Clinical trial NCT02715258
Conditions: Type 2 Diabetes Mellitus
Sponsor: Theracos
Start date: 2016-03-01; Completion date: 2017-04-01
Enrollment: 210 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the effect of bexagliflozin in lowering hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM).

Detailed description:
This was a phase 3, multi-center, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of once daily oral administration of bexagliflozin tablets, 20 mg or placebo tablets, in male and female subjects with T2DM who were treatment-naïve or previously treated with 1 oral hypoglycemic agent (OHA).

Prospective subjects being treated with one OHA were eligible if they had an HbA1c between 6.5% and 10.0% and were willing to complete a 6-week washout. Individuals taking thiazolidinediones were not eligible for the study. All eligible subjects were to start a 2-week placebo run-in period. Subjects who missed no more than 1 dose of the run-in medication, had fasting blood glucose values ≥ 250 mg/dL on no more than two consecutive days, and had an HbA1c level between 7.0% and 10.5% and a fasting glucose level \< 250 mg/dL after the run-in period were eligible for randomization.

Two hundred and ten (210) subjects were planned to be randomly assigned to receive oral bexagliflozin tablets, 20 mg or placebo, in a 2:1 ratio once daily for 24 weeks. Subjects with uncontrolled hyperglycemia based on blood glucose levels could receive additional approved anti-diabetic medications. Treatment group assignment at the start of the treatment period was stratified by baseline HbA1c level and background anti-diabetes treatment status (treatment naïve or not).

Each subject was contacted by telephone at week 2 and was instructed to return to the clinic at weeks 6, 12, 18, and 24 for efficacy assessment and safety monitoring. Subjects returned to the clinic for a follow-up visit at week 26 or 2 weeks after the last dose of investigational product if the subject terminated prior to week 24.

Arms: arm 1: Each subject will self-administer bexagliflozin tablets once daily for 24 weeks. arm 2: Each subject will self-administer placebo (inactive tablet) once daily for 24 weeks.
Interventions: intervention 1: Bexagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: tablets containing 20 mg bexagliflozin intervention 2: tablets matching the appearance of bexagliflozin tablets

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol:  
Study Title: 
A multi-center, randomized, double-blind, placebo-controlled, parallel 
group study to compare the efficacy and safety of bexagliflozin to 
placebo in subjects with type 2 diabetes mellitus and inadequate 
glycemic control 
Study Number: 
 
Study Phase: 
3 
Product Name: 
Bexagliflozin Tablets 
Indication: 
Type 2 Diabetes Mellitus 
Investigators: 
Multiple center 
Sponsor: 
Theracos Sub, LLC 
Sponsor Contact: 
Adrian Banerji   
Translational Medicine Group 
Massachusetts General Hospital 
185 Cambridge Street, Boston, MA 02114 
Phone: 617-643-9925 
Fax: 617-643-8203 
E-mail: abanerji@ccib.mgh.harvard.edu 
Medical Monitor: John Paul Lock MD 
Theracos Sub, LLC 
225 Cedar Hill Road, Suite 200, Marlborough, MA 01752 
Phone: 508-735-9491 
Fax: 617-643-8203 
E-mail: JPLock@theracos.com 
 
 
 
Date 
Version 4.0 
04 April 2017 
 
Confidentiality Statement 
The information contained in this protocol is confidential and provided only to the 
investigators, clinical study collaborators, investigational drug managers, study sites and 
institutional review boards participating in the study. The information may, therefore, not be 
disclosed to any third party except for subjects when receiving their consent, or used for 
purposes other than this study without the written consent of Theracos Sub, LLC.   


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................6 
LIST OF ABBREVIATIONS ..................................................................................................10 
1 
INTRODUCTION ...........................................................................................................13 
1.1 
Bexagliflozin for the treatment of type 2 diabetes mellitus ...................................13 
2 
STUDY OBJECTIVES ....................................................................................................15 
2.1 
Primary Efficacy Objective ....................................................................................15 
2.2 
Secondary Efficacy Objectives ..............................................................................15 
2.3 
Safety Objectives ...................................................................................................15 
3 
INVESTIGATIONAL PLAN ..........................................................................................16 
3.1 
Overall Study Design and Plan ..............................................................................16 
3.2 
Research Methods and Procedures ........................................................................16 
3.2.1 
Wash-out and Run-in Period ........................................................................16 
3.2.2 
Treatment Period ..........................................................................................17 
3.2.3 
Glycemic Control Monitoring......................................................................18 
3.2.3.1 
Washout Period ..................................................................................18 
3.2.3.2 
Placebo Run-in Period .......................................................................18 
3.2.3.3 
Main Treatment ..................................................................................19 
3.2.3.4 
Prescription of Rescue Medication ....................................................19 
3.2.4 
OTHER SAFETY MONITORING ACTIVITIES ......................................20 
3.3 
Rationale for Study Design and Dose Selection ....................................................20 
3.3.1 
Rational for Study Design and Control Group ............................................20 
3.3.2 
Rational for Dose Selection .........................................................................21 
3.4 
Study Duration and Dates ......................................................................................21 
4 
STUDY POPULATION SELECTION ...........................................................................23 
4.1 
Study Population ....................................................................................................23 
4.2 
Inclusion Criteria ...................................................................................................23 
4.3 
Exclusion Criteria ..................................................................................................24 
5 
STUDY TREATMENT(S) ..............................................................................................25 
5.1 
Description of Treatment(s) ...................................................................................25 
5.1.1 
Investigational Product ................................................................................25 
5.2 
Treatments Administered .......................................................................................25 
5.3 
Selection and Timing of Dose for Each Subject ....................................................25 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................25 
5.5 
Blinding..................................................................................................................26 
5.6 
Concomitant Therapy.............................................................................................26 
5.7 
Restrictions ............................................................................................................27 
5.7.1 
Prior Therapy ...............................................................................................27 


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5.7.2 
Fluid and Food Intake ..................................................................................27 
5.7.3 
Subject Activity Restrictions .......................................................................27 
5.8 
Treatment Compliance ...........................................................................................28 
5.9 
Packaging and Labeling .........................................................................................28 
5.10 
Storage and Accountability ....................................................................................29 
5.11 
Investigational Product Retention at Study Site ....................................................29 
6 
STUDY PROCEDURES .................................................................................................30 
6.1 
Informed Consent...................................................................................................30 
6.2 
Screening or Confirmation for I/E Criteria ............................................................30 
6.3 
Medical History .....................................................................................................30 
6.3.1 
General Demographics and Characteristics .................................................30 
6.3.2 
Diabetes History...........................................................................................30 
6.3.3 
Cardiovascular Disease History ...................................................................31 
6.3.4 
Medication History ......................................................................................31 
6.4 
Diet and Exercise Counseling ................................................................................31 
6.5 
Physical Examination.............................................................................................31 
6.6 
Abbreviated Physical Examination ........................................................................31 
6.7 
Vital Signs ..............................................................................................................32 
6.8 
Electrocardiography ...............................................................................................32 
6.9 
Clinical Laboratory Tests .......................................................................................33 
6.9.1 
Laboratory Parameters .................................................................................33 
6.9.2 
Sample Collection, Storage, and Shipping ..................................................33 
6.9.2.1 
Hematology, Blood Chemistry, Serum Lipids, and Glycemic 
Control Assessments ..........................................................................33 
6.9.2.2 
Urinalysis ...........................................................................................33 
6.9.2.3 
Urine Pregnancy Test (UPT) .............................................................34 
6.10 
Diary and Glucometer Dispensation and Review ..................................................36 
6.11 
Dispensing Run-in Drug ........................................................................................36 
6.12 
Dispensing Investigational Product .......................................................................36 
6.13 
Adverse Events Assessments .................................................................................36 
6.13.1 
Definition of Adverse Events.......................................................................36 
6.13.2 
Eliciting and Reporting AEs ........................................................................38 
6.13.3 
Immediately Reportable AEs .......................................................................39 
6.13.4 
Pregnancy .....................................................................................................39 
6.13.5 
Procedure for Breaking the Blind ................................................................40 
6.13.6 
Follow-up of Non-Serious AEs ...................................................................40 
6.13.7 
Follow-up of Post-Study SAEs ....................................................................40 
6.13.8 
Urinary Tract Infections (UTIs) ...................................................................41 
6.13.9 
Genital Mycotic Infections (GMIs) .............................................................41 


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6.13.10 Hepatotoxicity ..............................................................................................41 
6.13.11 Hypoglycemia ..............................................................................................42 
6.13.12 Diabetic Ketoacidosis (DKA) ......................................................................44 
6.13.13 Major Adverse Cardiovascular Event (MACE) ...........................................44 
6.13.14 Amputation ..................................................................................................45 
6.14 
Concomitant Medication Assessments ..................................................................45 
7 
STUDY ACTIVITIES .....................................................................................................46 
7.1 
V1 (Screening Visit (up to Week -11) ...................................................................46 
7.2 
V2 (Beginning of washout for OHA subjects) (Week -8) .....................................46 
7.3 
V3 (Phone interview for washout OHA subjects) (Week -6) ................................46 
7.4 
V4 (Beginning of run in) (Week -2) ......................................................................46 
7.5 
V5 (Baseline Visit) (Day -3 to -5) .........................................................................47 
7.6 
V6 (Randomization Visit) (Week 0) ......................................................................47 
7.7 
V7 (Phone Interview) (Week 2) .............................................................................47 
7.8 
V8 (Treatment Visit) (Week 6) ..............................................................................47 
7.9 
V9 (Treatment Visit) (Week 12) ............................................................................48 
7.10 
V10 (Treatment Visit) (Week 18) ..........................................................................48 
7.11 
V11 (Treatment Visit) (Week 24) ..........................................................................48 
7.12 
V12 (Follow Up Visit) (Week 26) .........................................................................48 
7.13 
Early Termination Procedures ...............................................................................49 
8 
QUALITY CONTROL AND ASSURANCE .................................................................50 
9 
PLANNED STATISTICAL METHODS ........................................................................51 
9.1 
General Considerations ..........................................................................................51 
9.1.1 
Multiple Comparisons / Multiplicity ...........................................................51 
9.2 
Determination of Sample Size ...............................................................................51 
9.3 
Analysis Populations ..............................................................................................52 
9.3.1 
Intention to Treat Analysis Set ....................................................................52 
9.3.2 
Safety Analysis Set ......................................................................................52 
9.3.3 
Per Protocol Analysis Set.............................................................................52 
9.4 
Demographics and Baseline Characteristics ..........................................................52 
9.5 
Primary Efficacy Analysis .....................................................................................52 
9.5.1 
Primary Efficacy Endpoint ..........................................................................52 
9.5.2 
Handling Dropouts and Missing Data..........................................................53 
9.6 
Secondary Efficacy Endpoints ...............................................................................54 
9.6.1 
Key secondary Efficacy Endpoints ..............................................................54 
9.6.2 
Exploratory Efficacy Endpoints ...................................................................54 
9.7 
Analysis of Safety ..................................................................................................55 
9.7.1 
Adverse Events ............................................................................................55 


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9.7.2 
Adverse Events of Special Interest ..............................................................55 
9.7.3 
Clinical and Laboratory Events and Analyses .............................................56 
9.7.4 
Physical Examination...................................................................................56 
9.7.5 
Concomitant Medications ............................................................................56 
9.8 
Interim Analysis .....................................................................................................56 
9.9 
Final Analysis ........................................................................................................56 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................57 
10.1 
Investigators and Study Administrative Structure .................................................57 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................57 
10.3 
Ethical Conduct of the Study .................................................................................57 
10.4 
Subject Information and Consent...........................................................................58 
10.5 
Subject Confidentiality ..........................................................................................58 
10.6 
Study Monitoring ...................................................................................................59 
10.7 
Case Report Forms and Study Records .................................................................59 
10.8 
Data Monitoring Committee ..................................................................................59 
10.9 
Protocol Violations/Deviations ..............................................................................59 
10.10 Access to Source Documentation ..........................................................................60 
10.11 Retention of Data ...................................................................................................60 
10.12 Publication and Disclosure Policy .........................................................................60 
11 REFERENCE LIST .........................................................................................................61 
 
LIST OF IN-TEXT TABLES 
Table 1 List of Laboratory Tests ........................................................................................35 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................62 
Appendix 2 
Schedule of  Laboratory Tests ...........................................................63 
Appendix 3 
Sponsor Signatures.............................................................................64 
Appendix 4 
Investigator’s Signature .....................................................................65 
 
 


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SYNOPSIS 
Sponsor: 
Theracos Sub, LLC 
Name of Finished Product: 
Bexagliflozin Tablets  
Name of Active Ingredient: 
Bexagliflozin 
Study Title: 
A multi-center, randomized, double-blind, placebo-controlled, parallel group study to 
compare the efficacy and safety of bexagliflozin to placebo in subjects with type 2 diabetes 
mellitus and inadequate glycemic control  
Study Number: 
 
Study Phase: 3 
Primary Objective:  
To determine the placebo-adjusted treatment effect of bexagliflozin tablets, 20 mg on the 
change in HbA1c from baseline to week 24 in subjects with type 2 diabetes mellitus and 
inadequate glycemic control. 
Key Secondary Objectives: 
• To assess the effect of bexagliflozin on systolic blood pressure compared to placebo 
• To assess the effect of bexagliflozin on body weight in subjects with a baseline BMI 
 ≥ 25 kg/m2 compared to placebo 
Exploratory Secondary Objectives 
• To compare the effect of bexagliflozin to the effect of placebo on the proportion of 
subjects with HbA1c of < 7%  
• To compare the effect of bexagliflozin to the effect of placebo on change in HbA1c over 
time 
To compare the effect of bexagliflozin to the effect of placebo on FPG over time 
Safety Objectives: 
• To assess the safety of bexagliflozin in subjects with T2DM 
• To assess the effect of bexagliflozin on the incidence of AE of special interest 
• To contribute MACE+ events to an eventual meta-analysis that is intended to exclude a 
hazard ratio of 1.8 or greater for subjects exposed to bexagliflozin compared to subjects 
exposed to placebo or comparator treatment 
 


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Study Design:  
THR-1442-C-450 is a phase 3, multi-center, randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the efficacy and safety of once daily oral administration of 
bexagliflozin tablets, 20 mg versus placebo, in subjects with T2DM who are treatment-naïve 
or previously treated with one oral hypoglycemic agent (OHA). 
The study will enroll male or female subjects with T2DM. If treatment naïve, they must have 
an HbA1c at the screening visit of between 7% and 10.5%. Alternatively, prospective 
subjects may be eligible if at the time of the screening visit they are being treated with one 
OHA, have an HbA1c of between 6.5% and 10.0% and are willing to complete a 6-week 
washout. Individuals taking thiazolidinediones are not eligible for the study. A candidate will 
be considered treatment-naïve if he or she has received no more than 14 days of prescription 
medication for diabetes in the 12 weeks prior to screening.  
All eligible subjects will start a 2 week placebo run-in period.  Subjects who miss no more 
than one dose of the run-in medication, have fasting blood glucose values ≥ 250 mg/dL on no 
more than two consecutive days, and who, at the baseline visit (Visit V5), have an HbA1c 
level between 7 and 10.5% and a fasting glucose level < 250 mg/dL will be eligible for 
randomization. 
Approximately 210 subjects will be randomly assigned to receive oral bexagliflozin tablets, 
20 mg or placebo, in a 2:1 ratio once daily for 24 weeks in an out-patient setting.  Subjects 
with uncontrolled hyperglycemia based on blood glucose levels may receive additional 
approved anti-diabetic medications.  Treatment group assignment at the start of the treatment 
period will be stratified by baseline (Visit V5) HbA1c level (7.0 to 8.5% or 8.6 to 10.5%) and 
background anti-diabetes treatment status (treatment naïve or not).  
Each subject will be contacted by telephone at week 2 (Visit V7) for safety monitoring and 
will be instructed to return to the clinic at weeks 6, 12, 18, and 24 (Visits V8, V9, V10, V11, 
respectively) for efficacy assessment and safety monitoring. Subjects will return to the clinic 
for a follow-up visit at week 26 or two weeks after the last dose of investigational product if 
the subject terminates prior to week 24 (Visit V12). 
Study Population and main eligibility criteria: 
Approximately 210 subjects are planned for this study. The study will enroll: 
1. Male or female adult subjects ≥ 18 years of age at screening.  
2. Subjects with T2DM who are treatment naïve or receiving one OHA in combination with 
diet and exercise. Subjects taking thiazolidinediones are not eligible. 
3. Subjects with HbA1c levels at screening (Visit V1) between 7.0% and 10.5% (inclusive) 
if treatment-naïve or with HbA1c levels between 6.5 and 10.0% (inclusive) if on one 
OHA 
4. Subjects with a body mass index (BMI) ≤ 45 kg/m2 
5. Subjects with a fasting plasma glucose < 250 mg/dL (13.9 mmol/L) at baseline (Visit V5) 
Test Product, Dose, and Mode of Administration:  
Bexagliflozin tablets, 20 mg or placebo, administered orally once daily 


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Duration of Treatment:  
24 weeks 
Efficacy Assessments:  
The primary efficacy measure will be the change in HbA1c from baseline to week 24. 
The key secondary measures will be the changes from baseline to week 24 of systolic blood 
pressure and body weight. The exploratory secondary measures will be the change from 
baseline of the fasting plasma glucose concentration over time, the change from baseline of 
HbA1c over time, and the proportion of subjects who achieve an HbA1c < 7% over time. 
Safety Assessments:  
The safety of bexagliflozin will be assessed over the 24-week treatment phase. Adverse 
events (AEs) of special interest include genital and urinary tract infections, diuretic effects, 
hepatotoxicity, MACE, hypoglycemia, fractures, malignancy, hypersensitivity reactions, 
hypotensive episodes, acid-base disorders, renal failure events, and amputations.  
Statistical Methods:  
Data summaries will report descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], Q1, median, Q3, minimum, and maximum for continuous variables, and 
frequency and percentage for categorical and ordinal variables.  If there are missing values, 
the number missing will be presented, but without a percentage.  All data collected will be 
included in by-subject data listings.  
The primary efficacy hypothesis is that bexagliflozin reduces HbA1c after 24 weeks of 
treatment when compared to placebo. The analysis of the change in HbA1c at week 24 will 
be based on ITT Analysis Set using all observed data and a mixed model repeated measures 
(MMRM) approach that will include terms for treatment, visit, treatment-by-visit interaction 
and randomization stratification factors as fixed effects and the baseline HbA1c value as a 
fixed effect covariate. Least squares mean treatment differences between the bexagliflozin 
group and the placebo group at week 24 will be estimated from the model with the 
corresponding p-values and their two-sided 95% CI presented. An unstructured covariance 
will be used to model the within-subject correlation. If the model with the unstructured 
covariance structure does not converge, an autoregressive(1) covariance structure will be 
used. HbA1c values obtained after the start of rescue medication will not be excluded from 
the analysis. 
The MMRM model is one approach to obtain treatment effect estimates in the presence of 
missing data. As sensitivity analyses for missing data, the following will be performed on the 
ITT analysis set: 
1. Missing HbA1c data will be imputed via multiple imputations, following which the 
MMRM will be repeated on the complete datasets with results combined across complete 
datasets using standard MI techniques; HbA1c values collected after the start of rescue 
medication will not be excluded from the analysis. 
2. HbA1c values collected after the start of rescue medication will be excluded (considered 
missing), and the MMRM analyses will be re-performed. 
3. A last observation carried forward (LOCF) method will then be used to impute the 
missing observations prior to carrying out the MMRM model. 
The effect of bexagliflozin on body weight and systolic blood pressure will be tested as key 


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secondary efficacy endpoints and will be analyzed in a hierarchical testing strategy only if 
the primary objective is met. ANCOVA models will also be used for the continuous 
secondary endpoints analyses.  Longitudinal data will be evaluated through repeated 
measures tests. A hierarchical testing in the following order will be applied to preserve 
experiment-wide alpha at 0.05 in the case each successive determination meets significance: 
1. To test the hypothesis that bexagliflozin reduces systolic blood pressure from baseline to 
week 24 compared with placebo 
2. To test the hypothesis that bexagliflozin reduces body weight from baseline to week 24 
compared with placebo in subjects with a BMI ≥ 25 kg/m2 
The effect of bexagliflozin on fasting plasma glucose, on the proportion of subjects reaching 
< 7.0% HbA1c, and on the change in HbA1c over time will be analyzed as exploratory 
efficacy endpoints and will not be adjusted for multiplicity.  
Safety data will include AEs, physical exam results, vital signs, ECG results, and clinical lab 
results including serum chemistry, hematology, serum lipids, glycemic control parameters 
and urinalysis. The general safety of bexagliflozin in subjects with type 2 diabetes mellitus 
will be analyzed as well as the contribution of bexagliflozin to AEs of special interest. 
For the primary efficacy endpoint, a power calculation was performed for significance 
calculated by a two group t-test with a two-sided α of 0.05. Taking the standard deviation for 
the change in HbA1c to be 1%, a sample size of 128 in the bexagliflozin group and 64 in the 
placebo group is predicted to have 90% power to detect a difference between groups of 0.5% 
in mean HbA1c change. To account for an estimated drop-out rate of approximately 10%, a 
study design was adopted in which 140 subjects are planned to be randomized to the 
bexagliflozin group and 70 subjects to the placebo group.  Statistical analyses and summaries 
will be performed using SAS® software (SAS Institute, Cary, NC).   


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LIST OF ABBREVIATIONS  
ADA 
American Diabetes Association 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALB 
albumin 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase  
ATC 
anatomic therapeutic chemical 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Ca 
calcium 
CEC 
Cardiovascular Endpoint Committee 
ConMed 
concomitant medicines 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cl 
chloride 
CRF 
case report form 
CRO 
contract research organization 
CV 
cardiovascular 
DKA 
diabetic ketoacidosis 
dL 
deciliter 
DPP4 
dipeptidyl peptidase-4 
DSMB 
data and safety monitoring board 
ECG 
electrocardiogram 
eGFR 
estimating glomerular filtration rate 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
GMI 
genital mycotic infection 
GLP-1 
glucagon-like peptide-1 
GGT 
gamma glutamyl transferase 
GMI 
genital mycotic infection 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
Hct 
hematocrit 
HDL-C 
high density lipoprotein cholesterol 
Hgb 
hemoglobin 


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HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization  
IEC 
independent ethics committee 
IRAE 
immediately reportable adverse event 
IRB 
Institutional Review Board 
ITT 
intention to treat 
IWRS 
Interactive Web Response System (IWRS) 
K 
potassium 
LDL-C 
low density lipoprotein cholesterol 
LOCF 
last observation carried forward 
MACE 
major adverse cardiovascular event 
MCH 
mean cell hemoglobin  
MCHC 
mean cell hematocrit 
MCV 
mean cell volume 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model repeated measurement 
mg 
milligram 
MI 
myocardial infarction 
mL 
milliliter 
Na 
sodium 
NYHA 
New York Heart Association 
OHA 
oral hypoglycemic agent 
PR 
time from the beginning of the P wave to the beginning of the QRS 
complex in electrocardiogram 
QRS 
graphical deflections corresponding to ventricular depolarization in a 
typical electrocardiogram 
QTC 
time between the start of the Q wave and the end of the T wave in the 
ECG, corrected for heart rate 
RBC 
red blood cell  
RR 
time between the start of one R wave and the start of the next R wave in 
the ECG 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SGLT2 
sodium glucose linked transporter 2 
SMBG 
self-monitored blood glucose 
SUSAR 
serious and unexpected suspected adverse reaction 
T2DM 
type 2 diabetes mellitus 


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TC 
total cholesterol 
TEAEs 
treatment emergent adverse events 
TG 
triglycerides 
UACR 
urine albumin to creatinine ratio 
UADR 
unexpected adverse drug reaction 
UGE 
urine glucose excretion 
UPT 
urine pregnancy test 
UTI 
urinary tract infection 
WBC 
white blood cell  
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of childbearing potential 


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1 
INTRODUCTION 
T2DM is the predominant form of diabetes and accounts for at least 90% of all diabetes 
cases, which is characterized by insulin resistance and relative or absolute insulin 
insufficiency. Despite the availability of several classes of therapeutics, the number of people 
with diabetes is projected to increase by nearly 55% to over 642 million adults by 2040 (IDF 
2015).  Among the debilitating consequences of T2DM are peripheral neuropathy, 
retinopathy, renal failure, peripheral ischemia and exacerbations of cardiovascular disease, 
which result in blindness, amputation, dialysis and death. 
T2DM is a disease strongly linked to increased body fat mass in the majority of cases 
(Schwartz, Fabricatore et al. 2012). Weight loss has been shown to improve glycemic control 
and to reduce the severity of diabetes-associated comorbidities, supporting the view that anti-
diabetic agents that promote weight loss may be particularly beneficial for the treatment of 
the disease (Look, Wing et al. 2013; Scheen and Van Gaal 2014).Several classes of agents 
are available for treating T2DM, including insulin and its secretagogues, PPARγ agonists, 
biguanides, alpha glucosidase inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, 
sulfonylureas, meglitinides and dipeptidyl peptidase 4 (DPP4) inhibitors.  However, the 
increasing incidence of T2DM has led to an increasing recognition that additional 
therapeutics are needed to provide safe and effective reductions of elevated plasma glucose 
levels.  New agents to treat T2DM would ideally treat hyperglycemia and avoid common 
side effects of currently available agents, such as weight gain, gastrointestinal disturbance, 
and hypoglycemia. 
The renal Na+/glucose transport protein SGLT2 actively transports extracellular glucose into 
cells using the driving energy of the transmembrane electrochemical potential for sodium 
ions.  Individuals with disruptions in SLC5A2, the gene encoding SGLT2, exhibit prominent 
glucosuria in the absence of significant co-morbidities (van den Heuvel, Assink et al. 2002; 
Santer, Kinner et al. 2003).  The excretion of glucose in the urine of diabetic subjects in 
amounts comparable to or greater than that seen in individuals harboring loss of functions 
mutations in SLC5A2 has the potential to improve fasting and postprandial hyperglycemia 
without increasing insulin secretion, causing weight gain, or inducing hypoglycemia. Several 
SGLT2 inhibitors have demonstrated these clinical benefits as well as sustained weight loss 
when used as a mono-therapy or in combination with other oral anti-diabetic medications 
including insulin (Nauck 2014; Seufert 2015). 
1.1 
Bexagliflozin for the treatment of type 2 diabetes mellitus 
Bexagliflozin is a candidate oral antidiabetic agent that is a potent and highly specific 
inhibitor of SGLT2. It was identified following a synthetic program aimed at creating 
molecules with high selectivity and potency for SGLT2 (Zhang, Welihinda et al. 2011). 
Bexagliflozin has been shown to cause dose-dependent increases in urinary glucose excretion 
(UGE) in humans, rats, dogs and monkeys and to reduce HbA1c in animal models of T2DM 
as well as in diabetic subjects. The safety and efficacy of bexagliflozin capsules, 20 mg, were 
evaluated in a 96-week study that measured reduction in hemoglobin A1c as the primary 
endpoint. Adverse event incidences, particularly for urinary tract infection (UTI) and genital 
mycotic infection (GMI), were similar between placebo and active agent cohorts. Details of 


