A Prospective, Non-Interventional Study of the Use of Alogliptin and Alogliptin Fixed-Dose Combinations With Pioglitazone and With Metformin in Standard Clinical Practice
Conditions: Diabetes Mellitus, Type 2
Sponsor: Takeda

This may include, but is not limited to, redaction of the following: 


•
Title: A Prospective, Non-Interventional Study of the Use of Alogliptin and Alogliptin Fixed-
Dose Combinations With Pioglitazone and With Metformin in Standard Clinical Practice
NCT Number: NCT02989649
Protocol Approve Date: 1st April 2016
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.

OBSERVATIONAL STUDY PROTOCOL 
A Prospective, Non-Interventional Study of the Use of Alogliptin and 
Alogliptin Fixed-Dose Combinations With Pioglitazone and With 
Metformin in Standard Clinical Practice 
Sponsor: 
Takeda Pharmaceutical (China) Co., Ltd. 
Study Number: 
Alogliptin-5009 
Compound: 
This is an observational study. Alogliptin or alogliptin 
fixed-dose combinations with pioglitazone and with 
metformin will be prescribed per routine clinical practice. 
Version of Protocol: 
1.1 
Date of Protocol:  
1st April 2016
CONFIDENTIAL  
All financial and non-financial support for this study will be provided by Takeda. The 
concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Takeda. 
This non-interventional study will be conducted according to Guidelines for Good 
Pharmacoepidemiology Practices (GPP). 

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Takeda 
 
Alogliptin-5009 
Protocol Version 1.1  
 
Page 3 
Table of Contents 
 
Table of Contents ...................................................................................................................... 3 
List of Tables ............................................................................................................................. 5 
Protocol Abstract ....................................................................................................................... 6 
List of Abbreviations................................................................................................................11 
1 
Introduction .................................................................................................................... 12 
2 
Study Objectives ............................................................................................................. 14 
2.1 
Primary Objective ..................................................................................................14 
2.2 
Secondary Objectives.............................................................................................14 
2.3 
Exploratory Objectives ..........................................................................................15 
3 
Investigational Plan ........................................................................................................ 16 
3.1 
Study Design ..........................................................................................................16 
3.1.1 
Rationale of Study Design ........................................................................17 
3.1.2 
Patient selection and procedure for avoiding of selection bias .................18 
4 
Patient Selection and Withdrawal Criteria ..................................................................... 19 
4.1 
Selection of Study Population ................................................................................19 
4.1.1 
Inclusion Criteria ......................................................................................19 
4.1.2 
Exclusion Criteria .....................................................................................19 
4.2 
Withdrawal of Patients From the Study .................................................................20 
4.2.1 
Reasons for Withdrawal ............................................................................20 
4.2.2 
Handling of Withdrawals ..........................................................................20 
5 
Study Treatments ............................................................................................................ 21 
6 
Study Assessments and Collection of Data .................................................................... 22 
6.1 
Study Assessments .................................................................................................22 
6.1.1 
Indication and Prescribing Physician-Related Data .................................22 
6.1.2 
Demographic Data and Medical History ..................................................22 
6.1.3 
Prior and Concomitant Medications .........................................................23 
6.1.4 
Clinical Response to Treatment With Alogliptin or Alogliptin Fixed-Dose 
Combinations ............................................................................................23 

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6.1.4.1 
HbA1c .................................................................................... 23 
6.1.4.2 
Other Assessments Related to Clinical Response .................. 24 
6.1.5 
Utilization of Alogliptin, Alogliptin Fixed-Dose Combinations, and Other 
Type 2 Diabetes Mellitus Therapies .........................................................24 
6.2 
Safety Assessments ................................................................................................24 
6.2.1 
Definitions of Adverse Events ..................................................................24 
6.2.2 
Eliciting and Documenting Adverse Events .............................................26 
6.2.3 
Reporting Adverse Events ........................................................................26 
6.2.4 
Assessment of Severity .............................................................................27 
6.2.5 
Assessment of Causality ...........................................................................28 
6.3 
Vital Sign Measurements .......................................................................................28 
6.4 
Pregnancy ...............................................................................................................29 
6.5 
Laboratory Analyses ..............................................................................................29 
7 
Statistical and Analytical Plan ........................................................................................ 30 
7.1 
Primary Endpoint ...................................................................................................30 
7.2 
Secondary Endpoints .............................................................................................30 
7.3 
Exploratory Endpoints ...........................................................................................31 
7.4 
Baseline Covariates ................................................................................................31 
7.5 
Sample Size Calculations .......................................................................................31 
7.6 
Analysis Sets ..........................................................................................................34 
7.7 
Description of Subgroups to be Analyzed .............................................................34 
7.8 
Statistical Analysis Methodology ..........................................................................34 
7.8.1 
Primary Analysis .......................................................................................35 
7.8.2 
Secondary Analyses ..................................................................................35 
7.8.3 
Exploratory Analyses ................................................................................36 
7.8.4 
Safety Analyses .........................................................................................37 
7.8.5 
Other Analyses ..........................................................................................37 
7.9 
Data Quality Control ..............................................................................................38 
7.9.1 
Data Management .....................................................................................38 
8 
Ethics .............................................................................................................................. 39 
8.1 
Independent Ethics Committee or Institutional Review Board .............................39 
8.2 
Ethical Conduct of the Study .................................................................................39 

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8.3 
Patient Information and Consent ...........................................................................39 
9 
Investigator’s Obligations............................................................................................... 41 
9.1 
Confidentiality .......................................................................................................41 
9.2 
Financial Disclosure and Obligations ....................................................................41 
9.3 
Investigator Documentation ...................................................................................41 
9.4 
Study Conduct and Adherence to Protocol ............................................................42 
9.5 
Adverse Events and Study Report Requirements ..................................................42 
9.6 
Investigator’s Final Report ....................................................................................42 
9.7 
Records Retention ..................................................................................................42 
9.8 
Publications ............................................................................................................43 
10 
Study Management ......................................................................................................... 44 
10.1 Monitoring .............................................................................................................44 
10.1.1 External Data Monitoring Committee ......................................................44 
10.1.2 Monitoring of the Study............................................................................44 
10.1.3 Inspection of Records ...............................................................................44 
10.2 Management of Protocol Amendments ..................................................................44 
10.2.1 Modification of the Protocol .....................................................................44 
10.3 Study Termination ..................................................................................................45 
11 
Reference List ................................................................................................................. 46 
12 
Appendices ..................................................................................................................... 48 
12.1 Appendix: Data Collection Schedule .....................................................................48 
12.2 Appendix: Signature Pages ....................................................................................51 
 
List of Tables 
Table 6-1 
Takeda Medically Significant AE List ............................................................ 26 
Table 12-1 
Data Collection Schedule ................................................................................ 49 
 

