Post Marketing Surveillance on Long Term Drug Use of Trazenta® Tablets in Patients With Type 2 Diabetes Mellitus
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

 
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1218-0095--protocol-revision-01
U12-1208-02
Post Marketing Surveillance on Long Term Drug Use of Trazenta Tablets
in Patients with type 2 Diabetes Mellitus
Author-Trial Clinical Monitor
4/4/2013 08:40:28
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4/4/2013 08:43:03
Approval-Team Member Medicine
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1218-0095--protocol-revision-01
U12-1208-02
Post Marketing Surveillance on Long Term Drug Use of Trazenta Tablets
in Patients with type 2 Diabetes Mellitus
Verify Paper Signature Completion
4/19/2013 08:25:16

 
 
 
 
Post Marketing Surveillance Study 
Protocol  
 
Doc. No.: U12-1208-02 
 
BI Study No.: 
1218.95 
 
BI Investigational 
Product: 
Linagliptin, BI 1356 
Title: 
Post Marketing Surveillance on Long Term Drug Use of Trazenta® 
Tablets in Patients with type 2 Diabetes Mellitus 
Clinical Phase: 
IV 
Trial Clinical 
Monitor: 
 
Phone: 
Fax:
Co-ordinating 
Investigator: 
Not applicable 
 
 
Status: 
Final Protocol (Revised Protocol (based on global amendment)) 
Version, and Date : 
Version: 2 
 
 
Date:  4 April 2013 
 
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TITLE PAGE 

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BI Trial No.: 1218.95 
 
 
Doc. No.: U12-1208-02 
Observational Plan 
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POST MARKETING SURVEILLANCE STUDY PROTOCOL SYNOPSIS 
Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
Trazenta ® Tablets 
Name of active ingredient: 
 
Linagliptin 
 
Protocol date 
Trial number 
 
Revision date: 
4 April 2013 
3 July 2012 
1218.95 
Title of study: 
Post Marketing Surveillance study on Long term Drug Use of Trazenta® Tablets in 
Patients with type 2 Diabetes Mellitus 
Co-ordinating 
Investigator: 
Not applicable 
Study sites : 
400600 
Clinical phase: 
IV 
Objectives: 
To investigate the safety and efficacy of long-term daily use of Trazenta® Tablets as 
monotherapy in patients with type 2 diabetes mellitus. 
To assess baseline characteristics of patients with type 2 diabetes mellitus starting 
Trazenta® Tablets or any other oral antidiabetic monotherapy (naïve or switched from 
prior therapy of different oral antidiabetic drug) . 
Methodology: 
Ｎon-interventional, prospective, observational 
No. of patients:  
 
 
Total entered: 
3,0006,000 
 
each treatment: 
Trazenta ® Tablets: 1,5003,000  
Oral antidiabetic drugs except Trazenta ® Tablets: 1,5003,000 
Diagnosis: 
Type 2 diabetes mellitus 
Main criteria for 
inclusion: 
Trazenta ® Tablets: Male and female patients with type 2 diabetes mellitus who have 
never been treated with Trazenta ® Tablets/ linagliptin (monotherapy) before 
enrollment.  
Other oral antidiabetic drug: Male and female patients with type 2 diabetes mellitus 
starting any other oral antidiabetic monotherapy (naïve and switch) except Trazenta ® 
Tablets. 
Test product : 
Trazenta ® Tablets 
 
dose: 
5 mg 
 
mode of admin. : Oral 
Comparator product: 
Oral antdiabetic drugs except Trazenta ® Tablets 

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BI Trial No.: 1218.95 
 
 
Doc. No.: U12-1208-02 
Observational Plan 
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Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
Trazenta ® Tablets 
Name of active ingredient: 
 
Linagliptin 
 
Protocol date 
Trial number 
 
Revision date: 
4 April 2013 
3 July 2012 
1218.95 
 
dose: 
Refer each package insert of the prescribed oral antidiabetic drug 
 
mode of admin. : Oral 
Duration of treatment: Trazenta ® Tablets: 156 weeks 
Other oral antidiabetic drug: Only baseline data and no observation period  
Criteria for efficacy:  
Trazenta ® Tablets: 
Primary endpoint: There is no primary efficacy endpoint in this study. 
Secondary endpoints: Change from the baseline in HbA1c to the last- observation on 
treatment 
Other oral antidiabetic drug: None 
Criteria for safety: 
Trazenta ® Tablets: 
Incidence of adverse drug reactions (ADRs) 
Incidence of serious adverse events (SAEs) 
 
Other oral antidiabetic drug: None 
Statistical methods: 
Descriptive 

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Doc. No.: U12-1208-02 
Observational Plan 
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FLOW CHART 
Trazenta ® Tablets: 
         Time 
 
 
 
 
 
 
 
 
Observation period*1 
Before 
first 
administ
ration of 
Trazenta
® 
Tablets 
12W 
(3M） 
26W 
(6M) 
40W 
(9M) 
52W 
(12M）
64W 
(15M）
78W 
(18M）
104W（
24M） 
130W 
（30M）
156W 
(36M） 
(or at 
discontinua
tion) 
Patient enrolment 
 
X *2 
 
 
 
 
 
 
 
 
 
Item： 
 
 
 
 
 
 
 
 
 
 
・Patient  
demographics 
X 
 
 
 
 
 
 
 
 
 
・Medical history/ 
Concomitant 
disease 
X 
 
 
 
 
 
 
 
 
 
・Pretreatment  
 drug 
X 
 
 
 
 
 
 
 
 
 
・Administration of 
Trazenta  ® 
Tablets 
 
X (to be recorded throughout the observation period) 
・Compliance and 
fasting condition 
 
 
X 
 
 
 
X 
 
 
X 
・Concomitant 
drug(s) and 
antidiabetic 
therapy 
X (to be recorded throughout the observation period) 
・Blood pressure  
pulse rate and 
ECG 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
・HbA1c and 
fasting plasma 
glucose  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
・Laboratory tests 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
・Body weight  
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
・Adverse Event 
 
X(to be recorded throughout the observation period) 
・Pregnancy 
status 
X 
X 
X 
X 
X   
X 
X 
X 
X 
X 
W: Weeks 
M: Approximate months 
*1: Time points during the observation period are approximate. Collected data should be 
reported as of the closest available visit.  

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Observational Plan 
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*2: Patients administered Trazenta® Tablets will be registered preferably within 14 days from 
the day of first administration． 
eCRF (electronic case report form): At 26 weeks, 78 weeks, 156 weeks or discontinuation 
and each time an adverse event has occurred, data in corresponding observation period should 
be entered into eCRF and transmitted using the EDC system. 
 (X): If applicable 

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FLOW CHART 
Other oral antidiabetic drug: 
         Time 
 
 
 
 
 
 
 
 
Observation point 
Before first administration of 
Oral antdiabetic drugs except 
Trazenta ® Tablets 
Patient enrolment 
 
X *1 
Item： 
 
・Patient  
demographics 
X 
・Medical history/ 
Concomitant disease 
X 
・Pretreatment  
 drug 
X 
・Administration of  Oral 
antdiabetic drugs except 
Trazenta ® Tablets 
 
・Concomitant drug(s) and 
antidiabetic therapy 
 
・Blood pressure  
pulse rate and 
ECG 
(X) 
・HbA1c and 
fasting plasma glucose  
X 
・Laboratory tests 
(X) 
・Body weight 
X 
*1: Patients administered Oral antdiabetic drugs except Trazenta ® Tablets will be registered 
preferably within 14 days from the day of first administration． 
eCRF (electronic case report form): After registration data should be entered into eCRF and 
transmitted using the EDC system. 
 (X): If applicable 
 
 

