Clinical trial NCT03259789
Conditions: Type2 Diabetes Mellitus
Sponsor: Theracos
Start date: 2017-11-28; Completion date: 2019-01-23
Enrollment: 351 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the effect of bexagliflozin compared to placebo as an add-on therapy to metformin in lowering hemoglobin A1c (HbA1c) levels in subjects with type 2 diabetes mellitus (T2DM).

Detailed description:
Approximately 300 subjects with inadequately controlled T2DM on metformin were to be recruited from the United States and Japan. Subjects were randomly assigned to receive bexagliflozin tablets, 20 mg, or bexagliflozin tablets, placebo, in a ratio of 1:1 once daily for 24 weeks. Subjects were to continue taking metformin for the duration of the study. The study also enrolled 50 subjects with extremely poorly controlled T2DM on metformin to receive open-label bexagliflozin tablets, 20 mg, for 24 weeks.

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Bexagliflozin tablets, 20 mg intervention 2: Bexagliflozin tablets, placebo intervention 3: Bexagliflozin tablets, 20 mg
Intervention descriptions: intervention 1: Each subject will receive bexagliflozin, 20 mg once daily for the duration of the study. intervention 2: Each subject will receive placebo (inactive tablet) once daily for the duration of the study. intervention 3: Each subject will receive bexagliflozin, 20 mg once daily for the duration of the study.

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol: THR-1442-C-419 
Study Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate Bexagliflozin in Subjects with Type 2 Diabetes Mellitus 
Who Are not Adequately Controlled by Metformin Alone 
Study Number: 
THR-1442-C-419 
Study Phase: 
3 
Product Name: 
Bexagliflozin Tablet 
Indication: 
Type 2 Diabetes Mellitus 
Investigators: 
Multicenter Study 
Sponsor: 
Theracos Sub, LLC 
225 Cedar Hill Road Suite 200, Marlborough, MA 01752 
Sponsor Contact: 
Donna Stram 
Phone: 978-340-0869 
Fax: 617-643-8203 
email: donna@chimeraclinical.com  
Medical Monitor: 
Robert Klugman, M.D.  
Phone: 508-735-9491 
Fax: 617-643-8203 
Email: rklugman@theracos.com. 
 
 
 
Date 
Protocol V1.0: 
26 July 2017  
 
 
 
Confidentiality Statement 
The information in this document is the confidential information of Theracos Sub, LLC 
(“Theracos”) and must not be disclosed, used, or copied except with prior written approval 
from Theracos or to the extent required by applicable laws, rules, and regulations. 
 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................10 
1 
INTRODUCTION ...........................................................................................................12 
1.1 
Type 2 Diabetes Mellitus .......................................................................................12 
1.2 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus ...............................13 
2 
STUDY OBJECTIVES ....................................................................................................14 
2.1 
Primary Objective ..................................................................................................14 
2.2 
Secondary Objectives.............................................................................................14 
2.3 
Safety Objectives ...................................................................................................14 
2.4 
Other Objectives: ...................................................................................................14 
3 
INVESTIGATIONAL PLAN ..........................................................................................15 
3.1 
Overall Study Design and Plan ..............................................................................15 
3.2 
Research Methods and Procedures ........................................................................16 
3.2.1 
Run-in Period ...............................................................................................16 
3.2.2 
Treatment Period ..........................................................................................16 
3.2.3 
Glycemic Control Monitoring......................................................................17 
3.2.3.1 
Placebo Run-in Period .......................................................................17 
3.2.3.2 
Treatment Period ................................................................................17 
3.2.3.3 
Rescue Medication .............................................................................18 
3.2.4 
Other Safety Monitoring Activities .............................................................19 
3.2.5 
Data and Safety Monitoring Board (DSMB) ...............................................19 
3.2.6 
Major Adverse Cardiovascular Event (MACE) Adjudication .....................19 
3.2.7 
Diabetic Ketoacidosis (DKA) Event Adjudication ......................................20 
3.3 
Rationale for Study Design and Control Group .....................................................20 
3.3.1 
Rationale for Study Design ..........................................................................20 
3.3.2 
Rationale for Background Medication .........................................................20 
3.3.3 
Rationale for Dose Selection .......................................................................20 
3.4 
Study Duration and Dates ......................................................................................20 
4 
STUDY POPULATION SELECTION ...........................................................................22 
4.1 
Study Population ....................................................................................................22 
4.2 
Inclusion Criteria ...................................................................................................22 
4.3 
Exclusion Criteria ..................................................................................................22 
5 
STUDY TREATMENT(S) ..............................................................................................24 
5.1 
Description of Treatment(s) ...................................................................................24 
5.1.1 
Investigational Product ................................................................................24 
5.2 
Treatments Administered .......................................................................................24 
5.2.1 
Investigational Product ................................................................................24 


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5.2.2 
Background Metformin Therapy .................................................................24 
5.3 
Selection and Timing of Dose for Each Subject ....................................................24 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................25 
5.5 
Blinding..................................................................................................................25 
5.6 
Concomitant Therapy.............................................................................................26 
5.6.1 
Diuretics and Medications for Treatment of Dyslipidemia and 
Hypertension ................................................................................................26 
5.7 
Restrictions ............................................................................................................26 
5.7.1 
Prior Therapy ...............................................................................................26 
5.7.2 
Fluid and Food Intake ..................................................................................26 
5.7.3 
Subject Activity Restrictions .......................................................................27 
5.8 
Treatment Compliance ...........................................................................................27 
5.9 
Packaging and Labeling .........................................................................................27 
5.10 
Storage and Accountability ....................................................................................28 
5.11 
Investigational Product Retention at Study Site ....................................................28 
6 
STUDY PROCEDURES .................................................................................................29 
6.1 
Informed Consent...................................................................................................29 
6.2 
Screening for I/E Criteria .......................................................................................29 
6.3 
Medical History .....................................................................................................29 
6.3.1 
General Demographics and Characteristics .................................................29 
6.3.2 
Diabetes History...........................................................................................30 
6.3.3 
Cardiovascular Disease History ...................................................................30 
6.3.4 
Medication History ......................................................................................30 
6.4 
Diet and Exercise Counseling ................................................................................30 
6.5 
Physical Examination.............................................................................................30 
6.6 
Abbreviated Physical Examination ........................................................................31 
6.7 
Vital Signs ..............................................................................................................31 
6.8 
Electrocardiography ...............................................................................................32 
6.9 
Clinical Laboratory Tests .......................................................................................32 
6.9.1 
Laboratory Parameters .................................................................................32 
6.9.2 
Sample Collection, Storage, and Shipping ..................................................34 
6.9.3 
Urinalysis .....................................................................................................34 
6.9.4 
Population PK Sampling ..............................................................................35 
6.10 
Diary and Glucometer Dispensation and Review ..................................................35 
6.11 
Dispensing Run-in Drug ........................................................................................35 
6.12 
Diary and Glucometer Record Review ..................................................................36 
6.13 
Dispensing Investigational Product .......................................................................36 
6.14 
Adverse Events Assessments .................................................................................36 


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6.14.1 
Definition of Adverse Events.......................................................................36 
6.14.2 
Eliciting and Reporting AEs ........................................................................38 
6.14.3 
Immediately Reportable AEs .......................................................................38 
6.14.4 
Pregnancy .....................................................................................................39 
6.14.5 
Procedure for Breaking the Blind ................................................................40 
6.14.6 
Follow-up of Non-Serious AEs ...................................................................40 
6.14.7 
Follow-up of Post-Study SAEs ....................................................................40 
6.14.8 
Urinary Tract Infections (UTIs) ...................................................................41 
6.14.9 
Genital Mycotic Infections (GMIs) .............................................................41 
6.14.10 Hepatotoxicity ..............................................................................................41 
6.14.11 Hypoglycemia ..............................................................................................42 
6.14.12 Major Adverse Cardiovascular Event (MACE) ...........................................44 
6.14.13 Diabetic Ketoacidosis (DKA) ......................................................................44 
6.14.14 Amputation ..................................................................................................45 
6.15 
Concomitant Medication Assessments ..................................................................45 
6.16 
Removal of Subjects from the Trial or Treatment Discontinuation ......................46 
6.17 
Appropriateness of Measurements .........................................................................46 
7 
STUDY ACTIVITIES .....................................................................................................47 
7.1 
Visit 1/ Screening (up to 3 weeks prior to randomization) ....................................47 
7.2 
Visit 2/ Run In (1 week prior to randomization)....................................................47 
7.3 
Visit 3/ Randomization ..........................................................................................47 
7.4 
Visit 4/ 6 Weeks .....................................................................................................48 
7.5 
Visit 5/ 12 Weeks ...................................................................................................48 
7.6 
Visit 6/ 18 Weeks ...................................................................................................48 
7.7 
Visit 7/ 24 Weeks ...................................................................................................48 
7.8 
Visit 8/ Follow Up .................................................................................................49 
7.9 
Early Termination Procedures ...............................................................................49 
8 
QUALITY CONTROL AND ASSURANCE .................................................................50 
9 
PLANNED STATISTICAL METHODS ........................................................................51 
9.1 
General Considerations ..........................................................................................51 
9.2 
Determination of Sample Size ...............................................................................51 
9.3 
Analysis Populations ..............................................................................................51 
9.3.1 
Intention-to-Treat Analysis Set ....................................................................51 
9.3.2 
Safety Analysis Set ......................................................................................52 
9.3.3 
Per Protocol Analysis Set.............................................................................52 
9.4 
Demographics and Baseline Characteristics ..........................................................52 
9.5 
Efficacy Analysis ...................................................................................................52 
9.5.1 
Primary Efficacy Endpoint ..........................................................................52 


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9.5.2 
Secondary Efficacy Endpoints .....................................................................53 
9.6 
Safety Analysis ......................................................................................................54 
9.6.1 
Adverse Events ............................................................................................54 
9.6.2 
Adverse Events of Special Interest ..............................................................54 
9.6.3 
Clinical and Laboratory Events and Analyses .............................................54 
9.6.4 
Physical Examination...................................................................................55 
9.7 
Other Analyses .......................................................................................................55 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................56 
10.1 
Investigators and Study Administrative Structure .................................................56 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................56 
10.3 
Ethical Conduct of the Study .................................................................................56 
10.4 
Subject Information and Consent...........................................................................57 
10.5 
Subject Confidentiality ..........................................................................................57 
10.6 
Study Monitoring ...................................................................................................57 
10.7 
Case Report Forms and Study Records .................................................................58 
10.8 
Data Monitoring Committee ..................................................................................58 
10.9 
Protocol Violations and Deviations .......................................................................58 
10.10 Access to Source Documentation ..........................................................................59 
10.11 Retention of Data ...................................................................................................59 
10.12 Publication and Disclosure Policy .........................................................................59 
11 REFERENCE LIST .........................................................................................................60 
 
LIST OF IN-TEXT TABLES 
Table 1. 
List of Laboratory Tests .............................................................................33 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
BP Measurement Procedure .......................................................................32 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .....................................................................................62 
Appendix 2 
Schedule of Clinical Laboratory Tests .......................................................63 
Appendix 3 
Examples of SGLT2 Inhibitors ..................................................................64 
Appendix 4 
Sponsor Signatures.....................................................................................65 
Appendix 5 
Investigator’s Signature .............................................................................66 


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SYNOPSIS 
Sponsor: Theracos Sub, LLC 
Name of Finished Product: Bexagliflozin Tablet 
Name of Active Ingredient: Bexagliflozin  
Study Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Bexagliflozin 
in Subjects with Type 2 Diabetes Mellitus Who Are not Adequately Controlled by 
Metformin Alone  
Study Number: THR-1442-C-419 
Study Phase: 3 
Primary Objective:  
The primary objective of this study is to determine the effect of bexagliflozin on the placebo-
corrected change in HbA1c from baseline to week 24 in adults with T2DM whose disease is 
inadequately controlled by metformin alone. 
Secondary Objectives: 
• 
To assess the effect of bexagliflozin on the change in FPG as a function of time 
• 
To assess the effect of bexagliflozin on the change in SBP as a function of time  
• 
To assess the effect of bexagliflozin on the proportion of subjects achieving HbA1c of 
≤ 7% as a function of time 
• 
To assess the change in total body weight as a function of time in subjects with baseline 
BMI ≥ 25 kg/m2 
• 
To assess the change in HbA1c as a function of time  
• 
To assess the change in HbA1c as a function of time among subjects who have baseline 
HbA1c of > 10.5% and ≤ 12.0% 
Study Design:  
Study THR-1442-C-419 is designed to evaluate the safety and effectiveness of bexagliflozin 
tablets, 20 mg, for the treatment of T2DM in adult diabetics whose disease is inadequately 
controlled by metformin alone. The study will recruit 300 subjects with HbA1c between 
7.5% and 10.5%, inclusive, to be randomized 1:1 to receive bexagliflozin tablets, 20 mg, or 
bexagliflozin tablets, placebo, in a double-blind treatment assignment. The primary endpoint 
of the study will be the placebo-corrected change from baseline to week 24 of the HbA1c 
percentage. This is the main study and the subjects are in the double-blind treatment group. 
The study will also recruit 50 subjects with HbA1c > 10.5% and ≤ 12.0 % into an open-label 
arm, to receive bexagliflozin tablets, 20 mg, for 24 weeks. The endpoint for the open-label 
arm will be the change from baseline to week 24 of the HbA1c percentage. The subjects are 
in the high glycemic group. 
All subjects are to have taken metformin at an optimal or near optimal stable dose for ≥ 8 
weeks prior to screening and are to have received diet and exercise counseling.  


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Subjects who meet all the inclusion criteria, none of the exclusion criteria, and who have 
consented to participate in the study, are eligible for study enrollment. Subjects who 
successfully complete a 1-week run-in and who remain eligible will be randomized. 
Approximately 300 subjects with HbA1c values ≥ 7.5 and ≤ 10.5% at screening will be 
randomized 1:1 to receive bexagliflozin tablets, 20 mg or placebo, in addition to their 
customary metformin dosage for 24 weeks in an outpatient setting.  Study subjects will not 
change their metformin dosage unless adjustment is medically necessary to manage 
hypoglycemia. The treatment period will last 24 weeks. Subjects will visit their study sites at 
weeks 6, 12, 18, and 24 for safety and efficacy evaluation, and at week 26 for a follow-up 
evaluation.   
Up to 50 subjects who have HbA1c > 10.5% and ≤ 12.0% at screening will be assigned to 
open label treatment group to receive bexagliflozin tablets, 20 mg, in addition to their 
existing metformin regimen. There will be no placebo arm for the high glycemic group. 
Subjects enrolled in the open label treatment group will be asked to follow the same 
procedures as subjects enrolled in the blinded arms of the study. 
Subjects with persistent hyperglycemia based on blood glucose levels may receive approved 
antidiabetic rescue medications. 
A sparse sampling assessment of bexagliflozin pharmacokinetics (PK) in the study 
population will also be performed. A net enrollment of approximately 200 subjects is planned 
for this aspect of the study. Samples will be taken between weeks 6 and 12. The population 
PK study design and analysis plan will be described in a designated study protocol and the 
analysis will be reported separately.  
Study Population:  
Approximately 350 subjects with T2DM will be enrolled in the study. The subjects must: 
1. have an age of ≥ 20 years at screening. Women of childbearing potential must test 
negative for pregnancy and agree to abstinence or contraception for the duration of the 
study to avoid any possible pregnancy.  Females who are surgically sterile (hysterectomy, 
oophorectomy) or postmenopausal (absence of menses greater than 12 months) are 
eligible if they test negative for pregnancy at screening.  
2. a) have a history of T2DM with an HbA1c level of ≥ 7.5% and ≤ 10.5% at screening, or  
b) have a history of T2DM with an HbA1c level of >10.5% and ≤ 12.0% at screening 
3. have been prescribed a stable dose of metformin (≥ 1500 mg per day in the US or 
≥ 1000 mg per day in Japan) as their sole anti-diabetic medication 
4. have a body mass index (BMI) ≤ 45 kg/m2 
5. be able to comprehend and willing to provide written informed consent in accordance 
with institutional and regulatory guidelines 
6. not have recently changed their medications for hypertension or hyperlipidemia (if 
applicable)  
7. be able to regularly self-administer medication, as evidenced by consumption of all, or at 
worst one less than all, doses of run-in medication prior to randomization (at visit 3) 
Test Product, Dose, and Mode of Administration:  
Bexagliflozin tablets, 20 mg or placebo, once daily oral administration in 300 subjects 