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the pharmacology, efficacy, and safety assessments are described in the Investigator’s 
Brochure. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Efficacy Objective 
The primary efficacy objective of this trial is to determine the placebo-adjusted treatment 
effect of bexagliflozin tablets, 20 mg on the change in HbA1c from baseline to week 24 in 
subjects with T2DM and inadequate glycemic control. 
2.2 
Secondary Efficacy Objectives 
The key secondary efficacy objectives of this study are: 
• To compare the effect of bexagliflozin to effect of placebo on the change in systolic 
blood pressure (SBP) from baseline to week 24  
• To compare the effect of bexagliflozin to the effect of placebo on the change in body 
weight from baseline to week 24 in subjects with a BMI ≥ 25 kg/m2  
 
The other exploratory secondary efficacy objectives are: 
• To compare the effect of bexagliflozin to the effect of placebo on the proportion of 
subjects with HbA1c of < 7%  
• To compare the effect of bexagliflozin to the effect of placebo on change in HbA1c over 
time  
• To compare the effect of bexagliflozin to the effect of placebo on FPG over time 
 
2.3 
Safety Objectives 
• To compare the safety of bexagliflozin to the safety of placebo in subjects with T2DM 
• To compare the effect of bexagliflozin to the effect of placebo on the incidence of 
adverse events (AE) of special interest. AEs of special interest include either upper or 
lower UTIs, GMI, hepatic toxicity, hypoglycemia, falls and fractures, cardiovascular 
events, malignancies, hypersensitivity reactions, hypotensive episodes, acid-base 
disorders, renal failure events and amputations. 
• To contribute major adverse cardiovascular events (MACE+) to an eventual meta-
analysis that is intended to exclude a hazard ratio of 1.8 or greater for subjects exposed to 
bexagliflozin compared to subjects exposed to placebo. MACE+ is defined as 
cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, or 
hospitalization for unstable angina. 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
THR-1442-C-450 is a multi-center, randomized, double-blind, placebo-controlled, parallel-
group study. It is designed to compare the efficacy and safety of once daily oral 
administration of bexagliflozin tablets, 20 mg to bexagliflozin tablets, placebo in treatment-
naïve type 2 diabetic subjects or subjects previously treated with no more than one oral 
hypoglycemic agent (OHA). 
The study will enroll both male and female subjects with T2DM. If treatment naïve, they 
must have an HbA1c at the screening visit of between 7% and 10.5%. Alternatively, 
prospective subjects may be eligible if at the time of the screening visit they are being treated 
with one OHA, have an HbA1c of between 6.5% and 10.0% and are willing to complete a 6-
week washout. Individuals taking thiazolidinediones are not eligible for the study. A 
candidate will be considered treatment-naïve if he or she has received no more than 14 days 
of prescription medication for diabetes in the 12 weeks prior to screening.  
All eligible subjects will start a 2 week placebo run-in period.  Subjects who miss no more 
than one dose of the run-in medication, have fasting blood glucose values ≥ 250 mg/dL on no 
more than two consecutive days, and who, at the baseline visit (Visit V5), have an HbA1c 
level between 7 and 10.5% and a fasting glucose level < 250 mg/dL will be eligible for 
randomization. 
Approximately 210 subjects will be randomly assigned to receive oral bexagliflozin tablets, 
20 mg or placebo, in a 2:1 ratio once daily for 24 weeks in an out-patient setting.  Subjects 
with uncontrolled hyperglycemia based on blood glucose levels may receive additional 
approved anti-diabetic medications.  Treatment group assignment at the start of the treatment 
period will be stratified by HbA1c level at the start of the run-in period (7.0 to 8.5% or 8.6 to 
10.5%) and background anti-diabetes treatment status (treatment naïve or not).  
Each subject will be contacted by telephone at week 2 (Visit V7) for safety monitoring and 
will be instructed to return to the clinic at weeks 6, 12, 18, and 24 (Visits V8, V9, V10, V11) 
for efficacy assessment and safety monitoring. Subjects will return to the clinic for a follow-
up visit at week 26 or two weeks after the last dose of investigational product if the subject 
terminates prior to week 24 (Visit V12). 
3.2 
Research Methods and Procedures 
3.2.1 
Wash-out and Run-in Period 
Eligible subjects who are not treatment naïve will discontinue their current OHA and enter a 
6 week wash-out period. At the start of the wash-out (Visit V2), each subject will be 
provided with diet and exercise counseling, a glucometer, a glycemic control diary in which 
to record symptoms related to any hyper- or hypoglycemic events, and instructions as to 
when to call the clinic for hyperglycemia (see Glycemic Control Monitoring, below). Two 
weeks after the start of the wash-out period (Visit V3), each subject will participate in a 


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phone interview visit with study staff for self-monitored blood glucose (SMBG) data review 
and general safety evaluation. Subjects who remain eligible at the end of the wash-out period 
will proceed to a 2-week placebo run-in period. Subjects who have fasting blood glucose 
values ≥ 250 mg/dl on two consecutive days during the washout will not be eligible for the 
run-in period. 
Eligible subjects who are treatment naïve will not require a wash-out period and will proceed 
to the run-in period. These subjects will be provided with diet and exercise counseling, a 
glucometer, and a glycemic control diary in which to record symptoms related to any hyper- 
or hypoglycemic events at the start of the placebo run-in period (Visit V4). 
Treatment naïve subjects and subjects on background anti-diabetic therapy who complete the 
6-week wash-out will enter the 2-week single-blind placebo run-in period. At the start of the 
run-in period, each subject will be provided with placebo drug, dosing instructions, and 
instructions as to when to call the clinic should hyperglycemia develop (see Glycemic 
Control Monitoring, below). During the run-in, placebo will be taken daily in the morning 
with 250 mL of water prior to eating or drinking. 
Subjects will not be eligible for randomization if, during the run-in period, they: 1) have 
fasting blood glucose values ≥ 250 mg/dL on two consecutive days, 2) miss more than 1 dose 
of placebo, 3) are deemed inappropriate for the study by the investigator or 4) at the base line 
visit (Visit V5), have HbA1c value < 7.0% or >10.5%. At the baseline visit, subjects must 
have a fasting glucose level < 250 mg/dL (13.9 mmol/L) to be eligible for randomization.   
Approximately 210 subjects will be randomly assigned in 2:1 ratio to receive bexagliflozin 
tablets, 20 mg or bexagliflozin tablets, placebo once daily for 24 weeks.  Randomization at 
the start of the treatment period will be stratified by HbA1c level at the final assessment prior 
to randomization (Visit V5) (7.0 to 8.5% or 8.6 to 10.5%) and by background anti-diabetes 
treatment status (treatment naïve or not). 
3.2.2 
Treatment Period 
The treatment period will start at randomization (Visit V6) and end after 24 weeks. At the 
start of the treatment period, each subject will be provided investigational product, dosing 
instructions, and glycemic control diary in which to record symptoms related to any hyper- or 
hypoglycemic events as well as information related to the occurrence of such events. 
Subjects with uncontrolled hyperglycemia based on blood glucose levels may receive 
additional approved anti-diabetic rescue medications (see Prescription of Rescue Medication 
below).  Bexagliflozin tablets will be orally administered in the morning with 250 mL of 
water prior to eating or drinking. 
Each subject will participate in a telephone consultation at week 2 (Visit V7) for safety 
monitoring. Each subject will be instructed to return to the clinic at weeks 6, 12, 18, and 24 
(Visits V8, V9, V10, V11, respectively) for efficacy assessment and safety monitoring, 
including review of adverse events and concomitant medication, evaluation of vital signs, 
electrocardiogram (ECG), and a physical examination, and for a blood draw and urine 


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collection for clinical laboratory. On the day of the clinic visit, a fasting time of 
approximately 10 hours must be confirmed prior to blood draw. 
To minimize the effect of missing values on data analysis and study outcome interpretation, 
considerable effort will be made to prevent missing data, to train site staff to encourage study 
subject participation and to remain vigilant to signs of non-compliance, to remain in contact 
with study subjects who have withdrawn from the study to collect as nearly complete a data 
set as is feasible, and to determine all reasons for missing data. 
Subjects will return to the clinic for a follow-up exit visit at week 26 (Visit V12) or two 
weeks after the last dose of investigational product if the subject terminates prior to week 24. 
Following the exit visit, subjects will be advised to see their primary physician and resume 
treatment to control their diabetes. The duration of participation for each subject can be up to 
37 weeks depending on prior treatment status. 
3.2.3 
Glycemic Control Monitoring 
3.2.3.1 
Washout Period 
During the wash-out period, subjects will be instructed to determine SMBG daily after an 
overnight fast of approximately 10 hour duration. If the fasting blood glucose is ≥ 250 mg/dL 
(13.9 mmol/L) during the wash-out period, the subject should contact the clinic within 24 
hours, and the investigator will determine whether the participant should attempt to improve 
diet and exercise to maintain glycemic control or if the participant must withdraw from the 
study and initiate a more intense pharmacological regimen for glucose control. If fasting 
blood glucose is ≥ 250 mg/dL (13.9 mmol/dL) on two consecutive days during the washout, 
the subject should contact the clinic staff and will be excluded from participation in the study 
Subjects with SMBG readings ≥ 250 mg/dL (13.9 mmol/L) and severe clinical signs or 
symptoms of hyperglycemia during the wash-out period, including weight loss, blurred 
vision, increased thirst, increased urination, or fatigue will be excluded from participation in 
the study. 
3.2.3.2 
Placebo Run-in Period 
During the placebo run-in period, subjects will be instructed to determine SMBG daily after 
an overnight fast of approximately 10 hour duration. If the fasting blood glucose is ≥ 250 
mg/dL (13.9 mmol/L) during the run-in period, the subject should contact the clinic within 24 
hours, and the investigator will determine whether the participant should attempt to improve 
diet and exercise to maintain glycemic control or if the participant must withdraw from the 
study and initiate a more intense pharmacological regimen for glucose control. If fasting 
blood glucose is ≥ 250 mg/dL (13.9 mmol/dL) on two consecutive days during the run-in, the 
subject should contact the clinic staff and will be excluded from participation in the study.  
The investigator or designee will review the glucometer data and glycemic control diary at 
the end of the run-in period. Subjects with fasting blood glucose ≥ 250 mg/dL (13.9 
mmol/dL) on two consecutive days during the run-in period will excluded from participation. 
In addition, subjects with SMBG readings  ≥ 250 mg/dl (13.9 mmol/L) and clinical signs or 


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symptoms of severe hyperglycemia, including weight loss, blurred vision, increased thirst, 
increased urination, or fatigue will be excluded from participation in the study. 
3.2.3.3 
Main Treatment  
During the 24-week treatment period, subjects will be advised to continue daily fasting 
SMBG measurements. Subjects should contact the clinic if any fasting SMBG is ≥ 270 
mg/dL (15 mmol/L) from week 1 to week 6, ≥ 240 mg/dL (13.3 mmol/L) after week 6 to 
week 12, or ≥ 200 mg/dL (11.1 mmol/L) after week 12 to week 24. Blood glucose values 
collected via SMBG will be evaluated at study visits by the investigator. In addition, 
hyperglycemia will be monitored by fasting plasma glucose (FPG) measurement at each 
study visit. 
If hyperglycemia is identified through SMBG or FPG measurements, the investigator will 
first determine whether the subject had fasted for approximately 10 hour prior to the blood 
draw to ensure that the FPG value is truly a fasting sample. If proper fasting had not 
occurred, the subject should be asked to return for a repeat blood test within a week.  
During the treatment period, hyperglycemia should be managed first with diet and exercise 
counseling and should be managed with changes in the medical therapy only if the 
investigator feels it is necessary for the well-being of the subject (see below, Prescription of 
Rescue Medication). After the treatment period, changes to the medical therapy for 
hyperglycemia should occur at the discretion of the investigator based on SMBG, FPG, and 
HbA1c information using local standards of care for subjects with T2DM.  
If a concomitant medication for hyperglycemia is to be prescribed, a blood sample must be 
drawn prior to the administration of the rescue medication so that a final HbA1c value can be 
determined. 
3.2.3.4 
Prescription of Rescue Medication 
Rescue medication for hyperglycemia should be prescribed by the investigator at any time it 
is deemed necessary for the well-being of the subject. During the 24 week treatment period, a 
review of diet and exercise counseling is suggested prior to prescription of rescue medication 
in the absence of specific medical indications for rescue medication. Rescue medication is 
suggested during the treatment period if, after a review of diet and exercise counseling:  
1. more than 3 consecutive, daily, fasting SMBG measures are ≥ 270 mg/dL (15 mmol/L) 
from week 1 to week 6, ≥ 240 mg/dL (13.3 mmol/L) from week 6 to week 12, or 
≥ 200 mg/dL (11.1 mmol/L) from week 12 to week 24 
2. persistent clinical signs or symptoms of hyperglycemia are present (e.g. weight loss, 
blurred vision, increased thirst, or increased urination, or fatigue) 
 
The investigator may provide rescue treatment with any approved medication for diabetes 
that is not otherwise contraindicated, with the exception of an SGLT2 inhibitor.  


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Subjects who receive rescue medication due to poor glycemic control will continue to receive 
investigational product and standard of care per investigator decision, according to current 
treatment guidelines, during the treatment period. Following the exit visit, subjects will be 
advised to see their primary care physician and resume standard treatment to control their 
diabetes. 
If hypoglycemia occurs in any subject prescribed rescue medication for hyperglycemia 
during the study, the total daily dose of the rescue medication should be reduced 50% or 
more at the discretion of the investigator. 
3.2.4 
OTHER SAFETY MONITORING ACTIVITIES  
The safety monitoring activities will include assessment of vital signs, physical 
examinations, urinalysis, blood chemistry, hematology, AEs, and concomitant medication 
(ConMed) use.  The occurrence of blood, liver, or skin disorders will be monitored through 
laboratory testing and evaluation of adverse event documentation.  Adverse events of special 
interest as defined in the statistical analysis plan will include any clinical signs and symptoms 
that indicate either upper or lower UTI, GMI, hepatic toxicity, hypoglycemia, falls and 
fractures, MACE+, malignancies, hypersensitivity reactions, hypotension episodes, acid-base 
disorders, and renal failure events.  All such events must be appropriately documented within 
source documentation. 
DATA AND SAFETY MONITORING BOARD (DSMB)  
An independent DSMB will review unblinded safety information during the bexagliflozin 
development program. The safety review activities and potential risk benefit assessments 
utilized by the DSMB are defined in its charter. 
MAJOR ADVERSE CARDIOVASCULAR EVENT ADJUDICATION 
An independent cardiovascular endpoint committee (CEC) has been established to review, 
under blind, all potential cardiovascular events occurring during the study.  The events of 
interest include cardiovascular mortality, myocardial infarction, stroke, hospitalization for 
acute coronary syndromes, urgent revascularization procedures, and other possible serious 
cardiovascular events.  The adjudicated events will be documented and archived to allow a 
meta-analysis to be performed at a later time.  Events occurring in this study will be 
classified as belonging to MACE+ or not. MACE+ is defined as cardiovascular death, non-
fatal MI, non-fatal stroke, or hospitalization for unstable angina. No separate cardiovascular 
risk assessment will be performed based on events in the study population of the current 
protocol. 
3.3 
Rationale for Study Design and Dose Selection 
3.3.1 
Rational for Study Design and Control Group 
This study is designed to evaluate the efficacy and safety of bexagliflozin for the treatment of 
subjects with T2DM. A randomized, double-blind study design reduces bias and confounding 
by unmeasured factors and is the most suitable design to evaluate a new agent as a 


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monotherapy in diabetic subjects. Under the close monitoring detailed in this protocol, 
placebo is the appropriate control for the subject population studied during the treatment 
period (24 weeks). In order to reduce the possibility that the change in HbA1c level from 
baseline to 24 weeks is determined by medications taken prior to the study, an up to 8 week 
washout and run-in period will be implemented prior to randomization of subjects on prior 
OHAs.  All subjects will receive a placebo in the 2 weeks immediately prior to 
randomization to allow compliance with the dosing regimen to be monitored.  Subjects with 
FPG levels ≥ 250 mg/dL at the visit prior to randomization (Visit V5) will be excluded as a 
safety measure. Diet and exercise counseling will be provided to all participating subjects to 
reduce risks of worsening diabetic conditions. A monitoring plan based on the measurements 
of SMBG, FPG, and HbA1c, as well as criteria to initiate rescue medications, is included in 
the protocol to prevent prolonged hyperglycemia.  
Results from studies of individuals with genetic mutations in the gene encoding SGLT2, of 
subjects that have been treated with other SGLT2 inhibitors, and of previous clinical studies 
in healthy or diabetic subjects treated with bexagliflozin, indicate that the risk of 
hypoglycemia caused by inhibition of SGLT2 activity is likely to be minimal.  
Reduction in HbA1c is considered a well validated surrogate for the long-term microvascular 
complications of diabetes mellitus. HbA1c levels reflect mean glycemic control over 2 to 3 
months, and therefore the primary endpoint of HbA1c measurement at 24 weeks will assess 
the effect of bexagliflozin compared to placebo over a sustained period.  
3.3.2 
 Rational for Dose Selection 
Bexagliflozin produces a dose-dependent, saturable increase in UGE in healthy volunteers 
and diabetic subjects. Near-maximal UGE is produced by 20 mg of bexagliflozin, whether 
delivered as an immediate release or an extended release formulation. Population 
pharmacodynamic modeling has indicated that bexagliflozin doses of 20 mg result in 90% of 
the maximal UGE. In a long term treatment study, daily administration of 20 mg 
bexagliflozin in an immediate release formulation was found to reduce HbA1c by 0.79% 
compared to placebo at week 24. The treatment benefit was observed to improve to 1.02% at 
week 96. FPG reduction, weight loss, and decreased systolic and diastolic blood pressure 
were also observed following 96 weeks of treatment. In addition, AEs, particularly those 
involving UTI and GMI, were found to be similar between placebo and active agent cohorts. 
To evaluate the safety and efficacy of bexagliflozin for the treatment of subjects with T2DM, 
bexagliflozin tablets, 20 mg will be administered in this trial. 
3.4 
Study Duration and Dates 
Potential subjects will be screened within 3 weeks of the start of wash-out or run-in period. 
Eligible subjects who are taking a background OHA and sign the informed consent will start 
a 6-week wash-out period, followed by a 2-week single-blind placebo run-in period. Eligible 
subjects who are treatment naïve and sign the informed consent form will immediately start 
the 2-week single blind placebo run-in period. Subjects who remain eligible at the end of the 
run-in period will receive 24 weeks of treatment. All subjects who are randomized will be 
followed for 2 weeks after the last dose of investigational product.  


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The overall study duration from screening to follow-up could be a maximum of 37 weeks.  
The duration of the overall study depends on the rate of subject accrual.  For details of the 
schedule and nature of the investigations, see the Schedule of Events in Appendix 1 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study population will include approximately 210 subjects diagnosed with T2DM who are 
inadequately controlled by diet and exercise or by treatment with a single OHA and who 
have an HbA1c level between 7% and 10.5% at the time of randomization. Clinical sites in 
the US and in Canada are anticipated to recruit subjects. Clinical sites in other countries may 
also participate in the trial. 
4.2 
Inclusion Criteria 
The study population will include: 
At the Screening Visit (V1) 
1. Male or female adults subject ≥ 18 years of age at screening.  
2. Subjects who are treatment naïve or receiving one OHA in combination with diet and 
exercise.  
3. Subjects with a diagnosis of T2DM  
4. Subjects with HbA1c levels at screening between 7.0% and 10.5% (inclusive) if 
treatment-naïve or with HbA1c levels between 6.5 and 10.0% (inclusive) if on one oral 
anti-diabetic agent 
5. Subjects with a body mass index (BMI) ≤ 45 kg/m2 
6. Subjects whose doses of medications for hypertension or hyperlipidemia (if applicable) 
have not changed for at least 30 days prior to screening 
7. Subjects who are willing and able to return for all clinic visits and to complete all study 
required procedures, including SMBG measurement 
8. Female subjects of childbearing potential who are willing to use an adequate method of 
contraception and to not become pregnant for the duration of the study. Adequate 
contraceptive measures include, but are not limited to, oral contraceptives, intrauterine 
devices, Depo-Provera®, Norplant®, hormonal contraceptive implants, bilateral tubal 
ligation, partner with vasectomy, condom or diaphragm plus contraceptive sponge, foam, 
or jelly, and abstinence 
 
At the Run-in Visit (V4) 
9. Subjects who have maintained glycemic control throughout washout, if applicable.  
 
Prior to Randomization (V5) 
10. Subjects who have HbA1c levels between 7.0 and 10.5% (inclusive)  
11. Subjects who have been compliant in investigational product administration by missing 
no more than one dose of run-in medication 
 


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4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. A diagnosis of type 1 diabetes mellitus or maturity–onset diabetes of the young  
2. Current use of injected therapy for treatment of diabetes (insulin or GLP-1 receptor 
agonist therapy) or thiazolidinedione class drugs 
3. Female subjects who are pregnant or breastfeeding  
4. Hemoglobinopathy or carrier status for hemoglobin alleles that affect HbA1c 
measurement 
5. Genitourinary tract infection (e.g. UTI, GMI, vaginitis, balanitis) within 6 weeks of 
screening or history of  ≥ 3 genitourinary infections requiring treatment within 6 months 
from screening 
6. Estimated glomerular filtration rate (eGFR), as calculated by the modification of diet in 
renal disease study equation (MDRD), < 60 mL/min/1.73 m2 at screening 
7. Uncontrolled hypertension defined as a sitting systolic blood pressure >160 mmHg or 
diastolic blood pressure > 95 mmHg at screening 
8. A positive result for hepatitis B surface antigen (HBsAg) or hepatitis C (HCV) 
9. History of alcohol or illicit drug abuse in the past 2 years 
10. Known human immunodeficiency virus (HIV) positive based on medical history 
11. Life expectancy < 2 years 
12. New York Heart Association (NYHA) Class IV heart failure within 3 months of 
screening 
13. MI, unstable angina, stroke, or hospitalization for heart failure within 3 months of 
screening 
14. Treatment with an investigational drug within 30 days or within 7 half-lives of the 
investigational drug, whichever is longer 
15. Previous treatment with bexagliflozin or EGT0001474 
16. Use of any SGLT2 inhibitors, either at the time of screening or in the prior 3 months 
17. Currently participating in another interventional trial 
18. Not able to comply with the study scheduled visits 
19. Any condition, disease, disorder, or clinically relevant abnormality that, in the opinion of 
the primary investigator, would jeopardize the subject’s appropriate participation in this 
study or obscure the effects of treatment 
20. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 x ULN or 
total bilirubin ≥ 1.5 x ULN with the exception of isolated Gilbert’s syndrome at screening 
21. Two or more consecutive FPG measures ≥ 250 mg/dL (13.9 mmol/L) prior to 
randomization or severe clinical signs or symptoms of hyperglycemia during the washout 
or run-in periods, including weight loss, blurred vision, increased thirst, or increased 
urination, or fatigue 
22. At last visit prior to randomization (Visit V5), FPG level ≥ 250 mg/dL 
23. Prior renal transplantation or evidence of nephrotic syndrome (defined as a urine 
albumin-to-creatinine ratio (UACR) > 2000 mg/g at screening). 