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TABLE OF CONTENTS 
TITLE PAGE .................................................................................................... 1 
POST MARKETING SURVEILLANCE STUDY PROTOCOL 
SYNOPSIS ................................................................................................. 2 
FLOW CHART ................................................................................................. 4 
FLOW CHART ................................................................................................. 6 
TABLE OF CONTENTS ................................................................................. 7 
ABBREVIATIONS ......................................................................................... 10 
1. 
INTRODUCTION ................................................................................... 11 
1.1 MEDICAL BACKGROUND ............................................................................ 11 
1.2 DRUG PROFILE ............................................................................................... 12 
2. 
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ........................................................................................ 15 
2.1 RATIONALE FOR PERFORMING THE STUDY ....................................... 15 
2.2 STUDY OBJECTIVES ...................................................................................... 16 
2.3 BENEFIT - RISK ASSESSMENT ................................................................... 16 
3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION ............ 17 
3.1 OVERALL DESIGN AND PLAN .................................................................... 17 
3.1.1 Administrative structure of the study .................................................. 19 
3.2 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP .......................................................................................... 20 
3.3 SELECTION OF POPULATION .................................................................... 20 
3.3.1 Main diagnosis for study entry ............................................................. 21 
3.3.2 Inclusion criteria .................................................................................... 21 
3.3.3 Exclusion criteria ................................................................................... 21 
3.3.4 Removal of patients from therapy or assessments .............................. 21 
3.3.4.1 Removal from individual patients .............................................. 21 
3.3.4.2 Discontinuation of the study by the sponsor .............................. 21 
4. 
TREATMENTS ....................................................................................... 22 
4.1 PRESCRIBED TREATMENTS TO BE OBSERVED ................................... 22 
4.1.1 Identity of test product and comparator product ............................... 22 
4.1.2 Method of assigning patients to treatment groups .............................. 22 
4.1.3 Selection of doses in the study ............................................................... 22 
4.1.4 Drug assignment and administration of doses for each patient ........ 22 
4.2 CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT .................................................................................................... 22 
4.2.1 Rescue medication, emergency procedures, and additional 
treatment ................................................................................................. 22 
4.2.2 Restrictions ............................................................................................. 22 
4.2.2.1 Restrictions regarding concomitant treatment ........................... 22 
4.2.2.2 Restrictions on diet and life style ............................................... 23 

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4.3 TREATMENT COMPLIANCE ....................................................................... 23 
5. 
VARIABLES AND THEIR ASSESSMENT ........................................ 24 
5.1 EFFICACY ......................................................................................................... 24 
5.1.1 Endpoints of efficacy .............................................................................. 24 
5.1.2 Assessment of efficacy ............................................................................ 24 
5.2 SAFETY .............................................................................................................. 25 
5.2.1 Endpoints of safety ................................................................................. 25 
5.2.2 Assessment of adverse events ................................................................ 25 
5.2.2.1 Definitions of adverse events ..................................................... 25 
5.2.2.2 Adverse event and serious adverse event reporting ................... 26 
5.2.3 Assessment of safety laboratory parameters ....................................... 27 
5.2.4 Electrocardiogram ................................................................................. 27 
5.2.5 Assessment of other safety parameters ................................................ 27 
5.3 OTHER ............................................................................................................... 27 
5.3.1 Other endpoint ....................................................................................... 27 
5.3.2 Other assessment .................................................................................... 27 
5.4 APPROPRIATENESS OF MEASUREMENTS ............................................. 27 
6. 
INVESTIGATIONAL PLAN ................................................................. 28 
6.1 VISIT SCHEDULE ............................................................................................ 28 
6.2 DETAILS OF STUDY PROCEDURES AT SELECTED VISITS ............... 28 
6.2.1 Screening and run-in period ................................................................. 28 
6.2.2 Treatment period ................................................................................... 30 
6.2.3 End of trial and follow-up period ......................................................... 31 
7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ........................................................................................ 32 
7.1 STATISTICAL DESIGN - MODEL ................................................................ 32 
7.2 NULL AND ALTERNATIVE HYPOTHESES .............................................. 32 
7.3 PLANNED ANALYSES .................................................................................... 32 
7.3.1 Primary analyses .................................................................................... 32 
7.3.2 Secondary analyses ................................................................................ 32 
7.3.3 Safety analyses ........................................................................................ 33 
7.3.4 Interim analyses ..................................................................................... 33 
7.4 HANDLING OF MISSING DATA .................................................................. 33 
7.5 RANDOMISATION .......................................................................................... 33 
7.6 DETERMINATION OF SAMPLE SIZE ........................................................ 33 
8. 
INFORMED CONSENT, DATA PROTECTION, STUDY 
RECORDS ............................................................................................... 35 
8.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT .......................................................................................................... 35 
8.2 DATA QUALITY ASSURANCE ..................................................................... 35 
8.3 RECORDS .......................................................................................................... 35 
8.3.1 Source documents .................................................................................. 35 
8.3.2 Direct access to source data and documents ........................................ 36 

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8.4 PROCEDURES FOR REPORTING ADVERSE EVENTS .......................... 36 
8.4.1 Time windows ......................................................................................... 36 
8.4.2 Documentation of adverse events and patient narratives .................. 37 
8.5 STATEMENT OF CONFIDENTIALITY ....................................................... 37 
8.6 COMPLETION OF TRIAL.............................................................................. 37 
9. 
REFERENCES ........................................................................................ 38 
9.1 PUBLISHED REFERENCES........................................................................... 38 
9.2 UNPUBLISHED REFERENCES ..................................................................... 38 
10. APPENDICES ......................................................................................... 39 
11 SUMMARY OF PMS STUDY PROTOCOL MODIFICATIONS .... 40 

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 ABBREVIATIONS 
ADR 
Adverse drug reaction 
AE 
Adverse Event 
BI 
Boehringer Ingelheim 
CABG 
Coronary Artery Bypass Graft 
CRF 
Case Report Form 
CTP 
Clinical Trial Protocol 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
DPP-4 
Dipeptidyl peptidase IV 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular filtration Rate 
FPG 
Fasting plasma glucose 
GIP 
Glucose-dependent insulinotropic peptides 
GLP-1 
Glucagon-like peptide 1 
GPSP 
Good Post-marketing Study Practice  
GVP 
Good Vigilance Practice  
IRB 
Institutional Review Board 
JDS 
Japan Diabetes Society 
J-PAL 
Japanese Pharmaceutical Affairs Law 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labour and Welfare 
MPH 
Master of Public Health 
NBI 
Nippon Boehringer Ingelheim 
MR 
Medical Representative 
NGSP 
National Glycohemoglobin Standardization Program 
OAD 
Oral Antdiabetic Drug 
PCI 
Percutaneous Coronary Intervention 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PMS 
Post Marketing Surveillance  
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 