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Protocol Version 1.1  
 
Page 6 
Protocol Abstract 
This is an observational study and no medication will be provided. Patients enrolled into the 
study will be patients that are currently being treated by their physician. No intervention or 
change in the patients’ management will be required as a result of this study. 
Protocol Number: 
Alogliptin-5009 
Title: 
A Prospective, Non-Interventional Study of the Use of 
Alogliptin and Alogliptin Fixed-Dose Combinations With 
Pioglitazone and With Metformin in Standard Clinical Practice 
Sponsor: 
Takeda Pharmaceutical (China) Co., Ltd 
Study Sites: 
Approximate 40 sites in China and Hong Kong. 
Indication: 
Type 2 diabetes mellitus 
Rationale: 
Alogliptin is a potent, highly selective, orally available, 
quinazolinone-based inhibitor of the serine protease dipeptidyl 
peptidase-4, which has received marketing approval in over 
40 countries worldwide as monotherapy and in over 35 countries 
worldwide as a fixed-dose combination (FDC) with pioglitazone 
and with metformin. 
The safety of alogliptin has been assessed in 28 clinical studies, 
alone or in combination with other compounds. Adverse 
reactions reported in ≥4% of patients treated with alogliptin 
25 mg and more frequently than in patients who received 
placebo are upper respiratory tract infections, nasopharyngitis, 
and headache; other common adverse reactions included 
abdominal pain, gastroesophageal reflux disease, pruritus, and 
rash. Additional adverse reactions that have been spontaneously 
reported post-marketing are hypersensitivity reactions including 
anaphylaxis, angioedema, urticaria, and severe cutaneous 
reactions including Stevens-Johnson syndrome. In addition, 
acute pancreatitis and hepatic dysfunction (including fulminant 
hepatic failure) have also been reported post-marketing. 
This study is designed to observe alogliptin and alogliptin FDCs 
in real-life settings in a non-interventional manner. Alogliptin or 
alogliptin FDCs will be prescribed independent of the inclusion 
of the patient in the study. All treatment decisions will be based 
on the prescribing physician’s current clinical practice. 
 
Objectives: 
Primary objective: 
 To describe the real-world clinical response to treatment with 

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Takeda 
 
Alogliptin-5009 
Protocol Version 1.1  
 
Page 9 
Assessments: 
Clinical response to treatment with alogliptin or alogliptin FDCs 
will be evaluated based on HbA1c levels. The HbA1c level goal 
for the patient will be collected at baseline, when determined as 
part of standard clinical practice. Response will be defined as 
(1)HbA1c level change from baseline; (2) HbA1c levels 
reduction to the goal of <7%; and (3) HbA1c reduction >0.3% 
with no tolerability findings (hypoglycemic event, or weight 
gain ≥5%). The HbA1c levels will be obtained from any 
assessments performed as per standard clinical practice. No 
study-specific measurements will be performed. If multiple 
HbA1c levels are available, then the assessment closest to the 
visit time point will be used. 
Data on the use of alogliptin or alogliptin FDCs will include 
start date, dose, and end date. Information will also be collected 
on any additional T2DM treatment, both added in combination 
to alogliptin or due to switching treatment from alogliptin or 
alogliptin FDCs to another T2DM treatment. 
Incidence of newly diagnosed co-morbidities and complications 
will be collected. 
Body weight will be obtained from any assessments performed 
as 
per 
standard 
clinical 
practice. 
No 
study-specific 
measurements will be performed. 
Healthcare resources utilization will be assessed by number of 
hospitalizations (including length 
of stay during each 
hospitalization, reason, and urgency [urgent/not urgent]), 
emergency room visits, and physician office visits. 
Safety will be assessed by ADRs, SAEs, and AEs of special 
interest. 
Study Drug: 
This is an observational study. Alogliptin or alogliptin FDCs will 
be prescribed per routine clinical practice. 
Sample Size: 
Approximate 1199 patients are planned to be enrolled, not less 
than1027, and no more than 1383.  
Statistical Methods: 
This study is observational and epidemiological methods will be 
employed for data analyses. Statistical analysis will be 
performed using SAS® software (SAS Institute, Inc., Cary, North 
Carolina) Version 9.2 or later. Continuous variables will be 
summarized using the mean, the standard deviation, median, 
25th percentile, 75th percentile, minimum value, and maximum 
value. Categorical variables will be summarized using frequency 
counts and percentages. Data will be listed in data listings. A 
flow chart according to CONSORT guidelines will capture the 

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patient enrollment and the analysis sets at each analysis. No 
formal significance testing will be performed. 
The HbA1c outcomes (change of HbA1c from baseline to 
different follow-up period, and HbA1c clinical response rates) 
will be summarized as descriptive statistics and incidence rates. 
Secondary study outcome - change from baseline in glycosylated 
hemoglobin level on alogliptin or its FDCs therapy in subgroups 
with different clinical characteristics, is proposed to use 
multifactorial regression model to determine factors related to 
effect of  alogliptin or its FDCs. 
Overall and center-specific proportion of participants remaining 
on alogliptin at the end of the follow-up period will be 
summarized as frequency and percentages. Treatment patterns 
will be summarized at each follow-up time and overall at 6 
months 
as 
descriptive 
statistics 
and 
incidence 
rates. 
Alternatively, Kaplan-Meier curves may be used. Receipt of 
another T2DM treatment will be summarized at each time period 
and overall at 6 months as incidence rates. Similar analyses will 
be performed for other time to event endpoints. 
Other endpoints (rates of comorbidities and complications, 
changes in body weight, number of hospitalizations and 
healthcare resources utilization, and length of hospitalization) 
will be summarized by descriptive statistics and incidence rates 
at each time period and for the overall duration. 
All safety endpoints (ADRs, SAEs, and AESIs) will be 
summarized. 
Date of Protocol: 
1st April 2016 
 

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Protocol Version 1.1  
 
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List of Abbreviations  
Abbreviation 
Definition 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRO 
contract research organization 
DPP-4 
dipeptidyl peptidase-4 
eCRF 
electronic case report form 
FDC 
fixed-dose combination 
GPP 
Good Pharmacoepidemiology Practices 
HbA1c 
glycated hemoglobin 
ICF 
informed consent form 
IEC 
independent ethics committee 
IRB 
institutional review board 
MedDRA 
Medical Dictionary for Regulatory Activities 
SAE 
serious adverse event 
T2DM 
type 2 diabetes mellitus 
 

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1 Introduction 
Over the past 30 years, the prevalence of diabetes has increased dramatically throughout the 
world due to population growth, aging, urbanization, increasing obesity, and physical 
inactivity (Zimmet et al 2001; Wild et al 2004). Globally, the prevalence of diabetes was 
8.3% in 2014 and was estimated to increase to 10.1% in 2035 (International Diabetes 
Federation [IDF] 2014). The total number of people with diabetes worldwide was projected 
to rise from 387 million in 2014 to 592 million in 2035 (IDF 2014). Type 2 diabetes mellitus 
(T2DM) accounts for approximately 90% to 95% of all diagnosed cases of diabetes (Centers 
for Disease Control and Prevention [CDC] 2014). Major risk factors for T2DM include 
race/ethnicity, age (elderly), obesity, family history of diabetes, history of gestational 
diabetes, and physical inactivity (CDC 2014). Over the coming years, a marked increase in 
the number of adults with T2DM is expected to place an ever increasing burden on families 
and the healthcare system (Hogan et al 2003; Wild et al 2004). 
Alogliptin is a potent, highly selective, orally available, quinazolinone-based inhibitor of the 
serine protease dipeptidyl peptidase-4 (DPP-4) developed to treat adult patients with T2DM. 
Alogliptin has received marketing approval in over 40 countries worldwide, including 
Australia, China, Europe, Japan, Mexico, South Korea, and the United States. Alogliptin has 
also received marketing approval as a fixed-dose combination (FDC) with pioglitazone and 
with metformin in over 35 countries worldwide. 
The safety of alogliptin has been assessed in 14 randomized, controlled clinical trials: 
2 placebo-controlled monotherapy trials; 4 placebo-controlled add-on combination therapy 
trials with metformin, with a sulfonylurea, with a thiazolidine, and with insulin; 
4 placebo-controlled trials and 1 active-controlled trial in combination with metformin, with 
pioglitazone, and with pioglitazone added to background metformin therapy; and 
3 active-controlled trials in patients treated with pioglitazone and metformin, in combination 
with metformin, and as monotherapy compared to glipizide.  
Adverse reactions reported in ≥4% of patients treated with alogliptin 25 mg and more 
frequently than in patients who received placebo are upper respiratory tract infections, 
nasopharyngitis, and headache; other common adverse reactions included abdominal pain, 
gastroesophageal reflux disease, pruritus, and rash. Additional adverse reactions that have 
been spontaneously reported post-marketing are hypersensitivity reactions including 

