A Regulatory Requirement Non Interventional Study to Monitor the Safety and Effectiveness of Trajenta (Linagliptin, 5 mg, q.d) in Korean Patients With Type 2 Diabetes Mellitus(SELINA Study)
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

 
 
Non-Interventional Study Protocol 
 
Doc. No.: UXX-XXXX 
 
BI Study No.: 
1218.104 
 
 
BI Investigational 
Product(s): 
Linagliptin 
Title: 
A regulatory requirement non interventional study to monitor the safety 
and effectiveness of Trajenta (Linagliptin, 5 mg, q.d) in Korean 
patients with type 2 diabetes mellitus 
(SELINA study) 
Clinical Phase: 
IV 
Trial Clinical 
Monitor: 
Phone: 
   Fax: 
 
Principal 
Investigator: 
Not Applicable 
 
 
Status: 
Final protocol (Revised protocol) 
Version and Date: 
Version: 
2.1 
         
    Date: 22 Feb 2017 
 
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 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 
 
 

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NON-INTERVENTIONAL STUDY PROTOCOL SYNOPSIS 
 
Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim Korea 
 
Name of finished product: 
Trajenta 
Name of active ingredient: 
 
Linagliptin 
 
Protocol date: 
Trial number: 
 
Revision date: 
22 Feb 2017 
1 December 2011 
1218.104/UXX-
XXXX 
Title of study: 
A regulatory requirement non interventional study to monitor the safety and 
effectiveness of Trajenta (Linagliptin, 5 mg, q.d) in Korean patients with type 2 
diabetes mellitus (SELINA study) 
Principal     
Investigator: 
To be decided 
Study site(s) : 
Multi-centre study 
Clinical phase: 
IV 
Objectives: 
To monitor the safety profile and effectiveness of linagliptin in Korean patients with 
type 2 diabetes mellitus in a routine clinical practice setting  
Methodology: 
Prospective, non-interventional, open-label, multi-centre national study 
No. of patients:  
 
 
Total entered: 
3,000 approximately 
 
each treatment: 
Single arm (N=3,000 approximately) 
Diagnosis: 
Patients diagnosed with type 2 diabetes mellitus  
Main criteria for 
inclusion: 
1) No previous exposure to Trajenta 
2) Patients who have been started on Trajenta in accordance with the approved label 
in Korea 
3) No current participation in clinical trials 
4) Patients who have signed on the data release consent form 
Test product(s) : 
Linagliptin 
 
dose: 
5 mg q.d 
 
mode of admin. : Oral administration 
Comparator product(s): Not applicable 
 
dose: 
 
mode of admin. : 
 

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Non-interventional study protocol 
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Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim Korea 
 
Name of finished product: 
Trajenta 
Name of active ingredient: 
 
Linagliptin 
 
Protocol date: 
Trial number: 
 
Revision date: 
22 Feb 2017 
1 December 2011 
1218.104/UXX-
XXXX 
Duration of treatment: 1) Treatment duration for short-term surveillance: 12±2 weeks,  
                                              long-term surveillance: 24±2 weeks. 
2) Study duration: 6 years. (KFDA set Trajenta re-examination period from 14 Sep 
2011 to 13 Sep 2017. Interim report planned biannually for the initial two years 
and annually thereafter by Dec 2017.)   
Criteria for 
effectiveness:  
1. Main endpoint  
1) Change from baseline in HbA1c after 24 weeks of treatment. 
2. Other endpoint   
1) Occurrence of treat to target effectiveness response, that is an HbA1c under 
treatment of < 6.5% after 24 weeks of treatment. 
2) Occurrence of relative effectiveness response (HbA1c lowering by at least 0.5% 
after 24 weeks)  
3) Change from baseline in fasting plasma glucose (FPG) after 24 weeks of 
treatment 
Criteria for safety: 
All reported adverse events including hypoglycemic events in patients who take at 
least one dose of Trajenta will be noted. 
Endpoints pertaining to safety will be presented as incidence rates of adverse events 
Statistical methods: 
Descriptive statistics 

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FLOW CHART 
Data points 
Baseline 
Follow-up 1 
Follow-up 2 
Visit Number 
1 
2 
3 
Week/s 
0 
12±2 
24±2 
Diagnosis 
X 
 
 
Inclusion / exclusion criteria 
X 
 
 
Demographics 
X 
 
 
Diabetes mellitus complications 
X 
 
 
Other medical history 
X 
 
 
Anti-hyperglycemic agents 
X 
X 
X 
Concomitant medications 
X 
X 
X 
Trajenta administration status 
X 
X 
X 
Renal function  
X A 
 
 
Effectiveness endpoints 
X 
X 
X 
Changes in lab tests 
 
X A 
X A 
Adverse events 
 
X 
X 
Study completion 
 
X 
X 
A: If applicable. 
 

