 Censoring for time to event endpoints for interim and final analyses...........56
7.4.1.3 Testing hierarchy ...........................................................................................56
7.4.1.4 Details on alpha-spending..............................................................................56
7.4.2 
Sensitivity analysis.........................................................................................57
7.4.2.1 Proportional hazards assumption violated.....................................................57
7.4.2.2 General sensitivity analysis ...........................................................................57
 
7.4.4
Interim analysis .............................................................................................59
7.5
SECONDARY ENDPOINTS............................................................................59
7.5.1
Key secondary endpoints..............................................................................59
7.5.2
(Other) Secondary endpoints .......................................................................61
7.5.2.1 Secondary/Tertiary cardiovascular endpoints ............................................61
7.5.2.2 Secondary/Tertiary diabetes related endpoints and UACR........................62
7.5.2.2.1 Continuous diabetes related endpoints (FPG, HbA1c, total cholesterol, 
HDL cholesterol, LDL cholesterol, triglycerides, creatinine, urinary 
albumin, eGFR, weight and UACR) ..........................................................62
7.5.2.2.2 C-peptide, plasma pro-insulin and antibodies ............................................65
7.5.2.2.3 Binary diabetes related endpoints...............................................................65
7.5.2.2.4 Time to and occurrence of antidiabetic rescue therapy ..............................65
7.7
EXTENT OF EXPOSURE................................................................................66
7.8
SAFETY ANALYSIS.........................................................................................67
7.8.1
Adverse events ...............................................................................................67
7.8.1.1
Assignment of AEs to treatments ..............................................................68
7.8.1.2
Analysis of other significant AEs..............................................................69
7.8.1.3
AE summaries............................................................................................69
7.8.1.3.1 Frequency of patients with adverse events................................................69
7.8.1.3.2 Adverse event incidence rates, rate ratio and rate difference....................70
7.8.1.4
AEs of special interest (AESI)...................................................................71
7.8.1.5
Events qualifying for external adjudication by the Clinical Event 
Committee (CEC).......................................................................................72
7.8.1.6
Analysis of hypoglycaemic events ............................................................72
7.8.1.7
Further adverse events...............................................................................73
7.8.1.8
Events qualifying for external adjudication by the Clinical Event 
Committee (CEC) for pancreatic events.....................................................73
7.8.1.9
Events qualifying for external assessment by the Oncologic Assessment 
Committee (oncAC) ...................................................................................74
7.8.2
Laboratory data.............................................................................................74
7.8.3
Vital signs.......................................................................................................79
7.8.4
ECG ................................................................................................................79
7.8.5
Others .............................................................................................................79


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8.
REFERENCES.....................................................................................80
10.
HISTORY TABLE...............................................................................83


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis......................................................25
Table 6.2: 1
Important Protocol Violations.........................................................................27
Table 6.3: 1
Patient sets for analyses...................................................................................32
Table 6.6: 1 
Summary of imputation methods for diabetes related endpoints....................40
Table 6.7.2: 1 
Endpoint specific follow-up time for assignment to active treatment........45
Table 6.7.3: 1 
Time windows for visits for FPG ...............................................................47
Table 6.7.3: 2 
Time windows until visit 6 for e.g. HbA1c and weight .............................48
Table 7.4.2.2: 1 
Overview of analyses on the primary endpoint .....................................58
Table 7.8.2: 1
MDRD staging............................................................................................77
Table 7.8.2: 2
UACR categorisation..................................................................................77
Table 7.8.2: 3 Prognosis of chronic kidney disease by GFR and albuminuria category.........78
Table 10: 1
History table ....................................................................................................83


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis data set
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
AR(1)
first-order autoregressive
ASA
Acetylsalicylic Acid
AST
Aspartate transaminase
ATC
Anatomical-Therapeutic-Chemical
BI
Boehringer Ingelheim
BMI
Body mass index
BRPM
Blinded report planning meeting
CABG
Coronary Artery Bypass Graft
CARE
Clinical data Analysis and Reporting Environment
CEC
Clinical Event Committee
CI
Confidence Interval
CRA
Clinical Research Associate
CRF
Case Report Form
CS
Compound symmetry
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Cardiovascular
DBL
Database Lock
DBP
Diastolic Blood Pressure
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DMC
Data Monitoring Committee
DPP-4
Dipeptidyl peptidase-4
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular filtration rate
EMA
European Medicines Agency
EOT
End of treatment


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Term
Definition / description
EX
Exclusion criterion
FAS
Full analysis set
FPG
Fasting Plasma Glucose
GAD
Glutamic acid decarboxylase
HbA1c
Glycosylated haemoglobin
HDL
High Density Lipoprotein
HR
Hazard Ratio
IA-2
Tyrosine phosphatase-like Insulinoma Antigen 2
IAA
Insulin Auto Antibodies
IC
Informed Consent
ICA
Islet Cell Autoantibody
ICH
International Conference on Harmonisation
IDEA
International Document management and Electronic Archiving system
IN
Inclusion criterion
IPV
Important Protocol Violation
IRC
Independent Review Committee
ITT
Intention-to-treat
IXRS
Interactive Voice and Web-based Response System
KM
Kaplan Meier
LADA
Latent autoimmune diabetes of adults
LDL
Low Density Lipoprotein
LOCF
Last observation carried forward
MACE
Major Adverse Cardiovascular Event
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MMRM
Mixed Model Repeated Measures 
mRS
modified Rankin Scale
N
Number of patients
NCF
Non completers considered failure
O*C
Oracle Clinical
OR
Odds Ratio
OS
On treatment set


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Term
Definition / description
PCI
Percutaneous Coronary Intervention
PPS
Per protocol set
PR
Pulse Rate
PT
Preferred term
PV
Protocol violation
RAGe
Report Appendix Generator system
REML
Restricted Maximum Likelihood
Q1
Lower quartile
Q3
Upper quartile
SA
Statistical Appendix
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard deviation
SE
Standard error
SMQ
Standardised MedDRA query
SNC
Serious Non-compliance
SOC
System Organ Class
SOP
Standard Operating Procedure
SU
Sulfonylurea
TIA
Transient ischemic attack
TOC
Table of contents
TS
Treated set
TSAP
Trial statistical analysis plan
UACR
Urine albumine to creatinine ratio
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary
3P-MACE/
4P-MACE
3 Point- Major Adverse Cardiovascular Event, 4 Point- Major Adverse 
Cardiovascular Event


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3.
INTRODUCTION
As per ICH E9 (9), 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 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 study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomisation.
CTP: The primary objective is to demonstrate non-inferiority (by means of comparing the
upper limit of a two-sided (1-2*alpha)*100% confidence interval with the non-inferiority
margin of 1.3) of treatment with linagliptin in comparison to glimepiride (as monotherapy or 
as add-on therapy) with respect to time to first occurrence of any of the adjudicated 
components of the primary composite endpoint (i.e. cardiovascular death, non-fatal stroke, 
or non-fatal myocardial infarction (excluding silent MI)) in patients with type 2 diabetes 
mellitus. If the noninferiority hypothesis with margin 1.3 has revealed a significant result, 
then secondly, the primary composite endpoint will be tested with a superiority hypothesis. If 
the superiority test has revealed a significant result, then thirdly the first key secondary 
endpoint of time to first occurrence of any of the adjudicated components of cardiovascular 
death, non-fatal stroke, non-fatal myocardial infarction (excluding silent MI) or 
hospitalisation for unstable angina pectoris will be tested hierarchically with a superiority 
hypothesis. If the test of the first key secondary hypothesis has revealed a significant result, 
then fourthly the second key secondary endpoint will be tested hierarchically. If the test of the 
second key secondary hypothesis has revealed a significant result, then fifthly the third key 
secondary endpoint will be tested hierarchically.
Other objectives are to compare HbA1c change from baseline, the incidence of
hypoglycaemia, weight gain and treatment sustainability defined as the proportion of
patients that are on study treatment at study end without need for rescue medication, that
at Final Visit maintain glycaemic control (HbA1c ≤ 7.0%).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
In the following the changes to the CTP and additional analyses are described: 
 
 
 
 
4. For the first key secondary endpoint another sensitivity analysis on the 30DTS will be
performed considering events until earliest date of treatment stop + 30 days or end of 
observation.
5. For the endpoints of occurrence of 4P-MACE and 3P-MACE sensitivity analysis on the 
FAS, PPS and 30DTS will be performed. For these analyses events until earliest date of 
treatment stop + 30 days or end of observation will be considered.
 
 
 
 
 
 
 
 
 
7. The time to overall mortality will be defined as the time to death, not the date of onset of 
a fatal event. 
8. The eGFR of patients from Japan that are of Asian Race will be calculated as described in 
Section 7.8.2.


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9.
 
 
Further aspects are clarified as follows:
1. In general rescue medication is not only considered during study medication intake. 
Rescue medication is defined as any dose increase of anti-diabetic background 
medication or introduction of new anti-diabetic treatment after first study medication 
intake until the time as specified in Section 6.8. Short term use of any insulin- up to two 
weeks - will not count as rescue medication. 
2. The endpoint of change from baseline to final visit is to be investigated for urinary 
albumin (secondary diabetes related endpoints).
Any transition in albuminuria classes will be investigated based on UACR, in order to 
allow correction of albumin for creatinine concentration.
 
 
4. The censoring rules including those for 4P-MACE are described in detail in Section 6.8.3. 
In the following the changes and additional analyses as compared to the first signed Trial
Statistical Analysis Plan from 22 JAN 2014 are described. This includes any changes based 
on clinical trial protocol amendments 5 and 6.
1.
Based on the clinical trial protocol amendment 6 the definitions of the primary and 
first key secondary endpoints were updated throughout this document. 
Details on control of the type I error are defined in Section 7.4.1.
Following the exchange of the primary and first key secondary endpoint in CTP 
amendment 6, and the first interim analysis performed for time to first 
4P-MACE, the allocation of alpha for the second interim analysis and the final 
analysis is defined in Section 7.4.1.
 
 


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Date of onset of silent MI and censoring of patients without silent MI was updated 
accordingly in Section 6.8.2 and 6.8.3.
 
 Derivation of time to event and censoring was 
updated accordingly in Section 6.8.1, 6.8.2 and 6.8.3. The approach for the analyses 
of these endpoints was defined in Section 7.6.
5.
Definition of important protocol violations in Table 6.2: 1 was updated. Criteria A1.2, 
A2.2, A2.3, A2.5, A2.6, A2.10 from initial TSAP have been removed as IPVs leading 
to exclusion from the PPS, as violations of these entry criteria are not expected to 
influence primary and key secondary CV outcome. 
IPV criterion C3.1 from initial TSAP was removed, as sensitivity analyses with 
respect to study drug exposure are addressed via analyses of the 30DTS and the ‘on-
treatment’ analyses on the FAS.
IPV criterion D1.1 from initial TSAP was revised to allow for a tolerance window of 
35 days (i.e. first planned visit following randomisation at 28 days 
+ 7 days visit window) to stop the use of glinide or SU when taken at baseline.
6.
The definition of the 30-days-treatment set in Section 6.3 was updated to require a 
cumulative exposure of at least 30 days to study drug.
9.
Section 6.7.3 was updated to include assignment of follow-up measurements
10.
Details on censoring with regard to the date of IC withdrawal were updated to allow 
use of information as allowed by local law. Date of PCI/CABG was added into
derivation of censoring date.
11.
Sensitivity analyses considering events until 7 days after last permanent treatment 
discontinuation or date of last documented study visit, whichever comes first, were 
added for time to first 3P-MACE and time to first 4P-MACE in 
Section 7.4.2 and 7.5.1. 
12.
Addition of cumulative incidence function for adjudicated CV endpoints accounting 
for competing risk.
 
 
14.
For all adjudicated CV endpoints including all-cause mortality additional sensitivity 
analysis will be performed on the FAS considering events until 
30 days after last permanent treatment discontinuation or date of last documented 
study visit, whichever comes first.
15.
OC analyses were added for total cholesterol, HDL cholesterol, LDL cholesterol, 
triglycerides, creatinine, urinary albumin, UACR, eGFR and weight in 
Section 7.5.2.2.1.
MMRM analyses following the ITT approach (OC-ALL) were added for
secondary/tertiary diabetes related endpoints.
Analysis of follow-up measurements was added.