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Bexagliflozin tablets, 20 mg once daily oral administration in 50 subjects 
Duration of Treatment:  
One week of run-in placebo treatment and 24 weeks of investigational product treatment  
Efficacy Assessments: 
The primary efficacy assessment is: 
• 
The effect of bexagliflozin on the placebo-corrected change in HbA1c from baseline to 
week 24 in adults with T2DM whose disease is inadequately controlled by metformin 
alone.  
The key secondary efficacy assessments are: 
• 
To assess the effect of bexagliflozin on the change in FPG as a function of time 
• 
To assess the effect of bexagliflozin on the change in SBP as a function of time  
• 
To assess the effect of bexagliflozin on the change in HbA1c as a function of time  
• 
To assess the effect of bexagliflozin on the change in total body weight as a function of 
time in subjects with baseline BMI ≥ 25 kg/m2  
• 
To assess the effect of bexagliflozin on the proportion of subjects achieving an HbA1c 
≤ 7.0% over time 
• 
To assess the change in HbA1c as a function of time among subjects who have baseline 
HbA1c level of ≥ 7.5% and ≤ 10.5% 
• 
To measure the change from baseline to week 24 in subjects with baseline HbA1c level 
of > 10.5% and ≤ 12.0%  
Other assessment: 
Evaluation of bexagliflozin pharmacokinetics 
Safety Assessments: 
Adverse events record, laboratory data including hematology, serum chemistry, urinalysis, 
ECG, vital signs, physical examinations, and concomitant medication use. 
Statistical Methods:  
Summaries will be presented for double-blinded portion of the study, separately from the 50 
subject open-label sub-study. No formal hypothesis testing will be performed for the sub-
study. 
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.   
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 the intention-to-treat (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 the baseline HbA1c value, country (US or Japan) as fixed 
effect covariates. 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% CIs presented. An unstructured covariance will be used to 


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model the within-subject correlation. If the model with the unstructured covariance structure 
does not converge, an autoregressive 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 analysis steps will be 
performed on the ITT analysis set: 
• 
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. 
• 
HbA1c values collected after the start of rescue medication will be excluded (considered 
missing), and the MMRM analyses will be re-performed. 
• 
A last observation carried forward (LOCF) method will be used to impute the missing 
observations prior to carrying out the MMRM model. 
 
The effect of bexagliflozin on fasting plasma glucose, the change in SBP, the proportion of 
subjects reaching ≤ 7.0% HbA1c, the change in HbA1c over time, and the change in total 
body weight, will be analyzed as secondary efficacy endpoints and will not be adjusted for 
multiplicity.  
Safety data will include AE descriptions, physical exam results, vital sign measurements, 
ECG results, and clinical lab results from analysis of 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. 
The sample size calculation for this study is based on two group t-test with a two-sided 
significance of 0.05 level. The assumptions that led to the estimated required sample size of 
150 per group with 1:1 ratio for a power of 90% are as follows: 
• 
A treatment effect of 0.4%. 
• 
A population HbA1c standard deviation of 1%. 
• 
A two-sided significance level of 0.05. 
• 
A drop-out rate of 12%. 
Date of Protocol V1.0: 26 July 2017 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
American Diabetes Association 
AE 
adverse event 
ALB 
albumin 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase  
ATC 
Anatomic Therapeutic Chemical classification 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CEC 
cardiovascular endpoint committee 
CI 
confidence interval 
CRF 
case report form 
CRO 
contract research organization 
DKA 
diabetic ketoacidosis  
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 
GLP-1 
glucagon-like peptide-1 
GMI 
genital mycotic infection 
h 
hour 
HbA1c 
hemoglobin A1c 
Hct 
hematocrit 
HDL-C 
high-density lipoprotein cholesterol 
HDPE 
high-density polyethylene 
Hgb 
hemoglobin 
HUA 
hospitalization for unstable angina 
ICH 
International Council for Harmonisation  
IEC  
Independent Ethics Committee 
IRAE 
immediately reportable adverse event 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 
IWRS 
Interactive Web Response System  
LDL-C 
low density lipoprotein cholesterol 
LOCF 
last observation carried forward 
MACE 
major adverse cardiovascular event 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 


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MCV 
mean corpuscular volume 
MDRD 
modification of diet in renal disease 
MedDRA 
medical dictionary for regulatory activities 
MI 
myocardial infarction 
MMRM 
mixed model repeated measures 
MODY 
maturity–onset diabetes of the young 
N 
number of subjects 
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 
QRS 
QRS complex the combination of three of the graphical deflections seen on a typical 
electrocardiogram 
QT 
a measure of the time between the start of the Q wave and the end of the T wave in the heart's 
electrical cycle 
RBC 
red blood cell (count) 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SGLT2 
sodium glucose cotransporter 2 
SMBG 
self-monitored blood glucose 
SOP 
standard operating procedure 
SU 
sulfonylurea 
SUSAR 
serious and unexpected suspected adverse event 
TIA 
transient ischemic attack 
T2DM 
type 2 diabetes mellitus 
TC 
total cholesterol 
TEAE 
treatment emergent adverse event 
TG 
triglycerides 
TZD 
thiazolidinedione 
UACR 
urine albumin to creatinine ratio 
UADR 
unexpected adverse drug reaction 
UGE 
urinary glucose excretion 
ULN 
upper limit of normal 
UPT 
urinary pregnancy test 
UTI 
urinary tract infection 
WBC 
white blood cell (count) 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of childbearing potential 
 


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1 
INTRODUCTION 
Type 2 diabetes mellitus (T2DM) is one of the leading causes of morbidity and mortality 
worldwide, affecting an estimated 415 million people in 2015. Approximately 187 million of 
those affected are thought to be unaware of their condition and over 80% reside in low- and 
middle-income countries(IDF, (2015)). 
1.1 
Type 2 Diabetes Mellitus 
T2DM is the predominant form of diabetes and accounts for at least 90% of all diabetes 
cases. T2DM 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 acceleration of cardiovascular disease. 
Diabetes is the leading cause in the developed world of blindness, amputation and dialysis. . 
T2DM is a disease strongly linked to increased body fat mass(Schwartz 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 et al., 2013; Scheen 
and Van Gaal, 2014)Scheen2014. Several classes of agents are available for treating T2DM, 
including insulin, insulin secretagogues, (such as sulfonylureas (SU) and meglitinides), 
PPAR agonists, biguanides, alpha glucosidase inhibitors, glucagon-like peptide 1 (GLP-1) 
receptor agonists, dipeptidyl peptidase 4 (DPP4) inhibitors, and sodium glucose linked 
transporter 2 inhibitors (SGLT2i).   
Metformin is often prescribed for the initial management of T2DM. However the disease 
typically progresses and additional agents must be prescribed to maintain adequate glycemic 
control.  
The rapid growth rate in the 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, either as monotherapy or add-on therapy to other 
anti-diabetic medications, 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(Santer et al., 2003; van den Heuvel et 
al., 2002). The excretion of glucose in the urine of diabetic subjects in amounts comparable 
to or greater than that seen in individuals harboring loss of function 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 


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demonstrated these clinical benefits, as well as sustained weight loss, when used as a 
monotherapy or in combination with other oral anti-diabetic medications including insulin 
(Nauck, 2014; Seufert, 2015). 
1.2 
 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus 
Bexagliflozin is a candidate oral hypoglycemic agent (OHA) 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 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. In a 12 week monotherapy study, bexagliflozin tablets, 20 mg, 
elicited a greater placebo-adjusted HbA1c reduction (-0.80%) than bexagliflozin tablets, 
10 mg (-0.68%), or bexagliflozin tablets, 5 mg (-0.55%). Bexagliflozin administration has 
been well tolerated. The safety and efficacy of bexagliflozin capsules, 20 mg, have been 
demonstrated in a 96-week study that measured reduction in hemoglobin A1c (HbA1c) as the 
primary endpoint. Details of the pharmacology, efficacy, and safety assessments are 
described in the Investigator’s Brochure. The safety profile supports continued evaluation of 
the treatment effect of bexagliflozin when used in combination with metformin. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to determine the placebo-corrected change in HbA1c 
from baseline to week 24 in adults with T2DM whose disease is inadequately controlled by 
metformin alone. 
2.2 
Secondary Objectives  
• 
To assess the effect of bexagliflozin on the change in FPG as a function of time 
• 
To assess the effect of bexagliflozin on the change in SBP as a function of time  
• 
To assess the effect of bexagliflozin on the proportion of subjects achieving HbA1c of 
≤ 7% as a function of time 
• 
To assess the change in total body weight as a function of time in subjects with baseline 
BMI ≥25 kg/m2 
• 
To assess the change in HbA1c as a function of time  
• 
To assess the change in HbA1c as a function of time among subjects who have baseline 
HbA1c of > 10.5% and ≤ 12.0% 
 
2.3 
Safety Objectives 
The safety objectives of the study are: 
• 
To determine the frequency and severity of treatment emergent adverse events 
• 
To determine the frequency and severity of treatment emergent adverse events of interest 
• 
To record and evaluate changes in concomitant medication use that may affect subject 
safety 
• 
To evaluate any potentially adverse changes in laboratory test values 
• 
To assess changes in cardiac rhythm through 12-lead ECG 
• 
To evaluate vital signs 
• 
To assess general health by physical examination 
 
2.4 
Other Objectives: 
The other objective is: 
• 
To measure bexagliflozin plasma concentrations as a function of time from dosing 
(sparsely sampled) 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
THR-1442-C-419 is a phase 3, multi-center study in which 300 subjects will participate in a 
randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 
orally administered bexagliflozin tablets, 20 mg or placebo, in subjects whose T2DM is not 
adequately controlled by metformin along with diet and exercise. The primary endpoint is the 
placebo corrected change in HbA1c from baseline at week 24 in subjects whose HbA1c 
values are ≥ 7.5% and ≤ 10.5% at screening.  This is the main study and the subjects are in 
the double-blind treatment group.  In addition, 50 subjects who have baseline HbA1c values 
> 10.5% and ≤ 12.0% will participate in an open labelled, uncontrolled sub-study to assess 
bexagliflozin effects on glycemic control. The subjects are in the high glycemic group. 
All subjects must have taken metformin at an optimal or near-optimal stable dose for ≥ 8 
weeks prior to screening and have received diet and exercise counseling.  
Approximately 350 subjects who meet all the inclusion criteria, none of the exclusion 
criteria, and who consent to participate in the study, are eligible for study enrollment. 
Approximately 300 subjects with HbA1c values ≥ 7.5% and ≤ 10.5% at screening (the 
double-blind treatment group) who successfully complete a 1-week run-in and who remain 
eligible will be randomized in a 1:1 ratio to receive once daily double-blind treatment of 
bexagliflozin tablets, 20 mg or placebo.  Study subjects will continue receiving open-labeled 
metformin background medication during the entire study at a stable dose and frequency. The 
treatment period will last 24 weeks.  The study will be conducted in an outpatient setting. 
Study subjects will have clinic visits at weeks 6, 12, 18, and 24 for safety and efficacy 
evaluation. A final follow up visit will be conducted at week 26. 
Up to 50 subjects who have HbA1c > 10.5% and ≤ 12.0% at screening will be assigned to the 
high glycemic group to receive open labeled bexagliflozin tablets, 20 mg, in addition to 
metformin. There will be no placebo control cohort for the high glycemic group.  Subjects 
assigned to the high glycemic group will be asked to follow the same study procedures as 
subjects assigned to the two study arms. 
Subjects with persistent hyperglycemia based on blood glucose levels may receive approved 
antidiabetic rescue medications. 
A sparse sampling assessment of bexagliflozin pharmacokinetics (PK) in the study 
population will also be performed. A net enrollment of approximately 200 subjects is planned 
for this aspect of the study. Samples will be taken between weeks 6 and 12. The population 
PK study design and analysis plan will be described in a designated study protocol and the 
analysis will be reported separately. 


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3.2 
Research Methods and Procedures 
3.2.1 
Run-in Period 
All subjects who are eligible at the screening visit will begin a one-week run-in period. At 
the start of the run-in period, subjects will receive diet and exercise counseling as well as 
instructions to contact the clinic in the event of hyperglycemia, hypoglycemia, or symptoms 
that may suggest ketoacidosis. At the start of the run-in period, subjects will be provided with 
a glucometer and instructions for its daily use. During the run-in period, subjects will be 
asked to self-administer placebo tablets. The tablets are to be taken with water at the same 
time every day. The metformin dose and frequency are expected to remain unchanged from 
the time of screening through the end of the study. 
Subjects will not be eligible for randomization if during the run-in period they:  
1. omit more than 1 day of run-in medication, or 
2. are deemed inappropriate for the study by the investigator,  
 
Inclusion and exclusion criteria are described in more detail in Section 4.2 and Section 4.3. 
 
Changes in the doses of medications used to treat dyslipidemia or hypertension will not be 
permitted during the screening and run-in periods. Management of concomitant medications 
is described in Section 5.6.  
If a change in treatment for hypertension or dyslipidemia is deemed necessary by the 
investigator for the well-being of the study subject during the run-in period, the subject will 
be considered a screen failure and will discontinue study activities; there will be no 
opportunity to re-screen subjects.  
3.2.2 
Treatment Period 
The double-blind treatment period will start at randomization and end after 24 weeks of 
treatment. Approximately 300 subjects with 7.5% ≤ HbA1c ≤ 10.5% will be randomized in a 
1:1 ratio to the active or placebo arms.  
Randomization will be stratified by HbA1c (≤ 8.5% or ˃ 8.5%) and country (US or Japan) at 
screening (Visit 1). At the start of the treatment period, each subject will be provided with 
bexagliflozin or placebo tablets and dosing instructions. Symptoms and blood glucose 
measurements related to the occurrence of hyperglycemia, hypoglycemic events, or 
symptoms that may suggest ketoacidosis will be recorded. Bexagliflozin tablets, 20 mg or 
placebo, will be taken once daily at approximately the same time each day either before or 
after breakfast with approximately one cup (250 mL) of water. Metformin shall be taken at 
the same dose and frequency throughout the study.  
Each subject will be instructed to return to the clinic at weeks 6, 12, 18 and 24 for efficacy 
assessment and safety monitoring, including review of AEs and concomitant medications, 


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measurements of vital signs and ECG, physical examination, and blood and urine specimen 
collections. On the day of a clinic visit at which blood samples are scheduled to be collected, 
a fast of approximately 8 hours (h) duration must be confirmed prior to blood draw. On the 
day of the scheduled clinic visits, administration of study drug shall be withheld until after 
blood is drawn and taken with water at the clinic. 
Up to 50 subjects in the high glycemic group will follow the same study procedures as the 
randomized subjects. 
Subjects will return to the clinic for a follow-up exit visit at week 26 or 2 weeks after the last 
dose of study drug if the subjects terminate prior to week 24. Following the exit visit, 
subjects will be advised to see their customary physician to undergo treatment to control their 
diabetes. 
3.2.3 
Glycemic Control Monitoring 
3.2.3.1 
Placebo Run-in Period  
During the placebo run-in period, subjects will be instructed to determine self-monitored 
blood glucose (SMBG) daily after fasting overnight for approximately 8 h. Subjects in the 
double-blind treatment group should contact the clinic if any fasting glucose value is ≥ 250 
mg/dL (13.9 mmol/L).  Subjects in the high glycemic group should contact the clinic if any 
fasting glucose value is ≥ 300 mg/dL (16.7 mmol/L).  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.  
Subjects with clinical signs or symptoms of severe hyperglycemia during the run-in period, 
including weight loss, blurred vision, increased thirst, increased urination, or fatigue, should 
also be excluded. 
3.2.3.2 
Treatment Period 
During the treatment period, subjects will be advised to continue daily, fasting SMBG 
measurements. Subjects should contact the clinic if fasting SMBG is ≥ 270 mg/dL 
(15 mmol/L) from week 0 to week 6 if in the double-blind treatment group or ≥ 300 mg/dL 
(16.7 mmol/L) if in the high glycemic group, ≥ 240 mg/dL (13.3 mmol/L) after week 6 to 
week 12, or ≥ 200 mg/dL (11.1 mmol/L) after week 12. Blood glucose values collected via 
SMBG will be evaluated at study visits by the investigator. In addition, hyperglycemia will 
be monitored by measurement of FPG at scheduled visits. 
If hyperglycemia is identified through SMBG or FPG measurements, the investigator will 
determine whether the subject has fasted for approximately 8 h prior to the morning blood 
draw to ensure that the SMBG or FPG value is based on a fasting sample. If proper fasting 
has not occurred, the subject will be asked to return for a repeat blood test within a week. 