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TABLE OF CONTENTS 
TITLE PAGE ............................... 오류! 책갈피가 정의되어 있지 않습니다. 
NON-INTERVENTIONAL STUDY PROTOCOL SYNOPSIS .................. 2 
FLOW CHART ................................................................................................. 4 
TABLE OF CONTENTS ................................................................................. 5 
ABBREVIATIONS ........................................................................................... 8 
1. 
INTRODUCTION ..................................................................................... 9 
1.1  MEDICAL BACKGROUND .............................................................................. 9 
1.2  DRUG PROFILE ................................................................................................. 9 
2. 
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT ........................................................................................ 10 
2.1  RATIONALE FOR PERFORMING THE STUDY ....................................... 10 
2.2  STUDY OBJECTIVES ...................................................................................... 10 
2.2.1  Primary objective ................................................................................... 10 
2.2.2  Secondary objective ............................................................................... 10 
2.3  BENEFIT-RISK ASSESSMENT ..................................................................... 10 
3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION ............ 11 
3.1  OVERALL DESIGN AND PLAN .................................................................... 11 
3.1.1  Administrative structure of the study .................................................. 11 
3.2  DISCUSSION OF STUDY DESIGN ................................................................ 11 
3.3  SELECTION OF POPULATION .................................................................... 12 
3.3.1  Main diagnosis for study entry ............................................................. 12 
3.3.2  Inclusion criteria .................................................................................... 12 
3.3.3  Exclusion criteria ................................................................................... 12 
3.3.4  Removal of patients from therapy or assessments .............................. 12 
3.3.4.1  Removal of individual patients (therapy or assessments) .......... 12 
3.3.4.2  Discontinuation of the study by the sponsor .............................. 12 
4. 
TREATMENTS ....................................................................................... 13 
4.1  PRESCRIBED TREATMENTS TO BE OBSERVED ................................... 13 
4.1.1  Identity of test product(s) and comparator product(s) ...................... 13 
4.1.2  Method of assigning patients to treatment groups .............................. 13 
4.1.3  Selection of doses in the study ............................................................... 13 
4.1.4  Drug assignment and administration of doses for each patient ........ 13 
4.2  CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT .................................................................................................... 13 
4.2.1  Rescue medication, emergency procedures, and additional 
treatment(s) ............................................................................................ 13 
4.2.2  Restrictions ............................................................................................. 13 
4.2.2.1  Restrictions regarding concomitant treatment ............................ 13 
4.2.2.2   Restrictions on diet and life style ............................................... 13 
5. 
VARIABLES AND THEIR ASSESSMENT ........................................ 14 
5.1  SAFETY .............................................................................................................. 14 

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5.1.1  Endpoint(s) of safety .............................................................................. 14 
5.1.2  Assessment of adverse events ................................................................ 14 
5.1.2.1  Definitions of adverse events ..................................................... 14 
5.1.2.2  Adverse event and serious adverse event reporting ................... 16 
5.1.3  Assessment of safety laboratory parameters ....................................... 17 
5.1.4  Electrocardiogram ................................................................................. 17 
5.1.5  Assessment of other safety parameters ................................................ 17 
5.2  EFFECTIVENESS ............................................................................................. 17 
5.2.1  Endpoint(s) of effectiveness ................................................................... 17 
5.2.2  Assessment of effectiveness ................................................................... 18 
5.3  OTHER ............................................................................................................... 18 
5.4  APPROPRIATENESS OF MEASUREMENTS ............................................. 18 
6. 
SURVEILLANCE PLAN ....................................................................... 19 
6.1  VISIT SCHEDULE ............................................................................................ 19 
6.2  DETAILS OF STUDY PROCEDURES AT SELECTED VISITS ............... 19 
6.2.1  Screening and run-in period(s) ............................................................. 19 
6.2.2  Treatment period(s) ............................................................................... 19 
6.2.3  End of trial and follow-up period ......................................................... 20 
7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ........................................................................................ 21 
7.1  STATISTICAL DESIGN - MODEL ................................................................ 21 
7.2  NULL AND ALTERNATIVE HYPOTHESES .............................................. 21 
7.3  PLANNED ANALYSES .................................................................................... 21 
7.3.1  Safety analyses ........................................................................................ 21 
7.3.2  Main analyses of effectiveness ............................................................... 21 
7.3.3  Other analyses of effectiveness ............................................................. 21 
7.3.4  Interim analyses ..................................................................................... 22 
7.4  HANDLING OF MISSING DATA .................................................................. 22 
7.5.  RANDOMISATION .......................................................................................... 22 
7.6  DETERMINATION OF SAMPLE SIZE ........................................................ 22 
8. 
DATA PROTECTION, STUDY RECORDS ....................................... 23 
8.1  STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT .......................................................................................................... 23 
8.2  DATA QUALITY ASSURANCE ..................................................................... 24 
8.3  RECORDS .......................................................................................................... 24 
8.3.1  Source documents .................................................................................. 24 
8.3.2  Direct access to source data and documents ........................................ 24 
8.3.3  Storage of records .................................................................................. 24 
8.4  PROCEDURES FOR REPORTING ADVERSE EVENTS .......................... 25 
8.4.1  Time windows ......................................................................................... 25 
8.4.2  Documentation of adverse events and patient narratives .................. 25 
8.5  STATEMENT OF CONFIDENTIALITY ....................................................... 25 
8.6  PUBLICATION POLICY ................................................................................. 25 
9. 
REFERENCES ........................................................................................ 26 
9.1  PUBLISHED REFERENCES........................................................................... 26 