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16.
Additional approaches for the investigation of adverse events were added in Section 
7.8.1.1 and 7.8.1.3.2.
17.
Further details including serious adverse events and adverse events leading to 
discontinuation will be presented for the adverse events of special interest as defined 
in Section 7.8.1.4. Further adverse events as outlined in Section 7.8.1.7 will be 
analysed.
18.
Analysis of adjudicated pancreatic events was added in Section 7.8.1.8.
19.
Analysis of assessment results for cancer events was added in Section 7.8.1.9.
20.
A shift table based on KDIGO categories as defined in Section 7.8.2 will be prepared. 
Investigation of amylase and lipase was added in Section 7.8.2.
21.
Vital signs will be analysed as a continuous parameters only as outlined in 
Section 7.8.3. Heart rate as defined in Section 7.8.4 will be analysed in addition.
22.
For the analyses of first disabling or fatal stroke (based on the Modified Rankin 
scale), a supporting analysis will be performed, with no data imputation 
(Section 7.8.5).
Below all changes since the Trial Statistical Analysis Plan was signed on 11 August 2016 are 
listed. These include changes based on FDA feedback for CARMELINA (1218.22) as well as 
clarifications regarding analysis specifications added to the text.
1.
To align the definitions with CARMELINA (1218.22), all endpoints will be 
analysed on treated set (TS), which means no change in content as outlined below.
Patients considered for FAS – the previously defined primary population – need to be 
randomised and have received at least one dose of study medication. Patients 
considered for TS have received at last one dose of study medication (Section 6.3). 
Since all patients that had treatment  assigned before IXRS was called are considered 
as forced randomised (Section 6.1.1) the FAS population and TS population of this 
study are identical.
2.
Population 30-days-treatment set (30DTS) is re-named on-treatment set (OS) to align 
terminology with CARMELINA (Section 6.3).
3.
Based on FDA feedback for CARMELINA an additional censoring timepoint +0 is 
added for analysis. Censoring rules aligned with CARMELINA based on FDA
advise (Section 6.8.3). Sensitivity analysis for 3P-MACE and 4P-MACE will be 
conducted on TS+0.
 
 
6.
Sensitivity analysis for diabetes related endpoints specified for parameters HbA1c, 
FPG and weight. MMRM model up to week xxx will be applied (Section 7.5.2.2.1).
7.
Arthralgia and bullous conditions are considered as safety endpoints (further adverse 
events) only. Since the TSAP was signed in August 2016, both medical concepts have 
been further investigated and assessed on project level. In accordance with the trial 
protocol, arthralgia and bullous conditions are no adverse events of special interest 
(AESI).


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8.
Definition of medical concept for immunological reaction, malignancy and bullous 
condition added (Section 7.8.1.7).
 
 
 
 
 


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5.
ENDPOINTS
The study is set up with prospective adjudication of all cardiovascular, cerebrovascular and
pancreatic trigger events. 
The prospectively defined adjudication process will ensure the assessment of 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.
The primary and first key secondary endpoints are based on adjudicated (i.e. CEC confirmed) 
events.
Additionally, a separate independent, blinded, external committee will be set up for 
adjudication of pancreatic events. The adjudication process for these events will be clarified 
in another charter.
For all time to event analyses, the time to the (first) occurrence of an endpoint will be 
computed as described in Section 6.8.
5.1
PRIMARY ENDPOINT
The primary endpoint in this trial is time to the first occurrence of any of the following CEC 
confirmed adjudicated components of the primary composite endpoint: CV death (including 
fatal stroke and fatal MI), non-fatal MI (excluding silent MI),or non-fatal stroke.
This endpoint will be further referred to also as time to first 3-Point-MACE (3P-MACE).
To clarify: Silent MI is not an endpoint to be confirmed by adjudication. Any investigator 
reported silent MI that is adjudicated and confirmed as being an MI by the CEC will be 
counted as MI.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
The key secondary efficacy endpoints are:

time to the first occurrence of any of the following CEC confirmed adjudicated 
components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding 
silent MI), non-fatal stroke or hospitalisation for unstable angina pectoris
This endpoint will be further referred to also as time to first 4-Point-MACE (4P-MACE).
To clarify: Silent MI is not an endpoint to be confirmed by adjudication. Any investigator 
reported silent MI that is adjudicated and confirmed as being an MI by the CEC will be 
counted as MI.

composite endpoint of (treatment sustainability defined as the proportion of patients that 
are on study treatment at study end, that at Final Visit maintain glycaemic control 
(HbA1c ≤ 7.0%) without need for rescue medication (between end of titration [Visit 6] 


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and Final Visit) and patients without any moderate/severe hypoglycaemic episodes 
(between Visit 6 and Final Visit) and without > 2% weight gain at Final Visit (between 
Visit 6 and Final Visit))
(A patient fulfilling all these criteria is considered a ‘responder’.)

composite endpoint of (treatment sustainability defined as the proportion of patients that 
are on study treatment at study end, that at Final Visit maintain glycaemic control 
(HbA1c ≤ 7.0%) without need for rescue medication (between Visit 6 and Final Visit) 
and patients without > 2% weight gain at Final Visit (between Visit 6 and Final Visit))
(A patient fulfilling all these criteria is considered a ‘responder’.)
Study end/ Final visit for second and third key secondary endpoints
Please refer to Section 7.5.1 for the derivation.
Rescue medication in general:
Rescue medication is defined as any dose increase of anti-diabetic background medication (as 
compared to one day prior to first drug administration) or introduction of new anti-diabetic 
treatment, for insulin any new onset and intake for at least 15 days, starting from the date of 
first drug administration until the time as specified in Section 6.8.3.
In general, any therapy with the start date equal to the date of first trial drug intake is 
considered as being taken after first trial drug intake.
If a patient switches to or adds protocol defined background medication at or after the date of 
first trial drug intake, this will be considered rescue medication. (The same applies for a 
change from metformin or alpha-glucosidase inhibitor to metformin + alpha-glucosidase 
inhibitor.)
Moderate and severe hypoglycaemic episodes are defined as follows:
A moderate hypoglycaemic event is defined as documented symptomatic hypoglycaemia 
with plasma glucose concentration ≤ 70 mg/dL, without the need for external assistance.
A severe hypoglycaemic event is defined as documented hypoglycaemic episode requiring
assistance of another person to actively administer carbohydrate, glucagon or other 
resuscitative actions need for external assistance.
5.2.2
(Other) Secondary endpoints
5.2.2.1 Secondary cardiovascular endpoints
Secondary CV endpoints are:

occurrence of at least one of the following CEC confirmed adjudicated components of 
CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI), non-


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fatal stroke and hospitalisation for unstable angina pectoris
This endpoint will be further referred to also as ‘occurrence of 4P-MACE’.

occurrence of at least one of the following CEC confirmed adjudicated components of 
CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI) and 
non-fatal stroke 
This endpoint will be further referred to also as ‘occurrence of 3P-MACE’.

occurrence of and time to the first occurrence of any of the following components of the 
composite endpoint of all CEC confirmed adjudicated events of:
- CV death (including fatal stroke and fatal MI)
- non-fatal MI
- non-fatal stroke
- hospitalisation for unstable angina pectoris
- TIA
- hospitalisation for congestive* heart failure
- hospitalisation for coronary revascularization procedures (CABG, PCI)
*refers to all heart failure events as adjudicated and confirmed by CEC and will
be referred to as ‘heart failure’ in the CTR
5.2.2.2 Secondary diabetes related endpoints
Secondary diabetes related endpoints include change from baseline to Final Visit in the
following laboratory parameters:

HbA1c

Fasting plasma glucose

Total cholesterol

LDL cholesterol

HDL cholesterol

Triglycerides

Creatinine

eGFR (MDRD formula)

Urinary albumin
In addition any transition in albuminuria classes will be investigated by using UACR. Please 
refer to Table 7.8.2: 2 for the definition of classes.
For these endpoints, the final visit value refers to the last value obtained on treatment. 
Parameter-specific on-treatment phases are defined according to Section 6.7.2. The intake of
rescue medication is considered as described in Section 5.2.1.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
The following treatments are investigated in this study:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
A
Linagliptin tablet 5 mg / Placebo Glimepiride capsule 
1-4 mg
Lina
B
Glimepiride capsule 1-4 mg / Placebo Linagliptin tablet 
5 mg
Glim
6.1.1
Treatment regimens / study intervals
The treatment setup in the O*C database will contain the following study intervals: screening 
(starting with the date of informed consent at 0:00 h), run-in (starting with the date of run-in 
medication, time 0:00 h), linagliptin and glimepiride (each of the treatments starting with the 
date and time of first drug administration), off-treatment (starting with any date and time of 
last drug administration + 1 day, time 0:00 h, if the study drug is re-started afterwards), post-
treatment (starting with the last date and time of last drug administration + 1 day,
time 0:00 h), and post-study (starting with the date of trial completion + 1 day, time 0:00 h). 
During the study treatment phase, patients are allowed to go off study drug and subsequently 
re-start study drug.  This may happen not at all or repeatedly for a given patient, as this study 
is expected to go on for a number of years. This is reflected by the off-treatment phase. 
Further, a patient might die or discontinue from the study.
If the date of last drug administration is identical to the date of trial completion, post-
treatment starts with the date of trial completion + 1 day and post-study period starts with the 
date of trial completion + 2 days, both at time 0:00 h. 
For specific safety and efficacy parameters the duration of the on-treatment phase is given in 
Section 6.7.2.
For detailed information on the handling of the treatment in the O*C views and the definition 
of analysis treatments refer to Technical TSAP ADS plan.
A summary table will display the actual dose of glimepiride at the different visits, including 
the number of patients on each dose and the mean, SD, median and mode of dose per visit. 
However, none of the treatment comparisons will take into account the actual doses of 
glimepiride, only the treatment groups ‘glimepiride’and ‘linagliptin’ will be displayed.
Patients will be analysed as randomised for all analyses (safety and efficacy). 
If the Interactive Voice and Web-based Response System (IXRS)-assigned study medication 
is not available at the site, a forced randomisation will occur, and the IXRS will assign a 


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treatment that is available at the site. Also, if a site assigns treatment to a patient before 
calling the IXRS, this is considered a forced randomisation. In both cases, that patient will 
receive the same treatment for the remainder of the trial.
(If a patient erroneously receives the wrong trial drug, patients are asked to return to the site 
and dispensed correct drug as soon as possible.)
6.2
IMPORTANT PROTOCOL VIOLATIONS
Data discrepancies and deviations from the CTP will be identified for all patients randomised 
and/or treated. 
A protocol violation (PV) is important, if it affects the rights or safety of the study patients or 
if it can potentially influence the primary and/or key secondary outcome measures for the 
respective patients in a way that is neither negligible nor in accordance with the study 
objectives. 
This second category of important PV forms the basis for the decision of whether a patient 
belongs to an analysis set. 
The following table contains the categories which are considered to be important protocol
violations in this trial. If the data show other important PVs, this table will be supplemented
accordingly, latest at the BRPM.
The important PVs will be described in the CTR. A listing of patients with medication code 
broken will be provided, although this is not defined as IPV.


