Clinical trial NCT02558296
Conditions: Type 2 Diabetes Mellitus
Sponsor: Theracos
Start date: 2015-10-01; Completion date: 2019-10-23
Enrollment: 1700 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

The data from this study will be combined with the data from other bexagliflozin studies in a meta-analysis of CV safety outcomes.

Detailed description:
Approximately 130 investigative sites globally are planned to participate in this study.

An estimated 1650 subjects with inadequately controlled T2DM and an elevated risk of cardiovascular adverse events will be randomized to bexagliflozin tablets, 20 mg, or placebo in a ratio of 2:1 in addition to the background anti-diabetic medications.

The study is an event-driven trial. The treatment period will end when the last randomized subject has completed at least 52 weeks of treatment and a total of at least 134 subjects have experienced a cardiac event.

Arms: arm 1: Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. arm 2: Each subject will receive placebo (inactive tablet) once daily for the duration of the study.
Interventions: intervention 1: Bexagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: 20 mg, tablet intervention 2: 20 mg tablet to match active comparator

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Clinical Trial Protocol with Statisitical Analysis Plan: 
THR-1442-C-476 
Study Title: 
A double blind placebo controlled study to evaluate the 
effects of bexagliflozin on hemoglobin A1c in patients 
with type 2 diabetes and increased risk of cardiovascular 
adverse events 
Study Number: 
THR-1442-C-476 
Study Phase: 
3 
Product Name: 
Bexagliflozin Tablets 
Indication: 
Type 2 diabetes mellitus 
NCT Number: 
02558296 
EudraCT 
Number: 
2015-001760-19 
Sponsor: 
Theracos Sub, LLC. 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information in this document is 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.   
 
 
Date 
Protocol Version 8.0 
01 December 2016 
SAP Version 2.0 
20 November 2019 


Clinical Trial Protocol: THR-1442-C-476 
Study Title: 
A double blind placebo controlled study to evaluate the effects of 
bexagliflozin on hemoglobin A1c in patients with type 2 diabetes and 
increased risk of cardiovascular adverse events 
Study Number: 
THR-1442-C-476 
Study Phase: 
3 
Product Name: 
Bexagliflozin Tablets 
Indication: 
Type 2 diabetes mellitus 
Investigators: 
Multicenter study 
EudraCT number: 
2015-001760-19 
Sponsor: 
Theracos Sub, LLC. 
Sponsor Contact: 
Roger Albright 
Translational Medicine Group 
Massachusetts General Hospital 
185 Cambridge Street, Boston, MA 02114 
Phone:  617-643-5696 
Fax:  617-643-8203 
E-mail:  ralbright@ccib.mgh.harvard.edu 
 
Medical Monitor: 
J. Paul Lock, M.D. 
225 Cedar Hill Street, Suite 200 
Marlborough, MA 01752 
Phone:  508-735-9491 
Fax:  617-643-8203 
E-mail:  jplock@theracos.com 
 
 
 
Date 
Version 8.0 
01 December 2016 
 
Confidentiality Statement 
The information in this document is 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 .................................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................15 
1 
INTRODUCTION ...........................................................................................................17 
1.1 
Bexagliflozin Tablets for T2DM ...........................................................................18 
2 
STUDY OBJECTIVES ....................................................................................................19 
2.1 
Primary Efficacy Objectives ..................................................................................19 
2.2 
Secondary Efficacy Objectives ..............................................................................19 
2.3 
Safety Objectives ...................................................................................................19 
2.4 
Other Objectives ....................................................................................................20 
3 
INVESTIGATIONAL PLAN ..........................................................................................21 
3.1 
Overall Study Design and Plan ..............................................................................21 
3.2 
Research Methods and Procedures ........................................................................21 
3.2.1 
Screening Period ..........................................................................................21 
3.2.2 
Treatment Period ..........................................................................................22 
3.2.3 
Interim Analyses ..........................................................................................23 
3.3 
Rationale for Study Design and Control Group .....................................................23 
3.3.1 
Rationale for the Study Design ....................................................................23 
3.3.2 
Rationale for the Dose Selection..................................................................24 
3.3.3 
Rationale for the Selection of Patient Population ........................................25 
3.3.4 
Treatment Duration ......................................................................................26 
3.3.5 
Rationale for the Overall Analysis ...............................................................26 
4 
STUDY POPULATION SELECTION ...........................................................................27 
4.1 
Study Population ....................................................................................................27 
4.2 
Inclusion Criteria ...................................................................................................27 
4.3 
Exclusion Criteria ..................................................................................................28 
5 
STUDY TREATMENT(S) ..............................................................................................30 
5.1 
Description of Treatment(s) ...................................................................................30 
5.1.1 
Investigational Product ................................................................................30 
5.2 
Treatments Administered .......................................................................................30 
5.2.1 
Investigational Product ................................................................................30 
5.2.2 
Background Oral Hypoglycemic Agents (OHAs) .......................................30 
5.2.3 
Background Insulin Therapy ........................................................................30 
5.2.4 
Anti-hypertensive Medications Including Diuretics ....................................30 
5.2.5 
Rescue Medications for Hyperglycemia ......................................................31 
5.3 
Selection and Timing of Dose for Each Patient .....................................................31 


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5.4 
Method of Assigning Patients to Treatment Groups..............................................32 
5.5 
Blinding..................................................................................................................32 
5.6 
Concomitant Therapy.............................................................................................33 
5.7 
Restrictions ............................................................................................................34 
5.7.1 
Prior Therapy ...............................................................................................34 
5.7.2 
Fluid and Food Intake ..................................................................................34 
5.7.3 
Patient Activity Restrictions ........................................................................34 
5.8 
Treatment Compliance ...........................................................................................34 
5.9 
Packaging and Labeling .........................................................................................34 
5.9.1 
Run-in Kit ....................................................................................................35 
5.9.2 
Investigational Product Kit ..........................................................................35 
5.10 
Storage and Accountability ....................................................................................35 
5.11 
Investigational Product Retention at Study Site ....................................................35 
6 
STUDY PROCEDURES .................................................................................................36 
6.1 
Informed Consent...................................................................................................36 
6.2 
Medical History .....................................................................................................36 
6.2.1 
General Demographics and Characteristics .................................................36 
6.2.2 
Diabetes History...........................................................................................36 
6.2.3 
Cardiovascular Disease History ...................................................................36 
6.2.4 
Medication History ......................................................................................36 
6.3 
Physical Examination.............................................................................................37 
6.4 
Vital Signs ..............................................................................................................37 
6.5 
Electrocardiography ...............................................................................................38 
6.6 
Diet and Exercise Counseling ................................................................................38 
6.7 
Clinical Laboratory Tests .......................................................................................38 
6.7.1 
Laboratory Parameters .................................................................................38 
6.7.2 
Sample Collection, Storage, and Shipping ..................................................40 
6.7.2.1 
Hematology, Blood Chemistry, Serum Lipids, and Glycemic 
Control Assessments ..........................................................................40 
6.7.3 
Urinalysis .....................................................................................................40 
6.7.4 
Population PK Sampling ..............................................................................41 
6.7.5 
Biomarker Sampling ....................................................................................41 
6.7.6 
NT-proBNP Sampling .................................................................................41 
6.7.7 
Laboratory Testing in Unscheduled Visits ..................................................42 
6.8 
Dispensing Investigational Product .......................................................................42 
6.9 
Efficacy Assessments.............................................................................................42 
6.9.1 
HbA1c Determination ..................................................................................42 
6.9.2 
Body Weight ................................................................................................42 


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6.9.3 
Blood Pressure .............................................................................................42 
6.9.4 
Hospitalization for Heart Failure .................................................................42 
6.10 
Adverse Events Assessments .................................................................................43 
6.10.1 
Definition of Adverse Events.......................................................................43 
6.10.2 
Eliciting and Reporting AEs ........................................................................44 
6.10.3 
Immediately Reportable AEs .......................................................................45 
6.10.4 
Pregnancy .....................................................................................................45 
6.10.5 
Procedure for Breaking the Blind ................................................................46 
6.10.6 
Follow-up of AEs .........................................................................................47 
6.10.6.1 
Follow-up of Non-Serious AEs .........................................................47 
6.10.6.2 
Follow-up of Post-Study SAEs ..........................................................47 
6.10.7 
Urinary Tract Infections (UTIs) ...................................................................47 
6.10.8 
Genital Mycotic Infections (GMIs) .............................................................48 
6.10.9 
Hepatotoxicity ..............................................................................................48 
6.10.10 Hypoglycemia ..............................................................................................48 
6.10.11 Diabetic Ketoacidosis (DKA) ......................................................................50 
6.10.12 Major Adverse Cardiovascular Event (MACE) ...........................................51 
6.10.13 Amputation ..................................................................................................51 
6.11 
Concomitant Medication Assessments ..................................................................52 
6.12 
End of Treatment Procedure ..................................................................................52 
6.13 
Removal of Patients from the Trial or Discontinuation of Investigational 
Product Administration ..........................................................................................53 
6.14 
Appropriateness of Measurements .........................................................................53 
7 
STUDY ACTIVITIES .....................................................................................................55 
7.1 
Screening Visit V1 (up to 3 weeks before run-in period) ......................................55 
7.2 
Run-in Period .........................................................................................................55 
7.2.1 
Visit V2 (two weeks prior to randomization) ..............................................55 
7.3 
Treatment Period ....................................................................................................56 
7.3.1 
Visit V3 (day 1 of week 1) ...........................................................................56 
7.3.2 
Visit V4 (week 2, a phone interview) ..........................................................56 
7.3.3 
Visit V5 (week 6) .........................................................................................56 
7.3.4 
Visit V6 (week 12) .......................................................................................57 
7.3.5 
Visit V7 (week 18, a phone interview) ........................................................57 
7.3.6 
Visit V8 (week 24) .......................................................................................57 
7.3.7 
Visit V9 (week 36) .......................................................................................57 
7.3.8 
Visit V10 (week 48) .....................................................................................58 
7.3.9 
Visit V11, V13, V15, V17, etc. (week 60 to end of treatment; phone 
interviews)....................................................................................................58 


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7.3.10 
Visits V12, V14, V16, V18, etc. (week 72 to end of treatment, clinic 
visits) ............................................................................................................58 
7.3.11 
Visit EV (end of treatment, a clinic visit) ....................................................59 
7.4 
Exit Visit ................................................................................................................59 
7.4.1 
Visit FU (4 weeks after the last dose of investigational product is 
administered or if a subject withdraws consent) ..........................................59 
7.5 
Discontinuation of Investigational Product Administration ..................................59 
7.6 
Early Termination Procedures ...............................................................................60 
8 
QUALITY CONTROL AND ASSURANCE .................................................................61 
9 
PLANNED STATISTICAL METHODS ........................................................................62 
9.1 
General Considerations ..........................................................................................62 
9.2 
Determination of Sample Size ...............................................................................62 
9.3 
Analysis Populations ..............................................................................................63 
9.3.1 
Intention-to-Treat Analysis Set ....................................................................63 
9.3.2 
Safety Analysis Set ......................................................................................64 
9.3.3 
Per Protocol Analysis Set.............................................................................64 
9.4 
Demographics and Baseline Characteristics ..........................................................64 
9.5 
Primary Endpoints .................................................................................................64 
9.5.1 
Primary Efficacy Endpoint ..........................................................................64 
9.5.2 
Handling Dropouts, and Missing Data.........................................................65 
9.5.3 
Multiple Comparisons / Multiplicity ...........................................................66 
9.6 
Secondary Endpoints .............................................................................................66 
9.6.1 
Key Secondary Efficacy Endpoints .............................................................66 
9.6.2 
Exploratory Efficacy Endpoints ...................................................................67 
9.6.3 
Safety Endpoint ............................................................................................67 
9.6.4 
Other Safety Endpoints ................................................................................68 
9.7 
Other Assessments or Analyses .............................................................................70 
9.8 
Interim Analysis .....................................................................................................71 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................72 
10.1 
Investigators and Study Administrative Structure .................................................72 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................72 
10.3 
Ethical Conduct of the Study .................................................................................72 
10.4 
Subject Information and Consent...........................................................................73 
10.5 
Subject Confidentiality ..........................................................................................73 
10.6 
Study Monitoring ...................................................................................................73 
10.7 
Case Report Forms and Study Records .................................................................74 
10.8 
Data Monitoring Committee ..................................................................................74 


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10.9 
Cardiovascular Endpoint Committee .....................................................................74 
10.10 Protocol Violations/Deviations ..............................................................................75 
10.11 Access to Source Documentation ..........................................................................75 
10.12 Retention of Data ...................................................................................................76 
10.13 Publication and Disclosure Policy .........................................................................76 
11 REFERENCE LIST .........................................................................................................77 
 
LIST OF IN-TEXT TABLES 
Table 1. 
List of Laboratory Tests ...............................................................................39 
Table 2. 
Estimated Event Rates in Patients with Cardiovascular Risks1 ...................63 
Table 3. 
NYHA Classification of Heart Failure ........................................................85 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Eligibility Criteria for the Study Population ................................................21 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................80 
Appendix 2 
Schedule of Laboratory Tests ............................................................83 
Appendix 3 
Examples of SGLT2 Inhibitors ..........................................................84 
Appendix 4 
Congestive Heart Failure Classes ......................................................85 
Appendix 5 
Sponsor Signatures.............................................................................86 
Appendix 6 
Investigator’s Agreement ...................................................................87 
 
 


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SYNOPSIS 
Sponsor: Theracos Sub, LLC. 
Name of Finished Product: Bexagliflozin Tablets  
Name of Active Ingredient: Bexagliflozin 
Study Title: 
A double blind placebo controlled study to evaluate the effects of bexagliflozin on 
hemoglobin A1c in patients with type 2 diabetes and increased risk of cardiovascular adverse 
events  
Study Number: THR-1442-C-476 
Study Phase: 3 
Primary Efficacy Objective: 
The primary efficacy objective of this trial is to evaluate the placebo-adjusted change in 
hemoglobin A1c (HbA1c) from baseline after 24 weeks of exposure to bexagliflozin in type 
2 diabetic subjects at high risk of cardiovascular adverse events. 
Secondary Efficacy Objectives: 
The key secondary efficacy objectives are: 
• 
To evaluate the effect of bexagliflozin compared to placebo on the change in HbA1c 
from baseline to week 24 in randomized subjects who have been prescribed insulin to 
control their diabetes 
• 
To evaluate the effect of bexagliflozin on the change in body weight from baseline to 
week 48 in randomized subjects with a BMI ≥ 25 kg/m2 compared to placebo 
• 
To evaluate the effect of bexagliflozin on the change in systolic blood pressure (SBP) 
from baseline to week 24 in subjects with baseline systolic blood pressure ≥ 140 mmHg 
compared to placebo 
Additional exploratory efficacy objectives are: 
• To assess the effect of bexagliflozin treatment on the change in HbA1c versus placebo 
over time 
• To evaluate the effect of bexagliflozin treatment on the change in fasting plasma glucose 
(FPG) versus placebo over time 
• To measure the proportion of subjects requiring an intensification of anti-diabetic 
regimen versus placebo over time 
• To measure the proportion of subjects requiring a relaxation of their anti-diabetic regimen 
versus placebo over time 
• To measure the incidence of hospitalization for heart failure among all subjects and 
among subjects with a history of heart failure at baseline. 
 