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During the treatment period, hyperglycemia should be managed first with diet and exercise 
counseling. If hyperglycemia continues after diet and exercise counseling, the investigator 
may prescribe rescue medication if it is necessary for the well-being of the subject. 
3.2.3.3 
Rescue Medication 
Rescue medication is suggested during the treatment period if, after diet and exercise 
counseling, subjects meet the following glycemic criteria:  
1. More than 3 consecutive, daily, fasting SMBG measures are ≥ 270 mg/dL (15 mmol/L) 
from baseline to week 6 if in the double-blind treatment group or ≥ 300 mg/dL (16.7 
mmol/L) if in the high glycemic group, ≥ 240 mg/dL (13.3 mmol/L) from week 6 to week 
12, or ≥ 200 mg/dL (11.1 mmol/L) or HbA1c > 8.0% from week 12 to week 24 
2. Fasting SMBG values are ≥ 250 mg/dL (13.9 mmol/L) and associated with clinical signs 
or symptoms of hyperglycemia (e.g., weight loss, blurred vision, increased thirst, 
increased urination, or fatigue), and the signs or symptoms are severe. 
 
If a rescue 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 
ascribed to the latest date upon which the subject’s glycemic control will not be impacted by 
the rescue medication. 
The investigator may provide rescue treatment with any approved medication for diabetes 
that is not otherwise contraindicated. Other SGLT2 inhibitors (Appendix 3) may not be 
prescribed.  
If hypoglycemia occurs in any subject who has been 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. If recurrent symptomatic 
hypoglycemia occurs after discontinuation of administration of the rescue medication, the 
study drug administration can be discontinued at the discretion of the investigator. 
If recurrent symptomatic hypoglycemia occurs in subjects who are not prescribed rescue 
medication, the total daily dose of metformin can be decreased at the discretion of the 
investigator. If recurrent symptomatic hypoglycemia continues after decreasing the dose of 
metformin, subjects should be withdrawn from the study and treated in accordance with local 
standards of care. 
Subjects who receive rescue medication due to poor glycemic control will continue to receive 
investigational products and treatment according to the present standard of care per 
investigator decision, according to current treatment guidelines. Following the exit visit, 
subjects will be advised to see their customary physician to undergo treatment to control their 
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3.2.4 
Other Safety Monitoring Activities  
The safety monitoring activities will include assessments of vital signs, 12-lead ECGs, 
physical examinations, urinalysis, and analyses of blood chemistry, hematology, AEs, and 
concomitant medication use. The occurrence of blood, liver, or skin disorders will be 
monitored through laboratory testing and evaluation of AE documentation.  
AEs of special interest as defined in the statistical analysis plan will include any clinical 
signs and symptoms that indicate adverse experience in the categories listed below. All such 
events must be appropriately documented within the source documentation. 
• 
Acid-base disorders including diabetic ketoacidosis (DKA) 
• 
Amputations 
• 
Diuretic effects including hypovolemia 
• 
Falls and fractures 
• 
Genital mycotic infections (GMI) 
• 
Hepatotoxicity 
• 
Hypersensitivity reactions 
• 
Hypoglycemia 
• 
Hypotension episodes 
• 
Major adverse cardiovascular events (MACE) 
• 
Malignancies 
• 
Renal failure events 
• 
Urinary tract infections including urosepsis and pyelonephritis 
 
3.2.5 
Data and Safety Monitoring Board (DSMB)  
An independent Data and Safety Monitoring Board (DSMB) will monitor overall safety 
information during the bexagliflozin development program. The safety review activities and 
potential risk benefit assessments utilized by the DSMB will be defined in its charter. 
3.2.6 
Major Adverse Cardiovascular Event (MACE) 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 (MI), 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. No separate cardiovascular risk 
assessment will be performed based on events in the study population of the current protocol. 


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3.2.7 
Diabetic Ketoacidosis (DKA) Event Adjudication  
An independent adjudicator will review all potential DKA events without unblinding the 
subject treatment. The adjudicated events will be documented and archived. All adjudicated 
DKA events in the bexagliflozin phase 3 program will be pooled at the end of the program 
and a final analysis will be conducted.  
3.3 
Rationale for Study Design and Control Group 
3.3.1 
Rationale for Study Design 
THR-1442-C-419 is designed to assess the effect of the addition of bexagliflozin or placebo 
to an existing dose of metformin in subjects inadequately controlled by metformin alone. The 
metformin dosage should not have changed within the 8 weeks prior to screening. The dose 
of metformin should remain unchanged throughout the treatment period.  
Diet and exercise counseling will be provided to all participating subjects. A monitoring plan 
and criteria to initiate rescue medications are included in the protocol to reduce the risk of 
prolonged hyperglycemia.  
The HbA1c percentage reflects average plasma glucose concentration and is considered a 
well-validated surrogate for the degree of diabetes control. 
3.3.2 
Rationale for Background Medication 
Metformin is the most commonly prescribed OHA and is often recommended as a first-line 
therapy for the treatment of T2DM. It is a biguanide that decreases hepatic glucose 
production and may improve peripheral glucose uptake and utilization.  The mechanism of 
action of metformin is not believed to overlap with that of bexagliflozin, and hence the 
addition of bexagliflozin to metformin monotherapy is likely to produce improvement in 
glycemic control. Metformin prescribing practices vary by country. In the US a maximum 
dose of 1500 mg per day is typical, whereas in Japan a maximum dose of 1000 mg per day is 
typical.  
3.3.3 
Rationale for Dose Selection 
In a 12 week monotherapy study, bexagliflozin tablets, 20 mg, elicited a greater placebo-
adjusted HbA1c reduction (-0.80%) than bexagliflozin tablets, 10 mg (-0.68%), or 
bexagliflozin tablets, 5 mg (-0.55%). Bexagliflozin administration has been well tolerated in 
multiple studies. The safety and efficacy of bexagliflozin capsules, 20 mg, for the treatment 
of T2DM have been demonstrated in a 96-week study that measured reduction in HbA1c at 
week 24 as the primary endpoint. 
3.4 
Study Duration and Dates 
Subjects will be enrolled within 2 weeks of screening. Eligible subjects who provide written 
consent will start a run-in period of 1 week prior to randomization to demonstrate 


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compliance. Subjects who successfully complete the run-in will begin 24 weeks of treatment 
and will be followed for 2 weeks after the last dosing. The study duration from screening to 
follow-up will be no more than 29 weeks overall. For details of the schedule and nature of 
the investigations, see the Schedule of Events in Appendix 1 and Appendix 2. 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study population will include approximately 350 subjects whose T2DM is inadequately 
controlled by metformin and who meet all of the inclusion criteria and none of the exclusion 
criteria. Eligible subjects who consent to participate in the study will be enrolled in clinical 
investigational sites. Study subjects will be informed of the purpose of the study, the 
potential risks of participation, and will be requested to consent to the procedures and blood 
collection. 
Plasma samples will be collected for population PK analysis. Study subjects will be informed 
of the purpose of the PK study and requested to consent to the additional procedures and 
blood collection.  
Clinical sites in the US and Japan are anticipated to recruit subjects. 
4.2 
Inclusion Criteria 
Approximately 350 subjects with T2DM will be enrolled in the study. The subjects must: 
1. have age ≥ 20 years at screening. Women of childbearing potential must test negative for 
pregnancy and agree to abstinence or contraception for the duration of the study to avoid 
any possible pregnancy.  Females who are surgically sterile (hysterectomy, 
oophorectomy) or postmenopausal (absence of menses greater than 12 months) are 
eligible if they test negative for pregnancy at screening.  
2. a) have a history of T2DM with an HbA1c level of ≥ 7.5% and ≤ 10.5% at screening, or  
b) have a history of T2DM with an HbA1c level of >10.5% and ≤ 12.0% at screening 
3. have been prescribed a stable dose of metformin (≥1500 mg per day in the US or 
≥ 1000 mg per day in Japan) as their sole anti-diabetic medication 
4. have a body mass index (BMI) ≤ 45 kg/m2 
5. be able to comprehend and willing to provide written informed consent in accordance 
with institutional and regulatory guidelines 
6. not have recently changed their medications for hypertension or hyperlipidemia (if 
applicable)  
7. be able to regularly self-administer medication, as evidenced by consumption of all, or at 
worst one less than all, doses of run-in medication prior to randomization (at visit 3) 
 
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria are to be excluded from the study: 
1. Having a diagnosis of type 1 diabetes mellitus or maturity–onset diabetes of the young  
2. Pregnant or breastfeeding  


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3. Having one or more hemoglobin alleles that affect HbA1c measurement 
4. Having a history of genitourinary tract infection (e.g., UTI, GMI, vaginitis, balanitis) 
within 6 weeks of screening or a history of ≥3 genitourinary infections requiring 
treatment within 6 months of screening 
5. Having an 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 
6. Having a sitting systolic blood pressure >180 mmHg or a sitting diastolic blood pressure 
> 110 mmHg at screening 
7. Subject is taking any hypoglycemic agent(s) other than metformin during the 8 weeks 
prior to screening 
8. Having a history of illicit drug use or alcohol abuse in the past 2 years 
9. Having a life expectancy < 2 years 
10. Having received a diagnosis of New York Heart Association (NYHA) Class IV heart 
failure within 3 months of screening 
11. Having experienced an MI, unstable angina, stroke, or hospitalization for heart failure 
within 3 months of screening 
12. Having been exposed to an investigational drug within 30 days 
13. Having previously received bexagliflozin or EGT0001474 
14. Having a history of SGLT2 inhibitor treatment 
15. Currently participating in another interventional trial 
16. Not able to comply with the study scheduled visits 
17. Having 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 
18. Having an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 × 
ULN or total bilirubin ≥ 1.5 × ULN 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 
5.2.1 
Investigational Product 
Bexagliflozin tablets, 20 mg or placebo, should be taken at approximately the same time each 
day, before or after breakfast, with one cup (250 mL) of water. 
On the day of scheduled clinic visits at which blood is to be drawn, administration of 
bexagliflozin should be delayed until after blood is drawn and bexagliflozin tablet should be 
taken in the clinic or at home with one cup (250 mL) of water. 
5.2.2 
Background Metformin Therapy 
The metformin dose should reflect the prevailing standard of care.  In the United States, 
metformin ≥ 1500 mg/day is recommended (Garber et al., 1997).  In Japan, metformin 
≥ 1000 mg/day is recommended (Suzuki et al., 2014). 
The dose, frequency, and time of administration should remain stable unless the investigator 
deems a decrease in the daily dose necessary for the medical well-being of the subject.  
5.3 
Selection and Timing of Dose for Each Subject 
The type of investigational product, whether active or placebo, will be based on randomized 
assignment at the beginning of the treatment period. All study subjects will be instructed to 
take bexagliflozin tablets once daily in the morning, before or after breakfast, with one cup 
(250 mL) of water. The dose and frequency of bexagliflozin will be unchanged during the 
24-week treatment period.  
On the day of each scheduled clinic visit, subjects must fast for 8 h prior to the collection of 
blood samples. During the fasting period, only water will be permitted.  


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5.4 
Method of Assigning Subjects to Treatment Groups 
Eligible subjects who complete the run-in period, meet all study inclusion/exclusion 
requirements, and have HbA1c ≥ 7.5% and ≤ 10.5% at screening will be randomized in a 1:1 
ratio to receive bexagliflozin tablets, 20 mg or 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 by high (8.5% ≤ HbA1c ≤ 10.5%) and low (7.5% ≤ HbA1c 
< 8.5%) baseline measurement at screening (Visit V1) and by country (US or Japan). Eligible 
subjects who have HbA1c > 10.5% and ≤ 12.0% at screening will be assigned to the open 
label treatment group. 
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 30 randomized subjects. However, after a site has recruited 30 randomized 
subjects, if a potential subject at that site is in the run-in phase and wishes to continue with 
the study, the subject will be allowed to continue and, if eligible, to be randomized.  
5.5 
Blinding 
Approximately 300 subjects will participate in the double-blind placebo-controlled portion of 
the trial.  The sponsor, investigators, study coordinators, pharmacists, study subjects, the 
CEC members or DKA adjudicator will be blinded to the study medication of these 
participants.  Upon randomization, each subject will receive a subject randomization number 
and a drug kit.  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 a 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 or the DKA 
event adjudicator at the conclusion of the study until all global investigational studies are 
completed and a meta-analysis to assess cardiovascular risk is conducted. 
Subjects in the high glycemic group (i.e., > 10.5% and ≤ 12.0% at screening) will receive 
open labeled study drug.  There will be no placebo cohort for the high glycemic group. 


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5.6 
Concomitant Therapy 
During the course of the study, investigators will manage glucose, BP, and lipid levels 
according to local or regional standard of care guidance documents for the management of 
T2DM. Instructions for rescue medication for hyperglycemia are provided in Section 3.2.3.3. 
Subjects will be allowed to take medications or medicinal supplements prescribed to manage 
non-diabetic medical conditions during the study. Any concurrent medication or 
supplemental treatment of other non-diabetes medical conditions should be continued at a 
stable dose and frequency for the entire study duration unless there is a clinical reason to 
change the dose or frequency.  
Subjects may receive any medications for AEs that are necessary in the investigators’ 
judgment. Medications prescribed after the informed consent are to be recorded 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.  
5.6.1 
Diuretics and Medications for Treatment of Dyslipidemia and Hypertension 
Subjects who are prescribed diuretics, anti-hypertensive agents, or medications to treat 
dyslipidemia will continue the dose, frequency, and time of administration of these 
medications throughout the study. Subjects do not need to be treated for dyslipidemia or 
hypertension to be eligible for the study. Adjustment of these medications will not be 
permitted during the screening and run-in periods.  
During the treatment period, adjustments in the treatment for hypertension or dyslipidemia 
are permitted if required for the well-being of the subject. New diuretic medications should 
not be initiated during the first 2 weeks of the treatment period. The dose and frequency of 
existing diuretic medications should not be changed during the first 2 weeks of therapy. 
Changes to the dose or frequency of anti-hypertensive and diuretic medications will be 
recorded in the concomitant medications log. 
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.   No subject shall have been treated with an SGLT2 inhibitor 
within 3 months of screening. Subjects taking any hypoglycemic agents other than metformin 
during the 8 weeks prior to screening are not eligible for this study.  During the treatment 
period, metformin dose may not be up-titrated. 
5.7.2 
Fluid and Food Intake  
During the study, subjects will be counseled to remain adequately hydrated at all times. In 
addition, subjects will receive counseling regarding an appropriate diet to achieve glycemic 


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control based on standards of medical care in diabetes. For example, the recommended diet 
might be low in saturated fat, high in fiber, low in simple carbohydrates, and contain 
appropriate caloric intake to maintain weight. Subjects will also be counseled to avoid 
alcohol or to consume alcohol in moderation. Subjects with a known history of alcohol abuse 
should be excluded from the study as indicated in Section 4.3. 
Subjects will fast for approximately 8 h 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 to be counseled and encouraged to engage in a 
level of physical activity that is appropriate for their physical condition. For those without 
specific restrictions or limitations, at least 150 min/week of moderate activity is advised by 
the American Diabetes Association (ADA) ((American Diabetes, 2014). Alternatively, local 
regulatory guidelines may be used. 
5.8 
Treatment Compliance 
Subjects will be provided with dosing instructions when the investigational products are 
dispensed. Subjects will also be instructed to bring their medications with them at every visit. 
During the run-in period, subjects will be excluded from randomization if more than 1 day of 
placebo run-in medication doses has been omitted. If, in the judgement of the investigator, it 
was appropriate for the subject to omit these doses, this requirement may be waived (e.g., if 
the subject was hospitalized overnight during run-in). 
At each visit after the start of the run-in period, the study staff will review the SMBG diary 
and medications history 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 sealed with a child-resistant cap. Bottles of 15 placebo tablets will be 
provided for the 1-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 below 30°C (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 V3) and a new investigational product kit 
at 12 weeks (Visit V5). 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. 