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1. 
INTRODUCTION 
1.1 
MEDICAL BACKGROUND 
Type 2 diabetes mellitus accounts for 90-95% of diabetes and its prevalence tends to 
increase. Type 2 diabetes affects 180 million people worldwide and its incidence is estimated 
to double in the next 20 years. In Japan, there are about 7.4 million people “strongly 
suspected of having diabetes” and about 8.8 million people “for whom the possibility of 
diabetes may not be ruled out,” making a total of about 16.2 million people, which indicates 
that one out of six adults are considered to have diabetes or the potential of developing 
diabetes (Ministry of Health, Labour and Welfare “Diabetes Surveillance” in 2002). The total 
number of patients with diabetes (estimated number of patients who are continuously 
receiving medical care) is 2,284,000 and ranks third (35.9%) in terms of the number of male 
outpatients amongst patients experiencing accidents and sickness. Diabetes causes 12,879 
deaths (1.3% of the total) and ranks 10th amongst causes of death for males and ninth for 
females in Japan. 
Multiple metabolic abnormalities have been described in Type 2 diabetes. It appears, 
however, that almost invariably a failure of the pancreatic ß-cells is involved. In most cases, 
insulin resistance cannot be compensated by an adequately increased insulin secretion, 
ultimately leading to increased fasting and postprandial glucose concentrations. Currently 
available antidiabetic agents are not sufficient to maintain long term glycaemic control. Loss 
of glycaemic control appears to be related to the progressive loss of beta cell function in 
patients with type 2 diabetes, resulting in secondary drug failure and the necessity to institute 
insulin therapy in many patients. 
Traditional insulin secretagogues such as the sulphonylurea drugs increase insulin secretion 
in a non-glucose-dependent manner and carry an increased risk for hypoglycaemia. 
Additionally, it is unclear whether such a glucose independent stimulation of insulin secretion 
accelerates the loss of beta cell function. 
An improved understanding of the interaction between gut-derived hormones and the 
endocrine pancreas has led to the incretin concept and, based on this concept, to the 
development of a new class of antidiabetic agents. The incretin effect is a phenomenon where 
the glucose-stimulated insulin secretion is augmented by intestinally derived peptides, which 
are released in the presence of glucose or nutrients in the gut. Glucagon-like peptide 1 
(GLP-1) is an important member of the incretin hormone family together with glucose 
dependant insulinotropic polypepitide (GIP). It is important to note that the glucose-lowering 
actions of GLP-1 depend on the actual plasma glucose concentration and the GLP-1- 
dependent stimulation of insulin secretion ceases when glucose concentrations fall below 55 
mg/dL. Therefore, elevation of GLP-1 levels bears little to no risk of hypoglycaemia.  
Circulating GLP-1 is almost instantaneously rendered inactive by the enzyme dipeptidyl 
peptidase IV (DPP-4), which explains its short half-life of only 2-3 minutes. Postprandial 
GLP-1 secretion has been reported to be attenuated in type 2 diabetes, which may partially 
explain the increased postprandial glucose excursions. Therefore, a prolongation of the 

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half-life of active GLP-1 may be seen as a therapy which compensates for the reduced 
incretin effect in diabetes patients. In addition to its stimulatory effects on insulin secretion, 
GLP-1 has been shown to suppress glucagon secretion, to delay gastric emptying, to induce 
satiety, and, in animal models, to reduce β-cell apoptosis, increase β-cell mass, and preserve 
β-cell function and to show cardio-protective effects. The maintenance of ß-cell function is of 
particular interest, due to the fact that loss of ß-cell function has been identified as a major 
contributor to the deterioration of long term glycaemic control in type 2 diabetes. 
DPP-4 is an enzyme that is widely expressed in many tissues including kidney, liver, 
intestine, lymphocytes and vascular endothelial cells. In addition, a significant level of DPP-4 
activity is also observed in plasma, DPP-4 is believed to play an important role in the 
degradation of a number of peptides, thus regulating their half-life. However, physiological 
evidence for the role of DPP 4 in this process is only available for a few DPP-4 substrates, 
e.g. GLP-1 and glucose-dependent insulinotropic peptides (GIP) both of which exert 
glucose-dependent insulinotropic actions and thereby contribute to the maintenance of 
post-meal glycaemic control. Rodents with a targeted mutation in the DPP-4 gene (DPP-4 
knock-out) rodents exhibit improved glycaemic control and are resistant to diet induced 
obesity, indicating a physiological role of this enzyme in glucose homeostasis and body 
weight regulation. 
Linagliptin is a potent inhibitor of DPP-4 activity. This has been shown in vitro, in various 
animal models, and in clinical trials. Linagliptin inhibits the proteolysis of GLP-1 and 
prolongs its half-life. Linagliptin is orally available and has a low risk for hypoglycaemic 
episodes. Furthermore, it may carry the potential for weight stabilization or even loss rather 
than weight gain as compared to the majority of other available oral treatments for Type 2 
diabetes. 
An autopsy study has shown that in diabetic patients, the apoptotic rate of pancreatic ß-cells 
is increased and ß-cell mass is diminished [R04-2630]. In an animal model, it has been 
demonstrated that DPP-4 inhibition preserves ß-cell mass through increased proliferation and 
decreased apoptosis [R04-2631]. Therefore, DPP-4 inhibitors such as linagliptin may also 
carry the potential to halt the deterioration of glycaemic control over time, thus preventing 
secondary failure of oral antidiabetic therapy. 
1.2 
DRUG PROFILE 
The DPP-IV inhibitor compound linagliptin was discovered by Boehringer Ingelheim [BI] 
Pharma GmBH & Co. KG, Biberach, Germany. 
It has been tested in phase I and phase II clinical trials of up to 12 weeks duration and has 
shown efficacy (reduced levels of fasting glucose, postprandial glucose and HbA1c) in type 2 
diabetic patients at a daily dose of 5 mg.  
Linagliptin has, until 16 February 2010, been tested in eight phase III trials (and several 
others are planned or ongoing) involving 5,239 patients (44.5% females, mean ±SD age 
58±10 years, BMI 28.9±5.0 kg/m2) with T2DM (HbA1c 8.1±0.9%, fasting plasma glucose 

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168±42 mg/dL, 52.4% diabetes duration > 5 years, 60.8% with metabolic syndrome, 10-year 
Framingham risk for coronary heart disease 10.0±8.3% [29.0% > 15%], 35.4% received 
statin treatment). Of the total number of recruited patients, 17.3% were treatment naïve and 
45.5%, 37.0% and 0.2%, respectively, were previously treated with one, two and three or 
more oral antidiabetic drugs. 3,319 patients received treatment with linagliptin (5 mg: 
n=3159, 10 mg: n=160), 977 placebo and 943 active comparator (glimepiride or voglibose) 
and were followed for median periods of 175, 169 and 409 days respectively. Cumulative 
exposure (person years) was 2,060 for linagliptin and 1,372 for the total comparators.  
In the phase III studies accounting for exposure up to 24 weeks, the overall incidence of 
adverse events (AEs) with linagliptin was comparable to placebo (linagliptin: 58.3%, 
placebo: 57.3%). In addition, the number of patients with AEs leading to discontinuation of 
trial drugs (linagliptin: 2.0%, placebo: 2.3%) and with investigator defined drug-related AEs 
(linagliptin: 11.0%, placebo: 8.3%) did not differ between linagliptin and placebo. AEs with 
the highest incidence in the linagliptin-treated patients were hypoglycaemia (linagliptin: 
9.7%, placebo: 6.1%), nasopharyngitis (linagliptin: 5.5%, placebo: 5.3%), hyperglycaemia 
(linagliptin: 5.3%, placebo: 12.2%), upper respiratory tract infection (linagliptin: 4.1%, 
placebo: 6.0%), headache (linagliptin 3.3%, placebo: 3.4%), hypertension (linagliptin: 2.8%, 
placebo: 2.2%), urinary tract infection (linagliptin: 2.5%, placebo: 3.3%), dizziness 
(linagliptin: 2.2%, placebo: 1.9%), diarrhoea (linagliptin 2.2%, placebo: 2.2%) and back pain 
(linagliptin: 2.1%, placebo: 2.4%).  
The increased incidence of hypoglycaemia observed in the phase III studies came from one 
study (1218.18 [U09-2458-02]), when linagliptin was added to a background treatment of 
metformin and sulfonylurea. There were no SAEs in the 1218.18 study related to 
hypoglycaemia.  
The Phase III trial (1218.23 [U10-1466-01]) in Japan was a multi-centre, randomized, 
double-blind parallel group comparative study designed to investigate the efficacy, safety, 
and tolerability of linagliptin (5 mg or10 mg once daily) compared with placebo for 12 weeks 
and voglibose for 26 weeks in-patients with type 2 diabetes mellitus with insufficient 
glycaemic control. In addition, one-year safety of linagliptin was evaluated in an 26-week 
open label extension of this 26-week randomized trial. A total of 700 patients were enrolled 
and 561 patients were entered into the trial at 47 trial sites in Japan. At the start of 
randomized study medication, 80 patients were randomly assigned to receive placebos, 159 
patients to receive linagliptin at 5 mg, 160 patients to receive linagliptin at10 mg, and 162 
patients to receive voglibose (0.2 mg, tid).Linagliptin showed clinically significant reduction 
in HbA1c from baseline to Week 12, in comparison to placebo, and from baseline to Week 26, 
in comparison to voglibose. Superiority of linagliptin over placebo and voglibose in HbA1c 
reduction was shown and treatment with linagliptin was well tolerated, and assessment of 
safety did not reveal any trends of clinical relevance for up to52 weeks of treatment. The 
incidence of hypoglycaemic events during treatment with linagliptin was considerably low. 
The safety data figures were consistent with the reported safety profile of other DPP-4 
inhibitors, and no new safety concerns were reported. 