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5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
Investigational Product 
Bexagliflozin tablets, 20 mg or placebo, are blue caplet-shaped, film-coated tablets that are 
intended for use in investigational studies in humans. The tablets contain excipients designed 
to promote extended release through a gastroretentive mechanism. The active tablets exhibit 
a greater than 75% release of drug substance by 8 hour in simulated gastric fluid in vitro.  
The following investigational products will be used for oral administration: 
• Bexagliflozin tablets, 20 mg: tablets containing 20 mg of bexagliflozin 
• Bexagliflozin tablets, placebo: tablets containing no bexagliflozin 
 
5.2 
Treatments Administered 
Bexagliflozin tablets, 20 mg or placebo, should be taken with 250 mL of water in the 
morning prior to eating or drinking. 
5.3 
Selection and Timing of Dose for Each Subject 
Dosing with bexagliflozin tablets, 20 mg or placebo, will be based on randomized 
assignment.  All study subjects will be instructed to self-administer tablets once daily with 
250 mL of water in the morning prior to eating or drinking.  There will be no change of dose 
during the 24-week treatment period.  
On the day of each scheduled clinic visit, subjects must fast for approximately 10 hours prior 
to the collection of blood samples. On the day of each scheduled clinic visit, bexagliflozin 
tablets should be taken with water in the morning prior to eating or drinking (as above) and 
prior to the collection of blood samples. During the fasting period, only water will be 
permitted. 
5.4 
Method of Assigning Subjects to Treatment Groups 
Eligible subjects who complete the run-in period and meet all study inclusion/exclusion 
requirements will be randomized in a 2:1 ratio to receive once daily bexagliflozin tablets, 20 
mg or bexagliflozin tablets, placebo during the 24-week treatment period. Subjects will be 
assigned to treatment groups in sequential order as they qualify for the study, using a 
centrally located and managed Interactive Web Response System (IWRS). Randomization 
will be stratified according to HbA1c measured at the last assessment prior to randomization 
(Visit V5) (HbA1c at 7.0 to 8.5% or 8.6 to 10.5%) and background anti-diabetic treatment 
status (treatment-naïve or on treatment).  
The study will be conducted at multiple investigative sites and will likely involve a variable 
numbers of subjects at each site. Enrollment will be on a competitive basis but each site will 


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be capped at 21 randomized subjects. However, when a site reaches 21 randomized subjects, 
if a potential subject at that site is in washout or run in already and wishes to continue with 
the study, the subject will be allowed to continue and, if eligible, to be randomized. Subject 
randomization will be deactivated for all sites when the planned number of subjects has been 
enrolled.  However, if a potential subject is in washout or run in already and wishes to 
continue with the study, the subject will be allowed to continue and, if eligible, to be 
randomized. 
5.5 
Blinding 
This is a double-blind placebo-controlled study.  The sponsor, investigators, study 
coordinators, pharmacists, study subjects, and the CEC members will be blinded to the study 
medication.  Upon randomization, each subject will receive a subject randomization number 
and a drug kit assigned to the subject.  To maintain blinding of the individual treatment 
assignments, central laboratory glucose urinalysis data will not be made available to any 
study personnel or subjects. 
If knowledge of the test substance is needed to manage the subject’s condition, the 
investigator will contact the IWRS to obtain the treatment assignment.  If unblinding occurs 
for any reason, the time and reason for breaking the blind will be recorded in the case report 
form (CRF) and the sponsor must be notified within 24 hours.  
A designated statistician who is not involved with the study operation will hold the treatment 
codes.  The unblinded treatment information can be provided to the DSMB to facilitate the 
evaluation of any clinically important increase in the rate of a serious suspected adverse 
reaction or to the designated safety contact when the treatment information is required to 
determine if an expedited safety report must be submitted to regulatory agencies.   
The treatment assignment will continue to be withheld from the CEC members at the 
conclusion of the study until all global investigational studies are completed and a meta-
analysis to assess cardiovascular risk is conducted. 
5.6 
 Concomitant Therapy 
Subjects will be allowed to take medications or medicinal supplements prescribed to manage 
non-diabetic medical conditions during the study. Any concurrent medication or supplement 
treatment of non-diabetic medical conditions should be continued at a stable dose and 
frequency for the entire study duration unless there is clinical reason to change the dose or 
frequency.  
During the run-in period, blood pressure medications can be altered to optimize blood 
pressure control at the discretion of the investigator, although adjustment of blood pressure 
medications during the first 12 weeks of the treatment period should be avoided unless it is 
medically necessary to do so. If it is medically necessary to alter blood pressure medications 
during the first 12 weeks of the treatment period, new diuretic medications should not be 
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Subjects who do not meet protocol-specified glycemic targets at specified time points during 
the study will review diet and exercise counseling and/or receive rescue medication at the 
discretion of the investigator during the study. Anti-diabetic therapies prescribed to subjects 
for the purpose of treating hyperglycemia will be considered rescue medications if they are 
continued for at least 2 weeks (see Prescribing Rescue Medication, above). A blood sample 
will be collected for the measurement of the last HbA1c value prior to administration of any 
rescue medications. The rescue medications must be recorded as concomitant medications in 
the CRF. 
To minimize the effect of missing values on data analysis and study outcome interpretation, 
considerable effort will be made to prevent missing data, to train site staff to encourage study 
subject participation and to remain vigilant to signs of non-compliance, to remain in contact 
with study subjects who have withdrawn from the study to collect as nearly complete a data 
set as is feasible, and to determine all reasons for missing data. 
Subjects may receive any medications for AEs that are necessary in the investigators’ 
judgment. Concomitant medications prescribed at the time of the run-in period and during the 
study are to be recorded in the CRF. The medication name, dose, frequency, route of 
administration, date(s) of administration and reason for administration must be recorded. 
This documentation should continue through the treatment period and the follow up period.  
Any medication prescribed to a subject after enrollment and prior to randomization, 
including contraceptives, must be recorded in the CRF. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
All subjects will continue regimens for medical conditions other than diabetes during the 
study as indicated above.  No subject shall have been treated with an investigational drug 
within 30 days of screening or within a period equal to less than 7 half-lives of the 
investigational drug, whichever is longer. No subject shall have been treated with an SGLT2 
inhibitor within 3 months of screening. Subjects taking insulin or GLP-1 receptor agonists or 
members of the thiazolidinedione class of drugs are not eligible for this study. 
5.7.2 
Fluid and Food Intake  
During the study, subjects will be counseled to remain well hydrated at all times. In addition, 
subjects will receive counseling regarding an appropriate diet to achieve glycemic control 
based on standards of medical care in diabetes. The diet should be low in saturated fat, high 
in fiber, and low in simple carbohydrates and should contain appropriate caloric content to 
maintain weight.  Subjects will fast for approximately 10 hours prior to the scheduled blood 
sample draws. During fasting, only water will be permitted. 
5.7.3 
 Subject Activity Restrictions 
Throughout the study period, subjects are counseled and encouraged to engage in a level of 
physical activity that is appropriate for their physical condition. For those without specific 


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restrictions or limitations, at least 150 min/week of moderate activity is advised by the 
American Diabetes Association (ADA, 2013).  Alternatively, local guidelines may be 
followed. 
5.8 
Treatment Compliance 
Subjects will be provided with dosing instructions each time that study medication is 
dispensed.  Subjects will also be instructed to bring their medication with them at every visit.  
During the run-in period, subjects will be considered compliant in investigational product 
administration by missing no more than one dose of run-in medication. Subjects who are not 
compliant during the run-in period will be excluded from randomization. 
At each visit the study staff will review the SMBG control diary, glucometer data and 
medication use with the subject and record the drug consumption in the CRF. Reasons for 
non-adherence will also be recorded in the protocol deviation log if applicable. 
5.9 
Packaging and Labeling 
Investigational product will be provided to the pharmacist or designated site personnel in 
bottles of 90 tablets enclosed with a child-resistant cap. Bottles of 15 placebo tablets will be 
provided for the 2-week run-in portion of the study. All investigational product supplies will 
be prepared and labeled according to the requirements of local laws and regulations and will 
be kept in a secure storage facility at controlled room temperature, 15 to 30 °C (59 to 86°F).  
The pharmacist or designated site personnel will dispense the investigational products for 
each subject according to randomization assignment made in the Interactive Web Response 
System (IWRS). During the treatment period, subjects will be provided with an 
investigational product kit at randomization (Visit V6) and a new investigational product kit 
at 12 weeks (Visit V9). There will be no intra-subject dose escalation or back-titration. 
Subjects who require rescue medication due to hyperglycemia will receive standard care for 
T2DM in addition to the investigational product. 
There are two types of investigational product kits: 
RUN-IN KIT 
One run-in kit contains a bottle of 15 bexagliflozin tablets, placebo.  
The label attached to each run-in kit will contain the protocol number, product identification, 
lot number, subject number, storage condition, sponsor’s name and address, and the 
investigational drug caution statement. 
INVESTIGATIONAL PRODUCT KIT 
One investigational product kit contains a bottle of 90 bexagliflozin tablets, 20 mg or 
bexagliflozin tablets, placebo.  


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The label attached to each investigational product kit will contain the following information: 
the kit number, protocol number, product identification, blinded batch number, subject 
number, storage conditions, sponsor’s name and address, investigator’s name, and the 
investigational drug caution statement. 
5.10 Storage and Accountability 
Bexagliflozin tablets will be stored at controlled room temperatures of 15 °C to 30 °C (59 °F 
to 86 °F). The rescue medications will be stored in conditions specified in the manufacturers’ 
prescription information. The sponsor will notify the sites of the process for returning unused 
drug. 
5.11 Investigational Product Retention at Study Site 
The investigational products should be stored in a secure area with limited access.  The drug 
storage facility must comply with the medication storage instructions.  Bexagliflozin tablets 
should be stored at controlled room temperature until ready for dispensing to study subjects. 
The trial staff must record the amount of investigational product dispensed to each subject on 
the dosing record.  To ensure adequate recordkeeping, subjects must bring all investigational 
products to each visit.  The remaining tablets will be accounted for in the CRF and drug 
consumption forms.  The procedures for obtaining drug resupply will be provided by the 
sponsor.  At the completion of the trial, all unused drug must be returned to a sponsor-
designated depot after drug accounting is verified by Theracos or its designee. 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent  
Before each subject is enrolled in the clinical study, written informed consent will be 
obtained from the patient according to the regulatory and legal requirements of the 
participating country.  As part of this procedure, the investigator or designee must explain 
orally and in writing the nature, duration, and purpose of the study, and the action of the drug 
in such a manner that the study subject is aware of the potential risks, inconveniences, or AEs 
that may occur.  The investigator or designee should educate potential subjects about the 
scientific importance of their data and the vital role that their participation has for the 
outcome of the entire study. The subject must be informed that he/she is free to withdraw 
from the study at any time. He/She will receive all information that is required by federal 
regulations and ICH guidelines.   
The informed consent document must be signed and dated; one copy will be given to the 
patient, and the investigator will retain a copy as part of the clinical study records.  The 
investigator will not undertake any investigation specifically required for the clinical study 
until written consent has been obtained.  The terms of the consent and when it was obtained 
must also be documented. 
6.2 
Screening or Confirmation for I/E Criteria  
At the initial screening, the investigator should review the inclusion and exclusion criteria 
based on the information collected at the screening visit. He or she should evaluate any 
change to status affecting conformance to inclusion and exclusion criteria at subsequent visits 
prior to randomization.  At randomization, the investigator should confirm the run-in drug 
compliance. 
6.3 
Medical History  
The following information will be collected at the screening visit: 
6.3.1 
General Demographics and Characteristics  
1. Date of birth, age, sex, and race, and whether a female subject is of childbearing potential 
or not. 
2. Significant medical (including alcohol/illicit drug abuse within the last 2 years) and 
surgical history, including dates of diagnoses and procedures and whether the condition is 
ongoing, if applicable. 
 
6.3.2 
Diabetes History  
1. History of all medications used to treat diabetes (to be recorded in the concomitant 
medication form), including start date, duration of use, and stop date, if applicable. 


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2. History of complications due to diabetes, including nephropathy, retinopathy, 
neuropathy, non-traumatic amputations, and diabetic ketoacidosis, including date of 
diagnosis 
3. Frequency of hypoglycemic events (per week) that are symptomatic or require assistance. 
  
6.3.3 
Cardiovascular Disease History  
History of cardiovascular disease including presence of angina, congestive heart failure 
(including NYHA classification), known atherosclerotic cardiovascular disease, prior MI, 
transient ischemic attack or stroke, and prior cardiac or peripheral re-vascularization 
procedures. The history should include date of diagnosis and current status of diagnosis 
(resolved or ongoing). 
6.3.4 
Medication History  
1. Use of prescribed or non-prescribed medications, including name of medication, 
indications for usage, start and stop dates, dose, and frequency 
2. Use of supplements, including over the counter drugs, vitamins, herbal preparations, and 
dietary supplements within the past 30 days prior to screening. Each medication history 
will include the agent used, indication for usage, start and stop dates, dose, and 
frequency. 
 
6.4 
Diet and Exercise Counseling  
Subjects will receive counseling regarding an appropriate diet and exercise to aid in glycemic 
control based on standards of medical care in diabetes throughout the study. In addition, all 
subjects are encouraged to consume enough liquid to maintain adequate hydration. 
6.5 
Physical Examination  
A complete physical examination will be performed by the investigator at the time points 
indicated in the Schedule of Events (Appendix 1). The examination will include 
measurement of body weight, and a general assessment of all body systems including the 
skin, head, eyes, ears, nose, throat, neck, heart, lungs, abdomen, lymph nodes, and 
extremities. 
The body weight must be determined using a scale that is calibrated. Every effort should be 
made to use the same scale throughout the study duration. 
6.6 
Abbreviated Physical Examination  
An abbreviated physical examination will include body weight and height (height will be 
measured only at screening), and general assessment of the skin, heart, lungs and abdomen. 
Abbreviated physical examinations will be performed by the investigator at the time points 
indicated in the Schedule of Events (Appendix 1), unless clinically indicated. 


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The body weight must be determined using a scale that is calibrated. Every effort should be 
made to use the same scale throughout the study duration. 
6.7 
Vital Signs  
Vital signs will be measured at the time points indicated in the Schedule of Events 
(Appendix 1) and will include supine, sitting and standing blood pressure (BP) 
measurements, and heart rate. Only the BP measured in the sitting position will be used to 
determine eligibility. 
Devices designed to measure BP from the finger or wrist may not be used. The left arm and 
same cuff sizes should be used for each measurement at all visits. If the left arm cannot be 
used at the screening visit or during the study for BP measurements, the reason should be 
documented, and the right arm should be used for BP measurements for all subsequent visits. 
At each visit, BP measurements will be obtained using a calibrated sphygmomanometer 
while the subject is in sitting, supine, and standing positions. A single heart rate measurement 
should be taken just prior to the BP evaluation in the sitting, supine, and standing positions.  
All readings are to be entered into the source document and CRF for all subjects. The date 
and time of BP measurements should be captured in the source document and CRF. BP will 
be assessed first in the sitting position. Sitting BP and heart rate will be measured after the 
subject has been sitting for at least 5 minutes with feet on the floor and arm supported at 
heart level.  
After sitting BP measurement has been completed, supine and standing BP will be measured 
to evaluate orthostatic vital signs. Supine and standing blood pressure measures will not be 
used to determine eligibility for the study. First, the subject will lie flat for 5 minutes and 
have heart rate and supine blood pressure measured using the same equipment and arm as 
described for sitting BP. Once the supine BP measurement is complete, the subject will 
stand. Standing BP and heart rate will be measured after 2 minutes of standing. For standing 
BP measurements, the arm should be supported and extended such that the cuff is at heart 
level.  
6.8 
Electrocardiography  
A 12-lead electrocardiogram (ECG) will be conducted at the time points indicated in the 
Schedule of Events in Appendix 1 and whenever clinically indicated. This procedure should 
be performed in the supine position after at least 10 minutes of rest. ECG parameters 
measured will be the RR interval, PR interval, QRS duration, and QT interval. Each ECG 
should also be assessed by the investigator for signs of ischemia, clinically significant 
hypertrophy, and clinically significant T-wave abnormalities or arrhythmia.  
It is the investigator’s responsibility to review the results of the ECG as they become 
available. For each abnormal ECG result, the investigator shall ascertain if the observation 
represents a clinically significant change from the screening ECG for that individual subject 
(this determination, however, does not necessarily need to be made the first time an abnormal 


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result is observed. The investigator may repeat the ECG to verify the results of the original 
result). If the ECG result is determined to be a clinically significant and abnormal change 
from baseline for that subject, it is considered to reflect an AE. 
6.9 
Clinical Laboratory Tests  
6.9.1 
Laboratory Parameters 
Clinical laboratory tests are listed in Table 1. 
6.9.2 
Sample Collection, Storage, and Shipping 
6.9.2.1 
Hematology, Blood Chemistry, Serum Lipids, and Glycemic Control 
Assessments  
Blood samples for hematology, chemistry, serum lipids and glycemic control assessments 
will be collected.  Subjects will be in a seated or supine position during blood collection. 
Samples will be collected at the time points indicated in the schedule of events in Appendix 1 
and Appendix 2. 
The study staff will contact each subject prior to a scheduled clinic visit to confirm the time 
of the visit and to remind the subject of proper fasting practice. A subject must be queried to 
assess compliance with an approximately 10 hours fast prior to blood draw to ensure the FPG 
and triglycerides values can be accurately determined. If a subject has not fasted for 
approximately 10 hours, the subject must return as soon as can be arranged (within 1 week) 
to provide a specimen after proper fasting. Blood samples will be transported to the central 
lab for analysis. Samples should be stored and shipped as detailed in the Laboratory Manual. 
LDL-C will be calculated by the Friedewald equation. If triglycerides are > 400 mg/dL, the 
calculated LDL-C value is invalid by this equation and will be set as missing. Direct LDL-C 
will be determined in subjects whose triglycerides are > 350 mg/dL at screening visit. All 
subsequent LDL-C of these subjects will be determined by the same direct LDL-C 
measurements only. 
6.9.2.2 
Urinalysis  
Urine samples will be collected routinely at designated clinic visits from a clean catch 
sample. Urinalysis will be performed at the time points indicated in the schedule of events 
(Appendix 1 and Appendix 2). Investigator or staff should document if pre-menopausal 
female subjects are menstruating and note it in the source documents since hematuria is 
likely to be identified on dipstick urinalysis. 
Urine samples will be transported to the central laboratory for urinalysis. Samples should be 
stored and shipped as detailed in the Laboratory Manual. Microscopy will be conducted if the 
subject has a positive result on the leukocyte esterase or nitrite dipstick tests to clarify the 
significance of the finding.  Results of glucose measurement in the urinalysis must be 
suppressed from the laboratory reports so the sponsor, investigators, study coordinators, 


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pharmacists, study subjects, and the CEC members will remain blinded to the dosing 
assignment. 
In addition, strips to assess leukocyte esterase and nitrite but not glucose will be provided for 
immediate assessment at the clinical sites.  If more than traces of positive results are shown 
in the leukocyte esterase and /or nitrite testing, a urine culture should be performed in a 
designated laboratory regardless of patient reported signs or symptoms.  Results of the 
urinalysis and possible urine culture will be documented in the CRFs. 
Renal functional testing by UACR will be determined at time points specified in the schedule 
of events (Appendix 1 and Appendix 2).  
6.9.2.3 
Urine Pregnancy Test (UPT) 
UPT will be performed for all women, including surgically sterile or post-menopausal 
women, at the screening visit.  Additionally, women of child bearing potential (WOCBP) 
will receive a UPT at the clinical visits indicated in Appendix 2.  


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Table 1 List of Laboratory Tests 
Test Name (sample volume) 
 
Hematology (2 mL blood) 
 
• Mean corpuscular hemoglobin 
(MCH) 
• Mean corpuscular hemoglobin 
concentration (MCHC) 
• Mean corpuscular volume (MCV) 
• White blood cell (WBC) count 
with differential  
• Red blood cell (RBC) count  
• Hematocrit (Hct) 
• Hemoglobin (Hgb) 
• Platelet count  
Serum Chemistry and Electrolytes (3 mL serum) 
 
• Albumin (ALB) 
• ALT 
• AST 
• Blood urea nitrogen (BUN) 
• Creatinine  
• Uric acid 
 
• Calcium (Ca) 
• Magnesium 
• Phosphorus 
• Potassium (K) 
• Sodium (Na) 
• Total Protein 
 
• Glucose 
• Bicarbonate (HCO3) 
• Chloride (Cl) 
• Total bilirubin 
• Direct bilirubin  
 
Glycemic Control (2 mL plasma, 2 mL blood) 
• FPG 
• HbA1c 
 
Serum Lipids  
 
• Total cholesterol (TC) 
• High-density lipoprotein cholesterol 
(HDL-C) 
• Low-density lipoprotein 
cholesterol (LDL-C), calculated, 
or  
• LDL-C, direct 
• Triglycerides (TG) 
Infectious Disease Testing (3 mL serum) 
• Hepatitis B surface antigen 
(HBsAg) 
• Hepatitis C virus (HCV) 
 
Urinalysis 
• Appearance 
• Bilirubin 
• Color 
• Glucose (blinded) 
• Ketones 
• Microscopic examination of 
sediment 
• Nitrite  
• Leukocyte esterase  
• Occult blood 
• pH 
• Protein 
• Specific gravity 
• Urobilinogen 
 
Renal Functional Test 
• UACR 
 
 
Urine Pregnancy Test 
 
 


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6.10 Diary and Glucometer Dispensation and Review 
A glucometer, testing strips, and a glycemic control diary will be provided to each subject at 
the start of OHA washout or when a potential subject starts taking run-in medications for 
SMBG.  Subjects will be trained to use the glucometer and record any events in the glycemic 
control diary.  The SMBG record from the glucometer and diary entries must be reviewed by 
the investigator at all subsequent visits including both phone interview and clinic visits. The 
SMBG record for all subjects should be sent to the site monitor once per month or as directed 
by the sponsor.  
During the SMBG training, symptoms that may indicate hypoglycemia, hyperglycemia, or 
ketoacidosis will be reviewed with study subjects.  Instructions to contact the clinic when the 
subjects experience potential hypoglycemia or diabetic ketoacidosis must be provided. 
6.11 Dispensing Run-in Drug  
Each eligible study subject will receive one bottle of run-in drug based on the scheduled visit 
outlined in Appendix 1.  
Patients should self-administer first dose of run-in drug with 250 mL of water under 
observation during the scheduled visit. 
6.12 Dispensing Investigational Product  
At randomization and at every 12 weeks of treatment thereafter, each study subject will 
receive one bottle of the investigational product based on the kit number assigned to the 
subject by the IWRS. One bottle of the investigational product will provide daily dosing for 
12 weeks. 
Patients should self-administer first dose of investigational product with 250 mL of water 
under observation during the scheduled visits, if they have not already taken investigational 
product that day. 
 
6.13 Adverse Events Assessments  
6.13.1 
Definition of Adverse Events  
Adverse event (AE): Any untoward medical occurrence in a subject administered a 
pharmaceutical product that does not necessarily have a causal relationship with the 
treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not it is considered related to the medicinal product use. 


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Serious adverse event (SAE): A serious adverse event (experience) or reaction is any 
untoward medical occurrence that at any dose:  
• results in death,  
• is life-threatening,  
(NOTE: The term "life-threatening" in this context 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.) 
• requires inpatient hospitalization or prolongation of existing hospitalization,  
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, or  
• is a medically important event or reaction.  
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious such as important medical events that might not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.  
Adverse Reaction: An adverse reaction means any adverse event caused by a drug. Adverse 
reactions are a subset of all suspected adverse events in which there is a reason to conclude 
that the drug caused the event. 
Unexpected Adverse Drug Reaction (UADR): An adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g., Investigator’s 
Brochure for an unapproved investigational medicinal product). 
Serious and Unexpected Suspected Adverse Reaction (SUSAR): The sponsor must report 
in an IND safety report any suspected adverse reaction to study treatment (i.e., including 
active comparators) that is both serious and unexpected (21 CFR 312.32(c)(1)(i)). Before 
submitting an IND safety report, the sponsor needs to ensure that the event meets all three of 
the definitions:  
• Suspected adverse reaction  
• Serious  
• Unexpected  
 
Severity: AEs will be graded on a 3-point scale and reported as indicated in the CRF. The 
intensity of an adverse experience is defined as follows: 
1 = Mild: event is medically significant but produces no disruption to daily activity; 
2 = Moderate: event is medically significant and reduces or affects normal daily activity; 


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3 = Severe: event is medically significant and results in inability to work or perform 
normal daily activity. 
 
Investigational Product Causality: An assignment made by the investigator based on the 
circumstances of the event and its analysis. Cases with causal relationship classified as 
possible, probable or definite are defined as related. Cases with causal relationship 
categorized as not likely or unrelated are defined as not related. Relationship of an AE to 
dosing will be assessed as follows: 
• Definite: The event responds to withdrawal of the investigational product (dechallenge), 
and recurs with rechallenge by administration of the investigational product. 
• Probable: There is a reasonable causal relationship between the investigational product 
and the AE. The event responds to dechallenge. Rechallenge is not required. 
• Possible: There is a reasonable causal relationship between the investigational product 
and the AE. Dechallenge is lacking or dechallenge response is unclear. 
• Not Likely: There is a temporal relationship to investigational product administration, 
but there is not a reasonable causal relationship between the investigational product and 
the event. 
• Unrelated: There is not a temporal or causal relationship to investigational product 
administration. 
 
6.13.2 
Eliciting and Reporting AEs  
The investigator will periodically assess subjects for the occurrence of AEs after subject 
consents to participation in the study. To avoid bias in collecting information about AEs, the 
investigator should ask subjects the following question: "How have you felt since you were 
last checked?" All AEs (serious and non-serious) reported by the subject must be recorded in 
the source documents and CRFs provided by the sponsor. 
It is the investigator’s responsibility to review the results of all laboratory tests as they 
become available. For each abnormal laboratory test result the investigator needs to ascertain 
if this is a clinically significant change from baseline for that individual subject (this 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed. The investigator may repeat the laboratory test or request additional tests 
to verify the results of the original laboratory tests). If the laboratory value is determined to 
be a clinically significant and abnormal change from baseline for that subject, this is 
considered a laboratory AE. 
Hypoglycemia is defined as any FPG or SMBG value ≤ 70 mg/dL and should be documented 
based on the ADA hypoglycemia categories. 
Any increase in liver function tests (AST, ALT, or bilirubin) greater than 3 times the ULN 
for the laboratory utilized will be considered a laboratory AE. 
In addition, the sponsor’s Medical Monitor and designated personnel must be notified 
immediately by telephone, email, or fax of any immediately reportable AEs (IRAE) 


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according to the procedure outlined below. Special attention should be paid to recording 
hospitalization and concomitant medications. 
6.13.3 
Immediately Reportable AEs  
The investigator must report any SAE to the sponsor or its representative immediately after 
the investigator becomes aware of the event. An SAE form should be completed and sent to 
the sponsor within 24 hours of knowledge of the event. 
Non-serious events that require discontinuation of investigational product (including 
laboratory abnormalities) should be reported to the sponsor within 3 working days. The CRF 
AE form should be completed and sent to the sponsor. 
Subjects experiencing an SAE should be followed clinically until their health has returned to 
baseline status or no further improvement in condition can be expected with further care. It is 
expected that the investigator will provide or arrange appropriate supportive care for the 
subject. 
6.13.4 
Pregnancy  
WOCBP who are sexually active must use an effective method of birth control during the 
course of the study, in a manner such that risk of failure is minimized. 
Before enrolling WOCBP in this clinical trial, investigators must review guidelines about 
study participation for WOCBP. The topics should generally include: 
1. General information 
2. Informed consent form 
3. Pregnancy prevention information 
4. Drug interactions with hormonal contraceptives. 
5. Contraceptives in current use. 
6. Guidelines for the follow-up of a reported pregnancy. 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy. The 
subject must sign an informed consent form stating the above-mentioned risk factors and that 
the consequences were discussed with her. 
During the study, all WOCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (e.g. missed or late menstrual cycle). 
If a subject or investigator suspects that the subject may be pregnant prior to investigational 
product administration, the investigational product administration must be withheld until the 
results of serum pregnancy tests are available. If the pregnancy is confirmed, the subject must 
not receive the investigational product and must not be enrolled or remain in the study. If 
pregnancy is suspected while the subject is receiving study treatment, the investigational 
product must be withheld immediately until the result of the pregnancy test is known. If 
pregnancy is confirmed, the investigational product will be permanently discontinued and the 


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subject will be withdrawn from the trial. (Exceptions to study discontinuation may be 
considered for life-threatening conditions only after consultations with a sponsor Medical 
Monitor or designated personnel.) The investigator must notify the Medical Monitor within 3 
working days of any female subject who becomes pregnant. This reporting requirement will 
continue until 4 weeks after the last investigational product exposure.  
The investigator must record the event on the Pregnancy Surveillance Form and forward it to 
sponsor’s clinical or designated personnel. 
Protocol required procedures for study discontinuation and follow-up must be performed on 
the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator must report to the sponsor, on the appropriate Pregnancy Surveillance Form, 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants will be followed for a minimum of six months. 
6.13.5 
Procedure for Breaking the Blind  
As indicated in Section 5.5 above, the sponsor, medical monitor, study coordinators, 
pharmacists, study subjects, and the CEC members will be blinded to the treatment 
assignment during the study period. The investigator should also remain blinded to the 
subject treatment during the entire study unless knowledge of the subject’s treatment is 
required for clinical care and safety. The Emergency Code Break module in the IWRS is 
used for such situations. The investigator must confirm the intention to unblind the subject’s 
treatment to obtain the dose information in IWRS. Upon completion of the unblinding, the 
system will send an alert to designated study team members that an unblinding event has 
occurred. Documentation of breaking the blind should be recorded in the subject’s medical 
record with the date and time the blind was broken, and the names of the personnel 
requesting and authorizing unblinding. The treatment assignment will continue to be 
withheld from the CEC members until all phase 3 studies are completed. 
6.13.6 
Follow-up of Non-Serious AEs  
Non-serious AEs that are identified on the last scheduled contact must be recorded in the AE 
CRF with the current status noted. All non-serious events that are ongoing at the time will be 
recorded as ongoing in the CRF. 
6.13.7 
Follow-up of Post-Study SAEs  
SAEs that are identified on the last scheduled contact must be recorded on the AE CRF page 
and reported to the sponsor according to the reporting procedures outlined in Section 6.13.3. 
These may include unresolved previously reported SAEs, or new SAEs. The investigator 
should follow these SAEs until the events are resolved, or the subject is lost to follow-up. 
Resolution means the subject has returned to the baseline state of health, or the investigator 
does not expect any further improvement or worsening of the subject’s condition. The 
investigator should continue to report any significant follow-up information to the sponsor 
until the event has been resolved.  