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Protocol Version 1.1  
 
Page 13 
anaphylaxis, 
angioedema, 
urticaria, 
and 
severe 
cutaneous 
reactions 
including 
Stevens-Johnson syndrome. In addition, acute pancreatitis and hepatic dysfunction (including 
fulminant hepatic failure) have also been reported post-marketing. 
The EXAMINE study was conducted in 5380 patients (2679 receiving placebo and 2701 
receiving alogliptin) to assess potentially elevated cardiovascular risk related to alogliptin 
through a composite primary endpoint including death from cardiovascular causes, non-fatal 
myocardial infarction, and non-fatal stroke (White et al 2013). The results of this study 
showed that the composite primary endpoint occurred at similar rates in both treatment 
groups after a median exposure of 18 months (alogliptin: 11.3%; placebo: 11.8%; hazard 
ratio: 0.96; upper boundary of the 1-sided repeated confidence interval [CI]: 1.16; p<0.001 
for non-inferiority; p=0.32 for superiority).  
This study is designed to observe alogliptin and alogliptin with pioglitazone and with 
metformin (alogliptin FDCs) (depends on the different drugs available in China and Hong 
Kong) in real-life settings a non-interventional manner. Patients will be enrolled after they 
and their healthcare provider make the decision to employ alogliptin or alogliptin FDCs for 
the treatment of T2DM. Therefore, alogliptin or alogliptin FDCs will be prescribed 
independent of the inclusion of the patient in the study. All treatment decisions will be based 
on the prescribing physician’s current clinical practice. 

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2 Study Objectives 
2.1 Primary Objective 
The primary objective of this study is to describe the real-world clinical response to treatment 
with alogliptin or alogliptin FDCs as assessed by glycated hemoglobin (HbA1c) level change 
in patients who have been diagnosed with T2DM and initiated alogliptin or alogliptin FDCs 
therapy during the observational period. 
2.2 Secondary Objectives 
The secondary objectives of this study are: 
 To describe real-world clinical response to treatment with alogliptin or alogliptin FDCs in 
patients who have been diagnosed with T2DM and initiated alogliptin or alogliptin FDCs 
therapy during the observational period, as assessed by:  
o Change from baseline in HbA1c level on alogliptin or its FDCs therapy in subgroups 
with different clinical characteristics. 
o HbA1c levels reduction to the goal of <7.0%;  
o HbA1c reduction >0.3% with no tolerability findings (hypoglycemic event, or weight 
gain ≥5%); 
o To evaluate fasting blood glucose dynamics in patients with diabetes mellitus type 2 
over time (V1-V2-V3) 
o To evaluate the effect of alogliptin or alogliptin FDCs  on glycosylated hemoglobin 
(HbA1c) level dynamics in patients with diabetes mellitus type 2 (V3) in dependence 
on clinical characteristics. 
o Safety (as assessed by adverse drug reactions [ADRs], serious AEs [SAEs], and AEs 
of special interest [AESI]) to treatment with alogliptin or alogliptin FDCs in standard 
clinical practice. 
 To describe utilization pattern information of alogliptin and alogliptin FDCs (as assessed 
by percentage of patients who remain on treatment, and time to alogliptin or alogliptin 
FDCs dose escalation or dose reduction) during the observation period in patients who 
have been diagnosed with T2DM and initiated alogliptin or alogliptin FDCs therapy 
during the observational period. 

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Takeda 
 
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Protocol Version 1.1  
 
Page 16 
3 Investigational Plan 
3.1 Study Design 
This is an observational, prospective, multicenter study in adult patients with T2DM 
diagnosis who have made the decision, along with their treating physician, to begin treatment 
with alogliptin or alogliptin FDCs. 
This is a non-interventional study as defined in the Directive 2001/20/EC (The European 
Parliament and the Council of the European Union 2001) and will follow the Good 
Pharmacoepidemiology Practices (GPP) guidelines (Epstein 2005). This means that: 
 The assignment of a patient to a particular therapeutic strategy is not decided in advance 
by the study protocol but falls within current practice. 
 No additional diagnostic or monitoring procedures shall be applied to the patients. 
 Epidemiological methods shall be used for the analysis of collected data. 
 The prescription of alogliptin or alogliptin FDCs is clearly separated from the decision to 
include the patient in the study. 
The purpose of this study is to observe alogliptin and alogliptin FDCs utilization patterns, as 
well as clinical response to treatment with alogliptin or alogliptin FDCs, in standard clinical 
practice. No investigational product will be administered in this study. 
The observational study will include approximate 1199 patients with T2DM treated with 
alogliptin or alogliptin FDCs in approximately 40 sites. 
The planned maximum duration of this study per patient will be 6 months or up to loss to 
follow-up or death, whichever occurs first. China Guideline For Type 2 Diabetes 
recommends HbA1c as the gold standard for blood glucose monitoring. The guideline 
recommends HbA1c should be tested every 3 months when new treatment regimen is 
initiated, and when HbA1c is in the treatment target, HbA1c test can be followed every 6 
months. In this study, since the treatment of all the patients recruited are with alogliptin 
initiated, according to the guideline and the standard clinical practice, HbA1c is normally 
tested every 3 months before HbA1c hits the treatment target and keep stable. So in this 
study,  Patients will attend a baseline visit followed by visits approximately at Month 3 and 6. 

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Patients will not be asked to travel to the site only for the purpose of this study; the study 
visits will be performed during regular doctor’s appointments. 
The data collected for this study are detailed in Section 6, and the Data Collection Schedule 
is provided in Table 12-1. 
3.1.1 Rationale of Study Design  
This study is intended to describe the real-world clinical response as assessed by HbA1c 
level change from baseline in a real world setting. An observational design is adequate to 
fulfill the primary objective of this study, as it will not interfere with the prevailing standard 
of care for patients with T2DM. 
The proposed data collection schedule has been designed to have a negligible impact on the 
site standard clinical practice for the treatment of patients with T2DM, and thus to ensure the 
validity of the study results. Although the patients included in this study will be treated as per 
standard clinical practice and will not receive any direct benefit from the study, the study will 
provide an opportunity to gain a better understanding on what type of patients are being 
treated with alogliptin or alogliptin FDCs, and what type of patients benefit the most from 
treatment with alogliptin or alogliptin FDCs in a real-world setting as this is different from 
the clinical trial setting. This will allow providing real-life data to prescribers to best serve 
patients, and will contribute to increase scientific knowledge about alogliptin and alogliptin 
FDCs. 
The primary endpoint of HbA1c level, as well as the additional secondary endpoints related 
to HbA1c levels reduction to the goal <7.0%, will be achieved by collection of available 
HbA1c levels, a well-documented biomarker of disease control in T2DM. To preserve the 
observational nature of the study, this information will be obtained from any assessments 
performed as per standard clinical practice, and no study-specific measurements will be 
performed.  
The proposed number of patients (approximate 1199 enrolled patients) and the planned 
duration of the study (6 months or up to loss to follow-up or death, whichever occurs first) 
are considered to be sufficient to achieve a satisfactory degree of precision and to provide 
valuable data on the study objectives, as described in Section 7.5. 