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9.2  UNPUBLISHED REFERENCES ..................................................................... 26 
10.  APPENDICES ......................................................................................... 27 
10.1  ELECTRONIC CASE REPORT FORM ........................................................ 27 
10.2  SAE REPORT FORM ....................................................................................... 27 
10.3  PREGNANCY MONITORING FORM .......................................................... 27 
11.  SUMMARY OF NIS PROTOCOL MODIFICATIONS ..................... 28 
 

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ABBREVIATIONS 
AE 
Adverse Event 
ACR 
Albumin Creatinine Ratio 
ADR 
Adverse Drug Reaction 
CA 
Competency Authority 
CEU 
Case Entry Unit 
CML 
Clinical Monitor Local 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSO 
Clinical Safety Officer 
DPP-4 
Dipeptidyl-peptidase 4  
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate  
EDC 
Electronic Data Capture 
FU 
Follow up 
FPG 
Fasting Plasma Glucose 
GIP 
Glucose dependent Insulinotropic Peptide 
GLP-1 
Glucagon-Like Peptide-1 
HbA1c 
Glucosylated Hemoglobin 
KFDA 
Korea Food and Drug Administration 
KIMS 
Korea Index of Medical Specialties 
KPAC 
Korean Pharmaceutical Affairs Code 
KPMA 
Korea Pharmaceutical Manufacturers Association 
KRPIA 
Korean Research-based Pharmaceutical Industry Association 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
ID 
Identification 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
NCE 
New Chemical Entity 
NIS 
Non Interventional study 
SAE 
Serious Adverse Event 
T2DM 
Type 2 Diabetes Mellitus 
TSAP 
Trial Statistical Analysis Plan 
 

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1. 
INTRODUCTION 
1.1 
MEDICAL BACKGROUND 
Type 2 diabetes mellitus (T2DM) accounts for 90% to 95% of all cases of diabetes and is an 
increasingly prevalent disease with an estimated 180 million affected people worldwide. Its 
incidence is expected to double during the next 20 years (R09-4240). In Korea, the 
prevalence of T2DM patient was 9% in 2010 according to the Diabetes Atlas 4th edition from 
International Diabetes Foundation.1 Complications induced by hyperglycaemia are currently 
the most frequent cause of adult-onset loss of vision, renal failure, and non-traumatic lower 
extremity amputations in the industrialized world. T2DM is also associated with 
macrovascular complications with a 2- to 4-fold increase in cardiovascular disease risk. The 
high frequency of complications leads to a significant reduction of life expectancy (R09-
4241). 
 
Although several antidiabetic compounds have been developed to improve glucose control 
and attenuate the metabolic derangements that accompany uncontrolled T2DM, none of these 
compounds has been able to maintain long-term glycaemic control. 
 
The improved understanding of the incretin effect has contributed to the development of a 
new class of antidiabetic agents. The incretin effect results from glucagon like peptide-1 
(GLP-1) and glucose dependent insulinotropic peptide (GIP), two intestinal peptides that are 
released in the presence of glucose or nutrients in the gut. GLP-1 stimulates insulin secretion, 
thereby augmenting glucose-stimulated insulin release. However, there is little risk of 
hypoglycaemia due to GLP-1 because GLP-1 activity decreases when glucose concentrations 
fall below 55 milligrams per deciLiter (mg/dL). Normally, GLP-1 is almost instantaneously 
inactivated by the enzyme DPP-4 that is widely expressed in many tissues including kidney, 
liver, intestine, lymphocytes and vascular endothelial cells. Therefore, inhibiting DPP-4 
would prolong the activity of GLP-1 for stimulating insulin secretion. 
 
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 (U04-1767-09). 
1.2 
DRUG PROFILE 
Linagliptin is an orally administered, highly selective DPP-4 inhibitor which is primarily 
excreted via bile and gut for the treatment of patients with T2DM 2; its pharmacokinetic and 
pharmacodynamic profile make it suitable for once-daily dosing (P08-06359, P09-09556). 
 
 

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2. 
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT 
2.1 
RATIONALE FOR PERFORMING THE STUDY 
According to the local regulations, when a new chemical entity (NCE) is registered, a 
regulatory non interventional study (rNIS) of an extended period (4 or 6 years) should be 
conducted. Such rNIS can provide supplementary data to monitor the safety of NCEs in a 
real-life situation. Data collected in randomised clinical trials with strict inclusion/exclusion 
criteria and rigorous monitoring schemes have limitations. 
This is a prospective, non-interventional, open-label, multi-centre study. It will provide 
additional safety information of Trajenta in Korean patients with type 2 diabetes mellitus in 
routine clinical settings. 
2.2 
STUDY OBJECTIVES 
2.2.1 
Primary objective 
The primary objective of this study is to monitor the safety profile of Trajenta in Korean 
patients with type 2 diabetes mellitus (T2DM) in a routine clinical setting. 
2.2.2 
Secondary objective 
The secondary objective of the study is to monitor the effectiveness of Trajenta by evaluating 
the change from baseline to endpoint in the glycosylated hemoglobin (HbA1c), fasting plasma 
glucose (FPG) of Korean T2DM patients. 
2.3 
BENEFIT-RISK ASSESSMENT 
Patients will be managed according to the local practice guidelines. The choice of treatment 
will be solely at the discretion of the participating physician. Trajenta will be administered 
according to the approved label in Korea. Hence there are no additional risks to patients by 
participating in this rNIS.  