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Any new SAEs reported by the subject to the investigator that occur after the last scheduled 
contact, and are determined by the investigator to be reasonably associated with the use of 
the investigational product, should be reported to the sponsor or designated personnel. This 
may include SAEs that are captured on follow-up telephone contact or at any other time point 
after the defined study period (i.e., up to last scheduled contact). The investigator should 
follow SAEs identified after the last scheduled contact until the events are resolved, or the 
subject is lost to follow-up. The investigator should continue to report any significant follow-
up information to the sponsor until the event has been resolved. This study requires that 
subjects be actively monitored for SAEs for at least 4 weeks after the last treatment. 
6.13.8 
Urinary Tract Infections (UTIs)  
Events potentially representing UTIs, including cystitis, urethritis, pyelonephritis, or 
urosepsis, should be carefully evaluated and documentation of signs, symptoms, culture 
results for infectious agent, and treatment should be undertaken when appropriate.  
The investigator should query the subject at every clinical visit for symptoms that may be 
related to a UTI and, if appropriate, document these events as symptomatic UTI in the CRF 
unless an alternative diagnosis is present. In addition, a clean catch urine sample will be 
obtained at all clinical visits and a urinalysis will be performed on that sample at every 
clinical visit. A positive urinalysis will be defined as one with detectable leukocyte esterase 
and/or nitrites (1+ or greater). If the subject reports symptoms consistent with a UTI or the 
urinalysis at the clinical site is positive, a urine culture will be performed in a designated 
laboratory. A positive urine culture will be defined as one with ≥ 105 CFU of any species. 
The investigator may also perform a urine culture using local resources if necessary for 
clinical care.  
6.13.9 
Genital Mycotic Infections (GMIs)  
The investigator will query the subjects for signs or symptoms that may represent a GMI at 
all clinic visits. GMIs will be diagnosed based on symptoms and, if appropriate, physical 
exam and laboratory findings. Investigators must exclude the possibility of sexually 
transmitted infections before diagnosing GMI. Diagnosis of GMIs must be documented in 
the CRF. 
6.13.10 Hepatotoxicity  
If plasma AST and/or ALT concentrations > 3 x ULN are detected, the investigator will 
record in the source documents the date corresponding to the date of the laboratory 
abnormality; the type, frequency, and dose of any concurrent medications or supplements 
taken by the subject within the 14 days of the detected abnormality; and any symptoms or 
change in physical exam that have occurred since the prior assessment. The investigator 
should perform additional laboratory and imaging tests to attempt to establish the cause of 
the AST and ALT elevations, including ruling out any potential contribution from bone or 
muscle etiologies. 
Any clinically significant increase in hepatic enzymes and specifically any ALT or AST 
> 3 x ULN requires immediate repeat test within 48 to 72 hour to confirm the hepatic enzyme 


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elevation and should be repeated based on the clinical situation at least every 96 hour (4 
days) until ALT and AST return to < 2.5 x ULN. Study medication should be stopped and the 
event should be reported as a laboratory AE within the CRF if the enzyme elevation is 
confirmed or worsening.  
Hepatotoxicity will be diagnosed and entered as an AE should any of the following occur: 
• ALT or AST > 8 x ULN; 
• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or INR > 1.5 
• ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
 
In the event of hepatotoxicity, investigational product should be permanently discontinued. 
The investigator is encouraged to consult with the Medical Monitor regarding diagnostic 
evaluation for the hepatic enzyme elevations. Consultation with a hepatologist may also be 
appropriate in some circumstances. 
6.13.11 Hypoglycemia  
Events of hypoglycemia or potentially representing hypoglycemia should be carefully 
evaluated.  
All subjects will be provided with a glucometer and glycemic control diary in which to 
record symptoms related to any hyper- or hypoglycemic events. During the study the subject 
is expected to record all signs and symptoms that may potentially reflect hypoglycemia. In 
the event of such signs or symptoms, the subject is expected to check the blood glucose if it 
is reasonably safe to do so, and consume carbohydrates, if appropriate, to treat 
hypoglycemia.  
The subject will be expected to record in the glycemic control diary the following 
information for each hypoglycemic event: 
1. Signs and symptoms attributed to hypoglycemia and the time and date on which they 
occurred  
2. SMBG reading at the time of the signs and symptoms attributed to hypoglycemia 
3. Time elapsed from the most recent meal to the onset of signs and symptoms 
4. Duration, intensity, and type of any exercise within the 24 hour prior to the signs and 
symptoms 
5. Type of treatment used (e.g., juice, crackers) for the signs and symptoms and whether 
assistance was required from another person to administer the treatment 
6. SMBG reading 15 minutes after treatment with carbohydrate and the time at which 
this was measured 
7. Whether or not the signs and symptoms attributed to hypoglycemia resolved after 
blood glucose returned to normal. 
 


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Subjects are encouraged to call the study clinic should signs and symptoms potentially 
related to hypoglycemia occur. 
At each study visit, the investigator is expected to review the glucometer and glycemic 
control diary with particular attention to any SMBG value ≤ 70 mg/dL and any recorded 
signs or symptoms potentially related to hypoglycemia. In addition, the investigator should 
query the subject with regard to the occurrence of signs and symptoms potentially related to 
hypoglycemia even if none are recorded in the diary.  
In the event of a blood glucose value ≤ 70 mg/dL or signs and symptoms potentially related 
to hypoglycemia, the investigator should complete the supplemental CRF which will include 
data from the glucometer, and glycemic control diary as well as action items to reduce future 
hypoglycemia episodes.  
Hypoglycemia events will be recorded in the hypoglycemia log under 5 categories: 
1. Severe hypoglycemia: an event requiring assistance by another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions. These episodes may 
be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma 
glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of plasma glucose to normal is considered 
sufficient evidence that the event was induced by a low plasma glucose concentration. 
All such events should be recorded as SAEs in the CRF. 
2. Documented symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by a measured plasma glucose concentration 
≤ 70 mg/dL (3.9 mmol/L).  
3. Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of 
hypoglycemia but with a measured blood glucose concentration ≤ 70 mg/dL 
(3.9 mmol/L).  
4. Probable symptomatic hypoglycemia: an event during which symptoms of 
hypoglycemia are not accompanied by a blood glucose determination but that is 
presumably caused by a blood glucose concentration ≤ 70 mg/dL (3.9 mmol/L). 
5. Relative hypoglycemia: An event during which the person with diabetes reports any 
of the typical symptoms of hypoglycemia, and interprets those as indicative of 
hypoglycemia, but with a measured plasma glucose concentration > 70 mg/dL 
(3.9 mmol/L). 
 
While each event meeting the criteria above will be entered into the hypoglycemia log, only 
severe hypoglycemia, documented symptomatic hypoglycemia, asymptomatic hypoglycemia, 
and probable hypoglycemia will be entered as AEs.  
In the event of asymptomatic hypoglycemia, the investigator should review the signs and 
symptoms of hypoglycemia with the subject to elicit a complete description and should 
review proper glucometer technique to ensure that the low glucose value is not due to 
improper use of the glucometer. 


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The investigator should be alerted to the likelihood of improper glucose measurement 
technique if a study subject reports an SMBG value ≤ 55 mg/dL (3.1 mmol/L) that is not 
associated with any signs or symptoms of hypoglycemia and is not treated by some form of 
glucose administration.  
In the event of probable symptomatic hypoglycemia, the investigator should encourage the 
subject to obtain glucose values, when possible, in the context of signs and symptoms of 
hypoglycemia, even if the glucose value is measured after treatment for the symptoms is 
administered. 
If hypoglycemia occurs in any subject prescribed rescue medication for hyperglycemia 
during the study, the total daily dose of the rescue medication should be reduced 50% or 
more at the discretion of the investigator. 
6.13.12 Diabetic Ketoacidosis (DKA) 
DKA is a serious, acute complication of diabetes and can be life-threatening.  Subjects will 
be educated on the signs and symptoms of DKA and are required to call the study clinic and 
seek treatment should such signs and symptoms occur. 
During the clinical trial period, potential DKA will be monitored by the routine measurement 
of urinary ketones and assessment for signs or symptoms of acidosis at every clinic visit. 
Clinical presentations, such as difficulty breathing, abdominal pain, nausea, vomiting, 
lethargy, or a fruity smell in the breath, or laboratory values that suggest clinically-significant 
acidosis should be documented; treatment of DKA should be provided when appropriate.  
If ongoing symptoms or signs suggest a possible DKA, the investigator should perform 
relevant laboratory testing while directing appropriate medical care for the subject. If DKA is 
suspected, regardless of the blood glucose level, the following assessments should be done 
immediately: physical exam and serum glucose, bicarbonate, electrolytes, and serum ketones 
measured STAT at a local laboratory. If ketoacidosis is likely, investigational product 
administration should be discontinued and immediate appropriate medical therapy, including 
insulin, should be initiated.  A glucose infusion may be provided if necessary to avoid 
hypoglycemia during insulin therapy. Insulin treatment should continue until resolution of 
the ketoacidosis and stabilization of the subject’s clinical condition. Investigational product 
administration may be resumed following stabilization of the subject’s condition. 
Investigator should collect the data necessary for the completion of the DKA CRF. 
If symptoms suggestive of DKA may have occurred but are not ongoing, investigator should 
review available data in order to complete the DKA CRF.  The investigator may also perform 
laboratory assessment using local resources if necessary for clinical care. 
6.13.13 Major Adverse Cardiovascular Event (MACE) 
Evaluation of MACE will be undertaken across the development program for bexagliflozin. 
All MACE reports should also be captured as SAEs and every effort will be made to ensure 
that events recorded as MACE are coded in a similar manner within the safety database. The 
SAE listing will also be reviewed periodically by the CEC members to identify potential 


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MACE that may not have been reported by the site investigators. All subjects will be 
followed by investigators for MACE for the duration of the study even if study medication 
has been permanently withdrawn. 
The independent CEC will receive and adjudicate the following events.  
• 
All deaths 
• 
Suspected non-fatal myocardial infarction (MI) 
• 
Suspected hospitalization for unstable angina (HUA) 
• 
Suspected transient ischemic attack (TIA) and stroke  
• 
Suspected hospitalization for heart failure (HF) 
• 
Reported coronary revascularization procedure 
 
6.13.14 Amputation 
Amputation and related adverse events will be recorded in a dedicated case report form. 
During each study visit, the investigator should query the subject for any amputation and 
related adverse events and procedures. Investigators are reminded to counsel appropriate foot 
care to avoid cuts or sores and to treat even minor cuts or sores to prevent infection and 
ulceration. Patients who have had a previous amputation should be closely monitored. 
Special attention may be appropriate for patients who are also receiving thiazide diuretics as 
these have been shown to increase the risk of amputation in diabetics.  
6.14 Concomitant Medication Assessments  
A concomitant medication is any medication that the subject has been taking prior to 
enrollment and that the subject is expected to continue to take for some portion of the trial, as 
well as any medication other than the investigational product that the subject takes during the 
course of the trial.  
The medications or treatment for controlling hypoglycemia must be recorded as concomitant 
medications in the CRF. Any medication given to treat hyperglycemia and continued for 
more than 2 weeks is considered a rescue therapy and should be recorded in the concomitant 
medication log. 
Changes from baseline anti-hypertensive therapy and their rationale must be recorded in the 
CRF. 
All prescription and over-the-counter medications, including vitamins and herbal 
supplements, that subjects receive during the trial must be documented on the CRF. This 
documentation should continue until the subjects complete the study.  
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A table of concomitant medications based on the anatomic 
therapeutic chemical classification (ATC) and preferred name will be produced. A listing of 
concomitant medications will include all medications taken by any subjects during the course 
of the study. 


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7 
STUDY ACTIVITIES  
The activities that must be performed at each clinic visit listed below are presented in 
Appendix 1. The required laboratory tests scheduled at each visit are listed in Appendix 2. 
Detailed study procedures are described in Section 6.  
A visit window of ± 3 days is allowed for all visits except Visit 6. V6 is the day of 
randomization and the basis for the visit window.  
7.1 
V1 (Screening Visit (up to Week -11) 
• Explain the content of the informed consent materials to the subject and collect signed 
informed consent 
• Collect needed information and evaluate conformance to inclusion and exclusion criteria 
• Obtain medical history and demographic information 
• Perform an abbreviated physical exam 
• Measure vital signs, including blood pressures and heart rate 
• Perform a 12-lead ECG measurement 
• Draw blood if an approximately 10 hour fast has been completed by the subject. The 
specific laboratory tests scheduled for this visit are listed in Appendix 2  
• Collect a clean-catch, mid-stream urine sample 
 
7.2 
V2 (Beginning of washout for OHA subjects) (Week -8) 
• Evaluate any change to status affecting conformance to inclusion and exclusion criteria. 
Verify compliant fasting status 
• Counsel subject on appropriate diet and exercise 
• Dispense glucometer and instruct subject in SMBG determination and recording 
• Assess adverse events and DKA 
• Record concomitant medications 
 
7.3 
V3 (Phone interview for washout OHA subjects) (Week -6) 
• Review SMBG and glycemic control record 
• Assess adverse events and DKA 
• Record concomitant medications 
 
7.4 
V4 (Beginning of run in) (Week -2) 
• Counsel subject on appropriate diet and exercise if treatment naive subject 
• Dispense glucometer and instruct subject in SMBG determination and recording if 
treatment naive subject 
• Dispense run-in kit for run-in period 


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• Review SMBG and glycemic control record if subject was on prior OHA treatment 
• Assess adverse events and DKA 
• Record concomitant medications 
 
7.5 
V5 (Baseline Visit) (Day -3 to -5) 
• Evaluate any change to status affecting conformance to inclusion and exclusion criteria. 
Verify compliant fasting status 
• Perform a complete physical examination 
• Measure vital signs, including blood pressures and heart rate 
• Perform a 12-lead ECG measurement 
• Draw blood if an approximately 10 hour fast has been completed by the subject. The 
specific laboratory tests scheduled for this visit are listed in Appendix 2  
• Collect a clean-catch, mid-stream urine sample. 
• Review SMBG and glycemic control record 
• Assess adverse events and DKA 
• Record concomitant medications 
 
7.6 
V6 (Randomization Visit) (Week 0) 
• Review SMBG and glycemic control record 
• Dispense investigational product based on randomization 
• Assess adverse events and DKA 
• Record concomitant medications 
 
7.7 
V7 (Phone Interview) (Week 2) 
• Review SMBG and glycemic control record 
• Assess adverse events and DKA 
• Record concomitant medications 
 
7.8 
V8 (Treatment Visit) (Week 6) 
• Measure vital signs, including blood pressures and heart rate 
• Draw blood if an approximately 10 hour fast has been completed by the subject. The 
specific laboratory tests scheduled for this visit are listed in Appendix 2  
• Collect a clean-catch, mid-stream urine sample. 
• Review SMBG and glycemic control record 
• Assess adverse events and DKA 
• Record concomitant medications 
 


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7.9 
V9 (Treatment Visit) (Week 12) 
• Measure vital signs, including blood pressures and heart rate 
• Draw blood if an approximately 10 hour fast has been completed by the subject. The 
specific laboratory tests scheduled for this visit are listed in Appendix 2  
• Collect a clean-catch, mid-stream urine sample. 
• Review SMBG and glycemic control record 
• Dispense investigational product based on randomization 
• Assess adverse events and DKA 
• Record concomitant medications 
 
7.10 V10 (Treatment Visit) (Week 18) 
• Measure vital signs, including blood pressures and heart rate 
• Draw blood if an approximately10 hour fast has been completed by the subject. The 
specific laboratory tests scheduled for this visit are listed in Appendix 2  
• Collect a clean-catch, mid-stream urine sample. 
• Review SMBG and glycemic control record 
• Assess adverse events and DKA 
• Record concomitant medications 
 
7.11 V11 (Treatment Visit) (Week 24) 
• Perform an abbreviated physical examination 
• Measure vital signs, including blood pressures and heart rate 
• Perform a 12-lead ECG measurement 
• Draw blood if an approximately 10 hour fast has been completed by the subject. The 
specific laboratory tests scheduled for this visit are listed in Appendix 2  
• Collect a clean-catch, mid-stream urine sample. 
• Review SMBG and glycemic control record 
• Assess adverse events and DKA 
• Record concomitant medications 
 
7.12 V12 (Follow Up Visit) (Week 26) 
• Perform a complete physical examination 
• Measure vital signs, including blood pressures and heart rate 
• Perform a 12-lead ECG measurement 
• Draw blood if an approximately 10 hour fast has been completed by the subject. The 
specific laboratory tests scheduled for this visit are listed in Appendix 2  
• Collect a clean-catch, mid-stream urine sample. 


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• Review SMBG and glycemic control record 
• Assess adverse events and DKA 
• Record concomitant medications 
 
7.13 Early Termination Procedures 
Subjects removed from the study due to drug related toxicity will be followed until resolution 
or stabilization of the adverse event. The sponsor must be notified in the event that a subject 
withdraws or is withdrawn from the study.  
To minimize the effect of missing values on data analysis and study outcome interpretation, 
every effort should be made to prevent missing data.  Site staff should explain that 
withdrawing consent is the study subjects’ decision and emphasize to the subjects the 
importance of continued participation to complete the full study. If study subjects express 
dissatisfaction with the trial conduct and have not withdrawn yet, the investigator shall make 
efforts to address the subjects’ concerns, explain the impact of withdrawal on the study 
outcomes, and retain subjects in the study to the best of her or his ability. In doing so, the 
investigator must be careful to avoid coercion. 
Subjects who withdraw consent and have received investigational product will have a follow-
up examination, including a complete physical examination, vital signs, ECG, and clinical 
laboratory tests (hematology, serum chemistry, and glycemic control). Study investigators 
shall understand the value of data collection after early termination and make effort to 
collecting data after a subject discontinues the study treatment. 


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8 
QUALITY CONTROL AND ASSURANCE 
The clinical research sites will be monitored by study monitors to ensure correct performance 
of the study procedures and to ensure that the study is conducted according to the protocol 
and relevant regulatory requirements. CRF entries will be verified with the source 
documentation. 
Quality control principles will be applied throughout the performance of this study by 
following the Standard Operating Procedures (SOPs) of the contract research organization 
(CRO) and the sponsor. Review procedures will be implemented at the CRO for all 
documents that are generated in relation to the study. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The following sections provide a summary of the planned analysis of the trial but a complete 
statistical analysis plan will be developed as a separate document and will become the final 
plan. All statistical analyses will be performed using SAS Version 9.4 or higher.   
Data summaries will use descriptive statistics (number of subjects [N], mean, standard 
deviation [SD], Q1, median, Q3, minimum and maximum) for continuous variables, and 
frequency and percentage of subjects for categorical and ordinal variables.  If there are 
missing values, the number missing will be presented, but without a percentage. 
Unless otherwise specified, all statistical tests will be two-tailed using a 0.05 level of 
significance.  All confidence intervals (CIs) will be two-sided 95% confidence intervals. 
9.1.1 
Multiple Comparisons / Multiplicity 
A sequential testing procedure will be used to control familywise error rate for the primary 
efficacy endpoint and key secondary efficacy endpoints at a two-sided 5% significant level. 
The key secondary efficacy endpoints will be tested only if the primary efficacy measure 
achieves significance. 
9.2 
Determination of Sample Size 
Approximately 210 subjects will be randomized 2:1 to bexagliflozin tablets, 20 mg or 
bexagliflozin tablets, placebo.   
The sample size calculation for this study was based on a two group t-test with a two-sided 
significance test at the 5% level and the following assumptions:  
1. The difference in mean change from baseline to week 24 in HbA1c in the bexagliflozin 
group compared to that of the placebo group will be -0.5%.   
2. The standard deviation for the difference in mean change from baseline to week 24 in 
HbA1c between the bexagliflozin group and the placebo group will be 1.0%. 
 
Under the above assumptions, an estimated sample size of 128 and 64 evaluable subjects in 
the bexagliflozin and placebo arms, respectively, yielded a 90% power that bexagliflozin 
treatment will be found to be significantly different from placebo. To account for an 
estimated drop-out rate of approximately 10%, the study design anticipates randomizing 140 
and 70 subjects in the bexagliflozin or placebo arm, respectively. 
This study will be conducted at multiple investigative sites and will likely randomize 
different numbers of subjects at each site.  Enrollment will be on a competitive basis but will 
be capped at 21 subjects from any one site. 


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9.3 
Analysis Populations  
9.3.1 
Intention to Treat Analysis Set 
All subjects who are randomized will be included in the Intention to Treat (ITT) Analysis 
Set. All analyses of the ITT Analysis Set will be based on the randomization schedule. The 
ITT analysis set will serve as the primary set for the efficacy analyses.  
9.3.2 
Safety Analysis Set 
All subjects who are randomized and take at least one dose of double-blind study medication 
will be included in the Safety Analysis Set (SAS). Safety analyses will be based on the 
medication that each subject has taken. The SAS is the primary analysis set for safety 
evaluation.  
9.3.3 
Per Protocol Analysis Set 
The Per Protocol (PP) Analysis Set will include all subjects in the ITT who meet the study 
eligibility requirements and have no major protocol deviations that affect the validity of the 
efficacy measurements. Protocol deviations that may result in subject exclusion from the PP 
Analysis Set will be detailed in the Statistical Analysis Plan. The PP analysis set will serve as 
the secondary set for efficacy assessment. 
9.4 
Demographics and Baseline Characteristics 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria in order to 
participate in the study. Demographic characteristics include age, gender, race, ethnicity and 
country of investigational site. Baseline characteristics will be determined at Visit 5 and 
include HbA1c, blood pressure, body weight, BMI, FPG, duration of diabetes from diagnosis 
to V1, and stratification factors including HbA1c values at V5 and background anti-diabetic 
treatment status (treatment naïve or not). Summary descriptive statistics by treatment will 
include counts and percentages for discrete variables and estimation of means, standard 
deviations, medians, inter-quartile range, minimum, and maximum for continuous variables. 
Baseline is defined as the last non-missing value before randomization date. 
9.5 
Primary Efficacy Analysis 
Efficacy data include HbA1c, FPG, body weight, and blood pressure. All changes from 
baseline will be calculated as the post-treatment value minus the last non-missing assessment 
before randomization (Visit V5).   
9.5.1 
Primary Efficacy Endpoint 
The primary efficacy hypothesis is that bexagliflozin reduces HbA1c after 24 weeks of 
treatment when compared to placebo. The analysis of the change in HbA1c at week 24 will 
be based on ITT Analysis Set using all observed data and a mixed model repeated measures 
(MMRM) approach that will include terms for treatment, visit, treatment-by-visit interaction 
and randomization stratification factors as fixed effects and the baseline HbA1c value as a 


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fixed effect covariate. Least squares mean treatment differences between the bexagliflozin 
group and the placebo group at week 24 will be estimated from the model with the 
corresponding p-values and their two-sided 95 % CI presented. An unstructured covariance 
will be used to model the within-subject correlation. If the model with the unstructured 
covariance structure does not converge, an autoregressive(1) covariance structure will be 
used. HbA1c values obtained after the start of rescue medication will not be excluded from 
the analysis. 
Sensitivity analyses will be performed as: 
1. A multiple imputation method will be used to impute missing observations (including 
observations obtained after rescue medication) in the ITT Analysis Set prior to carrying 
out the MMRM analysis. 
2. A multiple imputation method will be used to impute missing observations (not including 
observations obtained after rescue medication) in the ITT Analysis Set prior to carrying 
out the MMRM analysis.  
3. A last observation carried forward (LOCF) method will be used to impute the missing 
observations in the ITT Analysis Set prior to carrying out the MMRM model. 
 