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3.1.2 Patient selection and procedure for avoiding of selection bias 
In order to reduce selection bias, each patient who is planned to treat diabetes by 
alogliptin or its FDCs has to be documented in an anonymous patient log file (independent of 
prescribed treatment and signing of the Informed Consent Form) in a consecutive manner at 
each site. 
Eligible patients who receive alogliptin or its FDCs must be enrolled consecutively into 
the study and documented in the case report form. No eligible patient must be skipped. In 
case a patient is not eligible (e.g. no informed consent signed), the reason for non-eligibility 
must be documented in the patient log file. Additionally, for each informed consent signed, 
there will be CRFs recorded with the patient data. 
 

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4 Patient Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
4.1.1 Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in this study: 
1. 
Is capable of understanding the written informed consent, provides signed and 
written informed consent, and agrees to comply with protocol requirements. In 
case the patient is blind or unable to read, informed consent will also be 
witnessed. 
2. 
Is 18 years of age or older. 
3. 
Has a diagnosis of T2DM. 
4. 
Has made the decision, along with his/her treating physician, to begin treatment 
with alogliptin or alogliptin FDCs. 
5. 
Has an HbA1c value recorded at most 3 months before initiation of treatment 
with alogliptin or alogliptin FDCs. 
6. 
Alogliptin or alogliptin FDCs is prescribed according to the approved label for 
China and Hong Kong. 
Alogliptin or alogliptin FDCs will be prescribed independent of the inclusion of the patient in 
the study and as per standard clinical practice. 
4.1.2 Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. 
Has gestational diabetes or type 1 diabetes mellitus. 
2. 
Patients who has used Dipeptidyl peptidase-4 inhibitors (DPP-IV inhibitors) or 
Glucagon like peptide-1 agonists (aGLP-1) within the 3 months prior to the 
start of alogliptin or alogliptin FDCs treatment. 
3. 
The patients is an immediate family member, study site employee, or is in a 
dependent relationship with a study site employee who is involved in conduct 
of this study (eg, spouse, parent, child, sibling). 

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4. 
Is currently participating in a clinical trial. Participation in non-interventional 
registries is permitted.  
5. 
Is being treated with any investigational drug. 
6. 
In the opinion of the physician, the patient has any reasons of medical and non-
medical in character, which should prevent patient participation in the study. 
4.2 Withdrawal of Patients From the Study 
The duration of the study is defined for each patient as the date signed written informed 
consent is provided through to the last study visit. Patients may withdraw their consent at any 
time and for any reason without prejudice to their future medical care by the investigator or 
at the study site. 
Patients switching treatment from alogliptin or alogliptin FDCs to another T2DM treatment 
will be followed until the end of the study. 
4.2.1 Reasons for Withdrawal 
This study does not require administration of any investigational product and therefore does 
not require any stopping criteria. 
The reasons for patients not completing the study will be recorded. A patient may be 
withdrawn from the study for any of the following reasons: 
1. The patient does not meet the protocol inclusion/exclusion criteria. 
2. The patient withdraws consent or the investigator or Takeda decides to discontinue 
the patient’s participation in the study. 
The investigator will also withdraw a patient if Takeda terminates the study. 
4.2.2 Handling of Withdrawals 
When a patient withdraws from the study, the reason(s) for withdrawal shall be recorded by 
the investigator on the relevant page of the electronic case report form (eCRF). Patients lost 
to follow-up will be contacted by the site in an attempt to determine the reason for study 
withdrawal. A maximum of 3 telephone call attempts should be documented on different 
days. 
Patients who withdraw from the study will not be replaced. 

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5 Study Treatments 
This is an observational study in patients with T2DM. No study medications will be 
administered in this study. Patients enrolled in the study will have been under the care and 
treatment of their physician and will be treated according to their physician criteria and as per 
standard clinical practice. Alogliptin or alogliptin FDCs will have been prescribed as part of 
the patients’ T2DM treatment program, independent of participation in this study. Alogliptin 
or alogliptin FDCs will be prescribed as determined by the physician and standard clinical 
practice. No intervention or change in the patients’ T2DM management will be required as a 
result of this study. 

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6 Study Assessments and Collection of Data 
Before collecting any data, all potential patients will sign an informed consent form (ICF). 
Patients will have the opportunity to have any questions answered before signing the ICF. 
The investigator must address all questions raised by the patient. The investigator will also 
sign the ICF. Refer to Section 8.3 for additional details on patient’s consent. 
Study assessments will be performed as outlined in this section and in the approximate time 
points indicated in the Data Collection Schedule (Table 12-1). The time points reflect the 
standard clinical practice, and patients will not be asked to travel to the site only for the 
purpose of this study (see Section 3.1). 
6.1 Study Assessments 
6.1.1 Indication and Prescribing Physician-Related Data 
The following information related to the drug indication and treating physician will be 
collected as shown in the Data Collection Schedule (Table 12-1): 
 Indication information: alogliptin and alogliptin FDCs market status, T2DM standard 
of care 
 Prescribing physician-relevant information: general/specialized practitioner 
6.1.2 Demographic Data and Medical History 
Patient demographic data will include date of birth (if allowed by local regulations), sex, 
race, ethnicity, height, and body weight. 
Medical history will include general medical history (including medications, co-morbidities, 
and hospitalizations), as well as specific T2DM history (including date of diagnosis and 
previous treatments received). 
Demographic data and medical history will be obtained from medical records and as shown 
in the Data Collection Schedule (Table 12-1). 

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6.1.3 Prior and Concomitant Medications 
All prior and concomitant medications, including but not limited to T2DM treatments, will 
be collected and recorded in the eCRF as shown in the Data Collection Schedule 
(Table 12-1). Changes in all medication will also be collected. 
For each prior and concomitant medication, the following information will be collected: 
medication name, start date, dose, and end date. 
6.1.4 Clinical Response to Treatment With Alogliptin or Alogliptin 
Fixed-Dose Combinations 
6.1.4.1 HbA1c 
The latest HbA1c value available before the starts of alogliptin or alogliptin FDC(but within 
3 months before the first dosage) will be considered the baseline value. 
The HbA1c level goal for the patient will be collected at baseline, when determined as part of 
standard clinical practice. 
Clinical response to treatment with alogliptin or alogliptin FDCs will be evaluated based on 
HbA1c levels, as per the following endpoints:  
 Change from baseline in HbA1c levels. 
 Change in HbA1c levels over time 
 Clinical response rates: incidence rates of responders. The following definitions of 
response will be used: 
o HbA1c level reduction to the goals of <7.0%. 
o HbA1c reduction >0.3% with no tolerability findings (hypoglycemic event, or weight 
gain ≥5%) (Mathieu et al 2013). 
The HbA1c levels will be recorded in the eCRF as shown in the Data Collection Schedule 
(Table 12-1). The HbA1c levels will be obtained from any assessments performed as per 
standard clinical practice. No study-specific measurements will be performed. If multiple 
HbA1c levels are available, then the assessment closest to the visit time point will be used. 