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Table 6.2: 1
Important Protocol Violations
Category 
/ Code
Description
Comment/Example
Affects 
rights or
safety 
(R/S) or 
primary/
key 
secondary 
outcome 
(E)
Exclud
ed 
from
A
Entrance Criteria 
Not Met
Inclusion criteria 
violated
A1.1
No type 2 diabetes
Inclusion criterion IN1 ticked 
„No“
E
PPS
Exclusion criteria 
violated
A2.1
Type I diabetes
Exclusion criterion  EX1 ticked 
„Yes“
E
PPS
A2.4
Preplanned planned 
coronary artery re-
vascularization 
(PCI, CABG)
Exclusion criterion  EX7 ticked 
„Yes“
E
PPS
A2.7
Congestive heart 
failure of NYHA 
class III or IV
Exclusion criterion  EX10 ticked 
„Yes“
E
PPS
A2.8
Specific exclusion 
criterion for 
premenopausal 
women violated
Exclusion criterion  EX17  ticked 
„Yes“ 
R/S
None
A2.9
Patient considered 
unreliable by the 
investigator for safe  
participation in the 
study
Exclusion criterion  EX18 ticked 
„Yes“ 
E
PPS


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Table 6.2: 1 (cont’d.)
Important Protocol Violations
Category 
/ Code
Description
Comment/Example
Affects
rights or
safety 
(R/S) or 
primary/
key 
secondary 
outcome 
(E)
Exclud
ed 
from
B
Informed Consent
B1
Informed consent 
not available
Inclusion criterion  IN6 ticked 
„No“ 
or
Date of informed consent 
missing
or
No signature on patient’s 
“Declaration of Informed 
Consent” (to be identified by 
CRA)
E, R/S
TS, 
OS, 
PPS, 
Screen
ed 
patients
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 1a/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
TS, 
OS, 
PPS


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Table 6.2: 1 (cont’d.)
Important Protocol Violations
Category 
/ Code
Description
Comment/Example
Affects 
rights or
safety 
(R/S) or 
primary/
key 
secondary 
outcome 
(E)
Exclud
ed 
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 of a patient.
This is identified by the 
medication kit number recorded 
in eCRF as well as the 
medication kit number as 
assigned by IXRS.
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 
calling IXRS
Date of randomisation call after 
date of study drug intake at 
visit 2 
E
PPS
C3
Non-compliance
C3.2
Non-compliance 
with criteria for 
removal from study 
medication
This includes only the following 
case: although a patient is 
pregnant, she is treated. A 
missing pregnancy test does not 
qualify as IPV.
R/S
None


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Table 6.2: 1 (cont’d.)
Important Protocol Violations
Category 
/ Code
Description
Comment/Example
Affects 
rights or 
safety 
(R/S) or 
primary/
key 
secondary 
outcome 
(E)
Exclud
ed 
from
D
Concomitant 
Medication
D1
Improper 
medication 
washout
D1.1
Glinide or SU not 
stopped until 35 
days after first 
study drug intake 
For patients on SU/glinide at 
baseline: Date of termination of 
glinide or SU > Date of first trial 
drug intake + 35 days
E
PPS
D2
Prohibited 
medication use 
during the 
treatment period of 
the trial
Not applicable.
D3
Mandatory 
medication not 
taken
Not applicable.
E
Missing data
Not applicable.
F
Incorrect timing
Not applicable.
G
Trial specific 
protocol violations
G1.1
Previous 
participation within 
this study
E, R/S
PPS
G1.2
Serious non-
compliance 
potentially 
affecting primary 
endpoint*
E, R/S
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

Treated set (TS):
All patients treated with at least one dose of study drug. The TS is the basis for all 
efficacy and safety analyses.

Per protocol set (PPS):
Patients included in the TS who have important protocol violations will be excluded from 
the PPS. A protocol violation will be considered important if it can be expected to have a 
distorting influence on the assessment of the primary endpoint and/or key secondary 
endpoints.

On-treatment set (OS):
The 30-days-treatment set will include all randomised patients with a minimum treatment 
duration of 30 days. It is used for sensitivity analysis.
The time from last permanent treatment stop (excluding reported treatment gaps) minus 
first drug intake + 1 day has to be equal or greater than 30 days to qualify a patient to be 
included in this analysis set.
The following table defines for each planned analysis, which patient set is to be used.


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Table 6.3: 1
Patient sets for analyses
Patient set
Endpoint
TS
PPS
OS
Primary/Key secondary endpoints
X
X*
X*
Occurrence of 4P-MACE, 3P-
MACE
X
X*
X*
Occurrence of and time to the first 
occurrence of composite endpoint of 
all CEC confirmed adjudicated 
events/ Tertiary CV endpoints/ 
non-CV death
X
Secondary/Tertiary diabetes related 
endpoints
X
Adverse events, safety laboratory, 
vital signs, hypoglycaemia related 
endpoints
X
Other endpoints not mentioned 
above (excluding adverse events, 
safety laboratory, vital signs, 
hypoglycaemia related endpoints, 
non-CV death)
X
Demographic/baseline 
characteristics
X
Important PVs
X
Disposition is based on enrolled (defined as patients with signed informed consent), randomised and treated patients. Patient
analysis sets are displayed on all randomised patients.
* Sensitivity analysis
Note that the number of patients with available data for an endpoint may differ. For details, 
see section “Handling of missing data”.
6.3.1 
Serious non-compliance potentially affecting primary endpoint
If an individual site is closed for serious non-compliance (SNC), any decisions regarding the 
use of the data will be made as detailed in (6) before unblinding and documented separately. 


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Further, any decisions with respect to inclusion/exclusion from the PPS will be documented 
separately.
The analysis of data from patients who participated at more than one investigator site in this 
study will be described in a separate document.


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6.5
POOLING OF CENTRES
As stated in the CTP, no centre effect is included into the model, as the centre size is usually 
expected to be rather small.
Furthermore, due to the anticipated low event rate a sufficient number of events per centre for 
the analysis of a centre effect and a centre by treatment interaction are not expected. 


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A pooling of centres is not planned; primary and key secondary endpoints will be explored by 
geographical region only.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Every effort will be made to collect data as complete as possible. Missing data will be 
handled as outlined below.
For time to event analysis, patients who do not have a specific event will be censored (for 
details, refer to Section 6.8).
Different methods will be used to handle missing data for diabetes related endpoints of this 
trial. The following paragraphs outline the general approach. Refer to Table 6.6: 1 below for 
more details.
Observed cases (OC) 
Only the available data that were observed while patients were on study medication (defined 
as time from first drug intake until last permanent treatment stop date plus the endpoint 
specific follow-up time) will be considered. Missing data will not be replaced. Any values 
taken after rescue medication intake will be set to missing.
Observed cases – Rescue observed cases (OC-ROC) 
Only the available data that were observed while patients were on study medication (defined 
as time from first drug intake until last permanent treatment stop date plus the endpoint 
specific follow-up time) will be considered. Missing data will not be replaced. Any values 
taken after rescue medication intake will be kept.
Observed cases - ALL (OC-ALL) 
All available data will be considered, including values obtained on treatment and post-
treatment. Missing data will not be replaced. Any values taken after rescue medication intake 
will be kept.
Last observation carried forward (LOCF)
Any values taken after rescue medication intake will be set to missing.
The last observed on-treatment value (within the time window from first drug intake until last 
permanent treatment stop date plus the endpoint specific follow-up time) will be carried 
forward, whether or not it is selected/picked as the value for the respective previous week (if
multiple measurements were performed within a time window for a visit, as described in 
Section 6.7.3). That means, for patients receiving rescue therapy the last on-treatment 
measurement prior to the intake of rescue therapy will be carried forward.
Missing values before baseline will not be imputed. 


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One missing value within a course of measurements on treatment will be interpolated based 
on the last observed value before the missing visit and the first observed value after the 
missing visit. 
(This is independent from the selection of a value as the picked visit value to be used in the 
descriptive analysis by week, as described in Section 6.7.3).
Interpolation will be done according to the formula described below. Let:
D0 = 
date of a visit with a missing value for an endpoint;
D1 = 
date of the next visit, with endpoint value non-missing, after the visit with missing 
value;
D-1 = date of the previous visit, with endpoint value non-missing, before the visit with
missing value;
Ei = 
endpoint values for visits D-1, D0, D1 for i= -1, 0 and 1.
Then the missing value will be interpolated as:












1-
1
1-
0
1-
1
1-
0
D
D
D
D
)
E
E
(
E
E
Replacement of missing values will be performed for all weeks up to the last planned week 
that could have been reached by a patient, based on individual randomisation into the trial. 
Refer to Section 7.5.1 for the definition of this planned final visit.
In general baseline results will not be carried forward in case of missing on-treatment values, 
but can be used for interpolation. 
Only, if a patient receives rescue therapy before the first available on-treatment HbA1c 
measurement, the HbA1c baseline value will be carried forward. 
For all other parameters, except HbA1c, no baseline values will be used to replace post 
rescue measurements.
All values documented after last permanent study treatment stop will be set to missing for the 
analysis; instead, values derived by on-treatment LOCF will be analysed. That means, post-
treatment values following the last permanent study treatment stop will not be considered, not
even for interpolation.
Last observation carried forward – Rescue observed cases (LOCF-ROC)
Any values taken after rescue medication intake will be kept. LOCF (as described above) will 
be applied thereafter.
The following table provides an overview of the different approaches.


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Last observation carried forward - ALL (LOCF-ALL)
All available data will be considered, including values obtained on treatment and post-
treatment. Any values taken after rescue medication intake will be kept.
Missing values will be replaced by LOCF (including interpolation for a missing value within 
a course of measurements).


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Table 6.6: 1 
Summary of imputation methods for diabetes related endpoints
Imputation 
method
Endpoint
Handling of missing values
Handling of values after 
rescue therapy
OC
Continuous 
endpoints
No imputation
Excluded (considered  
missing)
LOCF
HbA1c (at each 
visit and change 
from baseline)
Missing values following 
the last on-treatment value
are replaced by the last on-
treatment value. 
Missing values with 
subsequently available on-
treatment values are 
imputed by interpolation. 
Baseline values are not 
carried forward, but will be 
used in interpolation.
Values after the start of 
rescue therapy are 
replaced by the last 
available on-treatment 
measurement. 
If no on-treatment HbA1c 
measurement prior to 
rescue therapy is available 
baseline values are carried 
forward.  
Other continuous  
endpoints
As for HbA1c.
Values after the start of 
rescue therapy are 
replaced by the last 
available on-treatment 
measurement. 
If no on-treatment  
measurement prior to 
rescue therapy is available 
baseline values are not 
carried forward and 
consequently, in this case 
values in the LOCF 
analysis are missing.   
OC-ROC
Continuous 
endpoints
No imputation
Included 
LOCF-
ROC
All continuous 
endpoints
As for LOCF of HbA1c.
Included 
Pro-insulin, C-peptide, antibodies
Only patients with available baseline values will be presented descriptively. Missing values 
will not be replaced.


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Binary key secondary endpoints and binary tertiary diabetes related endpoints 
Binary diabetes related endpoints including the restriction as of being on treatment
If a patient was off-drug before trial stop, without re-start, or already died prior to regular 
completion, the patient will be handled as non-completers considered failure (NCF). 
For further details refer to Section 7.5.1.
Binary diabetes related endpoints including HbA1c and/or weight
If a patient did not permanently and prematurely discontinue from treatment and has a 
missing value of HbA1c and/or weight at the last on-treatment visit, the missing value will be 
imputed by LOCF-ROC (weight)/LOCF (HbA1c).
If a patient has a missing value for weight at week 16 (corresponding to visit 6), the latest 
value before the week 16 window start will be used. 
For the sensitivity analysis of the second and third key secondary endpoints on the OS
patients who prematurely discontinue study treatment will not be counted as non-responders. 
Instead, their last on-treatment value will be used. 
Missing dates and times
Adverse event data and non-fatal outcome events
Missing or incomplete AE dates are imputed according to BI standards (see DM&SM 
“Handling of missing and incomplete AE dates”).(1)
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.
Missing information on the date of first administration of trial drug
If a patient was randomised, but the date of first drug administration is missing, the date of 
the first drug administration will be set to the date of randomisation. If the date of first 
administration is partially missing with the month and year present, the day will be set to the 
date of randomisation, if randomisation was in the same month. 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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Missing information on the date of last administration of trial drug
If this date is missing, it will be imputed by the date of the respective visit. 
If the date is incomplete with only month and year and the respective visit date is missing, the 
date of last drug administration will be imputed by the last day of this month. If this would be 
later than the date of trial completion, then the date of trial completion will be used for 
imputation.
If a patient is lost-to-follow up, no date of last drug administration is reported and the date of 
the respective visit is not available, the date of last drug administration is set as the date of 
trial completion.
For a patient who dies in the treatment phase with no information on the date of last drug 
administration, the date 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 6.1.1.
If after imputation, the date of trial completion is before the date of last drug administration, 
the start of the post-study period is defined as the maximum of trial completion +1 day, the 
date of the last visit +1 day and the start of the post-treatment period+1 day.
Missing information on other dates of administration of trial drug (excluding first and last 
administration)
A missing date 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 the documented month is later than the month of the visit date, the day 
will be imputed by the 1st of the month.
Missing information on date of randomisation
If the date of randomisation differs between IXRS and eCRF, the randomisation date as in 
IXRS will be used. If the date of randomisation is missing in the eCRF, it will be imputed by 
the date obtained from IXRS.
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 the midpoint of the possible interval will be
used. That means, 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.