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There are 3 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. 
BLINDED INVESTIGATIONAL PRODUCT KIT 
One blinded investigational product kit contains a bottle of 90 bexagliflozin tablets, 20 mg or 
bexagliflozin tablets, placebo.  
The label attached to each blinded 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.  
OPEN LABEL INVESTIGATIONAL PRODUCT KIT 
One open label investigational product kit contains a bottle of 90 bexagliflozin tablets, 20 
mg.  
The label attached to each blinded investigational product kit will contain the following 
information: the kit number, protocol number, product identification, 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 and placebo tablets will be stored below 30°C (86°F). The sponsor will 
notify the sites of the process for returning unused drug. 
Metformin tablets will be stored as specified in the prescribing information. 
5.11 Investigational Product Retention at Study Site 
The investigational products will be stored in a secure area with limited access. The drug 
storage facility must comply with the medication storage instructions. The investigational 
products should be stored at controlled room temperature until ready for dispensing to study 
subjects. The trial staff must record the amount of investigational products 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. All unused drug must be returned to a sponsor-designated depot after drug 
accountability is verified by the sponsor or its designee.  


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6 
STUDY PROCEDURES 
The following sections describe procedures that are conducted in the protocol.  The clinical 
investigator must personally conduct or supervise the procedures that are required in the 
protocol.  Study tasks may be delegated to qualified staff after training has been completed 
and documented.  Procedures that require clinical/medical knowledge must be performed by 
the investigator or qualified sub-investigators.   
For the purposes of this protocol, except as specifically noted, “Investigator” refers to the 
Principal Investigator or his/her staff who have been appropriately delegated to perform a 
study task. 
6.1 
Informed Consent 
Before each subject is enrolled in the clinical study, written informed consent will be 
obtained according to the regulatory and legal requirements of the participating country. As 
part of this procedure, the investigator must explain orally and in writing in appropriate 
language the nature, duration and purpose of the study, and the action of the drug, in such a 
manner that the study subject is made aware of the potential risks, inconveniences, or AEs 
that may occur. The investigator should educate potential subjects about the scientific 
importance of their contribution to the study 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 or she will receive all information that is required by 
applicable regulations.  
The informed consent document must be signed and dated by the study subject. One copy 
will be given to the subject, 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 
study until written consent has been obtained. The terms of the consent and when it was 
obtained must also be documented. 
6.2 
Screening for I/E Criteria  
At the initial screening visit, the investigator should review the inclusion and exclusion 
criteria based on the information collected. 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  
• 
Date of birth, age, sex, and race, and whether a female subject is of childbearing potential 
or not 


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• 
Significant medical and surgical history, including dates of diagnoses, procedures and 
whether the condition is ongoing, if applicable 
 
6.3.2 
Diabetes History  
• 
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 
• 
History of complications due to diabetes, including nephropathy, retinopathy, 
neuropathy, non-traumatic amputations, and DKA, including date of diagnosis 
• 
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 (TIA) or stroke, and prior cardiac or peripheral re-vascularization 
procedures. The history should include the date of diagnosis and the current status of 
diagnosis (resolved or ongoing). 
6.3.4 
Medication History  
• 
Use of prescribed or non-prescribed medications, including name of medication, 
indications for usage, start and stop dates, dose, and frequency 
• 
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 appropriate diet and exercise to aid in glycemic 
control based on standards of medical care for 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, vascular 
system and extremities. The body weight must be determined using a scale that is calibrated. 
The same scale should be used for the duration of the study if possible. 


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6.6 
Abbreviated Physical Examination  
An abbreviated physical examination will be performed by the investigator at the visits 
indicated in the Schedule of Events (Appendix 1). An abbreviated physical examination will 
include height (only at the screening visit), body weight, and general assessment of the skin, 
heart, lungs, abdomen and extremities. The body weight must be determined using a scale 
that is calibrated. The same scale should be used for the duration of the study if possible. 
6.7 
Vital Signs  
Vital signs will be measured at the visits indicated in the Schedule of Events (Appendix 1) 
and will include sitting, supine, and standing BP measurements, and heart rate. Only the BP 
measured in the sitting position will be used to determine eligibility. The vital signs shall be 
obtained before the scheduled blood draw. 
BP shall be measured using an appropriately sized cuff (cuff bladder encircling at least 80% 
of the arm) that is applied on the upper arm at heart level. The left arm and same cuff size 
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 shall be obtained using a calibrated sphygmomanometer 
while the subject is in sitting, supine, and standing (if subject is physically able to stand) 
positions. Prior to measuring sitting BP, the subject should be seated quietly in a chair, not an 
examination table, for at least 5 minutes with feet on the floor and arm supported at heart 
level.  
A single heart rate measurement shall be taken just prior to the BP evaluation in the sitting, 
supine, and standing positions. Blood pressure must be taken twice with at least 2 minutes 
apart with the cuff fully deflated between each reading. If any of the two SBP measurements 
differ by more than 8 mm Hg or if any of the two DBP measurements differ by more than 5 
mm Hg, a second set of 2 BP measurements should be obtained. The second set of readings 
should be entered into the CRF. Original and repeat readings must all be recorded in the 
source documents with an explanation. The average of the 2 serial blood pressure 
measurements will be used for the efficacy analyses.  
BP will be assessed first in the sitting position. 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. The subject will lie flat for 5 min 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 min of standing. For standing BP measurements, the arm should be supported and 
extended such that the cuff is at heart level. The procedure for vital sign measurement is 
shown in Figure 1. 


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Figure 1. 
BP Measurement Procedure 
 
The date, time, and all readings are to be entered into the source document and CRF for all 
subjects. 
6.8 
Electrocardiography  
A 12-lead ECG will be recorded 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 to be recorded on the CRF 
are 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 does not necessarily need to be made the first time an abnormal result is 
observed. The investigator may repeat the ECG to verify 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. 


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Table 1. 
List of Laboratory Tests 
TEST NAME 
SHIPMENT 
Hematology 
Ambient 
• Hematocrit (Hct) 
• Hemoglobin (Hgb) 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin concentration 
(MCHC) 
• Platelet count 
• Mean corpuscular volume (MCV) 
• Red cell distribution width (RDW) 
• Red blood cell (RBC) count  
• White blood cell (WBC) count with 
differential  
  
Serum Chemistry and Electrolytes  
Ambient 
• Albumin (ALB) 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Alkaline phosphatase (ALK-P) 
• Blood urea nitrogen (BUN) 
• Glucose 
• Bicarbonate (HCO3) 
• Creatinine 
• Chloride (Cl) 
• Total protein  
• Calcium (Ca) 
• Magnesium 
• Phosphorus 
• Potassium (K) 
• Sodium (Na) 
• Total bilirubin 
• Direct bilirubin 
• Uric acid 
Glycemic Control  
Ambient 
• Fasting plasma glucose (FPG) 
• Hemoglobin A1c (HbA1c) 
  
Serum Lipids  
Ambient 
• Total cholesterol (TC) 
• High-density lipoprotein cholesterol (HDL-C) 
• Triglycerides (TG) 
• Low-density lipoprotein cholesterol (LDL-
C), calculated 
• LDL-C, direct 
Urinalysis  
Ambient 
• Appearance 
• Bilirubin 
• Color 
• Glucose 
• Ketones 
• Microscopic examination of sediment  
• UACR 
• Nitrite  
• Occult blood 
• pH 
• Protein 
• Specific gravity 
• Urobilinogen 
• Leukocyte esterase 
Urine Pregnancy Test (WOCBP)   
Local 
Population PK Sampling 
Bexagliflozin plasma level 
Frozen 
 


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6.9.2 
Sample Collection, Storage, and Shipping  
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 8 h fast prior to blood draw to ensure the FPG and 
triglycerides values can be accurately determined. If a subject has not fasted for 
approximately 8 h, the subject must return as soon as can be arranged (within 1 week) to 
provide a specimen after proper fasting. 
Low density lipoprotein cholesterol (LDL-C) will be calculated by the Friedewald equation. 
If triglycerides are > 400 mg/dL (4.5 mmol/L), 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 (4.0 mmol/L) at screening visit. All subsequent LDL-C of 
these subjects will be determined by the same direct LDL-C measurements only. 
An investigator can perform additional laboratory testing to diagnose or to follow up an AE 
progression or resolution. Clinical samples should be analyzed in a local laboratory if a fast 
turn-around time is necessary to determine treatment plan.  
6.9.3 
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). The investigator or study 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. 
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 subject reported signs or symptoms. Results of the urinalysis and 
possible urine culture will be documented in the CRFs. 
Urine samples will be transported to the central laboratory for 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. 


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Urine pregnancy tests (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.  
6.9.4 
Population PK Sampling 
Blood samples for the population PK analysis will be drawn when the subjects return to the 
clinic during week 6 (V4) and/or week 12 (V5) from 200 subjects who consent to 
participating in the PK study in selected trial centers. One blood sample will be drawn at each 
of the 3 timepoints from each subject for a total of 3 post-dose samples per subject. 
Approximately 100 subjects will be sampled at 0.25 to1 h, 7 to 10 h, and 20 to 24 h post dose 
(routine 1). Another 100 subjects will be sampled at 1.5 to 3 h, 3.5 to 6.5 h and 7 to 10 h 
post-dose (routine 2). The sampling time should take into consideration the study subject 
availability and can be on any of the days during the week of the specified clinical visits. The 
precise dosing time and sample draw time must be recorded in the CRF.  Subjects in double 
blind or open labelled study may participate in the PK study. 
Two mL (2 mL) of whole venous blood will be collected from a peripheral vein. Samples 
will be placed in tubes containing K2EDTA, stored on ice, and centrifuged under 
refrigeration for at least ten minutes at 3,000 rpm. After centrifugation, plasma will be 
removed and stored frozen in 3 aliquots of 200 L at or below -20C. Processed frozen 
plasma samples will be transferred on dry ice to the analytical laboratory and will be stored at 
or below -20C until analysis.  
Plasma concentrations of bexagliflozin will be determined by a validated LC-MS/MS 
method. 
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 the run-in period for SMBG. Subjects will be trained to use the glucometer and 
record any hypoglycemic events in the glycemic control diary. The SMBG record from the 
glucometer and diary entries must be reviewed by the investigator (or designee) at all 
subsequent visits. 
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 DKA must be provided. 
6.11 Dispensing Run-in Drug  
Each eligible study subject will receive one bottle of run-in drug at the visit indicated in 
Appendix 1. 
Subjects should self-administer the first dose of each run-in drug with 1 cup (250 mL) of 
water under observation during the scheduled visit.  


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6.12 Diary and Glucometer Record Review  
At each visit after the beginning of run in, the investigator (or appropriate designee) will 
review the glycemic control diary, glucometer record, and symptoms that may indicate 
potential DKA with the subject and record the findings in the CRF. 
6.13 Dispensing Investigational Product  
At randomization and at every 12 weeks of treatment thereafter, each study subject will 
receive a bottle of investigational product based on the kit number assigned to the subject by 
the IWRS. The bottle will contain bexagliflozin tablets, 20 mg or placebo. The bottle 
provides sufficient tablets for daily dosing for 12 weeks with a 6 tablet overage. 
Subjects should self-administer the investigational product with one cup (250 mL) of water 
under observation during the scheduled visits. 
6.14 Adverse Events Assessments 
6.14.1 
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. 
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 


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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; 
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. 


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• 
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. 
 
6.14.2 
Eliciting and Reporting AEs  
After a subject consents to participation in the study, the investigator or designee will 
periodically assess subjects for the occurrence of AEs. 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. 
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. 
In addition, the sponsor’s Medical Monitor or its designated personnel must be notified 
immediately by telephone, email, or fax of any immediately reportable AEs (IRAE) 
according to the procedure outlined below. Special attention should be paid to recording 
hospitalization and concomitant medications. 
6.14.3 
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 administration 
(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. 


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6.14.4 
Pregnancy  
Women of childbearing potential (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: 
• 
General information 
• 
Informed consent form 
• 
Pregnancy prevention information 
• 
Drug interactions with hormonal contraceptives 
• 
Contraceptives in current use 
• 
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 confirming that 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, administration of the investigational product will be permanently 
discontinued and the subject will be withdrawn from the trial. Exceptions to study 
withdrawal 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 Medical Monitor. 
Protocol required procedures for discontinuation of dosing 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, 


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follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants will be followed for a minimum of six months. 
6.14.5 
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 the breaking of 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. 
6.14.6 
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. 
6.14.7 
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 6.14.2. 
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.  
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. 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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6.14.8 
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 shall be 
obtained at all clinical visits and a urinalysis shall 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 shall 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.  
6.14.9 
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. 
6.14.10 Hepatotoxicity  
If plasma AST and/or ALT concentrations > 3 × 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 
• 
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 × ULN requires immediate repeat test within 48 to 72 hours to confirm the hepatic enzyme 
elevation. Testing should be repeated based on the clinical situation at least every 96 hours (4 
days) until ALT and AST return to < 2.5 × ULN or until the liver function test results are 
stable and significant changes are not expected anymore. 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.  


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Should it be determined that the etiology is an unrelated acute or chronic medical condition 
(e.g.; NASH, Hepatitis A) and the return of LFT abnormalities to normal is unlikely during 
the course of the illness, further testing and follow up is at the investigator’s discretion. 
Hepatotoxicity will be diagnosed and entered as an AE should any of the following occur: 
• 
ALT or AST > 8 × ULN 
• 
ALT or AST > 3 × ULN and total bilirubin > 2 × ULN or INR > 1.5 
• 
ALT or AST > 3 × 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, administration of 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. 
6.14.11 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: 
• 
Signs and symptoms attributed to hypoglycemia and the time and date on which they 
occurred  
• 
SMBG reading at the time of the signs and symptoms attributed to hypoglycemia 
• 
Time elapsed from the most recent meal to the onset of signs and symptoms 
• 
Duration, intensity, and type of any exercise within the 24 h prior to the signs and 
symptoms 
• 
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 
• 
SMBG reading 15 minutes after treatment with carbohydrate and the time at which this 
was measured 
• 
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 (3.9 mmol/L) 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 (3.9 mmol/L) 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 and documented symptomatic 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. 
6.14.12 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 
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 review 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 
 
6.14.13 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 instructed 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, 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.  


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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. 
Laboratory values should be measured immediately 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.  The 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.  
6.14.14 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. Subjects who have had a previous amputation should be closely monitored. 
Special attention may be appropriate for subjects who are also receiving thiazide diuretics as 
these have been shown to increase the risk of amputation in diabetics.  
6.15 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. Changes in dose and/or frequency from therapies taken prior to 
randomization and their rationale must be recorded in the CRF. 
The medications or treatment for controlling hyperglycemia 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. 
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 


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concomitant medications will include all medications taken by any subjects during the course 
of the study. 
6.16 Removal of Subjects from the Trial or Treatment Discontinuation 
Participation in a clinical trial is voluntary. A subject can withdraw from the study at any 
time. The sponsor may terminate the study for medical or administrative reasons. An 
investigator may decline to participate in the conduct of the study if either the investigator or 
the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) determines that, 
based on good medical judgment, immediate cessation is appropriate for subject safety. If a 
decision is made to withdraw a subject from the study, no further investigational product 
should be administered. Even if the subject discontinues administration of study medication, 
every attempt should be made to complete all required study evaluations and procedures. 
Reasons for all withdrawals should be recorded on the CRF. 
The investigator may withdraw a subject from the study for any of the following reasons: 
• 
A protocol violation occurs, 
• 
A serious or intolerable adverse event occurs, 
• 
A clinically significant change in a laboratory parameter occurs,  
• 
The sponsor or investigator terminates the study, or 
• 
The subject requests to withdraw from the study. 
 
