Conditions: Type 2 Diabetes Mellitus
Keywords: type 2 diabetes mellitus interventional double blind phase 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 298
Healthy volunteers: no

Brief summary:
The hypothesis of this Phase 2, 12-week study, is that DS-8500a will improve glycemic control relative to placebo, based on changes in HbA1c, with acceptable safety and tolerability, in patients with Type 2 Diabetes Mellitus (T2DM) who are treated with metformin.

Detailed description:

Arms:
arm 1: One DS-8500a 25 mg tablet, 2 placebo tablets, and one placebo capsule in a once-daily oral dose arm 2: Two DS-8500a 25 mg tablets, 1 placebo tablet, and one placebo capsule in a once-daily oral dose arm 3: Three DS-8500a 25 mg tablets and one placebo capsule in a once-daily oral dose arm 4: Three placebo tablets and one placebo capsule in a once-daily oral dose arm 5: Three placebo tablets and one sitagliptin 100 mg over-capsule in a once-daily oral dose

Interventions: intervention 1: Sitagliptin 100 mg intervention 2: DS-8500a 25mg intervention 3: Placebo Tablet intervention 4: Placebo Capsule
Intervention descriptions: intervention 1: Two sitagliptin 50 mg tablets, over-encapsulated to provide a once-daily dose of 100 mg, for oral administration intervention 2: DS-8500a 25mg tablet for oral administration intervention 3: Placebo matching DS-8500a tablet for oral administration intervention 4: Placebo matching sitagliptin over-capsule for oral administration

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential
Page 1
CLINICAL STUDY PROTOCOL
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED WITH ACTIVE COMPARATOR,
12-WEEK STUDY OF DS-8500a IN SUBJECTS WITH 
TYPE 2 DIABETES MELLITUS ON METFORMIN
DS8500-A-U202
IND 125,803
VERSION 1.0, 28 OCT 2015
SPONSOR:
Daiichi Sankyo, Inc.
399 Thornall Street 
Edison, NJ 08837 United States
CONFIDENTIALITY STATEMENT
Information contained in this document is proprietary to Daiichi Sankyo.  The 
information is provided to you in confidence which is requested under an agreed upon 
and signed Confidentiality and Disclosure Agreement.  Do not give this document or any 
copy of it or reveal any proprietary information contained in it to any third party (other 
than those in your organization who are assisting you in this work and are bound by the 
Confidentiality and Disclosure Agreement) without the prior written permission of an 
authorized representative of Daiichi Sankyo.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 2
Proprietary and Confidential


Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 3
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 3
PROTOCOL SYNOPSIS
IND Number:
125,803
Protocol Number:
DS8500-A-U202
Investigational Product:
DS-8500a, sitagliptin (active comparator), and placebo
Active Ingredient(s)/INN:
Study Title:
A Randomized, Double-Blind, Placebo-Controlled with 
Active Comparator, 12-Week Study of DS-8500a in 
Subjects with Type 2 Diabetes Mellitus on Metformin 
Study Phase:
Phase 2
Indication Under 
Investigation:
Type 2 Diabetes Mellitus (T2DM)
Study Objectives:
The primary objective is to evaluate change in hemoglobin 
A1c (HbA1c) from baseline to Week 12 with DS-8500a 
compared with placebo in subjects with T2DM.
The secondary objectives are: 
!
To evaluate changes in lipids [total cholesterol 
(TC), low-density lipoprotein cholesterol (LDL-
C), high-density lipoprotein cholesterol (HDL-
C), non-high density cholesterol (non-HDL-C) 
and triglycerides (TG)] from baseline to Week 
12 with DS-8500a compared with placebo.
!
To evaluate change in 3h area under the curve 
(AUC0-3h) plasma glucose (PG) in response to a 
mixed meal tolerance test (MMTT) from 
baseline to Week 4 and Week 12 with DS-8500a 
compared with placebo. 
!
To evaluate change in fasting plasma glucose 
(FPG) from baseline to Weeks 2, 4, 8 and 12 
with DS-8500a compared with placebo.
!
To evaluate the proportion of subjects achieving 
HbA1c < 7.0% at Week 12 with DS-8500a 
compared with placebo.
!
To assess the pharmacokinetics (PK) of DS-
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 4
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 4
8500a and its metabolite (A209-3952). 
The safety objectives are:
!
To evaluate the safety and tolerability of DS-8500a 
in subjects with T2DM assessed by treatment 
emergent adverse events (TEAEs) and change in 
vital signs and safety laboratory values.
a.
The proportion of subjects with TEAE.
b. Changes in routine safety laboratory testing 
(i.e., hematology, chemistry) from baseline
to Week 12.
c.
The proportion of subjects with 
prospectively adjudicated cardiovascular 
events including cardiovascular death, non-
fatal myocardial infarction, transient 
ischemic attack and non-fatal stroke, 
hospitalization for unstable angina, urgent 
coronary revascularization intervention and 
hospitalization for congestive heart failure.
The exploratory objectives are:
!
 
 
 
 
 
 
 
 
 
 
 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 5
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 5
Study Design:
This is a randomized, dose ranging, double-blind, double-
dummy, placebo-controlled with active comparator, multi-
center, and 12-week study of DS-8500a in subjects with 
T2DM on a stable metformin dose.
Approximately 260 eligible subjects will be randomized in 
a 2:2:3:3:3 ratio with 40 subjects per arm in each of the DS-
8500a 25 mg and DS-8500a 50 mg treatment groups, and 
60 subjects per arm in each of the DS-8500a 75 mg , 
placebo, and sitagliptin 100 mg treatment groups. The 
randomization will be stratified on the basis of 3-hydroxy-
3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors 
(statins) treatment at the time of randomization. One 
stratum will include subjects who have been treated by 
statins, and the other stratum will include subjects who 
were not treated by statins at the time of randomization. 
The study will include 4 periods for a total of up to 18 
weeks:  
1. Screening Period (Weeks -4 to -3): 
There will be a period up to 2 weeks for subject screening 
based on medical history, physical examination and clinical 
labs, and meeting all inclusion and exclusion criteria. 
Subjects will receive basic dietary and exercise instruction 
at the time of screening. Subjects should not embark on 
aggressive, excessively restrictive or high fat content diets 
or change their physical activity level during this study.
2. Lead-in Period (Weeks -2 and -1):
During the Lead-in Period, subjects will take single blind 
DS-8500a matching placebo tablets and a sitagliptin 
matching placebo capsule to assess compliance with study 
regimen. Subjects will also be required to continue taking 
metformin as taken prior to screening. Subjects will be 
required to perform and record fasting self-monitoring of 
blood glucose (SMBG) daily.   
3. Randomization (Day 1):
At the end of the Lead-in Period, eligible subjects who 
demonstrate good compliance with study drug (taking ≥ 
80% and ≤ 120% of both dispensed DS-8500a placebo 
tablets and sitagliptin placebo capsules) and an appropriate 
Lead-in Period fasting glucose (≤ 240 mg/dL, at least 7 
days of recorded fasting SMBG required) will be 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 6
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 6
randomized in a 2:2:3:3:3 ratio to parallel double-blind 
treatment groups of DS-8500a 25 mg, DS-8500a 50 mg, 
DS-8500a 75 mg, placebo, or sitagliptin 100 mg. A 3-hour 
MMTT will be performed on Day 1 (prior to 
randomization).
4. Treatment Period (Day 2 to Week 12):
The Treatment Period will consist of 12 weeks of 
randomized double-blind, double dummy treatment with 
study medication, starting on Day 2 (one day after 
randomization day). Treatment visits will occur at Weeks 2, 
4, 8, and 12 of the randomized Treatment Period. HbA1c 
will be measured at Weeks 4, 8, and 12 and FPG will be 
measured at every visit. A 3-hour MMTT will be 
performed on Week 4 and End-of-Treatment /Early 
Termination visit (Week 12). Metformin treatment will 
continue at the same dose taken prior to screening 
throughout the Treatment Period.
Subjects who meet protocol discontinuation criteria will be 
asked to return to the clinic for follow-up assessment and 
confirmation of values prior to discontinuation. 
Discontinued subjects must complete Early Termination 
Visit procedures.
5. Post-study Follow-up Period (Weeks 13 and 14):
Subjects who complete the randomized Treatment Period 
or are discontinued will return to the clinic for a post-study 
follow-up safety assessment visit approximately 2 weeks 
after taking the final dose of randomized study medication.
Study Duration:
The study includes 4 periods for a total of up to 18 weeks: a 
Screening period up to 2 weeks, a 2 week single-blind 
placebo Lead-in (Weeks -2 and -1), a 12-week double-
blind, double-dummy Treatment period (Day 2 to Week 
12), and a 2-week post-dosing Follow-up (Weeks 13 and 
14).
Study Centers and Location: The study will be conducted at approximately 65 study 
centers in the United States and Canada.
Subject Eligibility Criteria:
Inclusion Criteria:
1. Able to provide written informed consent and 
adhere to the study visit schedule and treatment
2. Diagnosed with Type 2 diabetes mellitus as defined 
in the American Diabetes Association Standards of 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 7
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 7
Medical Care in Diabetes 2015a,6
3. Male or female ≥ 18 and ≤ 70 years of age
4. Screening fasting C-peptide > 0.5 ng/mL
5. Women of child bearing potential (WOCBP) must 
be willing to use double-barrier contraception for 
the entire study
6. WOCBP must have a negative pregnancy test 
(human chorionic gonadotropin, beta subunit 
[βhCG]) before entering the Lead-in Period
7. Body mass index ≥ 25 kg/m2 and ≤ 45 kg/m2 at the 
Screening Visit
8. On stable (≥8 weeks) metformin monotherapy ≥ 
1000 mg/day
9. Screening HbA1c ≥ 7.0% and ≤ 10%
10. Taking ≥ 80% and ≤ 120% of both dispensed DS-
8500a placebo tablets and sitagliptin placebo 
capsules during the Lead-in Period 
Exclusion Criteria:
1. History of type 1 diabetes and/or history of 
ketoacidosis
2. History of insulin use for > 2 weeks within 2 
months prior to the Screening Visit
3. Two or more readings of fasting SMBG > 240 
mg/dL or worsening symptoms of hyperglycemia 
with one SMBG level of > 240 mg/dL  during the 
second week of Lead-in Period, confirmed by 
laboratory measurement
4. Screening hemoglobin <12 g/dL for males and  <11 
g/dL for females
5. Blood donation within 2 months prior to the 
Screening Visit or plans to donate blood or blood 
products during the study 
6. Subjects after bariatric surgery or any gastric bypass
or planning to have such a procedure during the 
                                                
a HbA1c≥6.5%; or FGP≥126 mg/dL; or 2-hour PG≥200 mg/dL during an oral glucose tolerance test 
(OGTT); or classic symptoms of hyperglycemia with a random PG≥200 mg/dL  
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 8
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 8
study
7. Screening thyroid stimulating hormone (TSH) 
levels not within normal range (based on reference 
laboratory values )
8. Screening alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) > 2.0 x upper 
limit of normal (ULN), and/or total bilirubin > 1.5 x 
ULN. If a subject has total bilirubin > 1.5 x ULN, 
unconjugated and conjugated bilirubin fractions 
should be analyzed and only subjects documented 
to have Gilbert’s syndrome may be enrolled 
9. Screening Serum creatinine ≥ 1.5 mg/dL for males 
and ≥ 1.4 mg/dL for females, or creatinine clearance 
(CrCl) < 50 mL/min for both males and females
10. Screening Creatine kinase (CK) > 3.0 × ULN
11. History of unstable angina, myocardial infarction, 
cerebrovascular accident, transient ischemic attack, 
peripheral arterial event or any revascularization 
procedure during the 6 months prior to the 
Screening Visit or planned vascular procedures or 
surgery during study period
12. History of congestive heart failure (CHF)
13. Exclusionary concomitant medications: 
a.
Eight weeks prior to screening and throughout 
the duration of the study:
!
Any diabetes medication other than metformin; 
any prescription or over the counter medication 
for weight-loss.
!
Systemic corticosteroids (including nasal and 
inhaled), with the exception of use of topical 
and ophthalmic corticosteroids.
!
Rosuvastatin > 20 mg daily. 
b. During treatment periods, additional 
medications will be prohibited based on 
potential drug-drug interaction (DDI) (see 
Section 5.6)
14. Subjects with anticipated interruption in metformin 
or study drug use during the course of the clinical 
trial (e.g., due to an imaging procedure involving 
iodinated contrast media)
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 9
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 9
15. Subjects in whom treatment with sitagliptin 100 mg 
is contraindicated ( e.g., known hypersensitivity or 
intolerance to sitagliptin) or may not be medically 
advisable  (e.g., history of pancreatitis)
16. Abuse of or dependence on prescription 
medications, illicit drugs, or alcohol within the last 
1 year
17. Any history of a malignancy other than basal cell 
carcinoma within the past 5 years
18. Pregnancy or breast-feeding, or intent to become 
pregnant during the study period
19. Known (or evidence of) infection with human 
immunodeficiency virus
20. Any condition, laboratory abnormality, or 
concomitant therapy which, in the opinion of the 
Investigator, might pose a risk to the subject or 
make participation not in the subject’s best interest
21. Subject is currently enrolled in or has not yet 
completed at least 30 days since ending another 
investigational device or drug study or is receiving 
other investigational agents
22. A direct or familial relationship with the Sponsor, 
Investigator, or site personnel affiliated with the 
study
Dosage Form, Dose and 
Route of Administration:
Double-blind, double-dummy study medication will be 
provided in blister cards (“wallets”).  
DS-8500a is supplied in the form of 25 mg tablets for oral 
administration. Doses of DS-8500a include 25 mg, DS-
8500a 50 mg, and 75 mg once a day (QD). Matching 
placebo tablets are also used.  
Sitagliptin 50 mg tablets will be over-encapsulated to 
provide a once daily dose of 100 mg. Matching placebo 
capsules will also be used.  
DS-8500a or matching placebo tablets and sitagliptin or 
matching placebo capsules will be administered orally once 
daily after breakfast for 12 weeks, except for study visit 
days. The first dose of randomized study drug will be taken 
after breakfast on Day 2 after the Day 1 visit. On days of 
study visits that involve MMTT, study drug will be taken 
after ingestion of the liquid meal [Day 1 (Lead-in tablets 
and capsule) and Visits 5 and 7 at Weeks 4 and 12]. On 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 10
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 10
days of Visits 4 and 6 (Weeks 2 and 8, respectively), study 
drug should be taken after study laboratory blood draw and 
after having breakfast.
Study Endpoints:
The primary efficacy endpoint is change from baseline in 
HbA1c at Week 12.
The secondary endpoints are: 
!
Changes from baseline in lipids (TC, LDL-C, 
HDL-C, non-HDL-C and TG) at Week 12.
!
Changes from baseline in AUC0-3h and Cmax of 
PG in response to MMTT at Weeks 4 and 12.
!
Changes from baseline in FPG from baseline to 
Weeks 2, 4, 8, and 12.
!
The proportion of subjects achieving HbA1c < 
7.0% at Week 12.
Exploratory endpoints are: 
 
 
 
 
 
Planned Sample Size:
Approximately 260 eligible subjects will be randomized in 
a 2:2:3:3:3 ratio with 40 subjects per arm in each of the DS-
8500a 25 mg and DS-8500a 50 mg treatment groups, and 
60 subjects per arm in each of the DS-8500a 75 mg,
placebo, and sitagliptin 100 mg treatment groups. 
Assuming a common standard deviation of 1.0% and an 
early dropout rate of 10%, with a 2-sided significance level 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 11
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 11
of 0.1, it will provide at least 90% power to detect a 0.6% 
difference between DS-8500a 75 mg dose and placebo and 
at least 80% power to detect a 0.6% difference between 
each of the DS-8500a 25 mg and 50 mg doses and placebo 
in mean HbA1c change from baseline to Week 12.  No 
adjustment will be made for multiplicity.  
Statistical Analyses:
Primary Endpoint:
The primary estimand is the treatment difference between 
DS-8500a and placebo for the change in HbA1c from 
baseline to Week 12 attributable to the initially randomized 
treatment for all subjects in the modified Intent-To-Treat 
(mITT) population.  The primary estimand will be analyzed 
using a mixed-effect model with repeated measures 
(MMRM) with treatment, previous statins stratum, week, 
and treatment-by-week as fixed effects, week as a repeated 
factor, and baseline HbA1c as a covariate. 
Secondary Endpoints:
Secondary efficacy analyses will include comparisons of 
each DS-8500a dose level to placebo for the change from 
baseline to Week 4 and to Week 12 in lipids, 3h AUC PG 
in response to MMTT, changes in FPG at Weeks 2, 4, 8 
and 12 and the proportion of subjects achieving HbA1c < 
7.0% at Week 12. A MMRM with treatment, previous 
statins stratum, week, and treatment-by-week as fixed 
effects, week as a repeated factor, and baseline value as a 
covariate will be used for the analyses of changes from 
baseline in FPG, lipids and 3h AUC PG. A logistic 
regression model with treatment and previous statins 
stratum as fixed effects and baseline value as a covariate 
will be used for the analysis of proportion of subjects 
achieving HbA1c < 7.0% at Week 12.           
Exploratory Endpoints:
 
 
 
