A Regulatory Requirement Non Interventional Study to Monitor the Safety and Effectiveness of Trajenta Duo® (Linagliptin/Metformin HCl, 2.5 mg/500 mg, 2.5 mg/850 mg and 2.5 mg/1000 mg, b.i.d) in Korean Patients With Type 2 Diabetes Mellitus
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

 
 
Non-Interventional Study Protocol 
 
Doc. No.: U13-3721-01 
 
BI Study No.: 
1288.22 
 
 
BI Investigational 
Product(s): 
Linagliptin, Metformin 
Title: 
A regulatory requirement non interventional study to monitor the safety 
and effectiveness of Trajenta Duo® (Linagliptin/Metformin HCl, 2.5 
mg/500 mg, 2.5 mg/850 mg and 2.5 mg/1000 mg, b.i.d) in Korean 
patients with type 2 diabetes mellitus 
(SELINA Duo study) 
Clinical Phase: 
IV 
Trial Clinical 
Monitor: 
Phone: 
   Fax: 
 
Principal 
Investigator: 
Not Applicable 
 
 
Status: 
Final protocol  
Version and Date: 
Version: 
1.3 
         
    Date: 22 Feb 2017 
 
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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 Duo®. 
Name of active ingredient: 
 
Linagliptin/Metformin FDC 
 
Protocol date: 
Trial number: 
 
Revision date: 
22 Feb 2017 
25 January 2013 
1288.22/U13-3721-01 
Title of study: 
A regulatory requirement non interventional study to monitor the safety and 
effectiveness of Trajenta Duo®. (Linagliptin/Metformin HCl, 2.5 mg/500 mg, 2.5 
mg/850 mg and 2.5 mg/1000 mg, b.i.d) in Korean patients with type 2 diabetes mellitus
(SELINA Duo study) 
Principal     
Investigator: 
Not Applicable 
Study site(s) : 
Multi-centre study 
Clinical phase: 
IV 
Objectives: 
To monitor the safety profile and effectiveness of linagliptin, metformin fixed dose 
combination in Korean patients with type 2 diabetes mellitus in a routine clinical 
practice setting  
Methodology: 
observational, non-interventional, open-label, multi-centre national study 
No. of patients:  
 
 
Total entered: 
600 approximately 
 
each treatment: Single arm (N=600 approximately) 
Diagnosis: 
Patients diagnosed with type 2 diabetes mellitus  
Main criteria for 
inclusion: 
1) No previous exposure to Trajenta®, Trajenta Duo® 
2) Patients who have been started on Trajenta Duo® in accordance with the approved 
label in Korea 
3) No current participation in clinical trials 
4) No contraindications to linagliptin or metformin in accordance with local 
prescribing information 
5) Patients who have signed on the data release consent form 
Test product(s) : 
Linagliptin/Metformin FDC 
 
dose: 
2.5 mg/500 mg, 2.5 mg/850 mg and 2.5 mg/1000 mg, b.i.d 
 
mode of admin. : Oral administration 
Comparator 
product(s): 
Not applicable 

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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 Duo®. 
Name of active ingredient: 
 
Linagliptin/Metformin FDC 
 
Protocol date: 
Trial number: 
 
Revision date: 
22 Feb 2017 
25 January 2013 
1288.22/U13-3721-01 
 
dose: 
 
mode of admin. : 
 
Duration of treatment: 1) Treatment duration for short-term surveillance: 12±2 weeks,  
                                              long-term surveillance: 24±2 weeks. 
2) Study duration: 5 years. (MFDS set Trajenta Duo® re-examination period from 15 
Nov 2012 to 13 September 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 Duo® will be noted. 
Endpoints pertaining to safety will be presented as incidence rates of adverse events 
Statistical methods: 
Descriptive statistics 

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Non-interventional study protocol 
25 Jan 2013 
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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 Duo® administration status 
X 
X 
X 
Renal function  
X A 
 