Subjects who do not complete the study but who have received investigational product 
should have a follow-up examination, including a physical examination, vital signs, ECG and 
clinical laboratory tests. 
6.17 Appropriateness of Measurements 
The percentage of HbA1c is a widely used surrogate measure of diabetes control, reflecting 
average blood glucose levels over a 2- to 3-month period of time. It is an accepted surrogate 
marker for the risk of microvascular complications. Other study procedures and 
measurements in this protocol are widely used and generally recognized as reliable, accurate, 
and relevant for subjects with T2DM. 
 


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7 
STUDY ACTIVITIES 
The study activities 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 V3. Visit 3 is the day of 
randomization and the basis for the visit window.  
7.1 
Visit 1/ Screening (up to 3 weeks prior to randomization) 
• 
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 examination 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Draw blood if an approximately 8 h fast has been completed by the subject as described 
in Section 6.9.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 
 
7.2 
Visit 2/ Run In (1 week prior to randomization) 
• 
Counsel subject on appropriate diet and exercise 
• 
Dispense glucometer and instruct subject in SMBG determination and recording 
• 
Dispense the run-in kits for run-in period 
• 
Assess adverse events 
• 
Record concomitant medications 
 
7.3 
Visit 3/ Randomization 
• 
Collect needed information and evaluate conformance to inclusion and exclusion criteria 
• 
Perform a complete physical examination 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Perform urine pregnancy test (WOCBP only) 
• 
Perform a 12-lead ECG measurement 
• 
Review SMBG and glycemic control record 
• 
Dispense investigational product based on randomization 
• 
Assess adverse events 
• 
Record concomitant medications 
 


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7.4 
Visit 4/ 6 Weeks 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Draw blood if an approximately 8 h fast has been completed by the subject as described 
in Section 6.9.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2  
• 
Perform urine pregnancy test (WOCBP only) 
• 
Review SMBG and glycemic control record 
• 
Assess adverse events 
• 
Record concomitant medications 
 
7.5 
Visit 5/ 12 Weeks  
• 
Measure vital signs, including blood pressures and heart rate 
• 
Draw blood if an approximately 8 h fast has been completed by the subject as described 
in Section 6.9.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• 
Perform urine pregnancy test (WOCBP only) 
• 
Review SMBG and glycemic control record 
• 
Dispense investigational product based on randomization 
• 
Assess adverse events 
• 
Record concomitant medications 
 
7.6 
Visit 6/ 18 Weeks  
• 
Measure vital signs, including blood pressures and heart rate 
• 
Draw blood if an approximately 8 h fast has been completed by the subject as described 
in Section 6.9.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• 
Perform urine pregnancy test (WOCBP only) 
• 
Review SMBG and glycemic control record 
• 
Assess adverse events 
• 
Record concomitant medications 
 
7.7 
Visit 7/ 24 Weeks  
• 
Perform an abbreviated physical examination 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Perform a 12-lead ECG measurement 


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• 
Draw blood if an approximately 8 h fast has been completed by the subject as described 
in Section 6.9.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• 
Perform urine pregnancy test (WOCBP only) 
• 
Review SMBG and glycemic control record 
• 
Assess adverse events 
• 
Record concomitant medications 
 
7.8 
Visit 8/ Follow Up  
• 
Perform a complete physical examination 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Draw blood if an approximately 8 h fast has been completed by the subject as described 
in Section 6.9.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• 
Perform urine pregnancy test (WOCBP only) 
• 
Review SMBG and glycemic control record 
• 
Assess adverse events 
• 
Record concomitant medications 
 
7.9 
Early Termination Procedures 
Subjects who withdraw consent and have received investigational products should have a 
follow-up visit that captures the V8 procedures, if possible.     The sponsor must be notified 
in the event that a subject withdraws or has been withdrawn from the study. 
• 
Perform a complete physical examination 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Draw blood if an approximately 8 h fast has been completed by the subject as described 
in Section 6.9.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• 
Perform urine pregnancy test (WOCBP only) 
• 
Review SMBG and glycemic control record 
• 
Assess adverse events 
• 
Record concomitant medications 
 


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8 
QUALITY CONTROL AND ASSURANCE 
The clinical research facility will be monitored by the study monitor 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 9.2 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.   
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. 
In general, 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. 
Note that data for subjects with screening HbA1c > 10.5% and ≤ 12% will be separately 
summarized and/or listed.  Only descriptive summaries will be provided for this group of 
subjects. No formal hypothesis testing will be performed. The following sections of analysis 
methods will be applied to this sub-study with exceptions of modeling and hypothesis testing. 
Henceforth, analyses for this sub-study will not be specifically mentioned unless it differs 
from the main study. 
9.2 
Determination of Sample Size 
In the blinded segment of the study approximately 300 subjects will be randomized 1:1 to 
bexagliflozin tablets, 20 mg or bexagliflozin tablets, placebo.  With this sample size, the 
study has approximately 90% power to detect a 0.4% difference in HbA1c between the active 
arm and the placebo arm, assuming a standard deviation of 1% HbA1c for the study 
population and that 12% of the study participants will have dropped out by week 24.  
With similar assumptions, a single group of 50 subjects has approximately 90% power to 
detect a difference from baseline of 0.5% HbA1c, assuming a 12% dropout rate and a 
population standard deviation of 1%. 
9.3 
Analysis Populations  
9.3.1 
Intention-to-Treat Analysis Set 
All subjects who are randomized regardless of treatment adherence or availability of follow-
up, data will be included in the intention-to-treat analysis set (ITT). All analyses of the ITT 
will be based on each subject’s randomized assigned treatment. The ITT analysis set will 
serve as the primary set for the efficacy analyses. 


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9.3.2 
Safety Analysis Set 
All subjects who are randomized and take at least one dose of study medication will be 
included in the Safety Analysis Set. Safety analyses will be based on the medication that was 
actually taken by each subject.  The Safety Analysis Set is the primary analysis set for safety 
evaluation. For sub-study, all subjects who take at least one active dose of the study 
medication will be included in this analysis set, and all analyses will be based on this analysis 
set. 
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 assessments. 
9.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively for the safety, 
ITT and PP analysis sets for each treatment group and for all subjects combined. Key 
variables include (but are not limited to): age, gender, race, ethnicity and country of 
investigational site, baseline HbA1c and FPG assessments, baseline blood pressures, baseline 
body weight, BMI, and stratification factors including HbA1c value categories at 
randomization. 
9.5 
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.  For the main study, all efficacy analyses will be based on ITT 
analysis set, and if it is deemed that the PP analysis set is much different from the ITT 
analysis set, the analyses applied to the ITT set will be applied to the PP analysis set as well. 
For the sub-study, all summaries will be based on the Safety analysis set. 
9.5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change of HbA1c from baseline to week 24 in the 20 
mg dose group compared to placebo group. 
The MMRM analysis of covariance model (ANCOVA) will be fitted to the available data, 
incorporating all visits at which HbA1c was measured (i.e., including the scheduled and the 
unscheduled visits for measurement of HbA1c (NationalResearchCouncil, 2010). Treatment, 
visit, treatment-by-visit, baseline HbA1c value and country (US or Japan) will be applied as 
fixed effects. From this model, an estimate of the treatment difference at week 24 will be 
generated, as will an assessment of whether the effect is significant at a two-sided 0.05 level. 
An unstructured within-patient covariance structure will be assumed. If the model with the 


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unstructured covariance structure does not converge, an autoregressive covariance structure 
will be used. HbA1c values obtained after the start of rescue medication will not be excluded 
from this primary analysis.  
The MMRM model is one approach to obtain treatment effect estimates in the presence of 
missing data. As for the sensitivity analyses for missing data, the following will be 
performed: 
1. Missing HbA1c data will be imputed via multiple imputation (MI), 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 considered missing. Non-monotone (intermediate visits) missing 
data will be imputed first using the Monte Carlo Markov Chain (MCMC) method under 
the Missing at Random (MAR) assumption in both treatment groups. One method to 
impute monotone missing values of the HbA1c will be 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 treatment group only. 
2. Missing HbA1c data will be imputed via LOCF, following which the MMRM will be 
repeated; HbA1c values collected after the start of rescue medication will be considered 
missing. 
3. HbA1c values collected after the start of rescue medication will be considered missing, 
and the MMRM analyses will be re-performed. 
 
9.5.2 
Secondary Efficacy Endpoints 
To assess the treatment effect on the change of FPG, similar methods as described for the 
primary endpoint will be implemented. The model will also include treatment, the baseline 
value of FPG, and country as fixed effects/covariates. Least squares mean treatment 
differences between the bexagliflozin and placebo arms will be estimated from the model. 
The corresponding 95% CI and p-value will be provided as well. 
Analysis of the change in systolic blood pressure (SBP) in the bexagliflozin group compared 
with placebo over time will also be performed using a similar method as for the primary 
endpoint with baseline SBP measure and country as fixed covariates.  
A summary of the proportion of subjects achieving HbA1c ≤7% by visit will be provided. 
Generalized estimation equations (GEE) method will be used for estimation of treatment effect.   
The change in total body weight in subjects with baseline BMI ≥25 kg/m2 will be analyzed 
using the MMRM method with baseline body weight as a fixed covariate.   
The change in HbA1c over time will also be presented by treatment groups and differences 
between bexagliflozin and placebo at each time point will be estimated using same methods as 
described for the primary end point.  


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9.6 
Safety Analysis 
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 using safety analysis set.  
9.6.1 
Adverse Events 
AEs will be mapped to preferred term and body system using the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. AEs that begin at or after the first 
administration of double-blind study medication or existing AEs that worsen in severity 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. Further summaries 
by severity and by relationship to study treatment will also be provided. Drug-related AE will 
be considered those to be at least possibly related to the study treatments 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. 
9.6.2 
Adverse Events of Special Interest 
AE of special interest include UTIs, GMIs, diuretic effects, hypotension episodes, 
hypoglycemia, hepatotoxicity, MACE, falls and fractures, malignancy, hypersensitivity 
reactions, DKA, pancreatitis, amputations and renal failure events. These AEs of special 
interest except MACE and amputations will be prospectively identified based on the 
MedDRA preferred terms in the AE log by a medical expert prior to the data base lock and 
unblinding of the individual subject treatment assignment. The list of AE of special interest 
will be confirmed in a peer review process. MACE will be identified by the investigator and 
documented in the CRF, and subsequently adjudicated by an independent committee. 
Adjudicated results will be used for summary.  Amputation events will be recorded in the 
procedures and amputation CRF.   
The number and percentage of subjects who have experienced a TEAE of special interest will 
be summarized for each treatment group by types of events. 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, 
if there are sufficient samples. 
9.6.3 
Clinical and Laboratory Events and Analyses 
Clinical laboratory parameters (see Section 6.9 for a complete list), vital signs, and 12-lead 
ECG will be measured at scheduled visits (see Appendix 1). These data will be summarized 
as actual values and changes from baseline by treatment for each visit for selected 
parameters.  


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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.  
9.6.4 
Physical Examination 
Physical examination findings will be presented in a by-subject listing. 
9.7 
Other Analyses 
A population pharmacokinetic assessment of bexagliflozin will be conducted across multiple 
phase 3 studies and will include approximately 200 subjects from THR-1442-C-419.  
Samples will be taken from these subjects at Weeks 6 or 12 of treatment. Analysis methods 
will be specified in a separate document. 
 


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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 
independent review board (IRB) or independent ethics committee (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 his or her 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 
ICH GCP guidelines (E6) 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 their assigned tasks and that written and contemporaneously signed 
records documenting the training be retained at the study site. 
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. 


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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 
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 IEC or IRB 
the written approval or favorable opinion of a competent authority 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 
filed. The informed consent form must contain all elements required by authorized regulatory 
authorities 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 the 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, if not English. Signed consent forms must remain in 
each subject’s study file and must be available for verification by study monitors at any time. 
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. 
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, GCP, and the respective 
national and local government regulations and guidelines. 


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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 has withdrawn must be recorded in the 
CRF. 
Entries made in the CRF must be verifiable against source documents. Source documents are 
defined as all medical records, medical notes, laboratory results, imaging studies, diagnostic 
tests, ECG traces, and any additional documents or data collections other than the CRF that 
has original subject information contained within it. 
All CRFs and source documents should be completed following GCP and the sponsor or its 
designee’s SOPs. 
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 and Deviations 
Protocol violations include departures from the inclusion and exclusion criteria, concomitant 
medication restrictions, and any other protocol requirement that results in a significant added 
risk to the subject or has an impact on the quality of the data collected or the outcome of the 
study.  
A protocol deviation is a non-adherence to study procedures or schedules, as specified by the 
protocol, which does not involve inclusion/exclusion criteria or the primary endpoint and 
which does not place the subject at any added risk or affect the data quality or study outcome. 
Examples of deviations may include out-of-window visits, missed procedures, etc.  
Protocol violations will reported in the final clinical study report, whereas protocol 
deviations may be mentioned but are not required to be reported. 
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 protocol violations 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. 


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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/violations will be recorded in the subject’s CRF, and the principal 
investigator must notify the sponsor. 
Protocol deviations/violations must be reported in the final study report. 
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 are 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 Sub, LLC 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 
American Diabetes, A. (2014). Standards of medical care in diabetes--2014. Diabetes Care 
37 Suppl 1, S14-80. 
Garber, A.J., Duncan, T.G., Goodman, A.M., Mills, D.J., and Rohlf, J.L. (1997). Efficacy of 
metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response 
trial. The American journal of medicine 103, 491-497. 
IDF ((2015)). International Diabetes Federation Diabetes Atlas Seventh Edition. 
Look, A.R.G., Wing, R.R., Bolin, P., Brancati, F.L., Bray, G.A., Clark, J.M., Coday, M., 
Crow, R.S., Curtis, J.M., Egan, C.M., et al. (2013). Cardiovascular effects of intensive 
lifestyle intervention in type 2 diabetes. The New England journal of medicine 369, 145-154. 
NationalResearchCouncil (2010). The Prevention and Treatment of Missing Data in Clinical 
Trials. In 978-0-309-15814-5, N.R. Council, ed., pp. 162. 
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., Kinner, M., Lassen, C.L., Schneppenheim, R., Eggert, P., Bald, M., Brodehl, J., 
Daschner, M., Ehrich, J.H., Kemper, M., et al. (2003). Molecular analysis of the SGLT2 gene 
in patients with renal glucosuria. J Am Soc Nephrol 14, 2873-2882. 
Scheen, A.J., and Van Gaal, L.F. (2014). Combating the dual burden: therapeutic targeting of 
common pathways in obesity and type 2 diabetes. The Lancet Diabetes & Endocrinology 2, 
911-922. 
Schwartz, S., Fabricatore, A.N., and Diamond, A. (2012). Weight reduction in diabetes. 
Advances in experimental medicine and biology 771, 438-458. 
Seufert, J. (2015). SGLT2 inhibitors - an insulin-independent therapeutic approach for 
treatment of type 2 diabetes: focus on canagliflozin. Diabetes, metabolic syndrome and 
obesity : targets and therapy 8, 543-554. 
Suzuki, K., Yoshioka, T., and Wakui, Y. (2014). Quantifying the Effect of Metformin 1000 
mg/day in Japanese Patients with Type 2 Diabetes. International Journal of Clinical Medicine 
Vol.05No.15, 8. 
van den Heuvel, L.P., Assink, K., Willemsen, M., and Monnens, L. (2002). Autosomal 
recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter 
(SGLT2). Human genetics 111, 544-547. 
Zhang, W., Welihinda, A., Mechanic, J., Ding, H., Zhu, L., Lu, Y., Deng, Z., Sheng, Z., Lv, 
B., Chen, Y., et al. (2011). EGT1442, a potent and selective SGLT2 inhibitor, attenuates 


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blood glucose and HbA(1c) levels in db/db mice and prolongs the survival of stroke-prone 
rats. Pharmacol Res 63, 284-293. 
 