 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 12
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 12
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 13
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 13
TABLE OF CONTENTS
INVESTIGATOR AGREEMENT...................................................................................................2
PROTOCOL SYNOPSIS ................................................................................................................3
TABLE OF CONTENTS...............................................................................................................13
LIST OF TABLES.........................................................................................................................19
LIST OF FIGURES .......................................................................................................................20
LIST OF ABBREVIATIONS........................................................................................................21
1.
INTRODUCTION......................................................................................................24
1.1.
Background.................................................................................................................24
1.1.1.
Investigational Product(s)...........................................................................................24
1.1.1.1.
Name...........................................................................................................................24
1.1.1.2.
Description..................................................................................................................24
1.1.1.3.
Intended Use Under Investigation ..............................................................................24
1.1.1.4.
Nonclinical Studies.....................................................................................................24
1.1.1.5.
Clinical Experience.....................................................................................................24
1.2.
Study Rationale...........................................................................................................26
2.
STUDY OBJECTIVES AND HYPOTHESIS ...........................................................28
2.1.
Study Objectives.........................................................................................................28
2.1.1.
Primary Objectives .....................................................................................................28
2.1.2.
Secondary Objectives .................................................................................................28
2.1.3.
Safety Objectives........................................................................................................28
2.1.4.
Exploratory Objectives ...............................................................................................29
2.2.
Study Hypothesis........................................................................................................29
3.
STUDY DESIGN .......................................................................................................30
3.1.
Overall Design............................................................................................................30
3.2.
Discussion of Study Design........................................................................................30
4.
STUDY POPULATION.............................................................................................32
4.1.
Inclusion Criteria ........................................................................................................32
4.2.
Exclusion Criteria.......................................................................................................32
4.3.
Women of Child-Bearing Potential (WOCBP) ..........................................................34
5.
STUDY TREATMENT(S).........................................................................................35
5.1.
Assigning Subjects to Treatments and Blinding.........................................................35
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 14
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 14
5.1.1.
Treatment during Lead-in Period................................................................................35
5.1.2.
Treatment Group(s) ....................................................................................................35
5.1.3.
Method of Treatment Allocation ................................................................................36
5.1.4.
Blinding ......................................................................................................................36
5.1.5.
Emergency Unblinding Procedure..............................................................................37
5.2.
Study Drug(s)..............................................................................................................37
5.2.1.
Description..................................................................................................................37
5.2.2.
Labeling and Packaging..............................................................................................38
5.2.3.
Preparation..................................................................................................................38
5.2.4.
Administration............................................................................................................38
5.2.5.
Storage ........................................................................................................................38
5.2.6.
Drug Accountability ...................................................................................................38
5.3.
Control Treatment.......................................................................................................39
5.4.
Dose Interruptions and Reductions.............................................................................39
5.5.
Method of Assessing Treatment Compliance.............................................................39
5.6.
Prior and Concomitant Medications...........................................................................40
5.7.
Subject Withdrawal/Discontinuation..........................................................................41
5.7.1.
Reasons for Withdrawal .............................................................................................41
5.7.2.
Withdrawal Procedures...............................................................................................43
5.7.3.
Subject Replacement ..................................................................................................43
5.7.4.
Subject Re-screening Procedures ...............................................................................43
6.
STUDY PROCEDURES............................................................................................44
6.1.
Screening Period.........................................................................................................44
6.1.1.
Screening Visit (Visit 1; Week -4 to Week -3)...........................................................44
6.2.
Placebo Lead-in (Visit 2, Week -2) ............................................................................46
6.3.
Randomization (Visit 3, Day 1)..................................................................................47
6.4.
Treatment Period (Visit 4 to Visit 7, Week 2 to Week 12, 
respectively)................................................................................................................48
6.4.1.
Visit 4 (Week 2)..........................................................................................................48
6.4.2.
Visit 5 (Week 4)..........................................................................................................49
6.4.3.
Visit 6 (Week 8)..........................................................................................................50
6.4.4.
Visit 7 (End-of-Treatment Visit, Week 12) or Early Termination 
Visit.............................................................................................................................51
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 15
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 15
6.5.
Follow-Up (Visit 8, Week 14)....................................................................................52
7.
EFFICACY ASSESSMENTS ....................................................................................53
7.1.
Primary Efficacy.........................................................................................................53
7.2.
Secondary Efficacy.....................................................................................................53
7.3.
Exploratory Efficacy...................................................................................................53
8.
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS......................54
8.1.
Pharmacokinetic (PK) Endpoint(s).............................................................................54
8.2.
Pharmacodynamic (PD) Endpoint(s)..........................................................................54
8.3.
Biomarker Endpoint(s) ...............................................................................................55
8.4.
Immunogenicity..........................................................................................................56
8.5.
Pharmacogenomic Analysis........................................................................................56
9.
SAFETY EVALUATION AND REPORTING.........................................................57
9.1.
Adverse Event Collection and Reporting ...................................................................57
9.2.
Safety Endpoint Event(s)............................................................................................58
9.3.
Events of Special Interest ...........................................................................................58
9.3.1.
Adjudicated Cardiovascular Events............................................................................58
9.3.2.
Anemia Monitoring and Stopping Criteria.................................................................58
9.3.2.1.
Rules for Anemia Evaluation and Stopping of Study Subjects ..................................58
9.3.2.2.
Anemia Monitoring ....................................................................................................59
9.3.3.
Combined Elevations of Aminotransferases and Bilirubin ........................................59
9.4.
Adverse Event.............................................................................................................59
9.4.1.
Definition of Adverse Event (AE)..............................................................................59
9.4.2.
Definition of Serious Adverse Event (SAE)...............................................................60
9.4.3.
Severity Assessment ...................................................................................................60
9.4.4.
Causality Assessment .................................................................................................61
9.4.5.
Action Taken Regarding the Study Product ...............................................................61
9.4.6.
Adverse Event Outcome.............................................................................................61
9.4.7.
Other Action Taken for Event ....................................................................................61
9.5.
Reporting Procedure For Investigators.......................................................................62
9.6.
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee ...............................................................................62
9.7.
Exposure In Utero During Clinical Studies................................................................63
9.8.
Clinical Laboratory Evaluations.................................................................................63
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 16
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 16
9.8.1.
Hematology.................................................................................................................63
9.8.2.
Blood Chemistry.........................................................................................................64
9.8.2.1.
Estimation of Creatinine Clearance............................................................................65
9.8.3.
Urinalysis....................................................................................................................65
9.8.4.
Pregnancy Testing ......................................................................................................65
9.8.5.
Thyroid Stimulating Hormone (TSH) ........................................................................65
9.9.
Vital Signs ..................................................................................................................65
9.10.
Body Height and Weight ............................................................................................66
9.11.
Electrocardiograms.....................................................................................................66
9.12.
Physical Examinations................................................................................................66
9.13.
Other Examinations ....................................................................................................66
9.13.1.
Medical History and Demographics ...........................................................................66
9.13.2.
Home Self-Monitoring of Blood Glucose ..................................................................67
9.13.3.
Study Diary.................................................................................................................67
9.14.
Patient Reported Outcomes ........................................................................................67
9.15.
Pharmacoeconomic Assessments ...............................................................................67
10.
OTHER ASSESSMENTS ..........................................................................................68
10.1.
Patient Reported Outcomes ........................................................................................68
10.2.
Pharmacoeconomic Assessments ...............................................................................68
11.
STATISTICAL METHODS.......................................................................................69
11.1.
Analysis Sets...............................................................................................................69
11.2.
General Statistical Considerations..............................................................................69
11.3.
Study Population Data................................................................................................69
11.4.
Statistical Analysis......................................................................................................70
11.4.1.
Efficacy Analyses .......................................................................................................70
11.4.1.1.
Primary Efficacy Analyses .........................................................................................70
11.4.1.2.
Secondary Efficacy Analyses .....................................................................................70
11.4.1.3.
Exploratory Efficacy Analyses...................................................................................71
11.4.1.4.
Subgroup Efficacy Analyses.......................................................................................71
11.4.2.
Pharmacokinetic/Pharmacodynamic Analyses...........................................................72
11.4.2.1.
Pharmacokinetic Analyses..........................................................................................72
11.4.2.2.
Pharmacodynamic Analyses.......................................................................................72
11.4.2.3.
Biomarker Analyses....................................................................................................73
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 17
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 17
11.4.2.4.
Pharmacogenomic Analyses.......................................................................................73
11.4.3.
Safety Analyses ..........................................................................................................73
11.4.3.1.
Adverse Event Analyses.............................................................................................73
11.4.3.2.
Clinical Laboratory Evaluation Analyses...................................................................73
11.4.3.3.
Vital Sign Analyses ....................................................................................................73
11.4.3.4.
Electrocardiogram Analyses.......................................................................................74
11.4.3.5.
Physical Examination Analyses..................................................................................74
11.4.3.6.
Exploratory Safety Analyses ......................................................................................74
11.4.4.
Other Analysis ............................................................................................................74
11.5.
Interim Analyses.........................................................................................................74
11.5.1.
Data Monitoring Committee.......................................................................................74
11.6.
Sample Size Determination ........................................................................................74
11.7.
Statistical Analysis Process ........................................................................................74
12.
DATA INTEGRITY AND QUALITY ASSURANCE..............................................76
12.1.
Monitoring and Inspections........................................................................................76
12.2.
Data Collection...........................................................................................................76
12.3.
Data Management.......................................................................................................77
12.4.
Study Documentation and Storage .............................................................................78
12.5.
Record Keeping ..........................................................................................................78
13.
FINANCING AND INSURANCE.............................................................................80
13.1.
Finances ......................................................................................................................80
13.2.
Reimbursement, Indemnity, and Insurance ................................................................80
14.
PUBLICATION POLICY ..........................................................................................81
15.
ETHICS AND STUDY ADMINISTRATIVE INFORMATION..............................82
15.1.
Compliance Statement, Ethics and Regulatory Compliance ......................................82
15.2.
Subject Confidentiality...............................................................................................82
15.3.
Informed Consent .......................................................................................................82
15.4.
Regulatory Compliance ..............................................................................................83
15.5.
Protocol Deviations ....................................................................................................84
15.6.
Supply of New Information Affecting the Conduct of the Study...............................84
15.7.
Protocol Amendments ................................................................................................84
15.8.
Study Termination ......................................................................................................85
15.9.
Data and Safety Monitoring Board.............................................................................85
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 18
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 18
15.10.
Address List................................................................................................................85
16.
REFERENCES ...........................................................................................................86
17.
APPENDICES ............................................................................................................87
17.1.
Cockcroft-Gault Equation...........................................................................................87
17.2.
Schedule of Events .....................................................................................................88
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 19
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 19
LIST OF TABLES
Table 5.1: Study Treatment Administration by Treatment Group...............................................35
Table 5.2: Prohibited Medications during Treatment Periods.....................................................41
Table 6.1: Screening Laboratory Values .....................................................................................45
Table 8.1: PK Sampling for DS-8500a and Its Metabolite (A209-3952)....................................54
Table 8.2: PD Sampling for Plasma Glucose, Insulin, C-peptide, total GLP-1, 
active GLP-1, PYY and Glucagon..............................................................................55
Table 9.1: Hematology Analytes .................................................................................................64
Table 9.2: Blood Chemistry Analytes..........................................................................................64
Table 9.3: Urinalysis Determinations ..........................................................................................65
Table 17.1: Schedule of Events .....................................................................................................89
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 20
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 20
LIST OF FIGURES
Figure 3.1: Design of Phase 2 study of DS-8500a in Subjects with T2DM .................................30
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 21
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 21
LIST OF ABBREVIATIONS
ABBREVIATION
DEFINITION
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Plasma Concentration-Time Curve
AUC0-3h
Area Under Plasma Concentration-Time Curve for 0 to 3.0 hours 
AUClast
Area Under the Plasma Concentration–Time Curve from Time 0 to the 
Time of the Last Quantifiable Concentration
AUCtau
Area Under the Plasma Concentration-Time Curve for a Dosing 
Interval
BCRP
Breast Cancer Resistance Protein
CBC
Complete Blood Count
CEC
Cardiovascular Endpoints Committee
CHF
Congestive Heart Failure
CI
Confidence Intervals
Cmax
Maximum Plasma Concentration
eCRF
Electronic Case Report Form
CRO
Contract Research Organization
CrCl
Creatinine Clearance
DDI
Drug-Drug Interaction
DI
Disposition Index
ECG
Electrocardiogram
EDC
Electronic Data Capture
FPG
Fasting Plasma Glucose
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice 
GLP-1
Glucagon-Like Peptide-1
GPR119
G-Protein Coupled Receptor 119
HbA1c
Hemoglobin A1c
HDL-C
High-Density Lipoprotein Cholesterol
HMG-CoA
3-hydroxy-3-methyl-glutaryl-CoA
HOMA-IR
Homeostatic Model Assessment-Insulin Resistance
HOMA-%β
Homeostatic Model Assessment-Beta-Cell Function
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 22
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 22
ABBREVIATION
DEFINITION
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference On Harmonisation
IEC
Independent Ethics Committee
INN
International Non-Proprietary Name
IRB
Institutional Review Board
ISI
Insulin Sensitivity Index
ITT
Intent-To-Treat
IXRS
Interactive Web/Voice Response System
LDL-C
Low-Density Lipoprotein Cholesterol
MedDRA
Medical Dictionary For Regulatory Activities
mITT
Modified ITT
MMTT
Mixed Meal Tolerance Test 
Non-HDL-C
Non-High Density Lipoprotein Cholesterol
OGTT
Oral Glucose Tolerance Test 
OTC
Over the Counter
PD
Pharmacodynamic
PG
Plasma Glucose
P-gp
P-Glycoprotein 
PIC
Powder in Capsule 
PK
Pharmacokinetic
QD
Once a Day
TEAE
Treatment-emergent Adverse Event
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SID
Subject Identifier 
SMBG
Self-monitoring of Blood Glucose
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
T2DM
Type 2 Diabetes Mellitus
TC
Total Cholesterol
TG
Triglycerides
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 23
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 23
ABBREVIATION
DEFINITION
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
WMG
Weighted Mean Glucose 
WOCBP
Women of Child-Bearing Potential
βhCG
Human Chorionic Gonadotropin, Beta Subunit
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 24
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 24
1.
INTRODUCTION
1.1.
Background
1.1.1.
Investigational Product(s)
1.1.1.1.
Name
DS-8500a is the compound code for 
1.1.1.2.
Description
DS-8500a is a novel 
 
are expected to reduce plasma glucose levels by promoting insulin secretion in a glucose-
dependent manner and to improve pancreatic β-cell function over long-term treatment.
1.1.1.3.
Intended Use Under Investigation
DS-8500a is being developed for treatment of type 2 diabetes mellitus (T2DM).
1.1.1.4.
Nonclinical Studies
In nonclinical pharmacology studies, DS-8500a exerted agonistic activity in Chinese 
hamster 
and improved 
glucose intolerance in Zucker fatty rats. Administration of DS-8500a to fasted rats 
showed a low risk of hypoglycemia compared with sulfonylureas. 
Data from nonclinical studies of DS-8500a are summarized in the DS-8500a 
Investigator’s Brochure (IB).
1.1.1.5.
Clinical Experience
In Phase 1 studies in healthy Japanese adult males, DS-8500a, provided as powder in 
capsule (PIC), was well tolerated as a single oral dose of up to 600 mg and in multiple 
oral doses up to 300 mg daily for 7 days and 75 mg daily for 14 days. The area under the 
plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) 
increased in less than a dose-proportional manner following single oral administration of 
≥ 30 mg and following 7-day multiple oral administration, at all doses studied. When DS-
8500a tablets at a dose of 50 mg or 100 mg were administered once daily for 7 days to 
Japanese healthy adult male subjects under fed condition, Cmax and area under the plasma 
concentration-time curve for a dosing interval (AUCtau) of DS-8500a increased in less 
than a dose-proportional manner. The ratios of Cmax and area under the plasma 
concentration–time curve from time 0 to the time of the last quantifiable concentration 
(AUClast) of subjects who received the tablets to those who received with the PIC were 
2.3 and 2.2, respectively. 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 25
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 25
A Phase 2, randomized, multicenter, double-blind, placebo-controlled, parallel-group 
study was conducted in Japanese patients with T2DM. Subjects were treated daily with 
DS-8500a 10 mg (32 subjects), DS-8500a 75 mg (34 subjects) or placebo (33 subjects) 
for 28 days as monotherapy.  After 28 days of treatment weighted mean glucose 
(WMG) reduction from baseline, compared with placebo, was -13.3 mg/dL (p=0.0093) 
for the 10 mg dose and -18.9 mg/dL (p=0.0002) for the 75 mg dose. Subjects treated with 
DS-8500a also had a reduction in total cholesterol, LDL-C and triglycerides and an 
increase in HDL-C. The number of reported treatment-emergent adverse events (TEAEs) 
was small, balanced across treatment groups and none were considered drug related. 
There were no reports of hypoglycemia.
Based on in vitro studies, DS-8500a or its metabolites may affect plasma concentrations 
of concomitant drugs that act as substrates of 
 or 
 by the 
 In addition, DS-8500a is a 
 A drug-drug interaction (DDI)
study assessing DS-8500a’s induction potential 
 showed that the magnitude 
of the effect on the exposure of 
 was considered not 
clinically meaningful (i.e., < 20% change in 
AUC). Therefore, it was 
concluded that DS-8500a is not a moderate or strong 
. A DDI study was 
conducted to assess the effect of DS-8500a on
which is metabolized by 
and eliminated through
. Preliminary results showed 
that following administration of 75 mg of DS-8500a tablets for 15 days, the mean (90% 
confidence intervals (CI)) change in the ratios of Cmax and AUC of 
 were 
1.28 (1.12, 1.48) and 0.96 (0.86, 1.00), respectively, for concomitant administration with 
DS-8500a compared to 
 alone.  These results suggest a modest increase in 
exposure. An additional DDI study was conducted in the US to assess the 
effect of DS-8500a on 
 a substrate 
  Preliminary results showed that 
following administration of 75 mg of DS-8500a once daily for 16 days, the mean (90% 
CI) change in the ratios of Cmax and AUC of 
 were 1.66 (1.48, 1.88 ) and 1.32 
(1.20, 1.45), respectively,  for  administration with DS-8500a compared with 
  These results suggest that co-administration of 
 
with DS-8500a results in a clinically meaningful increase in exposure, apparently 
mediated by 
    