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6.1.4.2 Other Assessments Related to Clinical Response 
Data for other assessment related to clinical response will be collected as shown in the Data 
Collection Schedule (Table 12-1) and will include the following: 
 To evaluate the effect of alogliptin and its FDCs  on fasting blood glucose dynamics in 
patients with diabetes mellitus type 2 over time (V1-V2-V3) 
 Incidence of newly diagnosed co-morbidities and complications. 
 Body weight: this information will be obtained from any assessments performed as per 
standard clinical practice. No study-specific measurements will be performed. 
 Healthcare resources utilization: number of hospitalizations (including length of stay 
during each hospitalization, reason, and urgency [urgent/not urgent]), emergency room 
visits, and physician office visits. 
6.1.5 Utilization of Alogliptin, Alogliptin Fixed-Dose Combinations, and 
Other Type 2 Diabetes Mellitus Therapies 
Data on the use of alogliptin and alogliptin FDCs will include start date, dose, and end date. 
Information will also be collected on any additional T2DM treatment, both added in 
combination to alogliptin or due to switching treatment from alogliptin or alogliptin FDCs to 
another T2DM treatment. Additional T2DM treatment may include glucagon-like peptide-1 
agonists, other oral glucose lowering agents, injectable insulin, other insulins, and other 
injectable glucose lowering agents. 
Information on alogliptin, alogliptin FDCs, and other T2DM treatments will be collected as 
shown in the Data Collection Schedule (Table 12-1). 
6.2 Safety Assessments 
The investigator or site staff will be responsible for eliciting, documenting, and reporting 
events that meet the definition of ADR, AESI, or SAE, as described in Sections 6.2.1 to 
6.2.5. Any AE volunteered by the patient will also be recorded. 
6.2.1 Definitions of Adverse Events 
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to treatment. 

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An ADR is defined as any response to a medicinal product that is noxious and unintended 
and that occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy 
of diseases or for the restoration, correction, or modification of physiological function. 
Response in this context means that a causal relationship between a medicinal product and an 
AE is at least a reasonable possibility. Adverse reaction also includes adverse clinical 
consequences associated with use of the product outside the terms of the Summary of 
Product Characteristics or other conditions laid down for the marketing and use of the 
product (including prescribed doses higher than those recommended, overdoses, or abuse). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. 
Results in DEATH. 
2. 
Is immediately LIFE THREATENING. The term “life threatening” refers to an 
event in which the subject was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death if it were more 
severe. 
3. 
Requires 
inpatient 
HOSPITALIZATION 
or 
prolongation 
of 
existing 
hospitalization. 
4. 
Results in persistent or significant DISABILITY/INCAPACITY. 
5. 
Is a CONGENITAL ANOMALY/BIRTH DEFECT.  
6. 
Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
a. May require intervention to prevent items 1 through 5 above. 
b. May expose the subject to danger, even though the event is not immediately 
life threatening or fatal or does not result in hospitalization. 
c. Includes any event or synonym described in the Takeda Medically Significant 
AE List (Table 6-1). 

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Table 6-1 
Takeda Medically Significant AE List 
Term 
Acute respiratory failure/Acute respiratory distress 
syndrome (ARDS) 
Hepatic necrosis 
Torsade de pointes/Ventricular fibrillation/Ventricular 
tachycardia 
Acute liver failure 
Malignant hypertension 
Anaphylactic shock 
Convulsive seizure 
Acute renal failure 
Agranulocytosis 
Pulmonary hypertension 
Aplastic anaemia 
Pulmonary fibrosis 
Toxic epidermal necrolysis/Stevens-Johnson 
syndrome 
Neuroleptic malignant syndrome/Malignant 
hyperthermia 
 
Spontaneous abortion/stillbirth and fetal death 
 
Confirmed or suspected transmission of infection 
agent by a medicinal product 
 
Confirmed or suspected endotoxin shock 
 
The following AEs will be considered AESIs: pancreatitis, hepatic disorders, and 
hypersensitivity reactions (including angioedema, anaphylaxis, and Stevens-Johnson 
syndrome). Targeted follow-up forms have been developed to further guide the collection of 
data of AESIs and the forms need to be submitted to the sponsor as part of the AE source 
documents. 
6.2.2 Eliciting and Documenting Adverse Events 
Adverse drug reactions, AESIs, and SAEs will be assessed from the time the patient signs the 
ICF until the end of study participation. Any AE volunteered by the patient will also be 
recorded. 
The investigator is responsible for following SAEs and AESIs until resolution, until the 
patient returns to baseline status, or until the condition has stabilized with the expectation 
that it will remain chronic, even if this extends beyond study participation. 
6.2.3 Reporting Adverse Events 
All ADRs, AESIs, and SAEs reported or observed during the study, as well as any AE 
volunteered by the patient, will be recorded on the AE page of the eCRF. Information to be 
collected includes drug treatment, dose, event term, time of onset, investigator-specified 

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assessment of severity and relationship to study drug, time of resolution of the event, 
seriousness, any required treatment or evaluations, and outcome. Adverse drug reactions, 
AESIs, and SAEs resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all AEs.  
Any medical condition that is present at baseline but does not deteriorate should not be 
reported as ADRs, AESIs, or SAEs. However, if it deteriorates at any time during the study, it 
should be recorded as an ADR, AESI, or SAE. 
Any AE that meets SAE criteria (Section 6.2.1) must be reported to Takeda immediately (i.e., 
within 24 hours) after the time site personnel first learn about the event. Any ADR or AESI 
must be reported to Takeda within 1 business day after the time site personnel first learn 
about the event. Adverse events of special interest will be followed up with specific target 
forms provided by Takeda. The (S)AEs will be reported by telephone and faxing the 
appropriate forms to Takeda. After office hours, the emergency telephone number is the one 
of Takeda as mentioned in the appropriate (S)AE forms. 
6.2.4 Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the patient’s 
daily activities. The intensity of the AE will be rated as mild, moderate, or severe using the 
following criteria:  
Mild: 
An event usually transient in nature and generally not interfering with normal 
activities. 
Moderate: 
An AE that is sufficiently discomforting to interfere with normal activities. 
Severe: 
An AE that is incapacitating and prevents normal activities. 
 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent do not require documentation of onset and duration of each episode. 

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6.2.5 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The relationship or association of alogliptin or alogliptin FDCs in causing or contributing to 
the AE will be characterized using the following classification and criteria: 
Unrelated: 
This relationship suggests that there is no association between the study drug 
and the reported event. 
 