Safety Objectives:  
The primary safety objective of this study is the contribution of at least 134 major adverse 
cardiovascular events (MACE+) to an eventual meta-analysis that is intended to exclude a 


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hazard ratio of 1.8 or greater for subjects exposed to bexagliflozin compared to subjects 
exposed to placebo. MACE+ is defined as cardiovascular death, non-fatal myocardial 
infarction (MI), non-fatal stroke, or hospitalization for unstable angina. 
An additional objective is the evaluation of the safety of exposure to bexagliflozin for a 
minimum of 52 weeks in a treatment population that is at elevated risk for major adverse 
cardiovascular events. 
Other Objectives: 
• 
Measurement of bexagliflozin plasma concentration as a function of time from dosing 
(sparsely sampled) will be conducted at 30 sites and will include approximately 240 
subjects 
• 
Measurement of cardiovascular biomarkers at baseline and week 12 in an exploratory 
study to increase the understanding of bexagliflozin treatment effect on the biomarkers 
that are relevant in the CV disease diagnosis and prognosis  
Study Design:  
THR-1442-C-476 is a multi-center, randomized, double-blind, placebo-controlled, parallel-
group study. Approximately 1650 subjects with poorly controlled T2DM and at high risk of 
cardiovascular (CV) adverse events will be randomized to bexagliflozin tablets, 20 mg, or 
placebo in a ratio of 2:1 in addition to the background anti-diabetic medications. 
Potential participants with suboptimal glycemic control (HbA1c between 7.0 % and 11 %) 
despite treatment as recommended in local guidelines and at high risk of cardiovascular 
adverse events will enter a screening period of up to 3 weeks. Qualified participants will 
enter a single-blind, placebo run-in period to allow for diabetes education and optimization of 
compliance with diet and exercise recommendations. Qualified subjects will continue their 
pre-screening regimen for glycemic control and will be instructed to take the run-in 
medication once daily for 13 ± 2 days. Adjustment of treatment for hypertension or 
dyslipidemia will not be permitted during the screening and run-in periods although initiation 
of anti-coagulant therapy (if clinically indicated) will be permitted. If a change in treatment is 
required to improve management of hypertension or dyslipidemia, the subject may re-enter 
the screening after the clinical condition and treatment regimen have not changed for at least 
4 weeks. Subjects who continue to qualify for the study and who have demonstrated 
compliance by missing no more than 1 dose of the run-in doses as instructed will be 
randomized to receive the investigational product. 
Assignment to treatment groups will be stratified by baseline HbA1c (> or ≤ 9.5%), baseline 
eGFR (eGFR ≥ or < 60 mL/min/1.73m2), baseline BMI (≥ or < 25 kg/m2) and history of heart 
failure. The study subjects will visit the clinic or complete phone interviews for evaluation at 
2, 6, 12, 18, 24, 36 and 48 weeks post-randomization with subsequent visits scheduled every 
24 weeks and a phone interview at 12 weeks after each clinic visit. The study duration will be 
determined by event accumulation. The treatment period will end when all randomized 
subject have completed at least 52 weeks of treatment and a total of 134 subjects have 
experienced a MACE+. A follow-up visit will take place 4 weeks after the conclusion of 


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treatment.  
During the first 24 weeks of the efficacy assessment period, hyperglycemia should be 
managed with diet and exercise counseling.  Changes in the medical therapy are allowed if 
the investigator feels it is necessary for the well-being of the subject. After 24 weeks, 
changes to the medical therapy for hyperglycemia should occur at the discretion of the 
investigator based on SMBG, FPG, and HbA1c information using local standards of care for 
subjects with T2DM. During the course of the study investigators will adjust other 
medications to effect changes in blood pressure and serum lipid values according to national 
or local guidelines. At every visit participants will be queried regarding adverse events and 
information on all events that potentially represent a MACE endpoint will be forwarded to a 
Cardiovascular Endpoint Committee (CEC) for blinded adjudication. An investigator should 
also query the subject about symptoms that may be associated with possible diabetic 
ketoacidosis (DKA) at every visit. A DKA Adjudication Committee will review and 
adjudicate all suspected DKA cases. 
In this study, the incidence of MACE+ will be recorded for subsequent meta-analysis. 
MACE+ is defined as CV death, non-fatal MI, non-fatal stroke, or hospitalization for 
unstable angina. It is estimated that the required total of 134 patients with a MACE+ will 
accrue over a treatment period of 2 to 3 years.  
During the trial, a Data and Safety Monitoring Board (DSMB) will review the unblinded data 
periodically and may recommend an early termination of the trial for safety reasons. No 
interim analysis will be performed for efficacy assessment and the study will not be stopped 
for futility or benefit of bexagliflozin treatment. 
Measurement of bexagliflozin plasma concentration as a function of time (sparsely sampled) 
will also be conducted at 30 centers and will include approximately 240 study subjects as 
part of a bexagliflozin population PK study. Samples will be drawn at weeks 6 or 12. 
Cardiovascular biomarkers will be measured at baseline before treatment is administered and 
after 12 weeks of treatment in an exploratory study to evaluate the effect of bexagliflozin 
treatment on biomarkers that are relevant in cardiovascular disease diagnosis and prognosis. 
Study Population:  
The study population will consist of approximately 1650 subjects who have been diagnosed 
with sub-optimally controlled T2DM and who exhibit an elevated risk of cardiovascular 
events. The study population will comprise: 
1. Male or female adult subjects (age ≥ 40 years) 
2. Subjects with a diagnosis of T2DM  
3. Subjects with HbA1c values of 7.0 – 11 %, inclusive 
4. Subjects with fasting plasma glucose (FPG) ≤ 300 mg/dL at screening 
5. Subjects who have a regimen for treatment of T2DM that has been stable for the past 
3 months. A stable regimen is defined as: no changes in dose or frequency of oral 
hypoglycemic agents or GLP-1 agonists, or < 20% variability in total daily insulin dose. 


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6. Subjects with either established cardiovascular disease or with multiple cardiovascular 
risk factors (if no documented cardiovascular disease) having the following attributes:  
 
Group 1: A history of atherosclerotic vascular disease as defined by one or more of the 
following: a) myocardial infarction (MI) or ischemic (non-hemorrhagic) stroke > 
3 months but ≤ 5 years prior to screening or b) documented history of coronary, 
carotid, or peripheral arterial revascularization (coronary artery bypass grafting 
must have occurred ≥ 5 years prior to screening) 
 
Group 2: A history of NYHA class II or class III heart failure (Appendix 4) at the time of 
screening. A history of heart failure is defined as:  
• documented left ventricular ejection fraction (LVEF) ≤ 40% and no subsequent 
LVEF > 40% within 6 months of screening, or  
• (i) an NT-proBNP >300 pg/mL and no evidence of atrial fibrillation/flutter 
(AF) at the time of the screening ECG or an NT-proBNP >900 pg/mL and 
evidence of AF at the time of the screening ECG and (ii) either (a) structural 
heart disease documented by report of left atrial enlargement or left ventricular 
hypertrophy, or (b) exhibiting symptom(s) of HF requiring treatment with 
diuretic(s) for at least 30 days prior to screening. 
 
Group 3: Age ≥ 55 years with 2 or more of the following:  
a. diabetes duration of ≥ 10 years,  
b. uncontrolled hypertension defined as SBP > 140 mmHg despite 3 or more 
anti-hypertensive medications, 
c. current smoking,  
d. urine albumin:creatinine ratio (UACR) > 30 mg/g,  
e. eGFR of 45 to 60 mL/min/1.73 m2, or  
f. HDL < 1 mmol/L (38 mg/dL) 
 
To ensure that subjects with various cardiovascular risks are adequately represented, a 
minimum of 352 subjects (21%) from each of the three groups will be recruited and ≤ 400 
subjects who have a history of heart failure will be randomized in the study. The intended 
population is presented in the figure below. 
 


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If a subject has a history of class II or III heart failure, the subject will be allocated to group 
2, regardless of any history of atherosclerotic vascular disease or cardiovascular risk factors. 
If a subject does not have a heart failure history and has a history of atherosclerotic vascular 
disease, the subject will be allocated to group 1 regardless of having other cardiovascular 
risks. 
Test Product, Dose, and Mode of Administration:  
Bexagliflozin tablets, 20 mg, or placebo administered orally once per day 
Duration of Treatment:  
The study is an event-driven trial. The treatment period will end when the last randomized 
subject has completed at least 52 weeks of treatment and at least 134 subjects have 
experienced a MACE+. 
Efficacy Assessments: 
Primary efficacy endpoint: 
• Change in HbA1c from baseline to week 24, compared to placebo 
Secondary efficacy endpoints: 
• Change in HbA1c from baseline to week 24 in randomized subjects who have been 
prescribed insulin to control their diabetes 
• Change in body weight from baseline to week 48 in subjects with a BMI ≥ 25 kg/m2 
• Change in SBP from baseline to week 24 in subjects with baseline systolic blood pressure 
≥ 140 mmHg 
Exploratory efficacy endpoints: 
• Change in HbA1c from baseline over time 
• Change in FPG from baseline over time 
• Change in body weight from baseline over time 
• Change in SBP over time 


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• Requirement of additional anti-diabetic medications, including insulin, over time 
• Requirement of reduced anti-diabetic medications, including insulin, over time 
• Incidence of hospitalization for heart failure among all subjects and among subjects who 
have a history of heart failure 
Other endpoint: 
Samples for population PK analysis will be collected and the plasma concentration of 
bexagliflozin determined. The PK parameters will be assessed separately as part of the 
population PK analysis. Biomarker samples will be collected.  The biomarker analysis will 
be performed separately. 
Safety Assessments: 
The safety endpoints will include: 
• A 5-point composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalization 
for unstable angina, or coronary revascularization 
• A 6-point composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalization 
for unstable angina, coronary revascularization or hospitalization for heart failure 
• Individual events including all-cause mortality, CV death, fatal and non-fatal MI, fatal 
and non-fatal stroke, hospitalization for unstable angina, hospitalization for CHF, or 
coronary revascularization. Both first events and total events, taking account of repeat 
events will be examined 
• Change in eGFR from baseline 
• Change in UACR from baseline 
• Incidence of adverse events of interest. Adverse events of interest including urinary tract 
infections including urosepsis and pyelonephritis, genital mycotic infections, diuretic 
effects including hypovolemia, hypotension episodes, hypoglycemia, hepatotoxicity, falls 
and fractures, malignancies, hypersensitivity reactions, acid-base disorders, renal failure 
events, and amputations 
Other safety assessments: 
 Adverse events 
 Clinical laboratory events 
 Physical examinations 
 Vital signs including orthostatic blood pressure 
 Use of concomitant medications 
Statistical Methods:  
The primary endpoint is the difference in the change in HbA1c from week 0 (randomization 
visit) to week 24 among subjects exposed to bexagliflozin, 20 mg, compared to subjects 
exposed to placebo. Statistical significance will be declared at a two-sided 0.05 level of 
significance. The intention-to-treat population that includes all randomized subjects 
regardless of treatment adherence or availability of follow-up data will be analyzed. A mixed 
model repeated measures (MMRM) analysis of covariance model (ANCOVA) with baseline 
HbA1c as a covariate will be performed on the available data, incorporating all visits from 


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each patient at which HbA1c was measured. 
Three key secondary endpoints are: 
1. Change in HbA1c from baseline to week 24 in randomized subjects who have been 
prescribed insulin to control their diabetes 
2. Change in body weight from baseline to week 48 in subjects with a BMI ≥ 25 kg/m2 
3. Change in SBP from baseline to week 24 in subjects with baseline systolic blood 
pressure ≥ 140 mmHg 
 
A hierarchical testing strategy in the following order will be undertaken, if the null 
hypothesis is excluded for the primary efficacy endpoint: 
1. Effect of bexagliflozin on the change in HbA1c from baseline to week 24 in subjects 
who have been prescribed insulin to control diabetes at baseline, using MMRM 
ANCOVA adjusting for baseline HbA1c at a two-sided 0.05 level of significance; if a 
significant bexagliflozin effect is found, then: 
2. Comparison of treatments on the change in body weight at week 48 in subjects with 
baseline BMI ≥ 25 kg/m2, using MMRM ANCOVA adjusting for baseline body weight. 
at a two-sided 0.05 level of significance; if a significant bexagliflozin effect is found, 
then: 
3. Comparison of treatments on the change in SBP at Week 24 in subjects with baseline 
systolic blood pressure ≥ 140 mmHg, using MMRM ANCOVA, adjusting for baseline 
SBP, at a two-sided 0.05 level of significance. 
 
Additional effects of bexagliflozin on FPG, changes in HbA1c over time, changes in body 
weight over time, frequency of hospitalization for heart failure (in all subjects and in subjects 
with a history of heart failure), and general safety of bexagliflozin in subjects with T2DM 
will be analyzed as exploratory endpoint and will not be adjusted for multiplicity. 
The sample size of 1650 patients is estimated based on the required number of events of 
MACE+ for the program-wide meta-analysis to assess bexagliflozin effect on cardiovascular 
safety, and provides adequate power to compare treatments on the primary endpoint of 
change in HbA1c from baseline to 24 weeks. 
Statistical analyses and summaries will be performed using SAS® software (SAS Institute, 
Cary, NC).   
Date of Revised Protocol Version 8.0: 01 December 2016 
 
Protocol History 
Date 
Version 1.0: 
06 May 2015 
Version 2.0: 
22 June 2015 
Version 3.0: 
07 July 2015 
Version 4.0: 
25 August 2015 


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Protocol History 
Date 
Version 5.0: 
08 September 2015 
Version 5.1 (Canada only) 
26 October 2015 
Version 6.0 
02 February 2016 
Version 7.0 
12 October 2016 
Version 8.0 (US) 
28 October 2016 
Version 8.0 (EU and AP) 
01 December 2016 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
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 
CRT 
cardiac resynchronization therapy 
CV 
cardiovascular 
DBP 
diastolic blood pressure 
DKA 
diabetic ketoacidosis 
DPP4 
dipeptidyl peptidase-4 
DSMB 
data and safety monitoring board 
ECG 
electrocardiogram 
ED50 
dose conveying 50% of the maximal effect 
FAS 
full analysis set 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equation  
GLP-1 
glucagon-like peptide-1 agonist 
GMI 
genital mycotic infection 
GFR 
glomerular filtration rate 
h 
hour/s 
HbA1c 
hemoglobin A1c 
HDL 
high density lipoprotein  
HF 
heart failure 
HF-REF 
heart failure with reduced ejection fraction 
HIV 
human immunodeficiency virus 
HUA 
hospitalization for unstable angina 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRAE 
immediately reportable adverse event 
IRB 
institutional review board 
IWRS 
interactive web response system 
LDL 
low density lipoprotein 
LC- MS/MS 
liquid chromatography–tandem mass spectrometry 
LOCF 
last observation carried forward 
LVEF 
left ventricular ejection fraction 
MACE 
major adverse cardiovascular event 


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MDRD 
modification of diet in renal disease 
MI 
myocardial infarction 
min 
minute/s 
MMRM 
mixed model repeated measures 
MODY 
maturity onset diabetes of the young 
N 
total sample size 
NYHA 
New York Heart Association 
OHA 
oral hypoglycemic agent 
PD 
pharmacodynamics 
PI 
principal investigator 
PK 
pharmacokinetics 
PP 
per protocol 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SGLT2 
sodium-glucose linked transporter 2 
SMBG 
self- monitored blood glucose  
SOP 
Standard Operating Procedures  
T2DM 
type 2 diabetes mellitus 
TEAE 
treatment emergent adverse event 
TIA 
transient ischemic attack 
UADR 
unexpected adverse drug reaction 
UACR 
urine albumin to creatinine ratio 
UGE 
urinary glucose excretion 
ULN 
upper limit of normal 
UPT 
urinary pregnancy test 
UTI 
urinary tract infection 
WHO-DD 
World Health Organization-Drug Dictionary 
WOCBP 
woman 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 382 million people in 2013 (IDF, 2014). More than 95% 
of people with diabetes have type 2 diabetes, and more than 80% of those with T2DM are 
overweight or obese. In Western societies, individuals with diabetes have at least twice the 
risk of hypertension and major cardiovascular complications compared to individuals without 
diabetes (Bhatt et al., 2010; Preis et al., 2009; Sarwar et al., 2010) and the major cause of 
death among patients with T2DM is cardiovascular disease (Go et al., 2013). In addition, 
congestive heart failure is highly prevalent among men and women with T2DM, and T2DM 
increases the occurrence of heart failure independently of underlying coronary disease 
(Boudina and Abel, 2007; Domanski et al., 2003; Kannel and McGee, 1979). 
Although glycemic control clearly reduces microvascular diabetic complications (ADA, 
2013), it is less clear whether any specific approach to reducing blood glucose concentration, 
particularly among patients with long standing T2DM or established cardiovascular risk 
factors,  confers additional risk with respect to cardiovascular events (Duckworth et al., 2009; 
Patel et al., 2008). As a result of this uncertainty, both FDA and European Medicines Agency 
(EMA) require demonstration of long-term cardiovascular safety prior to the approval of new 
drugs for treatment of T2DM (FDA Guidance 2008, ucm071627.pdf). 
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 functions 
mutations in SLC5A2 has the potential to improve both fasting and postprandial 
hyperglycemia without increasing insulin secretion, causing weight gain, or inducing 
hypoglycemia.  Several SGLT2 inhibitors have demonstrated these clinical benefits as a 
mono- or combination therapy with other oral anti-diabetic medications including insulin 
(Nauck, 2014).  Studies of the three SGLT2 inhibitors licensed in the US, dapagliflozin, 
canagliflozin, and empagliflozin, have demonstrated that long term use of an SGLT2 
inhibitor does not increase the incidence of major adverse cardiovascular events (MACE). 
Because heart failure is exacerbated by fluid retention, the development of diuretic oral anti-
diabetic agents is potentially attractive for the treatment of diabetic patients with comorbid 
heart failure and may be similarly attractive in patients with both diabetes and hypertension. 
The potential benefit in macrovascular disease outcome has been demonstrated in diabetic 
patients with increased CV risks who have been treated with empagliflozin. In a post-hoc 
analysis, a 30% reduction in CV mortality and hospitalization for heart failure were shown in 
the empagliflozin treated groups in all study subjects or in subjects with a history of heart 
failure (Zinman et al., 2015). 


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1.1 
Bexagliflozin Tablets for T2DM 
Bexagliflozin is a candidate oral antidiabetic agent that is a potent and highly specific 
inhibitor of SGLT2. It was identified following a synthetic program aimed at creating 
molecules with high selectivity and potency for SGLT2 (Zhang et al., 2011). Bexagliflozin 
has been shown to cause dose-dependent increases in urinary glucose excretion in humans, 
rats, dogs and monkeys and to reduce HbA1c in animal models of T2DM and in diabetic 
patients. The safety and efficacy of bexagliflozin capsules, 20 mg, were evaluated in a 96-
week study that established efficacy in reducing hemoglobin A1c (HbA1c). Adverse event 
incidences, particularly for urinary tract infection (UTI) and genital mycotic infection, were 
similar between placebo and active agent cohorts. Details of the pharmacology, efficacy, and 
safety assessments are described in the Investigator’s Brochure. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Efficacy Objectives  
The primary efficacy objective of this trial is to evaluate the placebo-adjusted change in 
HbA1c from baseline after 24 weeks of exposure to bexagliflozin in type 2 diabetic subjects 
with increased risk of cardiovascular adverse events. 
2.2 
Secondary Efficacy Objectives 
The key secondary efficacy objectives are: 
• 
To evaluate the effect of bexagliflozin compared to placebo on the change in HbA1c 
from baseline to week 24 in randomized subjects who have been prescribed insulin to 
control their diabetes 
• To evaluate the effect of bexagliflozin on the change in body weight from baseline to 
week 48 in randomized subjects with a BMI ≥ 25 kg/m2 compared to placebo 
• To evaluate the effect of bexagliflozin on the change in systolic blood pressure (SBP) 
from baseline to week 24 in subjects with baseline systolic blood pressure ≥ 140 mmHg 
compared to placebo 
 
Additional exploratory efficacy objectives are: 
• To assess the effect of bexagliflozin treatment on the change in HbA1c versus placebo 
over time 
• To evaluate the effect of bexagliflozin treatment on the change in fasting plasma glucose 
(FPG) versus placebo over time 
• To measure the proportion of subjects requiring an intensification of anti-diabetic 
regimen versus placebo over time 
• To measure the proportion of subjects requiring a relaxation of their anti-diabetic regimen 
versus placebo over time 
• To measure the incidence of hospitalization for heart failure among all subjects and 
among subjects with a history of heart failure at baseline 
 
2.3 
Safety Objectives  
The primary safety objective of this study is the contribution of at least 134 major adverse 
cardiovascular events (MACE+) to an eventual meta-analysis that is intended to exclude a 
hazard ratio of 1.8 or greater for subjects exposed to bexagliflozin compared to subjects 
exposed to placebo. MACE+ is defined as cardiovascular death, non-fatal myocardial 
infarction (MI), non-fatal stroke, or hospitalization for unstable angina. 
An additional objective is the evaluation of the safety of exposure to bexagliflozin for a 
minimum of 52 weeks in a treatment population that is at elevated risk for major adverse 
cardiovascular events. 
 