For supportive analyses, the primary efficacy endpoint will be analyzed with observed 
available data using the PP analysis set in a similar manner as above. 
9.5.2 
Handling Dropouts and Missing Data 
Randomized subjects who withdraw consent to participate in the study will not be replaced. 
The early termination rate is estimated to be 10%. To the extent possible, attempts will be 
made to minimize the amount of missing data through measures planned in the study 
conduct. But if data are missing for the primary endpoints, they will be handled as follows: 
1. Only available data will be analyzed and data obtained after rescue will not be excluded. 
This will be considered the primary analysis. 
2. Missing endpoint information will be imputed by a multiple imputation linear regression 
approach for continuous variables. Adequate imputed datasets will be generated, and the 
corresponding primary analyses will be carried out on each imputed dataset; the results 
will be combined across the datasets using the standard techniques for multiple imputed 
data sets in order to yield overall treatment comparison results using the imputed data. 
 
The number, timing, pattern, reason for and possible implications of missing values in 
efficacy assessments will be investigated. The dropout patterns will be assessed by Kaplan-
Meier plots if applicable to assess whether they differ between treatment groups. 
For all other endpoints, the missing data will not be imputed and only the observed data will 
be used in the analyses. 


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9.6 
Secondary Efficacy Endpoints 
9.6.1 
 Key secondary Efficacy Endpoints 
The key secondary efficacy endpoints include: 
• Change in SBP from baseline to week 24  
• Change in body weight from baseline to week 24 in subjects with a BMI ≥ 25 kg/m2 
 
A hierarchical testing procedure will be applied to these endpoints in the sequence provided 
above. These key secondary endpoints will only be tested sequentially when significant 
treatment differences are established for the primary efficacy endpoint in the comparisons 
between the bexagliflozin and placebo groups. 
The comparison between randomized treatments at week 24 in SBP will be carried out using 
the MMRM ANCOVA model with unstructured covariance assumption. The model will 
include terms for treatment, visit, treatment-by-visit interaction, and randomization 
stratification factors as fixed effects and the corresponding baseline SBP value as an 
additional fixed effect covariate. Treatment comparison p-values and the least square mean 
difference at week 24 will be estimated from the model, with the two-sided 95 % CIs of the 
difference also presented. If the model does not converge with the unstructured correlation 
assumption, an autoregressive(1) model will be used. 
Change from baseline in body weight at week 24 will be analyzed using ANCOVA method. 
9.6.2 
Exploratory Efficacy Endpoints 
The exploratory secondary efficacy endpoints include: 
• Change from baseline in HbA1c over time 
• Proportion of subjects reaching HbA1c < 7% over time 
• Change from baseline in FPG over time 
 
For changes from baseline in HbA1c, FPG over time, a similar MMRM ANCOVA model 
will be used as for the key secondary efficacy endpoint of change in SBP at week 24 in 
subjects with baseline SBP ≥ 130 mmHg (the treatment-by-visit interaction term will be 
removed if not significant). Of interest in the MMRM ANCOVA model is the difference 
between treatments on these endpoints across all post-baseline time points. Also, changes 
from baseline for each endpoint will be estimated and analyzed at each study visit using this 
MMRM model. Specifically, for each endpoint, treatment difference in least squares means 
will be estimated by visit from the model with the corresponding p-values and the two-sided 
95% CIs of the difference between treatments. 
Endpoints measuring proportions over time will be analyzed using generalized estimating 
equation logistic regression using similar independent variables as the MMRM ANCOVA 
models above (the treatment-by-visit interaction term will be removed if not significant), and 
using an unstructured correlation structure (or autoregressive(1) if the model with the 


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unstructured structure does not converge). Of interest is the difference between treatments 
across all post-baseline time points. Also, odds ratios will be estimated from the model with 
the corresponding p-values and their two-sided 95% CIs presented at each visit. 
9.7 
Analysis of Safety 
Safety data include AEs, physical exam results, vital signs, ECG results, and clinical lab 
results including serum chemistry, hematology, serum lipids, glycemic control parameters 
and urinalysis. Observed data will be summarized by treatment group as counts and 
percentages for discrete variables and means, standard deviations, medians, inter-quartile 
range, minimum, and maximum for continuous variables. All subjects who are randomized 
and receive at least one dose of double-blind study medication will be included in the safety 
analysis. All safety data will be presented in by-subject listings and included in the clinical 
trial report. 
9.7.1 
Adverse Events 
AEs will be mapped to preferred term and body system using the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. AEs that begin after the first administration of 
double-blind study medication or existing AEs that worsen after the first dose of double-
blind study medication are considered treatment emergent AEs (TEAE). The number and 
percentage of subjects reporting TEAEs will be summarized for each treatment group by 
MedDRA system organ class and preferred term, then by severity, and by relationship to 
study treatment. Drug-related adverse events will be considered those to be at least possibly 
related to bexagliflozin administration based on the investigators assessment.  
The number and percentage of subjects reporting serious AEs, and the number and 
percentage of subjects reporting AEs leading to treatment discontinuation will also be 
summarized for each treatment group by MedDRA system organ class and preferred term.  
Adverse event listings will be provided for the following subsets: 
1. TEAEs 
2. All TEAEs at least possibly related to bexagliflozin 
3. Serious AEs  
4. AEs leading to treatment discontinuation  
5. AEs leading to death  
 
9.7.2 
Adverse Events of Special Interest  
AE of special interest include UTI, GMI, diuretic effects, hepatotoxicity, cardiovascular 
events, hypoglycemia, fracture, malignancy, hypersensitivity reactions, hypotensive 
episodes, acid-base disorders, renal failure events, and amputations. These AEs of special 
interest will be prospectively identified based on the MedDRA preferred terms in the adverse 
event log by a medical expert prior to the data base lock and unblinding of the individual 
subject treatment assignment.  The list of adverse events of special interest will be confirmed 
in a peer review process.  


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The number and percentage of subjects experienced TEAE of special interest will be 
summarized for each treatment group by types of events. The incidence rate of AE of special 
interest per 100 patient years will also be summarized.  Additional analyses will be specified 
in the statistical analysis plan to evaluate other event associated safety parameters and 
potential risks in subpopulations based on age, gender, or other baseline characteristics. 
9.7.3 
Clinical and Laboratory Events and Analyses 
Clinical and laboratory metrics will be measured at the time points indicated in the Schedule 
of Events (Appendix 1). These measurements include vital signs, clinical laboratory (see 
Section 6 for a complete list) and ECGs. These data will be summarized as actual values and 
changes from baseline by treatment for each visit for selected parameters. 
Laboratory data will be classified as low, normal or high relative to the parameter’s reference 
range.  Laboratory abnormalities for each treatment will also be summarized with shift tables 
for selected parameters. 
All clinical laboratory, ECG and vital sign data will be listed. 
9.7.4 
Physical Examination 
Physical examination findings will be presented in a by subject listing.  
9.7.5 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD).  A by-subject listing of concomitant medications will include all 
medications taken during the study regardless of the timing for the start of the medication.  
All medications started prior to the administration of the investigational product will be listed 
and flagged as prior in the listing. Only the concomitant medications will be summarized by 
ATC term and treatment. 
9.8 
Interim Analysis 
No interim analysis will be performed during this study.  
9.9 
Final Analysis 
After all subjects have completed the planned 24 weeks of blinded study treatment and the 
subsequent follow-up period, the final analysis of the clinical study will be completed.  At 
this time, the database will be cleaned and locked, and the treatment codes will be unblinded.  


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
Information regarding key personnel involved in the conduct of the study, including names 
and contact details of participating investigators, monitors, clinical laboratories, and technical 
departments and/or institutions, as well as information on members of additional study 
committees, will be found in the study files of the investigational site. 
10.2 Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
The study protocol, informed consent document, relevant supporting information, and all 
types of subject recruitment or advertisement information must be submitted to the IRB/IEC 
for review and must be approved by the sponsor and the IRB/IEC before the study is 
initiated.  Any amendments or addenda to the protocol must also be approved by the 
IRB/IEC prior to implementing changes in the study. The investigator is responsible for 
keeping the IRB/IEC informed of the progress of the study and of any changes made to the 
protocol as deemed appropriate, but in any case at least once a year. The investigator must 
also keep the IRB/IEC informed of any SAEs occurring to subjects under their supervision. 
10.3 Ethical Conduct of the Study 
The procedures set out in this protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the sponsor and investigator follow 
Good Clinical Practice Guidelines and the guiding principles detailed in the Declaration of 
Helsinki. The study will also be carried out in keeping with applicable local laws and 
regulations. An inspection by the sponsor representatives and/or their designee and/or other 
authorized regulatory authorities representatives may occur at any time.  The investigator 
must agree to the inspection of study-related records by the regulatory authority/sponsor 
representatives, and must allow direct access to source documents to the regulatory 
authority/sponsor representatives. 
The investigator is responsible for complying with the protocol and all appropriate 
regulations and guidelines governing global clinical research. Additionally, he/she is 
responsible for ensuring that all participating staff members are adequately trained and 
competent to perform his/her assigned tasks. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator may implement a 
deviation from or a change of the protocol to eliminate any immediate hazards to the trial 
subjects without prior IRB/IEC or sponsor approval/favorable opinion. As soon as possible, 
the implemented deviation or change, the reasons for it, and if appropriate, the proposed 
protocol amendment should be submitted to the IRB/IEC and sponsor. 
Any deviations from the protocol must be fully explained and documented by the 
investigator. The circumstances, action taken, and impact of the deviation on the trial must be 


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communicated by the principal investigator to the designated medical monitor. Any 
subsequent actions will be assessed by the designated medical monitor and documented. 
10.4 Subject Information and Consent 
Prior to the beginning of the study, the investigator must have received, from the IRB/IEC, 
the written approval or favorable opinion of the informed-consent form and any other written 
information to be provided to subjects. The written approval of the IRB/IEC together with 
the approved subject information/ informed consent forms must be maintained at the site.  
The informed consent form must contain all elements required by authorized regulatory 
authorities and the International Conference on Harmonization (ICH) Good Clinical Practices 
(GCP) Guidelines (E6), in addition to any other elements required by local regulations or 
institutional policy. 
Written informed consent must be obtained before any study-specific procedure takes place.  
Participation in the study and date of informed consent given by the subject should be 
documented appropriately in the subject’s files. A copy of the signed informed consent form 
must be provided to the subject. If applicable, it will be provided in a certified translation in 
the language understood by the subject. Signed consent forms must remain in each subject’s 
study file and must be available for verification by study monitors at any time. 
If a protocol amendment is required, then the informed consent document may need to be 
revised to reflect the changes to the protocol.  If the informed consent document is revised, it 
must be reviewed and approved by the responsible IRB/Independent Ethics Committee 
(IEC), and signed by all patients subsequently enrolled in the clinical study as well as those 
currently enrolled in the clinical study. 
10.5 Subject Confidentiality 
The information obtained during the conduct of this clinical study is confidential, and 
disclosure to third parties other than those noted below is prohibited. Information obtained 
during the conduct of this study will be used by the sponsor in connection with the 
development of the investigational product. The study investigator is obliged to provide the 
sponsor with complete test results and all data developed in this study. Subject-specific 
information may be provided to other appropriate medical personnel only with the subject’s 
permission. To ensure compliance with current ICH guidelines, data generated by this study 
must be available for inspection upon request by representatives of national and local health 
authorities, the sponsor, and the IRB/IEC for each study site. Study information from this 
protocol will be posted on clinicaltrials.gov and any local regulatory registry websites, as 
required by regulation. 
Subject names and other identifiers, such as photographs, audio, or videotapes, may not be 
disclosed in any publication without prior written authorization from the subject. 


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10.6 Study Monitoring 
An authorized sponsor representative will conduct site visits to inspect study data, subjects’ 
medical records, and CRFs in accordance with ICH guidelines, GCPs, and the respective 
national and local government regulations and guidelines. 
The investigator will permit authorized representatives of the sponsor and the respective 
national or local health authorities, other authorized regulatory authorities, and IRB/IEC to 
inspect facilities and records relevant to this study. 
10.7 Case Report Forms and Study Records 
For each subject consented, a CRF, in paper or electronic format, will be supplied and 
maintained by the CRO staff and signed by the investigator or authorized designee to indicate 
that he/she has reviewed and agrees with the entered data. This also applies to those subjects 
who fail to complete the trial. The reason a subject is withdrawn must be recorded in the case 
report form. 
Entries made in the CRF must be verifiable against source documents. Source documents are 
defined as all medical records, medical notes, laboratory results, ECG traces and any 
additional document other than the CRF that has original subject information contained 
within it. 
All CRFs and source documents should be completed following GCPs and the CRO’s 
standard operating procedures. 
10.8 Data Monitoring Committee 
An independent DSMB will monitor overall safety information during the bexagliflozin 
development program. The safety review activity and potential risk benefit assessments 
utilized by the DSMB will be defined in its charter. 
10.9 Protocol Violations/Deviations 
It is important to conduct the study according to the protocol. Protocol deviation waivers will 
not be prospectively granted by the sponsor. If minor protocol deviations occur, the 
investigator must decide the most appropriate way to proceed with study activities and 
should consult the study representative for assistance. If major protocol deviations occur, the 
sponsor’s medical monitor must be notified immediately so that a decision about whether to 
keep the subject in the study can be made. 
Only when an emergency occurs that requires a departure from the protocol for an individual 
subject can there be a departure without the sponsor’s pre-approval. The nature and reasons 
for the protocol deviation will be recorded in the subject’s CRF, and the investigator must 
notify the Sponsor. 
Protocol violations/deviations must be reported in the final study report. 


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10.10 Access to Source Documentation 
Authorized sponsor representatives will conduct site visits to inspect study data, subjects’ 
medical records, and CRFs in accordance with ICH guidelines, GCPs, and the respective 
local and national government regulations and guidelines. 
The investigator will permit authorized representatives of the sponsor and the respective 
national or local health authorities, other authorized regulatory authorities, and IRB/IEC to 
inspect facilities and records relevant to this study. 
Each center will be visited at regular intervals by a monitor to ensure compliance with the 
study protocol, GCP, and legal aspects. This will include on-site checking of the CRFs for 
completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters. 
All CRF data will be entered into a clinical database. Following the correction of any errors, 
the clinical database will be locked. 
10.11 Retention of Data 
The study file and all source data should be retained until notification is given by the sponsor 
for destruction. 
If the investigator withdraws from the trial and relinquishes his/her responsibility for the 
maintenance and retention of records, he/she must notify the sponsor in writing so that 
arrangements can be made to properly store the trial materials. 
10.12 Publication and Disclosure Policy 
All data and results and all intellectual-property rights in the data and results derived from 
the study will be the property of the sponsor, who may utilize the data in various ways, such 
as for submission to government regulatory authorities or disclosure to other investigators. 
No publication or disclosure of study results will be permitted except as specified in a 
separate, written agreement between Theracos, Inc. and the investigator.  If results of this 
study are reported in medical journals or at meetings, all subjects’ identities will remain 
confidential. 
 


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11 REFERENCE LIST 
IDF (2015). "International Diabetes Federation Diabetes Atlas Seventh Edition." 
Look, A. R. G., R. R. Wing, et al. (2013). "Cardiovascular effects of intensive lifestyle 
intervention in type 2 diabetes." N Engl J Med 369(2): 145-154. 
Nauck, M. A. (2014). "Update on developments with SGLT2 inhibitors in the management 
of type 2 diabetes." Drug Design, Development and Therapy 8: 1335-1380. 
Santer, R., M. Kinner, et al. (2003). "Molecular analysis of the SGLT2 gene in patients with 
renal glucosuria." J Am Soc Nephrol 14(11): 2873-2882. 
Scheen, A. J. and L. F. Van Gaal (2014). "Combating the dual burden: therapeutic targeting 
of common pathways in obesity and type 2 diabetes." Lancet Diabetes Endocrinol 2(11): 
911-922. 
Schwartz, S., A. N. Fabricatore, et al. (2012). "Weight reduction in diabetes." Adv Exp Med 
Biol 771: 438-458. 
Seufert, J. (2015). "SGLT2 inhibitors - an insulin-independent therapeutic approach for 
treatment of type 2 diabetes: focus on canagliflozin." Diabetes Metab Syndr Obes 8: 543-
554. 
van den Heuvel, L. P., K. Assink, et al. (2002). "Autosomal recessive renal glucosuria 
attributable to a mutation in the sodium glucose cotransporter (SGLT2)." Hum Genet 111(6): 
544-547. 
Zhang, W., A. Welihinda, et al. (2011). "EGT1442, a potent and selective SGLT2 inhibitor, 
attenuates blood glucose and HbA(1c) levels in db/db mice and prolongs the survival of 
stroke-prone rats." Pharmacol Res 63(4): 284-293. 
 
 


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Appendix 1 
 Schedule of Events 
Procedure 
Screen
-ing 
Washout 
Run In 
Treatment Period 
Follow-
Up 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
Time to Randomization Visit (weeks)  
-11 
-8 
-6 
-2 
-0.5 
0 
2 
6 
12 
18 
24 
26 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Screening or Confirmation for I/E Criteria 
X 
X 
 
 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Diet and Exercise Counseling 
 
X 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 
 
 
 
 
X 
 
 
 
 
 
 
X 
Abbreviated Physical Examination 
X 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
Electrocardiography 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
Hematology, Blood Chemistry, Serum 
Lipids, and Glycemic Control Assessments 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
Diary and Glucometer Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 
 
Dispensing Run-in Drug 
 
 
 
X 
 
 
 
 
 
 
 
 
Diary and Glucometer Record Review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispensing Investigational Product 
 
 
 
 
 
X 
 
 
X 
 
 
 
Adverse Events & DKA Assessments 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication Assessments 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Appendix 2 
 Schedule of  Laboratory Tests 
Procedure 
Screening 
Washout 
Run-In 
Treatment Period 
Follow-
up 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
Time to Randomization Visit 
(weeks) 
-11 
-8 
-6 
-2 
-0.5 
0 
2 
6 
12 
18 
24 
26 
Hematology 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry and Electrolytes 
X 
X 
X 
X 
X 
X 
X 
Glycemic Control 
X 
X 
X 
X 
X 
X 
X 
Serum Lipids 
X 
X 
 
X 
 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
Infectious Disease Testing 
X 
UACR 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Urine Pregnancy Test  
(all women) 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test (WOCBP) 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
 




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Appendix 4 
Investigator’s Signature 
Study Title: 
A multi-center, randomized, double-blind, placebo-controlled, 
parallel group study to compare the efficacy and safety of 
bexagliflozin to placebo in subjects with type 2 diabetes mellitus 
and inadequate glycemic control 
Study Number: 
THR-1442-C-450 
Final Date: 
04 April 2017 
I have read the protocol described above. I agree to comply with the International Conference 
on Harmonisation (ICH) Tripartite guideline on Good Clinical Practice (GCP) and all 
applicable regulations and to conduct the study as described in the protocol.  
I agree to ensure that Financial Disclosure Statements will be completed by myself and my 
subinvestigators at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation without 
the prior written consent of Theracos Sub, LLC.  
 
 
Signed: 
 
 
Date:  
 
Clinical Investigator 

SAP_001.pdf: 
Statistical Analysis Plan 
Theracos Sub, LLC 
Version 2.0 
THR-1442-C-450 
 
1007728 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
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Page 1 of 60 
Sponsor Name: 
Theracos Sub, LLC 
Protocol Number and Title: 
 
THR-1442-C-450 A multi-center, randomized, 
double-blind, placebo-controlled, parallel 
group study to compare the efficacy and safety 
of bexagliflozin to placebo in subjects with 
type 2 diabetes mellitus and inadequate 
glycemic control 
Protocol Version and Date: 
Version 4.0, 04 April 2017 
 
 
INC Research Project Code: 
1007728 
Author(s): 
Fang Zhu, Senior Biostatistician 
SAP Version: 
Version 2.0 
SAP Version Date:  
14-Apr-2017 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Theracos Sub, LLC. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Theracos Sub, LLC.  However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation, INC Research should be notified 
promptly. 


Statistical Analysis Plan 
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Version 2.0 
THR-1442-C-450 
 
1007728 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
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Page 2 of 60 
Revision History 
 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
Version 0.1 
10-May-2016 
Fang Zhu 
Initial Release Version 
Version 0.2 
15-Jun-2016 
Fang Zhu 
Update based on sponsor’s 
comments 
Version 1.0 
15-Jul-2016 
Fang Zhu 
Update based on sponsor’s 
comments 
Version 1.1 
30-Jan-2017 
Fang Zhu 
Update to be consistent with 
other Theracos SAP.  Update 
due to protocol amendment  
Version 1.2 
12-Apr-2017 
Fang Zhu 
Update per sponsor comments 
and protocol amendment 
Version 2.0 
14-Apr-2017 
Fang Zhu 
Update version number 
 
 


Statistical Analysis Plan
Verslon 2.0
I confirm that I have reviewed this document and agree with the content'
Thls decurnent is proprletary and confl fiat to lNC Research LLC'
INC Researdt @ LLC
Theracos Sub, LLC
THR.1442-C-450
1A07728
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Statistical Analysis Plan 
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1007728 
 
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TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................ 8 
2. 
PURPOSE ..................................................................................................... 11 
2.1. 
Responsibilities ................................................................................................................. 11 
2.2. 
Timings of Analyses .......................................................................................................... 11 
3. 
STUDY OBJECTIVES ................................................................................... 12 
3.1. 
Primary Objective .............................................................................................................. 12 
3.2. 
Key Secondary Objectives ................................................................................................ 12 
3.3. 
Safety Objectives ............................................................................................................... 12 
3.4. 
Brief Description ................................................................................................................ 13 
3.5. 
Subject Selection ............................................................................................................... 13 
3.5.1. 
Inclusion Criteria ......................................................................................................... 14 
3.5.2. 
Exclusion Criteria ........................................................................................................ 14 
3.6. 
Determination of Sample Size .......................................................................................... 14 
3.7. 
Treatment Assignment & Blinding ................................................................................... 14 
3.7.1. 
Treatment Assignment ................................................................................................ 14 
3.7.2. 
Blinding ........................................................................................................................ 15 
3.8. 
Administration of Study Medication ................................................................................ 15 
3.9. 
Study Procedures and Flowchart ..................................................................................... 16 
4. 
ENDPOINTS .................................................................................................. 19 
4.1. 
Primary Efficacy Endpoint ................................................................................................ 19 
4.2. 
Secondary Efficacy Endpoints ......................................................................................... 19 
4.3. 
Safety Endpoints ................................................................................................................ 19 


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5. 
ANALYSIS SETS .......................................................................................... 20 
5.1. 
Screened Analysis Set ...................................................................................................... 20 
5.2. 
Safety Analysis Set ............................................................................................................ 20 
5.3. 
Intention to Treat Analysis Set ......................................................................................... 20 
5.4. 
Per Protocol Analysis Set ................................................................................................. 20 
5.5. 
Protocol Deviations ........................................................................................................... 20 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 22 
6.1. 
General Methods ................................................................................................................ 22 
6.2. 
Key Definitions ................................................................................................................... 22 
6.2.1. 
Baseline Values .......................................................................................................... 22 
6.2.2. 
First Dose Date ........................................................................................................... 22 
6.2.3. 
Study Day .................................................................................................................... 23 
6.2.4. 
Duration ....................................................................................................................... 23 
6.2.5. 
End of Study ................................................................................................................ 23 
6.3. 
Missing Data ....................................................................................................................... 23 
6.4. 
Analysis Visit Windows ..................................................................................................... 23 
6.5. 
Pooling of Centers ............................................................................................................. 24 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ....................................................................................................... 25 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 25 
7.2. 
Subject Eligiblity and Protocol Deviations ..................................................................... 25 
7.3. 
Demographic and Other Baseline Characteristics ......................................................... 25 
7.4. 
Medical History .................................................................................................................. 26 
7.5. 
Medication .......................................................................................................................... 26 
7.5.1. 
Prior Medication .......................................................................................................... 27 
7.5.2. 
Concomitant Medication .............................................................................................. 27 
8. 
EFFICACY ..................................................................................................... 28 


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8.1. 
Primary Efficacy Endpoint and Analysis ......................................................................... 28 
8.1.1. 
Primary Efficacy Analysis ............................................................................................ 28 
8.1.2. 
Sensitivity Analyses .................................................................................................... 29 
8.1.3. 
Subgroups ................................................................................................................... 31 
8.2. 
Secondary Efficacy Endpoint(s) and Analyses .............................................................. 32 
8.2.1. 
Key secondary efficacy endpoints and analyses ........................................................ 32 
8.2.2. 
Exploratory secondary efficacy endpoints and analyses ............................................ 33 
9. 
SAFETY ......................................................................................................... 34 
9.1. 
Extent of Exposure ............................................................................................................ 34 
9.2. 
Treatment Compliance ...................................................................................................... 35 
9.3. 
Adverse Events .................................................................................................................. 35 
9.3.1. 
Derived Data ............................................................................................................... 36 
9.3.2. 
Data Summarization .................................................................................................... 36 
9.3.3. 
AE of Special Interest .................................................................................................. 37 
9.4. 
Laboratory Evaluations ..................................................................................................... 39 
9.5. 
Vital Signs ........................................................................................................................... 42 
9.6. 
Electrocardiogram ............................................................................................................. 42 
9.7. 
Physical Examination ........................................................................................................ 42 
10. 
INTERIM ANALYSES ................................................................................ 44 
11. 
DATA AND SAFETY MONITORING BOARD ........................................... 44 
12. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ......................... 44 
13. 
REFERENCE LIST .................................................................................... 45 
14. 
PROGRAMMING CONSIDERATIONS ...................................................... 46 
14.1. 
General Considerations .................................................................................................... 47 
14.2. 
Table, Listing, and Figure Format .................................................................................... 47 
14.2.1. 
General ........................................................................................................................ 47 
14.2.2. 
Headers ....................................................................................................................... 47 
14.2.3. 
Display Titles ............................................................................................................... 48 


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14.2.4. 
Column Headers ......................................................................................................... 48 
14.2.5. 
Body of the Data Display ............................................................................................. 48 
14.2.6. 
Footnotes .................................................................................................................... 51 
15. 
QUALITY CONTROL ................................................................................. 51 
16. 
INDEX OF TABLES ................................................................................... 52 
17. 
INDEX OF FIGURES ................................................................................. 56 
18. 
INDEX OF LISTINGS ................................................................................. 57 
19. 
MOCK-UPS ................................................................................................ 60 
20. 
APPENDICES ............................................................................................ 60 
 
 


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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
ADA 
American Diabetes Association 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass index 
CEC 
Cardiovascular Endpoint Committee 
CI 
Confidence Interval 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
dL  
Deciliter 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eGFR 
Estimating Glomerular Filtration Rate 
FPG 
Fasting Plasma Glucose 
GLP-1 
Glucagon-like Peptide-1 
GMI 
Genital Mycotic Infection 
GGT 
Gamma Glutamyl Transferase 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
Hct 
Hematocrit 
HDL-C 
High Density Lipoprotein Cholesterol 
Hgb 
Hemoglobin 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 


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Abbreviation 
Description 
ITT 
Intention to Treat 
IVRS 
Interactive Voice Randomization System 
IWRS 
Interactive Web Randomization System 
LDL-C  
Low Density Lipoprotein Cholesterol  
LOCF  
Last Observation Carried Forward  
MACE  
Major Adverse Cardiovascular Event  
MCH  
Mean Cell Hemoglobin  
MCHC  
Mean Cell Hematocrit  
MCV  
Mean Cell Volume  
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram  
MI 
Myocardial Infarction  
Min 
Minimum 
mL 
Milliliter 
MMRM 
Mixed Model Repeated Measures 
N/A 
Not Applicable 
NA 
Not Applicable 
Na 
Sodium 
NCI 
National Cancer Institute 
OHA 
Oral Hypoglycemic Agent 
PP 
Per Protocol  
PR 
Time from the beginning of the P wave to the beginning of the 
QRS complex in electrocardiogram 
PT 
Preferred Term 
QRS 
Graphical deflections corresponding to ventricular 
depolarization in a typical electrocardiogram 
QTc 
Time between the start of the Q wave and the end of the T 
wave in the ECG, corrected for heart rate 
RBC 
Red Blood Cell  


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Abbreviation 
Description 
RR 
Time between the start of one R wave and the start of the 
next R wave in the ECG 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SE 
Standard Error 
SGLT2 
Sodium Glucose Linked Transporter 2 
SI 
Standard International System of Units 
SMBG 
Self-Monitored Blood Glucose 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
T2DM 
Type 2 Diabetes Mellitus 
TC 
Total Cholesterol 
TEAE 
Treatment Emergent Adverse Event 
TG 
Triglycerides 
TLF 
Table, Listing And Figure 
UACR 
Urine Albumin To Creatinine Ratio  
UGE  
Urine Glucose Excretion  
UPT  
Urine Pregnancy Test  
UTI 
Urinary Tract Infection 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives.   
2.1. 
RESPONSIBILITIES 
Theracos has designed the study protocol and is responsible for the conduct of the 
study.  INC Research is responsible for the development and validation of a clinical 
database using MediData RAVE platform.   
INC Research will perform the statistical analyses and are responsible for the production 
and quality control of all tables, figures and listings. 
Serious adverse event data on adverse event form will be reported. Detailed serious 
adverse event follow-up data will be reported from ARGUS database and is not included 
in this report. 
Theracos will perform review of all tables, figures and listings before the finalization. 
2.2. 
TIMINGS OF ANALYSES 
The final analysis of safety and efficacy is planned after all subjects complete the 
planned 24 weeks of blinded study treatment and the subsequent follow-up period or 
terminate early from the study.  
 