Possible: 
This relationship suggests that treatment with the study drug caused or 
contributed to the AE, ie, the event follows a reasonable temporal sequence 
from the time of drug administration or follows a known response pattern to the 
study drug, but could also have been produced by other factors. 
 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with drug administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the drug 
or class of drugs, or judgment based on the investigator’s clinical experience, 
the association of the event with the study drug seems likely. The event 
disappears or decreases on cessation or reduction of the dose of study drug. 
 
Definite: 
This relationship suggests that a definite causal relationship exists between drug 
administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do 
not appear to explain the event. The event reappears or worsens if the study 
drug is re-administered. 
 
 
6.3 Vital Sign Measurements 
Vital sign data will include systolic and diastolic blood pressure. 
Vital sign measurements will be recorded in the eCRF as shown in the Data Collection 
Schedule (Table 12-1). Vital sign data will be obtained from any assessments performed as 

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per standard clinical practice. No study-specific measurements will be performed. If multiple 
vital sign data are available, then the assessment closest to the visit time point will be used. 
6.4 Pregnancy 
Pregnancy is not regarded as an AE unless there is a suspicion that an investigational product 
may have interfered with the effectiveness of a contraceptive medication. Any pregnancy that 
occurs during study participation must be reported using a clinical study pregnancy form. To 
ensure patient safety, each pregnancy must be reported to Takeda within 24 hours of learning 
of its occurrence. The pregnancy must be followed up to determine outcome (including 
spontaneous miscarriage, elective termination, normal birth, or congenital abnormality) and 
status of mother and child, even if the patient was discontinued from the study. Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or 
SAE. Spontaneous miscarriages must be reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention 
after the patient has completed the study, and considered by the investigator as possibly 
related to alogliptin or alogliptin FDCs, must be promptly reported to Takeda. 
6.5 Laboratory Analyses 
The following biochemistry parameters will be collected, if available: creatinine, liver 
enzymes, lipid profile, and urinary albumin. 
No laboratory analyses will be performed as part of this study. Any laboratory information 
(ie, HbA1c and biochemistry parameters) will be obtained from any assessments performed 
as per standard clinical practice. 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiograms, radiological scans, vital sign measurements) 
(including those that worsen from baseline), obtained as part of standard clinical practice and 
considered to be clinically significant in the medical and scientific judgment of the 
investigator, are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the patient’s 
condition, are not to be reported as AEs or SAEs. 

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7 Statistical and Analytical Plan 
A complete description of the statistical analyses and methods will be provided in the 
statistical analysis plan, which will be finalized before the database is locked. 
7.1 Primary Endpoint 
 The primary endpoint is Change from baseline in HbA1c level on alogliptin or its FDCs 
therapy(V3) . 
7.2 Secondary Endpoints 
The secondary endpoints related to real-world clinical response to alogliptin or alogliptin 
FDCs are the following:  
 Clinical response rates: incidence rates of responders. The following definitions of 
response will be used as secondary endpoints: 
o 
Change from baseline in HbA1c level on alogliptin or its FDCs therapy in subgroups 
with different clinical characteristics(V3). 
o HbA1c levels reduction to the goals of <7.0%(V3). 
o HbA1c reduction >0.3% with no tolerability findings (hypoglycemic event, or weight 
gain ≥5%) (V3). 
o To evaluate the effect of alogliptin and its FDCs  on fasting blood glucose dynamics 
in patients with diabetes mellitus type 2 over time (V1-V2-V3). 
 To evaluate the effect of alogliptin or alogliptin FDCs on glycosylated hemoglobin 
(HbA1c) level dynamics in patients with diabetes mellitus type 2 in dependence on 
clinical characteristics(V1-V2-V3). 
 ADRs, SAEs, and AESIs. 
The secondary endpoints related to alogliptin or alogliptin FDCs utilization patterns are the 
following: 
 Percentage of patients who remain on treatment with alogliptin or alogliptin FDCs(V2-
V3). 
 Time to alogliptin or alogliptin FDCs dose escalation or dose reduction(V2-V3). 

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Company Confidential Information

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Fixed Scenario Elements 
Distribution 
Normal 
Method 
Exact 
Correlation 
0.35 
Nominal Prob(Width) 
0.9 
Number of Sides 
2 
Alpha 
0.05 
Prob Type 
Conditional 
Standard deviation was assessed based on S. Del Prato et al study and was considered 
to be at most 0.70% (for glycosylated hemoglobin level dynamics). To determine required 
number of patients values from 0.60% to 0.70% were taken.  Desired half-wide for 
parameter estimation was set as range between 0.05 – 0.1. Following required number of 
pairs were calculated:  
 
Computed N Pairs 
Index Half-Width Std Dev Actual Prob(Width) N Pairs 
1 
0.05 
0.60 
0.904 
770 
2 
0.05 
0.65 
0.904 
899 
3 
0.05 
0.70 
0.900 
1037 
4 
0.06 
0.60 
0.904 
542 
5 
0.06 
0.65 
0.903 
632 
6 
0.06 
0.70 
0.903 
729 
7 
0.07 
0.60 
0.906 
404 
8 
0.07 
0.65 
0.902 
470 
9 
0.07 
0.70 
0.904 
542 

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10 
0.08 
0.60 
0.902 
313 
11 
0.08 
0.65 
0.907 
365 
12 
0.08 
0.70 
0.905 
420 
13 
0.09 
0.60 
0.905 
251 
14 
0.09 
0.65 
0.906 
292 
15 
0.09 
0.70 
0.907 
336 
16 
0.10 
0.60 
0.904 
206 
17 
0.10 
0.65 
0.902 
239 
18 
0.10 
0.70 
0.904 
275 

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For the worst-case scenario of half-width as 0.05, if Std Dev is 0.65, the required 
number of pairs is 899. Taking into account a possible dropout of 25%, to reach study 
objectives in regard to this endpoint, it is recommended to enroll at least 1199. If taking Std 
Dev as 0.60 or 0.70, the required number of pairs is from 770 or 1037. Taking into account a 
possible dropout of 25%, it is recommended to enroll at least 1027 or 1383 patients into the 
study. 
 
7.6 Analysis Sets 
The analysis will be performed on the complete set of patients enrolled in the study. 
Subgroup analyses will be carried out on the subgroups defined in Section 7.4. 
7.7 Description of Subgroups to be Analyzed 
Subgroup analysis may be performed using any relevant baseline covariates listed in 
Section 7.4. 
7.8 Statistical Analysis Methodology 
This study is observational and longitudinal statistical methods will be employed for data 
analyses. 
Statistical analysis will be performed using SAS® software (SAS Institute, Inc., Cary, North 
Carolina) Version 9.2 or later. Continuous variables will be summarized using the mean, the 
standard deviation, median, 25th percentile, 75th percentile, minimum value, and maximum 
value. Categorical variables will be summarized using frequency counts and percentages. 
Data will be listed in data listings. A flow chart according to CONSORT guidelines will 
capture the patient enrollment and the analysis sets at each analysis. 
Index date or date of study entry will be the patient’s first day on alogliptin. Details of the 
statistical analyses, methods, and data conventions are described in the statistical analysis 
plan. 
No formal significance testing will be performed. 