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2.4 
Other Objectives 
• 
Measurement of bexagliflozin plasma concentration as a function of time from dosing 
(sparsely sampled) will be conducted at 30 sites and will include approximately 240 
subjects. 
• 
Measurement of cardiovascular biomarkers from baseline and on week 12 will be 
performed in an exploratory study to increase the understanding of bexagliflozin 
treatment effect on the biomarkers that are relevant in the CV disease diagnosis and 
prognosis.  
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
THR-1442-C-476 is a multi-center, randomized, double-blind, placebo-controlled, parallel-
group study. Approximately 1650 subjects with sub-optimally controlled T2DM and elevated 
risk for cardiovascular adverse events will be randomized to bexagliflozin tablets, 20 mg, or 
placebo in a 2:1 ratio as an add-on therapy to background anti-diabetic medications. 
3.2 
Research Methods and Procedures 
3.2.1 
Screening Period 
All participants must provide written informed consent and be willing and able to adhere to 
the protocol requirements. Potential participants with sub-optimal glycemic control and 
additional cardiovascular risk factors will enter a screening period of up to 21 days. Subjects 
will be eligible if they exhibit any of the following 3 characteristics: (i) a history of 
atherosclerotic vascular disease, (ii) a history of heart failure, or (iii) an age of ≥ 55 years 
plus at least two additional risk factors chosen from long diabetes duration, hypertension, 
smoking, renal impairment, or dyslipidemia. To ensure that subjects with diverse 
cardiovascular risks are adequately represented, a minimum of 352 subjects (21%) from each 
of the three groups will be recruited in the study and ≤ 400 subjects who have a history of 
heart failure will be randomized in the study. The intended population is presented below. 
 
 
Figure 1 
Eligibility Criteria for the Study Population 
 
If a subject has a history of heart failure, the subject will be allocated to the heart failure 
group, regardless of any history of atherosclerotic vascular disease or additional 
cardiovascular risk factors. If a subject does not have a heart failure history and has a history 


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of atherosclerotic vascular disease, the subject will be allocated to group 1 regardless of other 
cardiovascular risks. 
Qualified participants will start a single-blind, placebo 2-week run-in period intended to 
familiarize subjects with trial procedures and to identify and reject subjects at high risk for 
non-compliance. During the run-in period, subjects will receive diet and exercise counseling 
and instructions on contacting the clinic in the event of hypoglycemia or symptoms that may 
suggest ketoacidosis. Participants will be provided with a glucometer and instructions for its 
daily use. Eligible subjects will be instructed to take the run-in (placebo) dosages once daily 
for 13 ± 2 days. Adjustment of treatment for hypertension or dyslipidemia will not be 
permitted during the screening and the run- in periods. If a change in treatment is required to 
appropriately manage hypertension or dyslipidemia, the subject may re-enter the screening 
after the clinical condition and treatment regimen have not changed for at least 4 weeks. 
Subjects will not be eligible for randomization if during the run-in period they: 1) have 
fasting blood glucose values ≥ 300 mg/dL on two or more consecutive days, 2) omit more 
than one dose of the run-in drug due to non-compliance, or 3) are deemed inappropriate for 
the study by the investigator.  
3.2.2 
Treatment Period 
The treatment period for each study subject will start at randomization. Randomization will 
be stratified by baseline HbA1c (> or ≤ 9.5%), baseline estimated glomerular filtration rate 
(eGFR) (< or ≥ 60 mL/min/1.73m2), baseline BMI (< or ≥ 25 kg/m2) and history of heart 
failure. The study subjects will be in contact with the study site at 2, 6, 12, 18, 24, 36 and 48 
weeks post-randomization.  The interactions at week 2 and week 18 will be conducted by 
phone unless a clinic visit is necessary.  After week 48, clinic visits will be scheduled every 
24 weeks and a phone interview will be conducted at 12 weeks after each clinic visit. The 
treatment period will vary from subject to subject and will end for all subjects after the last 
randomized subject has completed at least 52 weeks of treatment and a total of 134 subjects 
have experienced a MACE+. It is anticipated that subjects will receive treatment for 2 to 3 
years. A follow-up visit will take place 4 weeks after the conclusion of treatment.  
At the start of the treatment period each subject will be provided investigational product, 
dosing instructions, and a glycemic control diary in which to record glucose measurements 
obtained through self-monitored blood glucose (SMBG) testing. Information related to the 
occurrence of hyperglycemic or hypoglycemic events as well as symptoms that may suggest 
ketoacidosis will be recorded. The subjects will be instructed to take the investigational 
product with water in the morning prior to eating. Additional medications for hyperglycemia 
and for control of other medical conditions will be allowed if deemed medically necessary by 
the investigator, and will be recorded (Section 5.2.5 and Section 5.6). 
During the first 24 weeks of the treatment period, hyperglycemia should be managed with 
diet and exercise counseling and only with changes in the medical therapy if the investigator 
feels it is necessary for the well-being of the subject. Intensification of the antidiabetic 
regimen should adhere to the following guidelines upon the report by a study subject of two 
fasting blood glucose self-measurements exceeding the following values on consecutive 


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days: (i) ≥ 270 mg/dL (15 mmol/L) from week 1 to week 6; ≥ 240 mg/dL (13.3 mmol/L) 
between week 6 and week 12; and ≥ 200 mg/dL (11.1 mmol/L) between week 12 and week 
24. After 24 weeks, changes to the medical therapy for hyperglycemia should occur at the 
discretion of the investigator based on SMBG, FPG, and HbA1c information using local 
standards of care for subjects with T2DM. During the course of the study investigators will 
manage blood pressure and lipid values according to accepted standards of care for the 
management of hypertension and dyslipidemia.  
Rescue medications may include any approved anti-diabetic medication except an SGLT2 
inhibitor. Adjustment by the investigator to the anti-diabetic therapies is recommended if 
hypoglycemia occurs. 
The safety information will be drawn from review of adverse events (AEs), concomitant 
medications, vital signs, electrocardiograms (ECGs), and results from physical examinations 
and blood and urine specimen collections. On the day of the clinic visit a minimum fasting 
period of 10 hours (h) must be confirmed prior to blood draw. At every visit, including the 
phone interviews, participants will be queried regarding AEs and information on all events 
that potentially represent major adverse cardiovascular events will be forwarded to a 
cardiovascular endpoint committee (CEC) for blinded adjudication of the event. Following 
the exit visit, subjects will be advised to see their primary physician to undergo treatment to 
control their diabetes and cardiovascular conditions. The scheduled visits and procedures for 
each visit are provided in Appendix 1. The duration of participation for each subject is 
estimated to be 2 to 3 years but may vary based on the projected recruitment rate and the 
estimated event rate. An assessment of bexagliflozin pharmacokinetics (PK) will also be 
conducted at 30 centers to include approximately 240 subjects. Samples will be taken during 
weeks 6 and 12. 
3.2.3 
Interim Analyses 
No interim analysis will be performed and the study will not be stopped for futility or 
overwhelming benefit of bexagliflozin treatment.  During the trial, a Data and Safety 
Monitoring Board (DSMB) will review the unblinded aggregate data periodically and may 
recommend an early termination of the trial for safety reasons. 
An estimated total of 134 MACE+ are required for the CV meta-analysis. During the study, 
subjects will continue to receive various OHAs and/or insulin. All AEs that potentially 
represent a major cardiovascular event will be submitted to the CEC for an independent and 
blinded adjudication. 
3.3 
Rationale for Study Design and Control Group 
3.3.1 
Rationale for the Study Design 
Patients with T2DM have increased risk of developing micro- and macrovascular 
complications. Improved control of hyperglycemia or blood pressure reduces the risk of 
diabetic complications (UKPDS(1998)). Administration of bexagliflozin, a potent SGLT2 
inhibitor, has been shown to be well tolerated and to decrease HbA1c in subjects with T2DM 


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drawn from a general population. Study THR-1442-C-476 is designed to demonstrate that 
bexagliflozin also improves glycemic control in patients at higher risk of CV AEs. The 
glucosuria and diuresis induced by bexagliflozin may additionally benefit the study subjects 
through caloric wasting and reduction of blood pressure.  Thus, the potential for weight loss 
in overweight subjects and for blood pressure improvement in hypertensive subjects will be 
tested. This study is designed to contribute a minimum of 134 MACE+ events to an eventual 
meta-analysis intended to evaluate whether treatment with bexagliflozin is associated with an 
unacceptable increase in cardiovascular risk in a T2DM population (FDA Guidance 
ucm071627, 2008 and EMA CPMP/EWP/1080/00 Rev. 1, 2012). The study is also designed 
to permit an assessment of the safety of exposure to bexagliflozin for a minimum of 52 
weeks in a treatment population at elevated risk of major adverse cardiovascular events. 
A placebo-controlled, double-blind, parallel-arm design was chosen for this study. The 
inclusion of a placebo group will allow medication effects to be differentiated from 
influences of confounding factors. The subjects will continue to receive background glucose 
lowering therapies as well as other medications to manage co-morbidities throughout the 
study. Study subjects may receive additional approved antidiabetic medications if their 
hyperglycemia is not well controlled. 
3.3.2 
Rationale for the Dose Selection 
Bexagliflozin produces a dose-dependent, saturable increase in UGE in healthy volunteers 
and diabetic subjects. Near-maximal UGE is produced by 20 mg of bexagliflozin, whether 
delivered as an immediate release or an extended release formulation. A single dose of 20 mg 
produces a significant reduction in fasting plasma glucose (FPG) and a modest diuretic 
effect. Population pharmacodynamic modeling has indicated that bexagliflozin doses of 20 
mg would result in 90% of the maximal UGE, respectively. In a long term treatment study, 
daily administration of 20 mg bexagliflozin in an immediate release formulation was found 
to reduce HbA1c by 0.79% compared to placebo at week 24. The treatment benefit was 
observed to improve to 1.02% at week 96. FPG reduction, weight loss, and decreased systolic 
and diastolic blood pressure were also observed following 96 weeks of treatment. In addition, 
AEs, particularly those involving UTI and genital mycotic infections (GMI), were found to 
be similar between placebo and active agent cohorts. To evaluate the safety and efficacy of 
bexagliflozin for the treatment of patients with T2DM and increased CV risk, bexagliflozin 
tablets, 20 mg, will be administered in this trial. 
The PK and pharmacodynamic (PD) effects of bexagliflozin administration have been 
determined in patients with T2DM and renal impairment. Absorption of bexagliflozin was 
not affected by diminished renal function. Reduced clearance due to renal impairment was 
associated with a 34 % higher systemic exposure in subjects with GFR between 30 and 
60 mL/min/1.73/m2. Mean glucosuria decreased to 40 g/d in patients with moderate renal 
impairment compared to 99.6 g/d in patients with normal renal function.  The decreased 
glucosuria is consistent with a reduced renal filtration rate. However, an improvement in 
glycemic control can be predicted by the UGE of nearly 40 g of glucose per day. Given the 
modest increase in drug exposure, dose adjustment in patients with mild to moderate renal 
impairment is not expected to be necessary. A thorough QT study has demonstrated that 


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100 mg of bexagliflozin administered in an immediate release formulation did not prolong 
the QT interval or produce adverse changes in any other parameters measured by ECG. 
3.3.3 
Rationale for the Selection of Patient Population 
Study THR-1442-C-476 will include patients with increased CV risk factors including older 
age, hypertension, smoking, renal impairment, dyslipidemia, and history of cardiovascular 
disease. Among patients with T2DM, approximately 12% have been reported to exhibit heart 
failure (HF) (Nichols et al., 2001); the prevalence of HF increases to 39% among elderly 
diabetic patients (Aronow and Ahn, 1999). A study population that includes subjects with 
additional CV risks will allow an efficacy assessment of bexagliflozin in this vulnerable 
population and will permit any potential benefits of weight reduction or blood pressure 
lowering to be recorded. While reduction of HbA1c has not been shown to alter the course of 
HF, weight reduction has been found to lower the risk for hospitalization. 
To ensure that subjects with various cardiovascular risks will be adequately represented, a 
minimum of 352 subjects (21%) from each of the three groups will be recruited in the study. 
In a 2 year cardiovascular outcomes study in patients with T2DM the event rate for CV death 
was 0.0365 or 0.0115 per subject per year for subjects with or without a heart failure history, 
respectively (Scirica et al., 2013; Scirica et al., 2014b). Because the CV mortality rate is 
higher among subjects with a HF history, the number of subjects with HF will be limited to 
400 in this trial.  The projected number of CV deaths from subjects with HF history is 
anticipated to be < 50% of the total CV deaths. Because a subject may be qualified in one or 
all of the groups based on the risk factors at baseline, subjects will be allocated to whichever 
group represents the highest projected event rate. For example, if a subject has a history of 
class II or III heart failure, the subject will be allocated to group 2, regardless of any history 
of atherosclerotic vascular disease or additional cardiovascular risk factors. If a subject does 
not have a heart failure history and does have a history of atherosclerotic vascular disease, 
the subject will be allocated to group 1 regardless of other cardiovascular risks. 
Identification of heart failure in the setting of preserved ejection fraction will rely on 
symptomatic evidence of heart failure together with specific criteria for N-terminal pro-BNP 
levels. An NT-proBNP > 300 pg/mL with no evidence of atrial fibrillation/flutter (AF) at the 
time of the screening ECG or an NT-proBNP > 900 pg/mL with evidence of AF at the time 
of the screening ECG will be considered sufficient to exclude prospective subjects without 
heart failure. These limits are conservative. NT-proBNP levels increase with age and age-
dependent cutpoints provide superior decision value; in one study cutpoints ranging from 50 
ng/mL for males < 50 years to 250 ng/mL for males > 75 years were shown to provide higher 
sensitivity than an age-independent measure (Hildebrandt et al., 2010). For individuals in 
chronic heart failure the age-independent cutpoint to exclude non-failure etiologies is 
considered to be 125 pg/mL, whereas in an acute presentation the appropriate age-
independent cutpoint is considered to be 300 pg/mL (Januzzi et al., 2006; McMurray et al., 
2012; Ponikowski et al., 2016). Atrial fibrillation is associated with elevated NT-proBNP and 
hence higher cutpoints are required. Although there has yet to be a practice guideline 
recommendation, in the Biomarkers in ACute Heart Failure (BACH) study, comorbid atrial 
fibrillation decreased test specificity and in general eroded the diagnostic power of NT-


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proBNP measurement (Richards et al., 2013). From this study an age-independent cutpoint of 
1075 pg/mL for subjects with atrial fibrillation had the highest accuracy of three cutpoints or 
cutpoint algorithms (Richards et al., 2013). The sponsor’s subject matter experts have 
advised that to discriminate HF in the presence of preserved ejection fraction and AF, it is 
common in clinical trials to use an NT-proBNP cutpoint of 2 – 4 times that of the cutpoint in 
the absence of AF (J.J. McMurray, personal communication: S. Solomon, personal 
communication). The specific cutpoint chosen here reflects the midpoint, 3 times the cutpoint 
for subjects in sinus rhythm. 
3.3.4 
Treatment Duration 
The mean treatment duration is expected to fall between two and three years, depending on 
the accrual of MACE+. A minimum treatment duration of 52 weeks is planned to ensure 
sufficient bexagliflozin exposure to allow meaningful safety evaluation. 
3.3.5 
Rationale for the Overall Analysis 
The primary safety objective of this study is to contribute MACE+ to an eventual meta-
analysis that is intended to exclude a hazard ratio of 1.8 or greater. The study population 
planned in this protocol is enriched for CV risk and the anticipated event rate is based on a 
recently published CV outcomes study (Scirica et al., 2013; Scirica et al., 2014b). There will 
be no interim analysis. 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study population will include approximately 1650 subjects diagnosed with sub-optimally 
controlled T2DM who have a history of cardiovascular disease or who present with CV risk 
factors. Eligible subjects who consent to participate in the study will be enrolled in clinical 
investigational sites in multiple countries. 
At selected sites, 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. 
4.2 
Inclusion Criteria 
The study population will include: 
1. Male or female adult subjects with an age ≥40 years 
2. Subjects with a diagnosis of T2DM  
3. Subjects with HbA1c values of 7.0 – 11%, inclusive 
4. Subjects with fasting plasma glucose (FPG) ≤300 mg/dL at screening 
5. Subjects who have a regimen for treatment of T2DM that has been stable for the past 
3 months. A stable regimen is defined as: no changes in dose or frequency of OHAs or 
GLP-1 agonists, or < 20% variability in total daily insulin dose. 
6. Subjects who present with at least one of the following 3 histories: 
 
Group 1: A history of atherosclerotic vascular disease as defined by one or more of the 
following: a) myocardial infarction (MI) or ischemic (non-hemorrhagic) stroke > 
3 months but ≤ 5 years prior to screening or b) documented history of coronary, 
carotid, or peripheral arterial revascularization (coronary artery bypass grafting 
must have occurred ≥ 5 years prior to screening) 
 
Group 2: A history of NYHA class II or class III heart failure (Appendix 4) at the time of 
screening. History of heart failure is defined as:  
• a documented left ventricular ejection fraction (LVEF) ≤ 40% and no 
subsequent LVEF > 40% documented within 6 months of screening, or  
•  (i) an NT-proBNP >300 pg/mL and no evidence of atrial fibrillation/flutter 
(AF) at the time of the screening ECG or an NT-proBNP >900 pg/mL and 
evidence of AF at the time of the screening ECG and (ii) either (a) structural 
heart disease documented by report of left atrial enlargement or left ventricular 
hypertrophy, or (b) exhibiting symptom(s) of HF requiring treatment with 
diuretic(s) for at least 30 days prior to screening. 
 