 


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3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
To determine the placebo-adjusted treatment effect of bexagliflozin tablets, 20 mg on 
the change in HbA1c from baseline to week 24 in subjects with type 2 diabetes mellitus 
(T2DM) and inadequate glycemic control. 
3.2. 
KEY SECONDARY OBJECTIVES 
The key secondary efficacy objectives of this study are: 
• 
To compare the effect of bexagliflozin to effect of placebo on the change in 
systolic blood pressure (SBP) from baseline to week 24 
• 
To compare the effect of bexagliflozin to the effect of placebo on the change in 
body weight from baseline to week 24 in subjects with a BMI ≥ 25 kg/m2 
 
The other exploratory secondary efficacy objectives are: 
• 
To compare the effect of bexagliflozin to the effect of placebo on the proportion 
of subjects with HbA1c of < 7% over time 
• 
To compare the effect of bexagliflozin to the effect of placebo on change in 
HbA1c over Time  
• 
To compare the effect of bexagliflozin to the effect of placebo on FPG over time 
3.3. 
SAFETY OBJECTIVES 
• 
To compare the safety of bexagliflozin to the safety of placebo in subjects with 
T2DM. 
• 
To compare the effect of bexagliflozin to the effect of placebo on the incidence 
of adverse events (AE) of special interest. AEs of special interest include either 
upper or lower UTIs, GMI, hepatic toxicity, hypoglycemia, falls and fractures, 
cardiovascular events, malignancies, hypersensitivity reactions, hypotensive 
episodes, acid-base disorders, renal failure events, and amputations. 
• 
To contribute major adverse cardiovascular events (MACE+) to an eventual 
meta-analysis that is intended to exclude a hazard ratio of 1.8 or greater for 
subjects exposed to bexagliflozin compared to subjects exposed to placebo. 


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MACE+ is defined as cardiovascular death, non-fatal myocardial infarction (MI), 
non-fatal stroke, or hospitalization for unstable angina. 
3.4. 
BRIEF DESCRIPTION 
THR-1442-C-450 is a multi-center, randomized, double-blind, placebo-controlled, 
parallel-group study. It is designed to compare the efficacy and safety of once daily oral 
administration of bexagliflozin tablets, 20 mg to bexagliflozin tablets, placebo, in 
treatment-naïve type 2 diabetic subjects or subjects previously treated with no more 
than one oral hypoglycemic agent (OHA). 
All eligible subjects will start a 2 week placebo run-in period. Subjects who miss no 
more than one dose of the run-in medication, have fasting blood glucose values ≥ 
250 mg/dL on no more than two consecutive days, and who, at the baseline visit (Visit 
V5), have an HbA1c level between 7 and 10.5% and a fasting glucose level < 250 mg/dL 
will be eligible for randomization. 
Approximately 210 subjects will be randomly assigned to receive oral bexagliflozin 
tablets, 20 mg or placebo, in a 2:1 ratio once daily for 24 weeks in an out-patient 
setting. Subjects with uncontrolled hyperglycemia based on blood glucose levels may 
receive additional approved anti-diabetic medications. Treatment group assignment at 
the start of the treatment period will be stratified by HbA1c level at the start of the 
run-in period (7.0 to 8.5% or 8.6 to 10.5%) and background anti-diabetes treatment 
status (treatment naïve or not). 
Each subject will be contacted by telephone at week 2 (Visit V7) for safety monitoring 
and will be instructed to return to the clinic at weeks 6, 12, 18, and 24 (Visits V8, V9, 
V10, V11) for efficacy assessment and safety monitoring. Subjects will return to the 
clinic for a follow-up visit at week 26 or two weeks after the last dose of investigational 
product if the subject terminates prior to week 24 (Visit V12). 
3.5. 
SUBJECT SELECTION 
The study will enroll both male and female subjects with T2DM. If treatment naïve, 
they must have an HbA1c at the screening visit of between 7% and 10.5%. Alternatively, 
prospective subjects may be eligible if at the time of the screening visit they are being 
treated with one OHA, have an HbA1c of between 6.5% and 10.0% and are willing to 
complete a 6-week washout. Individuals taking thiazolidinediones are not eligible for 
the study. A candidate will be considered treatment-naïve if he or she has received no 
more than 14 days of prescription medication for diabetes in the 12 weeks prior to 
screening. 


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3.5.1. 
Inclusion Criteria 
Refer to protocol section 4.2 for inclusion criteria. 
3.5.2. 
Exclusion Criteria 
Refer to protocol section 4.3 for exclusion criteria. 
3.6. 
DETERMINATION OF SAMPLE SIZE 
Approximately 210 subjects will be randomized 2:1 to bexagliflozin tablets, 20 mg or 
bexagliflozin tablets, placebo. The sample size calculation for this study was based on a 
two group t-test with a two-sided significance test at the 5% level and the following 
assumptions: 
1. The difference in mean change from baseline to week 24 in HbA1c in the 
bexagliflozin group compared to that of the placebo group will be -0.5%. 
2. The standard deviation for the difference in mean change from baseline to week 
24 in HbA1c between the bexagliflozin group and the placebo group will be 1.0%. 
Under the above assumptions, an estimated sample size of 128 and 64 evaluable 
subjects in the bexagliflozin and placebo arms, respectively, yielded a 90% power that 
bexagliflozin treatment will be found to be significantly different from placebo. To 
account for an estimated drop-out rate of approximately 10%, the study design 
anticipates randomizing 140 and 70 subjects in the bexagliflozin and placebo arm, 
respectively. 
3.7. 
TREATMENT ASSIGNMENT & BLINDING 
3.7.1. 
Treatment Assignment 
Eligible subjects who complete the run-in period and meet all study inclusion/exclusion 
requirements will be randomized in a 2:1 ratio to receive once daily bexagliflozin 
tablets, 20 mg or bexagliflozin tablets, placebo, during the 24-week treatment period. 
Subjects will be assigned to treatment groups in sequential order as they qualify for the 
study, using a centrally located and managed Interactive Web Response System (IWRS). 
Randomization will be stratified according to HbA1c measured at the last assessment 
prior to randomization (Visit V5) (HbA1c at 7.0 to 8.5% or 8.6 to 10.5%) and background 
anti-diabetic treatment status (treatment-naïve or on treatment).  
Potential study subjects will be screened and assigned a subject number. Once all 
screening procedures are completed and the study eligibility is confirmed by the 
investigator, the randomization numbers will be allocated to subjects within the 


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appropriate treatment group by the randomization system. Once a screening or 
randomization number has been assigned, it will not be re-used in any event. No 
subjects will be randomized into the study more than once. If a randomization number 
has been allocated incorrectly, no attempt will be made to remedy the error once study 
medication has been dispensed. The subject will continue with the randomization 
number and study medication. The study staff will notify the Sponsor Contact as soon as 
the error is discovered without disclosing the study medication administered. Admission 
of subsequent eligible subjects will continue using the next unallocated number in the 
sequence. 
The study will be conducted at multiple investigative sites and will likely involve a 
variable numbers of subjects at each site.  Enrollment will be on a competitive basis but 
each site will be capped at 21 randomized subjects.  However, when a site reaches 21 
randomized subjects, if a potential subject at that site is in washout or run in already 
and wishes to continue with the study, the subject will be allowed to continue and, if 
eligible, to be randomized.  Subject randomization will be deactivated for all sites 
when the planned number of subjects has been enrolled.  However, if a potential 
subject is in washout or run in already and wishes to continue with the study, the 
subject will be allowed to continue and, if eligible, to be randomized. 
3.7.2. 
Blinding 
This is a double-blind placebo-controlled study. The sponsor, investigators, study 
coordinators, pharmacists, study subjects, and the cardiovascular endpoint committee 
(CEC) members will be blinded to the study medication. Upon randomization, each 
subject will receive a subject randomization number and a drug kit assigned to the 
subject. To maintain blinding of the individual treatment assignments, central 
laboratory glucose urinalysis data will not be made available to any study personnel or 
subjects. 
If knowledge of the test substance is needed to manage the subject’s condition, the 
investigator will contact the IWRS to obtain the treatment assignment. If unblinding 
occurs for any reason, the time and reason for breaking the blind will be recorded in the 
case report form (CRF) and the sponsor must be notified within 24 hours. 
The treatment assignment will continue to be withheld from the CEC members at the 
conclusion of the study until all global investigational studies are completed and a 
meta-analysis to assess cardiovascular risk is conducted. 
3.8. 
ADMINISTRATION OF STUDY MEDICATION 
The following investigational products will be used for oral administration: 
• 
Bexagliflozin tablets, 20 mg: tablets containing 20 mg of bexagliflozin 
• 
Bexagliflozin tablets, placebo: tablets containing no bexagliflozin 


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Bexagliflozin tablets, 20 mg or placebo, should be taken with 250 mL of water in the 
morning prior to eating or drinking. 
Dosing with bexagliflozin tablets, 20 mg or placebo, will be based on randomized 
assignment. All study subjects will be instructed to self-administer tablets once daily 
with 250 mL of water in the morning prior to eating or drinking. There will be no change 
of dose during the 24-week treatment period. 
On the day of each scheduled clinic visit, subjects must fast for approximately 10 hours 
prior to the collection of blood samples. On the day of each scheduled clinic visit, 
bexagliflozin tablets should be taken with water in the morning prior to eating or 
drinking (as above) and prior to the collection of blood samples. During the fasting 
period, only water will be permitted. 
3.9. 
STUDY PROCEDURES AND FLOWCHART 
The activities that must be performed at each clinic visit listed below are presented in 
Table 1.  
A visit window of ± 3 days is allowed for all visits except Visit 6. V6 is the day of 
randomization and the basis for the visit window. 
The study staff will contact each subject prior to a scheduled clinic visit to confirm the 
time of the visit and to remind the subject of proper fasting practice. A subject must be 
queried to assess compliance with an approximately 10 hours fast prior to blood draw to 
ensure the FPG and triglycerides values can be accurately determined. If a subject has 
not fasted for approximately 10 hours, the subject must return as soon as can be 
arranged (within 1 week) to provide a specimen after proper fasting. Blood samples will 
be transported to the central lab for analysis. 


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Table 1 
Schedule of Events 
Procedure  
Screen
 -ing  
Washout  
Run In  
Treatment Period  
Follow
-Up  
Visit number  
V1  
V2  
V3  
V4  
V5  
V6  
V7  
V8  
V9  
V10  
V11  
V12  
Time to Randomization Visit (weeks)  
-11  
-8  
-6  
-2  
-0.5  
0  
2  
6  
12  
18  
24  
26  
Informed Consent  
X  
 
 
 
 
 
 
 
 
 
 
 
Screening or Confirmation for I/E 
Criteria  
X  
X  
 
 
X  
 
 
 
 
 
 
 
Medical History  
X  
 
 
 
 
 
 
 
 
 
 
 
Diet and Exercise Counseling  
 
X  
 
X  
 
 
 
 
 
 
 
 
Physical Examination  
 
 
 
 
X  
 
 
 
 
 
 
X  
Abbreviated Physical Examination  
X  
 
 
 
 
 
 
 
 
 
X  
 
Vital Signs  
X  
 
 
 
X  
 
 
X  
X  
X  
X  
X  
Electrocardiography  
X  
 
 
 
X  
 
 
 
 
 
X  
X  
Hematology  
X  
 
 
 
X  
 
 
X  
X  
X  
X  
X  
Serum Chemistry and Electrolytes  
X  
 
 
 
X  
 
 
X  
X  
X  
X  
X  
Glycemic Control  
X  
 
 
 
X  
 
 
X  
X  
X  
X  
X  
Serum Lipids  
X  
 
 
 
X  
 
 
 
X  
 
X  
X  
Urinalysis  
X  
 
 
 
X  
 
 
X  
X  
X  
X  
X  
Infectious Disease Testing  
X  
 
 
 
 
 
 
 
 
 
 
 
UACR  
X  
 
 
 
X  
 
 
 
 
 
X  
 
Urine Pregnancy Test (all women)  
X  
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test (WOCBP)  
 
 
 
 
X  
 
 
X  
X  
X  
X  
X  
Diary and Glucometer Dispensation  
 
X  
 
X  
 
 
 
 
 
 
 
 
Dispensing Run-in Drug  
 
 
 
X  
 
 
 
 
 
 
 
 
Diary and Glucometer Record Review  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  


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Procedure  
Screen
 -ing  
Washout  
Run In  
Treatment Period  
Follow
-Up  
Dispensing Investigational Product  
 
 
 
 
 
X  
 
 
X  
 
 
 
Adverse Events & DKA Assessments  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Concomitant Medication Assessments  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 


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4. 
ENDPOINTS 
4.1. 
PRIMARY EFFICACY ENDPOINT 
• 
Change in HbA1c from baseline to week 24 in subjects with type 2 diabetes 
mellitus (T2DM) and inadequate glycemic control 
4.2. 
SECONDARY EFFICACY ENDPOINTS 
The key secondary efficacy endpoints include: 
• 
Change in SBP from baseline to week 24  
• 
Change in body weight from baseline to week 24 in subjects with a BMI 
≥ 25 kg/m2 
The exploratory secondary efficacy endpoints include: 
• 
Change from baseline in HbA1c over time 
• 
Proportion of subjects with HbA1c of < 7% over time 
• 
Change from baseline FPG over time 
4.3. 
SAFETY ENDPOINTS  
• 
AEs 
• 
AE of special interest 
• 
Clinical laboratory results 
• 
Physical exam results 
• 
Vital signs 
• 
ECG results 
• 
Medication use 
 
 


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5. 
ANALYSIS SETS 
5.1. 
SCREENED ANALYSIS SET 
The screened analysis set will include all subjects screened for eligibility prior to 
randomization. The screened population will include screen failures. Unless specified 
otherwise, this population will be used for subject listings and for summaries of subject 
disposition. 
5.2. 
SAFETY ANALYSIS SET  
All subjects who are randomized and have taken at least one dose of double-blind study 
medication will be included in the Safety Analysis Set. Safety analyses will be based on 
the first medication kit that was dispensed to a subject. The Safety Analysis Set is the 
primary analysis set for safety evaluation. 
 
5.3. 
INTENTION TO TREAT ANALYSIS SET  
All subjects who are randomized will be included in the Intention to Treat (ITT) Analysis 
Set. All analyses of the ITT Analysis Set will be based on the randomization schedule. 
The ITT analysis set will serve as the primary set for the efficacy analyses. 
 
5.4. 
PER PROTOCOL ANALYSIS SET  
The Per Protocol (PP) Analysis Set will include all subjects in the ITT who meet the 
study eligibility requirements and have no major protocol deviations that affect the 
validity of the efficacy measurements. Detailed protocol deviations that may result in 
subject exclusion from the PP Analysis Set are described in Section 5.5.  The PP analysis 
set will serve as the secondary set for efficacy assessment. 
 
5.5. 
PROTOCOL DEVIATIONS 
Protocol deviations will be captured during monitoring visits.  Major protocol deviations 
that could affect the primary and secondary variables, in the opinion of the medical 
monitor, will be considered when determining a subject’s eligibility for the PP 
population.  
Table 2 describes some possible types of major protocol deviations.  All protocol 
deviations will be reviewed and determined as major or minor before database lock. 
 
 


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Table 2 
Some Possible Types of Major Protocol Deviations 
Category  
Criteria 
Exclusion 
Inclusion/Exclusion Criteria  
 
 
Ineligible subject is enrolled  
- Subjects not satisfying HbA1c inclusion 
criteria  
- Subjects not satisfying eGFR inclusion criteria 
(inclusion #4 and #7) 
- Treated with SGLT2 within 3 months of 
screening 
 
Subject exclusion 
Prior or Concomitant 
Medication Restrictions  
 
 
Use of another SGLT2 inhibitor  
Use of an SGLT2 inhibitor as the rescue 
medication for hyperglycemia  
Visit exclusion [exclude 
data post SGLT2 starts] 
Use of new Diuretic medication 
Initiate of new diuretic medication within 12 
weeks of randomization 
Visit exclusion [exclude 
data post initiation of a 
new diuretic] 
Randomization/Blinding  
 
 
Unblinding  
Blind was broken (requested in IWRS)  
Visit exclusion [exclude 
data post blind broken] 
Dosing Non-Compliance 
-Subject missed more than 50% of the 
investigational product doses between week 12 
and week 24 
Subject exclusion 
 
 
 
 
 
 


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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
Statistical methodology and analyses are in accordance with the principles outlined by 
the ICH E9 guidelines.  All statistical analyses will be conducted using SAS statistical 
software version 9.3 or higher.  
Tables, listings and figures (TLFs) will be produced in accordance with the principles 
outlined by the ICH E3 guidelines.  For most summary statistics, data will be analyzed 
by the following treatment groups:  Bexagliflozin 20 mg; Placebo; and total of all 
treatment groups.  All available data from subjects who signed an informed consent will 
be presented in the subject listings.    
Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], Q1, median, Q3, minimum and maximum) for continuous variables, and 
frequency and percentage of subjects for categorical and ordinal variables, unless 
otherwise specified.  
Unless otherwise specified, all statistical tests will be two-tailed using a 0.05 level of 
significance. All confidence intervals (CIs) will be two-sided 95% CIs. 
The analysis visit window will be assigned to data collection.  One selected data point 
per visit will appear in summary tables and figures.  Refer to section 6.4 for details.  All 
visit assessment data will be included in shift tables and will appear in the subject 
listings. 
No data imputation will be applied for missing values, unless otherwise specified.  
6.2. 
KEY DEFINITIONS 
6.2.1. 
Baseline Values 
For safety endpoints, baseline is defined as the last non-missing value before the first 
dose of double-blind study medication.  For baseline demographics and efficacy 
endpoints, baseline is defined as the last non-missing value before the randomization 
date.  
6.2.2. 
First Dose Date 
Two “first dose dates” will be required – one for the Run-In period and one for the 
double-blind treatment period.  The first dose date for the Run-In period will be the 
date of administration of the first dose of single-blind placebo tablets during the Run-In 
period.  The first dose date for the double-blind treatment period will be the date that 


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the first dose of randomized, double-blind study drug is administered.  Both first dose 
dates will be obtained from the eCRF.  Study analyses will use the double-blind 
treatment period first dose date.   
6.2.3. 
Study Day 
Study Day is the number of days starting from the first administration of double-blind 
study drug, which is counted as Study Day 1.If the assessment date is after the date of 
the first double-blind medication, the study day is calculated as date of 
assessment - date of the first dose administration+1. If the assessment date is prior to 
the date of the first double-blind medication, the study day is calculated as date of 
assessment - date of the first dose administration. 
6.2.4. 
Duration 
Duration of double-blind treatment will be determined as Double-Blind Duration = 
Double-Blind Last Dose Date minus Double-Blind First Dose Date plus 1.  Duration of 
Run-In period will be determined as Duration = Last Dose Date in the run-in period 
minus First Dose Date in the run-in period plus 1. 
6.2.5. 
End of Study 
The end of study is defined as the date of final contact as entered on the End of Study 
page of the eCRF.  Any missing date of last contact on the End-of-Study eCRF will be 
imputed as the date of last contact recorded in the database.  
6.3. 
MISSING DATA 
The handling of missing or incomplete data is described for each endpoint and data type 
(as needed) in Section 7 to 9.   
6.4. 
ANALYSIS VISIT WINDOWS 
Table 3 shows how data will be mapped to analysis visits prior to selection of records 
for analysis. All post-baseline visits, including unscheduled and early termination visits, 
will be mapped.  After mapping the data to the analysis visits, the following rules will 
apply unless other handling is specified for a particular analysis.  
• 
If multiple records are available within a single analysis visit window, the record 
closest to the planned assessment day will be selected for analysis.  
• 
If 2 records are equidistant from the target day, then the later record will be 
selected.  
• 
If a subject has no record in an analysis window, the subject will be considered 
missing at that visit. 


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Table 3 
Analysis Visit Windows 
Study Day Window 
Scheduled day   
Scheduled Visit/Week 
Day  1 - 63 
Day 42 
Visit 8/Week 6 
Day 64 – 105 
Day 84 
Visit 9/Week 12 
Day 106 - 147 
Day 126 
Visit 10/Week 18 
>= Day 148  
Last Dose Date + 1 
Visit 11/Week 24 
* Week 24 is the end of treatment visit for those subjects completing the study per 
protocol.  For safety endpoint of lab, vital sign, and ECG, the first collection after 
assigned Week 24 and > 7 days from Week 24 visit will be considered as Week 26 visit.   
6.5. 
POOLING OF CENTERS 
Subjects will not be pooled based on site size, but rather by country, to ensure a 
sufficient number of subjects per treatment arm in both ITT and PP populations for 
analysis that contain country as a model effect.  Pooling by country will not be 
performed if the number of subjects at Canadian sites comprises less than 5% of 
enrolled subjects.  Otherwise, pooling by country will be performed. 
 
 


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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition data will be listed. A disposition table will present, by treatment 
group and overall, the number and/or percentage of subjects who signed the informed 
consent and entered the study (i.e., were screened, screen failed prior to Run-in, 
screen failed during the Day -14 to Day -1 Run-in, and randomized), complete the study 
drug, discontinued study drug, completed the study, and discontinued from the study 
after randomization.  The reasons for early withdrawal after randomization will be 
summarized.  A separate table will display the number of subjects who met eligibility 
criteria at screening and washout period but withdrew prior to randomization 
(non-randomized subjects) with a summary of the reasons for withdrawal prior to 
randomization. 
Assignment to the analysis sets (safety, ITT, and PP) will be summarized.  
7.2. 
SUBJECT ELIGIBLITY AND PROTOCOL DEVIATIONS 
All subjects, including screen failure subjects, who violate the Inclusion/exclusion 
criteria will be listed.  Reason for screen failure will be summarized. 
Deviations that could affect the primary and secondary variables will be considered 
when determining a subject’s eligibility for the PP population. The number and percent 
of subjects who had any major deviation and each type of major protocol deviation will 
be tabulated for the ITT Analysis Set. 
7.3. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic characteristics include age, gender, race, ethnicity and country of 
investigational site. Baseline characteristics will include HbA1c, blood pressure, body 
weight, BMI, FPG, duration of diabetes from diagnosis to the date of informed consent, 
and stratification factors including HbA1c values at V5 and background anti-diabetic 
treatment status (treatment naïve or not). Summary descriptive statistics by treatment 
will include counts and percentages for discrete variables and estimation of means, 
standard deviations, medians, inter-quartile range (Q1, Q3), minimum, and maximum 
for continuous variables. Subjects’ baseline demographic and personal baseline 
characteristics will be summarized by treatment group and overall for subjects in the 
safety, ITT, and PP analysis set. Subject age will be calculated as: 
Age at Study day 1 = (date of informed consent - date of birth + 1) / 365.25 and round 
down to complete years. 