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7.8.1 Primary Analysis 
HbA1c level change from baseline 
Change of HbA1c levels will be summarized as descriptive statistics. 
7.8.2 Secondary Analyses 
The secondary HbA1c or fasting blood glucose outcomes (HbA1c clinical response rates) 
will be summarized as descriptive statistics and incidence rates. 
 HbA1c level change from baseline in subgroups with different clinical characteristics. 
It is proposed to use multifactorial regression model to determine factors related to 
effect of  alogliptin and its FDCs on glycosylated hemoglobin (HbA1c) level 
dynamics. Change from baseline in glycosylated hemoglobin (HbA1c) level  on 
alogliptin or its FDCs therapy (V3)  in subgroups with different clinical 
characteristics will be summarized using relevant descriptive statistics and analyzed 
using Multiple Linear Regression with following predictors: prior therapy of DM, 
sex, age, cardiovascular risk group, therapy type (monotherapy or combined therapy), 
baseline BMI, initial glycemic control.  
In addition, change from baseline in glycosylated hemoglobin (HbA1c) level will be 
assessed and evaluated using Mixed model repeated measures (MMRM) 
methodology. The multiple visits for each patient will be incorporated as repeated 
measures within each patient. Visit will be treated as a categorical predictor and 
baseline glycosylated hemoglobin (HbA1c) level will be included as a covariate. An 
appropriate covariance structure will be selected to provide estimates (Least Square 
Means) of change from Baseline and to perform statistical analysis at Visit 3. The 
dose-response trend hypothesis test will be conducted using the appropriate contrast 
statement for a linear (ordinal dose) trend. In addition, Least Squares Means, the 
associated standard errors and 95% confidence intervals will be displayed by each 
individual dose group. 
 Proportion (%) of patients with diabetes mellitus type 2 whose HbA1c<7.0% (V3) 
will be described and presented in summary tables using absolute frequencies and 
percentages as well as 95% confidence intervals; 
 Proportion (%) of patients with diabetes mellitus type 2 who decrease in HbA1c ≥ 
0.3% over time (V3) will be described and presented in summary tables using 
absolute frequencies and percentages as well as 95% confidence intervals; 

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Summary statistical analyses will also be provided for country and prescribing physician-
related data (see Section 6.1.1) at baseline. 
7.9 Data Quality Control 
The handling of data, including data quality assurance, will comply with regulatory 
guidelines (eg, GPP) and applicable Takeda standards.  
The study will be monitored by the contract research organization (CRO) on a regular basis 
throughout the study period and will include an electronic data collection that has a set of 
automatic data checks with data queries for programmed data collection. 
7.9.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the patients with regard to from whom data are collected 
under this protocol. The investigator agrees to maintain accurate eCRFs and source 
documentation (which may include, but is not limited to, the patient’s clinic and/or office 
chart, hospital chart, ICFs, treatment notes, laboratory reports, radiographs, or and any other 
records maintained to conduct and evaluate this observational study) as part of the case 
histories. 
Study site personnel will enter patient data into the Medidata system. The analysis data sets 
will be a combination of these data and data from other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable Takeda standards 
and data cleaning procedures to ensure the integrity of the data, as outlined in the data 
management plan. 

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8 Ethics 
8.1 Independent Ethics Committee or Institutional Review Board 
Independent ethics committee (IEC)/institutional review board (IRB) must be constituted 
according to the applicable local law and requirements, and only when required. Each site 
will require documentation noting all names and titles of members who comprise the 
respective IEC. If any member of the IEC has direct participation in this study, written 
notification regarding his or her abstinence from voting must also be obtained. 
When IEC/IRB are required according to the applicable local law and requirements, the 
protocol, informed consent, advertisements to be used for the recruitment of study patients (if 
permitted), and any other written information regarding this study to be provided to the 
patient must be approved by the IEC/IRB before study onset. Documentation of all IEC/IRB 
approvals will be maintained by the site and will be available for review by Takeda or its 
designee. 
All IEC/IRB approvals should be signed by the IEC/IRB chairman or designee and must 
identify the IEC/IRB name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
Sites must adhere to the requirements stipulated by their respective IEC/IRB. This may 
include notification to the IEC/IRB regarding any amendments or updates to the documents 
initially submitted, materials intended for viewing by subjects, local safety reporting 
requirements and reports, and updates regarding the ongoing review of the investigator. 
8.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, GPP guidelines, and all applicable local regulations. 
8.3 Patient Information and Consent 
A written informed consent in compliance with local regulatory authority regulations and US 
Title 21 Code of Federal Regulations (CFR) Part 50 shall be obtained from each patient 
before entering the study. An informed consent template may be provided by Takeda to study 
sites. If the ICF is revised during the course of the study, all active participating patients must 
sign the revised form. 

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Before recruitment and enrollment, each prospective patient or his or her legal guardian will 
be given a full explanation of the study and be allowed to read the approved ICF. Once the 
investigator is assured that the patient/legal guardian understands the implications of 
participating in the study, the patient/legal guardian will be asked to give consent to 
participate in the study by signing the ICF. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the patient or legal guardian. 

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9 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IEC/IRB but will not result in protocol amendments. 
9.1 Confidentiality 
Patient data will not be released without the written permission of the patient (or the patient’s 
legal guardian), except as necessary for monitoring and auditing by Takeda, its designee, or 
regulatory authorities. 
The investigator and all employees and co-workers involved with this observational study 
may not disclose or use for any purpose other than performance of the study any data, record, 
or other unpublished, confidential information disclosed to those individuals for the purpose 
of the study. Prior written agreement from Takeda or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
9.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow Takeda to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR 54 (Food and Drug Administration, 2014). In addition, the investigator must provide 
to Takeda a commitment to promptly update this information if any relevant changes occur 
during the course of the investigation and for 1 year following the completion of the study. 
Neither Takeda nor the CRO is financially responsible for further testing or treatment of any 
medical condition that may be detected at baseline. In addition, in the absence of specific 
arrangements, neither Takeda nor the CRO is financially responsible for further treatment of 
the patient’s disease. 
9.3 Investigator Documentation 
Prior to beginning this observational study, the investigator will be asked to provide the 
following documents: 
 IEC/IRB approval, as required by country-specific regulations, as detailed in Section 8.1 

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 Authority approval, as required by country-specific regulations 
 Original investigator-signed investigator agreement page of the protocol 
 Curriculum vitae for the investigator 
 Financial disclosure information 
 IEC/IRB-approved informed consent and samples of site advertisements for recruitment 
for this study (if permitted by local regulations) 
 Laboratory certifications and normal ranges for any local laboratories used by the site 
 Local insurance certificate, if applicable 
 Written agreement between Takeda and study site 
9.4 Study Conduct and Adherence to Protocol 
The investigator agrees that the study will be conducted in accordance with the protocol, the 
principles of the declaration of Helsinki and GPP guidelines, and all national, state, and local 
laws or regulations.  
9.5 Adverse Events and Study Report Requirements 
By participating in this observational study, the investigator agrees to submit reports of AEs 
according to the timeline and method outlined in the protocol. In addition, the investigator 
agrees to submit reports to the study site IEC/IRB as stipulated by his or her respective 
IEC/IRB. 
9.6 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IEC/IRB with a summary of the 
study’s outcome and Takeda and regulatory authorities with any reports required. 
9.7 Records Retention 
Essential documents should be retained until at least 2 years after the end of study. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with Takeda. It is the responsibility of Takeda to 
inform the investigator/institution as to when these documents no longer need to be retained. 