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Group 3: Age ≥ 55 years with 2 or more of the following: 
a.  diabetes duration of ≥ 10 years,  
b. uncontrolled hypertension defined as SBP > 140 mmHg despite 3 or more 
anti-hypertensive medications, 
c. current smoking,  
d. urine albumin:creatinine ratio (UACR) > 30 mg/g,  
e. eGFR of 45 to 60 mL/min/1.73 m2, or  
f. HDL < 1 mmol/L (38 mg/dL) 
 
7. Female subjects of childbearing potential who are willing to use an adequate method of 
contraception and to not become pregnant for the duration of the study. Adequate 
contraceptive measures include, but are not limited to, oral contraceptives, intrauterine 
devices, Depo-Provera, Norplant, hormonal contraceptive implants, bilateral tubal 
ligation, partner with vasectomy, condom or diaphragm plus contraceptive sponge, 
foam, or jelly, and abstinence 
8. Subjects who are willing and able to return for all clinic visits and to complete all study-
required procedures, including self-monitored blood glucose (SMBG) measurement, and 
take run-in medication, missing no more than one dose due to non-compliance 
9. Subjects who receive anti-hypertensive medications at a stable dosage for ≥ 2 weeks 
prior to randomization 
10. Subjects who receive lipid modifying therapy on a stable regimen for 6 weeks prior to 
randomization 
11. Subjects who have seated SBP < 170 mmHg and DBP < 110 mmHg at screening. 
 
4.3 
Exclusion Criteria 
Patients who exhibit any of the following characteristics will be excluded from the study. 
1. Diagnosis of type 1 diabetes mellitus or maturity–onset/diabetes of the young (MODY) 
2. Hemoglobinopathy that affects HbA1c measurement 
3. Frequent symptomatic hypoglycemia (greater than one episode per week on average) 
4. Genitourinary tract infection within 6 weeks of screening or history of ≥ 3 genitourinary 
infections requiring treatment within the last 6 months 
5. Cancer, active or in remission for < 3 years (Non-melanoma skin cancer or basal cell 
carcinoma or carcinoma in situ of the cervix will not be grounds for exclusion) 
6. History of alcohol or illicit drug abuse in the past 2 years 
7. Evidence of abnormal liver function tests (total bilirubin or alkaline phosphatase > 1.5 x 
upper limit of normal (ULN) with the exception of isolated Gilbert’s syndrome); or 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x ULN 
8. History of MI, stroke or hospitalization for heart failure in the prior 3 months 
9. Evidence of NYHA class IV heart failure at screening or randomization 
10. Presently scheduled for percutaneous coronary intervention, coronary artery bypass 
grafting or any surgical procedure 
11. Previous treatment with bexagliflozin or EGT0001474 


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12. Currently or within 3 months of taking any SGLT2 inhibitors (Appendix 3) 
13. Any condition, disease, disorder, or clinically relevant laboratory abnormality that, in 
the opinion of the PI, would jeopardize the subject’s appropriate participation in this 
study or obscure the effects of treatment 
14. Prior renal transplantation or evidence of nephrotic syndrome, defined as a urine 
albumin: creatinine ratio (UACR) > 2000 mg/g, at screening 
15. Implantation of a cardiac resynchronization therapy device within 3 months prior to 
screening or intent to implant a cardiac resynchronization therapy (CRT) within 6 
months following screening 
16. Diagnosis of peripartum or chemotherapy-induced cardiomyopathy within 12 months 
prior to screening 
17. Symptomatic bradycardia or second or third degree atrioventricular block without a 
pacemaker 
18. eGFR, as calculated by the modification of diet in renal disease study equation 
(MDRD), < 45 mL/min/1.73 m2 or requiring dialysis  
19. Pregnant or nursing 
20. Currently participating in another interventional trial. 
 


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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 h 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 in the morning prior to eating or 
drinking. The tablets should be taken with 250 mL of water. 
5.2.2 
Background Oral Hypoglycemic Agents (OHAs) 
Subjects will continue OHAs that were prescribed prior to screening. The dose, frequency, 
and time of administration of these medications should remain stable throughout the study 
unless the investigator deems adjustment necessary for the medical well-being of the subject. 
Changes to the dose or frequency of oral anti-diabetic medications will be recorded in the 
concomitant medications log.  
5.2.3 
Background Insulin Therapy 
Subjects who are prescribed insulin prior to screening will continue the dose, frequency, and 
time of insulin administration throughout the study. The dose, frequency, and time of insulin 
injections should remain stable unless the investigator deems adjustment (decrease or 
increase) necessary for the medical well-being of the subject. Changes to the dose, frequency, 
or time of administration of insulin will be recorded in the concomitant medications log.  
5.2.4 
Anti-hypertensive Medications Including Diuretics 
Subjects who are prescribed anti-hypertensive medications will continue the current dose, 
frequency, and time of administration of these medications throughout the study. Adjustment 
of treatment for hypertension or dyslipidemia will not be permitted during the screening and 
run-in periods although initiation of anti-coagulant therapy (if clinically indicated) will be 
permitted. If a change in treatment is required to improve management of hypertension or 
dyslipidemia, the subject may re-enter screening after the clinical condition and treatment 
regimen have not changed for at least 4 weeks. Anti-hypertensive and diuretic medications 


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can be reduced to mitigate symptomatic hypotension at the discretion of the investigator at 
any time. Changes to the dose or frequency of anti-hypertensive and diuretic medications will 
be recorded in the concomitant medications log. 
5.2.5 
Rescue Medications for Hyperglycemia 
During the treatment period subjects will be advised to conduct daily fasting SMBG 
measurements. Blood glucose values collected via SMBG will be evaluated at study visits by 
the investigator. In addition, hyperglycemia will be monitored by FPG measurement at each 
study visit. HbA1c values will also be available to the investigator for decision-making 
regarding the need for rescue medication. 
If hyperglycemia is identified through SMBG or FPG measurements, the investigator will 
determine whether the subject has fasted for a minimum of 10 h prior to the morning blood 
draw to ensure that the FPG value is truly a fasting sample.  If proper fasting has not 
occurred, the subject will be asked to return for a repeat blood test within a week.  
During the first 24 weeks of the treatment period, hyperglycemia should be managed with 
diet and exercise counseling and only with changes in the medical therapy if the investigator 
feels it is necessary for the well-being of the subject. Intensification of the antidiabetic 
regimen should adhere to the following guidelines upon the report by a study subject of two 
fasting blood glucose self-measurements exceeding the following values on consecutive 
days: (i) ≥ 270 mg/dL (15 mmol/L) from week 1 to week 6; ≥ 240 mg/dL (13.3 mmol/L) 
between week 6 and week 12; and ≥ 200 mg/dL (11.1 mmol/L) between week 12 and week 
24. After 24 weeks changes to the medical therapy for hyperglycemia should occur at the 
discretion of the investigator based on SMBG, FPG, and HbA1c information using local 
standards of care for subjects with T2DM. If a 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 determined for the HbA1c efficacy analyses. 
The investigator may provide rescue treatment with any approved medication for diabetes 
that is not otherwise contraindicated, with the exception of an SGLT2 inhibitor. Dose or 
frequency increases in OHA or insulin regimens prescribed prior to screening will be 
considered rescue medication. During the treatment period, increments or decrements in the 
doses of OHA or insulin must be documented in the concomitant medications CRF. 
Subjects who receive rescue medication due to poor glycemic control will continue to receive 
investigational product and standard care according to current treatment guidelines. 
Following the exit visit subjects will be advised to see their primary care physician to 
undergo treatment to control their diabetes. 
5.3 
Selection and Timing of Dose for Each Patient 
Dosing with bexagliflozin tablets, 20 mg or placebo, will be based on randomized 
assignment. All study subjects will be instructed to self-administer tablets once daily in the 
morning prior to eating or drinking; the medication should be taken with water. There will be 
no change of dose during the treatment period. 


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On the day of each scheduled clinic visit, subjects must fast for a minimum of 10 h prior to 
the collection of blood samples. During the fasting period, only water will be permitted. The 
investigational product should be administered at the clinic under supervision on the day of 
visit V2 when the run-in drug is dispensed and on the day of visit V3 when the double-blind 
study drug is dispensed. Only one tablet per day should be administered. 
5.4 
Method of Assigning Patients to Treatment Groups 
The study will be conducted at investigative sites in multiple countries and will likely involve 
variable numbers of subjects at each site. Enrollment will be on a competitive basis but each 
site will be capped at 48 subjects per site. Activation of investigational sites in each country 
will be centrally controlled by a centrally managed Interactive Web Response system 
(IWRS). 
Eligible subjects who complete the run-in period and meet all study inclusion/exclusion 
requirements will be randomized in a 2:1 ratio to receive investigational product.  Subjects 
will be assigned to treatment groups in sequential order as they qualify for the study, using 
IWRS. Randomization will be stratified according to baseline HbA1c (≤ 9.5% or > 9.5% at 
screening visit), baseline eGFR (eGFR < 60 or ≥ 60 mL/min/1.73 m2 at screening), BMI (< 
25 kg/m2 or ≥ 25 kg/m2, and history of heart failure. 
Among the 3 groups of subjects based on the baseline CV risks, a minimum of 352 subjects 
(21%) from each of the three groups will be recruited and ≤ 400 subjects who have a history 
of heart failure can be randomized in the study. If a subject has a history of class II or III 
heart failure, the subject will be allocated to group 2, regardless of any history of 
atherosclerotic vascular disease or additional cardiovascular risk factors. If a subject does not 
have a heart failure history and has a history of atherosclerotic vascular disease, the subject 
will be allocated to group 1 regardless of other cardiovascular risks. 
5.5 
Blinding 
This is a double-blind placebo-controlled study. The sponsor, investigators, study 
coordinators, pharmacists, study subjects, and the CEC and DKA adjudication committee 
members will be blinded to the composition of the investigational product. Upon 
randomization, each subject will receive a subject randomization number and a drug kit 
assigned to the subject. To maintain blinding of the individual treatment assignments, central 
laboratory glucose urinalysis data will not be made available to any study personnel or 
subjects.  
If knowledge of the investigational product ingredients is needed to manage the subject’s 
condition, the investigator will contact the IWRS to obtain the treatment assignment. If 
unblinding occurs for any reason, the time and reason for breaking the blind will be recorded 
on the case report form (CRF) and the sponsor must be notified within 24 h.  
A designated statistician who is not involved in 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 


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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 until all 
investigational studies contributing to the MACE+ meta-analysis are completed and the 
meta-analysis has been conducted. 
5.6 
Concomitant Therapy 
During the course of the study investigators will manage glucose, blood pressure and lipid 
levels according to local or regional standard of care guidance documents for the 
management of T2DM and cardiovascular risk factors/disease as issued by the relevant 
professional bodies (e.g. ADA, AHA, ESC, etc.). Subjects should be provided access to all 
additional therapies and interventions during the course of the study (including appropriate 
anti-platelet and anti-thrombotic therapies, PCI, etc.) if these are clinically indicated and 
approved by local competent authorities. 
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 clinical reason to 
change the dose or frequency.  
Blood pressure medications should not be altered during the screening period and the first 12 
weeks of the main treatment period unless it is medically necessary to do so. If a change in 
treatment is required to appropriately manage hypertension or dyslipidemia during the run-in 
period, the subject may re-enter the screening after the clinical condition and treatment 
regimen have not changed for at least 4 weeks. If it is medically necessary to alter blood 
pressure medications during the first 12 weeks of the treatment period, new diuretic 
medications should not be initiated and the dose and frequency of existing diuretic 
medications should not be increased.  
Subjects who do not meet protocol-specified glycemic targets at specified time points during 
the study will review diet and exercise counseling and/or receive rescue medication at the 
discretion of the investigator during the study. Anti-diabetic therapies prescribed to subjects 
for the purpose of treating hyperglycemia for more than 2 weeks will be considered rescue 
medications (see Prescribing Rescue Medication, above). Concomitant use of other SGLT2 
inhibitors will not be permitted. A blood sample will be collected to measure the last HbA1c 
value prior to administration of any rescue medications. The rescue medications must be 
recorded as concomitant medications in the CRF. 
Subjects may receive any medications for AEs that are necessary in the investigators’ 
judgments. Concomitant medications prescribed at the time of the run-in period and during 
the study 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 and follow up periods.  


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Any medication prescribed to a subject after enrollment and prior to randomization, 
including contraceptives, must be recorded in the CRF. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
All subjects will continue regimens for medical conditions other than diabetes during the 
study as indicated above. No subject shall have been treated with an SGLT2 inhibitor within 
3 months of screening.  
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 
control based on standards of medical care in diabetes. Subjects will fast for a minimum of 
10 h prior to the scheduled blood sample draws. During fasting, only water will be permitted. 
5.7.3 
Patient Activity Restrictions 
Throughout the study period, subjects will 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 (American Diabetes, 2014). Alternatively, local guidelines 
may be used. 
5.8 
Treatment Compliance 
Subjects will be provided with dosing instructions each time that study medication is 
dispensed. Subjects will also be instructed to bring their medication with them at every visit. 
Subjects will be excluded from randomization if more than one dose of the run-in medication 
has been missed. 
At each visit the study staff will review the SMBG 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. 
5.9 
Packaging and Labeling 
Investigational product will be provided to the pharmacist or designated site personnel in 
bottles of 90 tablets enclosed with a child-resistant cap. Bottles of 15 placebo tablets will be 
provided for the 2-week run-in portion of the study. All investigational product supplies will 
be prepared and labeled according to the requirements of local laws and regulations and will 
be kept in a secure storage facility at controlled room temperature, 15 to 30°C (59 to 86°F). 
The pharmacist or designated site personnel will dispense the investigational products for 
each subject according to randomization assignment made in the Interactive Web Response 
System (IWRS). During the treatment period, subjects will be provided with a new bottle 


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every 12 weeks in the first 48 weeks and two bottles every 24 weeks after week 48. There 
will be no intra-subject dose escalation or back-titration. 
Subjects who require rescue medication due to hyperglycemia will receive standard care for 
T2DM in addition to the investigational product.  
There are two types of investigational product kits. 
5.9.1 
Run-in Kit 
Each kit contains one bottle of 15 tablets of bexagliflozin tablets, placebo. 
The labels attached to each run-in kit will contain the protocol number, product 
identification, lot number, subject number, storage condition, the sponsor’s name and 
address, expiration date, and the investigational drug caution statement. 
5.9.2 
Investigational Product Kit 
Each kit contains 1 bottle of 90 tablets of bexagliflozin tablets, 20 mg or placebo. 
The labels attached to each study kit will contain some or all of the following information: 
the kit number, protocol number, product identification, blinded batch number, subject 
number, storage conditions, sponsor’s name, manufacturer's name and address, investigator’s 
name, expiration date, and the investigational drug caution statement. 
5.10 Storage and Accountability 
Bexagliflozin tablets will be stored at controlled room temperatures of 15 °C to 30 °C (59 °F 
to 86 °F). The rescue medications will be stored in conditions specified in the manufacturers’ 
prescription information. The sponsor will notify the sites of the process for returning unused 
drug. 
5.11 Investigational Product Retention at Study Site 
The investigational products will be stored in a secure area with limited access. The drug 
storage facility must comply with the medication storage instructions. Bexagliflozin or 
placebo should be stored at controlled room temperature until ready for dispensing to study 
subjects. The trial staff must record the amount of investigational product dispensed to each 
subject in 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 
accounting is verified by the sponsor or its designee. 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All subjects will be informed of the nature and purpose of the study and their written 
informed consent will be obtained during the pre-study screening procedures. A copy of the 
informed consent forms, including subject information, will be provided to each subject. 
6.2 
Medical History 
The following information will be collected at the screening visit: 
6.2.1 
General Demographics and Characteristics 
1. Date of birth, age, sex, and race, and whether of childbearing potential if female 
2. Significant medical and surgical history, including dates of diagnoses and procedures 
and whether the condition is ongoing, if applicable. 
 
6.2.2 
Diabetes History 
1. History of all medications used to treat diabetes (to be recorded in the concomitant 
medication form), including start date, duration of use, and stop date, if applicable. 
2. History of complications due to diabetes, including nephropathy, retinopathy, 
neuropathy, non-traumatic amputations, and diabetic ketoacidosis, including date of 
diagnosis 
3. Frequency of hypoglycemic events (per week) that are symptomatic or require 
assistance. 
 