 
Effectiveness endpoints 
 
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 
NON-INTERVENTIONAL STUDY PROTOCOL SYNOPSIS .................. 2 
FLOW CHART ................................................................................................. 4 
TABLE OF CONTENTS ................................................................................. 5 
ABBREVIATIONS ........................................................................................... 8 
FPG ..................................................................................................................... 8 
FASTING PLASMA GLUCOSE .................................................................... 8 
GIP 8 
GLUCOSE DEPENDENT INSULINOTROPIC PEPTIDE ........................ 8 
GLP-1 ................................................................................................................. 8 
GLUCAGON-LIKE PEPTIDE-1 .................................................................... 8 
1. 
INTRODUCTION ..................................................................................... 9 
1.1 
MEDICAL BACKGROUND .............................................................................. 9 
1.2 
DRUG PROFILE ................................................................................................. 9 
1.2.1       Linagliptin ............................................................................................. 9 
1.2.2       Metformin ............................................................................................ 10 
1.2.3       Trajenta Duo® ..................................................................................... 11 
2. 
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT ........................................................................................ 12 
2.1 
RATIONALE FOR PERFORMING THE STUDY ....................................... 12 
2.2 
STUDY OBJECTIVES ...................................................................................... 12 
2.2.1 
Primary objective ................................................................................... 12 
2.2.2 
Secondary objective ............................................................................... 12 
2.3 
BENEFIT-RISK ASSESSMENT ..................................................................... 12 
3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION ............ 13 
3.1 
OVERALL DESIGN AND PLAN .................................................................... 13 
3.1.1 
Administrative structure of the study .................................................. 13 
3.2 
DISCUSSION OF STUDY DESIGN ................................................................ 13 
3.3 
SELECTION OF POPULATION .................................................................... 14 
3.3.1 
Main diagnosis for study entry ............................................................. 14 
3.3.2 
Inclusion criteria .................................................................................... 14 
3.3.3 
Exclusion criteria ................................................................................... 14 
3.3.4 
Removal of patients from therapy or assessments .............................. 14 
3.3.4.1  Removal of individual patients (therapy or assessments) .......... 14 
3.3.4.2  Discontinuation of the study by the sponsor .............................. 14 
4. 
TREATMENTS ....................................................................................... 15 
4.1 
PRESCRIBED TREATMENTS TO BE OBSERVED ................................... 15 
4.1.1 
Identity of test product(s) and comparator product(s) ...................... 15 
4.1.2 
Method of assigning patients to treatment groups .............................. 15 
4.1.3 
Selection of doses in the study ............................................................... 15 
4.1.4 
Drug assignment and administration of doses for each patient ........ 15 

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4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT .................................................................................................... 15 
4.2.1 
Rescue medication, emergency procedures, and additional 
treatment(s) ............................................................................................ 15 
4.2.2 
Restrictions ............................................................................................. 15 
4.2.2.1  Restrictions regarding concomitant treatment ............................ 15 
4.2.2.2   Restrictions on diet and life style ............................................... 15 
5. 
VARIABLES AND THEIR ASSESSMENT ........................................ 16 
5.1 
SAFETY .............................................................................................................. 16 
5.1.1 
Endpoint(s) of safety .............................................................................. 16 
5.1.2 
Assessment of adverse events ................................................................ 16 
5.1.2.1  Definitions of adverse events ..................................................... 16 
5.1.2.2  Adverse event and serious adverse event reporting ................... 18 
5.1.3 
Assessment of safety laboratory parameters ....................................... 19 
5.1.4 
Electrocardiogram ................................................................................. 19 
5.1.5 
Assessment of other safety parameters ................................................ 19 
5.2 
EFFECTIVENESS ............................................................................................. 20 
5.2.1 
Endpoint(s) of effectiveness ................................................................... 20 
5.2.2 
Assessment of effectiveness ................................................................... 20 
5.3 
OTHER ............................................................................................................... 20 
5.4 
APPROPRIATENESS OF MEASUREMENTS ............................................. 20 
6. 
SURVEILLANCE PLAN ....................................................................... 21 
6.1 
VISIT SCHEDULE ............................................................................................ 21 
6.2 
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS ............... 21 
6.2.1 
Screening and run-in period(s) ............................................................. 21 
6.2.2 
Treatment period(s) ............................................................................... 21 
6.2.3 
End of trial and follow-up period ......................................................... 22 
7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ........................................................................................ 23 
7.1 
STATISTICAL DESIGN - MODEL ................................................................ 23 
7.2 
NULL AND ALTERNATIVE HYPOTHESES .............................................. 23 
7.3 
PLANNED ANALYSES .................................................................................... 23 
7.3.1 
Safety analyses ........................................................................................ 23 
7.3.2 
Effectiveness analyses ............................................................................ 24 
7.3.3 
Interim analyses ..................................................................................... 25 
7.4 
HANDLING OF MISSING DATA .................................................................. 25 
7.5.  RANDOMISATION .......................................................................................... 25 
7.6 
DETERMINATION OF SAMPLE SIZE ........................................................ 25 
8. 
DATA PROTECTION, STUDY RECORDS ....................................... 26 
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT .......................................................................................................... 26 
8.2 
DATA QUALITY ASSURANCE ..................................................................... 27 
8.3 
RECORDS .......................................................................................................... 27 
8.3.1 
Source documents .................................................................................. 27 
8.3.2 
Direct access to source data and documents ........................................ 27 