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Missing date of trial completion (=last contact or date of death)
If the date is completely missing the following rules will be applied:
If a patient did not die (no corresponding vital status and/or adverse event information), the 
date of trial completion will be imputed by the last date the patient was known to be alive.
If a patient died and has not withdrawn consent, this date will be imputed by the date of 
death.
If a patient has withdrawn informed consent, this date will be imputed by the date of IC 
withdrawal.
If the date is incomplete with only month and year reported, the date will be imputed by the 
first day of this month. 
Exception:
If the date last known to be alive, or respectively date of IC withdrawal is after the imputed 
date, the date of trial completion is to be imputed by this date.
If a patient died and has not withdrawn consent and the date of death is known, the date of 
trial completion will be imputed by the date of death.
Missing onset time of hypoglycaemia/ missing plasma concentration
If onset times are available for hypoglycaemic events then those events are only considered 
as on-treatment, if the onset is at or after the time of first drug administration. Missing onset 
times on the day of first drug administration will be imputed as the time of the start of drug 
administration and those hypoglycaemias will be counted as on treatment. Missing onset 
times on other days will be imputed as 0:00. 
If a patient has multiple hypoglyceamic episodes and some of them have missing plasma 
glucose values, those with missing values will be excluded from the derivation of the 
minimum glucose level (worst episode).
Laboratory data
Missing safety laboratory data will not be replaced.
Laboratory data outside the limits of quantification
Biomarker measurements of HbA1c, fasting plasma glucose, pro-insulin and c-peptide below 
the limit of quantification will be imputed by 2/3 times the lower limit of quantification for 
analysis. Values above the upper limit of quantification will be replaced by 1.5 times the 
upper limit of quantification. 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The actual number of visits that a patient attends depends on when the patient gave informed 
consent (randomisation period: Dec, 2010 to Dec, 2012).


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6.7.1 
Baseline
With regard to efficacy and safety endpoints, the term "baseline" refers to the last 
observed/available measurement prior to administration of any randomised study medication. 
A missing baseline value at the randomisation (Visit 2) may be replaced by a value at the 
beginning of the placebo run-in period (Visit 1b). 
The following rule applies to baseline laboratory and ECG measurements, if visit and 
date/time of lab/ECG sample is not in a corresponding sequence (i.e. earlier date/time 
documented for a later visit):
If such a discrepancy occurs before first study medication intake, then the observations are 
sorted by date, time and visit and the last observation up to and including the time of the first 
administration of study drug is selected as baseline value for analyses.
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 HbA1c, FPG, triglycerides, proinsulin, C-peptide and antibodies: the measurement 
will not be considered as baseline
b) For total cholesterol, HDL cholesterol, LDL cholesterol, creatinine, eGFR, urinary 
albumin, UACR and all safety 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 study drug 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 study drug
will be considered on-treatment values if they have been obtained up to the end of the 
parameter-specific follow-up period as defined in Table 6.7.2: 1: they will be assigned to the 
randomised study drug for analyses. 
Measurements taken after the end of the follow-up period will be considered post-treatment 
values.


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Table 6.7.2: 1 
Endpoint specific follow-up time for assignment to active treatment
Endpoint
Last day of assignment to treatment
(days after study drug stop date)
HbA1c 
7
FPG
1
Body weight
7
Adverse events 
7
Asymptomatic hypoglycaemia, that is not 
considered as adverse events
7
Laboratory measurements including eGFR 
and UACR
7
Vital signs
7
Waist circumference
7
6.7.3 
Time windows for assignment to visits in the on-treatment phase
Analyses by study visit are performed to assess the effects of treatment over time. Planned
measurements are not always taken on the exact day or time as planned in the protocol. 
To be able to use measurements in analyses over time, time windows are defined to also
assign measurements deviating from the planned schedule to a study visit.
Measurements deviating from the planned visit schedule will be allocated to the planned visit
on the basis of the actual number of days on treatment (defined as (date of 
measurement – treatment start date + 1)). 
Pre-treatment values will be assigned to a visit according to the nominal visit number as 
recorded on the eCRF or as provided by e.g. the laboratory.
On-treatment measurements of HbA1c, FPG, weight, Total cholesterol, LDL cholesterol,
HDL cholesterol, Triglycerides, Creatinine, eGFR, urinary albumin, UACR, vital signs and
waist circumference will be assigned to visits based on time windows around the planned
visit dates. 
These time windows are defined based on the planned number of days after the date of first
administration of study drug (Visit 2).
The midpoint between two on-treatment visits defines the end of a time window, with the
midpoint being included in the time window of the preceding visit. The end of the time
window of the last on-treatment visit (end of treatment (EOT)) is endpoint dependent.
Reasons to base the time windows on the actual treatment start date rather than the
randomisation date are:

If first intake of study drug shows a large delay by e.g. more than one week after the date 
of randomisation, a measurement taken four weeks after randomisation rather reflects the 


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drug effect after three weeks than after four weeks and thus may underestimate the 
treatment effect at this visit.

With large delays of the introduction of study drug after the randomisation, the time 
window for the first on-treatment visit could include times the patient was not yet on 
study drug.
The time window for the first visit after randomisation starts on the day after the first intake 
of study drug. This maximises the number of measurements used in by visit analyses and 
provides consistency with the planned last observation carried forward (LOCF) approach (as 
well as the approach to include patients with a baseline and at least one on-treatment 
measurement into the analysis). 
Table 6.7.3: 1 shows the time windows for FPG, planned to be measured at every visit.


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Table 6.7.3: 1 
Time windows for visits for FPG 
Visit number
Planned days 
after 
randomisation
Planned days 
on treatment
Time window 
start* based on 
planned days 
on treatment
Time window 
end* based on 
planned days 
on treatment
2
0
1
NA
1**
3
28
29
2
43
4
56
57
44
71
5
84
85
72
99
6
112
113
100
169
7
224
225
170
281
8
336
337
282
393
9
448
449
394
505
10
560
561
506
617
11
672
673
618
729
12
784
785
730
841
13
896
897
842
953
14
1008
1009
954
1065
15
1120
1121
1066
1177
16
1232
1233
1178
1289
17
1344
1343
1290
1401
18
1456
1457
1402
1513
19
1568
1569
1514
1625
20
1680
1681
1626
1737
21
1792
1793
1738
1849
22
1904
1905
1850
1961
23
2016
2017
1962
2073
24
2128
2129
2074
2185
25
2240
2241
2186
2297
26
2352
2353
2298
2409
27
2464
2465
2410
2521
28
2576
2577
2522
2633
29
2688
2689
2634
2745
30 
2800
2801
2746
Study drug stop 
date + x days***
*actual days on treatment
**has to be pre-treatment value
***The definition of x is endpoint specific, cf. Table 6.7.2: 1.
As e.g. HbA1c and weight are not measured at every visit, the time windows until visit 6 
would be as shown in Table 6.7.3: 2 (from visit 7 on windows as described above apply):


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Table 6.7.3: 2 
Time windows until visit 6 for e.g. HbA1c and weight
Visit number
Planned days 
after 
randomisation
Planned days 
on treatment
Time window 
start* based on 
planned days 
on treatment
Time window 
end* based on 
planned days 
on treatment
2
0
1
NA
1**
6
112
113
2
170
*actual days on treatment
**has to be pre-treatment value
For further visits beyond visit 30 the same concept is applied.
Only one observation per time window will be selected for analysis at a visit – the value will 
be selected which is closest to the protocol planned visit day. If there are two observations 
which have the same difference in days to the planned day or if there are two observations on 
the same day, the first value will be used. If there are multiple values within the time window 
of the last visit, including a value on the last day of drug intake, the value on the last day of 
drug intake is used as the value of the last visit.
For LOCF imputation (including interpolation), the last observed on-treatment value will be 
carried forward, whether or not it was selected in the previous time window (see Section 6.6).
The assignment of all measurements, including on-treatment and off-treatment 
measurements, to visits will be performed accordingly. 
For all variables any measurement obtained in the window of +8 days to + 44 days after last 
study drug intake will be assigned as “Follow-up measurement”, corresponding to planned 
measurement at 30 days after last study drug stop.
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 study (under risk). 
Consistent with that approach, the respective time intervals determine the start and end for 
the derivation of occurrence of a specific event.
For those patients with an event, the time to event is calculated as:
<date of event> - < start date> + 1
For those patients without an event, the time at risk is calculated as:
<date of censoring> - < start date > + 1
6.8.1
Start date
In general, the time to event will be derived from the date of randomisation. 
If study drug administration happened before calling IXRS, the date of first drug 
administration will be used as start date.


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For the endpoints of time-to-first-rescue-medication, time-to-first-hypoglycaemia and time-
to-AE analysis (refer to Section 7.8.1.3.2), time to first silent MI and laboratory based 
endpoints, the date of first drug intake will be considered as starting point. (The use of a 
different start date is justified as the general definition of rescue medication applies only to 
the time after first study drug intake and general AEs (including hypoglycaemia) are analysed 
based on the concept of treatment emergent adverse events, refer to Section 7.8.1.1.)
For composite endpoints that include component(s) using randomisation date and other 
component(s) using first drug intake date as start date, the time at risk for the composite will 
start with date of randomisation. For the individual components, the component specific start 
date is used.
6.8.2
Date of event
For composite outcomes, e.g. time to 4P-MACE, 3P-MACE and time to the first occurrence 
of any of the components of the composite endpoint of all CEC confirmed adjudicated 
events, the earliest onset date of the corresponding components will be used. For fatal MI and 
fatal stroke the onset date of the event is used while for other CV deaths, the date of death is 
used. 
The date determined by the adjudication committee will be used; this can be different from
the investigator reported date.
For the endpoints of time to CV death, time to all-cause mortality and time to non CV death 
the respective death date will be used.
The time to the first silent MI is determined by the onset date of the adverse event defined as 
silent MI by the investigator.
For events with multiple episodes, such as hypoglycaemia, the onset date of the first episode 
will be used. The same applies to time-to-AE analysis.
For time to rescue medication, the first intake of rescue medication (or respectively increase 
in background medication dose) will be used.
The time to first occurrence of endpoints based on laboratory data, e.g. ‘time to first new 
onset of macroalbuminuria’ is determined by the date of the first laboratory measurement, in 
this example UACR measurement, that fulfils this condition.
6.8.3
Censoring
Primary, key secondary, secondary CV and tertiary CV endpoints (except stand-alone 
endpoints of CV death, all-cause mortality, non CV-death and silent MI) and time to first 
disabling or fatal stroke
The underlying principle is that the censoring date should be the last date a patient was 
known to be free of an endpoint event (e.g. free of each component of the 4P-MACE).


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Patients without occurrence of a specific endpoint (composite endpoint or individual 
components) will be considered censored at their last documented study visit*.  
* This includes any dates as of 

adverse event/outcome event start dates (if non-fatal events), 

onset dates of adjudicated (confirmed and non-confirmed) events (if non-fatal event), 

date of PCI/CABG

date of trial completion (defined as latest of date of last clinic visit, last telephone call, 
date of last contact if lost to follow-up).
Censoring is considered independent from study drug intake.
Any information as permitted by local law will be used in the analyses.
Time to first rescue medication (overall and protocol-defined)
Patients without rescue medication intake that have prematurely and permanently stopped 
trial drug intake will be considered censored at their last documented study visit* as 
described above.
Patients without rescue medication intake that have regularly completed trial drug intake until 
study end will be considered censored at their last treatment stop date.
Primary endpoint sensitivity analyses
Please refer to Section 7.4.2.
Endpoints of CV death, non-CV death and all-cause mortality
A patient who did not die/died from another event will be censored at the latest date of the 
dates as described above, (for e.g. the primary endpoint) and the date of vital status (if alive)/ 
date last known to be alive (if LTFU)/ date of death (if died from another than event of 
interest).
Censoring rules and their application:

0-days censoring will be used for sensitivity analyis on TS (label: TS+0)

7-days censoring will be used for all adverse events - for hypoglycemia refer below
(label: TS+7)

30-days censoring will be used for sensitivity analysis done on PPS (label: PPS) and 
OS (label: OS) and as additional sensitivity analysis regarding censoring on TS (label: 
TS+30)
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 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, whichever is earlier.


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Silent MI
A patient without this event will be considered censored at the last documented study visit* 
as defined above. 
Time to first hypoglycaemia
To keep the analysis of hypoglycaemia consistent with the overall AE analysis, a patient 
without an event will be considered censored at the date of last trial drug intake + 7 days or 
date of death, if earlier. For further details refer to Section 7.8.1.6.
Time to first investigator reported heart failure (based on narrow SMQ cardiac failure)
Censoring will be performed as described above for the primary endpoint.
Endpoints based on laboratory data only
Patients who already fulfil the respective condition at baseline are 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..
Composite endpoints based on laboratory data and adverse events
Only patients that are included in the analyses for all components of the composite endpoint 
will be included in the analysis of the composite.
Of those, a patient with at least one event in any of the components of the composite will be 
considered to have an event and the date of the first event will be used for the composite 
endpoint. 
A patient without an event will be considered censored at the earliest of all censoring dates of 
the component endpoints. 
6.8.4
Definition of lost-to follow-up
If a patient could not be followed-up (vital status could not be collected) at the end of study
(considering a certain close-out period), that patient will be flagged as Lost To Follow Up 
(LTFU). Patients who died are not considered LTFU.