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9.8 Publications 
After completion of this observational study, the data may be considered for reporting at a 
scientific meeting or for publication in a scientific journal.  
Data are the property of Takeda and cannot be published without prior authorization from 
Takeda, but data and publication thereof will not be unduly withheld. 

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10 Study Management 
10.1 Monitoring 
10.1.1 External Data Monitoring Committee 
As this is an observational study, no external data monitoring committee has been planned. 
10.1.2 Monitoring of the Study 
The clinical monitor, as a representative of Takeda, has the obligation to follow the study 
closely. This study will be monitored by the CRO. Also, the monitor may visit the 
investigator and study site at periodic intervals, in addition to maintaining necessary 
telephone and letter contact.  
All aspects of the study will be monitored, by Takeda or its designee, for compliance with 
applicable government regulation with respect to current GPP guidelines and current standard 
operating procedures. 
10.1.3 Inspection of Records 
Takeda may audit the study site to evaluate study conduct and compliance with protocols, 
standard operating procedures, GPP guidelines, and applicable regulatory requirements. The 
Takeda quality assurance unit, independent of the Clinical Research Department, is 
responsible for determining the need for (and timing of) a study site audit. Each investigator 
must accept that regulatory authorities and Takeda representatives may conduct inspections 
to verify compliance of the study with GPP guidelines. 
Investigators and their relevant personnel must be available during the monitoring visits and 
possible audits or inspections and sufficient time must be devoted to the process. 
10.2 Management of Protocol Amendments 
10.2.1 Modification of the Protocol 
No changes from the final approved (signed) protocol will be initiated without the prior 
written approval or favorable opinion of a written amendment by the IEC/IRB, except when 
the change involves only logistics or administration. Amendments must be reviewed and 
approved by Takeda or its designee.  

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10.3 Study Termination 
Although Takeda has every intention of completing the study, Takeda reserves the right to 
discontinue the study at any time for clinical or administrative reasons. 
The end of this observational study is defined as the date on which the last patient completes 
the last visit or loss of contact or death, whichever occurs first. 

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11 Reference List 
American Diabetes Association. Standards of Medical Care in Diabetes—2015. Diabetes 
Care. 2015;38(Suppl 1):S1-94. 
Centers for Disease Control and Prevention (CDC). Basics about diabetes. [updated 
21 October 2014] [cited 12 January 2015]. Available from: 
http://www.cdc.gov/diabetes/consumer/learn.htm.  
Epstein M; for International Society of Pharmacoepidemiology (ISPE). Guidelines for good 
pharmacoepidemiology practices (GPP). Pharmacoepidemiol Drug Saf. 2005;14(8):589-95. 
Food and Drug Administration. Code of Federal Regulations Title 21, Part 54 Financial 
Disclosure by Clinical Investigators. [revised 01 April 2014] [cited 28 January 2015]. 
Available from: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=54&show
FR=1. 
Hogan P, Dall T, Nikolov P; and American Diabetes Association. Economic costs of diabetes 
in the US in 2002. Diabetes Care. 2003;26(3):917-32. 
International Diabetes Federation (IDF). Diabetes Atlas Sixth edition. Brussels, 2014. [cited 
12 January 2015]. Available from: http://www.idf.org/diabetesatlas. 
International Diabetes Federation (IDF). Global Guideline for Type 2 Diabetes. Brussels, 
2012. [cited 07 Apr 2015]. Available from: http://www.idf.org/global-guideline-type-2-
diabetes-2012. 
Mathieu C, Barnett AH, Brath H, et al. Effectiveness and tolerability of second-line therapy 
with vildagliptin vs. other oral agents in type 2 diabetes: a real-life worldwide observational 
study (EDGE). Int J Clin Pract. 2013;67(10):947-56. 
Rydén L, Grant PJ, Anker SD, et al. ESC Guidelines on diabetes, pre-diabetes, and 
cardiovascular diseases developed in collaboration with the EASD: the Task Force on 
diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology 
(ESC) and developed in collaboration with the European Association for the Study of 

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Diabetes (EASD). Eur Heart J. 2013;34(39):3035-87; erratum in Eur Heart J. 
2014;35(27):1824. 
The European Parliament and the Council of the European Union. Directive 2001/20/EC of 
the European Parliament and of the Council of 04 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. Off J Eur Communities. 2001;L121:34-44. 
White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients 
with type 2 diabetes. N Engl J Med. 2013;369(14):1327-35. 
Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 
and projections for 2030. Diabetes Care. 2004;27(5):1047-53. 
Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. 
Nature. 2001;414(6865):782-7. 

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12 Appendices 
12.1 Appendix: Data Collection Schedule  
Patients will not be asked to travel to the site only for the purpose of this study; the study 
visits will be performed during the regular doctor’s appointments. 
 

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Table 12-1 
Data Collection Schedule 
Procedure 
Baseline1 
Month 31 
Month 61 
Country-relevant information: alogliptin or alogliptin 
FDCs market status, T2DM standard of care 
X 
 
 
Prescribing physician-relevant information: 
general/specialized practitioner 
X 
 
 
Patient Data 
 
 
 
Informed consent 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
Demographic data2,3 
X 
 
 
General medical history and prior medications2 
X 
 
 
T2DM diagnosis and previous T2DM treatments2 
X 
 
 
Alogliptin or alogliptin FDCs status: start date4 
X 
 
 
Concomitant medications2 
X 
X 
X 
Alogliptin or alogliptin FDCs status: dose, end date (if 
applicable)4 
X 
X 
X 
Other T2DM treatment4,5 
X 
X 
X 
HbA1c and fasting blood glucose levels6,7  
X2 
X 
X 
Biochemistry parameters6,7 
X 
X 
X 
Health status (general and T2DM related)6 
X2 
X 
X 
Body weight 6 
X2 
X 
X 
Vital sign measurements6,9 
X2 
X 
X 
Healthcare resources utilization: number of 
hospitalizations (including length of stay during each 
hospitalization, reason, and urgency [urgent/not urgent]), 
ER visits, and physician office visits4 
 
X 
X 
SAFETY REPORT(ADR/SAE/SADR/AESI) 4 
 
X 
X 
Abbreviations: ER, emergency room; FDC, fixed-dose combination; HbA1c, glycated hemoglobin; T2DM, type 2 diabetes mellitus. ADR, adverse 
drug reaction; SAE, serious adverse events; SADR, serious adverse drug reaction; AESI, adverse event of special interest   

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1. 
Patients will not be asked to travel to the site only for the purpose of this study; the study visits will be performed during regular doctor’s 
appointments. 
2. 
Obtained from medical records. 
3. 
Including date of birth (if allowed by local regulations), sex and height. 
4. 
May be collected from medical records since previous visit. 
5. 
Including glucagon-like peptide-1 agonists, other oral glucose lowering agents, injectable insulin, other insulins, and other injectable glucose 
lowering agents. 
6. 
Obtained from any assessments performed as per standard clinical practice. No study-specific measurements will be performed. 
7. 
The latest HbA1c or fasting blood glucose value available before the starts of alogliptin or alogliptin FDC(but within 3 months before the first 
dosage) will be considered the baseline value. The fasting blood glucose can be either a blood test or SMBG of the patient. 
8. 
Including creatinine, liver enzymes, lipid profile, and urinary albumin. 
9. 
Systolic and diastolic blood pressure. 
 

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