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8.3.3 
Storage of records .................................................................................. 27 
8.4 
PROCEDURES FOR REPORTING ADVERSE EVENTS .......................... 28 
8.4.1 
Time windows ......................................................................................... 28 
8.4.2 
Documentation of adverse events and patient narratives .................. 28 
8.5 
STATEMENT OF CONFIDENTIALITY ....................................................... 28 
8.6 
PUBLICATION POLICY ................................................................................. 29 
9. 
REFERENCES ........................................................................................ 30 
9.1 
PUBLISHED REFERENCES........................................................................... 30 
9.2 
UNPUBLISHED REFERENCES ..................................................................... 30 
10.  APPENDICES ......................................................................................... 31 
10.1  ELECTRONIC CASE REPORT FORM ........................................................ 31 
10.2  SAE/ SPECIAL INTEREST OF AE REPORT FORM ................................. 31 
10.3  PREGNANCY MONITORING FORM .......................................................... 31 
10.4  LIST OF ALWAYS SERIOUS ADVERSE EVENTS .................................... 31 
10.5  LIST OF SPECIAL INTEREST OF ADVERSE EVENTS ........................... 31 
11.  SUMMARY OF NIS PROTOCOL MODIFICATIONS ..................... 32 
 

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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 
MFDS 
Ministry of Food and Drug Safety 
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 347 million affected people worldwide. Its 
incidence is expected to double during the next 20 years1. About 3.2 million Korean people 
(10.1%) aged over 30 years or older had diabetes in 2010. Based on fasting glucose, 19.9% of 
adults had prediabetes (impaired fasting glucose). Accordingly 3 out of 10 people in Korea 
are diabetes or at high risk of future diabetes in 2010. Diabetes will affect 6.0 million people 
in Korea by 2050, which will be twice higher than that of 2010.The growth rate would be 183% 
for the next 40 years.2. 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 [U04-1767-11]. 
1.2 
DRUG PROFILE 
1.2.1       Linagliptin 
Treatment with 5 mg linagliptin, once daily, has been shown to result in clinically meaningful 
and statistically significant reductions in HbA1c, FPG and PPG. There was a consistent 
pattern in the improvement in HbA1c when linagliptin was used in patients with different 
background therapies. In phase III trials in monotherapy (including a trial in patients 
intolerant of metformin), combination with metformin, combination with sulfonylurea, 
combination with metformin and sulfonylurea, and initial combination with pioglitazone, 