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Trough plasma concentrations of linagliptin were stable over 26 weeks after once daily 
administration of linagliptin, indicating that the pharmacokinetics profile of linagliptin does 
not change after multiple administrations over a long period. The trough concentration of 
linagliptin increased less than dose-proportionally when the dose was increased from 5 mg to 
10 mg. In this trial, linagliptin was more efficacious than both placebo and voglibose, was 
well tolerated, and no new safety concerns arose. The 5 mg and 10 mg doses of linagliptin 
showed comparable efficacy over 52 weeks. 
The 5 mg dose of linagliptin once daily was found to be the safe and efficacious dose in a 
number of phase III studies and hence appears to be the appropriate dose. Trazenta® Tablet 
5mg was approved on 1st July 2011 by the Japanese Ministry of Health, Labour and Welfare 
(MHLW). 
 

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2. 
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT 
2.1 
RATIONALE FOR PERFORMING THE STUDY 
In Japan, post-approval execution of post marketing surveillance (PMS) is requested by the 
Japanese Pharmaceutical Affairs Law (J-PAL) in order to accumulate safety and efficacy data 
for reexamination. Reexamination period is defined by Japanese Pharmaceutical Affairs Low 
(J-PAL). New integrant is 8 years for reexamination. Eight years after approval of a new 
substance, results of PMS need to be submitted as a part of reexamination dossier to the 
Japanese regulatory authority, the Ministry of Health, Labour and Welfare (MHLW).  
Collected data from PMS will be included in the Japanese periodic safety reports and 
submitted to MHLW on designated dates until the end of reexamination period. 
The protocol may be revised because of new information or knowledge obtained in the course 
of conducting PMS. When a change of the approved label such as in dosage and 
administration or indications is made during the reexamination period of Trazenta® Tablets 
(except that for this change a reexamination period is newly designated by MHLW) and NBI 
finds it necessary to revise this protocol, handling each matter should be discussed and the 
protocol may be revised. If any issue or concern arises (e.g. suggestion of a potential for 
clinically significant adverse reaction, remarkable increase in incidence of an adverse 
reaction, or any issue or concern on safety or efficacy assessment made prior to the approval 
of Trazenta® Tablets) in the course of PMS, implementation of additional special surveillance 
or post-marketing clinical trial should be discussed to identify or confirm a cause or estimated 
cause of such issue. Special surveillance is defined by Japanese Pharmaceutical Affairs Low 
(J-PAL). It means surveillance for long use or special patient population (elderly, 
renal/hepatic dysfunction etc.).  
The surveillances for long term use in patients with type 2 diabetes mellitus and for type 2 
diabetes mellitus patients with renal/hepatic dysfunction as concomitant disease were 
requested by the PMDA. The rationale of the sample size for surveillance was agreed with 
the PMDA. To ensure achievement of number of patients entered, NBI will monitor the 
numbers of patients with type 2 diabetes mellitus and patients with renal or hepatic 
dysfunction at registration and collection of eCRFs for book 1. 
The assessment of baseline characteristics of patients with type 2 diabetes mellitus starting 
any other oral antidiabetic monotherapy (naïve or switched from prior therapy of different 
oral antidiabetic drug) except Trazenta® Tablets is included in the surveillance.  
There is only limited information available about clinical characteristics of patients using 
different oral antdiabetic drug (OAD) in Japan. In this study patient characteristics will be 
assessed at baseline for the different OADs in order to assess potential differences.  

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2.2 
STUDY OBJECTIVES 
Study objectives are to investigate the safety and efficacy of long-term daily use of Trazenta® 
Tablets as monotherapy in patients with type 2 diabetes mellitus and to assess baseline 
characteristics of patients with type 2 diabetes mellitus starting Trazenta® Tablets or any other 
oral antidiabetic monotherapy (naïve or switched from prior therapy of different oral 
antidiabetic drug) . 
2.3 
BENEFIT - RISK ASSESSMENT 
In this non-investigational PMS, marketed products will be used. ADRs as risk of Trazenta® 
Tablets are listed in package insert. 
 

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3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION 
3.1 
OVERALL DESIGN AND PLAN 
Trazenta ® Tablets: 
This PMS is a prospective study using a continuous investigation system. Patients with type 2 
diabetes mellitus who are treated as monotherapy are included in the surveillance. No 
specific criteria (e.g., demographics, baseline characteristics, concomitant drugs in use) are 
defined for patient enrolment. 
Planned number of patients to be entered and have at least one observation after treatment is 
1,5003,000. Patients with type 2 diabetes mellitus who have never received Trazenta® Tablets 
(monotherapy) will be enrolled in the surveillance. It is exclusively at the physician’s 
discretion whether to initiate linagliptin on patients. 
Patients administered Trazenta® Tablets will be registered preferably within 14 days from the 
day of first administration. Each patient will be observed for 156 weeks (approximately 36 
months) after start of the treatment with this product until the end of the PMS or at premature 
discontinuation and dropout from the PMS. Observations are made at the following time 
points: before first administration of Trazenta® (baseline) and 12, 26, 40, 52, 64, 78, 104, 130 
and 156 weeks after the start of treatment, or at discontinuation. 
There are 3 eCRFs for 0-26 (Book 1), 40- 78 (Book 2) and 104-156 weeks (Book 3) 
individually. 
At 26, 78 and 156 weeks after the start of treatment or at discontinuation, data are to be 
transmitted immediately after entered into eCRF. In case of occurrence of any adverse events, 
data in corresponding observation period should be immediately entered into eCRF and 
transmitted. 
 
 

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Figure 3.1: 1 
Overall design of PMS 
 
Other oral antidiabetic drug:  
Patients with type 2 diabetes mellitus are included in the surveillance. No specific criteria 
(e.g., demographics, baseline characteristics, concomitant drugs in use) are defined for patient 
enrolment. 
After the enrolment of each patient for whom Trazenta® Tablets are prescribed, the patient 
immediately following and initiating any other oral antidiabetic drug should be enrolled. 
Planned number of patients to be entered is 1,5003,000. Patients with type 2 diabetes mellitus 
starting any other oral antidiabetic monotherapy (naïve or switched from prior therapy of 
different oral antidiabetic drug) except Trazenta ® Tablets will be enrolled in the surveillance. 
Patients administered Oral antdiabetic drugs except Trazenta ® Tablets will be registered 
preferably within 14 days from the day of first administration． 
After registration data should be entered into eCRF and transmitted using the EDC system. 
The baseline data is collected and there is no observation period. 
 
Administration 
0w 
156w 
78w 
40w
Preferable registration Period:14 days, including the day of first administration  
 ： Data should be entered into each eCRF (Book1, Book2, Book3) and transmitted.  
14d 
130w 
104w 
64w 
52w
26w 
Book 1 
Book 2 
Book 3
12ｗ

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3.1.1 
Administrative structure of the study 
Sponsor 
Representative
 
Nippon Boehringer Ingelheim Co., Ltd. 
 
 
Co-sponsor 
Representative
 
 
 
Trial statistician 
Medical Data Services Department, 
Nippon Boehringer Ingelheim Co., Ltd. 
 
Data management  
Medical Data Services Department, 
Nippon Boehringer Ingelheim Co., Ltd. 
 
Contract research organizations 

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3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP 
This is a non-interventional, observational prospective study based on newly collected data 
under routine medical practice. 
 