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7.4. 
MEDICAL HISTORY 
Significant medical and surgical history, including dates of diagnoses and procedures 
and whether the condition is ongoing, if applicable, will be collected. Each condition 
will be recorded as a verbatim term, date of onset, date resolved, and a checkbox that 
indicates ongoing conditions.  Significant surgical and medical history will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) version 19.0. 
Medical and surgical history will be summarized for the Safety Analysis Set by treatment 
group, system organ class (SOC), and MedDRA preferred term (PT), overall. Subject data 
will be listed. 
Subject diabetes and cardiovascular diseases history will be summarized for all 
categorical variables by frequency and percentage.  Listing will be provided. 
7.5. 
MEDICATION 
All prescription and over-the-counter medications, including vitamins and herbal 
supplements, that subjects receive during the trial must be documented on the CRF. 
The medication name, dose, frequency, route of administration, date(s) of 
administration and reason for administration must be recorded. This documentation 
should continue through the treatment period and the follow up period. Changes from 
baseline anti-hypertensive therapy and their rationale must be recorded in the CRF.  
All medication will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) version March 2016.  Preferred drug name, 
Anatomical/Therapeutic/Chemical (ATC) class will be reported for inclusion in the 
database.   
Medication summaries based on ATC level 2, and the preferred drug names will be 
produced for the Safety Analysis Set. The summaries will present, by treatment group, 
the frequency and percentage of subjects who used any medication in an ATC class, or 
any medication based on a single preferred drug name. Medication summaries will be 
sorted by descending total frequency of ATC class and by PT within ATC class. Subjects 
will be counted only once for each medication class and each preferred drug name.  
For subject listings, medications will be reported based on ATC class and PT; multiple 
medications for an individual subject will be listed by start date and then by stop date, 
from earliest to latest medications.  


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7.5.1. 
Prior Medication 
Any medication with a start date prior to or on first dose date for the double-blind 
treatment period will be considered a prior medication.  If the entire start date of a 
given medication is missing, then the medication will be considered as prior medication.   
No summary for prior medication will be presented.  Prior and concomitant medications 
will be presented together on a single listing.  The listing will be ordered by subject 
number, and medication start/end dates. Prior medication will be flagged.   
7.5.2. 
Concomitant Medication 
A concomitant medication is any medication that the subject has been taking prior to 
the first dose of double blind study medication and that the subject is expected to 
continue to take for some portion of the study treatment period, as well as any 
medication other than the investigational product that the subject takes during the 
course of the study treatment period.  In the case of completely missing stop date, 
medication will be assumed to be concomitant.  A medication can be both prior and 
concomitant.  
The medications or treatment for controlling hypoglycemia must be recorded as 
concomitant medications in the CRF. Any medication given to treat hyperglycemia and 
continued for more than 2 weeks during the treatment period is considered a rescue 
therapy and should be recorded in the concomitant medication log.  All medication 
given to treat hyperglycemia will be recorded in CRF.   
Concomitant medications will be presented in a summary table as well as in a subject 
listing.  Rescue medications will be summarized in a separate table and flag in the same 
listing.  
 
 


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8. 
EFFICACY 
Efficacy data include HbA1c, FPG, body weight, and blood pressure. All changes from 
baseline will be calculated as the post-treatment value minus the last non-missing 
assessment before randomization (Visit V5).  All continuous efficacy data will be 
summarized for observed and change values by treatment and visit. Proportion of 
subjects with HbA1c of < 7% will be summarized by frequency and proportion by 
treatment and visit. 
8.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
The primary efficacy hypothesis is that bexagliflozin reduces HbA1c after 24 weeks of 
treatment when compared to placebo. 
8.1.1. 
Primary Efficacy Analysis 
Let μBexagliflozon and μPBO represent the mean changes from baseline in HbA1c at Week 24 
for bexagliflozin and placebo arms, respectively. The following hypotheses will be 
tested: 
H0: μBexagliflozon = μPBO versus H1: μBexagliflozon ≠ μPBO  
This hypothesis will be tested based on ITT analysis set using all observed data and a 
mixed model repeated measures (MMRM) approach.  The MMRM model will include terms 
for background anti-diabetes treatment status (treatment naïve or not), treatment, 
visit, treatment-by-visit interaction and the baseline HbA1c value as a fixed effect 
covariate.  Country will be used as a fixed effect if pooling by country is used.  The 
analysis will evaluate the mean change from baseline in HbA1c over the 24-week 
double-blind treatment period. An unstructured covariance will be used to model the 
within-subject correlation. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. If the model with the unstructured covariance 
structure does not converge, an autoregressive(1) covariance structure will be used. 
HbA1c values obtained after the start of rescue medication will not be excluded from 
the analysis. 
Based on the MMRM model, the treatment and treatment-by-visit interaction terms 
allow for comparisons of the treatment groups at each visit, and over week 6 to week 
24. Least squares (LS) mean treatment differences between the bexagliflozin group and 
the placebo group at week 24 will be estimated from the model with the corresponding 
p-values and their two-sided 95 % CIs presented. Sample SAS code will be provided in 
Appendix 1. 
Descriptive statistics (n, mean, Q1, median, Q3, SD, minimum, and maximum) will be 
reported by treatment group and visit, along with the least squares means, differences 


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between LS means, a 2-sided 95% confidence interval for each difference, p-values from 
the model effects. In addition, the LS means with standard errors of the change from 
baseline over time and difference between treatment groups with 95% will be presented 
graphically for the ITT population.   
For supportive analyses, the primary efficacy endpoint will be analyzed with observed 
available data using the PP analysis set in a similar manner as above. 
8.1.2. 
Sensitivity Analyses 
Randomized subjects who withdraw consent to participate in the study will not be 
replaced. The early termination rate is estimated to be 10%. To the extent possible, 
attempts will be made to minimize the amount of missing data through measures 
planned in the study conduct, but if data are missing for the primary endpoints, the 
number, timing, pattern, and reason for the missing value will be summarized. The 
reason for missing value will be evaluated to investigate possible implications of missing 
values in efficacy assessments.  The dropout patterns will be assessed by Kaplan-Meier 
plots, if applicable, to assess whether they differ between treatment groups.  If there 
are missing values for the primary analysis, only available data will be analyzed and 
data obtained after rescue will not be excluded.  To account for subjects for whom the 
post-baseline endpoint (ie, at the time when the last post-baseline double-blind 
assessment was performed) occurs at a time point before Week 24, a MMRM approach 
will be used as the primary method.  It is assumed that the majority of the missing 
values will be one of the following:  
• 
“Missing Completely at Random” (ie, probability of an observation being missing 
does not depend on observed or unobserved measurements) or 
• 
“Missing at Random” (ie, probability of an observation being missing depends 
only on observed measurements) 
In such situations, likelihood-base methods like MMRM are appropriate. 
Sensitivity analyses will be performed as: 
1. A multiple imputation method will be used to impute missing observations (including 
observations obtained after rescue medication) in the ITT Analysis Set prior to carrying 
out the MMRM analysis.  All intermediate missing, drop-out, and data after rescue 
medication will be imputed. 
2. A multiple imputation method will be used to impute missing observations (not 
including observations obtained after rescue medication) in the ITT Analysis Set prior to 
carrying out the MMRM analysis.  All intermediate missing and drop-out will be imputed.  


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Observed data after rescue medication will be used in the MMRM analysis and not 
considered missing. 
3. A last observation carried forward (LOCF) method will be used to impute the missing 
observations in the ITT Analysis Set.  Subjects who are rescued before Week 24 will 
have their HbA1c recorded at the time of rescue and carried forward.  
For sensitivity analysis 1 and 2, data will be imputed in the framework of a pattern 
mixture model (PMM) with placebo-based pattern imputation for missing visits.  The 
method described here is based on methodology described by Little and Yau (1996) and 
extended in a PharmaSUG paper by Ratitch and O’Kelly (2011).  The concept for the 
imputation used here is that subjects who drop out of the study from the active treated 
arms will exhibit the same evolution of the disease under study as those subjects 
assigned to the placebo arm.  It is assumed, as well, that subjects who discontinue from 
the placebo arm would have the same evolution of the disease as those subjects on the 
placebo arm who remained in the study.  The three-step approach outlined below will 
be followed (Ratitch B and O’Kelly M, 2011): 
1. 
Non-monotone (intermediate visits) missing data will be imputed first using the 
Monte Carlo Markov Chain method under the Missing at Random (MAR) assumption 
in all treatment arms (using the MCMC statement in PROC MI). Multiple chains 
option (CHAIN=MULTIPLE option in the MCMC statement of PROC MI) will be used. 
For the non-monotone imputation of the HbA1c missing data, a multivariate normal 
model will be used including variables for the HbA1c at baseline and all 
post-baseline visits within each treatment group.  
2. 
After the non-monotone missing data have been imputed, the remaining monotone 
missing data will be imputed under the Missing Not at Random (MNAR) assumption 
that subjects who withdraw from the bexagliflozin group will have correlations with 
future (post-withdrawal) visits similar to subjects in the placebo group, adjusted 
for baseline covariates and observed outcomes prior to withdrawal. Monotone 
missing data of withdrawn subjects from the placebo group will be imputed under 
the MAR assumption and will follow the pattern of placebo completers. In other 
words, monotone missing values of the HbA1c will be imputed for all subjects who 
withdrew from the study (regardless of treatment group) using an imputation model 
at each time point estimated from subjects with available data in the placebo 
group only.  A regression imputation model for the HbA1c at each time point t will 
include explanatory variables including background anti-diabetes treatment status 
(treatment naïve or not) and HbA1c at all previous time points, including baseline.  
Data from bexagliflozin group with time t data observed will not be used to impute 
time point t.  Imputations will be performed using a sequence of regression-based 
imputations (using PROC MI statement MONOTONE REG) for each post-baseline time 
point as described in (Ratitch B and O’Kelly M, 2011).  


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3. 
Imputed data in each of the multiple imputed datasets will be analyzed using the 
same mixed model for repeated measures as in the primary analysis. The results 
from all imputed datasets will be combined using the Rubin’s combination rule 
(PROC MIANALYZE).  
The sample SAS codes can be found in Appendix 1. 
The number of imputation will be determined using the method described by White, 
et.al., 2011.  We will use Bodner’s approximation to estimate the fraction of missing 
information (FMI) as the proportion of the incomplete cases in the data.  Since the 
parameter of interest is the mean changes from baseline in HbA1c at Week 24 for 
bexagliflozin and placebo groups, FMI will be approximated using the proportion of 
subjects missing Week 24 values.  As indicated by Bodner, this is a very conservative 
approach and will work with FMI≤0.5.  The number of imputations m will be determined 
to provide sufficient level of reproducibility using formula: 
m≥100×FMI 
as recommended by White.  The Monte Carlo error of the P-value using m imputation 
datasets will be approximately 0.01 when the true P-value is 0.05, and 0.02 when the 
true P-value is 0.1. 
At least 10 datasets will be imputed.  We will examine the FMI estimated from the 
combined results.  If it is much larger than our initial approximation, a considerable 
volatility is observed from the imputed datasets.  In this case, we will increase the 
number of m using the estimated FMI. 
For sensitivity analysis using LOCF, the observed data and the imputed values will be 
analyzed using the same MMRM model.  Model will include terms for background 
anti-diabetes treatment status (treatment naïve or not), treatment, and the baseline 
HbA1c value as a fixed effect covariate. LS mean treatment differences between the 
bexagliflozin group and the placebo group will be estimated from the model with the 
corresponding p-values and their two-sided 95 % CIs presented. 
8.1.3. 
Subgroups 
The primary efficacy endpoint will be summarized and analyzed by the following 
subgroups: 
• 
Age (<65 years or ≥65 years) 
• 
Gender (male or female) 
• 
Race (white or caucasian; black or African-American; other) 
• 
Baseline HbA1c (7.0% to 8.5% or 8.6% to 10.5%) 
• 
Background anti-diabetic treatment status (treatment-naïve or on treatment) 


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• 
Country (USA or Canada) 
8.2. 
SECONDARY EFFICACY ENDPOINT(S) AND ANALYSES 
The key secondary efficacy endpoints include: 
• 
Change in SBP from baseline to week 24.  
• 
Change in body weight from baseline to week 24 in subject with 
BMI≥ 25 kg/m2  
The exploratory efficacy endpoints include: 
• 
Change from baseline in HbA1c over time 
• 
Proportion of subjects with HbA1c of < 7% over time 
• 
Change from baseline FPG over time.   
8.2.1. 
Key secondary efficacy endpoints and analyses 
A hierarchical testing procedure will be applied to these endpoints in the sequence 
provided above. These key secondary endpoints will only be tested sequentially when 
significant treatment differences are established for the primary efficacy endpoint in 
the comparisons between the bexagliflozin and placebo groups. 
Analysis for key secondary endpoints will be based on the ITT analysis set and repeated 
for the PP analysis set.  The sensitivity analyses stated in Section 8.1.2 will be 
performed on all key secondary endpoints.   
8.2.1.1. 
Change in SBP from baseline to week 24  
This will be tested if the primary efficacy endpoint is significant.  Change from baseline 
in sitting SBP at week 24 will be analyzed using the MMRM ANCOVA model with 
unstructured covariance assumption. The model will include terms for treatment, visit, 
treatment-by-visit interaction, baseline HbA1c and background anti diabetes treatment 
status as fixed effects and the corresponding baseline SBP value as an additional fixed 
effect covariate. Treatment comparison p-values and difference at week 24 will be 
estimated from the model, with the two-sided 95% CIs of the treatment difference also 
presented. If the model does not converge with the unstructured correlation 
assumption, an autoregressive (1) model will be used. 
 


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8.2.1.2. 
Change in body weight from baseline to week 24 in subjects with a BMI 
≥ 25 kg/m2 
This will be tested if the primary efficacy endpoint and the key secondary 
endpoint-change from baseline SBP are significantly different between bexagliflozin and 
placebo groups based on ITT analysis set.  The comparison of change in body weight 
between randomized treatments at week 24 will be carried out using the ANCOVA 
model. The model will include terms for treatment, background anti diabetes treatment 
status and baseline HbA1c as fixed effects, and the corresponding baseline weight value 
as an additional fixed effect covariate. Treatment comparison p-values and difference 
at week 24 will be estimated from the model, with the two-sided 95 % CIs of the 
treatment difference also presented. If the primary hypothesis is not significant, the 
nominal p-value will not be used for inferential purposes. 
8.2.2. 
Exploratory secondary efficacy endpoints and analyses 
All endpoints in this section are exploratory.  No sensitivity analyses and adjustment for 
multiple comparisons will be conducted.  Nominal p-values will be used to examine any 
trends in these endpoints.  
8.2.2.1. 
Changes from baseline in HbA1c, and in FPG over time 
These endpoints will be analyzed using similar MMRM ANCOVA models as for the key 
secondary efficacy endpoint, Section Error! Reference source not found..  The 
treatment-by-visit interaction term will be removed if it is not significant.  Of interest 
in the MMRM ANCOVA model is the difference between treatments on these endpoints 
across all post-baseline time points. Also, changes from baseline for each endpoint will 
be estimated and analyzed at each study visit using this MMRM model. Specifically, for 
each endpoint, treatment difference in least squares means will be estimated by visit 
from the model with the corresponding p-values and the two-sided 95% CIs of the 
difference between treatments. 
8.2.2.2. 
Proportions of subjects with HbA1c of < 7% over time  
This endpoint will be analyzed using generalized estimating equation logistic regression. 
The treatment-by-visit interaction term will be removed if not significant.  An 
unstructured correlation structure will be used (or autoregressive(1) if the model with 
the unstructured structure does not converge). Of interest is the difference between 
treatments across all post-baseline time points. Also, odds ratios will be estimated from 
the model with the corresponding p-values and their two-sided 95% CIs presented at 
each visit. The odds ratios of bexagliflozin group over the placebo group at each visit 
and across all post-baseline time points will be estimated from LS means based on the 
model with the corresponding p-values and their two-sided 95 % CIs presented. Sample 
SAS code will be provided in Appendix 1. 
 


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9. 
SAFETY 
All analyses described in this section will be performed separately for each part of the 
study. The analysis population used for safety analyses will be the Safety Analysis Set.  
Safety data include AEs; physical examination results; vital signs, including blood 
pressures; ECG results; and clinical laboratory results, including serum chemistry, 
hematology, serum lipids, and urinalysis.  
Observed data will be summarized by treatment group as counts and percentages for 
discrete variables and means, standard deviations, medians, inter-quartile range, 
minimum, and maximum for continuous variables. All subjects who are randomized and 
receive at least one dose of double-blind study medication will be included in the safety 
analysis. All safety data will be presented in by-subject listings and included in the 
clinical trial report.  
9.1. 
EXTENT OF EXPOSURE 
Study drug exposure will include: 
• 
Treatment duration by treatment group 
• 
Total dose received by treatment group 
Treatment duration of tablets (in weeks) is calculated as (the date of the last dose of 
study drug – the date of the first dose of study drug + 1) / 7 and rounded to 1 decimal 
place.  
The specific definitions of the first dose and last dose dates of study drug are given 
below: 
• 
First dose date: The date of the first dose of study treatment during the 
double-blind treatment period obtained from the study drug exposure CRF.  
• 
Last dose date: The date of the last dose of study medication in the 24 week 
treatment period for subjects who have completed the study or discontinued 
early.  If the date of last dose is unknown, this date will be estimated using 
the last study drug return date, if available; otherwise, the date of the last 
completed visit will be used.  Total dose received will be calculated as 
number of tablets dispensed – number of tablets returned.  
Summary statistics for treatment duration (in weeks) and total dose received, as well as 
a frequency summary of treatment duration categories (e.g., < 1, 1 - < 6 weeks), will be 
provided. 


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9.2. 
TREATMENT COMPLIANCE  
Subjects will be provided with dosing instructions each time study medication is 
dispensed. Subjects will also be instructed to bring their medication with them to every 
visit. During the run-in period, subjects will be considered compliant in investigational 
product administration by missing no more than one dose of run-in medication. Subjects 
who are not compliant during the run-in period will be excluded from randomization. 
At each visit the study staff will review the self-monitored blood glucose (SMBG) control 
diary, glucometer data and medication use with the subject and record the drug 
consumption in the CRF. Reasons for non-adherence will also be recorded in the 
protocol deviation log if applicable. 
Compliance in the run-in and double-blind phase is calculated for as follows: 
• 
Percent compliance = (number of tablets taken / number of tablets should have 
taken) x 100. 
• 
Number of tablets taken = number of tablets dispensed – number of tablets 
returned. 
• 
Number of tablets should have taken = (number of tablets supposed to take in a day) 
x (number of exposure days). 
• 
Number of exposure days = last dose date – first dose date + 1. 
If any of the bottles dispensed is not returned, it will not be possible to compute the 
compliance.  In this case, the number of tablets taken and compliance will be 
considered as missing.  Summary statistics for tablet compliance (%) will be provided by 
treatment group for the double-blind treatment period. A frequency summary of 
compliance will also be presented with the following categories: < 75%, 75-<100%, 
100-120%, and > 120%. 
9.3. 
ADVERSE EVENTS 
Adverse events will be collected and recorded from the time a subject signs the 
informed consent form (ICF) to the last scheduled contact.  And new serious adverse 
events (SAE) reported by the subject to the investigator that occur after the last 
scheduled contact, and are determined by the investigator to be reasonably associated 
with the use of the investigational product, should be reported to the sponsor or 
designated personnel. This may include SAEs that are captured on follow-up telephone 
contact or at any other time point after the defined study period (i.e., up to last 
scheduled contact). The investigator should follow SAEs identified after the last 
scheduled contact until the events are resolved, or the subject is lost to follow-up. The 
investigator should continue to report any significant follow-up information to the 
sponsor until the event has been resolved. This study requires that subjects be actively 
monitored for SAEs for at least 4 weeks after the last treatment.  


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For all AEs, preferred AE terms and system organ class (SOC) will be coded using 
terminology from the Medical Dictionary for Regulatory Activities (MedDRA), version 
19.0    
A treatment-emergent adverse event (TEAE) is defined as an AE that begin after the 
first administration of double-blind study medication or existing AEs that worsen after 
the first dose of double-blind study medication.  All reported AEs will be listed, but only 
TEAEs will be summarized in tables.  
Drug-related AEs will be considered those to be possibly, probably and definitely related 
to bexagliflozin administration based on the investigators assessment. 
Unless otherwise specified, AEs will be summarized by SOC and PT, with SOCs and PTs 
within SOCs presented in descending order of subject incidence. 
9.3.1. 
Derived Data 
AE onset day is calculated as (date of AE start – date of double-blind first dose + 1).  
The onset day will be missing if the start date is missing or partially missing.   
9.3.2. 
Data Summarization  
AE summary tables are listed below: 
• 
An overall summary of the number and percentage of subjects reporting any 
TEAEs, serious TEAEs, treatment-related TEAEs, serious treatment-related TEAE, 
any TEAEs leading to treatment discontinuation, any TEAEs leading to subject 
discontinuation and TEAEs leading to death.   
• 
TEAEs overall and by SOC and PT 
• 
TEAEs by severity, overall and by SOC and PT 
• 
Serious TEAEs, overall and by system organ class and preferred term 
• 
TEAEs by relationship to study treatment, overall and by system organ class and 
preferred term 
• 
TEAEs leading to treatment discontinuation, overall and by SOC and PT 
• 
TEAEs leading to study discontinuation, overall and by SOC and PT 
• 
Most common TEAEs.  Most common TEAEs are defined as TEAEs that occur in 
> 5% of the subjects in either of the treatment groups.  


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For summary tables, subjects having more than 1 event with the same PT will be 
counted once for that term.  Subjects having more than 1 event with the same SOC will 
be counted once for each event and once for that SOC.  For tabulations by severity, 
only a subject’s most severe event within the category (e.g. overall, SOC, PT) will be 
counted; similarly, for tabulations by relationship, only a subject’s most related event 
within a category will be counted.  The denominator for percentages will be the number 
of subjects in the Safety Analysis Set for the given treatment group (i.e., the N’s for the 
columns).   
Listings will be provided for all AEs and the following subsets: 
• 
All TEAEs 
• 
All TEAEs at least possibly related to bexagliflozin 
• 
Serious AEs 
• 
AEs leading to treatment discontinuation 
• 
AEs leading to death.  
Additional information will be collected for diabetic ketoacidosis (DKA).  These data will 
be listed. 
9.3.3. 
AE of Special Interest 
AE of special interest include urinary tract infection (UTI), genital mycotic infection 
(GMI), diuretic effects, hepatotoxicity, cardiovascular events, hypoglycemia, fracture, 
malignancy, hypersensitivity reactions, hypotensive episodes, acid-base disorders, renal 
failure events, and amputations. These AEs of special interest, except for 
cardiovascular events and amputations, will be prospectively identified based on the 
MedDRA PTs in the AEs log by a medical expert prior to the data base lock and 
unblinding of the individual subject treatment assignment. The list of AEs of special 
interest will be confirmed in a peer review process.  Cardiovascular events, 
hypoglycemia events by severity, and amputations will be summarized separately. 
9.3.3.1. 
AE of special interest identified by PTs 
The number and percentage of subjects experiencing these TEAEs of special interest 
will be summarized for each treatment group by type of event. The incidence rate of AE 
of special interest per 100 patient years will also be summarized.  Each category of 
events will be displayed in a separate listing.   
9.3.3.2. Hypoglycemic Events 
Hypoglycemic event categories include: 
 


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Category 
Description 
Severe 
Assistance required and blood glucose ≤70 mg/dL or no value 
available but responded to glucose treatment 
Documented 
Symptomatic 
Blood glucose ≤70 mg/dL and typical symptoms of hypoglycemia 
Asymptomatic Blood glucose ≤70 mg/dL and no typical symptoms of hypoglycemia 
Probable 
Symptomatic 
Typical symptoms of hypoglycemia and no value available but 
responded to glucose treatment 
Relative 
Typical symptoms of hypoglycemia and blood glucose >70 mg/dL 
 
While each event meeting the criteria above will be entered into the hypoglycemia log, 
only critical (severe) hypoglycemia, documented symptomatic hypoglycemia, 
asymptomatic hypoglycemia, and probable hypoglycemia will be entered as AEs.  
The number and percentage will be summarized by treatment for: 
• 
Each category of hypoglycemic events; 
• 
Any severe or documented hypoglycemic events. 
9.3.3.3. 
Major Adverse Cardiovascular Events 
Cardiovascular events considered as MACE by investigator will be submitted to an 
independent CEC for adjudication.  The events of interest include cardiovascular 
mortality, MI, stroke, hospitalization for acute coronary syndromes, urgent 
revascularization procedures, and other possible serious cardiovascular events.  The 
number, percentage and incidence rate per 100 patient years of suspected MACE and 
adjudicated MACE will by summarized for each treatment group.  Adjudicated MACE will 
be further summarized by PTs. 
9.3.3.4. 
Revascularization and Amputations 
Revascularization and amputations information are collected in a separate form.  
Frequency and percentage will be summarized for: 
• 
Type of procedures –cardiovascular related or amputation 
• 
Subjects with any amputation 
• 
Conditions that resulted in amputation 
• 
Location of amputation 
Only procedures performed after the first dose of double-blind study drug will be 
summarized. 


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9.4. 
LABORATORY EVALUATIONS 
Laboratory tests will include hematology panel, chemistry panel, serum lipids, and 
urinalysis testing. Hematology, chemistry, serum lipids, and urinalysis will be performed 
at the following time points: at the screening visit (Week - 11), on baseline visit (Day -3 
to -5), and at week 6, 12, 18, 24, and 26.  Serum lipids will be performed at the 
screening visit (Week - 11), on baseline visit (Day -3 to -5), and on week 12, 24, and 26. 
Renal functional testing by UACR will be determined at the screening visit, on baseline 
visit and at week 24. The study staff will contact each subject prior to a scheduled 
clinic visit to confirm the time of the visit and to remind the subject of proper fasting 
practice. A subject must be queried to assess compliance with an approximately 10-hour 
fast prior to blood draw to ensure the FPG and triglycerides values can be accurately 
determined. If a subject has not fasted for approximately 10 hours, the subject must 
return as soon as can be arranged (within 1 week) to provide a specimen after proper 
fasting. A list of laboratory tests is included in Table 4. 
Low density lipoprotein cholesterol (LDL-C) will be calculated by the Friedewald 
equation. If triglycerides are > 400 mg/dL, the calculated LDL-C value is invalid by this 
equation and will be set as missing. Direct LDL-C will be determined in subjects whose 
triglycerides are > 350 mg/dL at screening visit. All subsequent LDL-C of these subjects 
will be determined by the same direct LDL-C measurements only.  If triglycerides are 
>350 mg/dL, a reflex test will be performed based on direct LDL measurement.  The 
following algorithm will be used to obtain LDL-C values for the analyses: 
1. Select subjects (based on the SI unit) who had screening triglycerides >3.4 or 
>350 based on the conventional unit 
2. Take the LDL – direct measurement values only, throughout the study visits for 
those subjects 
3. If screening triglycerides > 350 and no direct LDL-C values have been 
determined, take the calculated.   
Among those subjects who have screening triglycerides >350 and have both calculated 
and direct LDL values, only take the direct LDL. 
Urinalysis microscopy will be conducted if the subject has a positive result on the 
leukocyte esterase or nitrite dipstick tests to clarify the significance of the finding. 
Results of glucose measurement in the urinalysis must be suppressed from the 
laboratory reports so the sponsor, investigators, study coordinators, pharmacists, study 
subjects, and the CEC members will remain blinded to the dosing assignment.  
The baseline value will be the latest value obtained prior to Day 1.  Change from 
baseline for all continuous parameters will be calculated as the post-baseline value 
minus the baseline value.  All continues variables will be summarized by number of 
subjects [n], mean, SD, Q1, median, Q3, minimum and maximum and categorical 


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variables will be summarized by frequency and percentage. 
All scheduled and unscheduled results will be considered in tables that assess maximum 
grade or toxicity.   
Observed values (in SI units) and change from baseline over time will be summarized by 
treatment group.  Laboratory data will be classified as low, normal, or high relative to 
the parameter’s reference range. Laboratory abnormalities for each treatment will also 
be summarized with shift tables for selected parameters. 
All laboratory data will be listed.  For hematology, chemistry, and serum lipids, columns 
will be included for normal ranges and individual abnormal laboratory values will be 
flagged and clinical significance will be indicated.  A listing for the microscopic 
examination will be provided for subjects who have a positive result from the urinalysis 
dipstick evaluation.  
 