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3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION 
3.1 
OVERALL DESIGN AND PLAN  
This rNIS is a prospective, non-interventional, open-label, multi-centre study. As per 
regulation, the re-examination period extends from 14 Sep 2011 until 13 Sep 2017 (6 years). 
However, active enrollment is to be initiated in 2012 after finalizing the re-imbursement 
agreement with the authority. Before initiation of the study, any newly reported adverse 
events collected from other sources such as spontaneous cases, literature cases etc will be 
closely monitored. The last patient follow up is expected in 2016. 
3.1.1 
Administrative structure of the study 
This study will be managed by a project manager of Boehringer Ingelheim Korea. Data 
management and statistics will be outsourced to a qualified contract research organization 
(CRO). 
3.2 
DISCUSSION OF STUDY DESIGN 
This is a single arm study with linagliptin. 
Loss to follow up 
All efforts will be made to minimize loss to follow up, particularly in the tracking of lost 
patients. To the extent possible, occurrence of adverse event, at minimum, for patients lost to 
follow up will be obtained. This allows assessing the impact of informative censoring due to 
treatment discontinuation. Also, patients lost to follow up will be characterized compared to 
the remaining patients and reason and time point of loss to follow up will be evaluated. 
Channeling bias 
 
Channeling bias can occur due to preferential prescribing in relation to different risks for the 
events of interest: e.g., if linagliptin would be more often prescribed to higher risk patients 
compared to other treatments, higher incidences of outcome events were then expected in the 
linagliptin group.  
 
Confounding 
As in any observational study, confounding may affect the estimation of associated between 
drug exposure and outcome of interest and statistical techniques. However, as only major 
confounders for selected research questions can be captured, residual (unmeasured) 
confounding may remain. 

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3.3 
SELECTION OF POPULATION 
A total of 3,000 patients will be enrolled at approximately 80 sites by as many as 100 or more 
NIS physicians. To minimize the selection bias at the site level, the goal is to have 
participating centers reflect a balance between general hospitals and clinics for surveillance. 
The treating physicians will mainly be internists. To minimize the selection bias, consecutive 
patients from each site who meet inclusion criteria will be enrolled in this study. 
3.3.1 
Main diagnosis for study entry 
Patients diagnosed with T2DM will be included.  
3.3.2 
Inclusion criteria 
 Patients who have been started on Trajenta in accordance with the approved label in 
Korea 
 Patients who have signed on the data release consent form  
3.3.3 
Exclusion criteria 
 Patients with previous exposure to Trajenta 
 Current participation in clinical trials  
3.3.4 
Removal of patients from therapy or assessments 
3.3.4.1 Removal of individual patients (therapy or assessments) 
This section is not applicable. 
3.3.4.2 Discontinuation of the study by the sponsor  
Boehringer Ingelheim Korea reserves the right to discontinue the study overall or at a 
particular study site at any time for the following reasons: 
1. Emergence of any effectiveness/safety information that could significantly affect 
continuation of the study 
2. Violation of applicable local regulations, the NIS protocol, or the contract by a study site 
or participating physician, disturbing the appropriate conduct of the study. 

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4. 
TREATMENTS 
4.1 
PRESCRIBED TREATMENTS TO BE OBSERVED 
4.1.1 
Identity of test product(s) and comparator product(s) 
Trajenta will be prescribed according to the local label and at the discretion of the treating 
physician. Since this is a non-interventional study, the drug will not be supplied by the 
sponsor. Furthermore, the sponsor will not cover the expenses related to other medications 
taken by the patient, interventions, procedures, or diagnostic tests.  
4.1.2 
Method of assigning patients to treatment groups 
The choice of treatment is fully at the discretion of the physician and the patient. There is no 
treatment assignment by a third party. 
4.1.3 
Selection of doses in the study 
Linagliptin will be administered 5 mg once a day which is within the authorized label in 
Korea. 
4.1.4 
Drug assignment and administration of doses for each patient 
The physicians indicate doses and timing. 
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT 
The protocol will allow additional drugs considered necessary for the patient’s welfare to be 
prescribed at the discretion of the treating physician. It is required, however, to record the 
details of all concomitant medication administered to the patient during the course of 
treatment in eCRF. This includes concomitant therapies started one month prior to Trajenta 
initiation until the patient completes the final follow-up visit. 
4.2.1 
Rescue medication, emergency procedures, and additional treatment(s) 
Please refer to the current local label. 
4.2.2 
Restrictions 
4.2.2.1 Restrictions regarding concomitant treatment 
Please refer to the current local label. 
4.2.2.2  Restrictions on diet and life style 
Please refer to the current local label. 

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5. 
VARIABLES AND THEIR ASSESSMENT 
5.1 
SAFETY 
5.1.1 
Endpoint(s) of safety 
All reported adverse events including hypoglycemic events in patients who take at least one 
dose of Trajenta will be noted. 
Hypoglycemic events include the overall hypoglycemic events, symptomatic hypoglycemia, 
confirmed hypoglycemia, nocturnal hypoglycemia, and severe hypoglycemia. 
Endpoints pertaining to safety will be presented as incidence rates of adverse events and will 
include: 
 
adverse events 
 
unexpected adverse events 
 
serious adverse events 
 
drug-related adverse events 
 
adverse events leading to discontinuation  
 
adverse events by intensity, outcome of the event, causality  
5.1.2 
Assessment of adverse events 
5.1.2.1 Definitions of adverse events 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment. 
 