6.2.3 
Cardiovascular Disease History 
History of cardiovascular disease including presence of angina, congestive heart failure 
(classification), known atherosclerotic cardiovascular disease, prior myocardial infarction, 
transient ischemic attack (TIA) or stroke, and prior cardiac or peripheral re-vascularization 
procedures. History should include date of diagnosis and current status of diagnosis (resolved 
or ongoing). 
6.2.4 
Medication History 
1. Use of prescribed or non-prescribed medications, including name of medication, 
indications for usage, start and stop dates, dose, and frequency 
2. Use of supplements, including over the counter drugs, vitamins, herbal preparations, and 
dietary supplements within the past 30 days prior to screening. Each medication history 
will include the agent used, indication for usage, start and stop dates, dose, and 
frequency.  
 


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6.3 
Physical Examination 
A complete physical examination will be performed by the investigator at visit V3 prior to 
randomization and at the last study visit. The examination will include measurement of body 
weight, 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 include body weight and general assessment of the 
skin, heart, lungs and abdomen.  Abbreviated physical examinations will be performed by the 
investigator at all other time points as defined in the schedule of events, unless clinically 
indicated. 
The body weight must be determined using a scale that is calibrated.  The same scale should 
be used throughout the study duration. Height will be measured only at screening. 
6.4 
Vital Signs 
Vital signs will be measured as indicated in the Schedule of Events (Appendix 1) and will 
include supine, sitting and standing blood pressure (BP) measurements, and heart rate. 
Devices designed to measure BP from the finger or wrist may not be used. The left arm and 
same cuff sizes should be used for each measurement at all visits. If the left arm cannot be 
used for BP measurements, the reason should be documented, and the right arm should be 
used for BP measurements at all study visits. 
At each visit, BP measurements will be obtained using a calibrated sphygmomanometer 
while the subject is in sitting, supine, and standing positions. A single heart rate measurement 
should be taken just prior to the BP evaluation in the sitting, supine, and standing positions.  
All readings are to be entered into the source document and CRF for all subjects. The date 
and time of BP measurements should be captured in the source document and CRF. BP will 
be assessed first in the sitting position. Sitting BP and heart rate will be measured after the 
subject has been sitting for at least 5 minutes with feet on the floor and arm supported at 
heart level.  
After sitting BP measurement has been completed, supine and standing BP will be measured 
to evaluate orthostatic vital signs. Supine and standing blood pressure measures will not be 
used to determine eligibility for the study. First, the subject will lie flat for 5 minutes and 
have heart rate and supine blood pressure measured using the same equipment and arm as 
described for sitting BP. Once the supine BP measurement is complete, the subject will 
stand. Standing BP and heart rate will be measured after 2 minutes of standing. For standing 
BP measurements, the arm should be supported and extended such that the cuff is at heart 
level.  


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6.5 
Electrocardiography 
A 12-lead electrocardiogram (ECG) will be recorded as listed in Schedule of Events in 
Appendix 1 and whenever clinically indicated. This procedure should be performed in the 
supine position after at least 10 minutes of rest. ECG parameters measured will be the RR 
interval, PR interval, QRS duration, and QT. Each ECG should also be assessed by the 
investigator for signs of ischemia, clinically significant hypertrophy, and clinically 
significant T-wave abnormalities or arrhythmia.  
It is the investigator’s responsibility to review the results of the ECG as they become 
available. For each abnormal ECG result, the investigator shall ascertain if the observation 
represents a clinically significant change from the screening ECG for that individual subject 
(this determination, however, does not necessarily need to be made the first time an abnormal 
result is observed. The investigator may repeat the ECG to verify the results of the original 
result). If the ECG result is determined to be a clinically significant and abnormal change 
from baseline for that subject, it is considered to reflect an AE. 
6.6 
Diet and Exercise Counseling 
Subjects will receive counseling regarding an appropriate diet and exercise to aid in glycemic 
control based on standards of medical care in diabetes throughout the study. In addition, all 
subjects are encouraged to consume enough liquid to maintain adequate hydration. 
6.7 
Clinical Laboratory Tests 
6.7.1 
Laboratory Parameters 
Subjects will be in a seated or supine position during blood collection. A schedule of each 
laboratory test is outlined in Appendix 1. Clinical laboratory tests will include the following: 


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Table 1. 
List of Laboratory Tests 
Test Name 
 
Blood or 
urine  
Vol. (mL) 
Shipment  
Hematology1 
2 (blood) 
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 Electrolytes1 
 
5 (serum) 
Ambient 
Albumin (ALB) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase (ALK) 
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 Control1 
 
 
Ambient 
Fasting plasma glucose (FPG) 
Hemoglobin A1c (HbA1c) 
 
2 (plasma) 
2 (blood) 
 
Serum Lipids 1, 2 
 
6 (serum) 
Ambient 
Total cholesterol (TC) 
High-density lipoprotein cholesterol (HDL-C) 
Triglycerides (TG) 
Low-density lipoprotein 
cholesterol (LDL-C), 
calculated 
LDL-C, direct 
 
 
Urinalysis3 
 
10 (urine) 
Ambient 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Microscopic examination of sediment  
UACR 
Nitrite  
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
Leukocyte esterase 
 
 
Infectious Disease Testing4 
 
9 (serum) 
Ambient 
HBsAg 
HCV 
 
 
HIV (Canada only) 
 
 
 
Urine pregnancy test (WOCBP)5 
 
2 (urine) 
Local 
Population PK Sampling6 
Bexagliflozin plasma level 
 
2 (plasma) 
Frozen 
Biomarker evaluation7  
 
5 (serum) 
Ambient 
NT-proBNP evaluation (select Group 2 
subjects)8 
 
5 (serum) 
Ambient 
1 
Blood for clinical chemistry and hematology will be drawn after 10 h of fasting prior to breakfast (i.e. only 
water is allowed, no caloric intake).   
2 
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 baseline triglycerides are > 350 mg/dL. All subsequent LDL-C of these subjects will be 


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determined by the same direct LDL-C measurements only. 
3 
Urinalysis will be collected routinely at designated clinic visits from a clean catch sample. Glucose in the 
urinalysis results must be suppressed from the central laboratory report so the dosing blind can be 
maintained.  UACR will be determined at screening (V1), at randomization (V3), and every 24 weeks until 
study ends. Testing strips measuring only leucocyte esterase and nitrite will be provided for immediate 
assessment at the clinical sites. 
4 
Infectious disease testing will be conducted at screening only. HIV testing at screening will be conducted in 
Canada. 
5 
Urine pregnancy test (UPT) will be performed for WOCBP at all clinic visits. For surgically sterile or 
post- menopausal women, it will only be done at visit V1. 
6 
Blood samples for the population PK analysis will be drawn at weeks 6 and/or 12 from 240 randomly 
selected subjects in participating trial centers.  
7 
Serum samples for biomarker evaluation will be drawn at baseline and at week 12 post-randomization 
8 
Serum samples for NT-proBNP evaluation will be drawn within 1 h of the ECG measurement during the 
screening (V1) visit for Group 2 subjects with undocumented ejection fraction or documented left 
ventricular ejection fraction (LVEF) > 40%. 
 
6.7.2 
Sample Collection, Storage, and Shipping 
6.7.2.1 
Hematology, Blood Chemistry, Serum Lipids, and Glycemic Control 
Assessments 
Blood samples for hematology, chemistry, serum lipids and glycemic control assessments 
will be collected.  Timing of collection is described in Section 7 and 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 a minimum 10 h fast prior to blood draw to ensure the FPG and 
triglycerides values can be accurately determined. If a subject has not fasted for 10 h, the 
subject must return as soon as can be arranged (within 1 week) to provide a specimen after 
proper fasting. 
6.7.3 
Urinalysis 
Urine samples will be collected per the schedule outlined in Section 7.  
Investigator or staff should document if pre-menopausal female subjects are menstruating 
and note it in the source documents since hematuria is likely to be identified on dipstick 
urinalysis. 
Urine samples will be transported to the central laboratory for urinalysis. In addition, strips 
for assessing leukocyte esterase and nitrite but not glucose will be provided for immediate 
assessment at the clinical sites.  Urine culture may be performed if more than a trace amount 
of positive leukocyte esterase or nitrite testing is shown or if subjects report symptoms that 
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Microscopy will be conducted by the central laboratory if the subject has a positive result on 
the leukocyte esterase or nitrite dipstick tests that requires microscopic follow-up 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 
adjudication committee members will remain blinded to the dosing assignment. 
6.7.4 
Population PK Sampling 
Blood samples for the population PK analysis will be drawn when the subjects return to the 
clinic during week 6 and/or week 12 from 240 subjects who consent to participating in the 
PK study in selected trial centers. One blood sample will be drawn at each of the 3 time 
points from each subject for a total of 3 post-dose samples per subject. Approximately 120 
subjects will be sampled at 0.25 to1 h, 7 to 10 h, and 20 to 24 h post dose (routine 1). 
Another 120 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. 
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 -20o C until analysis.  
Plasma concentrations of bexagliflozin will be determined by a validated LC-MS/MS 
method. Approximately 480 measurements of bexagliflozin plasma concentrations will be 
collected from an estimated 160 subjects who will have received active drug in this study. 
6.7.5 
Biomarker Sampling 
Samples for the exploratory biomarker study will be collected in a serum separation tube. 
The blood (5 mL) will be thoroughly mixed and allowed to clot for 30-60 minutes. After the 
clot has formed, the tube will be centrifuged at 1500 to 2000 x g for 15 min to separate clot 
and serum. The serum will be transferred to 2 cryovials and transported under ambient 
conditions to the central laboratory in which the samples will be stored at or below -70 °C 
until analysis is performed. 
6.7.6 
NT-proBNP Sampling  
Serum samples for NT-proBNP measurement will be drawn from Group 2 subjects with 
undocumented left ventricular ejection fraction (LVEF) or with LVEF > 40% (i.e. Group 2 
subjects who have a history of heart failure that require NT-proBNP evaluation for eligibility 
confirmation) within 1 h of the ECG evaluation during the V1 screening visit. 


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Samples for the NT-proBNP evaluation will be collected in a serum separation tube. The 5 
mL blood sample will be thoroughly mixed and allowed to clot for 30-60 minutes. After the 
clot has formed, the tube will be centrifuged at 1500 to 2000 × g for 15 min to separate the 
clot from serum. The serum will be transferred to a tube and transported under ambient 
conditions to the central laboratory for evaluation. 
6.7.7 
Laboratory Testing in Unscheduled Visits 
An investigator can perform additional laboratory testing to diagnose or to follow up an 
adverse event progression or resolution.  Clinical samples should be analyzed in a local 
laboratory if a fast turn-around time is necessary to determine treatment plan.   
6.8 
Dispensing Investigational Product 
Each study subject will receive one bottle of run-in drug on visit V2 and one bottle of 
investigational product every 12 weeks between week 1 and 48.  Each subject will receive 
two bottles of investigational product every 24 weeks after week 48. 
6.9 
Efficacy Assessments 
6.9.1 
HbA1c Determination 
The HbA1c values will be determined in a central laboratory using a method that is certified 
by the National Glycohemoglobin Standardization Program (NGSP) and standardized to the 
Diabetes Control and Complications Trial (DCCT) reference assay. 
6.9.2 
Body Weight 
Total body weight will be determined in every clinical visit as described in Section 6.3. 
6.9.3 
Blood Pressure 
Systolic and diastolic blood pressure will be determined as described in the vital signs section 
(Section 6.4). 
6.9.4 
Hospitalization for Heart Failure 
Hospitalization for heart failure is defined as an unplanned presentation to an acute care 
facility (i.e., hospital, emergency room, observation unit) for an exacerbation of heart failure 
requiring an overnight stay (change in calendar day) which meets the criteria described in 
Appendix 4.  


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6.10 Adverse Events Assessments 
6.10.1 
Definition of Adverse Events 
Adverse event (AE): Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product. An AE does not necessarily have to have a 
causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
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 the definition of "serious" refers to an event in 
which the patient 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, or  
• 
is a congenital anomaly/birth defect  
• 
is an important medical event.  An important medical event is an event that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.  
 
Adverse Reaction: An adverse reaction means any adverse event caused by a drug. Adverse 
reactions are a subset of all suspected adverse reactions where 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:  


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• 
Suspected adverse reaction  
• 
Serious  
• 
Unexpected  
 
Severity: AEs will be graded on a 3-point scale and reported as indicated on 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. 
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. 
6.10.2 
Eliciting and Reporting AEs 
The investigator will periodically assess subjects for the occurrence of AEs after a subject 
consents to participation in the study. To avoid bias in collecting information about AEs, the 
investigator should ask subjects the following question: "How have you felt since you were 
last checked?" All AEs (serious and non-serious) reported by the subject must be recorded on 
the source documents and CRFs provided by the sponsor. 
It is the investigator’s responsibility to review the results of all laboratory tests as they 
become available. For each abnormal laboratory test result the investigator should ascertain if 
this is a clinically significant change from baseline for that individual subject (this 


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determination, however, does not necessarily need to be made the first time an abnormal 
value is observed.  The investigator may repeat the laboratory test or request additional tests 
to verify the results of the original laboratory tests). If the laboratory value is determined to 
be a clinically significant and abnormal change from baseline for that subject, this is 
considered a laboratory AE. 
Hypoglycemia is defined as any FPG or SMBG value ≤ 70 mg/dL and documented as 
described in Section 6.10.10. 
Any increase in liver function tests (AST, ALT, or bilirubin) greater than 3 times the ULN 
for the laboratory utilized will be considered a laboratory AE. 
In addition, the sponsor’s Medical Monitor 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. 
6.10.3 
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 h of knowledge of the event. 
Non-serious events that require discontinuation of investigational product (including 
laboratory abnormalities) should be reported to the sponsor within 3 working days in the 
CRF AE form. 
Subjects experiencing an SAE should be followed clinically until their health has returned to 
baseline status or no further improvement in condition can be expected with further care. It is 
expected that the investigator will provide or arrange appropriate supportive care for the 
subject. 
6.10.4 
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: 
1. General information 
2. Informed consent form 
3. Pregnancy prevention information 
4. Drug interactions with hormonal contraceptives 
5. Contraceptives in current use 


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6. Guidelines for the follow-up of a reported pregnancy 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy. The 
subject must sign an informed consent form stating the above-mentioned risk factors and that 
the consequences were discussed with her. 
During the study, all WOCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (e.g. missed or late menstrual cycle). 
If a subject or investigator suspects that the subject may be pregnant prior to investigational 
product administration, the investigational product administration must be withheld until the 
results of serum pregnancy tests are available.  If the pregnancy is confirmed, the subject 
must not receive the investigational product and must not remain in or be enrolled 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 is 
known. If pregnancy is confirmed, the investigational product will be permanently 
discontinued and the subject will be withdrawn from the trial. (Exceptions to study 
discontinuation may be considered for life-threatening conditions only after consultations 
with the Medical Monitor or the sponsor’s designated personnel.) The investigator must 
notify the Medical Monitor within 3 working days of the receipt of information that any 
female subject has become 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 
the sponsor’s clinical or designated personnel. 
Protocol required procedures for study discontinuation and follow-up must be performed on 
the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator must report to the sponsor, on the appropriate Pregnancy Surveillance form, 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants will be followed for a minimum of six months. 
6.10.5 
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 from the IWRS. Upon completion of the unblinding, 
the system will send an alert to designated study team members that an unblinding event has 
occurred. Documentation of breaking the blind should be recorded in the subject’s medical 
record with the date and time the blind was broken, and the names of the personnel 


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requesting and authorizing unblinding. The treatment assignment will continue to be 
withheld from the CEC members until all phase 3 studies are completed. 
6.10.6 
Follow-up of AEs  
6.10.6.1 
Follow-up of Non-Serious AEs 
Non-serious AEs that are identified on the last scheduled contact must be recorded on the AE 
CRF with the current status noted.  All non-serious events that are ongoing at the time will be 
recorded as ongoing on the CRF. 
6.10.6.2 
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 Sponsor according to the reporting procedures outlined in Section 6.10.2. 
These may include unresolved previously reported SAEs, or new SAEs. The investigator 
should follow these subjects 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 Medical Monitor or the sponsor’s 
designated personnel. These 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 subjects with SAEs identified after the last 
scheduled contact until the events are resolved, or the subject is lost to follow-up. The 
investigator should continue to report any significant follow-up information to the sponsor 
until the event has been resolved. This study requires that subjects be actively monitored for 
SAEs for at least 4 weeks after the last treatment. 
6.10.7 
Urinary Tract Infections (UTIs) 
Events potentially representing UTIs, 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 UTIs in the CRF 
unless an alternative diagnosis is present. In addition, a clean catch urine sample will be 
obtained at all clinical visits and a urinalysis will be performed on that sample at every 
clinical visit. A positive urinalysis will be defined as one with detectable leukocyte esterase 
and/or nitrites. If the subject reports symptoms consistent with a UTI or the urinalysis at the 
clinical site is positive, a urine culture test will be performed at the central laboratory. A 


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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.  
6.10.8 
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. 
6.10.9 
Hepatotoxicity 
If plasma AST and/or ALT concentrations > 3 x ULN are detected, the investigator will 
record in the source documents the date corresponding to the date of the laboratory 
abnormality; the type, frequency, and dose of any concurrent medications or supplements 
taken by the subject within the 14 days of the detected abnormality; and any symptoms or 
change in physical exam that have occurred since the prior assessment.  The investigator 
should perform additional laboratory and imaging tests to attempt to establish the cause of 
the AST and ALT elevations, including ruling out any potential contribution from bone or 
muscle etiologies. 
Any clinically significant increase in hepatic enzymes and specifically any ALT or AST > 
3 x ULN requires immediate repeat test within 48 to 72 h to confirm the hepatic enzyme 
elevation and should be repeated based on the clinical situation at least every 96 h (4 days) 
until ALT and AST return to < 2.5 x ULN.  Study medication should be stopped and the 
event should be reported as a laboratory AE within the CRF if the enzyme elevation is 
confirmed or worsening.  
Hepatotoxicity will be diagnosed and entered as an AE should any of the following occur: 
• 
ALT or AST > 8 x ULN; 
• 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or INR > 1.5 (INR will not be 
measured as a routine laboratory but should be assessed when needed for medical 
decision making in the appropriate clinical scenario). 
• 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
 
In the event of hepatotoxicity, investigational product should be permanently discontinued.  
The investigator is encouraged to consult with the Medical Monitor regarding diagnostic 
evaluation for the hepatic enzyme elevations. Consultation with a hepatologist may also be 
appropriate in some circumstances. 
6.10.10 Hypoglycemia 
Events of hypoglycemia or potentially representing hypoglycemia should be carefully 
evaluated.  