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7.
PLANNED ANALYSIS
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 enroled, entered/randomised, treated as well as those who did/ did not 
prematurely discontinue trial medication, did/did not prematurely discontinue from trial.
The frequency of patients with important protocol violations and the frequency of patients in 
different analysis sets will be presented by treatment group.
For End-of-text tables and appendix tables, the set of summary statistics is: N / Mean / SD / 
Min / Median / Max. Q1 (lower quartile)  and Q3 (upper quartile) will be shown, if 
appropriate.
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 will 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. Percentages will be rounded to one decimal place. The category 
missing will be displayed only if there are missing values. 
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline “Reporting of Clinical Trials and Project Summaries” (3). 
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive analysis of the following demographic characteristics and variables measured at 
baseline will be presented by treatment groups and in total for the TS:

Gender, race, ethnicity, country, age (continuous and categories of <55 years to >=85 in 
steps of 5 years),

Height, weight (continuous and categorical), BMI (continuous and categorical), waist 
circumference

Smoking history and Alcohol status

Duration of formal education in years

eGFR (continuous and categorical)

Baseline HbA1c (continuous and categorical) and FPG (continuous and categorical)

Time since diabetes mellitus type 2 was first diagnosed (continuous and categories of 
<=1 year, >1 to <=5 years, >5 to >= 10 years, >10 years)


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7.2
CONCOMITANT DISEASES AND MEDICATION
Relevant medical history/concomitant diseases
Relevant medical history/concomitant diseases will be coded using the most recent version of
the Medical Dictionary for Regulatory Activities (MedDRA). 
Frequency tabulations of the following concomitant diseases as obtained at baseline will be
presented by treatment group and in total based on the TS:

Cardiovascular risk factor categories: Previous vascular disease, Evidence of vascular 
related end-organ damage, Multiple CV risk factors (hypertension, current smoking, 
dyslipidaemia, Type 2 Diabetes Mellitus >10 years) as well as combinations (Section 6.4)

Relevant medical history (presence of baseline conditions within the previous 6 month: 
Diabetic retinopathy, Diabetic nephropathy, Diabetic neuropathy, Diabetic foot, Coronary 
artery disease, Peripheral artery occlusive disease, Cerebrovascular disease and 
Hypertension
The number of patients (including percentages) with at least one concomitant disease (except 
diabetes mellitus type 2) at baseline will be presented. 
Concomitant diagnoses by MedDRA System Organ Class (SOC) or Preferred Terms at 
screening with incidence of >=1% in at least one treatment group will be summarised by
treatment group and in total in a frequency table based on the TS.
Concomitant medication
All frequency tabulations will be performed on the TS.
In general, any therapy with the start date equal to the date of first trial drug intake is 
considered as being taken after first trial drug intake.
Overall concomitant medication use (excluding antidiabetic/background therapy) with an 
incidence of >=1% in at least one treatment group per WHO−DD preferred name will be 
summarised by Anatomical-Therapeutic-Chemical classification level 3 (ATC3). Summaries 
will be presented for concomitant therapies taken during screening and those taken after first 
drug intake.
Separate summaries of use of acetylsalicylic acid (ASA), antihypertensives, lipid lowering 
drugs, P−gp or CYP 3A4 inhibitors and anti−coagulants during screening and those taken 
after first drug intake will be presented. 
Antidiabetic therapies including background therapies taken at screening as well as those 
started after the date of first trial drug intake will be presented, with categorisation into 
monotherapy/combination therapy and the number of (oral) antidiabetic drugs. Antidiabetic 
therapies at screening will be linked to the visit 1a HbA1c to reflect the different categories of 
inclusion criterion 2.


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An antidiabetic therapy that is not a background therapy is considered as being taken at 
screening, if the start date was before the date of IC and the end date was not earlier than 10 
weeks pior to IC. As the start and stop date of the protocol-defined background medication of 
alpha-glucosidase inhibitor and/or metformin is not recorded in the eCRF, it is assumed, that 
this background medication was already taken at screening.
Summaries on the total daily dose of metformin at the date before first trial drug intake and 
last date of trial drug intake will be provided, this includes a categorisation into ≤1500mg or 
>1500mg.
The number of patients with a change in background therapy at any time starting from the 
date of first intake of trial drug will be presented for metformin as well as alpha-glucosidase 
inhibitor.
7.3
TREATMENT COMPLIANCE
Compliance will be analysed descriptively
A table showing the frequency of patients within (yes) and respectively outside (no) of 80%-
120% compliance will be given, presenting information for all visits for each treatment 
group, as well as for the total of all patients, based on the treated set. 
The percent compliance was to be calculated by the investigator as described in Section 4.3 
of the CTP.
The time windows as described in Section 6.7.3 will also be used for compliance, except that 
the time window end for the last visit is determined by the last information entered for a 
patient. This means, that whenever compliance is documented due to premature treatment 
discontinuation, the information will be assigned to the respective week. That may result in 
varying denominators of patients with compliance information over time, as a patient might 
stop study drug permanently and restart again.
Whenever compliance information has been documented more than once within the same
time window, the following rules apply:

Compliance outside of 80-120% at least once in that window: This information is 
used and no is displayed

Compliance always inside 80-120% in that window: This information is used and yes 
is displayed

Compliance always missing in that window: Missing is displayed

Compliance missing at least once in that window and the other values is inside the 
window: The compliance is considered as being inside 80-120%.
7.4
PRIMARY ENDPOINT
7.4.1 
Primary analysis
For the primary endpoint of time to the first occurrence of any of the following CEC 
confirmed adjudicated components of the primary composite endpoint: CV death (including 


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fatal stroke and fatal MI), non-fatal MI (excluding silent MI), or non-fatal stroke an ITT-
analysis (as randomised) on the TS will be performed. The analysis will be performed on TS 
with patients considered as randomised (intention-to-treat) and all events up to individual day 
of trial completion considered.
The randomised study treatment will be used to assign patients and events to treatment 
groups; all adjudicated events which occur until study end will be taken into account
(i.e. independent of whether or not a patient was still on study medication).
The time to the primary endpoint will be derived from the date of randomisation.
The one-sided overall significance level will be alpha=2.5%. As described in the CTP, the 
DMC will perform formal interim analyses. The significance levels for the analyses are 
denoted by αi, i=1,…,K, where K is the total number of analyses.
The O’Brien & Fleming alpha-spending function defined the significance level
for the first interim analysis on 4P-MACE.
Due to the change of the primary endpoint after the first DMC interim analysis a
Bonferroni adjustment will be applied in addition, to control the overall alpha level.
That means, the alpha spent at the first DMC interim analysis (performed
for 4P-MACE and based on the O’Brien & Fleming alpha-spending function) is
subtracted from the initial overall alpha. The O’Brien & Fleming alpha spending
function based on the new overall alpha (after additional Bonferroni
adjustment) defines the allocation of the still available overall significance level
for the second interim analysis and the final analysis.
7.4.1.1 Statistical Methods
For the primary analysis a regression analysis using Cox's proportional hazards model 
including a term for treatment will be applied to compare linagliptin with glimepiride. 
Breslow’s method will be used for dealing with ties.
The hazard function of an event for patient j at time t is assumed to have the form
hj(t) = exp(β1x1j) h0(t), j=1,...,n,
where 

h0(t) is the non-negative baseline hazard function for a patient with a value of zero for 
the explanatory value x1j

β1 is the (unknown) coefficient of the explanatory variable x1

x1j is an indicator variable representing the treatment group for patient j=1,...,n.
The hazard ratio (HR) for the effect of treatment (linagliptin vs. glimepiride) will be 
presented with the corresponding (1-2*αi)*100% confidence interval (CI), the corresponding 
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 for the null hypothesis of equality based on the 
Wald chi-squared statistic. 


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The proportional hazards assumption will be explored by plotting log(-log(survival function)) 
against the log of time by treatment group and checked for parallelism. The interaction of 
treatment with log of time will be included in the model described above for an exploratory 
analysis. Further, Schoenfeld residuals will be plotted against time and log(time). 
The probability of the primary endpoint event over time will be displayed by treatment using 
Kaplan Meier (KM) estimates, which includes the presentation of certain quantiles of the 
failure times (e.g. 2.5%, 5%, 7.5% and 10% quantiles) and Kaplan-Meier rates after specific 
number of years. 
Any pointwise (1-2*αi)*100% CIs for KM failure rates will be determined using 
Greenwood’s variance estimate. 
The two-sided p-value resulting from the log-rank test will be presented. 
Tabular and graphical displays will present the (cumulative) number of patients at risk, 
failures as well as censored patients over time.
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.
7.4.1.2 Censoring for time to event endpoints for interim and final analyses
Please refer to Section 6.8 above.
7.4.1.3 Testing hierarchy
In the i-th analysis, i=1,…, K, the upper limit of the two sided (1-2*αi)*100% confidence 
interval of the hazard ratio will be compared with the non-inferiority margin of 1.3. Also the 
one-sided p-value of the non-inferiority test based on the Wald chi-squared statistic will be 
given. If the non-inferiority test is significant, i.e. non-inferiority within the margin of 1.3 has 
been demonstrated, a superiority test (Wald chi-squared statistic) will be performed. If the 
superiority test is significant, a superiority test on the first key secondary endpoint will be 
performed at the same significance level as used for the primary endpoint. If this superiority 
test is also significant, the second and third key secondary endpoints will be tested 
hierarchically. The second and third key secondary endpoints will be analysed with a Chi-
Square test at the same significance level (2*αi)*100% as the primary endpoint.
7.4.1.4 Details on alpha-spending
The following details on alpha-spending will hold:
a) Early stop of the study due to superiority or futility
If the decision is to terminate the study after a formal DMC interim analysis due to 
superiority of linagliptin over glimepiride or futility, further endpoint events are expected to
be documented before the study is stopped. These events will also be adjudicated and 
subsequently used for the final analysis.


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The final, confirmatory analysis will be based on all (primary) endpoint events observed until 
study end. This analysis will be performed based on the same significance level αi as the 
interim analysis that led to early stopping of the trial.
b) Early stop of the study due to safety reasons
If the study is terminated prematurely (before observation of 631 patients with primary 
endpoint events) as a consequence of DMC safety reviews, the remaining significance level 
alpha will be fully exhausted at this step (taking into account previous official interim 
analysis), and the analysis will be based on all observed and confirmed (primary) endpoints 
events.
c) Underrunning at study end (not stopping prematurely)
If, for logistical reasons, the study is terminated with fewer than 631 patients with primary 
endpoint events, the remaining significance level alpha will be fully exhausted at this step 
(taking into account previous official interim analysis).
d) Overrunning at study end (not stopping prematurely)
If, for logistical reasons, the study is terminated with more than 631 patients with primary 
endpoint events, the significance level alpha as determined for 631 patients with primary 
endpoint events will be used (taking into account previous official interim analysis).
7.4.2 
Sensitivity analysis
7.4.2.1 Proportional hazards assumption violated
In case the proportionality assumption is violated, an attempt will be undertaken to identify 
groups of patients for which the proportionality assumption holds and a stratified 
log-rank test will be performed. The HR and corresponding CI will be obtained from the 
stratified Cox model.
In addition a piecewise Cox model assuming proportional hazards in a series of consecutive 
time intervals as proposed by Collett (7) will be investigated.
7.4.2.2 General sensitivity analysis
For the primary endpoint sensitivity analyses will be done on the PPS, the OS and the TS
population in combination with censoring on day 0 (TS+0) and on day 30 (TS+30). For all 
these analyses, the allocated trial treatment at randomisation will be used for treatment 
assignment.
Sensitivity analyses done on the PPS, OS population and on TS population in combination 
with censoring on day 30 will be performed based on events occurring within the time 
patients are on-treatment + 30 days after permanent treatment discontinuation or date of last 
documented study visit, whichever comes first. 