Other concomitant medications with DDI potential for DS-8500a, as determined from in 
vitro studies, will be excluded from this study until additional clinical DDI data are 
available. 
DS-8500a is metabolized to form multiple metabolites 
in both animal species and in humans (preliminary data) which have relative 
abundance > 25% of parent and longer terminal elimination half-lives. 
appears to have a higher relative abundance than DS-8500a based on preliminary clinical 
data. Therefore, plasma concentrations of 
will be measured in this study.
In a food effect study, healthy adult subjects were administered a single oral dose of DS-
8500a 100 mg tablets either in a fasted state or after a meal. Cmax and AUClast were 
greater under fed condition than under fasting condition, in ratios of 1.8 and 1.9 for Cmax
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 26
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 26
and AUClast, respectively. Subjects in the present study should take study medication 
right after having their breakfast. 
1.2.
Study Rationale
T2DM is a chronic disease with long-term consequences including microvascular 
complications (nephropathy, neuropathy, and retinopathy), and macrovascular 
complications such as ischemic heart disease, stroke, and peripheral artery disease. The 
rapid increase in the number of patients with T2DM worldwide has become a serious 
challenge for global public health; it is critical to treat the disease early and appropriately 
in order to prevent long-term complications.1
At present, there are several classes of oral antidiabetic agents available for the treatment 
of T2DM: sulfonylureas, short-acting insulin secretagogues, and dipeptidyl peptidase-IV 
inhibitors to increase insulin secretion; thiazolidinediones to improve insulin resistance; 
biguanides (metformin) to reduce hepatic glucose production; sodium glucose transporter 
2 inhibitors to increase urinary glucose excretion; and α-glucosidase inhibitors to reduce 
and delay glucose absorption in the gut. Injectable glucagon-like peptide-1 (GLP-1) 
receptor agonists that slow gastric emptying, reduce appetite, and improve insulin 
secretion, are also available. Patients with long-term T2DM often require treatment with 
insulin. Patients with T2DM who have poor glycemic control with monotherapy are 
treated with a combination of these agents that differ in their mechanisms of action. 
However, given that 
is a major contributor to the 
progression of T2DM, a new drug with a mechanism that helps improve insulin secretion 
from 
in a mechanism distinct from available drugs may hold great 
promise as a new addition to conventional antidiabetic therapy. 
A novel target for antidiabetic drugs is the G-protein coupled receptor 119 (GPR119), 
which has been shown to be highly expressed in the human small intestinal L-cells of the 
gastrointestinal tract and in pancreatic β-cells.2, 3 GPR119 agonists promote a glucose-
dependent insulinotropic effect in isolated pancreatic islets in mice and improve glucose 
intolerance assessed by oral glucose tolerance test in mice.3, 4 GPR119 agonists 
upregulate insulin and genes essential for controlling pancreatic β-cells in a mouse model 
of T2DM.
 agonists dose-dependently increase the concentration of cyclic 
adenosine monophosphate in cells expressing 
and promote 
derived from the large 
intestinal L-cells in mice. Based on these findings, 
 are expected to 
reduce 
 by promoting insulin secretion in a glucose-dependent manner and to 
improve 
over long-term treatment.
DS-8500a is a novel 
discovered by Daiichi Sankyo Co., Ltd. In 
nonclinical pharmacology studies, DS-8500a exerted 
and improved glucose intolerance in Zucker fatty rats. 
Furthermore, DS-8500 administered for 4 weeks in Japanese subjects with T2DM 
provided significant reduction in WMG. Consequently, DS-8500a is being developed as 
an oral anti-diabetic agent for a novel approach for the treatment of T2DM, and 
additional clinical studies are being planned. 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 27
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 27
The present study is designed to assess efficacy and safety of DS-8500a administered in a 
double-blind, dose ranging, double dummy manner in subjects with T2DM on stable 
metformin, compared with placebo and sitagliptin 100 mg daily in US and Canada.   
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 28
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 28
2.
STUDY OBJECTIVES AND HYPOTHESIS
2.1.
Study Objectives
2.1.1.
Primary Objectives
The primary objective is to evaluate change in hemoglobin A1c (HbA1c) from baseline 
to Week 12 with DS-8500a compared with placebo in subjects with T2DM.
2.1.2.
Secondary Objectives
The secondary objectives are: 
!
To evaluate changes in lipids [total cholesterol (TC), low-density lipoprotein 
cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high 
density cholesterol (non-HDL-C) and triglycerides (TG)] from baseline to 
Week 12 with DS-8500a compared with placebo.
!
To evaluate change in 3h area under the curve (AUC0-3h) plasma glucose (PG) 
in response to a mixed meal tolerance test (MMTT) from baseline to Week 4 
and Week 12 with DS-8500a compared with placebo. 
!
To evaluate change in fasting plasma glucose (FPG) from baseline to Weeks 
2, 4, 8 and 12 with DS-8500a compared with placebo.
!
To evaluate the proportion of subjects achieving HbA1c < 7.0% at Week 12 
with DS-8500a compared with placebo.
!
To assess the pharmacokinetics (PK) of DS-8500a 
 
2.1.3.
Safety Objectives
!
To evaluate the safety and tolerability of DS-8500a in subjects with T2DM 
assessed by treatment emergent adverse events (TEAEs) and change in vital 
signs and safety laboratory values.
a.
The proportion of subjects with TEAE.
b. Changes in routine safety laboratory testing (i.e., hematology, chemistry) 
from baseline to Week 12.
c.
The proportion of subjects with prospectively adjudicated cardiovascular 
events including cardiovascular death, non-fatal myocardial infarction, 
transient ischemic attack and non-fatal stroke, hospitalization for unstable 
angina, urgent coronary revascularization intervention and hospitalization 
for congestive heart failure.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 29
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 29
2.1.4.
Exploratory Objectives
The exploratory objectives are:
 
 
2.2.
Study Hypothesis
The hypothesis of this Phase 2 study is that DS-8500a will improve glycemic control 
relative to placebo from baseline to Week 12, based on changes in HbA1c, with an 
acceptable safety and tolerability profile, in patients with T2DM.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 30
Proprietary and Confidential


3.
STUDY DESIG
3.1.
Overall Design
This is a randomized, dose ra
with active comparator, multi
on a stable metformin dose. T
Figure 3.1:
Design of Pha
*FU=Follow-Up
3.2.
Discussion of S
This will be a randomized, do
controlled with active compa
with T2DM who are on a stab
Approximately 260 eligible s
subjects per arm in each of th
and 60 subjects per arm in the
treatment groups. The random
methyl-glutaryl-CoA (HMG-
randomization. One stratum w
the other stratum will include
randomization. The study wil
period of up to 2 weeks, a 2 w
week double-blind, double-du
post-dosing follow-up (Week
clinic visits on Weeks 2, 4, 8
All subjects who enter the Le
treatment of metformin mono
and ≤ 10%. All subjects will 
throughout the study. 
Protocol DS8
Version 1.0, 2
Proprietary and Confidential
Page 30
GN
n
anging, double-blind, double-dummy, placebo-c
icenter, 12-week study of DS-8500a in subjects 
The study design is depicted in Figure 3.1.
ase 2 study of DS-8500a in Subjects with T2D
Study Design
ose-ranging, double-blind, double-dummy, place
arator, multicenter, 12-week study of DS-8500a i
ble metformin dose.
subjects will be randomized in a 2:2:3:3:3 ratio w
he DS-8500a 25 mg and DS-8500a 50 mg treatm
e each of DS-8500a 75 mg, placebo, and sitaglip
mization will be stratified on the basis of 3-hydr
-CoA) reductase inhibitors (statins) treatment at 
will include subjects who have been treated by s
e subjects who were not treated by statins at the 
ll include 4 periods for a total of up to 18 weeks
week single-blind placebo Lead-in (Weeks -2 an
ummy treatment period (Day 2 to Week 12), and
ks 13 and 14). During the treatment period subje
, and 12 after randomization.
ead-in Period must be on stable background diab
otherapy ≥1000 mg/day and have a screening Hb
continue the same metformin dose taken prior to
8500-A-U202
28 OCT 2015
ontrolled
with T2DM
DM
ebo-
in subjects
with 40 
ment groups, 
ptin 100 mg 
oxy-3-
the time of 
statins, and 
time of 
s: a screening 
nd -1), a 12-
d a 2-week 
ects will have 
betes 
bA1c ≥ 7.0% 
o screening 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 31
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 31
1. Screening Period (Weeks -4 to -3): 
There will be a period up to 2 weeks for subject screening based on medical history, 
physical examination and clinical labs, and meeting all inclusion and exclusion criteria. 
Subjects will receive basic dietary and exercise instruction at the time of screening. 
Subjects should not embark on aggressive, excessively restrictive or high fat content diets 
or change their physical activity level during this study.
2. Lead-in Period (Weeks -2 and -1):
During the Lead-in Period, subjects will take single blind DS-8500a matching placebo 
tablets and a sitagliptin matching placebo capsule to assess compliance with study 
regimen. Subjects will also be required to continue taking metformin as taken prior to 
screening. Subjects will be required to perform and record fasting self-monitoring of 
blood glucose (SMBG) daily.  
3. Randomization (Day 1):
At the end of the Lead-in Period, eligible subjects who demonstrate good compliance 
with study drug (taking ≥ 80% and ≤ 120% of both dispensed DS-8500a placebo tablets 
and sitagliptin placebo capsules) and an appropriate Lead-in Period fasting glucose (≤ 
240 mg/dL, at least 7 days of recorded fasting SMBG required) will be randomized in a 
2:2:3:3:3 ratio to parallel double-blind treatment groups of DS-8500a 25 mg, DS-8500a 
50 mg, DS-8500a 75 mg, placebo, or sitagliptin 100 mg. A 3-hour MMTT will be 
performed on Day 1 (prior to randomization).
4. Treatment Period (Day 2 to Week 12):
The Treatment Period will consist of 12 weeks of randomized double-blind, double 
dummy treatment with study medication, starting on Day 2 (one day after randomization
day). Treatment visits will occur at Weeks 2, 4, 8, and 12 of the randomized Treatment 
Period. HbA1c will be measured at Weeks 4, 8, and 12 and FPG will be measured at 
every visit. A 3-hour MMTT will be performed on Week 4 and at the End-of-Treatment 
/Early Termination visit (Week 12). Metformin treatment will continue at the same dose 
taken prior to screening throughout the Treatment Period.
Subjects who meet protocol discontinuation criteria will be asked to return to the clinic 
for follow-up assessment and confirmation of values prior to discontinuation.
Discontinued subjects must complete Early Termination Visit procedures.
5. Post-study Follow-up Period (Weeks 13 and 14):
Subjects who complete the randomized Treatment Period or are discontinued will return 
to the clinic for a post-study follow-up safety assessment visit approximately 2 weeks 
after taking the final dose of randomized study medication.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 32
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 32
4.
STUDY POPULATION
Investigators will maintain a confidential screening log of all potential study candidates 
that includes limited information of the subjects (initials, age, sex) date and outcome of 
screening process (e.g., enroll in the study, reason for ineligibility, refused to participate).
Prior to initiation of formal screening procedures, each subject will be asked to review 
and sign the informed consent form (ICF) provided by the site.  All subjects must 
personally sign and date the ICF before any study-specific activities occur.  For 
additional information on informed consent, see Section 15.3.
4.1.
Inclusion Criteria
Subjects must satisfy all of the following criteria to be included in the study:
1. Able to provide written informed consent and adhere to the study visit schedule 
and treatment
2. Diagnosed with Type 2 diabetes mellitus as defined in the American Diabetes 
Association Standards of Medical Care in Diabetes 2015b,6
3. Male or female ≥ 18 and ≤ 70 years of age
4. Screening fasting C-peptide > 0.5 ng/mL
5. Women of child bearing potential (WOCBP) must be willing to use double-
barrier contraception for the entire study
6. WOCBP must have a negative pregnancy test (human chorionic gonadotropin, 
beta subunit [βhCG]) before entering the Lead-in Period
7. Body mass index ≥ 25 kg/m2 and ≤ 45 kg/m2 at the Screening Visit
8. On stable (≥ 8 weeks) metformin monotherapy ≥ 1000 mg/day
9. Screening HbA1c ≥ 7.0% and ≤ 10%
10. Taking ≥ 80% and ≤ 120% of both dispensed DS-8500a placebo tablets and 
sitagliptin placebo capsules during the Lead-in Period 
4.2.
Exclusion Criteria
Subjects who meet any of the following criteria will be disqualified from entering the 
study:
1. History of type 1 diabetes and/or history of ketoacidosis
2. History of insulin use for > 2 weeks within 2 months prior to the Screening Visit
                                                