 


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Appendix 1 
Schedule of Events 
Procedure 
Screening 
Run-in 
Treatment 
Follow-up 
Visit Number 
V1/ Screening 
V2/ Run 
In 
V3/ Random-
ization 
V4 
V5 
V6 
V7 
V8/ Follow 
Up 
Time to Randomization (week) 
-3 
-1 
0 
6 
12 
18 
24 
26 
Informed Consent 
X 
 
 
 
 
 
 
 
Screening for I/E Criteria 
X 
 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Diet and Exercise Counseling 
 
X 
 
 
 
 
 
 
Physical Examination 
 
 
X 
 
 
 
 
X 
Abbreviated Physical Examination 
X 
 
 
 
 
 
X 
 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
X 
Electrocardiography 
 
 
X 
 
 
 
X 
 
Clinical Laboratory Tests 
X 
 
 
X 
X 
X 
X 
X 
Urine Pregnancy Test (local, WOCBP only) 
X (all women) 
 
X 
X 
X 
X 
X 
X 
Diary and Glucometer Dispensation and Review 
 
X 
 
 
 
 
 
 
Dispensing Run-in Drug 
 
X 
 
 
 
 
 
 
Diary and Glucometer Record Review 
 
 
X 
X 
X 
X 
X 
X 
Dispensing Investigational Product 
 
 
X 
 
X 
 
 
 
Adverse Events Assessments 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication Assessments 
 
X 
X 
X 
X 
X 
X 
X 
 


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Appendix 2 
Schedule of Clinical Laboratory Tests 
Screening 
Run-in 
Treatment 
Follow-up 
Visit number 
V1/ Screening 
V2/ Run In 
V3/ 
Randomization 
V4 
V5 
V6 
V7 
V8/ Follow Up/ 
ET 
Time to Randomization Visit (weeks)  
-3 
-1 
0 
6 
12 
18 
24 
26 
Hematology 
X 
 
X 
X 
X 
X 
Serum Chemistry and Electrolytes 
X 
 
X 
X 
X 
X 
X 
Glycemic Control 
X 
 
X 
X 
X 
X 
X 
Serum Lipids 
X 
 
X 
X 
X 
Urinalysis 
X 
 
X 
X 
X 
X 
X 
Urine Pregnancy Test (WOCBP) 
X (all women) 
X 
X 
X 
X 
X 
X 
Population PK sampling 
X 
X 
 
 


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Appendix 3 
Examples of SGLT2 Inhibitors 
The following medications are prohibited during the study. Other SGLT2 inhibitors that may 
be approved for the treatment of T2DM during the THR-1442-C-419 study will also be 
prohibited as a concomitant medication in this protocol. 
Generic Name 
Trade Name 
canagliflozin 
Invokana™ 
canagliflozin plus metformin 
Invokamet™ 
dapagliflozin 
Farxiga™ or Forxiga™ 
empagliflozin 
Jardiance® 
empagliflozin plus linagliptin 
Glyxambi® 
empagliflozin/metformin HCl 
Synjardy 
dapagliflozin/metformin HCl 
extended release tablet 
Xigduo XR 
 




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Appendix 5 
Investigator’s Signature 
Study Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate Bexagliflozin in Subjects with Type 2 Diabetes Mellitus 
Who Are not Adequately Controlled by Metformin Alone 
Study Number: 
THR-1442-C-419 
Final Date: 
26 July 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 me and my sub-
investigators 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-419 
 
1007780 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
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Page 1 of 51 
Sponsor Name: 
Theracos Sub, LLC 
Protocol Number and Title: 
 
A Phase 3, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate Bexagliflozin in 
Subjects with Type 2 Diabetes Mellitus Who Are 
not Adequately Controlled by Metformin Alone 
Protocol Version and Date: 
Version 1.0, 26 July 2017 
 
 
INC Research Project Code: 
1007780 
Author(s): 
Lu Wang, Biostatistician II 
Fang Zhu, Principal Biostatistician 
SAP Version: 
Version 2.0 
SAP Version Date:  
15-Feb-2019 
 
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 
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1007780 
 
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Revision History 
 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
Version 0.1 
13-Feb-2018 
Lu Wang 
Initial Release Version 
Version 0.2 
23-Feb-2018 
Lu Wang 
Update to Address Sponsor 
Comments 
Version 1.0 
28-Feb-2018 
Lu Wang 
Update to Address Sponsor 
Comments 
Version 1.1 
15-Jun-2018 
Lu Wang 
Update to Address FDA 
Comments 
Version 1.2 
06-Jul-2018 
Lu Wang 
Update to Address Sponsor 
Comments 
Version 2.0 
15-Feb-2019 
Fang Zhu 
Update per dry run comments: 
1. Correct WHODrug and 
MedDRA versions 
2. Use “high glycemic”, 
instead of “open-label”. 
Correct language to 
include high glycemic 
group, e.g. change first 
dose of double-blind study 
medication to first dose of 
study medication during 
treatment period. 
3. Add ITT analysis set to 
high glycemic group and 
updated safety analysis 
set definition to keep both 
groups be consistent. 
4. Added LOCF for HbA1c high 
glycemic group 
5. Correct section 12. LOCF 
will be conducted. Tipping 
point analysis is used to 
replace jump to reference 
MI. 
 
 




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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. 
Secondary Objectives ....................................................................................................... 12 
3.3. 
Safety Objectives ............................................................................................................... 12 
3.4. 
Other Objectives ................................................................................................................ 12 
3.5. 
Brief Description ................................................................................................................ 13 
3.6. 
Subject Selection ............................................................................................................... 13 
3.6.1. 
Inclusion Criteria ......................................................................................................... 14 
3.6.2. 
Exclusion Criteria ........................................................................................................ 14 
3.7. 
Determination of Sample Size .......................................................................................... 14 
3.8. 
Treatment Assignment & Blinding ................................................................................... 14 
3.8.1. 
Treatment Assignment ................................................................................................ 14 
3.8.2. 
Blinding ........................................................................................................................ 15 
3.9. 
Administration of Study Medication ................................................................................ 15 
3.10. 
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. 
Treatment Period ........................................................................................................ 22 
6.2.2. 
Baseline Values .......................................................................................................... 22 
6.2.3. 
First Dose Date ........................................................................................................... 23 
6.2.4. 
Study Day .................................................................................................................... 23 
6.2.5. 
Duration ....................................................................................................................... 23 
6.2.6. 
End of Study ................................................................................................................ 23 
6.3. 
Missing Data ....................................................................................................................... 24 
6.4. 
Analysis Visit Windows ..................................................................................................... 24 
6.5. 
Pooling of Centers ............................................................................................................. 24 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ....................................................................................................... 25 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 25 
7.2. 
Subject Eligibility 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 .......................................................................................................... 26 
7.5.2. 
Concomitant Medication .............................................................................................. 27 


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8. 
EFFICACY ..................................................................................................... 28 
8.1. 
Primary Efficacy Endpoint and Analysis ......................................................................... 28 
8.1.1. 
Primary Efficacy Analysis ............................................................................................ 28 
8.1.2. 
Sensitivity Analyses .................................................................................................... 30 
8.1.3. 
Subgroups ................................................................................................................... 31 
8.2. 
Secondary Efficacy Endpoint(s) and Analyses .............................................................. 31 
8.2.1. 
Change from baseline in FPG over time ..................................................................... 31 
8.2.2. 
Change in SBP over time ............................................................................................ 32 
8.2.3. 
Proportions of subjects with HbA1c of ≤ 7% over time ................................................ 32 
8.2.4. 
Change in body weight in subjects with baseline BMI ≥ 25 kg/m2 at week 24 ........... 32 
8.2.5. 
Change from baseline in HbA1c in subjects who have baseline HbA1c ≥ 7.5% and 
≤ 10.5% over time ......................................................................................................................... 32 
8.2.6. 
Change from baseline in HbA1c in high glycemic group (subjects who have baseline 
HbA1c > 10.5% and ≤ 12.0%) over time ....................................................................................... 33 
9. 
SAFETY ......................................................................................................... 33 
9.1. 
Extent of Exposure ............................................................................................................ 33 
9.2. 
Treatment Compliance ...................................................................................................... 34 
9.3. 
Adverse Events .................................................................................................................. 35 
9.3.1. 
Derived Data ............................................................................................................... 35 
9.3.2. 
Data Summarization .................................................................................................... 35 
9.3.3. 
AE of Special Interest .................................................................................................. 36 
9.4. 
Laboratory Evaluations ..................................................................................................... 38 
9.5. 
Vital Signs ........................................................................................................................... 41 
9.6. 
Electrocardiogram ............................................................................................................. 41 
9.7. 
Physical Examination ........................................................................................................ 42 
10. 
INTERIM ANALYSES ................................................................................ 43 
11. 
DATA AND SAFETY MONITORING BOARD ........................................... 43 
12. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ......................... 43 
13. 
REFERENCE LIST .................................................................................... 44 


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14. 
PROGRAMMING CONSIDERATIONS ...................................................... 45 
14.1. 
General Considerations .................................................................................................... 45 
14.2. 
Table, Listing, and Figure Format .................................................................................... 46 
14.2.1. 
General ........................................................................................................................ 46 
14.2.2. 
Headers ....................................................................................................................... 46 
14.2.3. 
Display Titles ............................................................................................................... 47 
14.2.4. 
Column Headers ......................................................................................................... 47 
14.2.5. 
Body of the Data Display ............................................................................................. 47 
14.2.6. 
Footnotes .................................................................................................................... 50 
15. 
QUALITY CONTROL ................................................................................. 50 
16. 
INDEX OF TABLES ................................................................................... 51 
17. 
INDEX OF FIGURES ................................................................................. 51 
18. 
INDEX OF LISTINGS ................................................................................. 51 
19. 
MOCK-UPS ................................................................................................ 51 
20. 
APPENDICES ............................................................................................ 51 
 
 


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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass index 
BP 
Blood Pressure 
CEC 
Cardiovascular Endpoint Committee 
CI 
Confidence Interval 
CRF 
Case Report Form 
DKA 
Diabetic Ketoacidosis 
dL  
Deciliter 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimating Glomerular Filtration Rate 
FPG 
Fasting Plasma Glucose 
GEE 
Generalized Estimating Equation 
GMI 
Genital Mycotic Infection 
HbA1c 
Hemoglobin A1c 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ITT 
Intention to Treat 
IWRS 
Interactive Web Randomization System 
LDL-C  
Low Density Lipoprotein Cholesterol  
LOCF  
Last Observation Carried Forward  
LS 
Least Squares 
MACE  
Major Adverse Cardiovascular Event  


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Abbreviation 
Description 
MAR 
Missing at Random 
MCAR 
Missing Completely at Random 
MCMC 
Monte Carlo Markov Chain 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram  
mL 
Milliliter 
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing not at Random 
N/A 
Not Applicable 
Na 
Sodium 
PK 
Parmacokinetics 
PP 
Per Protocol  
PR 
Time from the beginning of the P wave to the beginning of the QRS 
complex in electrocardiogram 
PT 
Preferred Term 
Q1 
1st Quartile 
Q3 
3rd Quartile 
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 
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 
SI 
Standard International System of Units 
SMBG 
Self-Monitored Blood Glucose 


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Abbreviation 
Description 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
T2DM 
Type 2 Diabetes Mellitus 
TEAE 
Treatment-emergent Adverse Event 
TLF 
Table, Listing And Figure 
UACR 
Urine Albumin To Creatinine Ratio  
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 (TLFs). 
Adverse events that have met the seriousness criteria defined in the protocol are 
reported on the serious adverse event (SAE) forms using the MediData RAVE platform. 
An SAE case consists of the information reported in the SAE forms, subject 
characteristics documented in the case report forms, and additional source data such as 
hospital discharge summaries. Each SAE case is recorded in a validated ARGUS database 
which is managed by Covance. Any discrepancies in critical data fields of each SAE will 
be reconciled between the ARGUS and THR-1442-C-419 clinical database prior to 
database lock. The SAE coding, analyses and summaries are based on the final study 
data recorded in the clinical database. Detailed serious adverse event follow-up data 
will be reported from the ARGUS database and are not included in this SAP. 
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 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-corrected change in hemoglobin A1c (HbA1c) from baseline to 
week 24 in adults with type 2 diabetes mellitus (T2DM) whose disease is inadequately 
controlled by metformin alone. 
3.2. 
SECONDARY OBJECTIVES 
The secondary efficacy objectives of this study are: 
• 
To assess the effect of bexagliflozin on the change in fasting plasma glucose 
(FPG) as a function of time 
• 
To assess the effect of bexagliflozin on the change in systolic blood pressure 
(SBP) as a function of time 
• 
To assess the effect of bexagliflozin on the proportion of subjects achieving 
HbA1c of ≤ 7% as a function of time 
• 
To assess the change in total body weight as a function of time in subjects with 
baseline body mass index (BMI) ≥25 kg/m2 
• 
To assess the change in HbA1c as a function of time 
• 
To assess the change in HbA1c as a function of time among subjects who have 
baseline HbA1c of > 10.5% and ≤ 12.0% 
3.3. 
SAFETY OBJECTIVES 
• 
To determine the frequency and severity of treatment emergent adverse events 
• 
To determine the frequency and severity of treatment emergent adverse events 
of interest 
• 
To record and evaluate changes in concomitant medication use that may affect 
subject safety 
• 
To evaluate any potentially adverse changes in laboratory test values 
• 
To assess changes in cardiac rhythm through 12-lead electrocardiogram (ECG) 
• 
To evaluate vital signs 
• 
To assess general health by physical examination 
3.4. 
OTHER OBJECTIVES 
The other objective is: 


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• 
To measure bexagliflozin plasma concentrations as a function of time from 
dosing (sparsely sampled) 
3.5. 
BRIEF DESCRIPTION 
THR-1442-C-419 is a phase 3, multi-center study to evaluate the efficacy and safety of 
orally administered bexagliflozin tablets, 20 mg or placebo, in subjects whose T2DM is 
not adequately controlled by metformin as the only therapy in addition to  diet and 
exercise. Approximately 350 subjects who meet all the inclusion criteria, none of the 
exclusion criteria, and who consent to participate in the study, are eligible for study 
enrollment. All subjects must have taken metformin at an optimal or near-optimal 
stable dose for ≥ 8 weeks prior to screening and have received diet and exercise 
counseling. 
Approximately 300 subjects with HbA1c values ≥ 7.5% and ≤ 10.5% at screening (the 
double-blind treatment group) who successfully complete a 1-week run-in and who 
remain eligible will be randomized in a 1:1 ratio to receive once daily double-blind 
treatment of bexagliflozin tablets, 20 mg or placebo. Study subjects will continue 
receiving open-labeled metformin background medication during the entire study at a 
stable dose and frequency. The treatment period will be 24 weeks. The study will be 
conducted in an outpatient setting. Study subjects will have clinic visits at weeks 6, 12, 
18, and 24 for safety and efficacy evaluation. A final follow up visit will be conducted at 
week 26. 
Up to 50 subjects who have HbA1c > 10.5% and ≤ 12.0% at screening will be assigned to 
the high glycemic group to receive open labeled bexagliflozin tablets, 20 mg, in 
addition to metformin. There will be no placebo control cohort for the high glycemic 
group. Subjects assigned to the high glycemic group will be asked to follow the same 
study procedures as subjects assigned to the two study arms. 
Subjects with persistent hyperglycemia based on blood glucose levels may receive 
approved antidiabetic rescue medications. 
A sparse sampling assessment of bexagliflozin pharmacokinetics (PK) in the study 
population will also be performed. A net enrollment of approximately 200 subjects is 
planned for this aspect of the study. Samples will be taken between weeks 6 and 12. 
The population PK study design and analysis plan will be described in a designated study 
protocol and the analysis will be reported separately. 
3.6. 
SUBJECT SELECTION 
The study population will include approximately 350 subjects whose T2DM is 
inadequately controlled by metformin and who meet all of the inclusion criteria and 
none of the exclusion criteria. Clinical sites in the US and Japan are anticipated to 


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recruit subjects. 
3.6.1. 
Inclusion Criteria 
Refer to protocol section 4.2 for inclusion criteria. 
3.6.2. 
Exclusion Criteria 
Refer to protocol section 4.3 for exclusion criteria. 
3.7. 
DETERMINATION OF SAMPLE SIZE 
In the blinded segment of the study approximately 300 subjects will be randomized 1:1 
to bexagliflozin tablets, 20 mg or bexagliflozin tablets, placebo. With this sample size, 
the study has approximately 90% power to detect a 0.4% difference in HbA1c between 
the active arm and the placebo arm, assuming a standard deviation of 1% HbA1c for the 
study population and that 12% of the study participants will have dropped out by week 
24.  
With similar assumptions, a single group of 50 subjects has approximately 90% power to 
detect a difference from baseline of 0.5% HbA1c, assuming a 12% dropout rate and a 
population standard deviation of 1%. 
3.8. 
TREATMENT ASSIGNMENT & BLINDING 
3.8.1. 
Treatment Assignment 
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 30 randomized subjects. However, after a site has recruited 
30 randomized subjects, if a potential subject at that site is in the run-in phase and 
wishes to continue with the study, the subject will be allowed to continue and, if 
eligible, to be randomized. 
Eligible subjects who complete the run-in period, meet all study inclusion/exclusion 
requirements, and have HbA1c ≥ 7.5% and ≤ 10.5% at screening will be randomized in a 
1:1 ratio to receive bexagliflozin tablets, 20 mg or 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 by high (8.5% ≤ HbA1c ≤ 10.5%) 
and low (7.5% ≤ HbA1c < 8.5%) baseline measurement at screening (Visit V1) and by 
country (US or Japan). Eligible subjects who have HbA1c > 10.5% and ≤ 12.0% at 
screening will be assigned to the open-label high glycemic group. 