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This means patients will be considered censored at the date of last treatment stop + 30 days, 
if their last documented study visit was performed thereafter. If the last documented study 
visit was performed earlier than 30 days after last treatment stop, the patient will be censored 
at the last documented study visit (refer to Section 6.8.3).
The sensitivity analysis done on the TS in combination with censoring on day 0 will be based 
on events occurring within the time patients are on-treatment or date of the individual day of 
trial completion, whichever comes first.
These sensitivity analyses will be performed as described in Section 7.4.1.1 at the 
significance level used for the primary analysis.
The following table provides an overview of the planned analyses.
Table 7.4.2.2: 1 
Overview of analyses on the primary endpoint
Censoring mechanism
Analysis set
TS
PPS
OS
Individual day of trial completion
x
0 days censoring
x
7 days censoring
x
30 days censoring
x
x
x
For the details on censoring refer to Section 6.8.3.
For the primary endpoint an additional sensitivity analysis will be performed in addition on 
the TS considering all events that occurred between randomisation and 7 days after the last 
permanent treatment discontinuation or date of last documented study visit, whichever comes 
first. Accordingly, patients without an event will be considered censored at the earliest of the 
date of last treatment discontinuation + 7 days or last documented study visit.
The cumulative incidence for the time to first occurrence of the primary endpoint will be 
presented, accounting for the time to non-CV death as competing risk. In addition, a Cox's 
proportional hazards model will be fitted to compare the distribution of competing risks 
between treatment groups.
 
 


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7.4.4
Interim analysis
The significance level alpha is determined as described in Section 7.4.1. 
For the interim analysis patients without events will be considered censored as described in 
Section 7.4.1.2.
The DMC will perform formal interim analyses as outlined in the DMC charter. A separate 
Statistical Analysis Plan for the interim analysis will be provided.
The transfer of data is outlined in the Interim Analysis Logistics Plan (logistical aspects), as 
well as the Data Transmission Agreement signed by the DMC Statistician.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
Primary analysis of key secondary endpoints
The first key secondary endpoint of time to first 4P-MACE will be analysed on the TS as 
described in Section 7.4.1, at the same significance level αi as the primary endpoint. 
The second and third composite key secondary endpoints will be analysed with a Chi-Square 
test at the same significance level αi as the primary endpoint, based on the TS.
The number and percentage of patients with response will be provided along with the 
95% Wilson confidence intervals.
A logistic regression model will be applied including a term for ‘treatment’. The Odds ratio 


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(OR) along with the (1-2*αi)*100% Wald CI and the two-sided p-value for treatment 
comparison will be presented.
General definition of second and third key secondary endpoints
If a patient has terminated study treatment permanently (i.e. without subsequent re-start) 
before trial stop, the patient is considered a non-responder (except in sensitivity analyses).
A patient who stops study treatment and restarts later, can still fulfill the second and third 
composite key secondary endpoint criteria, independent from how long the patient was off-
drug. Only the last information on ‘termination of trial medication’ (i.e. last treatment stop 
date) is considered.
If a patient died prior to completing the trial regularly, the patient is considered as non-
responder.
HbA1c and weight and hypoglycaemia are only considered for the (parameter-specific) time 
on-treatment and not e.g. at/until a follow-up visit, because the follow-up visit is planned to 
be performed after treatment discontinuation.
Sensitivity analysis of key secondary endpoints
For the first key secondary endpoint of time to first 4P-MACE sensitivity analyses will be 
done on the PPS, the OS and TS+0, TS+30. 
These sensitivity analyses will be performed based on events occurring within the time 
patients are on-treatment + 30 days after permanent treatment discontinuation or date of last 
documented study visit, whichever comes first. 
For further details refer to Section 7.4.2.
For the time to first 4P-MACE an additional sensitivity analysis will be performed on the TS
considering all events that occurred between randomisation and 7 days after the last 
permanent treatment discontinuation or date of last documented study visit, whichever comes 
first. Accordingly, patients without an event will be considered censored at the earliest of the 
date of last treatment discontinuation + 7 days or last documented study visit.
The cumulative incidence for the time to first 4P-MACE will be presented, accounting for the 
time to non-CV death as competing risk. In addition, a Cox's proportional hazards model will 
be fitted to compare the distribution of competing risks between treatment groups.
For the second and third key secondary endpoints sensitivity analyses will be done on the 
PPS and the 30-days-treatment set OS, including the same statistical procedures as described 
above for the TS.
For the sensitivity analysis on the PPS patients who prematurely discontinue study treatment 
will be counted as non-responders as in the primary analysis on the TS.
For the sensitivity analysis on the 30-days-treatment set patients who prematurely discontinue 
study treatment will not necessarily be counted as non-responders. The measurement of the 
last documented on-treatment study visit will be used in this case. 
The significance level from the primary analysis of key secondary endpoints will be used.


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7.5.2
(Other) Secondary endpoints
All other secondary analyses are of exploratory nature, no correction for multiple hypotheses 
testing will be made. All statistical tests and confidence intervals are two-sided with a 
significance level of alpha=0.05.
7.5.2.1 
Secondary/Tertiary cardiovascular endpoints
For all secondary and tertiary CV endpoints that include time-to-event data the same models 
and testing procedures as the primary analysis (refer to Section 7.4.1) will be applied to 
compare the two treatment groups. 
For time to first investigator reported heart failure (based on narrow SMQ cardiac failure) 
only frequencies and incidence rates will be provided. For time to first investigator reported 
heart failure (based on narrow SMQ cardiac failure) another analysis will be performed on 
the TS based on events occurring until + 7 days after permanent treatment discontinuation or 
date of last documented study visit, whichever comes first. Accordingly, patients without an 
event will be considered censored at the earliest of the date of last treatment stop + 7 days or 
last documented study visit.
The cumulative incidence function for time to first occurrence of each adjudicated CEC 
confirmed CV endpoint (except all-cause mortality), accounting for any death that is not part 
of the endpoint as a competing risk, will be provided. In addition a Cox's proportional 
hazards model will be applied to the competing risk.
For the secondary CV endpoints of occurrence of 4P-MACE and 3P-MACE sensitivity 
analysis on the TS, PPS and OS will be performed, considering events until earliest date of 
treatment stop + 30 days or date of last documented study visit. This covers the presentation 
of number and percentage of patients with an event.
For all adjudicated CV endpoints including all-cause mortality additional sensitivity analyses 
will be performed on the TS based on events occurring until + 30 days after permanent 
treatment discontinuation or date of last documented study visit, whichever comes first. 
Accordingly, patients without an event will be considered censored at the earliest of the date
of last treatment stop + 30 days or last documented study visit.
 


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7.5.2.2 
Secondary/Tertiary diabetes related endpoints and UACR
7.5.2.2.1 
Continuous diabetes related endpoints (FPG, HbA1c, total cholesterol, HDL 
cholesterol, LDL cholesterol, triglycerides, creatinine, urinary albumin, eGFR, 
weight and UACR)
Evaluation will be performed on standardized values. The analyses will be performed on the 
TS. Measurements will be assigned to weeks as described in Section 6.7.3.
The absolute change from baseline will be calculated for each timepoint by subtracting the 
baseline value from the selected value at the respective time point.
Treatment-emergent evaluation
Patients with a baseline measurement and at least one on-treatment measurement will be 
included for analysis over time. Only values obtained until last permanent treatment stop will 
be considered. The assignment of values to be on-treatment is defined in Table 6.7.2: 1. 
In general, for the evaluation of HbA1c and FPG, for patients receiving rescue therapy all on-
treatment efficacy measurement after the start of rescue therapy will not be used for analysis 
and hence set to missing (OC, LOCF). If a patient receives rescue therapy before the first 
available on-treatment measurement, this patient will not be included in the analysis, except 
for HbA1c LOCF analysis.
For total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, creatinine, urinary 
albumin, UACR, eGFR and weight values before and after rescue therapy intake will be 
considered (OC-ROC, LOCF-ROC).
In addition, analyses following the OC concept will be performed.
For the following parameters, only values obtained in the fasted state will be used for 
analyses: FPG, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides.
For UACR log10 transformed data will be used within the ANCOVA or respectively MMRM 
model, the results will be back-transformed to the original scale.
Change from baseline to final visit on-treatment
For the investigation of continuous diabetes related endpoints at the final visit, the following 
analysis of covariance (ANCOVA) model will be applied:
Efficacy endpoint as absolute change from baseline = overall mean + treatment + baseline 
measurement + random error
This model includes effects accounting for the following sources of variation: ‘Treatment’, 
and ‘baseline’. ‘Treatment’ is a fixed classification effect and ‘baseline’ is a linear covariate.
The random error is assumed to be normally distributed with mean 0 and variance σ². 


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The adjusted mean with SE for each treatment group, the adjusted mean difference with SE 
and the corresponding 95% CI will be reported.
Treatment-specific baseline will be investigated. 
Descriptive statistics will be presented.
The analysis will be performed on OC and OC-ROC for HbA1c, FPG and on OC-ROC for 
Total cholesterol, HDL cholesterol, LDL cholesterol, Triglycerides, Creatinine, eGFR, 
urinary albumin, UACR and weight.
Change from baseline over time – considering the design of the trial
Only data up to the planned week that could theoretically be achieved by all patients will be 
included in this analysis. This time-point depends on the duration of the trial. If e.g. the trial 
would run for 7 years in total with 2 years for re-cruiting, the last patient randomised could 
theoretically only reach the visit at week 260. Then for all patients only the data up to 
planned week 260 will be included in this analysis. 
a) MMRM
The change from baseline over time will be evaluated with a restricted maximum likelihood 
(REML) based mixed model repeated measures (MMRM) approach with the fixed, 
categorical effects of treatment, week, treatment-by-week interaction, with the continuous 
covariates of baseline and baseline-by-week interaction. 
The baseline and the available longitudinal observations at each post baseline visit until last 
permanent treatment stop will be used for the analysis of these endpoints at each week.
The adjusted least-squares mean with standard error (SE) per treatment group, the mean 
difference with SE and 95% CI will be reported at all timepoints.
The average treatment difference over time will be provided in addition to the treatment 
difference per week for continuous endpoints.
An unstructured covariance structure will be used to model the within-patient errors. 
In the event that this analysis cannot be applied for mathematical reasons or fails to converge, 
the AR(1) covariance structure will be employed. If this fails to converge, the compound 
symmetry (CS) covariance structure will be employed. 
The Kenward-Roger approximation will be used to estimate the denominator degrees of
freedom. Type III sums of squares will be used.
The analysis will be performed on OC and OC-ROC for HbA1c, FPG and for Total 
cholesterol, HDL cholesterol, LDL cholesterol, Triglycerides, Creatinine, eGFR, urinary 
albumin, UACR and weight.


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b) LOCF
The last observation carried forward (LOCF) approach will be performed to conduct a 
sensitivity analysis. The change from baseline after replacement by LOCF will be evaluated 
with the analysis of covariance (ANCOVA) model as described above for every week.
The adjusted mean with SE for every treatment group, the adjusted mean difference with SE 
and 95% CI will be reported.
The analysis will be performed on LOCF and LOCF-ROC for HbA1c, FPG and for Total 
cholesterol, HDL cholesterol, LDL cholesterol, Triglycerides, Creatinine, eGFR, urinary 
albumin, UACR and weight.
c) Descriptive statistics
Descriptive statistics will be provided based on OC data and after LOCF imputation (OC, 
OC-ROC, LOCF, LOCF-ROC).
Change from baseline over time 
MMRM analyses on OC and OC-ROC will be performed as described above.
Simple descriptive statistics will be calculated for the change from baseline over time based 
on observed case data (OC and OC-ROC). All weeks will be considered. 
Sensitivity analysis for determination of influence of rescue medication and fasting
For HbA1c and FPG and weight the above analyses considering the actual design of the trial
applying MMRM analysis will be repeated including also data obtained after rescue therapy 
intake (OC-ROC and LOCF-ROC).
As stated above, approaches of OC and LOCF will also be performed for Total cholesterol, 
HDL cholesterol, LDL cholesterol, triglycerides, creatinine, eGFR, urinary albumin, UACR 
and weight.
For total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides a sensitivity analysis 
using descriptive statistics will be performed for the change from baseline over time and at 
final visit based on OC-ROC, considering all values, obtained in fasted and non-fasted state.
Evaluation including all data independent of treatment
MMRM analyses on OC-ALL considering the actual design of the trial will be performed as 
described above for HbA1c, FPG and weight.
Descriptive statistics will be calculated for the change from baseline over time and to study 
end based on all observed data. All data obtained before and after intake of rescue therapy 
and independent of treatment stop will be considered (OC-ALL).
Descriptive statistics will also be provided after applying LOCF including all data obtained 
up to the planned week that could theoretically be achieved by all patients.