3.3 
SELECTION OF POPULATION 
Trazenta ® Tablets: 
 
Planned number of patients to be entered is 1,500 3,000. 
Patients with renal dysfunction should be entered as listed below: 
eGFR <60 mL/min/1.73m2: 70 140 patients (including 2040 patients with ≥15 
mL/min/1.73m2 and <30 mL/min/1.73m2 and 1530 patients with <15 mL/min/1.73m2) 
50100 patients with hepatic dysfunction should be also entered. 
Patients with hepatic dysfunction: >ULN (AST) x1 or >ULN (ALT) x1 or >ULN (Total 
bilirubin) x1 or >ULN (alkaline phospatase) x1 
When both AST and CK increase, patients do not include in hepatic dysfunction. 
 
Sites throughout entire country will be equally listed according the size of the hospitals or 
general clinics at which Trazenta® tablets are available for prescription.  
Number of patients per site is 5-10 patients. Patients will be selected by using the continuous 
investigation system. The continuous investigation system is commonly used in Japanese 
PMS and accepted as a patient selection process by the PMDA. 
Continuous investigation system is a method of registration that the investigator enrols the 
patients who will start administration of marketed product into the PMS continuously 
(without exception) until the requested number of patients is reached. 
Preferably, investigators will register patients within 14 days including the day on which the 
administration of Trazenta® Tablets is started. However, patients who are registered over 15 
days after starting administration of Trazenta® Tablets are also used for safety and efficacy 
analysis. 

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Other oral antidiabetic drug: 
Planned number of patients to be entered is 1,500 3,000. 
After the enrolment of each patient for whom Trazenta® Tablets are prescribed, the patient 
immediately following and initiating any other oral antidiabetic drug should be enrolled.The 
total number of Trazenta® Tablets patients and comparators are the same at each site. 
3.3.1 
Main diagnosis for study entry  
The PMS is performed in patients with type 2 diabetes mellitus. 
3.3.2 
Inclusion criteria 
Trazenta ® Tablets: Patients with type 2 diabetes mellitus who have never been treated with 
Trazenta® Tablets / linagliptin (monotherapy) before enrollment will be included. 
Other oral antidiabetic drug: Patients with type 2 diabetes mellitus starting any other oral 
antidiabetic monotherapy (naïve or switched from prior therapy of different oral antidiabetic 
drug) except Trazenta ® Tablets. 
3.3.3 
Exclusion criteria 
None 
3.3.4 
Removal of patients from therapy or assessments 
3.3.4.1 Removal from individual patients 
Patients may voluntarily discontinue the treatment under surveillance for any reason. Patients 
may also discontinue the PMS if the investigator judges that the patient is no longer able to 
participate for any medical reason (pregnancy, surgery, adverse events, or other disease). 
3.3.4.2 Discontinuation of the study by the sponsor 
 
NBI reserves the right to discontinue the overall surveillance or a surveillance at a particular 
study site at any time for the following reasons: 
1. Failure to meet expected enrolment overall goals or goals at a particular study site, 
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the PMS, 
3. Violation of Good Post-marketing Study Practice (GPSP) or the contract of a study site or 
investigator, thereby disturbing the appropriate conduct of the PMS. 
The investigator / the study site will be reimbursed for reasonable expenses incurred as a 
result of study termination (except in case of the third reason). 

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4. 
TREATMENTS 
4.1 
PRESCRIBED TREATMENTS TO BE OBSERVED 
4.1.1 
Identity of test product and comparator product 
In this non-interventional PMS, marketed products will be used. There will be no 
investigational products in this PMS. It is solely in the decision of the investigator to initiate 
Trazenta® Tablet or other oral antidiabetic drug. 
4.1.2 
Method of assigning patients to treatment groups 
There will be no randomisation, since this is an observational surveillance. 
4.1.3 
Selection of doses in the study 
Trazenta ® Tablets: The dose of linagliptine (5mg) used in this PMS is the dosage approved in 
Japan for Trazenta® Tablets. 
Other oral antidiabetic drug: Refer to the package insert of the prescribed oral antidiabetic 
drug 
4.1.4 
Drug assignment and administration of doses for each patient 
Trazenta ® Tablets: The investigators indicate doses of 5mg and timing based on package 
insert. 
Other oral antidiabetic drug: The investigators indicate doses and timing based on the 
package insert of the prescribed oral antidiabetic drug. 
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT 
4.2.1 
Rescue medication, emergency procedures, and additional treatment 
There are no special emergency procedures to be followed stipulated by the protocol. It is 
solely the responsibility of the investigator to initiate such measures according to local 
clinical practice. 
 
4.2.2 
Restrictions 
4.2.2.1 Restrictions regarding concomitant treatment 
None 

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4.2.2.2 Restrictions on diet and life style 
There are no restrictions on diet and life style. 
4.3 
TREATMENT COMPLIANCE 
Trazenta ® Tablets: The investigators advise patients to take the prescribed product correctly 
and verbally confirm compliance to treatment medications at every patient visit.  

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5. 
VARIABLES AND THEIR ASSESSMENT 
5.1 
EFFICACY 
5.1.1 
Endpoints of efficacy 
There is no primary endpoint for efficacy as the primary objective of a PMS is evaluating 
safety. 
The secondary endpoint for this PMS is the change from baseline in HbA1c at the last 
observation during the observation period. 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
5.1.2 
Assessment of efficacy 
HbA1c: 
The blood samples can be taken at any time and will be measured at the sites by using 
National Glycohemoglobin Standardization Program (NGSP). Based on the value measured 
according to the method of the Japan Diabetes Society (JDS), an estimated NGSP value will 
be calculated by using the following expression.  
  Estimated NGSP（%）= measured value + 0.4 
 

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5.2 
SAFETY 
5.2.1 
Endpoints of safety 
y Incidence of adverse drug reactions (ADRs) 
y Incidence of serious adverse events (SAEs) 
y 
 
   
 
5.2.2 
Assessment of adverse events 
5.2.2.1 Definitions of adverse events 
Adverse event 
An AE is defined as any untoward medical occurrence, including an exacerbation of a 
pre-existing condition, in a patient in a PMS who received a pharmaceutical product. The 
event does not necessarily have to have a causal relationship with this treatment. 
Serious adverse event 
A SAE is defined as any AE which results in death, is immediately life-threatening, results in 
persistent or significant disability / incapacity, requires or prolongs patient hospitalisation, is 
a congenital anomaly / birth defect, or is to be deemed serious for any other reason if it is an 
important medical event when based upon appropriate medical judgment which may 
jeopardise the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definitions. 
An AE which possibly leads to disability will be reported as an SAE. Every new occurrence 
of cancer will be reported as a SAE regardless of the duration between discontinuation of the 
drug and the occurrence of the cancer. 
Intensity of adverse event 
The intensity of the AE should be judged based on the following: 
Mild: 
 
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe:  
Incapacitating or causing inability to work or to perform usual activities 
 

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Causal relationship of adverse event 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms 
(CRFs). The reason for the decision on causal relationship needs to be provided in the CRF. 
Yes: 
There is a reasonable causal relationship between Trazenta® Tablets 
administered and the AE. 
Probably Yes: 
It seems there is a reasonable causal relationship between Trazenta® 
Tablets administered and the AE. 
Can't be denied: 
Physician has no clear idea on causal relationship. 
No: 
There is no reasonable causal relationship between Trazenta® Tablets 
administered and the AE. 
ADRs are defined that causal relationship is "Yes" or "Probable Yes" or "Can't be denied". 
Worsening of underlying disease or other pre-existing conditions 
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the (e)CRF. 
Changes in vital signs, Electrocardiogram (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 investigator. 
. 
5.2.2.2 Adverse event and serious adverse event reporting 
All AEs, serious and non-serious, occurring during the course of the PMS will be collected, 
documented and reported to the sponsor by the investigator on the appropriate CRFs.  
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 PMS, the package insert etc.). 
For each AE, the investigator will provide the onset, end, intensity, outcome, seriousness and 
action taken with Trazenta® Tablets. The investigator will determine the relationship of 
Trazenta® Tablets to all AEs as defined in the 'Adverse Event Reporting' section of the site 
materials. 
The investigator has the responsibility to report AEs during the specified observational phase.  
Any SAE, whether or not considered related to Trazenta® Tablets, or whether or not 
Trazenta® Tablets has been administered, must be reported immediately via EDC system or 
by a NBI MR. Further details regarding this reporting procedure are provided in the site 
materials. 