Serious adverse event 
A 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. 
 

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Adverse drug reaction 
Adverse drug reaction (ADR) refers to any harmful, unintended reaction to the 
pharmaceutical product of any dose at which a causal relationship with the pharmaceutical 
product cannot be ruled out. 
 
Non serious adverse drug reaction 
Non serious adverse drug reaction is defined as any ADR which does not meet the SAE 
criteria.  
 
Intensity of adverse event 
The intensity of the AE should be defined based on the following three categories and 
according to medical and scientific judgment: 
Mild: 
Transient symptoms which are subjective or objective but no interference with 
the patient’s daily activities. No change in dosage is needed to continue the 
treatment. 
Moderate: 
Marked symptoms with moderate interference with the patient’s daily 
activities. Reduced dosage or unplanned treatment is necessary for the relief of 
adverse events. 
Severe: 
Considerable and unacceptable interference with the patient’s daily activities. 
Discontinuation of the study drug is required because of significant adverse 
events. 
 
To ensure that no confusion or misunderstanding of the difference between the terms ‘serious’ 
and ‘severe’ which are not synonymous, it should be noted that SAE does not necessarily 
correspond to serious or not serious AE to severe ones. All SAEs will be reported regardless 
of the intensity as mentioned above. 
Causal relationship of adverse event 
Medical judgment will be used to determine the causal relationship, after 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 will be recorded in the eCRF.  
Related 
a. Certain: An event occurring in a plausible time relationship to drug administration and that 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event must be 
definitive pharmacologically or phenomenologically, using a satisfactory rechallenge 
procedure if necessary. 
b. Probable/Likely: An event with a reasonable time sequence to administration of the drug, 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows 

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a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not 
required to fulfill this definition. 
c. Possible: An event with a reasonable time sequence to administration of the drug, but 
which could also be explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear. 
d. Conditional/Unclassified: Case of requiring more data or reviewing the additional data for 
the appropriate assessment 
e. Unassessable/Unclassifiable: Case that it cannot be judged and complemented or 
confirmed due to the insufficient or contradictory information  
 
Unrelated 
d. Unlikely: An event with a temporal relationship to drug administration which makes a 
causal relationship improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations. 
Worsening of the underlying disease or other pre-existing conditions 
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the (e)CRF. 
 
Changes in vital signs, ECG, physical examination, and laboratory test results  
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the (e)CRF, if they are judged clinically relevant by the NIS 
physician. 
 
5.1.2.2 Adverse event and serious adverse event reporting 
All adverse events occurring from the start of Trajenta treatment up to 7 days after last 
follow‐up visit need to be collected, documented and reported to the sponsor using the AE 
reporting form of eCRF (Attachment 1). All SAEs must be reported with details of non-
serious AEs occurring at the same time, within 24 hours of occurrence via telephone/fax to 
the Clinical Safety Officer (CSO) of BI Korea using the SAE report form (Attachment2). If 
any new or further information to these events is available, a follow-up SAE report has to be 
sent to BI. All SAEs and non-serious AEs must include a causal relationship assessment from 
the physician.  
 
All other Adverse Events must be reported using eCRFs within 2 weeks to the Sponsor.  
 
Contact details:   
Clinical Safety Officer 
Tel:  
 
Fax:  
 

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Address: 
  
 
 
 
Pregnancy 
Rarely, patients taking part in regulatory non interventional studies can get pregnant. Once a 
patient enrolled into the study and exposed to Trajenta becomes pregnant, the NIS physician 
will stop the drug and report immediately to the sponsor. Drug exposure during pregnancy 
has to be reported immediately (within 24 hours or next business day, whichever is shorter) to 
CSO. Furthermore, the details of all the drugs to which the patient exposed at the time of 
pregnancy will be recorded. The outcome of the pregnancy associated with the drug exposure 
will be assessed. In the absence of an (S)AE, only the Pregnancy Monitoring Form 
(Attachment 3) for NIS, not the SAE form is to be completed.  
 
5.1.3 
Assessment of safety laboratory parameters 
This section is not applicable. 
5.1.4 
Electrocardiogram 
This section is not applicable. 
5.1.5 
Assessment of other safety parameters 
This section is not applicable. 
5.2 
EFFECTIVENESS 
5.2.1 
Endpoint(s) of effectiveness 
The main effectiveness endpoint in this study is the change from baseline in HbA1c after 24 
weeks of treatment.  
The other effectiveness endpoints are the following: 
 
Occurrence of treat to target effectiveness response, that is an HbA1c under treatment 
of < 6.5%  after 24 weeks of treatment. 
 
Occurrence of relative effectiveness response (HbA1c lowering by at least 0.5% after 
24 weeks)  
 
Change from baseline in fasting plasma glucose (FPG) after 24 weeks of treatment 

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5.2.2 
Assessment of effectiveness 
HbA1c: 
HbA1c should be collected within 1 month prior to baseline and after 12weeks and 24 weeks 
of treatment.  
Fasting plasma glucose (FPG): 
FPG should be collected within 1 month prior to baseline and after 12weeks and 24 weeks of 
treatment.  
5.3 
OTHER 
This section is not applicable. 
5.4 
APPROPRIATENESS OF MEASUREMENTS 
This section is not applicable. 