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All subjects will be provided with a glucometer and diary for recording blood glucose 
measurements and signs and symptoms that may be related to hypoglycemia, hyperglycemia, 
or potential diabetic ketoacidosis. During the study the subject is expected to perform daily 
fasting blood glucose readings and record all signs and symptoms. In the event of possible 
signs or symptoms of hypoglycemia, 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: 
1. SMBG reading at the time of the signs and symptoms attributed to hypoglycemia 
2. Time elapsed from the most recent food to the onset of signs and symptoms 
3. 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 
4. SMBG reading 15 minutes after treatment  
5. Signs and symptoms attributed to hypoglycemia, hyperglycemia, or potential symptoms 
that may suggest ketoacidosis  
 
Subjects will be encouraged to call the study clinic should signs and symptoms be potentially 
related to hypoglycemia or ketoacidosis. 
At each study visit, the investigator is expected to review the glucometer recordings and 
glycemic control diary with particular attention to any SMBG value ≤ 70 mg/dL and any 
recorded signs or symptoms potentially related to hypoglycemia. In addition, the investigator 
should query the subject with regard to the occurrence of signs and symptoms potentially 
related to hypoglycemia even if none are recorded in the diary.  
In the event of a blood glucose value ≤ 70 mg/dL or signs and symptoms potentially related 
to hypoglycemia, the investigator should complete the supplemental CRF which will include 
data from the glycemic control diary and 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).  


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3. Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of 
hypoglycemia but with a measured blood glucose concentration ≤ 70 mg/dL 
(3.9 mmol/L).  
4. Probable symptomatic hypoglycemia: an event during which symptoms of hypoglycemia 
are not accompanied by a blood glucose determination but that is presumably caused by a 
blood glucose concentration ≤ 70 mg/dL (3.9 mmol/L). 
5. Relative hypoglycemia: An event during which the person with diabetes reports any of 
the typical symptoms of hypoglycemia, and interprets those as indicative of 
hypoglycemia, but with a measured plasma glucose concentration > 70 mg/dL 
(3.9 mmol/L). 
 
While each event meeting the criteria above will be entered into the hypoglycemia log, only 
severe hypoglycemia, documented symptomatic hypoglycemia, asymptomatic hypoglycemia, 
and probable hypoglycemia will be entered as AEs.  
In the event of asymptomatic hypoglycemia, the investigator should review the signs and 
symptoms of hypoglycemia with the subject to elicit a complete description and should 
review proper glucometer technique to ensure that the low glucose value is not due to 
improper use of the glucometer. 
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. 
6.10.11 Diabetic Ketoacidosis (DKA) 
DKA is a serious, acute complication of diabetes and can be life-threatening.  Subjects will 
be educated on the signs and symptoms of DKA and are required to call the study site and 
seek treatment should such signs or symptoms occur. 
During the clinical trial period, potential DKA events will be monitored by the routine 
measurement of urinary ketones and assessment for signs or symptoms of acidosis at each 
clinic visit. Clinical presentations, such as difficulty breathing, abdominal pain, nausea, 
vomiting, lethargy, or a fruity smell on the breath, or laboratory values that suggest 
clinically-significant acidosis should be documented; treatment of DKA should be provided 
as 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 
measured STAT at a local laboratory. If ketoacidosis is likely, investigational product 
administration should be discontinued and immediate appropriate medical therapy, including 
insulin and volume repletion, should be initiated.  A glucose infusion may be provided if 
necessary to avoid hypoglycemia during insulin therapy. Insulin treatment should continue 
until resolution of the ketoacidosis and stabilization of the subject’s clinical condition. 
Investigational product administration may be resumed following stabilization of the 
subject’s condition. Investigator should collect the data necessary for the completion of the 
DKA CRF. 
If symptoms suggestive of DKA may have occurred but are not ongoing, the 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. 
6.10.12 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 receive and adjudicate the following events.  
• 
All Deaths 
• 
Suspected non-fatal myocardial infarction (MI) 
• 
Suspected hospitalization for unstable angina (HUA) 
• 
Suspected transient ischemic attack (TIA) and stroke  
• 
Suspected hospitalization for HF (HF) 
• 
Reported coronary revascularization procedure 
 
The CDISC Draft Definitions for Cardiovascular and Stroke Endpoint Events in Clinical 
Trials  will be applied by the CEC (Hicks KA, 2014). 
6.10.13 Amputation 
Investigators should request that subjects provide information about any amputation or 
related adverse event or procedures during each study visit. A case report form for adverse 
events that require amputations will be completed to capture the date and type of procedure, 
anatomic location, and causes. 


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Investigators are reminded to counsel appropriate foot care to avoid cuts or sores and to treat 
even minor cuts or sores to prevent infection and ulceration. Patients who have had a 
previous amputation should be closely monitored. Special attention may be appropriate for 
patients who are also receiving thiazide diuretics as these have been shown to increase the 
risk of amputation in diabetics.  
6.11 Concomitant Medication Assessments 
A concomitant medication is any medication that the subject has been taking prior to 
enrollment and that the subject is expected to continue to take for some portion of the trial, as 
well as any medication other than the investigational product that the subject takes during the 
course of the trial.  
The medications or treatment for controlling hypoglycemia must be recorded as concomitant 
medications in the CRF.  Any medication given to treat hyperglycemia is considered a rescue 
therapy and should be recorded in the concomitant medication log. 
Changes from baseline anti-hypertensive therapy and their rationale must be recorded in the 
CRF. 
All prescription and over-the-counter medications, including vitamins and herbal 
supplements, that subjects receive during the trial must be documented in the CRF.  This 
documentation should continue until the subjects complete the study.  
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD).  A table of concomitant medications based on the anatomic 
therapeutic chemical classification (ATC) and preferred name will be produced.  A listing of 
concomitant medications will include all medications taken by any subjects during the course 
of the study. 
6.12 End of Treatment Procedure 
The treatment period will end when (i) all randomized subjects have either completed at least 
52 weeks of treatment or withdrawn from the study, and (ii) at least 134 subjects have an 
adjudicated MACE+ event confirmed by the CEC. 
The sponsor or its designee will complete the following tasks within 7 days: 
1. Notify all investigational sites, IRB/EC, and DSMB that the treatment period has ended 
2. Inactivate the IWRS function for assigning investigational product 
 
The investigators will complete the following procedures upon the notification that the 
treatment period has ended: 
1. Contact all study subjects and schedule the end of treatment visit promptly 
2. Schedule the follow up visit (FU) to occur 4 weeks after the end of treatment visit 
 


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6.13 Removal of Patients from the Trial or Discontinuation of 
Investigational Product Administration 
The investigator must emphasize to potential subjects the importance of continued 
participation for the full duration of the trial during the informed consent process. Potential 
subjects should be informed that the trial procedures will allow additional medications to 
control hyperglycemia or other adverse conditions. It is also important to emphasize that 
missing data and missed visits could affect the entire trial. If subjects are dissatisfied with the 
conduct of the trial but have not withdrawn, the investigators should make an effort to 
address their concerns and retain them in the trial if possible. In doing so, investigators must 
be careful that the efforts do not cross over into coercion. Investigators should encourage a 
subject to remain in the study even if the investigational product administration is stopped so 
that safety information can be collected. If a patient is unwilling to return for study 
visits/assessments the investigator should ask the patient whether follow-up by telephone, 
through medical or other records or by contact with the patient’s primary care physician is 
possible. The investigator should emphasize the importance for regulatory and public 
health/safety reasons of being able to obtain patient vital status at the end of the trial. 
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 IRB/EC 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 
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.  Examples of 
reasons for withdrawal include:   
1. A protocol violation has occurred, 
2. A serious or intolerable AE has occurred, 
3. A clinically significant change in a laboratory parameter has occurred,  
4. The sponsor terminates the study, or 
5. The patient requests to be withdrawn 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 according to Section 7. 
Subjects who withdraw from the study will not be replaced. 
6.14 Appropriateness of Measurements 
The percentage of HbA1c is a widely used measure of chronic glycemia, reflecting average 
blood glucose levels over a 2- to 3-month period of time. It is an accepted surrogate marker 
for risk of microvascular complications and is widely used as a measurement for the 


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adequacy of glycemic management. 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 
Screening Visit V1 (up to 3 weeks before run-in period) 
The screening can be performed from 3 weeks to 3 days before the start of the run-in period 
for subjects. At the screening visit the staff at the investigational site will: 
• 
Explain the content of the informed consent materials to the subject and collect signed 
informed consent 
• 
Evaluate inclusion and exclusion criteria based on the information collected at the 
screening visit. Verify compliant fasting status as described in Section 6.7.2.1.  
• 
Obtain medical history and demographic information 
• 
Perform a brief physical examination  
• 
Measure vital signs, including blood pressures and heart rate 
• 
Measure body weight and height 
• 
Perform a 12-lead ECG measurement 
• 
Draw serum sample for NT-proBNP evaluation within 1 h of the ECG measurement from 
Group 2 subjects with undocumented left ventricular ejection fraction (LVEF) or LVEF > 
40% 
• 
Draw blood if a minimum 10-h fast has been completed by the subject as described in 
Section 6.7.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 
• 
Collect clean-catch, mid-stream urine sample for urinalysis, and pregnancy test for all 
females 
 
7.2 
Run-in Period 
7.2.1 
Visit V2 (two weeks prior to randomization) 
• 
Counsel subject on appropriate diet and exercise 
• 
Dispense glucometer and instruct subject in SMBG determination and recording 
• 
Measure body weight 
• 
Dispense run-in kit for run-in period 
• 
Assess pre-treatment signs and symptoms and potential DKA and record pre-treatment 
concomitant medications 
 


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7.3 
Treatment Period 
At the end of the run-in period, subjects who have successfully completed run-in period and 
continue to meet inclusion/exclusion criteria will be randomized and enter the treatment 
period. At the following visits staff at the investigational site will: 
7.3.1 
Visit V3 (day 1 of week 1) 
• 
Confirm inclusion/exclusion criteria for eligibility and review run-in drug compliance 
• 
Perform a complete physical examination 
• 
Review glycemic control and SMBG.  Dispense glycemic control diary. 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Measure body weight 
• 
Perform 12-lead ECG 
• 
Draw blood from subjects who have completed a compliant fast as described in Section 
6.7.2.1. The specific laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Collect a clean-catch, mid-stream urine sample for urinalysis and UPT for women of 
child bearing potential.  
• 
Dispense investigational product based on randomization 
• 
Assess pre-treatment signs and symptoms and potential DKA and record pre-treatment 
concomitant medications. 
 
7.3.2 
Visit V4 (week 2, a phone interview) 
• 
Review SMBG and glycemic control record  
• 
Assess AEs and potential DKA and record concomitant medications 
• 
Schedule an unscheduled clinic visit if clinically indicated 
 
7.3.3 
Visit V5 (week 6) 
• 
Review SMBG and glycemic control record  
• 
Measure vital signs, including blood pressures and heart rate 
• 
Measure body weight 
• 
Draw blood from subjects who have completed a compliant fast as described in Section 
6.7.2.1. The specific laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Collect a clean catch mid-stream urine sample for urinalysis in all subjects and for UPT 
for women of child bearing potential 
• 
Assess AEs and potential DKA and record concomitant medications. 
• 
Collect blood specimens for sparse PK sampling from selected subjects in participating 
centers 
 


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7.3.4 
Visit V6 (week 12) 
• 
Perform an abbreviated physical examination  
• 
Review SMBG and glycemic control record  
• 
Measure vital signs, including blood pressures and heart rate 
• 
Measure body weight  
• 
Draw blood from subjects who have completed a compliant fast as described in Section 
6.7.2.1. The specific laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Collect a clean catch mid-stream urine sample for urinalysis in all subjects and for UPT 
for women of child bearing potential 
• 
Dispense study medication  
• 
Assess AEs and potential DKA, and record concomitant medications. 
• 
Collect blood specimens for sparse PK sampling from selected subjects in participating 
centers 
 
7.3.5 
Visit V7 (week 18, a phone interview) 
• 
Review daily SMBG and glycemic control record 
• 
Assess AEs, potential DKA, and record concomitant medications 
• 
Schedule an ad hoc visit if clinically indicated 
 
7.3.6 
Visit V8 (week 24) 
• 
Review SMBG and glycemic control record  
• 
Perform an abbreviated physical examination 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Measure body weight 
• 
Perform 12-lead ECG  
• 
Draw blood from subjects who have completed a compliant fast as described in Section 
6.7.2.1.  The specific laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Collect a clean catch mid-stream urine sample for urinalysis in all subjects and for UPT 
for women of child bearing potential; 
• 
Dispense investigational product 
• 
Assess AEs, potential DKA, and record concomitant medications 
 
7.3.7 
Visit V9 (week 36) 
• 
Review SMBG and glycemic control record  
• 
Perform an abbreviated physical examination 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Measure body weight 


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• 
Draw blood from subjects who have completed a compliant fast as described in Section 
6.7.2.1.  The specific laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Collect a clean catch mid-stream urine sample for urinalysis in all subjects and for UPT 
for women of child bearing potential; 
• 
Dispense investigational product 
• 
Assess AEs, potential DKA, and record concomitant medications 
 
7.3.8 
Visit V10 (week 48) 
• 
Review SMBG and glycemic control record  
• 
Perform an abbreviated physical examination 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Measure body weight 
• 
Perform 12-lead ECG  
• 
Draw blood from subjects who have completed a compliant fast as described in Section 
6.7.2.1.  The specific laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Collect a clean catch mid-stream urine sample for urinalysis in all subjects and for UPT 
for women of child bearing potential; 
• 
Dispense investigational product 
• 
Assess AEs, potential DKA, and record concomitant medications 
 
7.3.9 
Visit V11, V13, V15, V17, etc. (week 60 to end of treatment; phone 
interviews) 
• 
Review daily SMBG and glycemic control record 
• 
Assess AEs, potential DKA, and record concomitant medications 
• 
Schedule an ad hoc visit if clinically indicated 
 
7.3.10 
Visits V12, V14, V16, V18, etc. (week 72 to end of treatment, clinic visits) 
• 
Review SMBG and glycemic control record  
• 
Perform an abbreviated physical examination  
• 
Measure body weight 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Perform 12-lead ECG 
• 
Draw blood from subjects who have completed a compliant fast as described in Section 
6.7.2.1. The specific laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Collect a clean catch mid-stream urine sample for urinalysis in all subjects and for UPT 
for women of child bearing potential 
• 
Dispense study medication 
• 
Assess AEs, potential DKA, and record concomitant medications 


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7.3.11 
Visit EV (end of treatment, a clinic visit) 
An End of Treatment Visit should be scheduled within 2 weeks after the end of treatment is 
declared or as soon as scheduling allows. 
• 
Review SMBG and glycemic control record  
• 
Perform an abbreviated physical examination  
• 
Measure body weight 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Perform 12-lead ECG 
• 
Draw blood from subjects who have completed a compliant fast as described in Section 
6.7.2.1. The specific laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Collect a clean catch mid-stream urine sample for urinalysis in all subjects and for UPT 
for women of child bearing potential 
• 
Perform the drug accountability procedure and record the last day of dose administration 
• 
Assess AEs, potential DKA, and record concomitant medications 
 
7.4 
Exit Visit  
7.4.1 
Visit FU (4 weeks after the last dose of investigational product is 
administered or if a subject withdraws consent) 
• 
Review SMBG and glycemic control record 
• 
Perform a complete physical examination  
• 
Measure vital signs, including blood pressures and heart rate 
• 
Measure body weight 
• 
Perform 12-lead ECG if clinically indicated 
• 
Draw blood from subjects who have completed a compliant fast as described in Section 
6.7.2.1.  The specific laboratory tests scheduled for this visit are listed in Appendix 2  
• 
Collect a clean-catch, mid-stream urine sample for urinalysis in all subjects and for UPT 
for women of child bearing potential 
• 
Assess AEs, potential DKA, and record concomitant medications: If a subject has an 
ongoing SAE, the subject will be followed until the AE has resolved or no meaningful 
further improvement can be expected.  Every possible attempt should be made to 
document resolution of acute and chronic toxicities. 
 
7.5 
Discontinuation of Investigational Product Administration 
Subjects who discontinue the investigational product administration early but are willing to 
remain in the study to allow safety information to be collected should complete the End of 
Treatment visit procedures. Safety data may be documented following the scheduled clinic 
visit and/or phone interview procedures as much as possible without the study drug 


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dispensation and accountability procedures. Alternative follow up methods to allow safety 
assessment to be recorded may be implemented as unscheduled visits.  
7.6 
Early Termination Procedures 
Subjects who withdraw consent and have received investigational product should have a 
follow-up examination, including a complete physical examination, vital signs, ECG, and 
clinical laboratory tests (hematology, serum chemistry, and glycemic control). The sponsor 
must be notified in the event that a subject withdraws or has been withdrawn from the study. 