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An ANCOVA will be performed for the change from baseline to final week per patient using 
the model as described above for HbA1c, FPG and weight.
Treatment-specific baseline will be investigated for the change from baseline to final week. 
Investigation of follow-up information obtained after treatment stop
A comparison of baseline, last value on-treatment and follow-up value will be performed for 
measures of SBP, DBP, pulse rate, FPG, eGFR.
 
A model including subgroup, subgroup-by-treatment interaction will be used.
7.5.2.2.2 
C-peptide, plasma pro-insulin and antibodies
Descriptive statistics of baseline values will be provided based on the TS and include 
geometric mean and geometric coefficient of variation. For C-peptide and pro-insulin only 
values obtained in fasted state will be considered.
7.5.2.2.3 
Binary diabetes related endpoints
The Chi-Square test is used to compare the two treatment groups and a logistic regression 
with factor treatment is performed to report the OR along with the 95% CI. The number and 
percentage of patients with response will be provided along with the 95% Wilson confidence 
intervals. The analysis will be performed on the TS.
7.5.2.2.4 
Time to and occurrence of antidiabetic rescue therapy
Time to first rescue therapy use among patients will be analysed by Kaplan-Meier estimates 
and compared using a log-rank test based on the TS.
 
 
The time to first rescue medication will be calculated as date of first intake of rescue therapy 
minus the date of first intake of randomised study drug plus one day. 
For censoring refer to Section 6.8.
The number and percentage of patients with rescue medication will be provided along with 
the 95% Wilson confidence intervals. The analysis will be performed on the TS.


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7.7
EXTENT OF EXPOSURE
Extent of exposure to active study medication will be calculated as the difference between the 
date of last intake of study drug (or respectively date of death) and the first administration of 
study drug + 1 day (i.e. including off-treatment periods) per patient.
The end of time in study is defined as the latest date as of the date of last documented study 
visit (defined in Section 6.8.3) and the date of vital status (if alive)/ date last known to be 
alive (if LTFU)/ date of death (if died). The time in study is the difference between the end of 
time in study and the date of randomisation.


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A descriptive statistics table of the treatment exposure and time in study will be provided. 
This table will also include the total exposure/time in study summed over all patients within 
each treatment group and transformed to patient years as obtained by:
Patient years = Σ (individual patient total exposure/time in study in days)
365.25 days
In addition, the table will include the sum of exposure/time in study without/prior to rescue 
medication [years] and the sum from first intake of rescue medication [years] per treatment 
group.
A frequency table of number and percentage of patients with exposure/time in study for 
specific time periods will be provided by treatment group.
A Kaplan-Meier plot will be provided for exposure time and time in study.
7.8
SAFETY ANALYSIS
Safety analyses of adverse events and laboratory data will be performed on the treated set. 
7.8.1
Adverse events
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. 
The analyses of adverse events will be descriptive in nature. All analyses of AEs will be 
based on the number of patients with AEs (not the number of AEs). For this purpose, AE data 
will be combined in a 2-step procedure into AE records.
In a first step, AE occurrences, i.e. AE entries on the eCRF, will be collapsed into AE 
episodes provided that all of the following applies:

The same MedDRA lowest level term was reported for the occurrences

The occurrences were time-overlapping or time-adjacent. Time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day after 
the end of the first occurrence. 

Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence
In a second step, AE episodes will be condensed into AE records provided that the episodes 
were reported with the same term on the respective MedDRA level and that the episodes are 
assigned to the same treatment. For further details on summarization of AE data, please refer 
to the guideline 'Handling and summarization of adverse event data for clinical trial reports 
and integrated summaries' (2).
The general AE analysis will include all adverse events (including outcome events).


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For the hypoglycaemic events (reported as adverse events or separately) further evaluation is 
performed on episodes. The occurrences are only collapsed if they occur within ≤60 minutes 
of each other. The period will begin with the first hypoglycaemia onset time. If another event 
occurs outside this initial 60 minutes window a new period for collapsing will begin. 
Hypoglycaemic episodes with a missing onset time will be counted as separate episodes, 
regardless of other episodes on the same day.
7.8.1.1
Assignment of AEs to treatments
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake until 7 days 
after last permanent treatment stop will be considered as on-treatment (see Table 6.7.2: 1), 
which means, that possible treatment interruption phases of a patient will be part of the on-
treatment phase. 
All adverse events occurring prior to first drug intake will be assigned to ‘screening/run-in’. 
All adverse events occurring after last drug intake + 7 days will be assigned to treatment 
related ‘post-treatment’, whereby the post-treatment phase according to the previous 
treatment will be used (post-Lina and post-Glim respectively). Adverse events reported after 
the latest date as of the date of last documented study visit (defined in Section 6.8.3) and the 
date of vital status (if alive)/ date last known to be alive (if LTFU)/ date of death (if died)+ 1 
day will be assigned to post-study. For details on the treatment definition, see Section 6.1. 
Patients who died before last drug intake + 7 days will have their on-treatment phase assigned 
until the date of death. 
In section 15, only adverse events assigned to on-treatment phase of linagliptin or glimepiride 
of the respective drug will be displayed. Further tables including also adverse events which 
occurred during screening/run-in and post-treatment phase will be included in Appendix 
16.1.9.2 and 16.2.7.
All AEs observed during the study starting from first treatment intake will be presented in 
further tables.
A listing of patients with on-treatment adverse events with an onset during the non-
randomised treatment will be provided.
Further additional approaches will be implemented for the presentation of adverse events: 

For cancer and pancreatic cancer in addition to the ‘7-day-on-treatment 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


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
For renal events, hepatic events, pancreatitis and skin reactions all adverse events that 
occurred between first study drug intake up until treatment stop + 30 days will be 
presented based on the treated set.

For pancreatitis all adverse events that occurred between first study drug intake up until 
study end will be presented based on the treated set. 

Investigator reported cardiac failure will be analysed following the
‘7-day-on-treatment approach’ and also considering all events up to individual day of trial 
completion (refer to Section 7.5.2.1).
 
 
 
7.8.1.2
Analysis of other significant AEs
According to ICH E3 (8), AEs classified as ‘other significant’ will include those non-serious 
adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or 
(iii) lead to significant concomitant therapy as identified by the Clinical Monitor/Investigator 
at a Blinded Report Planning Meeting. 
7.8.1.3
AE summaries
7.8.1.3.1
Frequency of patients with adverse events
Frequency of patients with adverse events will be summarised by treatment, primary system 
organ class (SOC) and preferred term. 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). No inferential analysis is planned for routine safety comparisons.
An overall summary of patients with adverse events will be presented (including patients 
with any AE, severe AEs, investigator defined drug-related AEs, other significant AEs, AEs 
leading to discontinuation of trial drug, serious AEs).
The frequency of patients with adverse events will be summarised by treatment, primary 
system organ class and preferred term. Separate tables will be provided for patients with 
other significant adverse events according to ICH E3 (8), for patients with serious adverse 
events, for patients with drug-related adverse events, patients with adverse events leading to 
treatment discontinuation, patients with fatal adverse events, and by AE intensity.
An overview of adverse events from patients screened, but not treated, will be included.


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7.8.1.3.2
Adverse event incidence rates, rate ratio and rate difference
In addition to the frequency tabulations, time-adjusted adverse event analyses will be 
performed for certain types of events (severe AEs, investigator defined drug-related AEs, 
other significant AEs, AEs leading to discontinuation of trial drug, serious AEs, and adverse 
events of special interest and further adverse events) by SOC and PT, respectively HLT and 
PT.
Therefore, the time at risk in patient years is derived as follows:

Patients with AE: 
time at risk (AE) in days = date of start of AE with specified PT/SOC – study 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 + 7 days and date 
of death, if applicable.
Depending on the specific approach for how long adverse events are assigned to 
treatment, ‘+30 days’ or respectively the date of trial termination may be used for the 
derivation of time at risk.
Total AE-specific time at risk per treatment group is then derived as: 
Time at risk (AE) [years] = Sum of time at risk [days] over all patients in a treatment group/ 
365.25
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 = 
date of start of AE with specified PT in a SOC – start of study treatment + 1.
The AE incidence rate per 1000 patient years can then be calculated as follows:
Incidence rate [1/1000 Patient years (pt-yrs)] = 1000 * number of patients with AE / time at
risk (AE) [years].
Further the rate ratio of the incidence rates and the rate differences with the 95% CIs will be 
presented for hypoglycaemia. The estimates and confidence intervals for incidence rate ratios 
are based on a Cochran-Mantel-Haenszel option, while estimates and confidence intervals for 
incidence rate differences are derived as follows:
The rate difference is defined as 
m
y
n
x


ˆ
, where
x denotes the number of patients with event in treatment 1,
y denotes the number of patients with event in treatment 2, 


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n denotes the number of patient days at risk with treatment 1 and
m denotes the number of patients days at risk with in treatment 2. 
The estimated variance of ˆ is defined as:
2
2
2
)
(
)
ˆ
r(
aˆ
v
nm
n
y
m
x





.
Assuming normal distribution of ˆ , an approximate 95% confidence interval is given as 
follows, where z0.975 is the 97.5% quantile of the standard normal distribution: 
])
ˆ
r(
aˆ
v
z
ˆ
[
0.975





CI
.
7.8.1.4
AEs of special interest (AESI)
Analysis of protocol specified AEs (=events of special interest)
According to the CTP the following events are considered as adverse events of special 
interest (AESI):

Hypersensitivity reactions such as angioedema, angioedema-like events, and
Anaphylaxis (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’, 
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 events (defined by narrow SMQ 20000003 ‘acute renal failure’) 

Pancreatitis (defined by narrow SMQ 20000022 ’acute pancreatitis’ and PT ’Pancreatitis 
chronic’)
Patients with these AESIs will be tabulated by treatment group.
Further, patients with pancreatic cancer (defined based on narrow BIcMQ) will be tabulated 
by treatment group.
For all AESIs, in addition frequency tables for serious adverse events (except for pancreatic 
cancer as these events are on the always-SAE list), adverse events leading to discontinuation 
from trial drug, drug related adverse events and adverse events by severity and outcome will 
be presented.
The most recent version of the definitions of these AESIs according to the respective most 
recent MedDRA version will be used. These will be stored in the PDMAP.


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7.8.1.5
Events qualifying for external adjudication by the Clinical Event Committee (CEC)
Tabulations with frequency of patients with adverse events triggering CEC adjudication 
(based on specified SMQs according to CEC charter and manually identified) will be 
provided by treatment/overall, primary SOC and preferred term and result of adjudication. 
Further, outcome events captured by the investigators will be contrasted with those defined 
by the adjudication committee.
All by adjudication confirmed events will be summarised.
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 strokes, stent thrombosis and all 
not assessable cases will be presented.
7.8.1.6
Analysis of hypoglycaemic events
All symptomatic hypoglycaemic events, all asymptomatic events with glucose levels less 
than 3.0 mmol/L (or less than 54 mg/dL) and all asymptomatic hypoglycaemic events that are 
considered as adverse events by the investigator have to be recorded as an adverse event with 
additional information to assess the intensity of the hypoglycaemic event.
For asymptomatic hypoglycaemia with a measured plasma glucose concentration >=3.0 and 
<=3.9 mmol/L (>=54 and <=70 mg/dL), if not considered as adverse event, the plasma 
glucose levels values will be recorded in the CRF.
Analyses on hypoglycaemic events will be performed on the TS.
Different tables will be shown for (i) patients with investigator defined asymptomatic or 
symptomatic hypoglycaemia reported on the CRF, and (ii) patients with (by the investigator) 
confirmed hypoglycaemic adverse events and (iii) asymptomatic hypoglycaemia.
The number of patients with investigator defined hypoglycaemia (adverse events) will be 
tabulated by treatment group. In addition, the number of patients with different characteristics 
of hypoglycaemic events, including severity, symptoms, glucose level, minimum glucose 
level of the worst episode, number of episodes per patient as well as time to first 
hypoglycaemic episode will be presented.
The number of patients with hypoglycaemic events and investigator defined hypoglycaemia
adverse events will be shown by age group and by use of rescue medication (yes, no).
Time to the onset of the first hypoglycaemia and first hypoglycaemia adverse event will be 
analysed by Kaplan-Meier estimates. A log rank test will be performed. For the details on 
censoring refer to Section 6.8 and 7.8.1.3.2.
 