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Pregnancy 
Once a female pregnancy patient has been enrolled into the PMS, after having taken 
Trazenta® Tablets the investigator must report immediately any drug exposure during 
pregnancy to the sponsor. 
 
 
 
 
 
5.2.3 
Assessment of safety laboratory parameters 
The laboratory tests will be performed when required by investigator. 
5.2.4 
Electrocardiogram 
The ECG will be performed when required by investigator. 
5.2.5 
Assessment of other safety parameters 
Not applicable. 
5.3 
OTHER 
5.3.1 
Other endpoint 
Not applicable. 
5.3.2 
Other assessment 
Not applicable. 
5.4 
APPROPRIATENESS OF MEASUREMENTS 
All measurements performed during this PMS are widely used measurements to monitor 
safety and efficacy aspects of treatment of type 2 diabetes mellitus. 
 

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6. 
INVESTIGATIONAL PLAN 
6.1 
VISIT SCHEDULE 
Trazenta ® Tablets: 
The investigators will enrol patients who are prescribed Trazenta® Tablets. The observation 
time points will be as follows: before administration of Trazenta® Tablets (baseline), at 12 
weeks, 26 weeks, 40 weeks, 52 weeks, 64 weeks, 78 weeks, 104 weeks, 130 weeks and 156 
weeks after the start of administration, and at the time of discontinuation of administration. 
Other oral antidiabetic drug: 
After the enrolment of each patient for whom Trazenta® Tablets are prescribed, the patient 
immediately following and initiating any other oral antidiabetic drug should be enrolled. 
Only patient demographic and baseline characteristics will be collected at enrolment. No 
further assessment is needed. 
6.2 
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS 
6.2.1 
Screening and run-in period 
Trazenta ® Tablets: 
Before administration 
The investigator will enter the following data of the patient into eCRF for registration. 
Preferably, registration should be executed within 14 days from the day of first administration 
of Trazenta® Tablets. 
y 
Name of site, department and Investigator 
y 
Patient ID, date of birth, gender, treatment group, start date of administration, indication, 
serum creatinine  
 
The observation items are followings: 
y 
Gender, date of birth, indication, pregnancy status, patient status (inpatient/outpatient), 
height, body weight, waist circumference, hypersensitivity factor, concomitant disease 
and medical history, pre-treatment drug, duration of type 2 diabetes mellitus, smoking 
status, start date of administration 
y 
Concomitant drugs and antidiabetic therapy 
y 
Measurement of vital signs (blood pressure , pulse rate and ECG) as safety measurement 
(if applicable) 
y 
HbA1c , Fasting plasma glucose 
y 
Laboratory tests (blood,biochemistry and urinalysis) (if applicable) 

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Haematology 
• Leukocyte counts (WBC) 
• Erythrocyte count (RBC) 
• Platelet count  
 • Haemoglobin (Hb) 
• Haematocrit (Hct) 
 
Blood chemistry 
• AST (aspartate transaminase, 
SGOT) 
• ALT (alanine transaminase, SGPT)
• γ-GTP 
(gamma-glutamyl-transferase) 
• Total bilirubin (T-BIL) 
• Alkaline phosphatase (ALP) 
• Lactic dehydrogenase (LDH)  
• CK (creatine kinase) 
• Total cholesterol (T-CHO) 
 
 • HDL cholesterol (HDL) 
• LDL cholesterol (LDL) 
• Triglycerides (TG) 
• Blood urea nitrogen (BUN) 
• 
Amylase (AMY) 
• 
Lipase（LIP） 
• Creatinine (CRE) 
• Uric acid (UA)  
• Sodium (Na) 
• Potassium (K) 
• Chlorine(Cl) 
 
Urinalysis 
• Protein 
• Glucose 
• Urobilinogen 
 • Sediment  
• Albumin 
• Creatinine 
 
eGFR 
eGFR（mL/min/1.73 m2）= 194×Creatinine（mg/dL）－1.094×Age－0.287 
For female, ×0.739 
 
Other oral antidiabetic drug: 
 
Before administration 
The investigator will enter the following data of the patient into eCRF for registration. 
Preferably, registration should be executed within 14 days from the day of first administration 
of oral antdiabetic drugs except Trazenta ® Tablets. 
y 
Name of site, department and Investigator 
y 
Patient ID, date of birth, gender, treatment group, start date of administration, indication, 
serum creatinine  
 
The observation items are followings: 
y 
Gender, date of birth, indication, pregnancy status, patient status (inpatient/outpatient), 
height, body weight, waist circumference, hypersensitivity factor, concomitant disease 
and medical history, pre-treatment drug, duration of type 2 diabetes mellitus, smoking 

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status, name of other oral antidiabetic drug, start date of administration, total daily dose 
y 
Concomitant drugs and antidiabetic therapy 
y 
Measurement of vital signs (blood pressure and pulse rate and ECG) (if applicable) 
y 
HbA1c , Fasting plasma glucose 
y 
Laboratory tests (blood,biochemistry and urinalysis) (if applicable) 
Haematology 
• Leukocyte counts (WBC) 
• Erythrocyte count (RBC) 
• Platelet count  
 • Haemoglobin (Hb) 
• Haematocrit (Hct) 
 
Blood chemistry 
• AST (aspartate transaminase, 
SGOT) 
• ALT (alanine transaminase, SGPT)
• γ-GTP 
(gamma-glutamyl-transferase) 
• Total bilirubin (T-BIL) 
• Alkaline phosphatase (ALP) 
• Lactic dehydrogenase (LDH)  
• CK (creatine kinase) 
• Total cholesterol (T-CHO) 
 
 • HDL cholesterol (HDL) 
• LDL cholesterol (LDL) 
• Triglycerides (TG) 
• Blood urea nitrogen (BUN) 
• 
Amylase (AMY) 
• 
Lipase（LIP） 
• Creatinine (CRE) 
• Uric acid (UA)  
• Sodium (Na) 
• Potassium (K) 
• Chlorine(Cl) 
 
Urinalysis 
• Protein 
• Glucose 
• Urobilinogen 
 • Sediment  
• Albumin 
• Creatinine 
 
6.2.2 
Treatment period 
Trazenta ® Tablets: 
12 weeks, 26 weeks, 40 weeks, 52 weeks, 64weeks, 78 weeks, 104 weeks , 130 weeks, 156 
weeks  
The observation items are followings: 
y 
Administration (compliance and fasting condition: 26, 78, 156 weeks) 
y 
Concomitant drugs and antidiabetic therapy 
y 
Adverse event 
y 
Body weight 
y 
Measurement of vital signs (blood pressure , pulse rate and ECG) (if applicable) 
y 
HbA1c , Fasting plasma glucose 
y 
Laboratory tests (blood biochemistry and urinalysis) (if applicable) 
y 
Pregnancy status  

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6.2.3 
End of trial and follow-up period  
Trazenta ® Tablets: 
The visit at 156 weeks after starting Trazenta® Tablets treatment or the last visit before 
discontinuation will be the end of the PMS. There is no follow-up period. 