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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 (SOP) of the 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 full 
analysis plan will be developed as a separate document and will become the final plan. All 
statistical analyses will be performed using SAS Version 9.4 or higher.   
Data summaries will use descriptive statistics (number of subjects [N], mean, standard 
deviation [SD], Q1, median, Q3, minimum, and maximum) for continuous variables, and 
frequency and percentage of subjects for categorical and ordinal variables.  If there are 
missing values, the number missing will be presented, but without a percentage. 
Unless otherwise specified, all tests will be two-tailed using a 0.05 level of significance.  All 
confidence intervals (CIs) will be two-sided 95% confidence intervals.   
9.2 
Determination of Sample Size 
The sample size is determined based on the required number of MACE+ for the program-
wide meta-analysis of bexagliflozin cardiovascular safety assessment, where non-inferiority 
of bexagliflozin to control will be formally assessed from a hazard ratio perspective.  There 
will be no formal non-inferiority statistical testing of MACE+ rate within THR-1442-C-476; 
the only primary endpoint is the change in HbA1c from baseline to Week 24. 
The following are the assumptions for protocol THR-1442-C-476 to have an adequate 
number of events to appropriately power the meta-analysis: 
1. Enrollment will take 1 year. 
2. Every subject is followed for a minimum of 1 years and a maximum of 3 years, except 
for premature withdrawals. 
3. The annual premature withdrawal rate is 6.5% 
4. The randomization ratio is 2:1 (bexagliflozin vs. placebo) 
5. The primary analysis is non-inferiority of treatment vs. placebo from a hazard ratio 
perspective over a 3 year period, using a non-inferiority margin of 1.8 for MACE+. 
6. A one-sided 0.025 level of significance will be used to assess non-inferiority 
7. Non-inferiority to placebo for MACE + will be assessed by comparing the upper limit of 
a one-sided 97.5% CI of the hazard ratio (treatment vs. placebo) to a margin of 1.8; the 
hazard ratio will be calculated from Cox proportional hazards regression.  
8. The actual hazard ratio is an equivalence hazard ratio of 1.00 and the reference group 
monthly hazard rate is 0.00308.  
 
Under the above assumptions, 134 events across 1650 randomized patients (1100 vs. 550 
placebo) yields 87% power to detect non-inferiority of experimental treatment to placebo 
with respect to MACE+.  Thus, protocol C-476 will continue until at least 134 events have 
occurred. If the study accrues 134 MACE+ events before every subject has either been 
exposed to investigational product for at least 52 weeks or withdrawn from the study, the 


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study will continue until all subjects either complete the minimum 52 week course of 
exposure or withdraw. 
If the true hazard ratio is 0.9, the power to claim non-inferiority increases to 93%.  This 
should yield sufficient power for the meta-analysis (where all experimental dose groups are 
pooled and considered as one treatment group), since the number of patients with events in 
the meta-analysis will be at least the same as that in protocol THR-1442-C-476 and since the 
treatment to placebo ratio will remain approximately 2:1 across the meta-analysis. 
To determine the sample size of THR-1442-C-476 study, the event rates were estimated 
based on published cardiovascular outcome study SAVOR (Scirica et al., 2013; Scirica et al., 
2014a).  In the study, subjects with T2DM with a baseline HbA1c of 6.5% to 12.0%, and 
either a history of established cardiovascular disease or multiple risk factors for vascular 
disease were included.  The estimated 2 year event rate of the placebo group was 7.2%.  
Assuming a similar event rate in the THR-1442-C-476 study, a sample size of 1650 is 
planned so that 134 study subjects with an adjudicated MACE+ will occur with a treatment 
duration between 2 and 3 years.  The estimated numbers of MACE+ based on the heart 
failure background were shown in Table 2. The projected number of CV deaths from subjects 
with HF history is anticipated to be ≤50% of the total CV deaths. 
Table 2. 
Estimated Event Rates in Patients with Cardiovascular Risks1 
Event rate in 2 years 
No prior 
HF (%) 
Prior 
HF (%) 
From 1250 
non-HF 
From 400 
HF 
Total of 1650 
subjects 
Mortality 
3.5% 
8.8% 
44 
35 
79 
CV death 
2.3% 
7.3% 
29 
29 
58 
MI 
3.2% 
4.5% 
40 
18 
58 
Stroke 
 1.0%  
16 
16 
Hospital. for HF 
1.7% 
10.2% 
21 
41 
62 
Hospital. for unstable angina 
1.0% 
16 
16 
1 Event rate is based on the outcome of the placebo group in the SAVER study (Scirica et al., 2013; Scirica et 
al., 2014a) 
 
The estimated sample size of 1650 in a 2:1 active to placebo ratio will yield 90% power to 
detect a treatment effect of 0.22% in HbA1c reduction assuming the SD is 1.1% and HbA1c 
values from all subjects will be used for the primary efficacy analysis.   
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. 


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9.3.2 
Safety Analysis Set 
All subjects who are randomized and take at least one dose of double-blind study medication 
will be included in the Safety Analysis Set. Safety analyses will be based on the medication 
that was actually dispensed to each subject. This is the primary analysis set for safety. If a 
randomization error causes a subject in the placebo arm to receive active drug inadvertently, 
the subject will be considered exposed to active drug and will be analyzed accordingly in the 
SAS population.  If a subject in the active arm receives placebo inadvertently but receives 
active drug subsequently, the subject will be considered exposed to active drug and will be 
analyzed accordingly. 
9.3.3 
Per Protocol Analysis Set 
The Per Protocol (PP) Analysis Set will include all subjects in the FAS who meet the study 
eligibility requirements and have no major protocol deviations that will 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 subject assignment to 
the PP Analysis Set will be determined prior to database lock. 
9.4 
Demographics and Baseline Characteristics 
Demographic characteristics include age, gender, race, ethnicity, country, and CV history.  
Baseline characteristics include baseline HbA1c value, blood pressure (systolic and 
diastolic), body weight, fasting plasma glucose level, and stratification factors determined at 
screening visit, including HbA1c (< 9.5% or ≥ 9.5%), eGFR (< 60 or ≥ 60 mL/min/1.73 m2), 
body mass index (BMI < 25 kg/m2 or ≥ 25 kg/m2) and history of heart failure (yes or no).  
Summary statistics by treatment group will include counts and percentages for discrete 
variables, and means, SD, Q1, medians, Q3, minimum and maximum for continuous 
variables and counts and percentage of patients for categorical variables. A further 
descriptive summaries will be provided separately for subjects who enrolled prior to and 
subjects who enrolled post the modification of inclusion criteria.  
9.5 
Primary Endpoints 
9.5.1 
Primary Efficacy Endpoint 
The primary efficacy hypothesis is that bexagliflozin reduces HbA1c after 24 weeks of 
treatment when compared to placebo. The primary efficacy analysis on change in HbA1c at 
week 24 is based on the ITT using all observed data. Missing data will be handled using a 
mixed model repeated measures (MMRM) approach and will include terms for visit, 
treatment, treatment-by-visit interaction and randomization stratification factors as fixed 
effects and the corresponding baseline HbA1c value as a fixed effect covariate. Least squares 
mean treatment differences between the bexagliflozin group and the placebo group will be 
estimated from the model at week 24 with the corresponding p-values and their two-sided 
95% CIs presented. An unstructured covariance will be used to model the within-subject 
correlation. In the unlikely event the model with the unstructured covariance structure does 


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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. 
As a secondary sensitivity analysis, the multiple imputation method will be used to impute 
missing observations (including observations obtained after rescue medication) prior to 
carrying out the MMRM analysis.  To further examine the sensitivity of the analysis, a last 
observation carried forward (LOCF) method will then be used to impute the missing 
observations prior to carrying out the MMRM model. 
For supportive analyses, the primary efficacy endpoint will be analyzed with observed 
available data using the PP analysis sets in a similar manner as above.   
9.5.2 
Handling Dropouts, and Missing Data 
Discontinuation criteria are explained in Section 6.13.  Subjects who withdraw consent to 
participate in the study will not be replaced.  
The early termination rate is estimated to be 6.5% annually.  To the extent possible, attempts 
will be made to minimize the amount of missing data through measures planned in the study 
conduct. But if data are missing for the primary endpoint and the first key secondary 
endpoint (ie, change of HbA1c for subjects who have been prescribed insulin), they will be 
handled as follows: 
1. All observed data will be analyzed and data obtained after rescue will not be excluded 
and considered as missing. This will be considered the primary analysis. 
2. Missing primary efficacy endpoint information will be imputed via multiple imputation 
linear regression approach. A total of 10 imputed datasets will be generated, and the 
corresponding primary analyses will be carried out on each imputed dataset for each 
endpoint; the analyses results will be combined across the 10 datasets using the standard 
techniques for multiply imputed data sets in order to yield overall treatment comparison 
results on the imputed data for each endpoint. 
 
The number, timing, pattern, reason for and possible implications of missing values in 
efficacy assessments will be investigated. The dropout patterns will be assessed by Kaplan-
Meier plots if applicable to assess whether they differ between treatment groups. 
The handling of missing safety endpoint (MACE+) data is described below in section 9.6.3; 
however, analyses on MACE+, while being collected in C-476, will only be formally 
analyzed in the meta-analysis. 
For all other endpoints, the missing data will not be imputed and only the observed data will 
be used in the analyses. 


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9.5.3 
Multiple Comparisons / Multiplicity 
A sequential testing procedure will be applied to the testing of the treatment differences of 
the primary and key secondary efficacy endpoints, to control the familywise error rate at a 
two-sided 5% level. Each comparison will be done based on the pre-specified testing 
hierarchy, so multiplicity adjustment will not be performed. 
9.6 
Secondary Endpoints 
9.6.1 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints include: 
• Change in HbA1c from baseline to week 24 in randomized subjects who have been 
prescribed insulin to control their diabetes 
• Change in body weight from baseline to week 48 in subjects with a BMI ≥ 25 kg/m2 
• Change in SBP from baseline to week 24 in subjects with baseline systolic blood pressure 
≥ 140 mmHg 
 
It is anticipated that approximately 50% of the randomized subjects will have been 
prescribed insulin to manage their disease.  The sample size for the key secondary efficacy 
end point to evaluate the treatment effect of bexagliflozin compared to placebo on the change 
in HbA1c from baseline to week 24 in subjects who have been prescribed insulin to control 
their diabetes is estimated to be 800. For this key secondary endpoint, the estimated sample 
size will yield >90% power to detect a treatment effect of 0.3% assuming the SD is 1.1% for 
a two-sided superiority testing.   
It is also anticipated that a high proportion of the randomized subjects would have a baseline 
BMI ≥ 25 kg/m2 and baseline SBP ≥140 mmHg in this cardiovascular risk enriched 
population for the analysis in change in body weight and change in SBP. 
A hierarchical testing procedure will be applied to these endpoints in the sequence provided 
above.  These key secondary endpoints will only be tested sequentially when significant 
treatment differences are established for the primary efficacy endpoint in the comparisons 
between bexagliflozin and placebo. 
The comparison between treatment populations at week 24 (HbA1c and SBP) or 48 (body 
weight) will be carried out using an MMRM ANCOVA model with unstructured covariance 
assumption. The model will include terms for treatment, randomization stratification factors, 
visit, and treatment-by-visit interaction as fixed effects and the corresponding baseline value 
as an additional fixed effect covariate. Treatment comparison p-values and the difference at 
week 24 (HbA1c and SBP) or 48 (body weight) will be estimated from the model, with the 
two-sided 95 % CIs of the difference also presented.  If the model does not converge with the 
unstructured correlation assumption, an autoregressive (1) covariance structure will be used. 


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9.6.2 
Exploratory Efficacy Endpoints 
The exploratory secondary efficacy endpoints include: 
• 
Change from baseline in HbA1c over time 
• 
Change from baseline in FPG over time 
• 
Change from baseline in body weight over time 
• 
Change from baseline in SBP over time 
• 
Requirement of additional anti-diabetic medications, including insulin; and time to first 
use of additional anti-diabetic medication 
• 
Requirement of reduced anti-diabetic medications, including insulin dose over time 
• 
Hospitalization for heart failure in all subjects and in subjects with a history of heart 
failure 
• 
time to hospitalization for heart failure in subjects in all subjects and in subjects with a 
history of heart failure 
 
For changes from baseline in HbA1c, FPG, body weight, and SBP over time, a similar 
MMRM ANCOVA model will be used as for the key secondary efficacy endpoints.  Of 
interest in the MMRM ANCOVA model is the difference between treatments on these 
endpoints across all post-baseline time points.  Also, changes from baseline for each endpoint 
will be estimated and analyzed at each study visit using this MMRM model.  Specifically, for 
each endpoint, treatment difference in least squares means will be estimated by visit from the 
model with the corresponding p-values and the two-sided 95% CIs of the difference between 
treatments. 
Endpoints measuring proportions over time will be analyzed using generalized estimating 
equation (GEE) logistic regression using similar independent variables as the MMRM 
ANCOVA models above (the treatment-by-visit interaction term will be removed if not 
significant), and using an unstructured correlation structure (or autoregressive(1) if the model 
with the unstructured structure does not converge). Of interest is the difference between 
treatments across all post-baseline time points.  Also, odds ratios will be estimated from the 
model with the corresponding p-values and their two-sided 95% CIs presented at each visit. 
For time-to-event endpoints, Cox proportional hazards models with treatment and 
randomization stratification factors as the covariates will be used to estimate the hazard ratio 
of the endpoint, p-value and its two-sided 95% confidence interval comparing bexagliflozin 
to placebo. Subjects who withdraw from the trial and for whom no follow up event data are 
collected (i.e., lost to follow-up subjects) will be censored at the last known follow-up. 
9.6.3 
Safety Endpoint 
The safety endpoint of the program-wide meta-analysis is the hazard ratio for the time to first 
occurrence of adjudicated MACE+ which is defined as the composite of CV death, non-fatal 
MI, non-fatal stroke and hospitalization for unstable angina. All these events will be 
adjudicated by an independent CEC, blinded to treatment assignments. A Cox proportional 
hazards model with treatment and randomization stratification factors as the covariates will 


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be used to estimate the hazard ratio of the composite endpoint and its two-sided 95 % 
confidence interval comparing bexagliflozin to placebo. The analysis set is the Safety 
Analysis Set. Subjects who withdraw from the study early and subjects who did not 
prematurely terminate but who did not experience a MACE+ event by the end of the study 
will be censored at the last known follow-up.  
As a sensitivity analysis, the incidence of MACE+ will be compared between treatments 
following multiple-imputation of the MACE+ endpoint. The methodology for sensitivity 
analyses of time-to-event data to be used will be that described in Zhao, Yue, et al (Zhao et 
al., 2014). The dropout patterns will be assessed by Kaplan-Meier plots if applicable to 
assess whether they differ between treatment groups. 
In addition, a sensitivity analysis will be conducted separately for subjects who enrolled prior 
to inclusion criteria modification and subjects who enrolled post inclusion criteria 
modification. 
9.6.4 
Other Safety Endpoints 
The other safety endpoints include 
• 
Time to a 5-point composite adjudicated endpoint of CV death, non-fatal MI, non-fatal 
stroke, hospitalization for unstable angina, or coronary revascularization 
• 
Time-to a 6-point composite adjudicated endpoint of CV death, non-fatal MI, non-fatal 
stroke, hospitalization for unstable angina, hospitalization for heart failure, and coronary 
revascularization; and time to onset of event 
• 
Time to individual events including all-cause mortality, CV death, non-fatal MI, non-fatal 
stroke, transient ischemic attack, hospitalization for unstable angina, hospitalization for 
heart failure, and coronary revascularization; and time to onset of each event 
• 
Incidence of treatment emergent AEs (TEAEs) of interest 
• 
Incidence of amputations 
• 
Change from baseline in eGFR by study visit 
• 
Change from baseline in UACR by study visit 
 
AEs of special interest include the following categories:  
• 
Genital mycotic infections 
• 
Urinary tract infections including urosepsis and pyelonephritis 
• 
Diuretic effects including hypovolemia 
• 
Hypotension episodes 
• 
Hepatotoxicity 
• 
Hypoglycemia 
• 
Falls and fractures 
• 
Malignancies 


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• 
Hypersensitivity reactions 
• 
Acid-base disorders including DKA 
• 
Renal failure events 
 
AEs of special interest will be defined programmatically based on MedDRA system organ 
class and preferred terms which will be predefined by a blinded medical reviewer and will be 
specified in the Statistical Analysis Plan. 
Event terms, signs, and symptoms will be documented in the listings.  The number and 
percentage of subjects who have experienced treatment emergent adverse events (TEAEs) of 
special interest will be summarized for each treatment group by type of AE.  A TEAE is an 
AE that started or worsened in severity at or after start of randomized treatment. 
A case report form for adverse events that require amputation will be completed to capture 
the date and type of procedure, anatomic location, and causes. The number and percentage of 
subjects experienced any TEAE that requires amputation will be summarized for each 
treatment group by type of events. The incidence of lower extremity amputation per 100 
patient years will also be summarized. Additional analyses will be specified in the statistical 
analysis plan to evaluate potential risks in subpopulations based on age, gender, or other 
baseline characteristics (if sample size allows). 
MMRM ANCOVA will be used for the analyses of changes from baseline in eGFR in a 
similar manner as for the secondary endpoints. Least squares mean treatment differences 
between each bexagliflozin group and placebo will be estimated from the model with the 
two-sided 95% CIs presented. 
The time to event onset will be analyzed using the Cox proportional hazards model with 
treatment and randomization stratification factors as the covariates. For each endpoint, the 
hazard ratio and its 95% confidence interval comparing bexagliflozin to placebo will be 
presented. Subjects who dropped out of the trial and for whom no follow up event data were 
collected (i.e., lost to follow-up subjects) will be censored at the last known follow-up. 
Additional sensitivity analyses may also be conducted for subjects who enrolled prior to 
inclusion criteria modification separately from subjects who enrolled post inclusion criteria 
modification to assess a potential impact of subject population differences within the study 
due to inclusion criteria adjustment. 
Additional safety endpoints will also include: 
• 
Incidence of all TEAEs 
• 
Change from baseline as well as shift in clinical laboratory findings 
• 
Change from baseline in vital signs measurements including orthostatic blood pressure 
• 
Incidence of abnormal physical examination findings by body system 
• 
Incidence of concomitant medication use 
 


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AEs that begin after the first administration of double-blind study medication or existing AEs 
that worsen after the first dose of double-blind study medication will be considered TEAEs. 
The number and percentage of subjects reporting TEAEs will be summarized for each 
treatment group by MedDRA system organ class and preferred term, then by severity, and by 
relationship to study treatment. Drug-related AEs will be considered those to be at least 
possibly related to investigational product based on the investigator’s assessment. The 
number and percentage of subjects reporting SAEs, 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. By-patient listings will 
be provided for deaths, SAEs, and events leading to discontinuation of treatment.   
Descriptive statistics will be provided for clinical laboratory data, vital signs data, and ECG 
interval data, presented as both actual values and changes from baseline relative to each 
study visit. For each continuous laboratory parameter, results will be categorized as low, 
normal or high based on the laboratory normal ranges. Frequencies and percentages will be 
presented for subjects who had a shift to low and for patients who had a shift to high from 
baseline to any post-dosing assessment. Baseline values for all safety analyses will be 
defined as the last observation prior to dosing.  All out-of-range and clinically significant 
laboratory results will be identified in patient data listings. 
Abnormal physical examination findings will be tabulated by treatment and presented in a 
by-patient data listing. 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A by-subject listing of concomitant medications will include all 
medications taken during the study regardless of the timing for the start of the medication. 
All medications started prior to the administration of the investigational product will be 
included in the data but will be flagged as prior in the listing. Only the concomitant 
medication use will be summarized in terms of frequency and percentages by body system 
and medication name. 
In addition, safety profile for subjects who were prescribed with insulin will be separately 
analyzed, eg, adverse events of special interest, incidences of TEAEs, laboratory 
abnormalities, vital signs, physical exams, and concomitant medication usages. 
9.7 
Other Assessments or Analyses 
Blood samples will be collected at selected sites for pharmacokinetic analysis. The sampling 
times will be presented in a by-subject listing only. A population PK analysis will be 
performed based on a separate analysis plan after samples from all phase 3 studies are 
collected and bexagliflozin plasma concentrations determined. 
Biomarker samples will be collected.  A biomarker analysis will be performed separately.  
The results will not be included in the THR-1442-C-476 study report. 