b HbA1c≥6.5%; or FGP≥126 mg/dL; or 2-hour PG≥200 mg/dL during an oral glucose tolerance test 
(OGTT); or classic symptoms of hyperglycemia with a random PG≥200 mg/dL  
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 33
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 33
3. Two or more readings of fasting SMBG > 240 mg/dL or worsening symptoms of 
hyperglycemia with one SMBG level of > 240 mg/dL  during the second week of 
Lead-in Period, confirmed by laboratory measurement
4. Screening hemoglobin <12 g/dL for males and  <11 g/dL for females
5. Blood donation within 2 months prior to the Screening Visit or plans to donate 
blood or blood products during the study 
6. Subjects after bariatric surgery or any gastric bypass or planning to have such a 
procedure during the study
7. Screening thyroid stimulating hormone (TSH) levels not within normal range 
(based on reference laboratory values )
8. Screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 
2.0 x upper limit of normal (ULN), and/or total bilirubin > 1.5 x ULN. If a subject 
has total bilirubin > 1.5 x ULN, unconjugated and conjugated bilirubin fractions 
should be analyzed and only subjects documented to have Gilbert’s syndrome 
may be enrolled 
9. Screening Serum creatinine ≥ 1.5 mg/dL for males and ≥ 1.4 mg/dL for females, 
or creatinine clearance (CrCl) < 50 mL/min for both males and females
10. Screening Creatine kinase (CK) > 3.0 × ULN
11. History of unstable angina, myocardial infarction, cerebrovascular accident, 
transient ischemic attack, peripheral arterial event or any revascularization 
procedure during the 6 months prior to the Screening Visit or planned vascular 
procedures or surgery during study period
12. History of congestive heart failure (CHF)
13. Exclusionary concomitant medications: 
a.
Eight weeks prior to screening and throughout the duration of the study:
!
Any diabetes medication other than metformin; any prescription or over the 
counter medication for weight-loss.
!
Systemic corticosteroids (including nasal and inhaled), with the exception of 
use of topical and ophthalmic corticosteroids.
!
Rosuvastatin > 20 mg daily. 
b. During treatment periods, additional medications will be prohibited based on 
potential drug-drug interaction (DDI) (see Section 5.6)
14. Subjects with anticipated interruption in metformin or study drug use during the 
course of the clinical trial (e.g., due to an imaging procedure involving iodinated 
contrast media)
15. Subjects in whom treatment with sitagliptin 100 mg is contraindicated ( e.g.,
known hypersensitivity or intolerance to sitagliptin) or may not be medically 
advisable  (e.g., history of pancreatitis)
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 34
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 34
16. Abuse of or dependence on prescription medications, illicit drugs, or alcohol 
within the last 1 year
17. Any history of a malignancy other than basal cell carcinoma within the past 5 
years
18. Pregnancy or breast-feeding, or intent to become pregnant during the study period
19. Known (or evidence of) infection with human immunodeficiency virus
20. Any condition, laboratory abnormality, or concomitant therapy which, in the 
opinion of the Investigator, might pose a risk to the subject or make participation 
not in the subject’s best interest
21. Subject is currently enrolled in or has not yet completed at least 30 days since 
ending another investigational device or drug study or is receiving other 
investigational agents
22. A direct or familial relationship with the Sponsor, Investigator, or site personnel 
affiliated with the study
4.3.
Women of Child-Bearing Potential (WOCBP)
For the purposes of this study, all female participants will be considered as WOCBP 
unless they have undergone surgical sterilization or are postmenopausal and have a 
documented serum follicle stimulating hormone (FSH) level >35 mIU/mL (with or 
without hormone replacement therapy) and no menses for at least 12 months.
WOCBP are permitted in the study but must consent to avoid becoming pregnant by 
using an approved contraception method throughout the study and for up to 2 weeks after 
completion, as described below.
Study-acceptable methods of birth control are double-barrier methods, which include a 
combination of any 2 of the following: systemic contraceptives, diaphragm or sponge 
with spermicide, condom, intrauterine device, or partner’s vasectomy.  
All WOCBP subjects must have a negative serum pregnancy test (βhCG) at the Screening 
Visit (Visit 1) in order to continue in the study. A urine pregnancy test will be conducted 
at all other clinic visits through the Follow-up clinic visit (Visits 2-8) for all WOCBP 
subjects. If a urine test result is positive, a serum pregnancy test will be performed to 
confirm the result. 
Daiichi Sankyo must be notified of any study subject who becomes pregnant while 
participating in this clinical study, as described in Section 9.7.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 35
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 35
5.
STUDY TREATMENT(S)
5.1.
Assigning Subjects to Treatments and Blinding
5.1.1.
Treatment during Lead-in Period
All subjects will take single-blind DS-8500a placebo matching tablets and a sitagliptin 
matching placebo capsule (three placebo tablets and 1 placebo capsule) once daily after 
breakfast for 2 weeks. On Day 1 (randomization day) lead-in DS-8500a placebo tablets 
and sitagliptin placebo capsules will be taken during MMTT immediately after ingestion 
of the liquid meal.
5.1.2.
Treatment Group(s)
Subjects will be randomly assigned in a 2:2:3:3:3 ratio to 1 of the following 5 treatment 
arms (Table 5.1):
!
DS-8500a 25 mg + sitagliptin placebo
!
DS-8500a 50 mg + sitagliptin placebo
!
DS-8500a 75 mg + sitagliptin placebo 
!
DS-8500a placebo + sitagliptin placebo
!
DS-8500a placebo + sitagliptin 100 mg
DS-8500a tablets will be provided at strengths of 25 mg. Sitagliptin 50 mg tablets will be 
over encapsulated to provide once daily dose of 100 mg. 
A matching placebo tablet for DS-8500a and a matching placebo capsule for sitagliptin 
will be utilized to conduct the double-dummy, double-blind treatment period.  Three 
tablets and 1 capsule will be taken once daily.
Table 5.1:
Study Treatment Administration by Treatment Group
Treatment Arm
Tablet 
Capsule 
1
DS-8500a 25 mg
sitagliptin placebo
2
DS-8500a 50 mg
sitagliptin placebo
3
DS-8500a 75 mg
sitagliptin placebo
4
DS-8500a placebo
sitagliptin placebo
5
DS-8500a placebo
sitagliptin 100 mg
DS-8500a or matching placebo tablets and sitagliptin or matching placebo capsules will 
be administered orally once daily after breakfast for 12 weeks, except for study visit days. 
The first randomized study drug dose will be taken after breakfast on Day 2 after the Day 
1 visit. On days of study visits that involve MMTT study drug will be taken after 
ingestion of the liquid meal (Visits 5 and 7 at Weeks 4 and 12) (see Section 8.2). On days 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 36
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 36
of Visits 4 and 6 (Weeks 2 and 8, respectively), study drug should be taken after study 
laboratory blood draw and after having breakfast (see Section 8.1).
The schedule of events is provided in Section 17.2.  Additional information regarding 
study procedures is provided in Section 6.
5.1.3.
Method of Treatment Allocation
Randomization will be performed centrally using an Interactive Web/Voice Response 
System (IXRS).  At the Screening Visit, the investigator, or other site personnel under the 
direction of the investigator, should contact or access the IXRS to register the subject, 
obtain the subject identifier (SID). At Lead-in visit (Visit 2), after confirmation of a 
subject’s eligibility, the investigator, or designee, will contact the IXRS to register the 
subject to obtain the SID of the Lead-in drug carton to be dispensed to this subject. Upon 
confirmation of a subject’s eligibility at the Randomization Visit (Day 1), the 
investigator, or designee, will contact the IXRS to register the subject as randomized and 
obtain the SID of the initial study medication carton to be dispensed to this subject.  At 
Treatment Visits 5 and 6, the investigator or designee, should contact the IXRS to record 
the subject’s visit and status and obtain the correct carton number to be dispensed at that 
visit.  Study medication should only be dispensed in accordance with IXRS instructions 
and carton number assignment.  At the End-of-Treatment/Early Termination (Visit 7), the 
subject’s visit and status should also be recorded using the IXRS.
A draft randomization schedule generated by the IXRS vendor will be reviewed by the 
Daiichi Sankyo study statistician before the start of study. After approval, the live 
randomization schedule will be generated by the IXRS vendor by varying the 
randomization seed. The final randomization schedule will be reviewed and approved by 
an independent statistician at Daiichi Sankyo. Eligible subjects will be randomized in the 
ratio of 2:2:3:3:3 to receive 12 weeks of double-blind treatment with DS-8500a 25mg
QD, DS-8500a 50mg QD, DS-8500a 75mg QD, placebo, or sitagliptin 100 mg QD. The 
randomization will be stratified on the basis of HMG-CoA reductase inhibitors (statins)
treatment at the time of the Randomization Visit.  
IXRS and Clinical Supply Operations personnel will have access to medication 
identification codes.  IXRS personnel along with Clinical Supply Operations personnel 
will be unblinded.  All other personnel involved with the conduct and the interpretation 
of the study, including investigators, investigational site personnel, Daiichi Sankyo 
employees and designees will be blinded to the treatment until after the database lock.
5.1.4.
Blinding
The DS-8500a 25mg tablets and the matching placebo tablets have been manufactured to 
be identical in size and appearance.
Sitagliptin 50 mg tablets will be over encapsulated to provide a once daily dose of 100 
mg and a matching placebo capsule has been manufactured.
Throughout the study, sponsor and designee, the Investigator and the study subject will 
be blinded to the treatment assignment.  The bioanalytical laboratory will be unblinded.  
The bioanalytical laboratory will protect the randomization schedule in order to maintain 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 37
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 37
the blind outside of the laboratory.  In order to analyze PK samples, and to maintain the 
study blind, the drug concentration results will be shared outside of the bioanalytical 
laboratory ONLY AFTER the clinical study database has been unblinded.
The study blind will be broken at the end of the study once all the following prerequisites 
are met:
!
Database locked
!
Statistical analysis plan (SAP) finalized
!
Subjects and data inclusion in Analysis Sets finalized
Once the decision for unblinding is reached, the study team will prepare an unblinding 
memo with signatures from at least the study director and sponsor biostatistician.
5.1.5.
Emergency Unblinding Procedure
In the case of an emergency where, in the opinion of the Investigator, discontinuation of 
study drug is not sufficient and the study treatment must be unblinded in order to evaluate 
further a course of medical treatment, the Investigator can perform the unblinding by 
directly accessing the IXRS.
In the event of an emergency unblinding, the subject will be informed about their 
treatment assigned, but not their treatment dose.  Information about the treatment 
assignment must be restricted to designated study center staff/ personnel who are 
providing immediate care to the subject.  Any documentation of the treatment assignment 
must be maintained separately (i.e., a secured file).  The information must not be
included in the subject’s source files to ensure the treatment assignment will remain 
blinded to sponsor or designee’s Medical Monitor not involved with the subject’s 
immediate care.  
When an emergency unblinding has occurred, an automatic notification (via e-mail) will 
be sent to the investigator and selected Daiichi Sankyo study personnel from the IXRS 
vendor.  The notification will not contain any unblinded information.  This will trigger 
the follow-up process to document the unblinding by completing the Emergency 
Unblinding by Investigator Form (to be provided by study personnel upon receipt of 
IXRS notification) and submission to Daiichi Sankyo Clinical Safety and 
Pharmacovigilance (CSPV). Please refer to the form for completion instructions.
Once the study treatment has been unblinded for a specific subject, the study treatment 
should be discontinued for the subject, and the subject should leave the study treatment 
phase.  The End-of-treatment/Early termination and Follow-up assessments for the 
subjects will be performed as defined in the protocol.
5.2.
Study Drug(s)
5.2.1.
Description
DS-8500a is a novel 
expected to reduce PG levels 
by promoting insulin secretion in a glucose-dependent manner and to improve pancreatic 
β-cell function over long-term treatment.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 38
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 38
5.2.2.
Labeling and Packaging
Double-blind study medication will be provided in labeled blister cards (“wallets”) in 
cartons.  The blister label will include all information required by federal and local 
regulations. Additional details on the investigational drug products can be found in 
documentation accompanying drug shipment.  
Code-break envelopes or scratch-off labels will not be used for unblinding in this study.  
Unblinding of individual subjects will be controlled using the IXRS (see Section 5.1.5).
5.2.3.
Preparation
Study drug will be provided to sites as fully prepared blister cards (wallets) in cartons.  
All wallets will have 3 tablets and 1 capsule for each day of dosing.  Cartons will be 
individually numbered; only the correctly numbered cartons should be distributed to 
study subjects in accordance with IXRS instructions.
5.2.4.
Administration
DS-8500a or matching placebo tablets and sitagliptin or matching placebo capsules will 
be administered orally once daily after breakfast for 12 weeks, except for study visit days. 
The first randomized study drug dose will be taken after breakfast on Day 2 after Day 1 
visit. On study visit days that involve MMTT, study drug will be taken after ingestion of 
the liquid meal [Day 1 (Lead-in tablets and capsule) and Visits 5 and 7 at Weeks 4 and 
12, respectively] (see Section 8.2). On the days of Visits 4, and 6 (Weeks 2 and 8,
respectively), study drug should be taken after the study laboratory’s blood draw and 
after having a breakfast meal (see Section 8.1).
5.2.5.
Storage
Drug supplies must be stored appropriately in a locked cabinet in a room with limited and 
controlled access under the labeled storage conditions.  The labeled storage conditions 
are provided on the labeled drug supplies. Temperature measurement will be recorded 
daily on a temperature log excluding weekends and holidays.
NOTE:  If storage conditions go outside of the labeled storage conditions, the site must 
not dispense the affected supplies (affected supplies should be placed in quarantine) and 
Daiichi Sankyo personnel or designee must be contacted to determine if the affected 
supplies can be used.
5.2.6.
Drug Accountability
When a drug shipment is received, the investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label, and sign the 
Receipt of Shipment Form provided.  The original will be retained at the site.  In 
addition, the investigator or designee shall contact the sponsor as soon as possible if there 
is a problem with the shipment.
A Drug Accountability Record will be provided to each site for documenting the use of 
the investigational product. The record must be kept current and should include the date 
and quantity of drug (number of cartons) received at each shipment, the SID (and initials) 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 39
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 39
of each subject for whom the investigational product was dispensed, the carton numbers, 
date and quantities of investigational product dispensed at each visit, amount of 
remaining or returned product received at each subject visit (including the number of 
tablets/capsules inside or outside of returned wallets), and the initials of the dispenser.
At the end of the study, or as directed, all study treatment, including unused, partially 
used, or empty wallets, and any drug that may have been removed from the wallets (but 
not taken), will be destroyed on site according to the site’s drug handling and disposition 
standard operating procedures (SOPs). A copy of these SOPs must be available onsite. 
The certificate of destruction must be provided to Daiichi Sankyo documenting the drug, 
the quantity (in tablets and capsules), method of destruction, and date of destruction.
If sites are unable to destroy drug, the monitor will make arrangements to return drug to a 
designated depot for destruction.
Medications provided by the Sponsor will be destroyed (or returned) only after the study 
monitor has completed an inventory to verify the quantity to be destroyed (or returned).  
The destruction (or return) of medications provided by the sponsor must be documented 
and the documentation filed (and if returned, included in the shipment).
All investigational product inventory forms must be made available for inspection by the 
sponsor’s authorized representative (e.g., contract research organization (CRO) site 
monitor) and any authorized inspector from a regulatory agency.  The investigator is 
responsible for the accountability of all used and unused study supplies at the site.
5.3.
Control Treatment
Placebo and sitagliptin will serve as control treatments.  Inclusion of placebo is required 
in light of the known placebo effect in T2DM studies.  Inclusion of sitagliptin is intended 
to generate active comparator data for study reference. Sitagliptin will be initiated at the 
recommended starting dose for patients with normal renal function or mild renal 
impairment (administered as 100 mg QD). 
5.4.
Dose Interruptions and Reductions
Subjects who miss > 7 days of consecutive doses of study medication will be withdrawn 
from the study and early termination study procedures performed. There will be no dose 
reduction for DS8500a/sitagliptin/placebo.  
5.5.
Method of Assessing Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  The 
identification number of all dispensed and returned study drug wallets should be 
recorded, along with the SID.  The number of tablets/capsules used and remaining in each 
wallet should be documented at the Lead-in visit and each Treatment visit and the End-
of-Treatment/Early Termination visit.  If any tablets or capsules have been removed from 
the wallets (but not taken), these should be counted, documented, and retained.
Treatment compliance will be calculated by dividing the number of tablets and capsules
taken by the number of tablets and capsules assigned for the appropriate visit interval 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 40
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 40
(adjusted for any changes in the visit interval).  Compliance for each visit interval is 
defined as taking at least 80% and no more than 120% of the study drug prescribed for 
that interval.  If a subject is noncompliant, the subject will be counseled by study staff on 
the importance of taking the correct amount of study medication.  As the primary analysis 
will follow the intent-to-treat (ITT) principle, subjects should not be discontinued from 
the study for treatment noncompliance unless the subject meets the discontinuation 
criteria outlined in Section 5.7.1.
5.6.
Prior and Concomitant Medications
Subjects should be instructed not to take any diabetes medications (other than metformin) 
and/or any prescriptions or over the counter medications for weight-loss.  No systemic 
corticosteroids (including nasal and inhaled) can be taken during the study, but topical 
and ophthalmic corticosteroids are permitted. 
Any medication (other than study drug) taken by subjects during the course of the study 
will be recorded and coded using the World Health Organization (WHO) dictionary. If 
drug therapy other than that specified by the protocol is taken, a joint decision will be 
made by the Investigator and Sponsor on whether to continue or discontinue the subject.
Concomitant medications with DDI potential for DS8500a based on the in vitro studies 
will be excluded from this study until further clinical data is available.  These 
medications can be found in Table 5.2. The highest dose of rosuvastatin will be limited 
to 20 mg due to the potential for increased rosuvastatin exposure during concomitant 
administration with DS-8500a.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 41
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 41
Table 5.2:
Prohibited Medications during Treatment Periods
CYP3A4 substrates with narrow therapeutic windows
Quinidine
Cyclosporine
P-gp substrates with narrow therapeutic windows
Digoxin
Dabigatran
Strong CYP3A4 inhibitors
Boceprevir
Itraconazole
Posaconazole
Clarithromycin
Ketoconazole
Ritonavir
Conivaptan
Lopinavir
Saquinavir
Grapefruit 
Nefazodone
Telaprevir
Grapefruit Juice
Nelfinavir
Telithromycin
Indinavir
Voriconazole
CYP2C9 substrates with narrow therapeutic windows
Warfarin
Sulfonylureas
Valproic acid
Phenytoin
*Topical use (if available) is allowed for the prohibited medications in the table. 
5.7.
Subject Withdrawal/Discontinuation
Data from all randomized subjects are important to achieve study objectives, and subjects 
should be encouraged to adhere to protocol instructions and visit schedules.  However, in 
accordance with the Declaration of Helsinki and other applicable regulations, a subject 
has the right to withdraw from the study at any time, and for any reason, without 
prejudice to his or her future medical care by the study physician or at the study site.  The 
investigator is also free to terminate a subject’s involvement in the study at any time if 
the subject’s clinical condition warrants such action.  The sponsor or regulatory 
authorities also may request termination of the study at any time due to safety issues or 
concerns related to study conduct.
5.7.1.
Reasons for Withdrawal
Any subject who discontinues from the study treatment for any reason will have their 
study treatment discontinuation recorded.
If a subject discontinues from the study treatment for any reason, the reason for 
discontinuation or withdrawal must be recorded on the electronic case report form
(eCRF) using the following criteria:  
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 42
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 42
For subjects withdrawn prior to randomization but after signing informed consent
!
Did not satisfy all inclusion/exclusion criteria
!
Adverse event
!
Lost to follow-up
!
Withdrawal by subject (indicate reason) 
!
Physician decision
For subjects discontinued or withdrawn after randomization but before completing the 
treatment period
!
Persistent hyperglycemia defined as follows:
o
Up to and including Visit 6 (Week 8): two or more readings of fasting 
SMBG ≥ 240 mg/dL OR 1 reading of fasting SMBG ≥ 240 mg/dL and 
worsening symptoms of hyperglycemia, confirmed by repeating fasting 
laboratory glucose.
o
After Visit 6 (Week 8): two or more readings of fasting SMBG ≥ 220 
mg/dL OR 1 reading of fasting SMBG ≥ 220 mg/dL and worsening 
symptoms of hyperglycemia, confirmed by repeating fasting laboratory
glucose.
!
Severe hypoglycemia7,c requiring assistance  
!
Anemia (see Section 9.3.2)
!
Pregnancy
!
Adverse event
!
Death
!
Lack of efficacy
!
Lost to follow-up
!
Protocol deviation
!
Study terminated by sponsor
!
Withdrawal by subject (indicate reason)
!
Other (indicate reason)
Reasons recorded under “protocol deviation” may include failure to comply with protocol 
requirements or study procedures.
                                                
c Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrates, glucagon, or take other corrective actions. Plasma glucose concentrations may not be 
available during an event, but neurological recovery following the return of plasma glucose to normal is 
considered sufficient evidence that the event was induced by a low plasma glucose concentration7.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 43
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 43
A subject may be withdrawn due to non-compliance with any aspect of the protocol, as 
determined by the investigator and/or the sponsor’s medical monitor or designee.  
Subjects who miss > 7 days of consecutive doses of study medication will be withdrawn 
from the study and early termination study procedures performed.
All subjects who are withdrawn from the Treatment Period should complete 
protocol-specified withdrawal procedures (see Section 5.7.2 and Section 6.4.4).
5.7.2.
Withdrawal Procedures
If a subject withdraws (or is withdrawn) from the study, the investigator should complete 
and report all observations as thoroughly as possible up to the date of withdrawal, 
including the date of last treatment and the reason for withdrawal.
If the subject is withdrawn due to an adverse event (AE), the investigator should follow 
the subject until the AE has resolved or stabilized. 
All subjects who are withdrawn from the study should complete all End-of-
treatment/Early termination (Visit 7) procedures as soon as possible after early 
withdrawal (Section 6.4.4).
If a subject becomes lost to follow-up, the sites will be given instruction on actions to 
take to try to locate the subject.
5.7.3.
Subject Replacement
Subjects removed from the study for any reason will not be replaced.
5.7.4.
Subject Re-screening Procedures
Rescreening of subjects will not be permitted. 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 44
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 44
6.
STUDY PROCEDURES
A study visit schedule in tabular format is provided in Section 17.2.  Missing visits are 
strongly discouraged in this study.  It is expected that investigator site staff thoroughly 
explain the visit schedule to potential subjects.  Any missed visit that occurs during the 
double-blind treatment period must be rescheduled within 1 week. Two or more 
consecutive missed visits are grounds for immediate subject discontinuation from the 
study.
The study will include 4 periods for a total of up to 18 weeks: a Screening Period up to 2
weeks, a 2 week single-blind placebo Lead-in Period (Weeks -2 and -1), a 12-week 
double-blind, double-dummy Treatment Period (Day 2 to Week 12), and a 2-week post-
dosing Follow-up (Weeks 13 and 14). During the Treatment Period, subjects will have 
clinic visits on Weeks 2, 4, 8, and 12 after randomization. All visits except the Follow-Up 
Visit should be conducted after at least 8 hours of fasting (no food or drink except water).
6.1.
Screening Period
There will be a period up to 2 weeks for subject screening based on medical history, 
physical examination and screening laboratories, and meeting all inclusion and exclusion 
criteria. 
6.1.1.
Screening Visit (Visit 1; Week -4 to Week -3)
The initial Screening Visit should occur 4 to 3 weeks prior to the Randomization Visit
(Day 1).  At least 8 hours of fasting is required for the Screening Visit. Subjects will be 
screened for study participation. The initial eligibility will be determined by assessment 
of the applicable inclusion and exclusion criteria, listed in Section 4.1 and Section 4.2, 
respectively.  The following activities and/or assessments will be performed at/during the 
Screening Visit (Visit 1):
!
Obtain written informed consent
!
Confirm the subject fasted overnight.  If a subject has not fasted the 
investigator will reschedule the subject to collect the laboratories within 3 
days.
!
Assess all applicable inclusion and exclusion criteria
!
Record demographics
!
Obtain past medical and medication history
!
Record prior and concomitant medications
!
Record vital signs (see Section 9.9), body height and body weight (see 
Section 9.10)
!
Perform screening full physical examination (see Section 9.12)
!
Perform a 12-lead ECG (see Section 9.11)
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 45
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 45
!
Register screened subject in the IXRS.
!
Collect urine sample for evaluation of urinalysis (see Section 9.8.3). 
!
Collect blood samples for the following:
∀
Perform serum pregnancy test as applicable (see Section 9.8.4).
∀
Standard laboratory safety tests (chemistry, hematology) (see 
Section 9.8.1 and Section 9.8.2).
∀
HbA1c
∀
FPG
∀
Lipid panel 
∀
C-peptide
∀
TSH (see Section 9.8.5)
∀
FSH (in postmenopausal women who are not surgically sterile)
!
Subjects will be excluded based on screening laboratory values limits in Table 
6.1.
Table 6.1:
Screening Laboratory Values
Blood chemistry
TSH
Outside of normal range based on laboratory
reference values
Hemoglobin 
<12 g/dL for males and <11 g/dL for females
AST (SGOT)
> 2.0 × ULN
ALT (SGPT)
> 2.0 × ULN
Total bilirubina
> 1.5 × ULN
Creatine kinase
> 3.0 × ULN
Serum creatinine
≥1.5 mg/dL for males and ≥1.4 mg/dL for females
Calculated CrCl
< 50mL/min
Abbreviations: TSH = thyroid stimulating hormone, ALT (SGPT) = alanine aminotransferase, AST 
(SGOT) = aspartate aminotransferase, CrCl = creatinine clearance (determined by the central laboratory 
using the Cockcroft-Gault equation), ULN = upper limit of normal
a If a subject has total bilirubin > 1.5 x ULN, unconjugated and conjugated bilirubin fractions should be 
analyzed and only subjects documented to have Gilbert’s syndrome may be enrolled
!
Provide instructions on basic dietary and exercise:
-
Don’t embark on aggressive, excessively restrictive or high fat content 
diets 
-
Don’t change physical activity level during this protocol. 
!
Schedule Lead-in visit to occur in approximately 1-2 weeks (± 3 days).
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 46
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 46
6.2.
Placebo Lead-in (Visit 2, Week -2)
During the Lead-in Period, subjects will take single-blind DS-8500a-matching placebo 
tablets and a sitagliptin-matching placebo capsules. Subjects will also be required to 
continue taking metformin as taken prior to entering the Lead-in Period. Subjects will be 
required to perform and record fasting SMBG daily. The following activities and/or 
assessments will be performed at Lead-in Visit:
!
Review inclusion/exclusion criteria
!
Record vital signs (see Section 9.9) and body weight (see Section 9.10).
!
Perform a targeted physical examination (including lungs, heart, and as 
needed examination, see Section 9.12).
!
Assess for and record AEs and concomitant medications.
!
Perform urine pregnancy test as applicable (see Section 9.8.4).
!
Study Medication:
-
Contact IXRS to register the subject and obtain study medication kit 
number.
-
Dispense study medication kit (single-blind DS-8500a placebo tablets and 
sitagliptin placebo capsules) and instruct subject in proper dosing after 
breakfast each day.
!
Dispense blood glucose meter and provide instruction on use and daily 
recording of SMBG. (see Section 9.13.2).
!
Dispense study diary and instruct subject to fill out day and time of study drug 
dosing and record SMBG readings. (see Section 9.13.3).
!
At end of study visit review and remind subject to:
-
Begin using home blood glucose meter to check fasting SMBG each 
morning prior to eating.
-
Bring study diary and glucose meter to each visit.
-
Record exact time of morning medication doses and SMBG readings in 
the study diary.
-
Bring study medication to each visit.
-
Fast for at least 8 hours prior to the next visit and arrive at the study site 
approximately between 6am and 9am.
-
NOT take study medication in the morning prior to each clinic visit until 
instructed to do so at the site.
!
Schedule next clinic visit to occur in approximately 2 weeks (± 3 days).
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 47
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 47
6.3.
Randomization (Visit 3, Day 1)
At the end of the Lead-in Period, eligible subjects demonstrating good compliance with 
study drug (taking ≥ 80% and ≤120% of dispensed placebo tablets and placebo capsules) 
and an appropriate Lead-in Period fasting SMBG (≤ 240 mg/dL, at least 7 days of 
recorded fasting SMBG required) will be randomized in a 2:2:3:3:3 ratio to 1 of the 
following parallel double-blind treatment groups:  DS-8500a 25 mg, DS-8500a 50 mg, 
DS-8500a 75 mg, placebo, or sitagliptin 100 mg. The randomization will be stratified on 
the basis of HMG-CoA reductase inhibitors (statins) treatment at the time of the 
Randomization Visit.  
This is a fasting visit.  Subjects should be fasting (no food or drinks except water) for at 
least 8 hours prior to the visit, and arrive at the study site approximately between 6am 
and 9am.
The following procedures and assessments will be performed at the Randomization visit
(Day1):
!
Confirm subject has fasted and has not taken study medication this morning.  
If subject has not fasted, reschedule this visit to occur within 3 days.  All 
randomization laboratories must be collected on the same day in order to 
establish the proper baseline of laboratories and MMTT results for each 
subject.
!
Confirm inclusion/exclusion criteria.
!
Review study diary. 
!
Review fasting SMBG records and assess for eligibility criteria based on 
Exclusion Criterion 3 (see Section 4.2)
!
Assess for and record AEs and concomitant medications.
!
Record vital signs (see Section 9.9) and body weight (see Section 9.10).
!
Perform a targeted physical examination (including lungs, heart, and as 
needed examination, see Section 9.12).
!
Perform urine pregnancy test for WOCBP (see Section 9.8.4).
!
Prior to the randomization, conduct the MMTT test and collect a pre-dose 
blood sample (time 0) for PK analysis (see Section 8.1). Subjects should be 
fasting for at least 8 hours prior to the MMTT. The standardized meal will be 
given approximately between 7am and 10am. Study drug from the Lead-in 
Period will be administered immediately after consuming the liquid meal. (see 
Section 8.2).
!
Collect blood samples for the following during time 0 of MMTT:
-
Standard laboratory safety tests (chemistry, hematology) (see 
Section 9.8.1 and Section 9.8.2).
-
HbA1c 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 48
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 48
-
FPG 
-
Lipid panel 
!
Study Medication:
-
Contact IXRS to obtain new medication kit number.
-
Collect study medication and check study drug adherence.
-
Dispense randomized study medication.
-
Instruct subject to take study drug from the new kit after breakfast on the 
next day.
!
Schedule next clinic visit to occur in approximately 2 weeks (± 3 days).
!
At end of study visit review and remind subject to:
-
Fast for at least 8 hours prior to the next visit.
-
Record exact time of morning medication doses in the study diary.
-
Bring study medication, study diary and glucose meter to each visit to 
check drug adherence and SMBG.
-
Not take study medication in the morning prior to next clinic visit until 
instructed to do so at the site, after morning blood samples have been 
taken and having breakfast.
6.4.
Treatment Period (Visit 4 to Visit 7, Week 2 to Week 12, 
respectively)
6.4.1.
Visit 4 (Week 2)
This is a fasting visit.  Subjects should be fasting (no food or drinks except water) for at 
least 8 hours prior to the visit.
The following procedures and assessments will be performed:
!
Confirm subject has fasted for at least 8 hours prior to visit and has not taken 
study medication this morning.  If subject has not fasted, reschedule this visit 
to occur within 3 days.  
!
Review study diary. 
!
Review SMBG records (see Section 9.13.2).
!
Check study drug adherence.
!
Assess for and record AEs and concomitant medications.
!
Record vital signs (see Section 9.9) and body weight (see Section 9.10).
!
Perform a targeted physical examination (including lungs, heart, and as 
needed examination, see Section 9.12).
!
Perform urine pregnancy test for WOCBP (see Section 9.8.4).
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 49
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 49
!
Collect blood for the following:
-
Standard laboratory safety tests (chemistry, hematology) (see 
Section 9.8.1 and Section 9.8.2).
-
A pre-dose blood sample will be collected for PK analysis (see 
Section 8.1). 
-
FPG
!
Administer and record date and time of dose taken at this visit.
!
Schedule next clinic visit to occur in approximately 2 weeks (± 3 days).
!
At end of study visit review and remind subject to:
-
Fast for at least 8 hours prior to the next visit and arrive at the study site 
approximately between 6am and 9am.
-
Record exact time of morning medication doses in the study diary.
-
Bring study medication study diary and glucose meter to each visit to 
check drug adherence and SMBG.
-
Not take study medication in the morning prior to each clinic visit until 
instructed to do so at the site.
6.4.2.
Visit 5 (Week 4)
This is a fasting visit.  Subjects should be fasting (no food or drinks except water) for at 
least 8 hours prior to the visit, and should arrive at the study site approximately between 
6am and 9am.
The following procedures and assessments will be performed:
!
Confirm subject has fasted and has not taken study medication this morning.  
If subject has not fasted, reschedule this visit to occur within 3 days.  
!
Review study diary.
!
Review SMBG records (see Section 9.13.2).
!
Assess for and record AEs and concomitant medications.
!
Record vital signs (see Section 9.9) and body weight (see Section 9.10).
!
Perform a targeted physical examination (including lungs, heart, and as 
needed examination, see Section 9.12).
!
Perform a 12-lead ECG (see Section 9.11).
!
Perform urine pregnancy test for WOCBP (see Section 9.8.4).
!
Conduct the MMTT test. Subjects should be fasting for at least 8 hours prior 
to the MMTT. The standardized liquid meal will be given approximately 
between 7am and 10am. Study drug will be administered immediately after 
consuming the liquid meal (see Section 8.2). The PK samples for DS-8500a 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 50
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 50
and its metabolite 
evaluation will be collected at the same time 
points as MMTT, including pre-dose (time 0), 0.5, 1.0, 1.5, 2.0, 2.5 and 3.0 h 
after initiation of ingesting the liquid meal (see Section 8.1).
!
Collect blood for the following during time 0 of MMTT:
-
Standard laboratory safety tests (chemistry, hematology) (see 
Section 9.8.1 and Section 9.8.2).
-
HbA1c
-
FPG
-
Lipid panel 
!
Administer and record date and time of dose taken at this visit.
!
Study Medication:
-
Collect study medication and check study drug adherence.
-
Contact IXRS to obtain new medication kit number.
-
Dispense new study medication.
!
Schedule next clinic visit to occur in approximately 4 weeks (± 3 days).
!
At end of study visit review and remind subject to:
-
Fast for at least 8 hours immediately prior to the next visit. Fast for at least 
8 hours prior to the next visit and arrive at the study site approximately 
between 6am and 9am.
-
Record exact time of morning medication doses in the study diary.
-
Bring study medication study diary and glucose meter to each visit to 
check drug adherence and SMBG.
-
Not take study medication in the morning prior to each clinic visit until 
instructed to do so at the site, after morning blood samples have been 
taken and having breakfast.
6.4.3.
Visit 6 (Week 8)
This is a fasting visit.  Subjects should be fasting (no food or drinks except water) for at 
least 8 hours prior to the visit.
The following procedures and assessments will be performed:
!
Confirm subject has fasted and has not taken study medication this morning.  
If subject has not fasted, reschedule this visit to occur within 3 days.  
!
Review study diary.
!
Review SMBG records (see Section 9.13.2).
!
Assess for and record AEs and concomitant medications.
!
Record vital signs (see Section 9.9) and body weight (see Section 9.10).
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 51
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 51
!
Perform a targeted physical examination (including lungs, heart, and as 
needed examination, see Section 9.12).
!
Collect blood for the following:
-
Standard laboratory safety tests (chemistry, hematology) (See 
Section 9.8.1 and Section 9.8.2).
-
HbA1c
-
FPG
-
A pre-dose blood sample will be collected for PK sample (see 
Section 8.1). 
!
Perform urine pregnancy test for WOCBP (see Section 9.8.4).
!
Administer and record date and time of dose taken at this visit.
!
Study Medication:
-
Collect study medication and check study drug adherence.
-
Contact IXRS to obtain new medication kit number.
-
Dispense new study medication.
!
Schedule next clinic visit to occur in approximately 4 weeks (± 3 days).
!
At end of study visit review and remind subject to:
-
Fast for at least 8 hours prior to the next visit and should arrive at the 
study site approximately between 6am and 9am.
-
Record exact time of morning medication doses in the study diary.
-
Bring study medication study diary and glucose meter to each visit to 
check drug adherence and SMBG.
-
Not take study medication in the morning prior to next clinic visit until 
instructed to do so at the site.
6.4.4.
Visit 7 (End-of-Treatment Visit, Week 12) or Early Termination Visit
This is a fasting visit.  Subjects should be fasting (no food or drinks except water) for at 
least 8 hours prior to the visit, and should arrive at the study site approximately between 
6am and 9am.
The following procedures and assessments will be performed at the End-of-treatment 
Visit (Week 12 ± 3 days) or at Early Termination:
!
Confirm subject has fasted and has not taken study medication this morning.  
If subject has not fasted, reschedule this visit to occur within 3 days.  
!
Review study diary.
!
Review SMBG records (see Section 9.13.2).
!
Assess for and record AEs and concomitant medications.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 52
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 52
!
Record vital signs (see Section 9.9), body weight (see Section 9.10)
!
Perform full physical examination (see Section 9.12)
!
Perform a 12-lead ECG (Section 9.11)
!
Perform urine pregnancy test for WOCBP (see Section 9.8.4).
!
Collect urine sample for evaluation of urinalysis (see Section 9.8.3). 
!
Conduct the MMTT test. Subjects should be fasting for at least 8 hours prior 
to the MMTT. The standardized meal was given approximately between 7am 
and 10am. Study drug will be administered immediately after consuming the 
liquid meal (see Section 8.2). The PK samples of DS-8500a and its metabolite 
evaluation will be collected at the same time points as MMTT, 
including pre-dose (time 0), 0.5, 1.0, 1.5, 2.0, 2.5 and 3.0 h after initiation of 
ingesting the liquid meal (see Section 8.1).
!
Collect blood for the following during time 0 of MMTT:
∀
Standard laboratory safety tests (chemistry, hematology) (see 
Section 9.8.1 and Section 9.8.2).
∀
HbA1c
∀
FPG
∀
Lipid panel 
!
Administer and record date and time of dose taken at this visit.
!
Collect study medication and check study drug adherence.
!
Contact the IXRS.
!
Schedule Follow-up visit to occur in approximately 2 weeks (± 3 days) 
6.5.
Follow-Up (Visit 8, Week 14)
This is a non-fasting visit.
The following procedures and assessments will be performed at the Week 14 (± 3 days) 
visit:
!
Assess for and record AEs.
!
Record vital signs (see Section 9.9) and body weight (see Section 9.10).
!
Perform a targeted physical examination (including lungs, heart, and as 
needed examination, see Section 9.12).
!
Perform urine pregnancy test for WOCBP (see Section 9.8.4)
!
Collect urine and blood for the following:
-
Repeat any abnormal results from prior visit.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 53
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 53
7.
EFFICACY ASSESSMENTS
For all efficacy variables except lipids, baseline is defined as the last measurement prior 
to the first dose of randomized study medication. Baseline lipid variables will be the 
average of the screening and Week 0/Day 1 values. 
7.1.
Primary Efficacy 
The primary efficacy endpoint is change from baseline in HbA1c at Week 12.
7.2.
Secondary Efficacy 
The secondary endpoints are: 
!
Changes from baseline in lipids (TC, LDL-C, HDL-C, non-HDL-C and TG) at 
Week 12.
!
Changes from baseline in AUC0-3h and Cmax of PG in response to MMTT at 
Weeks 4 and 12.
!
Changes from baseline in FPG from baseline to Weeks 2, 4, 8, and 12.
!
The proportion of subjects achieving HbA1c < 7.0% at Week 12.
7.3.
Exploratory Efficacy 
Exploratory endpoints are: 
 
 
 
 
 