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3.8.2. 
Blinding 
Approximately 300 subjects will participate in the double-blind placebo-controlled 
portion of the trial. The sponsor, investigators, study coordinators, pharmacists, study 
subjects, the cardiovascular endpoint committee (CEC) members or Diabetic 
Ketoacidosis (DKA) adjudicator will be blinded to the study medication of these 
participants. Upon randomization, each subject will receive a subject randomization 
number and a drug kit. 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 a 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 or the 
DKA event adjudicator at the conclusion of the study until all global investigational 
studies are completed and a meta-analysis to assess cardiovascular risk is conducted. 
Subjects in the high glycemic group (HbA1c > 10.5% and ≤ 12.0% at screening) will 
receive open labeled study drug. There will be no placebo cohort for the high glycemic 
group. 
3.9. 
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 
 
Bexagliflozin tablets, 20 mg or placebo, should be taken at approximately the same 
time each day, before or after breakfast, with one cup (250 mL) of water. 


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On the day of scheduled clinic visits at which blood is to be drawn, administration of 
bexagliflozin should be delayed until after blood is drawn and bexagliflozin tablet 
should be taken in the clinic or at home with one cup (250 mL) of water. 
3.10. 
STUDY PROCEDURES AND FLOWCHART 
The activities that must be performed at each clinic visit are presented in Table 1. The 
required laboratory tests scheduled at each visit are listed in Table 2. 
A visit window of ± 3 days is allowed for all visits except Visit 3. Visit 3 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 8 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 8 hours, the subject must return as soon as can be 
arranged (within 1 week) to provide a specimen after proper fasting. 


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Table 1    Schedule of Events 
Procedure  
Screening  
Run-in  
Treatment  
Follow-up  
Visit Number  
V1/ Screening  
V2/ Run 
In  
V3/ Random-
ization  
V4  
V5  
V6  
V7  
V8/ Follow 
Up  
Time to Randomization (week)  
-3  
-1  
0  
6  
12  
18  
24  
26  
Informed Consent  
X  
 
 
 
 
 
 
 
Screening for I/E Criteria  
X  
 
X  
 
 
 
 
 
Medical History  
X  
 
 
 
 
 
 
 
Diet and Exercise Counseling  
 
X  
 
 
 
 
 
 
Physical Examination  
 
 
X  
 
 
 
 
X  
Abbreviated Physical Examination  
X  
 
 
 
 
 
X  
 
Vital Signs  
X  
 
X  
X  
X  
X  
X  
X  
Electrocardiography  
 
 
X  
 
 
 
X  
 
Clinical Laboratory Tests  
X  
 
 
X  
X  
X  
X  
X  
Urine Pregnancy Test (local, WOCBP only)  
X (all women)  
 
X  
X  
X  
X  
X  
X  
Diary and Glucometer Dispensation and Review  
 
X  
 
 
 
 
 
 
Dispensing Run-in Drug  
 
X  
 
 
 
 
 
 
Diary and Glucometer Record Review  
 
 
X  
X  
X  
X  
X  
X  
Dispensing Investigational Product  
 
 
X  
 
X  
 
 
 
Adverse Events Assessments  
 
X  
X  
X  
X  
X  
X  
X  
Concomitant Medication Assessments  
 
X  
X  
X  
X  
X  
X  
X  
 
 
 


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Table 2    Schedule of Clinical Laboratory Tests 
 
Screening  
Run-in  
Treatment  
Follow-up  
Visit number  
V1/ Screening  
V2/ Run In  
V3/ 
Randomization  
V4  
V5  
V6  
V7  
V8/ Follow Up/ 
ET  
Time to Randomization Visit (weeks)  
-3  
-1  
0  
6  
12  
18  
24  
26  
Hematology  
X  
 
 
X  
X  
 
X  
X  
Serum Chemistry and Electrolytes  
X  
 
 
X  
X  
X  
X  
X  
Glycemic Control  
X  
 
 
X  
X  
X  
X  
X  
Serum Lipids  
X  
 
 
 
X  
 
X  
X  
Urinalysis  
X  
 
 
X  
X  
X  
X  
X  
Urine Pregnancy Test (WOCBP)  
X (all women)  
 
X  
X  
X  
X  
X  
X  
Population PK sampling  
 
 
 
X  
X  
 
 
 
 
 


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4. 
ENDPOINTS 
4.1. 
PRIMARY EFFICACY ENDPOINT 
The primary efficacy endpoint is the change of HbA1c from baseline to week 24 in the 
20 mg dose group compared to placebo group. 
4.2. 
SECONDARY EFFICACY ENDPOINTS 
The key secondary efficacy endpoints include: 
• 
Change in FPG from baseline over time 
• 
Change in SBP from baseline over time 
• 
Proportion of subjects achieving HbA1c ≤ 7% over time 
• 
Change in body weight in subjects with baseline BMI ≥ 25 kg/m2 over time 
• 
Change in HbA1c over time 
• 
Change in HbA1c among subjects who have baseline HbA1c > 10.5% and ≤ 12.0% 
over time 
4.3. 
SAFETY ENDPOINTS  
• 
Adverse events (AEs) 
• 
AE of special interest 
• 
Medication use 
• 
Clinical laboratory results 
• 
ECG results 
• 
Vital signs 
• 
Physical exam results 
 
 
 


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5. 
ANALYSIS SETS 
5.1. 
SCREENED ANALYSIS SET 
The Screened Analysis Set will include all subjects screened for eligibility. The screened 
population will include screen failures. Unless specified otherwise, this population will 
be used for summaries of subject disposition. 
5.2. 
 SAFETY ANALYSIS SET  
All subjects who took at least one dose of study medications will be included in the 
safety analysis set. Safety analyses will be based on the medications that were taken 
first. The safety analysis set is the primary analysis set for safety evaluation.  
5.3. 
INTENTION TO TREAT ANALYSIS SET  
All subjects in double-blind treatment group who are randomized regardless of 
treatment adherence or availability of follow up data, or all subjects in the high 
glycemic group who enrolled into the study will be included in the Intention to Treat 
(ITT) Analysis Set. All analyses of the ITT analysis set will be based on each subject’s 
randomized assigned treatment. 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 double-blind treatment 
group and 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 or visit 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 and recorded in CRF. 
Deviation will be classified into each of the 9 categories: enrollment criteria, 
non-compliance, laboratory, dosing, visit schedule, visit/procedure requirement, 
concomitant medication, informed consent, and other. Date and details of the deviation 
will be recorded. The list of deviation will be reviewed before unblinding and major 
protocol deviations that, in the opinion of the medical monitor, could affect the 
primary and secondary variables will be determined. Some possible types of major 
protocol deviations are showing in Table 3. 


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Table 3    Some Possible Types of Major Protocol Deviations 
Category  
Criteria 
Exclusion 
Inclusion/Exclusion Criteria  
 
 
Ineligible subject is enrolled  
- Subjects not satisfying HbA1c inclusion criteria  
- 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 International Conference on Harmonization (ICH) E9 guidelines. All statistical 
analyses will be conducted using SAS statistical software version 9.4 or higher. 
Tables, listings and figures (TLFs) will be produced in accordance with the principles 
outlined by the ICH E3 guidelines. Unless otherwise specified, for all TLFs where 
applicable, double-blind group and high glycemic group will be presented in the same 
TLFs as different group. Double-blind group will be presented by treatment 
(Bexagliflozin 20 mg; Placebo) and overall where applicable. 
Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], 1st quartile [Q1], median, 3rd quartile [Q3], minimum and maximum) for 
continuous variables, and frequency and percentage of subjects for categorical and 
ordinal variables, unless otherwise specified.  
Unless otherwise specified, for double-blind group all statistical tests will be one-sided 
using a 0.025 level of significance. All confidence intervals (CIs) will be two-sided 95% 
CIs. No formal hypothesis testing will be performed for the high glycemic group. 
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. 
Treatment Period 
For double-blind treatment group, treatment period is defined as the period after 
subject is randomized to receive the double-blind study medication. For high glycemic 
group, treatment period is defined as the period when subject is dosed with active 
study medication. 
6.2.2. 
Baseline Values 
For subject who is dosed, baseline is defined as the last non-missing value on or prior to 
the first dose of study medication in treatment period. For subject who is not dosed in 


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double-blind treatment group, baseline is defined as the last non-missing value on or 
prior to the randomization date. 
6.2.3. 
First Dose Date 
Two “first dose dates” will be required – one for the Run-In period and one for the 
treatment period. The first dose date for the Run-In period will be the date of 
administration of the first dose of placebo tablets during the Run-In period. The first 
dose date for the treatment period will be the date that the first dose of the study 
medication in the treatment period. Both first dose dates will be obtained from the 
electronic case report form (eCRF). Study analyses will use the treatment period first 
dose date. 
6.2.4. 
Study Day 
Study Day is the number of days starting from the first administration of study 
medication in treatment period, which is counted as Study Day 1. If the assessment date 
is after the date of the first study medication in treatment period, the study day is 
calculated as date of assessment - date of the first dose administration (in treatment 
period) + 1. If the assessment date is prior to the date of the first study medication in 
treatment period, the study day is calculated as date of assessment - date of the first 
dose administration (in treatment period). 
6.2.5. 
Duration 
Duration of treatment period will be determined as Duration = last dose date (in 
treatment period) - first dose date (in treatment period) + 1. Duration of Run-In period 
will be determined as Duration = last dose date (in run-in period) - first dose date (in 
run-in period) + 1. 
6.2.6. 
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. 
6.2.7. 
Patient Years 
Patient years are calculated as sum of the duration from the first dose of double-blind 
treatment or active treatment in high glycemic group to the end of study/ 365.25 of all 
subjects in the specified analysis set and treatment arm. This is used as the 
denominator of the computation of incidence rate. 


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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 4 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. 
Table 4    Analysis Visit Windows 
Study Day Window 
Scheduled day  
Scheduled Visit/Week 
Day 2 - 63 
Day 42 
Visit 4/Week 6 
Day 64 – 105 
Day 84 
Visit 5/Week 12 
Day 106 - 147 
Day 126 
Visit 6/Week 18 
>= Day 148 
Day 168 or (Last dose date + 
1), select the less one 
Visit 7/Week 24 
* Week 24 is the end of treatment visit for those subjects completing the study per protocol. For 
endpoints 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. All data summary will base on the 
mapped visit. 
6.5. 
POOLING OF CENTERS 
Subjects will not be pooled based on site size, but rather by country (US or Japan), 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.  
 
 


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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 be presented by group 
(double-blind group and high glycemic group), treatment and overall where applicable, 
the number and/or percentage of subjects who have signed the informed consent, who 
have been screened, screen failed prior to Run-in, screen failed during the Day -7 to 
Day -1 Run-in, and who have entered treatment period, completed the study drug, 
discontinued study drug, completed the study, and discontinued from the study after 
entering treatment period. The reasons for early withdrawal after entering treatment 
period will be summarized. A separate table will display the number of subjects who 
have met the eligibility criteria at screening and Run-in period but have withdrawn 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 where applicable) will be 
summarized. 
7.2. 
SUBJECT ELIGIBILITY 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. Baseline 
characteristics will include HbA1c, baseline HbA1c group (≥ 8.5% and ≤ 10.5% vs. ≥ 7.5% 
and < 8.5%) at Visit 1, FPG, blood pressures, body weight, BMI. 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 group (double-blind group and 
high glycemic group) and treatment for subjects in the safety, ITT, and PP analysis set 
where applicable. Subject age will be calculated from the date of informed consented. 


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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 at the screening 
visit. 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 20.1. 
Medical and surgical history will be summarized for the Safety Analysis Set by group, 
treatment, system organ class (SOC), and MedDRA preferred term (PT), overall. 
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. 
All medication will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) version B2 September 2017 WHO DDE. 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 group, treatment, 
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. 
7.5.1. 
Prior Medication 
Any medication with a stop date prior to or on first dose date for both treatment groups 
during the treatment period will be considered a prior medication. 


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No summary for prior medication will be presented. Prior and concomitant medications 
will be presented together on a single listing. Prior medication will be indicated in the 
listing. 
7.5.2. 
Concomitant Medication 
A concomitant medication is any medication that the subject has been taking prior to 
the first dose of study medication during the treatment period 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. If a medication can be considered as 
both prior and concomitant due to partial stop date, it will be considered as 
concomitant. 
Any medication a subject takes to treat hyperglycemia after the first dose of double-
blind study drug starts and continues for more than 2 weeks before study treatment 
stops is considered a rescue therapy and should be recorded in the concomitant 
medication log. Increase total daily dose of metformin, the background hypoglycemic 
therapy, is also considered rescue medication if the dose is intensified during the 
double-blind treatment period for more than 2 weeks before study treatment stops. All 
medication given to treat hyperglycemia will be recorded in CRF. 
Concomitant medications will be presented in a summary table by group and treatment 
as well as in a subject listing. Rescue medications will be summarized in a separate 
table and will be indicated in the same listing for concomitant medications. 
 