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Table 4 
List of Laboratory Tests 
Test Name (sample volume)  
Hematology (2 mL blood) 
• Mean corpuscular hemoglobin 
(MCH)  
• Mean corpuscular hemoglobin 
concentration (MCHC)  
• Mean corpuscular volume 
(MCV)  
• White blood cell (WBC) count 
with differential  
• Red blood cell (RBC) count  
• Hematocrit (Hct)  
• Hemoglobin (Hgb)  
• Platelet count 
Serum Chemistry and Electrolytes (3 mL serum)  
• Albumin (ALB)  
• ALT  
• AST  
• Blood urea nitrogen (BUN)  
• Creatinine  
• Uric acid  
• Calcium (Ca)  
• Magnesium  
• Phosphorus  
• Potassium (K)  
• Sodium (Na)  
• Total Protein  
• Glucose  
• Bicarbonate (HCO3)  
• Chloride (Cl)  
• Total bilirubin  
• Direct bilirubin 
Glycemic Control (2 mL plasma, 2 mL blood)  
• FPG  
• HbA1c 
 
Serum Lipids  
• Total cholesterol (TC)  
• High-density lipoprotein 
cholesterol (HDL-C)  
• Low-density lipoprotein 
cholesterol (LDL-C), calculated, or 
• LDL-C, direct  
• Triglycerides (TG) 
Infectious Disease Testing (3 mL serum)  
• Hepatitis B surface antigen 
(HBsAg) 
• Hepatitis C virus (HCV) 
 
Urinalysis  
• Appearance 
 • Bilirubin  
• Color  
• Glucose (blinded)  
• Ketones  
• Microscopic examination of 
sediment  
• Nitrite  
• Leukocyte esterase 
 • Occult blood  
• pH  
• Protein  
• Specific gravity  
• Urobilinogen 
Renal Functional Test  
• UACR  
Urine Pregnancy Test  
 


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9.5. 
VITAL SIGNS  
Vital signs will be measured at the screening visit (Week -11), on baseline visit (Day -3 
to -5), and at week 6, 12, 18, 24, and 26. Measurements of vital signs will include 
measurement of supine, sitting and standing blood pressure (BP) measurements, and 
heart rate. Only the BP measured in the sitting position will be used to determine 
eligibility.  Orthostatic systolic and diastolic BP will be calculated as supine 
measurement – standing measurement.  
For BP, pulse rate, and respiration rate, observed values and change from baseline will 
be summarized by treatment group and nominal visit using descriptive statistics (n, 
mean and median, standard deviation, Q1, and Q3, minimum and maximum).  For BP,  
supine, sitting, standing, and orthostatic BP will be summarized.  Subjects vital sign 
measurements, including scheduled and unscheduled visits, will be listed.  
9.6. 
ELECTROCARDIOGRAM  
A 12-lead electrocardiogram (ECG) will be conducted at the screening visit (Week - 11), 
on baseline visit (Day -3 to -5), at week 24, and at week 26. ECG parameters measured 
will be the RR interval, PR interval, QRS duration, and QT interval. Each ECG should also 
be assessed by the investigator for signs of ischemia, clinically significant hypertrophy, 
and clinically significant T-wave abnormalities or arrhythmia. 
For each abnormal ECG result, the investigator shall ascertain if the observation 
represents a clinically significant change from the screening ECG for that individual 
subject (this determination, however, does not necessarily need to be made the first 
time an abnormal result is observed. The investigator may repeat the ECG to verify the 
results of the original result). If the ECG result is determined to be a clinically 
significant and abnormal change from baseline for that subject, it is considered an AE. 
For the ECG parameters, observed values and change from baseline from scheduled 
visits will be summarized with descriptive statistics by treatment group and overall at 
each visit.  The maximum change from baseline from scheduled visits will also be 
provided for ECG parameters. 
For the ECG overall assessment, the number and percentage of subjects in each overall 
assessment category (normal, abnormal but not clinically significant, abnormal and 
clinically significant, missing) will be presented by treatment group and overall at each 
visit.   
9.7. 
PHYSICAL EXAMINATION 
A complete physical examination will be conducted at the baseline visit (Day -3 to -5) 
and at week 26. The examination will include measurement of body weight, and a 


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general assessment of all body systems including the skin, head, eyes, ears, nose, 
throat, neck, heart, lungs, abdomen, lymph nodes, and extremities.  An abbreviated 
physical examination will be conducted at screening visit 1 (Week -11) and at week 24, 
or clinically indicated.  The examination will include body weight and height (height will 
be measured only at screening), and general assessment of the skin, heart, lungs and 
abdomen. Physical examination findings will be presented in a by-subject listing.  
 
 


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10. 
INTERIM ANALYSES 
No interim analyses are planned. 
11. 
DATA AND SAFETY MONITORING BOARD 
An independent data and safety monitoring board (DSMB) will review descriptive 
summaries of accumulating safety, subject disposition and limited efficacy data every 6 
months, or a frequency recommended by the DSMB.   
A designated statistician who is not involved with the study operation will hold the 
treatment codes. The unblinded treatment information can be provided to the DSMB to 
facilitate the evaluation of any clinically important increase in the rate of a serious 
suspected adverse reaction or to the designated safety contact when the treatment 
information is required to determine if an expedited safety report must be submitted to 
regulatory agencies. The data outputs for this review will be created by an unblinded 
team. Personnel involved in the conduct of the study will not participate in the 
preparation of these outputs, receive the data, or participate in the unblinded portions 
of the DSMB meetings.  More details will be provided for DSMB charter and DSMB SAP. 
12. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
There is no change from analysis planned in protocol. 
 
 


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13. 
REFERENCE LIST 
Little, R., Yau, L. Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs. 
Biometrics, 1996; 52: 1324—1333. 
Ratitch, B., O’Kelly, M. Implementation of Pattern-Mixture Models using Standard 
SAS/STAT Procedures.  Pharmasug 2011 – Paper SP04, PHARMASUG. 
Bodner TE. What improves with increased missing data imputations?  Structural Equation 
Modeling: A Multidisciplinary Journal 2008; 15: 651—675.  
White IR., Royston P., Wood AM. Multiple imputation using chained equations: Issues 
and guidance for practice.  Statistics in Medicine 2011; 30: 377—399. 
 
 


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14. 
PROGRAMMING CONSIDERATIONS 
The following conventions will hold for programming of outputs: 
• 
SAS® Version 9.3 or higher will be used for programming and production 
• 
The format of the table shells will be followed as closely as possible; however, in 
the course of programming and familiarization with the database, some changes may 
become necessary.  All changes will be documented.  Major changes will be documented 
through a formal amendment to this document.  
• 
Patients in this study will be identified as “Subjects.” 
• 
Descriptive statistics will be displayed in the following order: 
n 
Mean 
Standard deviation (SD) 
Q1 
Median 
Q3 
Minimum  
Maximum  
• 
Decimal places: For summary statistics, the minimum and maximum will be 
reported with the same number of decimal places as the collected measure, the mean, 
LS mean (if applicable) and median will have 1 more decimal place than the measure 
collected, and the SD and confidence interval (CI) will have 2 more decimal places than 
the collected measure.  For frequency distributions, percentages will be reported to 1 
decimal place.  For p-values, 4 decimal places will be reported or the SAS® p-value 
format of “< 0.0001” or “> 0.9999” will be reported.  
• 
Unless otherwise noted, the denominator for percentages is the number of 
subjects in the applicable analysis population and treatment group.  
• 
If the frequency for a particular table cell is zero, then “0”, properly aligned, 
will be displayed (i.e. “0 (0.0%)” will not be displayed.) 
• 
Non-numeric values:  Where variables are recorded using < (e.g., “< 10” or “≤ 
10”) the numeric portion of the result divided by 2 will be used (e.g., < 10 and ≤ 10 
becomes 5) for summary; where variables are recorded using > (e.g., “> 10” or “ ≥ 10”) 
the numeric portion of the result will be used (e.g. > 10 and ≥ 10 become 10) for 
summary; the actual recorded results, (e.g. “< 10” or “> 10”) will appear in listings. 


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14.1. 
GENERAL CONSIDERATIONS 
• 
A separate SAS program will be created for each output. 
• 
Output files will be delivered in Word format. 
• 
Numbering of TFLs will follow ICH E3 guidance 
 
14.2. 
TABLE, LISTING, AND FIGURE FORMAT 
14.2.1. 
General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size 8  
• 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
• 
Headers and footers for figures will be in Courier New font, size 8. 
• 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and 
programmer-supplied formats, as appropriate. 
 
14.2.2. 
Headers 
• 
All output should have the following header at the top left of each page: 
Theracos Sub, LLC 
Protocol Number: THR-1442-C-450       
• 
Draft or Final in top right corner. 
• 
All output should have Page n of N at the top of each page. TLFs should be internally 
paginated in relation to the total length (i.e., the page number should appear 
sequentially as page n of N, where N is the total number of pages in the table). 
• 
The date output was generated should appear along with the program name as a 
footer on each page. 


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14.2.3. 
Display Titles 
• 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination. A decimal system (x.y and x.y.z) should be 
used to identify TLFs with related contents. The title is centered. The analysis set 
should be identified on the line immediately following the title. The title and table 
designation are single spaced. A solid line spanning the margins will separate the 
display titles from the column headers. There will be 1 blank line between the last 
title and the solid line. 
 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Set 
 
14.2.4. 
Column Headers 
• 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values will be presented in a separate comparison column (if applicable).  
• 
For numeric variables, include “unit” in column or row heading when appropriate. 
• 
Analysis set sizes will be presented for each treatment group in the column heading 
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set. 
• 
The order of treatments in the tables and listings will be active treatment first, then 
placebo, followed by a total column (if applicable). 
14.2.5. 
Body of the Data Display 
14.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 


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14.2.5.2. Table Conventions 
• 
Units will be included where available 
• 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
• 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 
• 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
• 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
SD 
     X.XX 
Q1 
XXX.X 
Median 
XXX.X 
Q3 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
• 
P-values should be output in the format: “0.xxxx”, where xxxx is the value rounded 
to 4 decimal places. Any p-value less than 0.0001 will be presented as <0.0001.  If 
the p-value is returned as >0.9999 then present as >0.9999 
• 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). If the rounded 
percentage is 0.0, display as '<0.1'. Unless otherwise noted, for all percentages, the 
number of subjects in the analysis set for the treatment group who have an 
observation will be the denominator. Percentages after zero counts should not be 


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displayed and percentages equating to 100% should be presented as 100%, without 
any decimal places.  
• 
Tabular display of data for concomitant and rescue medications should be presented 
by treatment class with the highest occurrence in the total column in decreasing 
order.  Tabular display of data for medical history and adverse event data should be 
presented by the SOC using descending order.  Within the drug class and SOC, 
medical history (by preferred term), drugs (by ATC2 code), and adverse events (by 
preferred term) should be displayed in decreasing order in the total column. If 
incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics which cannot be estimated should be 
reported as “-”. 
• 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
• 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
• 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page.  The overall summary statistics for the subheading should only be 
output on the first relevant page. 
14.2.5.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 
• 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
• 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
• 
Units will be included where available 


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14.2.5.4. Figure Conventions 
• 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis. 
14.2.6. 
Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
• 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
• 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
• 
Subject specific footnotes should be avoided, where possible. 
• 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page.  
• 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’). 
15. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. INC Research SOP 03.010 
and 03.013 provide an overview of the development of such SAS programs. 
INC Research SOP 03.009 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the 
proper clinical trial output by checking for their logic, efficiency and commenting and 
by review of the produced output. 
 
 


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16. 
INDEX OF TABLES 
Number 
Title 
Table 14.1.1.1 
Subject Disposition (Screened Analysis Set) 
Table 14.1.1.2 
Reasons for Screen Failure (Non-randomized Subjects) 
Table 14.1.2 
Summary of Major Protocol Deviations  (Safety Analysis Set) 
Table 14.1.3.1 
Demographics and Baseline Characteristics  (Safey Analysis Set) 
Table 14.1.3.2 
Demographics and Baseline Characteristics  (ITT Analysis Set) 
Table 14.1.3.3 
Demographics and Baseline Characteristics  (PP Analysis Set) 
Table 14.1.4.1 
Summary of Significant Medical and Surgical History by System Organ 
Class and Preferred Term (Safety Analysis Set) 
Table 14.1.4.2 
Summary of Type 2 Diabetes History (Safety Analysis Set) 
Table 14.1.4.3 
Summary of Cardiovascular History  (Safety Analysis Set) 
Table 14.1.5.1  
Summary of Concomitant Medications  (Safety Analysis Set) 
Table 14.1.5.2  
Summary of Hyperglycemia Rescue Medications  (Safety Analysis Set) 
Table 14.1.6  
Study Drug Exposure and Compliance during Double-Blind Treatment 
Period, by Randomized Group  (Safety Analysis Set) 
Table 14.2.1.1 
Analysis of Change from Baseline in HbA1c (%) at Week 24  (ITT 
Analysis Set) 
Table 14.2.1.2 
Analysis of Change from Baseline in HbA1c (%) at Week 24  (PP 
Analysis Set) 
Table 14.2.1.3.1 
Summary of Reason for Missing Values by Visit- Change from Baseline 
in HbA1c (%)  (ITT Analysis Set) 
Table 14.2.1.3.2 
Missing Data Pattern - Change from Baseline in HbA1c (%) (ITT 
Analysis Set) 
Table 14.2.1.4.1 
Sensitivity Analysis 1: Multiple Imputation for Change from Baseline in 
HbA1c (%) Including Observations Obtained After Rescue Medication 
(ITT Analysis Set) 
Table 14.2.1.4.2 
Sensitivity Analysis 2: Multiple Imputation for Change from Baseline in 
HbA1c (%) Excluding Observations Obtained After Rescue Medication  
(ITT Analysis Set) 
Table 14.2.1.4.3 
Sensitivity Analysis 3: LOCF for Change from Baseline in HbA1c (%) 
Including Observations Obtained After Rescue Medication  (ITT 
Analysis Set) 
Table 14.2.1.5 
Analysis of Change from Baseline in HbA1c (%) Over Time  (ITT 
Analysis Set) 
Table 14.2.1.6 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by Age  
(ITT Analysis Set) 


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Number 
Title 
Table 14.2.1.7 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by Gender  
(ITT Analysis Set) 
Table 14.2.1.8 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by Race  
(ITT Analysis Set) 
Table 14.2.1.9 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by Baseline 
HbA1c Category  (ITT Analysis Set) 
Table 14.2.1.10 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by Anti-
diabetic Treatment Status  (ITT Analysis Set) 
Table 14.2.1.11 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by Country  
(ITT Analysis Set) 
Table 14.2.2.1 
Analysis of Change from Baseline in SBP (mmHg) at Week 24 (ITT 
Analysis Set) 
Table 14.2.2.2 
Analysis of Change from Baseline in SBP (mmHg) at Week 24 (PP 
Analysis Set) 
Table 14.2.2.3.1 
Sensitivity Analysis 1: Multiple Imputation for Change from Baseline in 
SBP (mmHg) Including Observations Obtained After Rescue Medication  
(ITT Analysis Set) 
Table 14.2.2.3.2 
Sensitivity Analysis 2: Multiple Imputation for Change from Baseline in 
SBP (mmHg) Excluding Observations Obtained After Rescue 
Medication (ITT Analysis Set) 
Table 14.2.2.3.3 
Sensitivity Analysis 3: LOCF for Change from Baseline in SBP (mmHg) 
Including Observations Obtained After Rescue Medication  (ITT 
Analysis Set) 
Table 14.2.3.1 
Analysis of Change from Baseline in Body Weight (kg) at Week 24 for 
Subjects with BMI ≥ 25 kg/m2 (ITT Analysis Set) 
Table 14.2.3.2 
Analysis of Change from Baseline in Body Weight (kg) at Week 24 for 
Subjects with BMI ≥ 25 kg/m2 (PP Analysis Set) 
Table 14.2.3.3.1 
Sensitivity Analysis 1: Multiple Imputation for Change from Baseline in 
Body Weight (kg) for Subjects with BMI ≥ 25 kg/m2   Including 
Observations Obtained After Rescue Medication  (ITT Analysis Set) 
Table 14.2.3.3.2 
Sensitivity Analysis 2: Multiple Imputation for Change from Baseline in 
Body Weight (kg) for Subjects with BMI ≥ 25 kg/m2  Excluding 
Observations Obtained After Rescue Medication  (ITT Analysis Set) 
Table 14.2.3.3.3 
Sensitivity Analysis 3: LOCF for Change from Baseline in Body Weight 
(kg) for Subjects with BMI ≥ 25 kg/m2  Including Observations 
Obtained After Rescue Medication  (ITT Analysis Set) 
Table 14.2.4 
Analysis of Change from Baseline in FPG (mmol/L) Over Time  (ITT 
Analysis Set)  
Table 14.2.5 
Summary of Proportion of Subjects with HbA1c < 7% Over Time  (ITT 
Analysis Set) 
Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events  (Safety 
Analysis Set) 


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Number 
Title 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term   (Safety Analysis Set) 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Maximum Severity  (Safety Analysis Set)  
Table 14.3.1.4 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Relationship to Study Drug  (Safety Analysis Set)  
Table 14.3.1.5 
Most Common Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term  (Safety Analysis Set) 
Table 14.3.1.6 
Treatment-Emergent Serious Adverse Events by System Organ Class 
and Preferred Term  (Safety Analysis Set) 
Table 14.3.1.7 
Serious Treatment-Emergent Treatment Related Adverse Events by 
System Organ Class, Preferred Term and Relationship to Study Drug  
(Safety Analysis Set) 
Table 14.3.1.8 
Summary of Treatment Related Treatment-Emergent Adverse Events 
by System Organ Class and Preferred Term  (Safety Analysis Set)  
Table 14.3.1.9 
Summary of Treatment Emergent Adverse Events Leading to 
Treatment Discontinuation by System Organ Class and Preferred Term  
(Safety Analysis Set)  
Table 14.3.1.10 
 Summary of Treatment Emergent Adverse Events of Interest  (Safety 
Analysis Set)  
Table 14.3.1.11 
Summary of Treatment Emergent Hypoglycemia Events   (Safety 
Analysis Set)  
Table 14.3.1.12 
Summary of Major Adverse Cardiovascular Events  (Safety Analysis 
Set) 
Table 14.3.1.13 
Summary of Revascularization and Amputations  (Safety Analysis Set) 
Table 14.3.2.1 
List of Treatment Related TEAEs  (Safety Analysis Set) 
Table 14.3.2.2 
List of Serious Adverse Events  (Safety Analysis Set) 
Table 14.3.2.3 
List of Adverse Events Leading to Treatment Discontinuation  (Safety 
Analysis Set) 
Table 14.3.2.4 
List of Adverse Events Leading to Death  (Safety Analysis Set) 
Table 14.3.4.1 
Summary of Hematology: Results and Change from Baseline by Visit  
(Safety Analysis Set) 
Table 14.3.4.2 
Shift in Clinical Laboratory Values: Hematology   (Safety Analysis Set) 
Table 14.3.4.3 
Summary of Serum Chemistry: Results and Change from Baseline by 
Visit (Safety Analysis Set) 


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Number 
Title 
Table 14.3.4.4 
Shift in Clinical Laboratory Values: Serum Chemistry  (Safety Analysis 
Set) 
Table 14.3.4.5 
Summary of Urinalysis: Results and Change from Baseline by 
Visit - Continuous Variables  (Safety Analysis Set) 
Table 14.3.4.6 
Summary of Urinalysis Results by Visit - Categorical Variables  (Safety 
Analysis Set) 
Table 14.3.4.7 
Shift in Clinical Laboratory Values: Urinalysis   (Safety Analysis Set) 
Table 14.3.4.8 
Summary of Serum Lipids: Results and Change from Baseline by Visit 
(Safety Analysis Set) 
Table 14.3.4.9 
Shift in Clinical Laboratory Values: Serum Lipids  (Safety Analysis Set) 
Table 14.3.5  
Summary of Vital Signs: Results and Change from Baseline by Visit  
(Safety Analysis Set) 
Table 14.3.6.1 
Summary of 12-Lead ECG Investigator Overall Assessment by Visit  
(Safety Analysis Set) 
Table 14.3.6.2 
Summary of 12-Lead ECG Parameters by Visit: Results and Change 
from Baseline   (Safety Analysis Set) 
 
 
 


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17. 
INDEX OF FIGURES 
Number 
Title 
Figure 14.1.1 
Kaplan-Meier Plot of Time to Discontinuation by Week 26  (ITT 
Analysis Set) 
Figure 14.2.1.1 
LS Mean (± SE) Change from Baseline in HbA1c (%) (ITT Analysis Set)  
Figure 14.2.1.2 
LS Mean Difference (95% CI) in Change from Baseline in HbA1c (%) 
(ITT Analysis Set) 
Figure 14.2.1.3 
LS Mean (± SE) Change from Baseline in HbA1c (%) (PP Analysis Set) 
Figure 14.2.1.4 
LS Mean Difference (95% CI) in Change from Baseline in HbA1c (%) (PP 
Analysis Set)  
Figure 14.2.1.5 
Sensitivity Analysis 1: Multiple Imputation LS Mean Difference (95% 
CI) in Change from Baseline in HbA1c (%)  Including Observations 
Obtained After Rescue Medication (ITT Analysis Set) 
Figure 14.2.1.6 
Sensitivity Analysis 2: Multiple Imputation LS Mean Difference (95% 
CI) in Change from Baseline in HbA1c (%)  Excluding Observations 
Obtained After Rescue Medication (ITT Analysis Set)  
Figure 14.2.2 
LS Mean (± SE) Change from Baseline in Fasting Plasma Glucose 
(mmol/L) (ITT Analysis Set) 
Figure 14.2.3 
Proportion of Subjects Reaching HbA1c < 7% (ITT Analysis Set) 
 
 
 


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18. 
INDEX OF LISTINGS 
Number 
Title 
Listing 16.2.1.1 
Subject Disposition  
Listing 16.2.1.2 
Subject Discontinuation 
Listing 16.2.2 
Protocol Deviation  
Listing 16.2.3.1 
Analysis Sets (All Randomized Subjects) 
Listing 16.2.3.2 
Subjects Who Did Not Meet Inclusion/Exclusion Criteria 
Listing 16.2.4.1 
Demographics 
Listing 16.2.4.2 
Significant Medical and Surgical History 
Listing 16.2.4.3 
Type 2 Diabetes History 
Listing 16.2.4.4 
Cardiovascular Disease History 
Listing 16.2.4.5 
Prior and Concomitant Medications  
Listing 16.2.5.1 
Study Drug Accountability 
Listing 16.2.5.2 
Study Drug Exposure and Compliance 
Listing 16.2.6.1 
Glycemic Control Tests: HbA1c (%) 
Listing 16.2.6.2 
Glycemic Control Tests: Fasting Plasma Glucose (mmol/L) 
Listing 16.2.6.3 
Hypoglycemia Events 
Listing 16.2.6.4 
Weight (kg) 
Listing 16.2.7.1  
Adverse Events 
Listing 16.2.7.2.1 
Urinary Tract Infection Adverse Events (Safety Analysis Set)  
Listing 16.2.7.2.2 
Genital Mycotic Infection Adverse Events (Safety Analysis Set)  


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Number 
Title 
Listing 16.2.7.2.3 
Diuretic Effects Adverse Events (Safety Analysis Set)  
Listing 16.2.7.2.4 
Hepatotoxicity Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.5 
Major Adverse Cardiovascular Events (Safety Analysis Set) 
Listing 16.2.7.2.6 
Hypoglycemia Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.7 
Fracture Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.8 
Malignancy Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.9 
Hypersensitivity Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.10 
Acid-base Disorders Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.11 
Renal Failure Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.12 
Revascularization and Amputations (Safety Analysis Set) 
Listing 16.2.7.3.1 
DKA Symptoms Assessment  
Listing 16.2.7.3.2 
Suspected DKA Assessment  
Listing 16.2.7.3.3 
Suspected DKA Clinic/Hospital Report 
Listing 16.2.7.3.4 
Suspected DKA Outpatient Clinic 
Listing 16.2.7.3.5 
Suspected DKA Hospitalization 
Listing 16.2.8.1 
Clinical Laboratory Tests: Hematology 
Listing 16.2.8.2 
Clinical Laboratory Tests: Serum Chemistry 
Listing 16.2.8.3 
Clinical Laboratory Tests: Urinalysis 
Listing 16.2.8.4 
Clinical Laboratory Tests: Serum Lipids 
Listing 16.2.8.5 
Urine Pregnancy Test 


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Number 
Title 
Listing 16.2.9.1 
Vital Signs 
Listing 16.2.9.2 
12-Lead Electrocardiogram 
Listing 16.2.9.3 
Physical Examination 
 
 
 


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19. 
MOCK-UPS 
 
Attachment 1: Planned Table Shells 
Attachment 2: Planned Listing Shells  
Attachment 3: Planned Figure Shells 
 
20. 
APPENDICES