 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 54
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 54
8.
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS
8.1.
Pharmacokinetic (PK) Endpoint(s)
Blood samples for the measurement of DS-8500a and its metabolite 
 will be 
collected as shown in Table 8.1. The subject will be instructed not to take study 
medication prior to the study visit for PK sampling. At Visits 3, 4, and 6 (Day 1, Week 2,
and Week 8) only pre-dose PK levels will be obtained. At Visits 5 and 7 (Weeks 4 and 
12, respectively), PK sampling will be obtained during the MMTT pre-dose (time 0) and 
every 30 minutes after MMTT ingestion up to 3 hours (see Section 8.2). The time of last 
dose and meal prior to the study visit must be recorded. 
Table 8.1:
PK Sampling for DS-8500a and Its Metabolite (A209-3952)
Week (Visit)
Pre-dose
Post Consumption of Liquid Meal (hour)
within 10 min 
prior to liquid 
meala
0.5h
(± 5 min)
1.0h
(± 5 min)
1.5h
(± 5 min)
2.0h
(± 5 min)
2.5h
(± 5 min)
3.0h
(± 5 min)
Week 0 (Day 1, Visit 3 )b
X
Week 2 (Visit 4)
X
Week 4 (Visit 5)b
X
X
X
X
X
X
X
Week 8 (Visit 6)
X
Week 12 (Visit 7)c
X
X
X
X
X
X
X
a Only applies to visit 3, 5 and 7
b Prior to randomization
c Mixed Meal Tolerance Test
DS-8500a and its metabolite will be measured by a validated Liquid Chromatography 
Mass Spectrometry (LC-MS)/ Mass Spectrometry (MS) bioanalytical method.
Plasma PK and standard noncompartmental PK parameters (area under the concentration 
versus time curve [ng•h/mL] from 0 to 3 hours [AUC0-3h] and trough concentrations 
[Ctrough] will be calculated for DS-8500a and its metabolite 
.
8.2.
Pharmacodynamic (PD) Endpoint(s)
Mixed Meal Tolerance Test (MMTT)
The MMTT will be performed in all subjects at randomization visit (Day 1, prior to the 
randomization), Week 4 and Week 12 (Visits 5 and 7, respectively). On study visit days
that involve MMTT, subjects will have fasted (no food or drinks except water) for at least 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 55
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 55
8 hours prior to the MMTT. The standardized meal will be given approximately between 
7am and 10am. The entire liquid meal is to be completed within a 10-minute period. 
Study drug will be administered immediately after consuming the liquid meal. On day 1 
Lead-in tablets and capsules will be taken after the liquid meal and on Week 4 and Week 
12 (Visits 5 and 7, respectively) randomized tablets and capsules will be taken.
During the MMTT, blood samples will be collected within 10 min prior to the start of the 
meal (time 0), and at 0.5, 1, 1.5, 2, 2.5, and 3 hours after initiation of ingesting the liquid 
meal for the measurement of plasma glucose.  
On Day 1, PK sample will be collected at time 0 of the MMTT. On Visits 5 and 7, PK 
samples will be collected at each time point of the MMTT.
Blood samples will be collected for PD assessment of plasma glucose and biomarkers 
such as insulin, C-peptide, total GLP-1, active GLP-1, PYY and glucagon as shown in
Table 8.2. The mean plasma glucose during the 3 h postprandial period (0–3 h) will be 
calculated as the AUC for the plasma glucose profile (calculated by the trapezoid rule) 
divided by the 3 h time interval. 
Table 8.2:
PD Sampling for
Week (Visit)
Pre-dose 
(min)
Post-Dose (hour)
within 10 min 
prior to liquid 
meal
0.5h
(± 5 min)
1.0h
(± 5 min)
1.5h
(± 5 min)
2.0h
(± 5 min)
2.5h
(± 5 min)
3.0h
(± 5 min)
Week 0 (Day 1, Visit 3 )a
X
X
X
X
X
X
X
Week 4 (Visit 5)b
X
X
X
X
X
X
X
Week 12 (Visit 7)b
X
X
X
X
X
X
X
a Prior to randomization, blood samples for plasma glucose and biomarkers at each time point. Plasma PK 
at pre-dose only
b Blood samples for plasma glucose, biomarkers. Plasma PK at all-time points.
Content of standardized meal for the MMTT:
The standardized meal consists of two servings of liquid supplement containing 
approximately 100 g of total carbohydrates and approximately 2930 kJ (700 kcal). (i.e.,
Ensure Plus© – each bottle contains 50 g carbohydrates, 11 g fat,  13 g protein for a total 
350 calories).
Instructions for specimen collection, storage, and shipping will be provided in in the lab 
manual.
8.3.
Biomarker Endpoint(s)
Blood samples for biomarker evaluation will be collected during MMTT test (see 
Section 8.2).
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 56
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 56
8.4.
Immunogenicity
Not applicable.
8.5.
Pharmacogenomic Analysis
Not applicable.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 57
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 57
9.
SAFETY EVALUATION AND REPORTING
9.1.
Adverse Event Collection and Reporting
All clinical AEs (see Section 9.4.1 for definitions) occurring after the subject signs the 
Informed Consent Form and through the Follow-up Visit, whether observed by the 
investigator or reported by the subject, will be recorded on the AE CRF page.  Medical 
conditions (including laboratory values/vital signs that are out of range) that were 
diagnosed or known to exist prior to Informed Consent will be recorded as part of 
medical history.  
All AEs, serious adverse events (SAEs), and Adverse Events of Special Interest are to be 
reported according to the procedures in Section 9.5.
All laboratory results, vital signs, physical examination and ECG findings should be 
appraised by the Investigator to determine their clinical significance. Isolated abnormal 
laboratory results, vital sign findings, or ECG findings (i.e., not part of a reported 
diagnosis) should be reported as AEs if they are symptomatic, lead to study drug 
discontinuation, dose reduction, require corrective treatment, or constitute an AE in the 
investigator’s clinical judgment.
At each visit, the investigator will determine whether any AEs have occurred by 
evaluating the subject.  Adverse events may be directly observed, reported spontaneously 
by the subject or by questioning the subject at each study visit.  Subjects should be 
questioned in a general way, without asking about the occurrence of any specific 
symptoms.  The Investigator must assess all AEs to determine seriousness, severity, and 
causality, in accordance with the definitions in Section 9.4. The Investigator’s assessment 
must be clearly documented in the site’s source documentation with the Investigator’s 
signature.
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, 
report the primary sign or symptom as the AE or SAE term with additional details 
included in the SAE narrative until the diagnosis becomes available.  If the signs and 
symptoms are distinct and do not suggest a common diagnosis, report as individual 
entries of AE or SAE.  
For events that are serious due to hospitalization, the reason for hospitalization must be 
reported as the SAE (diagnosis or symptom requiring hospitalization).  A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE. Preplanned (prior 
to signing the ICF) procedures or hospitalizations for pre-existing conditions which do 
not worsen in severity should not be reported as SAEs.  For deaths, the underlying or 
immediate cause of death should always be reported as an SAE.  
In addition, any serious, untoward event that may occur subsequent to the reporting 
period that the investigator assesses as related to study drug should also be reported and 
managed as an SAE.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 58
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 58
Any serious, untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study drug should also be reported and managed as an 
SAE.
Investigators should follow subjects with AEs until the event has resolved or the 
condition has stabilized.  Unresolved AEs, including significant abnormal laboratory 
values at the end of the study, should be followed up until resolution or until no longer 
clinically relevant.  
9.2.
Safety Endpoint Event(s)
Not applicable.
9.3.
Events of Special Interest
9.3.1.
Adjudicated Cardiovascular Events
A Cardiovascular Endpoints Committee (CEC) consisting of independent external 
experts in the field of cardiovascular medicine will blindly review and adjudicate any 
event that is potentially a cardiovascular event including cardiovascular death, non-fatal 
myocardial infarction, transient ischemic attack and non-fatal stroke, hospitalization for 
unstable angina, urgent coronary revascularization intervention and hospitalization for 
congestive heart failure.
The CEC will need to verify that the event meets pre-specified definitions. The 
definitions for each of these cardiovascular events and the process of identifying events 
that require adjudication will be detailed in the CEC Charter.
9.3.2.
Anemia Monitoring and Stopping Criteria
In toxicology studies anemia was observed in 3 monkeys in (see data in Investigator 
Brochure). All cases of anemia improved or tended to improve after drug withdrawal. 
The mechanism of anemia development was not identified. No anemia or reduction in 
hemoglobin has been observed in any human studies with DS-8500a.To ensure subjects’
safety, complete blood count and reticulocytes count will be measured at every study visit 
and anemia will be closely monitored throughout the study.
9.3.2.1.
Rules for Anemia Evaluation and Stopping of Study Subjects
!
If Hemoglobin decreases more than 1.5 g/dL but less than or equal to 2.0 g/dL 
compared to baseline level, the test should be repeated within a week. Additional 
tests should be conducted to evaluate the potential cause of anemia (see 
Section 9.3.2.2). The subject should be followed until labs return to baseline.
!
If Hemoglobin decreased more than 2.0 g/dL compared to baseline level and/or 
Hemoglobin level is lower than 10.0 g/dL for males and 9.5 g/dL for females, the
test should be repeated within 3 days. Additional tests should be conducted to 
evaluate the potential cause of anemia (see Section 9.3.2.2). If any of the above 
changes in hemoglobin are confirmed, the subject should stop taking study drug 
and discontinue from the study (see Section 5.7). Subject should be followed until 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 59
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 59
labs return to baseline. All early termination procedure (see Section 6.4.4) should 
be conducted except MMTT. This event should always be reported to the Sponsor 
using a SAVER form, with the investigator’s assessment of seriousness, causality, 
and a detailed narrative. This event should be reported within 24 hours of 
Investigator’s awareness of the event.
!
Additional tests and/or a referral to hematology consult may be done based on 
investigator’s discretion.
9.3.2.2.
Anemia Monitoring
The hematology test for CBC and reticulocytes count should be measured at each visit
(see Section 9.8.1). The following tests are recommended for the subjects who are 
developing anemia or having the reduction in Hemoglobin as described in Section 9.3.2.1: 
!
CBC and Reticulocytes
!
Blood smear
!
Chemistry including lactate dehydrogenase, total bilirubin, direct bilirubin
!
Ferritin
!
Haptoglobin
!
Hemoccult test
9.3.3.
Combined Elevations of Aminotransferases and Bilirubin
Combined elevations of aminotransferases and bilirubin, either serious or non-serious and 
whether or not causally related, meeting the laboratory criteria of a potential Hy’s Law 
case [ALT or AST ≥ 3 x ULN with simultaneous total bilirubin ≥ 2 x ULN] should 
always be reported to the Sponsor using a SAVER form, with the investigator’s 
assessment of seriousness, causality, and a detailed narrative.  These events should be 
reported within 24 hours of Investigator’s awareness of the event.
9.4.
Adverse Event
9.4.1.
Definition of Adverse Event (AE)
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product and that does not necessarily have to have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product (ICH E2A Guideline.  Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting, Oct 1994).
It is the responsibility of Investigators, based on their knowledge and experience, to 
determine those circumstances or abnormal laboratory findings which should be 
considered adverse events.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 60
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 60
9.4.2.
Definition of Serious Adverse Event (SAE)
A SAE is any untoward medical occurrence that at any dose:
!
Results in death,
!
Is life-threatening,
!
Requires inpatient hospitalization or prolongation of existing hospitalization,
!
Results in persistent or significant disability/incapacity,
!
Is a congenital anomaly/birth defect, or
!
Is an important medical event.
Note: The term “life-threatening” in the definition of “serious” 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 which 
hypothetically might have caused death if it were more severe (ICH E2A Guideline.  
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
Oct 1994).
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require treatment to prevent one of the other outcomes listed in the 
definition above.  Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias or development of drug dependency or drug abuse.
Note:
!
Procedures are not AEs or SAEs, but the reason for the procedure may be an 
AE or SAE.  
!
Pre-planned (prior to signing the Informed Consent Form) procedures or 
treatments requiring hospitalizations for pre-existing conditions that do not 
worsen in severity are not SAEs.
9.4.3.
Severity Assessment
The following definitions should be used to assess intensity of adverse events:
!
Mild: Awareness of sign or symptom, but easily tolerated (i.e., does not 
interfere with subject’s usual function).
!
Moderate: Discomfort enough to cause interference with usual activity.
!
Severe: Incapacitating with inability to work or do usual activity (i.e.,
interferes significantly with subject’s usual function).
Severity vs. Seriousness: Severity is used to describe the intensity of a specific event 
while the event itself, however, may be of relatively minor medical significance (such as 
severe headache).  This is not the same as "seriousness," which is based on patient/event 
outcome at the time of the event.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 61
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 61
9.4.4.
Causality Assessment
The Investigator should assess causal relationship between an AE and the study product 
on the basis or his/her clinical judgment and the following definitions.  The causality 
assessment should be made based on the available information and can be updated as new 
information becomes available.
!
1 = Related:
∀
The AE follows a reasonable temporal sequence from study drug 
administration, and cannot be reasonably explained by the subject’s 
clinical state or other factors (e.g., disease under study, concurrent 
diseases, and concomitant medications).
∀
The AE follows a reasonable temporal sequence from study drug 
administration, and is a known reaction to the drug under study or its 
chemical group, or is predicted by known pharmacology.
!
2 = Not Related:
∀
The AE does not follow a reasonable sequence from study product 
administration, or can be reasonably explained by the subject’s clinical 
state or other factors (e.g., disease under study, concurrent diseases, and 
concomitant medications).
9.4.5.
Action Taken Regarding the Study Product
!
1 = Dose Not Changed: No change in study drug dosage was made.
!
2 = Drug Withdrawn: The study product was permanently stopped.
!
3 = Drug Interrupted: The study product was temporarily stopped.
9.4.6.
Adverse Event Outcome
!
1 = Recovered/Resolved
∀
The subject fully recovered from the adverse event with no residual effect 
observed.
!
2 = Recovered/Resolved with Sequelae
∀
The residual effects of the adverse event are still present and observable.
∀
Include sequelae/residual effects.
!
3 = Not Recovered/Not Resolved
∀
The AE itself is still present and observable.
!
4 = Fatal
9.4.7.
Other Action Taken for Event
!
1 = None.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 62
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 62
∀
No treatment was required.
!
2 = Medication required.
∀
Prescription and/or over the counter (OTC) medication was required to 
treat the AE.
!
3 = Other.
9.5.
Reporting Procedure For Investigators
All AEs and SAEs will be reported in the eCRF.
In addition, the following events should be reported on a SAVER (Serious Adverse Event 
Report) form within 24 hours of awareness.
!
SAEs (see Section 9.4.2 for definition)
!
Hepatic events meeting combination abnormalities [ALT or AST ≥ 3 x ULN 
with simultaneous TBL ≥ 2 x ULN] (potential Hy’s Law case), both serious 
and non-serious (see Section 9.3.3 for additional details).
!
Hemoglobin decrease of > 2.0 g/dL from baseline level, and/or Hemoglobin < 
10.0 g/dL for males or < 9.5 g/dL for females, both serious and non-serious 
(see Section 9.3.2.1 for additional details).
All events (serious and non-serious) must be reported with Investigator's assessment of 
the event's seriousness, severity, and causality to the blinded study drug.  A detailed 
narrative summarizing the course of the event, including its evaluation, treatment, and 
outcome should be provided.  Specific or estimated dates of event onset, treatment, and 
resolution should be included when available.  Medical history, concomitant medications, 
and laboratory data that are relevant to the event should also be summarized in the 
narrative.  For fatal events, the narrative should state whether an autopsy was or will be 
performed, and include the results if available.  Source documents will be retained in 
site's files and should not be submitted to the Sponsor for SAE reporting purposes.
Urgent safety queries must be followed up and addressed promptly.  Follow-up 
information and response to non-urgent safety queries should be combined for reporting 
via the eCRF to provide the most complete data possible within each follow-up. 
Please call the local SAE Hotline or your study monitor for any questions on SAE 
reporting.
9.6.
Notifying Regulatory Authorities, Investigators, and 
Institutional Review Board/Ethics Committee
Daiichi Sankyo and/or CRO will inform Investigators, central Institutional Review 
Boards (IRBs), and regulatory authorities of any Suspected Unexpected Serious Adverse 
Reactions (SUSARs) occurring in other study centers or other  studies of the 
investigational drug, as appropriate per local reporting requirements. Daiichi Sankyo 
and/or CRO will comply with any additional local safety reporting requirements.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 63
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 63
In the US and Canada, upon receipt of the Sponsor’s notification of SUSARs that 
occurred with the study drug, unless delegated to the Sponsor, it is the Investigator’s 
responsibility to inform the IRB per Sponsor’s instruction.
9.7.
Exposure In Utero During Clinical Studies
Daiichi Sankyo must be notified of any subject who becomes pregnant while receiving or 
the study drug through the Follow-up Visit. 
Although pregnancy is not technically an adverse event, all pregnancies must be followed 
to conclusion to determine their outcome.  This information is important for both drug 
safety and public health concerns.  It is the responsibility of the Investigator, or designee, 
to report any pregnancy in a female subject via using the Exposure In Utero (EIU) 
Reporting form.  Please contact your study monitor to receive the EIU Reporting Form 
upon learning of a pregnancy.  The investigator should make every effort to follow the 
subject until completion of the pregnancy and complete the EIU Reporting Form with 
complete pregnancy outcome information, including normal delivery and induced 
abortion.  The adverse pregnancy outcome, either serious or non-serious, should be 
reported in accordance with study procedures.  If the outcome of the pregnancy meets the 
criteria for immediate classification as a SAE (i.e., post-partum complications, 
spontaneous or induced abortion, stillbirth, neonatal death, or congenital anomaly, 
including that in an aborted fetus), the Investigator should follow the procedures for 
reporting SAEs outlined in Section 9.5. 
9.8.
Clinical Laboratory Evaluations
Blood and urine samples for clinical laboratory evaluations will be shipped to a central 
laboratory for analysis.  Results of all laboratory tests will be reported in the subject’s 
eCRF or merged electronically with the clinical database.
9.8.1.
Hematology
Ethylenediamine tetraacetic acid (EDTA) tube of blood will be drawn for the hematology 
assessments and HbA1c listed in Table 9.1.  These will be measured from samples 
obtained at the Screening Visit, Randomization Visit, Treatment visits and End-of-
treatment/Early termination visit. All abnormal results from prior visit will be repeated at 
Follow-up Visit.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 64
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 64
Table 9.1:
Hematology Analytes 
Complete Blood Count (CBC)
a
Hemoglobin
Hematocrit
Red blood cell (RBC) count (with indices)
White blood cell (WBC) count (with differential)
Platelet count
Reticulocytes countb
HbA1cc
a CBC counts will be measured at each visit.
b Reticulocytes counts will be measured at each visit.
c HbA1c will only be measured at Screening Visit, Randomization Visit, Treatment Visits (Week 4 and 
Week 8) and End-of-treatment/Early Termination Visit (Week 12).
9.8.2.
Blood Chemistry
A serum separating tube of blood will be drawn for the blood chemistry assessments 
listed in Table 9.2.  These will be measured from samples obtained at the Screening Visit, 
Randomization Visit, Treatment visits and End-of-treatment/Early Termination visit. All
abnormal results from prior visit will be repeated at Follow-up Visit.
Table 9.2:
Blood Chemistry Analytes
Sodium
Lactate Dehydrogenase 
Potassium
Creatinine
Magnesium
Blood urea nitrogen
Bicarbonate
Total protein
Calcium
Albumin
Inorganic phosphorus
Uric acid
AST
Creatine kinase
ALT
Fasting blood glucose
Alkaline phosphatase
C-peptidea
Total bilirubinb
Lipid Panelc
- Total cholesterol (TC), 
- Low-density lipoprotein cholesterol (LDL-C) 
- High-density lipoprotein cholesterol (HDL-C) 
- Triglycerides (TG)
a C-peptide will be measured at the Screening Visit.
b Total bilirubin should be fractionated whenever total bilirubin > 1.5 x ULN. Unconjugated and 
conjugated bilirubin fractions should be analyzed and only subjects documented to have Gilbert’s 
syndrome may be enrolled.
c Lipid panel will only be measured at Screening Visit, Randomization Visit, Treatment Visit 5 (Week 4) 
and End-of-treatment/Early Termination Visit (Week 12).
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 65
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 65
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of 
normal
9.8.2.1.
Estimation of Creatinine Clearance
Creatinine clearance will be estimated from serum creatinine and subject demography by 
the central laboratory using the Cockcroft-Gault equation (Appendix 17.1).
9.8.3.
Urinalysis
Standard urinalysis including a microscopic examination will be conducted for all 
subjects at the Screening Visit and End-of-treatment/Early Termination visit (Table 9.3).
All abnormal results from prior visit will be repeated at Follow-up Visit.
Table 9.3:
Urinalysis Determinations
Specific gravity
Blood
pH
RBC
Protein
WBC
Glucose
Bilirubin
Ketones
Urobilinogen
Abbreviations: RBC = red blood cell; WBC = white blood cell.
For samples with findings on macroscopic analysis, microscopic examination for red 
blood cells, white blood cells, bacteria, and casts should be performed.
9.8.4.
Pregnancy Testing
All WOCBP must have a negative serum pregnancy test at the Screening Visit. A urine 
pregnancy test will also be performed for all WOCBP subjects at all clinic visits through 
the Follow-up Visit (as defined in Section 4.3). If a urine test result is positive, a serum 
pregnancy test will be performed to confirm the result.
9.8.5.
Thyroid Stimulating Hormone (TSH)
A serum TSH test will be performed at the Screening Visit (Visit 1) for all subjects.
Subjects with TSH not within normal range are excluded.
9.9.
Vital Signs
Vital signs will be recorded at all clinic visits and will include temperature, heart rate, 
and sitting blood pressure. 
Measurement of blood pressure should be conducted using a calibrated manometer or 
automatic inflatable cuff monitor.
Blood pressure should be measured using the same arm and measuring device throughout 
the study.  At the Screening Visit (Visit 1) only, a blood pressure reading should be taken 
in both arms (unless there is a medical reason not to use a particular arm).  The arm with 
the higher systolic reading should then be used throughout the rest of the study.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 66
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 66
Blood pressure should be recorded to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
After all blood pressures have been obtained; measure the subject’s heart rate using the 
same arm.
9.10.
Body Height and Weight
Measurement of height will be performed only at the Screening Visit (Visit 1) with the 
subject in a standing position and with shoes removed.  The subject’s knees should be 
straightened, head held erect, with eyes forward.
Measurement of weight should be performed at all clinic visits with the subject dressed in 
indoor clothing, shoes removed and bladder empty.  Subjects should be weighed on the 
same scale at all clinic visits. 
9.11.
Electrocardiograms
A 12-lead ECG will be conducted at the Screening Visit, Visit 5 (Week 4) and at the End-
of-treatment/Early termination visit (Visit 7).  ECG recordings should be assessed as 
normal or abnormal, and any abnormal findings should be assessed as not clinically 
significant or clinically significant. Clinically significant abnormal findings should be 
reported as medical history (if pre-existent).  Refer to Section 9.1 for general guidance on 
when to report abnormal findings as AEs. If new abnormal findings in ECG are identified
in Visit 5 or Visit 7, assessment should be made whether these changes meet criteria for 
event requiring review by CEC.  
9.12.
Physical Examinations
A full physical examination, with the exception of pelvis, breast, and rectum in women 
and the genitourinary system and prostate in men, will be performed at the Screening 
Visit (Visit 1) and End-of-treatment/Early termination visit (Visit 7). The full physical 
examination should minimally include clinical evaluations of the head, neck, thyroid, 
eyes, ears, nose, throat, chest, heart, lungs, lymph nodes, abdomen, skin, extremities, 
musculoskeletal and neurological.  
A targeted physical examination will be performed at Visits 2, 3, 4, 5, 6, and Follow-up 
Visit (Visit 8). The abbreviated physical examination should minimally include clinical 
evaluations of the heart and lungs.  Additional systems may be examined based on any 
symptoms exhibited by the subject.
9.13.
Other Examinations
9.13.1.
Medical History and Demographics
Demographic information including month and year of birth, race, sex, weight, and 
height will be collected on all subjects at screening.  Medical history, including details 
regarding all illnesses and allergies, date(s) of onset, whether condition currently 
persist(s), and smoking and alcohol use, will be collected on all subjects.  Additional 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 67
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 67
information to be collected includes past surgical and medical procedures as well as 
medications.
9.13.2.
Home Self-Monitoring of Blood Glucose 
All subjects enrolled will be provided with home blood glucose monitor to measure blood 
glucose levels throughout the study.  Subjects will be instructed to obtain blood glucose 
levels every morning, before having breakfast and taking study medication.  Subjects 
may also obtain blood glucose measurements, as instructed by the investigator, at any 
other time and specifically should be encouraged to measure and record if they 
experience symptoms of hypoglycemia or hyperglycemia.  Subjects will be instructed to 
call the clinic if the monitoring device indicates a fasting blood glucose level <70 mg/dL 
or >240 mg/dL, or blood glucose <70 mg with or without symptoms at any time.  
Subjects will receive appropriate medical advice based on their blood glucose level and, 
if deemed necessary by the investigator, a clinic visit will be scheduled within 3 days for 
a follow-up laboratory evaluation of fasting glucose.
At the Randomization Visit, subjects will report their fasting SMBG obtained during the 
Lead-in Period.  If a subject reports 2 or more values during Lead-in Period that were 
greater than 240 mg/dL, or 1 value greater than 240 mg/dL and worsening polyuria, 
polydipsia, dizziness, vision changes, or other symptoms of hyperglycemia, subject 
should have their FPG measured  and if values are confirmed by the laboratory should be 
discontinued prior to randomization.
Throughout the study, subjects should use provided glucose monitor to perform SMBG.  
Results, along with any symptoms of either hyper or hypoglycemia should be recorded in 
their study diary. For SMBG meeting discontinuation criteria please see Section 5.7.1.
9.13.3.
Study Diary
Subjects will be provided with a paper diary to help them to record their home SMBG, 
the time of study drugs taken, and any new symptoms. 
9.14.
Patient Reported Outcomes
Not applicable.
9.15.
Pharmacoeconomic Assessments
Not applicable.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 68
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 68
10.
OTHER ASSESSMENTS
10.1.
Patient Reported Outcomes
Not applicable.
10.2.
Pharmacoeconomic Assessments
Not applicable.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 69
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 69
11.
STATISTICAL METHODS 
11.1.
Analysis Sets
The following analysis sets will be used to summarize the data from this study: 
!
The Randomized Analysis Set will include all subjects who signed the ICF 
and were randomized into the study. 
!
The Safety Analysis Set will include all subjects who received at least 1 dose 
of randomized study drug. 
!
The modified Intent-To-Treat (mITT) analysis set will include all subjects in 
the Safety Analysis Set who have a baseline measurement and at least 1 post-
baseline measurement. 
!
The Per-protocol Analysis Set will include all subjects in the Safety Analysis 
Set and who were sufficiently compliant with the protocol, according to pre-
specified criteria which will be finalized prior to database unblinding.
!
The PK Analysis Set will include all subjects who received at least 1 dose of 
DS-8500a and have at least 1 PK concentration measured. 
11.2.
General Statistical Considerations
Unless otherwise specified, hypothesis testing will be performed at the 0.1 significance 
level (2-sided) and 2-sided 90% CI will be provided. 
Raw data will be presented with the same precision with which they were collected. 
For summary statistics, means and medians will be displayed to 1 more decimal place 
than was determined for raw data, dispersion statistics will have 2 more decimal places, 
and the minimum and maximum will be displayed to the same number of decimal places 
as the raw data. 
Quantitative data will be tabulated with descriptive summary statistics: arithmetic mean, 
standard deviation (SD), median, minimum and maximum values, and number of 
observations. For categorical data, frequency tables will be provided. 
For variables expressed as percent, the denominators for the calculations of percentages 
will be the number of subjects who had that variable assessed. 
11.3.
Study Population Data
Demographic characteristics will be summarized for the randomized subject population 
according to treatment assignment. Continuous demographic variables (age [calculated 
from date of birth to the date of signed informed consent], weight, height, and body mass 
index) for all randomized subjects will be summarized with descriptive statistics. 
Categorical demographic variables (sex, race, ethnicity, and age group will be 
summarized with frequency counts and corresponding percentages.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 70
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 70
Subject disposition will be summarized as the number of subjects screened, the number 
randomized, and the number and percent of those who completed treatment or withdrew 
(with the latter summarized by reason for withdrawal).
Prior and concomitant medications will be summarized by number and percent of 
subjects for each WHO-Drug preferred base name and Anatomical Therapeutic Chemical 
category.
11.4.
Statistical Analysis
11.4.1.
Efficacy Analyses
For all efficacy variables except lipids, baseline is defined as the last measurement prior 
to the first dose of randomized study medication. Baseline lipid variables will be the 
average of the screening and Week 0/Day 1 values. 
11.4.1.1.
Primary Efficacy Analyses
The primary estimand is the treatment difference between DS-8500a and placebo for the 
change in HbA1c from baseline to Week 12 attributable to the initially randomized 
treatment for all subjects in the mITT Analysis Set. The primary estimand will be 
analyzed using a mixed-effect model with repeated measures (MMRM) with treatment
group, previous statins stratum, week, and treatment-by-week as the fixed effects, week 
as a repeated factor, and baseline HbA1c as a covariate to compare each DS-8500a dose 
vs. placebo. No adjustment will be made for multiple comparisons.
The between-treatment group effects at Week 12 will be tested at 2-sided 10% level of 
significance. Point estimates and corresponding 90% CIs for the differences in least-
square mean changes between each DS-8500a dose and placebo will be calculated.  
To establish the assay sensitivity of the study, the comparison of sitagliptin and placebo 
will be carried out using the same method as that for the primary estimand. The point 
estimate and corresponding 90% CI for the difference in least-square mean change 
between sitagliptin and placebo will be calculated. 
Graphical presentations of change from baseline in HbA1c will be provided for each 
treatment group over 12 weeks. 
Similar analyses will be performed for the change in HbA1c from baseline to Week 12 
for the Per-protocol Analysis Set.
11.4.1.2.
Secondary Efficacy Analyses
The secondary efficacy variables will be analyzed for the mITT Analysis Set.
The secondary efficacy variables are:
!
The change and percent change from baseline at Weeks 4 and 12 in total 
cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density 
lipoprotein cholesterol (HDL-C), non-high density cholesterol (non-HDL-C), 
and triglycerides (TG).
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 71
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 71
!
The change from baseline in HbA1c at Weeks 4 and 8.
!
The change from baseline in FPG at Weeks 2, 4, 8, and 12.
!
The proportion of subjects achieving HbA1c<7% at Week 12.
For the change and percent change from baseline in lipid variables, a MMRM with 
treatment group, previous statins stratum, week, and treatment-by-week as the fixed 
effects, week as a repeated factor, and baseline value as a covariate will be applied to 
compare each DS-8500a dose vs. placebo and sitagliptin vs. placebo.    
For the change from baseline in HbA1c at Week 4 and Week 8, comparisons of each DS-
8500a dose vs. placebo and sitagliptin vs. placebo will be performed using the MMRM 
applied for the analysis of the primary estimand. 
For the change from baseline in FPG, the MMRM with treatment, previous statins 
stratum, week, and treatment-by-week as fixed effects, week as a repeated factor, and 
baseline FPG as a covariate will be used to compare each DS-8500a dose vs. placebo and 
sitagliptin vs. placebo.  
The responder analysis for the proportion of subjects achieving HbA1c<7% at Week 12 
will be carried out using a logistic regression model with treatment group and previous 
statins stratum as factors and baseline HbA1c as a covariate. 
The difference in changes from baseline in TG vs. placebo will be estimated using 
Hodges-Lehmann estimator and the corresponding non-parametric 2-sided 90% CI will 
be constructed using Moses’ method.
All comparisons will be tested at a 2-sided significance level of 0.1 for all variables.  
There will be no adjustment for multiplicity.
11.4.1.3.
Exploratory Efficacy Analyses
 