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linagliptin 5 mg led to a significant reduction of HbA1c (placebo corrected HbA1c changes 
from baseline were in the range of -0.47% to -0.87%).[U04-1767-11] 
The efficacy and safety of linagliptin in combination with metformin in patients with 
insufficient  glycaemic control on metformin monotherapy was evaluated in a double blind 
placebo controlled study of 24 weeks duration. Linagliptin added to metformin provided 
significant improvements in HbA1c, (-0.64 % change compared to placebo), from a mean 
baseline HbA1c of 8 %. Linagliptin also showed significant improvements in fasting plasma 
glucose (FPG) by -21.1 mg/dl and 2-hour post-prandial glucose (PPG) by -67.1 mg/dl 
compared to placebo, as well as a greater portion of patients achieving a target HbA1c of < 
7.0% (28.3% on linagliptin vs. 11.4% on placebo). The observed incidence of hypoglycaemia 
in patients treated with linagliptin was similar to placebo. Body weight did not differ 
significantly between the groups. 
The efficacy and safety of linagliptin 2.5 mg twice daily versus 5 mg once daily in 
combination with metformin in patients with insufficient glycaemic control on metformin 
monotherapy was evaluated in a double blind placebo controlled study of 12 weeks duration. 
Linagliptin 5 mg once daily and 2.5 mg twice daily provided comparable (CI: -0.07; 0.19) 
significant HbA1c reductions of -0.80% (from baseline 7.98%), and -0.74% (from baseline 
7.96%) compared to placebo. The observed incidence of hypoglycaemia in patients treated 
with linagliptin was similar to placebo. 
For further details, please see refer to the local prescribing information of Trajenta Duo®. 
1.2.2       Metformin 
Metformin is an oral antihyperglycaemic agent that reduces plasma glucose levels by 
decreasing intestinal glucose absorption and hepatic glucose production and enhancing the 
glucose uptake and utilization of peripheral tissue. Thus metformin renders a reduction of 
basal and postprandial plasma glucose in patients with type 2 diabetes. Unlike sulfonylureas 
(e.g. glyburide) metformin does not increase insulin secretion and is not associated with 
hypoglycaemia in either patients with type 2 diabetes or healthy volunteers [R10-5537]. 
Gastrointestinal absorption of metformin is incomplete with an absolute bioavailability of 50-
60 % under fasting conditions. The intake of food decreases the extent of absorption. A 40% 
lower Cmax and a 25% lower area under the curve were reported following a single dose 
administration of 850 mg metformin with food. Studies using single oral doses of 500 – 1500 
mg metformin indicate that there is a lack of dose proportionality with increasing doses, 
which is due to decreased absorption rather than an alteration in elimination [R10-5341]. 
In contrast to sulfonylureas metformin is negligibly bound to plasma proteins. The drug 
partitions into erythrocytes, which might represent a deep compartment of distribution. 
Intravenous studies in healthy volunteers demonstrate that metformin is excreted unchanged 
in the urine and neither undergoes hepatic metabolism nor biliary excretion. Following oral 
administration approximately 90% of the absorbed drug is eliminated via the renal route with 
a plasma-elimination half-life of about 6.2 hours [R10-5341]. 
Metformin is available as tablets for oral administration in the strength of 500, 850 and 1000 
mg [R10-5341]. The maximum recommended daily dose is 3000 mg in adults [R10-5537]. 

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In a double-blind, placebo-controlled US clinical trial involving obese patients with type 2 
diabetes whose hyperglycemia was not adequately controlled with diet alone, treatment with 
metformin (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in 
FPG, PPG and HbA1c of 59 mg/dl, 83 mg/dl, and 1.8 %, respectively, compared to the 
placebo group [R10-5341]. 
Metformin was well tolerated by healthy male volunteers given alone (3 x 850 mg daily) and 
in combination with linagliptin (1 x 10 mg daily) for 3 days. Drug related adverse events, 
which occurred in both treatment periods with the same frequency (12.5%), refer only to the 
gastrointestinal tract and represent well-known side-effects of metformin – abdominal pain, 
diarrhoea, nausea. The combined administration of both drugs did not increase the incidence 
of adverse events compared to single drug treatment. Hypoglycaemic events did not occur in 
any treatment period [U06-3414]. 
 
1.2.3       Trajenta Duo®  
Trajenta Duo® contains the active substances linagliptin which is a potent, synthetic, 
nonpeptide competitive, rapidly acting and reversible inhibitor of dipeptidyl-peptidase-4 
(DPP4) and the biguanide metformin hydrochloride The ATC code is A10BD11. Linagliptin 
inhibits proteolytic processing of the incretins GLP-1 and GIP by DPP-4, resulting in 
increased glucose-dependent insulin secretion, suppression of glucagon secretion, delay of 
gastric emptying and induction of satiety. Metformin suppresses hepatic gluconeogenesis. 
 
Trajenta Duo® tablets are supplied as immediate release film-coated tablets containing 
2.5 mg linagliptin and either 500 mg, 850 mg or 1000 mg metformin hydrochloride for twice 
daily adminstration. Theinactive ingredients of the tablet core are arginine, copovidone, 
magnesium stearate, maize 
starch, colloidal anhydrous silica. The film-coatings contain hypromellose, titanium dioxide, 
talc, propylene glycol, iron oxide red and/or iron oxide yellow. 
Further information is provided in the local prescribing information of Trajenta Duo®. 

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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 Duo®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 Duo® 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 Duo® 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 Duo® 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 15 Nov 2012 until 13 Sep 2017. However, 
active enrollment is to be initiated in 2013 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/metformin. 
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/metformin would be more often prescribed to higher risk 
patients compared to other treatments, higher incidences of outcome events were then 
expected in the linagliptin/metformin 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 600 patients will be enrolled at approximately 15 sites by as many as 20 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 who treat diabetes mellitus as an endocrine 
or cardiovascular disease, etc., in clinics or general hospitals which have internal medicine or 
family medicine department. 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 Duo® 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®, Trajenta Duo® 
 Current participation in clinical trials  
 Patients for whom metformin or linagliptin is contraindicationed according local label 
of Trajenta Duo® 
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 Duo® 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/Metformin will be administered 2.5 mg/500 mg, 2.5 mg/850 mg and 2.5 mg/1000 
mg twice 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 
Duo® 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 Duo® 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. 
 