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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
7.1 
STATISTICAL DESIGN - MODEL 
This is a non-interventional, observational study to investigate the safety and efficacy of 
long-term use of Trazenta® Tablets as monotherapy in patients with type 2 diabetes mellitus. 
7.2 
NULL AND ALTERNATIVE HYPOTHESES 
The analyses in this PMS are descriptive and exploratory by nature. Any statistical tests will 
be performed to provide a framework from which to view the results. No formal statistical 
inference will be made. 
7.3 
PLANNED ANALYSES 
The safety and efficacy analyses are applied only on Trazenta ® Tablets. 
The safety evaluation will be performed on the “safety set” that will include all patients who 
have received treatment of Trazenta® Tablets except those who are found to have no 
observation after enrolment, invalid registration, or invalid contract. The efficacy evaluation 
will be performed on the “efficacy set”, a subset of the safety set, which will include all 
patients in the “safety set” except those who have no available efficacy data and/or who do 
not suffer from type 2 diabetes mellitus from the safety set. 
Descriptive statistics for the baseline data will be calculated for the patients who are treated 
with Trazenta ® Tablets as well as other oral antidiabetic monotherapy. 
 
7.3.1 
Primary analyses 
In this PMS, the primary objective is safety. The details are given in Section 7.3.3. 
7.3.2 
Secondary analyses 
For the change from baseline in HbA1c at the last observation, descriptive statistics will be 
calculated. A 95% confidence interval for the mean change from baseline will also be 
calculated. 
  
 
 
 
 

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7.3.3 
Safety analyses 
AEs will be coded using lowest level terms of the Medical Dictionary for Drug Regulatory 
Activities (MedDRA). AEs occurring in routine medical practice will be evaluated. The 
relationship of an AE to Trazenta® Tablets will be assessed by the investigator and the 
sponsor. An ADR is defined as an AE if either the investigator or the sponsor (or both) assess 
the causal relationship of Trazenta® Tablets either as “Yes”, “Probably yes” or “Can’t be 
denied”. 
The frequency of ADRs will be tabulated by system organ class and preferred term according 
to the current MedDRA version. 
The incidence of ADRs stratified based on patient demographics will also be investigated.  
7.3.4 
Interim analyses 
Not applicable. 
7.4 
HANDLING OF MISSING DATA 
It is not planned to impute the missing data. 
7.5 
RANDOMISATION 
No randomisation of patients to treatment is performed, since this is an observational study. 
7.6 
DETERMINATION OF SAMPLE SIZE 
The sample size was determined based on the following: To detect an ADR with an incidence 
of 0.20.1% (or 0.310.16%) or greater in at least one patient with a probability of 95% (or 
99%) or greater, at least 1,500 3,000 patients need to be entered and have at least one 
observation after treatment. 
 
 

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All patients within renal and hepatic dysfunction will be assessed. 
If the number of patients is less than expected numbers, registration period or sample size 
will be extended. 
Other oral antidiabetic drug: 
Descriptive statistics for all baseline characteristics will be analyzed. 
  
As this will be exploratory and descriptive and no statistical tests will be performed the same 
number of patients for both groups is appropriate.  

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8. 
INFORMED CONSENT, DATA PROTECTION, STUDY 
RECORDS 
The PMS will be carried out in routine clinical practice without any intervention involving 
the patients, and there is no restriction on daily clinical practice. Principles are specified in 
accordance with the Japanese GPSP regulations (Ministry of Health and Welfare Ordinance 
No.1711, December 12, 2004), Japanese Good Vigilance Practice (GVP) regulations 
(Ministry of Health and Welfare Ordinance No.1315, October 22, 2004) and relevant BI 
Standard Operating Procedures (SOPs). Standard medical care (prophylactic, diagnostic and 
therapeutic procedures) remains the responsibility of the patient’s treating physician. 
The rights of the investigator and of the sponsor with regard to publication of the results of 
this PMS are described in the investigator contract. As a general rule, no PMS results should 
be published prior to finalisation of the Study Report. 
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT 
The review by IRB is not mandatory for conducting PMS in Japanese GPSP, due to the fact 
that required PMS by MHLW is an observational study using market products involved in 
normal therapeutic procedures without any interventional procedure. 
The same applies for the implementation of changes introduced by amendments. The sponsor 
will enter into a contract with a representative, e.g. head of hospital, in accordance with 
GPSP. 
Written informed consent prior to patient participation in the trial is not regulatory or legal 
requirements in accordance with GPSP. 
8.2 
DATA QUALITY ASSURANCE 
This PMS is to be conducted in accordance with both the in-house PMS SOP and working 
instructions which are in compliance with GPSP. 
8.3 
RECORDS 
eCRFs for individual patients will be provided by the sponsor via the Electronic Data Capture 
(EDC) System. 
8.3.1 
Source documents 
Source documents provide evidence of the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRFs that is transcribed from source documents must be consistent with 
the source documents, or the discrepancies must be explained. Depending on the PMS 

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conducting under GPSP, the investigator may need to request previous medical records or 
transfer records, and current medical records must be made available. For eCRFs, all of the 
following data must be derived from source documents: 
• 
Patient identification (gender, date of birth, hospitalization status) 
• 
Patient participation in the PMS (substance, patient number) 
• 
Dates of Patient’s visits, including dispensing of the medication 
• 
Medical history (including indication and concomitant diseases, if applicable) 
• 
Medication history 
• 
 AEs and outcome events (onset date, end date, treatment for AEs) 
• 
Concomitant therapy (start date, changes, reasons for therapy) 
• 
Laboratory results (in validated electronic format, if available) 
8.3.2 
Direct access to source data and documents 
The investigator / institution will permit PMS-related regulatory inspection, providing direct 
access to all related source data / documents. All source documents, including progress notes 
and copies of laboratory and medical test results, must be available at all times for inspection 
by health authorities (e.g. PMDA). The accuracy of the data will be verified by reviewing the 
documents described in Section 8.3.1. 
8.4 
PROCEDURES FOR REPORTING ADVERSE EVENTS 
8.4.1 
Time windows 
All AEs, serious and non-serious, occurring during the course of the PMS will be collected, 
documented and reported to the sponsor by the investigator on the appropriate 
CRFs.  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 PMS, 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 Trazenta® Tablets, or whether or not 
Trazenta® Tablets has been administered, must be reported immediately via EDC system or 
by a NBI MR. Further details regarding this reporting procedure are provided in the site 
materials. 
 

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8.4.2 
Documentation of adverse events and patient narratives 
Expedited reporting to health authorities of SAEs, e.g. suspected expected and suspected 
unexpected serious adverse reactions, will be done according to J-PAL requirements. To 
fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular AE is expected. 
For each AE, the investigator will provide the onset, end, intensity, outcome, seriousness and 
action taken with Trazenta® Tablets. The investigator will determine the relationship of 
Trazenta® Tablets to all AEs as defined in the 'Adverse Event Reporting' section of the site 
materials. 
8.5 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this PMS is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers. 
Data generated as a result of the PMS needs to be available for inspection on request by the 
regulatory authorities. 
8.6 
COMPLETION OF TRIAL 
Completion of the PMS will be notified to PMDA when the reexamination document is 
applied to in accordance with J-PAL and GPSP. 
 

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9. 
REFERENCES 
9.1 
PUBLISHED REFERENCES 
R04-2630 
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell 
deficit and increased beta-cell apoptosis in humans with type 2 diabetes. 
Diabetes 2003;52:102-110. 
R04-2631 
Pospisilik JA, Martin J, Doty T, Ehses JA, Pamir N, Lynn FC, et al. 
Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and 
islet neogenesis in streptozotocin-induced diabetic rats. Diabetes 
2003;52:741-750. 
R11-4205  Pharmacovigilance  sanofi-aventis K.K.. Special Surveillance of Amaryl® 
Tablets (in Long-term Use) –Special Surveillance of Glimepiride (Amaryl® 
Tablets 1mg and 3mg Tablets) 
 
9.2 
UNPUBLISHED REFERENCES 
U09-2458-02  
and
A randomised, double-blind, placebo-controlled parallel group 
efficacy and safety study of linagliptin (5 mg) administered orally once daily 
over 24 weeks in type 2 diabetic patients with insufficient glycaemic control 
despite a therapy of metformin in combination with a sulphonylurea 
 
U10-1466-01 
 A 
double-blind phase III study to evaluate the efficacy of BI 1356 5 mgand 10 
mg vs. placebo for 12 weeks and vs. voglibose 0.6 mg for 26weeks in patients 
with type 2 diabetes mellitus and insufficient glycaemic control, followed by 
an extension study to 52 weeks toevaluate long-term safety 
 
U11-1807-01 
Special surveillance on cerebrovascular 
and cardiovascular events under long-term use of Micardis Tablets 
 
U11-3170-01 
 A phase III, randomised, double-blind, 
placebo-controlled, parallelgroup, safety and efficacy study of BI 1356 (5 mg), 
compared toplacebo as add on to pre-existing antidiabetic therapy (insulin or 
anycombination with insulin; sulphonylurea or glinides as 
monotherapy;pioglitazone or any other antidiabetics, excluding only 
DPP-4inhibitors other than BI 1356) over 52 weeks in type 2 diabetic patients 
with severe chronic renal impairment 
 
 

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10. 
APPENDICES 
Not applicable. 
 