 
 
 
11.4.1.4.
Subgroup Efficacy Analyses
Descriptive summaries will be provided for the change from baseline in HbA1c at Week 
12 for each subgroup factor by treatment group. The following subgroup factors will be 
used:
!
Age (≤65 or >65 years),
!
Sex 
!
Race
!
Baseline HbA1c level (< 8.5, ≥ 8.5), 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 72
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 72
!
Disease duration (< 1 year; ≥ 1 to < 5 years; ≥ 5 years )
!
Body mass index (<30 kg/m2, ≥ 30 kg/m2).
11.4.2.
Pharmacokinetic/Pharmacodynamic Analyses
11.4.2.1.
Pharmacokinetic Analyses
 (A209-3952) will be assessed. The 
 
11.4.2.2.
Pharmacodynamic Analyses
The PD parameters will include 3h area under the curve (AUC0-3h), Cmax and mean for 
plasma glucose (PG) in response to MMTT. The analyses will be performed, using a 
MMRM with treatment group, previous statins stratum, week, and treatment-by-week as 
the fixed effects, week as a repeated factor, and baseline value as a covariate, for the 
following PD variables:
!
The change from baseline at Week 4 and at Week 12 in AUC0-3h and Cmax for 
PG;
!
The change from baseline at Week 4 and at Week 12 in mean PG over 3h 
period;
!
The change from baseline at Week 4 and at Week 12 in HOMA-IR and 
HOMA-%β;
!
The change from baseline at Week 4 and at Week 12 in MMTT derived 
measure of beta-cell function (AUCinsulin/AUCglucose) and insulin sensitivity 
[Matsuda’s insulin sensitivity index, (ISI)] and disposition index (DI, product 
of AUCinsulin/AUCglucose X Matsuda’s ISI);
!
The change in body weight from baseline at each scheduled visit.
For the beta-cell function, insulin sensitivity and disposition index data, the assumptions 
of normality and homogeneity of variance will be examined prior to fitting the models. If 
a significant departure from the assumption is observed, an appropriate non-parametric 
method will be applied.
The time-course of the PD measures will be plotted.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 73
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 73
11.4.2.3.
Biomarker Analyses
 
 
 