Adverse event of special interest 
Irrespective of whether an AE is serious or non-serious, some events are defined as ‘special 
interest of adverse events’ and have additional reporting requirements (See Section 8.4.1).  
‘Special interest of adverse events’ refers to the list in the Investigator’s Study File or in 
electronic CRF web page for the latest version(Attachment 5). 
 
Serious adverse event 

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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. 
 
Always serious adverse events 
BI has defined a list of adverse events that are considered as “always serious” (Attachment 4) 
by fulfilling the criterion “medically important event” by definition and are therefore judged 
as serious. If a non-serious AE meets this 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. The 
list of these adverse events can be found via the eCRF system. 
 
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. 

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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 
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 Duo® treatment up to 7 days after last 
follow‐up visit need to be collected, documented and reported to the sponsor using the AE 

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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:  
 
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 Duo® 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. 

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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 
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 12 or 24 weeks 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, alcohol consumption 
 
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 Duo® 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 Duo® 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 Duo® given 
 
Any changes in laboratory tests if there is any lab result which was clinically significant 
compared to data before Trajenta Duo® 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 Duo® given 
 
Any changes in laboratory tests if there is any lab result which was clinically significant 
compared to data before Trajenta Duo® 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 Duo® 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 statistics(N, mean, 
median, standard deviation, minimum and maximum, etc.). Demographic data and baseline 
characteristics will be described in each ratio including the confidence intervals. All analysis 
will be accomplished after dividing according to condition of the anti-diabetic agents 
use(patients who have no experience treated with DPP-4/patients who have experiences 
treated with DPP-4). In addition, data on special patients(children/patients with hepatic or 
renal disorder/elderly patients, etc.) will be analyzed separately. 
 
7.2 
NULL AND ALTERNATIVE HYPOTHESES 
No hypotheses are tested. (See Section 7.1) 
7.3 
PLANNED ANALYSES 
7.3.1 
Safety analyses 
Demographic(year of birth(age), gender, etc.) 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 Duo®. However, if data for patients who have been treated with Trajenta 
Duo® 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. 
Adverse events, unexpected adverse events, serious adverse events and each adverse drug 
reactions is classified into the system organ class(SOC), symptoms(preferred term) and 
presented the incidence and precision(95% confidence intervals). 
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. 
① Occurrence of adverse events after Trajenta Duo® administration: Contingency table for 
frequency and incidence of adverse events is presented according to occurrence situation 
of adverse events by sign/symptoms, action taken for Trajenta Duo®, intensity, 

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relationship, outcome and category and test for the differences of AE frequency is 
analyzed using Chi-square test(or Fisher’s exact test).  
②  Contingency table is presented based on nominal variables as demographic 
characteristics(gender, age(children and elderly, weight, etc.) and medical history(family 
history for diabetes mellitus, diabetic complication, hepatic/renal disorder, etc.) so on and 
test for the differences of AE frequency is analyzed using Chi-square test(or Fisher’s 
exact test). 
③ Logistic regression as a multivariate analysis is performed and presented odd ratio in 
order to find the factor affecting occurrence of adverse events by demographic 
characteristics(gender, age(children and elderly, weight, etc.) and medical history(family 
history for diabetes mellitus, diabetic complication, hepatic/renal disorder, etc.) so on. 
7.3.2 
Effectiveness analyses 
A descriptive analysis of endpoints is planned and for patients treated with Trajenta Duo®, 
the change of HbA1c from baseline and last follow-up visit(12/24weeks) is analyzed using 
paired t-test(or Wilcoxon signed rank test).  
The occurrence of treat to target effectiveness response, that is an HbA1c under treatment of 
< 6.5% after 24weeks and relative effectiveness response (HbA1c lowering by at least 0.5%) 
after 24 weeks is summarized with frequency distribution for patients’ number and 
percentage and presented 95% confidence intervals.  
The change of FPG from baseline and last follow-up visit(12/24weeks) is analyzed using 
paired t-test(or Wilcoxon signed rank test). 
 
In order to investigate the factor affecting effectiveness, the following analysis is performed 
with the case of HbA1c under treatment of < 6.5% after 24 weeks is considered as 
effectiveness and the other cases are considered as ineffectiveness. 
 