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6. 
SURVEILLANCE PLAN 
6.1 
VISIT SCHEDULE 
The flow chart at the front of the protocol summarizes the data to be collected at each 
visit(recommended visit schedule - Visit 2 : 12±2weeks/ Visit 3 : 24±2weeks). The 
procedures are further described below. 
6.2 
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS 
6.2.1 
Screening and run-in period(s) 
This section is not applicable as this is a non-interventional study. 
6.2.2 
Treatment period(s) 
As per regulations, enrolled patients will be followed up for 24 week treatment period. There 
will be a visit window of ±2 weeks. To minimize the selection bias at the site level, the goal 
is to have participating centers reflect a balance between general hospitals and clinics for 
surveillances. 
 
6.2.2.1 Visit 1 – Baseline Visit  
Upon patient enrollment, the following will be recorded on the patient’s eCRF. 
 
Visit date 
 
Diagnosis: date of the diagnosis of T2DM, family history  
 
Inclusion / exclusion criteria 
 
Demographic data: year of birth(age), gender, pregnancy, previous allergy, height, weight, 
waist circumference, smoking status  
 
Diabetes mellitus related complication  
 
Other medical history: history of concomitant disease within 6 months 
 
Renal Function: record Serum creatinine, eGFR, urin ACR if blood test result is available 
(collected within the latest 6-month period)  
 
Effectiveness endpoints : HbA1c, FPG (Lab data should be collected within 1month prior 
to baseline) 
 
Concomitant anti-hyperglycemic agent: record any anti-hyperglycemic agents have been 
taken prior to the baseline visit  
 
Concomitant medications: record all medications have been taken at least once since one 
month prior to the baseline visit  
 
Dose of Trajenta given 
 
At Visit 1, the patient will be requested to contact the treating physician in the event of any 
adverse events noted after initiating Trajenta treatment. 
 
 
6.2.2.2 Visit 2 (12±2 weeks from Visit 1)  
After 12±2 weeks from Visit 1, the patients will return for follow-up. The followings will be 
noted and recorded in the eCRF:  

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 
Visit date 
 
Any change of Trajenta given 
 
Any changes in laboratory tests if there is any lab result which was clinically significant 
compared to data before Trajenta therapy (This data is collected on the basis of medical 
need, i.e. independent of the NIS)  
 
 Effectiveness endpoints : HbA1c, FPG 
 
Concomitant anti-hyperglycemic agent including new medications taken since last visit: 
any change in the concomitant medications (dose and dosing intervals)  
 
Concomitant medications including new medications taken since last visit: any change in 
the concomitant medications (dose and dosing intervals)  
 
Any adverse events noted  
 
Study completion status  
 
6.2.2.3 Visit 3 (24±2 weeks from Visit 1)  
After 24±2 weeks from Visit 1, the patients will return for follow-up. The followings will be 
noted and recorded in the eCRF:  
 
Visit date 
 
Any change of Trajenta given 
 
Any changes in laboratory tests if there is any lab result which was clinically significant 
compared to data before Trajenta therapy (This data is collected on the basis of medical 
need, i.e. independent of the NIS)  
 
Effectiveness endpoints : HbA1c, FPG 
 
Concomitant anti-hyperglycemic agent including new medications taken since last visit: 
any change in the concomitant medications (dose and dosing intervals)  
 
Concomitant medications including new medications taken since last visit: any change in 
the concomitant medications (dose and dosing intervals)  
 
Any adverse events noted  
 
Study completion status  
 
NIS physician’s electronic signature for data integrity 
 
6.2.3 
End of trial and follow-up period 
Patients with adverse events noted at the final follow-up visit or upon premature 
discontinuation of Trajenta will be monitored further until the resolution of those adverse 
events. Alternatively, those patients will be followed up until the NIS physician and sponsor 
agree that no further follow-up is necessary. 
 

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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
Details are provided in the statistical Trial Statistical Analysis Plan (TSAP). 
7.1 
STATISTICAL DESIGN - MODEL 
In this non-interventional study, all statistical analyses will be descriptive. The degree of 
statistical significance (p-values) and precision (confidence intervals) for the statistical 
methods used for explorative purposes will be shown. No confirmatory hypotheses are pre-
specified. 
 
7.2 
NULL AND ALTERNATIVE HYPOTHESES 
No hypotheses are tested. (See Section 7.1) 
7.3 
PLANNED ANALYSES 
7.3.1 
Safety analyses 
Demographic and baseline characteristics will be summarized descriptively for the entire 
cohort of eligible patients. 
 
Adverse events (AEs) will be coded according to the latest version of Medical Dictionary for 
Drug Regulatory Affairs (MedDRA) coding system. Concomitant therapies will be coded 
according to the latest version of KIMS (Korea Index of Medical Specialties) coding system. 
The trial database will not be locked until coding is complete.  
 
Safety analyses will be based on all patients treated, i.e. all patients who received at least one 
dose of Trajenta. However, if data for patients who have been treated with Trajenta beyond 
the scope of approved label are collected, separate safety analyses will be performed. Safety 
analyses will be performed based on demographics and baseline characteristics. 
 