11.4.2.4.
Pharmacogenomic Analyses
Not applicable.
11.4.3.
Safety Analyses
Safety assessments include adverse events, clinical laboratory measurements 
(hematology, blood chemistry, and urinalysis and vital signs. The Safety Analysis Set 
will be used for all safety analyses.
11.4.3.1.
Adverse Event Analyses
Adverse events will be grouped by system organ class and by preferred term within 
system organ class according to the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary. Treatment-emergent adverse events are defined as adverse events 
that first occurred or worsened in severity after initiation of double-blind treatment. 
Tables summarizing subject incidence of all TEAEs, serious adverse events, severe 
adverse events, study drug-related TEAEs, study drug-related serious adverse events, 
study drug-related severe adverse events, and TEAEs leading to early withdrawal from 
study and/or death will be provided.
Adverse events collected from the Screening Period and the Lead-in Period will be 
presented separately.
11.4.3.1.1. Cardiovascular Event Adjudication
Selected cardiovascular events will be adjudicated by an independent board. Tables 
summarizing subject incidence of the cardiovascular events will be provided by treatment 
group. A subject listing of the cardiovascular events will be provided.
11.4.3.2.
Clinical Laboratory Evaluation Analyses
Tables summarizing baseline, post baseline, and change from baseline for each scheduled 
collection time point will be provided for hematology and blood chemistries.
The number and percentage of subjects with “markedly abnormal” laboratory values will 
be tabulated. The clinical laboratory data will be listed, and values outside the normal 
ranges will be flagged.
11.4.3.3.
Vital Sign Analyses
For vital signs, descriptive summary statistics for baseline and change from baseline 
values will be presented by treatment group.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 74
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 74
11.4.3.4.
Electrocardiogram Analyses
Clinically significant abnormal 12-lead ECG findings will be reported as AEs. Data from 
ECG findings will be listed. Shift tables for ECG results (normal or abnormal) will be 
presented by treatment group.
11.4.3.5.
Physical Examination Analyses
Clinically significant abnormal physical examination findings will be reported as AEs. 
Data from physical examinations will be listed and summarized by treatment group.
11.4.3.6.
Exploratory Safety Analyses
Not applicable
11.4.4.
Other Analysis
Not applicable
11.5.
Interim Analyses
Not applicable
11.5.1.
Data Monitoring Committee
A data monitoring committee will not be formed for this study.
11.6.
Sample Size Determination
Approximately 260 eligible subjects will be randomized in a 2:2:3:3:3 ratio with 40 
subjects per arm in each of the DS-8500a 25 mg and DS-8500a 50 mg treatment groups, 
and 60 subjects per arm in each of the DS-8500a 75 mg , placebo, and sitagliptin 100 mg 
treatment groups. Assuming a common SD of 1.0% and an early (prior to first post-
baseline assessment) dropout rate of 10%, with a 2-sided t-test at a significance level of 
0.1, it is estimated the sample size will provide at least 90% power to detect a 0.6% 
difference between DS-8500a 75 mg dose and placebo and at least 80% power to detect a 
0.6% difference between each of the DS-8500a 25 mg and 50 mg doses and placebo in 
mean HbA1c change from baseline to Week 12. No adjustment will be made for 
multiplicity.  
11.7.
Statistical Analysis Process
The clinical study data will be analyzed by the CRO.
The SAP will provide the statistical methods and definitions for the analysis of the 
efficacy and safety data, as well as describe the approaches to be taken for summarizing 
other clinical study information such as subject disposition, demographic and baseline 
characteristics, study drug exposure, and prior and concomitant medications. The SAP 
will also include a description of how missing, unused, and spurious data will be 
addressed.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 75
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 75
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical 
analysis and clinical study conclusions. Any deviations from the planned statistical 
analyses in the protocol will be fully described in the SAP.
All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS 
Institute, Cary, NC 27513).
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 76
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 76
12.
DATA INTEGRITY AND QUALITY ASSURANCE
The investigator/investigational site will permit study-related monitoring, audits, IRB/
Independent Ethics Committee (IEC) review, and regulatory inspections by providing 
direct access to source data/documents.  Direct access includes permission to examine, 
analyze, verify, and reproduce any records and reports that are important to the 
evaluation of a clinical study.
12.1.
Monitoring and Inspections
The sponsor or designee’s monitor and regulatory authority inspectors are responsible for 
contacting and visiting the Investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the study (e.g., CRFs, source data, and 
other pertinent documents).
The verification of adherence to the protocol; completeness, accuracy, and consistency of
the data; and adherence to ICH GCP and local regulations on the conduct of clinical 
research will be accomplished through a combination of onsite visits by the monitor and 
review of study data remotely.  The frequency of the monitoring visit will vary based on 
the activity at each study site.  The monitor is responsible for inspecting the CRFs and 
ensuring completeness of the study essential documents.  The monitor should have access 
to subject medical records and other study-related records needed to verify the entries on 
the CRFs.  Detailed information is provided in the monitoring plan.
The monitor will communicate deviations from the protocol, SOPs, GCP and applicable 
regulations to the Investigator and will ensure that appropriate action (s) designed to 
prevent recurrence of the detected deviations is taken and documented.
The Investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are addressed to the satisfaction of the 
sponsor and documented.
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected 
for audit by representatives from the Sponsor.  Audit of study center facilities (e.g.,
pharmacy, drug storage areas, laboratories) and review of study related records will occur 
in order to evaluate the study conduct and compliance with the protocol, ICH GCP, and 
applicable regulatory requirements.  The investigator should respond to audit findings.  
In the event that a regulatory authority informs the investigator that it intends to conduct 
an inspection, the Sponsor shall be notified immediately.
12.2.
Data Collection
All relevant observations and data related to the study, as per the study protocol, will be 
recorded on eCRF pages.  A representative of Daiichi Sankyo or their designee will 
provide instruction for completing the eCRF.  Adequate and accurate case records should 
be maintained, including the evaluation of inclusion and exclusion criteria, medical 
history, physical examinations, clinical assessments, a record of clinical safety laboratory 
sample collection, drug administration, AEs, and final evaluation.  
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 77
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 77
The eCRFs must be completed for each subject who signs the ICF and undergoes 
screening procedures.  For subjects who are screened but not randomized, minimal data
will be recorded on the eCRF, including demography, subject status, and AEs.  All study 
related data for these subjects will be maintained in the medical records at the site.
The eCRF data entry shall be completed on the day of the visit or as soon as possible 
thereafter.  The investigator must electronically sign and date the eCRF.  The signature 
shall indicate that the investigator has reviewed the data and data queries recorded on 
eCRFs and the site notifications, and agrees with the content.  After the completion of the 
study, eCRFs including audit trail will be returned to Daiichi Sankyo and stored in the 
archives.
12.3.
Data Management
Each subject will be identified in the database by a unique SID as defined by the sponsor.
To ensure the quality of clinical data across all subjects and study centers, a Clinical Data 
Management review will be performed on subject data according to specifications given 
to the sponsor or designee.  Data will be vetted both electronically and/or manually for 
CRFs and the data will be electronically vetted by programmed data rules within the 
application.  Queries generated by rules and raised by reviewers will be generated within 
the electronic data capture (EDC) application.  During this review, subject data will be 
checked for consistency, completeness and any apparent discrepancies.  In addition, the 
data will be reviewed for adherence to the protocol and GCP.  For eCRFs, the data will 
be electronically vetted by programmed data rules within the application.  Queries 
generated by rules and raised by reviewers will be generated within the EDC application 
and also resolved within the EDC application.
Data received from external sources such as central labs will be reconciled to the clinical 
database.
Serious Adverse Events in the clinical database will be reconciled with the safety 
database.
All Adverse Events (except terms pre-specified on the eCRF) will be coded using 
MedDRA. All prior and concomitant medications will be coded using WHO Drug 
Dictionary.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 78
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 78
12.4.
Study Documentation and Storage
The Investigator will maintain a Signature List of appropriately qualified persons to 
whom he/she has delegated study duties.  All persons authorized to make entries and/or 
corrections on CRFs will be included on the Signature List.
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical and 
office charts, laboratory and pharmacy records, diaries, microfiches, X-rays, and 
correspondence.
Records of subjects, source documents, monitoring visit logs, data correction forms, 
CRFs, inventory of study drug, regulatory documents (e.g., protocol and amendments, 
IRB/IEC correspondence and approvals, approved and signed informed consent forms, 
Investigator’s Agreement, clinical supplies receipts, distribution and return records), and 
other sponsor correspondence pertaining to the study must be kept in appropriate study 
files at the study center (Trial Master File).  Source documents include all recordings and 
observations or notations of clinical activities and all reports and records necessary for 
the evaluation and reconstruction of the clinical study.  These records will be retained in a 
secure file for the period required by the institution or study center policy.  Prior to 
transfer or destruction of these records, the Sponsor must be notified in writing and be 
given the opportunity to further store such records.
12.5.
Record Keeping
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system (Trial Master File) of all study-related (essential) 
documentation, suitable for inspection at any time by representatives from the Sponsor 
and/or applicable regulatory authorities.  Essential documents include:
!
Subject files containing completed CRFs, informed consent forms, and 
supporting copies of source documentation (if kept).
!
Study files containing the protocol with all amendments, IB, copies of 
relevant essential documents required prior to commencing a clinical study, 
and all correspondence to and from the EC/IRB and the Sponsor.
!
Records related to the study drug(s) including acknowledgment of receipt at 
study center, accountability records and final reconciliation and applicable 
correspondence.
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available.
All essential documentation will be retained by the institution until told otherwise by the 
sponsor.
No study document should be destroyed without prior written agreement between the 
sponsor and the investigator.  Should the investigator wish to assign the study records to 
another party or move them to another location, he/she must notify the sponsor in writing 
of the new responsible person and/or the new location.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 79
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 79
All investigators and site personnel must ensure subject confidentiality as outlined in 
Section 15.2.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 80
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 80
13.
FINANCING AND INSURANCE
13.1.
Finances
Prior to starting the study, the Principal Investigator and/or institution will sign a clinical 
study agreement with the sponsor or designee.  This agreement will include the financial 
information agreed upon by the parties.
13.2.
Reimbursement, Indemnity, and Insurance
The Sponsor provides insurance for study subjects to make available compensation in 
case of study-related injury.
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on 
terms agreed upon by the parties.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 81
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 81
14.
PUBLICATION POLICY
A study center may not publish results of a study until after a coordinated multicenter 
publication has been submitted for publication or until one year after the study has ended, 
whichever occurs first.  Therefore, the study center will have the opportunity to publish 
the results of the study, provided that Daiichi Sankyo has had the opportunity to review 
and comment on the study center’s proposed publication prior to its being submitted for 
publication with the prior advice of Daiichi Sankyo Legal Affairs (intellectual property 
council) and with proper regard to the protection of subjects’ identities.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 82
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 82
15.
ETHICS AND STUDY ADMINISTRATIVE INFORMATION
15.1.
Compliance Statement, Ethics and Regulatory Compliance
This study will be conducted in compliance with the protocol, the ethical principles that 
have their origin in the Declaration of Helsinki, the ICH consolidated Guideline E6 for 
Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory 
requirement(s) including the following:
!
US Food and Drug Administration (FDA) GCP Regulations: Code of Federal 
Regulations (CFR) Title 21, parts 11, 50, 54, 56 and 312 as appropriate 
and/or;
!
Other applicable local regulations.
15.2.
Subject Confidentiality
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking 
part in the study, in accordance with GCP and local regulations.
The Investigator must ensure that the subject’s anonymity is maintained.  On the CRFs or 
other documents submitted to the Sponsor or the CRO, subjects should be identified by a 
unique SID as designated by the Sponsor.  Documents that are not for submission to the 
Sponsor or the CRO (e.g., signed ICF) should be kept in strict confidence by the 
Investigator.
In compliance with ICH GCP Guidelines, it is required that the Investigator and 
institution permit authorized representatives of the company, of the regulatory agency(s), 
and the IRB/EC direct access to review the subject’s original medical records for 
verification of study-related procedures and data.  The Investigator is obligated to inform 
the subject that his/her study-related records will be reviewed by the above named 
representatives without violating the confidentiality of the subject.
15.3.
Informed Consent 
Before a subject’s participation in the study, it is the Investigator’s responsibility to 
obtain freely given consent, in writing, from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific procedures or any study drugs are administered.  Subjects should be 
given the opportunity to ask questions and receive satisfactory answers to their inquiries, 
and should have adequate time to decide whether or not to participate in the study.  The 
written ICF should be prepared in the local language(s) of the potential subject 
population.
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki.  The consent form and any 
revision(s) should be approved by the EC or IRB prior to being provided to potential 
subjects.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 83
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 83
The subject’s written informed consent should be documented in the subject’s medical 
records.  The ICF should be signed and personally dated by the subject and by the person 
who conducted the informed consent discussion (not necessarily the Investigator).  The 
original signed ICF should be retained in accordance with institutional policy, and a copy 
of the signed consent form should be provided to the subject.  The date and time (if 
applicable) that informed consent was given should be recorded on the CRF.
Suggested model text for the ICF for the study and any applicable subparts (genomic, PK, 
etc.) are provided in the Sponsor’s ICF template for the Investigator to prepare the 
documents to be used at his or her study center.  Updates to applicable forms will be 
communicated via letter from the Sponsor.
For studies in the US, an additional consent is required for the Health Insurance 
Portability and Accountability Act (HIPAA).  Also, a separate special consent will be 
required for Pharmacogenomic testing for this protocol.
15.4.
Regulatory Compliance
The study protocol, subject information and consent form, the Investigator Brochure, any 
subject written instructions to be given to the subject, available safety information, 
subject recruitment procedures (e.g., advertisements), information about payments and 
compensation available to the subjects, and documentation evidencing the Investigator’s 
qualifications should be submitted to the EC or IRB for ethical review and approval 
according to local regulations, prior to the study start.  The written approval should 
identify all documents reviewed by name and version.
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP.
The Investigator must submit and, where necessary, obtain approval from the EC or IRB 
for all subsequent protocol amendments and changes to the ICF.  The Investigator should 
notify the EC or IRB of deviations from the protocol or SAEs occurring at the study 
center and other AE reports received from the Sponsor/CRO, in accordance with local 
procedures.
As required by local regulations, the Sponsor’s local Regulatory Affairs group or 
representative to whom this responsibility has been delegated will ensure all legal aspects 
are covered, and approval from the appropriate regulatory bodies obtained, prior to study 
initiation, and that implementation of changes to the initial protocol and other relevant 
study documents happen only after approval by the relevant regulatory bodies.
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable
Regulatory Authorities in any area of the world, or if the investigator is aware of any new
information which might influence the evaluation of the benefits and risks of the
investigational drug, the Sponsor should be informed immediately.  
In addition, the investigator will inform the Sponsor immediately of any urgent safety 
measures taken by the investigator to protect the study subjects against any immediate 
hazard, and of any suspected/actual serious GCP non-compliance that the investigator 
becomes aware of.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 84
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 84
15.5.
Protocol Deviations
The investigator should conduct the study in compliance with the protocol agreed to by 
Sponsor and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the IRBs/ECs.
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed 
in this study except where necessary to eliminate immediate hazard(s) to the subject.  
Sponsor must be notified of all intended or unintended deviations to the protocol (e.g.,
inclusion/exclusion criteria, dosing, missed study visits) on an expedited basis.
The investigator, or person designated by the investigator, should document and explain 
any deviation from the approved protocol.
If a subject was ineligible or received the incorrect dose or study treatment, and had at 
least 1 administration of study drug, data should be collected for safety purposes.
If applicable, the Investigator should notify the IRB/IEC of deviations from the protocol 
in accordance with local procedures.
15.6.
Supply of New Information Affecting the Conduct of the Study
When new information becomes available that may adversely affect the safety of subjects 
or the conduct of the study, the Sponsor will inform all Investigators involved in the 
clinical study, ECs/IRBs, and regulatory authorities of such information, and when 
needed, will amend the protocol and/or subject information.
The Investigator should immediately inform the subject whenever new information 
becomes available that may be relevant to the subject’s consent or may influence the 
subject’s willingness to continue participation in the study.  The communication should 
be documented on medical records, for example, and it should be confirmed whether the 
subject is willing to remain in the study.
If the subject information is revised, it must be re-approved by the IEC/IRB.  The 
Investigator should obtain written informed consent to continue participation with the 
revised written information even if subjects were already informed of the relevant 
information.  The Investigator or other responsible personnel who provided explanations 
and the subject should sign and date the revised ICF.
15.7.
Protocol Amendments
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be communicated to the Investigator by Daiichi Sankyo or the CRO.  
Also, the Sponsor will ensure the timely submission of amendments to regulatory 
authorities.
A global protocol amendment will affect study conduct at all study centers in all regions 
of the world.  Such amendments will be incorporated into a revised protocol document.  
Changes made by such amendments will be documented in a Summary of Changes 
document.  These protocol amendments will undergo the same review and approval 
process as the original protocol.  
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 85
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 85
A local protocol amendment will affect study conduct at a particular study center(s) 
and/or in a particular region/country.  Sponsor approval of local amendments will be 
clearly documented.
A protocol amendment may be implemented after it has been approved by the IRB/EC 
and by regulatory authorities where appropriate, unless immediate implementation of the 
change is necessary for subject safety.
15.8.
Study Termination
Circumstances under which the study may be stopped based upon independent Data and 
Safety Monitoring Board (DSMB) recommendation are specified in Section 15.9.  In 
addition, the study may be terminated at any time at the sponsor’s discretion.   
15.9.
Data and Safety Monitoring Board
Not applicable.
15.10.
Address List
A list of key study personnel (including personnel at the sponsor, CRO, laboratories, and 
other vendors) and their contact information (address, telephone, fax, email) will be kept 
on file and updated in the Study Operations Manual.
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 86
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 86
16.
REFERENCES
1. International Diabetes Federation. IDF Diabetes Atlas, sixth edition; 2013.
2. Soga T, Ohishi T, Matsui T, et al. Lysophosphatidylcholine enhances glucose-
dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem 
Biophys Res Commun. 2005;326(4):744-51. Erratum in: Biochem Biophys Res 
Commun. 2005;329(1):417.
3. Chu ZL, Carroll C, Alfonso J, et al. A role for intestinal endocrine cell-expressed 
G protein-coupled receptor 119 in glycemic control by enhancing glucagon-like 
peptide-1 and glucose-dependent insulinotropic Peptide release. Endocrinology. 
2008;149(5):2038-47.
4.
Chu ZL, Jones RM, He H, et al. A role for beta-cell-expressed G protein-coupled 
receptor 119 in glycemic control by enhancing glucose-dependent insulin release. 
Endocrinology. 2007; 148 (6):2601-9
5. Yoshida S, Ohishi T, Matsui T, et al. The role of small molecule GPR119 agonist, 
AS1535907, in glucose-stimulated insulin secretion and pancreatic β-cell function. 
Diabetes Obes Metab. 2011;13(1):34-41
6. American Diabetes Association. Classification and diagnosis of diabetes. Sec. 2. 
In Standards of Medical Care in Diabetes 2015. Diabetes Care 2015;38(Suppl. 
1):S8–S16
7. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of 
a workgroup of the American Diabetes Association and the Endocrine Society. J 
Clin Endocrinol Metab. 2013 May;98(5):1845-59. 
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 87
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 87
17.
APPENDICES
17.1.
Cockcroft-Gault Equation
The estimated creatinine clearance rate (CrCl; mL/min) will be calculated using the 
Cockcroft-Gault equation based on weight kilograms (1 kilogram = 2.2 pounds):
Conventional  units – serum creatinine in mg/dL:
Male:
CrCl (mL/min) = 
Female:
CrCl (mL/min) = 
# 0.85
International System of Units (SI) – serum creatinine in μmol/L:
Male:
CrCl (mL/min) = 
Female:
CrCl (mL/min) = 
# 0.85
Source:
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16(1):31-41.
72
 x 
mg/dL)
(in 
creatinine
serum
kg)
(in 
 x weight 
years)]
(in 
age
-
[140
72
 x 
mg/dL)
(in 
creatinine
serum
kg)
(in 
 x weight 
years)]
(in 
age
-
[140
72
 x 
mg/dL)
(in 
creatinine
serum
kg)
(in 
 x weight 
years)]
(in 
age
-
[140
72
 x 
mg/dL)
(in 
creatinine
serum
kg)
(in 
 x weight 
years)]
(in 
age
-
[140
0.0113
 x 
72
 x 
mol/L)
(in 
creatinine
serum
kg)
(in 
 x weight 
years)]
(in 
age
-
[140
∃
0.0113
 x 
72
 x 
mol/L)
(in 
creatinine
serum
kg)
(in 
 x weight 
years)]
(in 
age
-
[140
∃
0.0113
 x 
72
 x 
mol/L)
(in 
creatinine
serum
kg)
(in 
 x weight 
years)]
(in 
age
-
[140
∃
0.0113
 x 
72
 x 
mol/L)
(in 
creatinine
serum
kg)
(in 
 x weight 
years)]
(in 
age
-
[140
∃
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 88
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 88
17.2.
Schedule of Events
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 89
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 89
Table 17.1:
Schedule of Events
Screening*
Lead-in
Randomization
Treatment
End-of-treatment/
Early Termination
Follow-Up
Visit number
1
2
3
4
5
6
7
8
Week number
-4 to -3
-2
0
2
4
8
12 or ET
14
Days
-14
1
14
28
56
84
98
Visit Window (days))
±3
±3
±3
±3
±3
±3
±3
Signed informed consent
X
Inclusion/exclusion criteria
X
X
X
Demographic information, medical/surgical history
X
Height a Vital signs and weight
X
X
X
X
X
X
X
X
Full b physical examination assessment
X
X
Targeted c physical examination  assessment
X
X
X
X
X
X
Electrocardiogram(s) (12-lead)
X
X
X
Pregnancy test (if WOCBP) d
X
X
X
X
X
X
X
X
TSH and serum FSH screening e
X
HbA1c 
X
X
X
X
X
FPG 
X
X
X
X
X
X
Lipid panel 
X
X
X
X
C-peptide 
X
Safety laboratory (Chemistry, Hematology f)
X
X
X
X
X
X
X g
Urinalysis: dipstick and microscopy
X
X
X g
Pharmacokinetics sampling h
X
X
X
X
X
MMTT
X
X
X
Adverse events 
X
X
X
X
X
X
X
Concomitant medications 
X
X
X
X
X
X
X
Dispense blood glucose meter and study diary
X
Review glucose meter reading and study diary i
X
X
X
X
X
Contact IXRS  
X
X
X
X
X
X
Study Drug dispensing
X
X
X
X
Drug adherence check
X
X
X
X
X
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 90
Proprietary and Confidential


Protocol DS8500-A-U202
Version 1.0, 28 OCT 2015
Proprietary and Confidential
Page 90
a Height measured only at Screening Visit.
b Includes head, neck, thyroid, eyes, ears, nose, throat, chest, lungs, heart, lymph nodes, abdomen, skin, extremities, musculoskeletal and neurological 
(see Section 9.12).
c Includes lungs, heart, and as needed examination (see Section 9.12).
d All WOCBP subjects must have a negative serum pregnancy test (βhCG) at the Screening Visit (Visit 1). Urine pregnancy tests will be conducted at 
all other clinic visits through the Follow-up clinic visit (Visits 2-8) for all WOCBP subjects. If a urine test result is positive, a serum pregnancy test 
will be performed to confirm the result. (see Section 4.3). 
e Screen serum FSH in postmenopausal women who are not surgically sterile (see Section 4.3). TSH = Thyroid-stimulating hormone; FSH = follicle 
stimulating hormone.
f CBC and reticulocytes counts will be measured at each visit. (see Section 9.8.1).
g Repeat any abnormal results from prior visit.
h Visits 3, 4, and 6 - Trough levels (time 0) only. Visits 5 and 7, - 3h sampling during the MMTT (see Section 8.1).
i Subjects should record exact time of morning medication doses and SMBG in the study diary and bring study diary to randomization and all treatment 
visits (Visit 3 to Visit 7). 
* Rescreening of subjects will not be permitted. If laboratory test is failed due to technological error, the test would be repeated.  
Clinical Study Report DS8500-A-U202
Version 1.0, 30 Aug 2017
16.1.1 Protocol and Amendments
Page 91
Proprietary and Confidential