 


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8. 
EFFICACY 
Efficacy data include HbA1c, FPG, SBP and body weight. All continuous efficacy data will 
be summarized for observed and change values by treatment and visit for double-blind 
treatment group and high glycemic group separately. Proportion of subjects with HbA1c 
of ≤ 7% will be summarized by frequency and proportion by treatment and visit for 
double-blind treatment group and high glycemic group separately. No formal inference 
analyses will be performed for the open-label study. 
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 for the double-blind groups. 
8.1.1. 
Primary Efficacy Analysis 
Let μBexagliflozon and μplacebo represent the mean changes from baseline in HbA1c at Week 24 
for bexagliflozin and placebo arms, respectively. The following hypotheses will be 
tested: 
H0: μ bexagliflozin - μ placebo ≥ 0 
Ha: μ bexagliflozin - μ placebo < 0 
This hypothesis will be tested based on ITT analysis set. Missing 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 multiple 
imputations techniques; HbA1c values collected after the start of rescue medication will 
not be excluded. A pattern-mixture model will be used to explore the impact of the 
missing data. Imputation will be conducted within each treatment arm and subgroup 
(treatment completer vs. treatment terminated early) under the assumption that non-
adherent subjects with missing data will follow the same trajectory of non-adherent 
subjects with values observed. All efforts will be made to retain subjects in the study. If 
treatment is discontinued, subjects are encouraged to remain in the study and complete 
all scheduled visits, including final follow-up visit. However, with all efforts, insufficient 
values may be available for reliable imputation. This analysis will be performed only if 
≥3% (approximately 5) of subjects in each treatment arm completed scheduled week 24 
visit after treatment is stopped. This number is chosen to allow sufficient data to 
establish a regression model for imputation. For this analysis, the following three-step 
approach outlined below will be used: 
a. Non-monotone (intermediate visits) missing data will be imputed first using the 
Monte Carlo Markov Chain (MCMC) method under the MAR assumption in all 
treatment arms (using the MCMC statement in PROC MI). Multiple chains option 


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(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. Five hundred imputed datasets 
will be generated.  
b. After the non-monotone missing data have been imputed, the remaining 
monotone missing data will be imputed within each treatment arm and 
subgroup, defined by whether subject completed 24 week of study treatment, 
using regression approach. The predictors for the regression imputation model at 
any time point will be country, and HbA1c at all previous time points, including 
baseline. Imputations will be performed using a sequence of regression-based 
imputations (using PROC MI statement MONOTONE REG) at each post-baseline 
time point.  
c. Imputed data in each of the multiple imputed datasets will be analyzed using a 
mixed model repeated measures (MMRM) approach. The MMRM model will 
include treatment, visit, treatment-by-visit interaction, the baseline HbA1c value 
and country (US or Japan) as a fixed effect covariate. 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. 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 The LS mean results from all imputed datasets will be combined using the 
Rubin’s combination rule (PROC MIANALYZE). 
If no sufficient week 24 values from treatment discontinued subjects are available for 
imputation, MMRM analysis will be performed using all available data. Method described 
in above step c will be utilized.  
Descriptive statistics (n, mean, Q1, median, Q3, SD, minimum, and maximum) will be 
reported by treatment group and visit, along with the LS means, differences 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 (SEs) of the change from 
baseline over time and difference between treatment groups with 95% CIs will be 
presented graphically for the ITT population. 


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For supportive analyses, regardless of having sufficient week 24 values from treatment 
discontinued subjects are available for imputation or not, MMRM analysis will be 
performed using all available data. The primary efficacy endpoint will also be analyzed 
with all available data using the PP analysis set using MMRM method. 
8.1.2. 
Sensitivity Analyses 
Randomized subjects who withdraw consent to participate in the study will not be 
replaced. The drop-out rate is estimated to be 12%. To the extent possible, attempts 
will be made to minimize the amount of missing data through measures planned in the 
study conduct. 
To investigate the possible implications of missing values in efficacy assessments, the 
number, timing, pattern, and reason for the missing value will be summarized. The 
reason for withdrawn will be reviewed. If there are missing values for the primary 
analysis, only available data will be analyzed and data obtained after rescue will not be 
excluded. The drop-out patterns will be assessed by a Kaplan-Meier plot of time to 
discontinuation by treatment group to assess whether they differ between treatment 
groups. 
To evaluate the impact from missing data and rescue medication, the following 
sensitivity analyses will be conducted: 
1) Tipping point analysis will be conducted. Data after rescue medication will be 
considered as missing. Following steps will be followed: 
a. Create monotone missing data as step a in Section of 8.1.1; 
b. Regression approach under MAR will be used to generate complete datasets. The 
predictors for the regression imputation model at any time point will be country, 
treatment, and HbA1c at all previous time points, including baseline. The first 
imputed values will be penalized or rewarded based on the treatment subject 
received: 
o Subjects in the bexagliflozin group: missing value will be analyzed assuming 
the treatment effect is worsened by δ1 (where δ = 0.1 to 0.5, in step of 0.1) 
compared to the subjects who have no missing value in the reduction of 
HbA1c value; 
o Subjects in the placebo group: missing value will be analyzed assuming the 
treatment effect is better by δ2 (where δ = 0 to 0.5, in step of 0.1) compared 
to the subjects who have no missing value in the reduction of HbA1c value; 


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The penalty or reward will not be applied to the values from later time points as 
these values are penalized or rewarded through regression on previous time 
points. 
c. Imputed datasets will be analyzed and results combined as step c in Section of 
8.1.1. 
For each combination of (δ1, δ2), 100 imputed datasets will be obtained. These 25 
combinations will be separately analyzed to explore under which condition where 
the null hypothesis can no longer having evidence to be rejected. 
2) Additionally, the impact of the data after the start of rescue medication will be 
evaluated. HbA1c values collected after the start of rescue medication will be 
considered missing, and the MMRM analyses will be performed. Model as specified in 
the primary analysis will be used.  
3) Furthermore, data that are missing or after rescue medication will be imputed using 
LOCF. All observed data and the imputed values will be analyzed using MMRM model. 
Model as specified in the primary analysis will be used. 
8.1.3. 
Subgroups 
The primary efficacy endpoint on available data will be summarized and analyzed by 
the following subgroups using MMRM model: 
• 
Age (<65 years or ≥65 years), adjusted by country and baseline HbA1c value; 
• 
Gender (male or female) , adjusted by country and baseline HbA1c value; 
• 
Race (Asian; Black of African American; White or Caucasian; Other) , adjusted by 
country and baseline HbA1c value; 
• 
Baseline HbA1c (≥ 8.5% and ≤ 10.5% vs. ≥ 7.5% and < 8.5%), adjusted by country; 
• 
Country (US or Japan), adjusted by baseline HbA1c. 
8.2. 
SECONDARY EFFICACY ENDPOINT(S) AND ANALYSES 
Analysis for secondary endpoints will be based on the ITT analysis set and repeated for 
PP analysis set. No formal hypothesis testing will be performed for secondary efficacy 
endpoints. All nominal p-values will be presented for exploratory purpose. 
8.2.1. 
Change from baseline in FPG over time 
The comparison of change in FPG between randomized treatments of the double-blind 
groups at each visit will be carried out using the similar MMRM model as section 8.1.1. 
The model will include terms for treatment, visit, treatment-by-visit interaction, 


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country as fixed effects and the corresponding baseline FPG value as covariate. LS 
means for each treatment and the difference between treatments, treatment 
comparison p-values and difference for each visit will be estimated from the model, 
with the two-sided 95 % CIs of the treatment difference also presented. Summary table 
will be presented and figures will be displayed for the ITT analysis set in both 
double-blind and high glycemic groups. The by-visit summary statistics will be provided 
for safety analysis set for high glycemic group. 
8.2.2. 
Change in SBP over time 
Change from baseline in SBP at each visit for the double-blind groups will be analyzed in 
a similar manner as change in FPG, Section 8.2.1, based on ITT analysis set for all 
subjects. Baseline SBP will be used in place of baseline FPG. Country and baseline HbA1c 
value will also be considered as fixed effects. Summary table will be presented and 
figures will be displayed for the ITT analysis set in both double-blind and high glycemic 
groups.  
8.2.3. 
Proportions of subjects with HbA1c of ≤ 7% over time 
Summary on the proportion of subjects achieving HbA1c < 7% at each visit will be 
presented over time for both double-blind and high glycemic groups. For the 
double-blind groups, data will be analyzed using Generalized Estimating Equation (GEE) 
logistic regression. The fixed effect will include country, treatment, visit, treatment-
by-visit interaction and baseline HbA1c. An unstructured correlation structure will be 
used (or autoregressive(1) if the model with the unstructured structure does not 
converge). The odds ratios of bexagliflozin group over the placebo group at each visit 
will be estimated from LS means based on the model with the corresponding p-values 
and their two-sided 95 % CIs presented. 
8.2.4. 
Change in body weight in subjects with baseline BMI ≥ 25 kg/m2 at 
week 24 
Change from baseline in body weight for the double-blind groups will be analyzed using 
an analysis of covariance model (ANCOVA), based on ITT analysis set for all subjects 
with baseline BMI ≥ 25 kg/m2. Baseline body weight will be used as covariate, and 
country and baseline HbA1c value will also be used as fixed effects.  
Summary table will be presented and figures will be displayed for both double-blind 
groups and high glycemic group based on the ITT analysis set.  
8.2.5. 
Change from baseline in HbA1c in subjects who have baseline HbA1c 
≥ 7.5% and ≤ 10.5% over time 
Change from baseline in HbA1c will be analyzed as part of primary efficacy analysis 


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(Section 8.1.1). 
8.2.6. 
Change from baseline in HbA1c in high glycemic group (subjects 
who have baseline HbA1c > 10.5% and ≤ 12.0%) over time 
The change from baseline in HbA1c over time for high glycemic group will be presented 
at each time point descriptively in a separate table. Point estimate of the change and 
its corresponding 95% CI (normal assumption) will be constructed for each time point. 
All observed values will be summarized at each visit that HbA1c is assessed. In addition, 
if week 24 value is missing or subject used rescue medication before week 24 
assessments, the last post-baseline value prior to the start of rescue medication will be 
carried forward to week 24. The LOCF week 24 will also be summarized. 
9. 
SAFETY 
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 group and treatment as counts and percentages 
for discrete variables and means, standard deviations, medians, inter-quartile range, 
minimum, and maximum for continuous variables. All subjects who receive at least one 
dose of study medication will be included in the safety analysis. High glycemic subjects 
safety observations will be summarized as a stand-alone group in the summary tables.  
9.1. 
EXTENT OF EXPOSURE 
For each group, study drug exposure will include: 
• 
Treatment duration by treatment 
• 
Total dose received by treatment  
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 in treatment 
period obtained from the study drug exposure CRF. 


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• 
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. 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. 
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 day of run-in medication. Subjects 
who are not compliant during the run-in period will be excluded from treatment period. 
If, in the judgment of the investigator, it was appropriate for the subject to omit these 
doses, this requirement may be waived (e.g., if the subject was hospitalized overnight 
during run-in). 
At each visit after the start of the run-in period, the study staff will review the 
self-monitored blood glucose (SMBG) control diary 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 treatment period 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 
group and treatment for the treatment period. A frequency summary of compliance will 
also be presented with the following categories: < 75%, 75-<100%, 100-120%, and 
> 120%. 


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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 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. 
For all AEs, preferred AE terms and system organ class SOC will be coded using 
terminology from the MedDRA, version 20.1. 
A Treatment-emergent Adverse Event (TEAE) is defined as an AE that begin after the 
first administration of the study medication during the treatment period or existing AEs 
that worsen after the first dose of the study medication during the treatment period. 
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 study medication 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 first dose in treatment period + 
1) if it is after the first dose of study drug. AE onset day is calculated as (date of AE 
start – date of first dose in treatment period) if it is before the first dose of study drug. 
The onset day will be missing if the start date is 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.  


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• 
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. 
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 study medication 
• 
Serious AEs 
• 
AEs leading to treatment discontinuation 
• 
AEs leading to death 
9.3.3. 
AE of Special Interest 
AE of special interest include Urinary Tract Infections (UTI), Genital Mycotic Infections 
(GMIs), diuretic effects, hypotension episodes, hypoglycemia, hepatotoxicity, Major 
Adverse Cardiovascular Event (MACE), falls and fractures, malignancy, hypersensitivity 
reactions, DKA, pancreatitis, amputations and renal failure events. These AEs of 
interest except MACE and amputations will be prospectively identified based on the 
MedDRA preferred terms in the AE log by a medical expert prior to the data base lock 
and unblinding of the individual subject treatment assignment. The list of AE of interest 
will be confirmed in a peer review process. MACE will be identified by the investigator 
and documented in the CRF, and subsequently adjudicated by an independent 
committee. Adjudicated results will be used for summary. Adjudicated results will be 
used for summary. Amputation events will be recorded in the procedures and 


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amputation CRF. Cardiovascular events, hypoglycemia events by severity, and 
amputations will be summarized separately. 
9.3.3.1. 
AE of special interest identified by PTs 
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. Other AE 
of special interest will be identified from the 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: 
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. 
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 


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• 
Subjects with any amputation 
• 
Conditions that resulted in amputation 
• 
Location of amputation 
Only procedures performed after the first dose of study drug during the treatment 
period will be summarized. 
9.4. 
LABORATORY EVALUATIONS 
Laboratory tests will include hematology panel, chemistry panel, serum lipids, and 
urinalysis testing. Chemistry, and urinalysis will be performed at the following time 
points: at the screening visi and week 6, 12, 18, 24, and 26. Hematology will be 
performed at the screening visit and week 6, 12, 24 and 26. Serum lipids will be 
performed at the screening visit, and on week 12 and 24, and 26. 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 8 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 5. 
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 


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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 
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 
group and treatment. 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 5    List of Laboratory Tests 
TEST NAME  
SHIPMENT  
Hematology  
Ambient  
• Hematocrit (Hct) 
• Hemoglobin (Hgb)  
• Mean corpuscular hemoglobin (MCH)  
• Mean corpuscular hemoglobin concentration 
       (MCHC)   
• Platelet count  
• Mean corpuscular volume (MCV)  
• Red cell distribution width (RDW)  
• Red blood cell (RBC) count  
• White blood cell (WBC) count with  
       differential 
Serum Chemistry and Electrolytes  
Ambient  
• Albumin (ALB)  
• Alanine aminotransferase (ALT)  
• Aspartate aminotransferase (AST)  
• Alkaline phosphatase (ALK-P)  
• Blood urea nitrogen (BUN)  
• Glucose  
• Bicarbonate (HCO3)  
• Creatinine  
• Chloride (Cl)  
• Total protein  
• Calcium (Ca)  
• Magnesium  
• Phosphorus  
• Potassium (K)  
• Sodium (Na)  
• Total bilirubin  
• Direct bilirubin  
• Uric acid 
Glycemic Control  
Ambient  
• Fasting plasma glucose (FPG)  
• Hemoglobin A1c (HbA1c)  
Serum Lipids  
Ambient  
• Total cholesterol (TC)  
• High-density lipoprotein cholesterol (HDL-C) 
• Triglycerides (TG)  
• Low-density lipoprotein cholesterol (LDL- 
      C), calculated  
• LDL-C, direct 
Urinalysis  
Ambient  
• Appearance  
• Bilirubin  
• Color  
• Glucose  
• Ketones  
• Microscopic examination of sediment  
• UACR  
• Nitrite  
• Occult blood  
• pH  
• Protein  
• Specific gravity  
• Urobilinogen  
• Leukocyte esterase 
Urine Pregnancy Test (WOCBP)  
Local  
Population PK Sampling  
Bexagliflozin plasma level  
Frozen  


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9.5. 
VITAL SIGNS  
Vital signs will be measured at the screening visit, on randomization visit, and at week 
6, 12, 18, 24, and 26. Measurements of vital signs will include measurement of supine, 
sitting and standing 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 group, treatment and mapped 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 ECG will be conducted at the screening visit, on randomization visit, and at 
week 24. 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. 
If a subject’s ECG parameters cannot be determined due to pacemaker placement or 
atrial fibrillation, the ECG parameters will be considered missing.  Any machine 
generated values such as 0 or 9999 will be excluded from the analyses. 
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 group, treatment 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 group and treatment at each visit. 


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9.7. 
PHYSICAL EXAMINATION 
A complete physical examination will be conducted at the randomization visit and at 
week 26. 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. An abbreviated physical 
examination will be conducted at screening visit 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 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 
Protocol section 9.3.2 says “Safety analyses will be based on the medication that was 
actually taken by each subject.” SAP changes to use ‘Safety analyses will be based on 
the medication that was taken first.’ in section 5.2. 
Protocol section 9.5.1 includes sensitivity analysis by imputing missing HbA1c data via 
multiple imputation (MI). SAP changes to impute missing HbA1c data via MI in primary 
efficacy analysis per FDA comments. 
Protocol section 9.5.1 includes a sensitive analysis using jump to reference multiple 
imputation method. This has been removed after tipping point analysis is added.  
 
 


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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 9.4 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, Q3 
Median 
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 will be used (e.g., < 10 and ≤ 10 becomes 10) 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. 
14.1. 
GENERAL CONSIDERATIONS 
• 
A separate SAS program will be created for each output. 


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• 
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 9  
• 
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 9. 
• 
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-419 
• 
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. 
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 2.0 
THR-1442-C-419 
 
1007780 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 51 of 51 
16. 
INDEX OF TABLES 
17. 
INDEX OF FIGURES 
18. 
INDEX OF LISTINGS 
19. 
MOCK-UPS 
Attachment 1: Planned Table Shells 
Attachment 2: Planned Listing Shells  
Attachment 3: Planned Figure Shells 
20. 
APPENDICES