Patients lost to follow up will be characterized compared to the remaining patients and reason 
and time point of loss to follow up will be evaluated. 
7.3.2 
Main analyses of effectiveness 
A descriptive analysis of endpoints is planned. For patients treated with Trajenta, the change 
of HbA1c from baseline and last follow-up visit will be calculated. Effectiveness analyses will 
be performed based on demographics and baseline characteristics.  
7.3.3 
Other analyses of effectiveness 
A descriptive analysis of effectiveness endpoints is planned. For patients treated with 
Trajenta, the occurrence of treat to target effectiveness response, that is an HbA1c under 
treatment of < 6.5% and relative effectiveness response (HbA1c lowering by at least 0.5%) 

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after 24 weeks will be calculated. In addition, the change of FPG from baseline and last 
follow-up visit will be calculated. Effectiveness analyses will be performed based on 
demographics and baseline characteristics.  
 
7.3.4 
Interim analyses 
In accordance with local regulation for rNIS, interim analyses are planned biannually for the 
initial two years and annually thereafter.  
7.4 
HANDLING OF MISSING DATA 
As this is non-interventional study, there are no required investigations and diagnostic 
procedures (e.g. lab, ultrasound).  
Maximum attempt will be made to ensure the completeness of data collection. All available 
data will be used in the data analysis. There will be no imputation of data to fill the missing 
values. 
 
7.5. 
RANDOMISATION 
This section is not applicable as this is a non-interventional study. 
7.6 
DETERMINATION OF SAMPLE SIZE 
Sample size of 3,000 patients is based on the requirement of the local regulatory authority 
(Korean FDA). As per regulation, long-term surveillance is necessary for the indication. Since 
T2DM is chronic disease, it might be restrictive to collect safety and effectiveness data in short-
term (12±2weeks) period, all patients will be enrolled for longer-term (24±2weeks) surveillance.  

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8. 
DATA PROTECTION, STUDY RECORDS 
The International Conference on Harmonization/Harmonized Tripartite Guideline for Good 
Clinical Practice (ICH/GCP) does not often apply to NIS as most elements are relevant for 
controlled clinical trials. However, in this NIS, all attempts will be made to adhere, as close 
as possible, to the standards of ICH/GCP.  
The protocol of this regulatory requisite NIS will be submitted to the Korea Food and Drug 
Administration (KFDA) for notification. It is not a local requirement in Korea to obtain 
Institutional Review Board (IRB) approval for the conduct of regulatory requisite NIS. 
However, the protocol of this NIS will be submitted to IRBs whenever required or requested 
by these institutions. This study will be conducted in accordance with the Standards for Re-
examination of New Medicines notified by KFDA, Korean Pharmaceutical Affairs Code 
(KPAC), Enforcement Regulation of KPAC and other applicable local laws and industry 
code (including but not limited to the Regulations on Fair Competition in the Trade of 
Medicines of KPMA and KRPIA).  
Boehringer Ingelheim Korea will submit periodic reports during re-examination period, and 
the final report to KFDA upon study completion. The periodic report for the final year will be 
substituted with the final report. When required, the interim reports and the final report will 
be submitted to the IRBs as well.  
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT 
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB/IEC and the competent authority (CA) according to the local 
regulations. The same applies for the implementation of changes introduced by amendments. 
Prior to patient participation in the study, written data release consent form shall be obtained 
from each patient (or the patient’s legally accepted representative). Each signature must be 
personally dated by each signatory and the data release consent and any additional patient-
information form retained by the NIS physician as part of the trial records. A signed copy of 
the data release consent and any additional patient information must be given to each patient 
or the patient’s legally accepted representative. 
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim Korea in accordance with the local data protection law. The level of 
disclosure shall also be explained to the patient. 
The patient shall be informed that his/her medical records may be examined by authorised 
monitors (MPMs) or Clinical Quality Assurance auditors appointed by sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 

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8.2 
DATA QUALITY ASSURANCE 
A quality assurance audit/inspection of this study 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 participating physician’s study-related 
files and correspondence, and the data release agreement documentation of this study. 
8.3 
RECORDS 
All of the clinical data will be captured via a web-based EDC (Electronic Data Capture) 
System. The site staff will enter and edit the data via a secure network, with secure access 
features (username, password and secure identification – an electronic password system). A 
complete electronic audit trail will be maintained. The treating physician will approve the 
data using an electronic signature. 
Patients will not be identified on the eCRF by name. Appropriate coded identification (i.e., 
patient number) will be used. The treating physician will make a separate confidential record 
of these details (patient identification code list) to permit identification of all patients enrolled 
in this study in case follow-up is required. Likewise, any supporting documentation will be 
redacted of any patient identifying information, and the patient ID number clearly written on 
the documents. 
 