① Contingency table is presented based on nominal variables as demographic 
characteristics(gender, age(children and elderly, weight, etc.) and medical history(family 
history for diabetes mellitus, diabetic complication, hepatic/renal disorder, etc.) so on and 
the test for the differences of frequency for effectiveness/ineffectiveness is analyzed using 
Chi-square test(or Fisher’s exact test). 
②  Logistic regression as a multivariate analysis is performed and presented odd ratio in 
order to find the factor affecting effectiveness by demographic characteristics(gender, 
age(children and elderly, weight, etc.) and medical history(family history for diabetes 
mellitus, diabetic complication, hepatic/renal disorder, etc.) so on. 
 

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7.3.3 
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 600 patients is based on the requirement of the local regulatory authority 
(Ministry of Food and Drug Safety, MFDS). 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 (MFDS) 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 MFDS, 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 MFDS 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 study 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., MFDS). 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 Duo® tablets, or whether or not 
Trajenta Duo® tablets has been administered, must be reported immediately via eCRF and  
SAE/Special interest of AE Report Form. 
 
For special interest of AE, even though they might be non-serious, require expedited 
reporting (within 24 hours or the next business day whichever is shorter) to the sponsor via 
eCRF and SAE/Special interest of AE Report Form. 
 
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 Duo® tablets. The investigator will determine the relationship of 
Trajenta Duo® 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. 

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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 
R09-4241 
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. 
 
R10-5341      Glucophage (metformin hydrochloride tablets), Glucophage XR (metformin 
                      hydrochloride extended-release tablets) (Bristol-Myers Squibb), Rx only 
                      (NDA 20-357/S-030, NDA 21-202/S-015, revised January 2009) 
 
R10-5537      Glucophage 500 and 850 mg film coated tablets (Merck Serono) (summary of 
                      product characteristics, last updated on the eMC: 17/08/2010) 
                      http://emc.medicines.org.uk/medicine/1043/SPC/Glucophage 500 mg and 850 
                      mg film coated tablets 
 
 
 
9.2 
UNPUBLISHED REFERENCES 
U04-1767-11  
, Linagliptin Investigator's Brochure. Version 11. 28 Nov 2012.  
 
U06-3414  
. Bioavailability of 
                   both BI 1356 and metformin after co-administration compared to the 
                   bioavailability of multiple oral doses of BI 1356 10 mg daily alone and 
                   metformin 850 mg three times a day alone in healthy male volunteers (an 
                   open-label, randomized, crossover study). 1218.4. 7 July 2006. 
 
1                     (WHO Fact sheet; no 312) Nov 2012                 
                       http://www.who.int/mediacentre/factsheets/fs312/en/index.html 
 
 2                    Korean Diabetes Association. 
http://www.diabetes.or.kr/temp/Diabetes_Fact_sheet2012.pdf  
 
3.                  Trajenta Duo® Prescription information for Korea 
 
 

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10. 
APPENDICES 
10.1 
ELECTRONIC CASE REPORT FORM 
See the Attachment 1. 
10.2 
SAE/ SPECIAL INTEREST OF AE REPORT FORM 
See the Attachment 2. 
10.3 
PREGNANCY MONITORING FORM 
See the Attachment 3. 
10.4 
LIST OF ALWAYS SERIOUS ADVERSE EVENTS 
See the Attachment 4. Please refer to “List of Always Serious Adverse Event” in site file or 
in electronic CRF web page for the latest version.  
10.5 
LIST OF SPECIAL INTEREST OF ADVERSE EVENTS 
See the Attachment 5. Please refer to “List of special interest of adverse events’” in site file 
or in electronic CRF web page for the latest version.  
 

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11. 
SUMMARY OF NIS PROTOCOL MODIFICATIONS 
Summary of Modifications Sheet (SOMS) 
 
Number of Protocol modification 
 
3 
Date of Protocol modification 
 
22 Feb2017 
BI Trial number 
 
1288.22 
BI Product(s) 
 
Trajenta DUO 
Title of protocol 
 
A regulatory requirement non interventional study 
to monitor the safety and effectiveness of Trajenta 
Duo® (Linagliptin/Metformin HCl, 2.5 mg/500 mg, 
2.5 mg/850 mg and 2.5 mg/1000 mg, b.i.d) in 
Korean patients with type 2 diabetes mellitus 
(SELINA Duo 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