 

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11 
SUMMARY OF PMS STUDY PROTOCOL MODIFICATIONS 
Summary of Modifications Sheet (SOMS) 
Number of Protocol modification 
 
1 
Date of Protocol modification 
 
4 April 2013 
BI Trial number 
 
1218.95 
BI Product(s) 
 
BI 1356 
Title of protocol 
 
Post Marketing Surveillance on Long Term Drug Use of 
Trazenta® Tablets in Patients with type 2 Diabetes 
Mellitus
 
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 
 
Study sites 
Description of change 
 
The total number of study sites has been 
changed from 600 to 400. 
 
Rationale for change 
 
Since the total number of entered sites has 
been increased. 
 
Section to be changed 
 
Objectives 
Description of change 
 
To investigate the safety and efficacy of 
long-term daily use of Trazenta® Tablets in 
patients with type 2 diabetes mellitus. 
 
has been changed to say: 
 
To investigate the safety and efficacy of 
long-term daily use of Trazenta® Tablets as 
monotherapy in patients with type 2 diabetes 
mellitus. 
Rationale for change 
 
To fulfil the requirements of PMDA that 

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Number of Protocol modification 
 
1 
should perform separate surveillance without 
control group for the add-on therapy. 
 
Section to be changed 
 
No. of patients: 
Description of change 
 
Total entered: 6,000 
each treatment: Trazenta ® Tablets: 3,000  
Oral antidiabetic drugs except Trazenta ® 
Tablets: 3,000 
 
has been changed to say: 
 
Total entered: 3,000 
each treatment: Trazenta ® Tablets: 1,500  
Oral antidiabetic drugs except Trazenta ® 
Tablets: 1,500 
Rationale for change 
 
To fulfil the requirements of PMDA that 
should perform separate surveillance without 
control group for the add-on therapy. 
Originally total entered (3,000) included 
patients with mono therapy and add-on 
therapy and it was reduced as only mono 
therapy patients to be enrolled. 
 
Section to be changed 
 
2.2  STUDY OBJECTIVES 
Description of change 
 
Study objectives are to investigate the safety 
and efficacy of long-term daily use of 
Trazenta® Tablets in patients with type 2 
diabetes mellitus and...... 
 
has been changed to say: 
 
Study objectives are to investigate the safety 
and efficacy of long-term daily use of 
Trazenta® Tablets as monotherapy in patients 
with type 2 diabetes mellitus and...... 
 
Rationale for change 
 
To fulfil the requirements of PMDA that 
should perform separate surveillance without 
control group for the add-on therapy. 
 
Section to be changed 
 
3.1  OVERALL DESIGN AND PLAN 
Description of change 
 
This PMS is a prospective study using a 
continuous investigation system. Patients with 

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Number of Protocol modification 
 
1 
type 2 diabetes mellitus are included in the 
surveillance. 
............... 
Planned number of patients to be entered and 
have at least one observation after treatment 
is 3,000. Patients with type 2 diabetes mellitus 
who have never received Trazenta® Tablets 
will be enrolled in the surveillance.  
............... 
Planned number of patients to be entered is 
3,000. 
has been changed to say: 
 
This PMS is a prospective study using a 
continuous investigation system. Patients with 
type 2 diabetes mellitus who are treated as 
monotherapy are included in the surveillance.
............... 
Planned number of patients to be entered and 
have at least one observation after treatment 
is 1,500. Patients with type 2 diabetes mellitus 
who have never received Trazenta® Tablets 
(monotherapy) will be enrolled in the 
surveillance.  
............... 
Planned number of patients to be entered is 
1,500. 
Rationale for change 
 
To fulfil the requirements of PMDA that 
should perform separate surveillance without 
control group for the add-on therapy. 
Originally total entered (3,000) included 
patients with mono therapy and add-on 
therapy and it was reduced as only mono 
therapy patients to be enrolled. 
 
Section to be changed 
 
3.3  SELECTION OF POPULATION 
Description of change 
 
Trazenta ® Tablets: 
Planned number of patients to be entered is  
3,000.  
Patients with renal dysfunction should be 
entered as listed below:     
eGFR <60 mL/min/1.73m2: 140 patients 

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Number of Protocol modification 
 
1 
(including 40 patients with ≥15 
mL/min/1.73m2 and <30 mL/min/1.73m2 and 
30 patients with <15 mL/min/1.73m2) 
100 patients with hepatic dysfunction should 
be also entered. 
.................. 
 Other oral antidiabetic drug: 
Planned number of patients to be entered is  
3,000. 
has been changed to say: 
 
Trazenta ® Tablets: 
Planned number of patients to be entered is 
1,500.  
Patients with renal dysfunction should be 
entered as listed below:   
eGFR <60 mL/min/1.73m2: 70  patients 
(including 20 patients with ≥15 
mL/min/1.73m2 and <30 mL/min/1.73m2 and 
15 patients with <15 mL/min/1.73m2) 
50patients with hepatic dysfunction should be 
also entered. 
.................. 
 Other oral antidiabetic drug: 
Planned number of patients to be entered is 
1,500. 
Rationale for change 
 
To fulfil the requirements of PMDA that 
should perform separate surveillance without 
control group for the add-on therapy. 
Originally total entered (3,000) included 
patients with mono therapy and add-on 
therapy and it was reduced as only mono 
therapy patients to be enrolled. 
 
Section to be changed 
 
3.3.1  Inclusion criteria 
Description of change 
 
Trazenta ® Tablets: Patients with type 2 
diabetes mellitus who have never been treated 
with Trazenta® Tablets / linagliptin before 
enrollment will be included. 
 
has been changed to say: 
 

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Number of Protocol modification 
 
1 
Trazenta ® Tablets: Patients with type 2 
diabetes mellitus who have never been treated 
with Trazenta® Tablets / linagliptin 
(monotherapy) before enrollment will be 
included. 
Rationale for change 
 
To fulfil the requirements of PMDA that 
should perform separate surveillance without 
control group for the add-on therapy. 
 
Section to be changed 
 
7.1  STATISTICAL DESIGN - MODEL 
Description of change 
 
This is a non-interventional, observational 
study to investigate the safety and efficacy of 
long-term use of Trazenta® Tablets in patients 
with type 2 diabetes mellitus. 
has been changed to say: 
 
This is a non-interventional, observational 
study to investigate the safety and efficacy of 
long-term use of Trazenta® Tablets as 
monotherapy in patients with type 2 diabetes 
mellitus. 
Rationale for change 
 
To fulfil the requirements of PMDA that 
should perform separate surveillance without 
control group for the add-on therapy. 
 
Section to be changed 
 
7.6  DETERMINATION OF SAMPLE SIZE 
Description of change 
 
The sample size was determined based on the 
following: To detect an ADR with an 
incidence of 0.1% (or 0.16%) or greater in at 
least one patient with a probability of 95% (or 
99%) or greater, at least 3,000 patients need to 
be entered and have at least one observation 
after treatment. 
.......................... 
 
 
 
 

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Number of Protocol modification 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Number of Protocol modification 
 
1 
Rationale for change