 
 


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7.8.1.7
Further adverse events
Patients with the following adverse events will be tabulated by treatment group: Malignancies
(defined by broad BIcMQ ‘Malignancy’), Immunological reaction (only on SOC level, 
‘Immune System Disorder’). Analysis regarding malignancies as defined by broad BIcMQ 
‘Malignancy’ will be presented separately by narrow SMQ ‘Malignant tumours’ and SMQ 
‘Tumours of unspecified malignancy’ and overall.
In addition, frequency tables will be provided for the following ‘AE-concepts’: 

angioedema (defined by narrow SMQ 20000024 ’angioedema’)

arthralgia (defined by HLGT ‘Joint disorders’) (by HLT and PT)

bullous conditions (by HLT ‘bullous condition’ and PT)
For all these ‘AE concepts’ in addition frequency tables for serious adverse events (except for 
cancer as these events are on the always-SAE list), adverse events leading to discontinuation 
from trial drug, drug related adverse events and adverse events by severity and outcome 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 PDMAP.
7.8.1.8
Events qualifying for external adjudication by the Clinical Event Committee (CEC) 
for pancreatic events
A separate independent, blinded, external committee regularly reviews events suspected of 
acute pancreatitis, chronic pancreatitis, asymptomatic pancreatic hyperenzymemia and 
pancreatic malignancy and will evaluate whether pre-specified criteria for these adjudication 
events are met. Details on composition of the CEC, responsibilities and clinical event 
definitions are provided in the corresponding CEC charter.
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 considering the individual day of trial completion and 
‘on-treatment + 7 days’.


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For CEC confirmed adjudicated acute pancreatitis a Kaplan Meier curve for time to first 
event will be presented along with a Hazard ratio and 95% CI from Cox regression based on 
all events up to individual day of trial completion.
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 
tumour malignancy as defined in the charter. 
The analysis will be performed on all events up to individual day of trial completion.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards. The process of standardisation and normalisation as well as standard analyses for 
safety laboratory data are described in the BI guidance for the Display and Analysis of 
Laboratory Data: (see DM&SM: Display and Analysis of Laboratory Data)(4).
Laboratory measurements will be assigned to trial phases screening/run-in, treatment period 
of Linagliptin or Glimepiride and post-treatment Linagliptin, post-treatment Glimepiridie, 
post-study period as described in Section 6.1.1 and 6.7.
Laboratory measurements will be analysed with an on-treatment approach. Further analyses 
will be provided summarizing on-treatment and post-treatment measurements per treatment 
group.
Baseline for safety laboratory parameters will be the last available measurement before the 
start of randomised study drug. The last measurement taken between the first intake of 
randomised trial drug and seven days after the last administration of trial drug will be 
analysed as the last value on-treatment. In case of repeated measurements per visit, the worst 
value will be used. 
Only patients with at least one available baseline and on-treatment value will be included in 
the analysis of an individual laboratory parameter. 
Descriptive statistics of continuous laboratory data for safety purposes will be based on 
normalised values. 


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Laboratory values will be compared to their reference ranges (and multiples of their reference 
ranges) and frequency tables will be provided for the number of patients within and outside 
the reference range at baseline, over time and the last measurement on treatment (continuous 
parameters). Descriptive statistics for changes from baseline will be provided by treatment 
group for baseline, over time, the minimum and maximum post baseline and last 
measurement on-treatment for continuous parameters. 
Categorical laboratory data will be presented in frequency tables for baseline, over time and 
last value on treatment.
Further frequency tables will summarise the number of patients with possible clinically 
significant abnormalities. 
Details on patients with potential Hy’s law cases will be listed. For the summaries on patients 
with elevated liver enzymes see below. A summary will also be created representing the 
number of patients per treatment group who experienced a doubling in creatinine on 
treatment compared to baseline.
A shift table from baseline, over time and last value on treatment for eGFR (MDRD) and 
UACR will be provided. 
For these analyses the continuous diabetes related endpoints will be included in the safety 
analyses with respect to the reference range and in the analysis of possible clinically 
significant abnormalities, as far as reference ranges and thresholds for potential clinical 
significance exist.
Specific considerations for hepatic parameters
To support analyses of liver related adverse drug effects potential Hy’s law cases are defined 
by the combination of the following events within one sample: 

any on-treatment value of ALT or AST (or both) >= 3 times upper limit of normal (ULN) 
with

total bilirubin >= 2 x ULN and 

alkaline phosphatase <= 2 x ULN.
Further, it will be investigated if the above events occurred within a time span of 30 days. 
The start of the 30 day time span is triggered by each liver enzyme elevation above the 
defined thresholds.
Patients who fulfil one or two of the criteria for ALT/AST or total bilirubin elevations above 
and have no information available for the remaining parameter(s) at the same timepoint or 
within the 30 day time windows will be presented as well. 
All calculations for the grading will be based on the originally measured laboratory values 
and the ULNs given by the laboratory, not on normalised values with BI standard reference 
ranges.
In addition ALT/AST will be used to investigate elevated liver enzymes:


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
ALT/AST ≥ 3 x ULN

ALT/AST ≥ 5 x ULN

ALT/AST ≥ 10 x ULN
Frequency tables of patients with elevated liver enzymes defined by ALT and/or AST, total 
bilirubin and AP combinations will be provided.  A scatter plot of peak ALT against peak 
total bilirubin will be presented with reference lines for 3 x ULN ALT and 2 x ULN total 
bilirubin, including an indicator for treatment received.  
Specific renal endpoints
The frequency of patients with  ≥2 fold increase of creatinine from baseline will be presented.
For non-Japanese adult patients, the glomerular filtration rate will be estimated according to 
the MDRD formula, consistent with the recommendation of the US NIH, NIDDK (National 
Institute of Diabetes and Digestive and Kidney Diseases of the the National Institute of 
Health) as of October 2012. In the formula for non-Japanese, adult patients the factor of 175 
accounts for IDMS traceable determination of creatinine:

MDRD formula for adult, non-Japanese patients
eGFR (mL/min/1.73m2) = 175 x (creatinine (µmol/L) / 88.4)-1.154 x age-0.203
x (0.742 if female) x (1.212 if black)

eGFR formula for adult Japanese patients
eGFR (mL/min/1.73m2) = 194 x creatinine (mg/dL)-1.094 x age-0.287 x (0.739 if female)
A patient will be considered to be of Japanese origin if the patient was screened at a site 
located in Japan and is of Asian Race.
Calculation of age will be done by:

age = (laboratory assessment date – date of birth + 1) / 365.25.
To support analysis of renal function, eGFR throughout the trial will be categorised according 
to the following MDRD staging and a shift table will be provided based on standardized 
observed values. (This shift table will be provided based on a treatment emergent approach 
and independent of treatment.)


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Table 7.8.2: 1
MDRD staging
Stage
eGFR
[mL/min/1.73m2]
Description
1
>=90
Normal renal function 
2
60 to <90
Mild renal function impairment
3a
45 to <60
Moderate renal function impairment 3a
3b
30 to <45
Moderate renal function impairment 3b
4
15 to <30
Severe renal function impairment
5
<15
Kidney failure
Only the albumine / creatinine ratio will be analysed as for urinary albumine and creatinine 
no normalised values can be derived. 
The UACR will be determined (by the laboratory) based on urinary albumine and urinary 
creatinine measures from the same urine sample as:
UACR (μg/mg crea) = urinary albumine (mg/dL) / urinary creatinine (g/dL)
= urinary albumine (mg/dL) / (8.84 x urinary creatinine (mmol/dL))
For descriptive analyses log10 transformed UACR values will be derived and their change 
from baseline (as difference between log10 transformed values) will be determined. 
A shift table will be provided based on standardized observed values. (This shift table will be 
provided based on a treatment emergent approach and independent of treatment.)
Table 7.8.2: 2
UACR categorisation
Stage
UACR
Description
Label for displays
1
<30
Normal UACR
<30 mg/g (normal)
2
>=30 to <=300
Microalbuminuria
>=30 to <=300 mg/g 
(elevated)
3
>300
Macroalbuminuria
>300 mg/g (high)
In addition, a shift table based on the KDIGO categories will be provided from baseline to 
last value on treatment:


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Table 7.8.2: 3 Prognosis of chronic kidney disease by GFR and albuminuria category
                                UACR (mg/gcrea)
<30
>=30 to <=300
>300
                              
eGFR (MDRD)
[mL/min/1.73m2]
>=90
low risk
moderately 
increased risk
high risk
60 to <90
low risk
moderately 
increased risk
high risk
45 to <60
moderately 
increased risk
high risk
very high risk
30 to <45
high risk
very high risk
very high risk
15 to <30
very high risk
very high risk
very high risk
<15
very high risk
very high risk
very high risk
Clinically significant abnormal laboratory values
The definition of clinically significant abnormal laboratory safety values will follow the BI 
standard rules (5) except for fasting plasma glucose. A fasting plasma glucose value less than 
54 mg/dL (<3.0 mmol/L) will be considered a clinically relevant decrease, a clinically 
relevant increase is not defined for this trial.  
Investigation of amylase and lipase
Following analyses will be performed for amylase and lipase:

Descriptive statistics for baseline, last value on-treatment and follow-up value

Descriptive statistics for values over time (on-treatment including values before and after
antidiabetic rescue therapy)

Shift tables for baseline, last value on treatment and maximum value on treatment with 
categorisation of <LLN, LLN to ULN, ULN to <=3ULN, >=3*ULN and for every week
 
 
 
 
 


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7.8.3
Vital signs
In-clinic pulse rate, SBP and DBP will be summarised by treatment group per week and as 
change from baseline to each week using descriptive statistics based on the treated set.
7.8.4
ECG
Clinically relevant abnormal findings will be reported as AEs or respectively as baseline 
conditions.
Any findings resulting in an assessment of silent MIs or adjudicated confirmed outcome 
events will be analysed as described in Sections 7.4 and 7.5. AE analysis will take place as 
planned in Section 7.8.1.
Heart rate will be summarised by treatment group per week and as change from baseline to 
each week using descriptive statistics based on the treated set.
7.8.5
Others
Waist circumference
Simple descriptive statistics over time is planned on the TS, based on observed values 
(without imputation).
Modified Rankin scale
The endpoint of occurrence of or time to first disabling or fatal stroke will be based on the 
MRS assessment. In case of a missing assessment, the grade will be set to 5, if the patient has 
not died, otherwise to grade 6. If an MRS assessment is available for a stroke, but has not 
been confirmed by the adjudication committee, this assessment will not be used for the 
endpoint of time and occurrence of first disabling or fatal stroke.
As a supporting analysis missing MRS assessments will not be imputed.
Titration
Overviews on titration including investigator’s reasons will be presented.


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8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", version 
2.0; IDEA for CON.
2
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON.
3
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current 
version; IDEA for CON.
4
001-MCG-157: "Display and Analysis of Laboratory Data", current version; IDEA 
for CON.
5
001-MCG-157_RD-02: " Handling, Display and Analysis of Laboratory Data: 
Standard Clinical Evaluation Criteria", current version; IDEA for CON.
6
001-MCS-80-606: " Handling of Non-Compliances in Medicine and QRPE”, 
current version; IDEA for CON.
7
R07-4680: “Modelling Survival Data in Medical Research”, Collet D (2003),
Chapman and Hall.
8
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version.
9
CPMP/ICH/363/96: “Statistical Principles for Clinical Trials”, ICH Guidline E9; 
current version.


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TSAP for BI Trial No: 1218.74
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Boehringer Ingelheim
TSAP for BI Trial No: 1218.74
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Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
First 
22-Jan-14
None
This is the draft TSAP without any 
modification
Second final
11-Aug-16
Refer to 
Section 
4
Refer to Section 4
Revised
16-March-18
Refer to 
Section 
4
Refer to Section 4,
Reference for ICH E9 added


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02152478
4.0
8-01-tsap-core
A multicentre, international, randomised, parallel group, double blind study to
evaluate Cardiovascular safety of linagliptin versus glimepiride in patients with type
2 diabetes mellitus at high cardiovascular risk.
Author-Statistician
19 Mar 2018 08:46 CET
Approval-Medical Writer
19 Mar 2018 10:31 CET
Approval-Trial Clinical Monitor
19 Mar 2018 11:47 CET
Approval-Project Statistician
19 Mar 2018 14:05 CET
Approval-Team Member Medicine
20 Mar 2018 17:52 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02152478
4.0