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 will be filed at the treating physician’s site. 
It is necessary that the data entered in the eCRFs that are transcribed from the source 
documents are consistent with the source documents or the discrepancies need to be 
explained. The treating physician may need to request previous medical records, transfer 
records, and current medical records.  
8.3.2 
Direct access to source data and documents 
The NIS physician / site will permit study-related monitoring, audits and regulatory 
inspection, providing direct access to all related source data/documents. All source 
documents including eCRFs will be made available for review by sponsor’s Medical Project 
Manager (MPM) or designees and inspection by health authorities (e.g., KFDA). The MPM 
and auditor may review all eCRFs, and written data release agreements.  The accuracy of the 
data will be verified by reviewing the documents described in Section 8.3.1. 
8.3.3 
Storage of records 
The NIS physician and the site are jointly responsible for maintaining essential study 
documents for 3 years after completion of the study (defined as termination date of re-
examination period) by the Pharmaceutical Affairs Law and shall take measures to prevent 
accidental or premature destruction of these documents.  

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8.4 
PROCEDURES FOR REPORTING ADVERSE EVENTS 
8.4.1 
Time windows 
All AEs, serious and non-serious, occurring during the course of the rNIS will be collected, 
documented and reported to the sponsor by the investigator on the appropriate eCRF. 
Reporting will be done according to the specific definitions and instructions detailed 
in the ‘Adverse Event Reporting’ section of the site materials (that include all necessary 
documents, the protocol, instructions for conducting rNIS, the package insert etc.). 
 
The investigator has the responsibility to report AEs during the specified observational phase. 
 
Any SAE, whether or not considered related to Trajenta tablets, or whether or not 
Trajenta tablets has been administered, must be reported immediately via eCRF.  
8.4.2 
Documentation of adverse events and patient narratives 
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 the local 
regulatory requirements. 
For each AE, the investigator will provide the onset, end, intensity, outcome, seriousness and 
action taken with Trajenta tablets. The investigator will determine the relationship of 
Trajenta tablets to all AEs as defined in the 'Adverse Event Reporting' section of the 
physician binder. 
 
8.5 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this study will be considered 
confidential and disclosure to third parties will be prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers. 
Treatment data will be made available to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated from the 
study will be made available for inspection on request by the participating physicians, the 
sponsor and/or its representatives and/or designees, by the IRBs/IECs and the regulatory 
authorities. 
8.6 
PUBLICATION POLICY 
Boehringer Ingelheim, to the best of their ability will support the process of free exchange of 
relevant scientific information. Any publication of the result of this NIS study must be 
consistent with the Boehringer Ingelheim publication policy. 

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9. 
REFERENCES  
9.1 
PUBLISHED REFERENCES 
 R09-4240 
World Health Organization. Diabetes. 
http://www.who.int/mediacentre/factsheets/fs312/en/ ; (WHO Fact sheet; no 
312) 2008.  
 
R09-4241 
Haffner SM, Letho S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from 
coronary heart disease in subjects with type 2 diabetes and in non-diabetic 
subjects with and without prior myocardial infarction. N. Engl. J. Med. 1998; 
339 (4): 229-234. 
 
P08-06359     Thomas L et al., (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-
methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel 
xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and 
longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J 
Pharmacol Exp Ther. 2008; 325: 175–82 
 
P09-09556     Graefe-Mody EU et al., Evaluation of the potential for steady-state 
pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor 
linagliptin and metformin in healthy subjects. Curr Med Res Opin. 2009; 25: 
1963–72 
 
9.2 
UNPUBLISHED REFERENCES 
U04-1767-09  
 Linagliptin Investigator's 
Brochure. Version 9. 10 Dec 2010.  
 
1                     International Diabetes Federation. 
http://www.idf.org/diabetesatlas/  
Prevalence extimates of diabetes mellitus, 2010, The Diabetes Atlas 4th 
edition   
 
2                     
 et al., Safety, tolerability, pharmacokinetics, and pharmacodynamics 
of single oral doses of BI 1356, an inhibitor of dipeptidyl peptidase 4, in 
healthy male volunteers. J Clin Pharmacol. 2008; 48: 1171–8  
 
3                     Treatment Guideline for Diabetes 2011, Korean Diabetes Association 

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10. 
APPENDICES 
10.1 
ELECTRONIC CASE REPORT FORM 
See the Attachment 1. 
10.2 
SAE REPORT FORM 
See the Attachment 2. 
10.3 
PREGNANCY MONITORING FORM 
See the Attachment 3. 
 
 

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11. 
SUMMARY OF NIS PROTOCOL MODIFICATIONS 
Summary of Modifications Sheet (SOMS) 
 
Number of Protocol modification 
 
1 
Date of Protocol modification 
 
13 Sep 2012 
BI Trial number 
 
1218.104 
BI Product(s) 
 
Trajenta 
Title of protocol 
 
A regulatory requirement non interventional study to 
monitor the safety and effectiveness of Trajenta 
(Linagliptin, 5 mg, q.d) in Korean patients with type 2 
diabetes mellitus 
SELINA study 
 
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 
 
Refer to amendment table 
Description of change 
 
Rationale for change 
 
 
 
 
 
 

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Number of Protocol modification 
 
2 
Date of Protocol modification 
 
22 Feb 2017 
BI Trial number 
 
1218.104 
BI Product(s) 
 
Trajenta 
Title of protocol 
 
A regulatory requirement non interventional study to 
monitor the safety and effectiveness of Trajenta 
(Linagliptin, 5 mg, q.d) in Korean patients with type 2 
diabetes mellitus 
SELINA study 
 
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 
 
Refer to amendment table 
Description of change 
 
Rationale for change