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9.8 
Interim Analysis 
No interim analysis will be performed for efficacy assessment and the study will not be 
stopped for futility or overwhelming benefit of bexagliflozin treatment. 


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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 will be submitted to the IRB/IEC 
for review and must be approved by the sponsor and the IRB/IEC before the study is 
initiated. Any amendments or addenda to the protocol must also be approved by the IRB/IEC 
prior to implementing changes in the study. The investigator is responsible for keeping the 
IRB/IEC informed of the progress of the study and of any changes made to the protocol as 
deemed appropriate, but in any case at least once a year. The investigator must also keep the 
IRB/IEC informed of any SAEs occurring to subjects under their supervision. 
10.3 Ethical Conduct of the Study 
The procedures set out in this protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the sponsor and investigator follow 
Good Clinical Practice (GCP) Guidelines and the guiding principles detailed in the 
Declaration of Helsinki. The study will also be carried out in keeping with applicable local 
laws and regulations. An inspection by the sponsor representatives and/or their designee 
and/or other authorized regulatory authorities representatives may occur at any time. The 
investigator must agree to the inspection of study-related records by the regulatory 
authority/sponsor representatives, and must allow direct access to source documents to the 
regulatory authority/sponsor representatives. 
The investigator is responsible for complying with the protocol and all appropriate 
regulations and guidelines governing global clinical research. Additionally, he/she is 
responsible for ensuring that all participating staff members are adequately trained and 
competent to perform his/her assigned tasks. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator may implement a 
deviation from or a change of the protocol to eliminate any immediate hazards to the trial 
subjects without prior IRB/IEC or sponsor approval/favorable opinion. As soon as possible, 
the implemented deviation or change, the reasons for it, and if appropriate, the proposed 
protocol amendment should be submitted to the IRB/IEC and sponsor. 


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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 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 and the 
ICH GCP Guidelines (E6), in addition to, any other elements required by regulations or 
institutional policy. 
Written informed consent must be obtained before any study-specific procedure takes place. 
Participation in the study and date of informed consent given by the subject should be 
documented appropriately in the subject’s files. A copy of the signed informed consent form 
must be provided to the subject. If applicable, it will be provided in a certified translation in 
the language understood by the subject, 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, GCPs, 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 case report form (CRF) in electronic format will be supplied 
and maintained by the sponsor or designated 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 case report form. 
Entries made in the CRF must be verifiable against source documents. Source documents are 
original documents, data, and records, such as hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories 
and at medical/analytical facilities engaged in the course of the clinical trial. 
All CRFs and source documents should be completed following GCP and the Sponsor or its 
designee’s standard operating procedures. 
10.8 Data Monitoring Committee 
An independent DSMB will monitor overall safety information during the bexagliflozin 
development program. The safety review activity and potential risk benefit assessments 
utilized by the DSMB are defined in its charter. 
For protocol THR-1442-C-476, the DSMB will review the unblinded aggregate data 
periodically and may recommend an early termination of the trial for safety reasons. No 
interim analysis will be performed for efficacy assessment and the study will not be stopped 
for futility or overwhelming benefit of bexagliflozin treatment. 
10.9 Cardiovascular Endpoint Committee 
An independent CEC has been established to prospectively adjudicate, in a blinded fashion, 
major cardiovascular events. These events will include CV mortality, MI, stroke, 
hospitalization for HF, acute coronary syndrome, urgent revascularization procedures, and 
possibly other endpoints. The CEC will have access to relevant CRFs, site data, hospital 
records, imaging studies, ECG records, or other laboratory testing results but will remain 
blinded to the subject treatment assignment throughout the entire development program. The 
end point definition is described in a separate CEC Manual of Operation. 
The protocol specific safety and efficacy analyses will be conducted based on the adjudicated 
CV events documented by the CEC. A separate meta-analysis will be performed after all 
controlled phase 2/3 clinical trials are completed and will include all CEC adjudicated end 


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points for the analyses that will be prospectively defined in a meta-analysis plan. The event 
terms determined by the CEC will not be reconciled with the Investigators’ assessment in 
each phase 2/3 study protocol.  
10.10 Protocol Violations/Deviations 
Protocol violations include deviations from the inclusion and exclusion criteria, concomitant 
medication restrictions, and any other protocol requirement that results in a significant added 
risk to the patient or has an impact on the quality of the data collected or the outcome of the 
study. A deviation occurs when there is 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 patient at any added risk or affect the data quality or 
study outcome. Examples of deviations may include common out-of-window visits, a missed 
procedure, 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 major protocol deviations occur, the 
sponsor’s medical monitor must be notified immediately so that a decision about whether to 
keep the subject in the study can be made. 
Only when an emergency occurs that requires a departure from the protocol for an individual 
subject can there be a departure without the sponsor’s pre-approval.  The nature and reasons 
for the protocol deviation will be recorded in the subject’s CRF, and the principal 
investigator must notify the Sponsor. 
10.11 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. 


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10.12 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. 
10.13 Publication and Disclosure Policy 
All data and results and all intellectual-property rights in the data and results derived from 
the study will be the property of 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 Sponsor, Inc. and the investigator.  If results of this 
study are reported in medical journals or at meetings, all subjects’ identities will remain 
confidential. 
The outcome of the study will not be published prior to completion of all pre-market phase 
2/3 clinical trials of bexagliflozin and the completion of the meta-analysis of CV risk 
assessment.  


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Gonzalez-Juanatey, J.R., Harjola, V.P., Jankowska, E.A., et al. (2016). 2016 ESC Guidelines 
for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the 
diagnosis and treatment of acute and chronic heart failure of the European Society of 
Cardiology (ESC). Developed with the special contribution of the Heart Failure Association 
(HFA) of the ESC. European journal of heart failure 18, 891-975. 
Preis, S.R., Hwang, S.J., Coady, S., Pencina, M.J., D'Agostino, R.B., Sr., Savage, P.J., Levy, 
D., and Fox, C.S. (2009). Trends in all-cause and cardiovascular disease mortality among 
women and men with and without diabetes mellitus in the Framingham Heart Study, 1950 to 
2005. Circulation 119, 1728-1735. 
Richards, M., Di Somma, S., Mueller, C., Nowak, R., Peacock, W.F., Ponikowski, P., 
Mockel, M., Hogan, C., Wu, A.H., Clopton, P., et al. (2013). Atrial fibrillation impairs the 
diagnostic performance of cardiac natriuretic peptides in dyspneic patients: results from the 
BACH Study (Biomarkers in ACute Heart Failure). JACC Heart failure 1, 192-199. 
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. 


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Sarwar, N., Gao, P., Seshasai, S.R., Gobin, R., Kaptoge, S., Di Angelantonio, E., Ingelsson, 
E., Lawlor, D.A., Selvin, E., Stampfer, M., et al. (2010). Diabetes mellitus, fasting blood 
glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 
prospective studies. Lancet 375, 2215-2222. 
Scirica, B.M., Bhatt, D.L., Braunwald, E., Steg, P.G., Davidson, J., Hirshberg, B., Ohman, 
P., Frederich, R., Wiviott, S.D., Hoffman, E.B., et al. (2013). Saxagliptin and cardiovascular 
outcomes in patients with type 2 diabetes mellitus. The New England journal of medicine 
369, 1317-1326. 
Scirica, B.M., Braunwald, E., Raz, I., Cavender, M.A., Morrow, D.A., Jarolim, P., Udell, 
J.A., Mosenzon, O., Im, K., Umez-Eronini, A.A., et al. (2014). Heart Failure, Saxagliptin, 
and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial. 
Circulation 130, 1579-1588. 
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 
blood glucose and HbA(1c) levels in db/db mice and prolongs the survival of stroke-prone 
rats. Pharmacol Res 63, 284-293. 
Zhao, Y., Herring, A.H., Zhou, H., Ali, M.W., and Koch, G.G. (2014). A multiple imputation 
method for sensitivity analyses of time-to-event data with possibly informative censoring. 
Journal of biopharmaceutical statistics 24, 229-253. 
Zinman, B., Wanner, C., Lachin, J.M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., 
Devins, T., Johansen, O.E., Woerle, H.J., et al. (2015). Empagliflozin, Cardiovascular 
Outcomes, and Mortality in Type 2 Diabetes. The New England journal of medicine 373, 
2117-2128. 
 
 


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Appendix 1 
Schedule of Events 
A. SCHEDULE OF EVENTS FROM SCREENING TO WEEK 48 
Procedure 
Screening 
Run-in 
Treatment Period 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Time to Randomization Visit (weeks)1 
-2 to -5 
-2 
0 
2 
6 
12 
18 
24 
36 
48 
Type of visit2 
C 
C 
C 
P 
C 
C 
P 
C 
C 
C 
Informed Consent 
X 
 
 
 
Screening for I/E criteria 
X 
 
X 
 
 
Demographics and medical history 
X 
 
 
 
Diet & exercise counseling3 
X 
 
 
Physical exam4 
X 
 
X 
 
 
X 
 
X 
X 
X 
Weight and height5 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
Diary & glucometer record review6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Run-in Medication 
X 
 
 
 
Randomization 
 
X 
 
 
Vital signs 
X 
 
X 
X 
X 
 
X 
X 
X 
ECG 
X 
 
X 
 
 
X 
X 
Dispense study medication7 
 
X 
X 
 
X 
X 
X 
Blood draw for clinical lab test8 
X 
 
X 
 
X 
X 
 
X 
X 
X 
Population PK sampling9 
 
 
 
 
X 
X 
 
 
 
 
Urine collection10 
X 
 
X 
X 
X 
 
X 
X 
X 
AE and potential DKA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Med 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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B. SCHEDULE OF EVENTS AFTER WEEK 48 TO END OF STUDY 
Procedure 
Treatment Period 
Follow Up 
Visit number 
V  11, 13, 15, 17, etc. 
V  12, 14, 16, 18, etc. 
EV 
FU 
Time to Randomization Visit (weeks)1 
60, 84, 108, 132, 156, 
etc. 
72, 96, 120, 144, 168, 
etc. 
End of treatment 
visit 
4 weeks after EV 
Type of Visit2 
P 
C 
C 
C 
Informed Consent 
 
Screening for I/E criteria 
 
Demographics and medical history 
 
Diet & exercise counseling3 
 
Physical exam4 
 
X 
X 
X 
Weight and height5 
 
X 
X 
X 
Diary & glucometer record review6 
X 
X 
X 
X 
Dispense Run-in Medication 
 
Randomization 
 
Vital signs 
 
X 
X 
X 
ECG 
X 
X 
X 
Dispense study medication7 
X 
 
Blood draw for clinical lab test8 
X 
X 
X 
Population PK sampling9 
 
 
 
 
Urine collection10 
X 
X 
X 
AE and potential DKA 
X 
X 
X 
X 
Con Med 
X 
X 
X 
X 


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Footnotes for the Schedules of Events: 
1 
Screening period may last up to 3 weeks (V1 to V2); run-in period is to be 2 weeks (V2); the efficacy assessment period (V3 to V8) will be 24 weeks; the 
total treatment period will be 104 to 156 weeks.  A visit window of ± 3 days is allowed for all visits except visit V3.  Visit V3 is to be scheduled between 13 
and 15 days after visit V2 is complete. Visits V4 and V7 will be phone interviews. 
2 
Visits will be conducted as phone interviews (P) or clinic visits (C). 
3 
Diet and exercise counseling will be performed at V2. 
4 
A complete physical examination will be performed by the investigator at V3 prior to randomization and at the follow up visit (FU).  Abbreviated physical 
examinations will be performed by the investigator at all other time points, unless clinically indicated. During the abbreviated physical examinations, 
general assessment of the skin, heart, lungs and abdomen will be performed.   
5 
Weight will be determined at all clinic visits and height will be determined at screening visit only (V1). 
6 
Glucometer will be dispensed to each enrolled subject at visit V2. Glycemic control diary will be dispensed at visit V3. Subjects will be trained on using 
glucometer and SMBG recording. SMBG record will be reviewed by the investigator at all subsequent visits including both phone interview and clinic 
visits. 
7 
One bottle of the investigational product will be dispensed between V3 and V9.  Two bottles of the investigational product will be dispensed between V10 
and end of treatment visit EV. 
8 
Blood sample collection and laboratory tests at designated visits are listed in Appendix 2.  A minimum fasting time of 10 h must be confirmed prior to 
blood draw. 
9 
PK samples will be drawn in selected subjects in participating trial centers only.  The samples will be drawn during the weeks 6, and 12.   
10 
Urine pregnancy test (UPT) is scheduled for all women at screening and just for WOCBP thereafter. 
 
 


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Appendix 2 
Schedule of Laboratory Tests 
Procedure 
Screening 
Treatment 
Follow up 
Visit Number 
V1 
V3 
V5 
V6 
V8, 9, 10 
V 12, 14, 
16, 18, etc. 
EV 
FU 
Time to Randomization Visit (weeks) 
 
0 
6 
12 
24, 36, 48 
every 24 
weeks 
End of 
treatment 
 
Hematology1 
X 
X 
  
X 
X 
X 
X 
X 
Serum chemistry electrolytes1 
X 
X 
  
X 
X 
X 
X 
X 
Fasting Plasma Glucose1 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c1 
X 
X 
X 
X 
X 
X 
X 
X 
Lipids1, 2 
X 
X 
  
X 
X 
X 
X 
X 
Urinalysis3 
X 
X 
X 
 X 
X 
X 
X 
X 
UACR4 
X 
X 
 
 
X 
X 
X 
 
Infectious disease testing5 
X 
 
  
  
  
  
  
  
Urine pregnancy test (UPT) 6 
X 
 X 
X 
X 
X 
X 
X 
X 
PK sampling7 
 
 
X 
X 
 
 
 
 
Biomarker sampling 
 
X 
 
X 
 
 
 
 
NT-proBNP sampling8 
X 
 
 
 
 
 
 
 
1 
Blood for clinical chemistry and hematology will be drawn after 10 h of fasting prior to breakfast (i.e. only water is allowed).   
2 
LDL-C will be calculated by the Friedewald equation. At screening, the calculated LDL-C value is invalid by this equation and will be set as missing if 
triglycerides are > 400 mg/dL. Direct LDL-C will be determined in subjects whose baseline triglycerides are > 350 mg/dL. All subsequent LDL-C of these 
subjects will be determined by the same direct LDL-C measurements only. 
3 
Urine samples will be collected at all clinic visits. Glucose in the urinalysis results must be suppressed from the laboratory report so the dosing blind can be 
maintained.  Testing strips with only the leucocytes and nitrate will be provided for immediate assessment at the sites. 
4 
UACR will be determined at screening V1, V3, and every 24 weeks until the end of treatment visit is conducted.  
5 
Infectious disease testing will be conducted at screening only. HIV testing will be conducted at screening in Canada. 
6 
UPT will be performed for WOCBP at all clinic visits. For surgically sterile or post- menopausal women, it will only be done at Visit V1. 
7 
Samples for the PK analysis will be drawn at weeks 6 and/or 12 from 240 subjects who consent to the PK study in participating trial centers. 
8 
Samples for NT-proBNP evaluation will be drawn within 1 h of the ECG measurement during the screening (V1) visit for Group 2 subjects with 
undocumented ejection fraction or documented left ventricular ejection fraction (LVEF) > 40%. 


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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 THR1442-C-476 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® 
 
 
 


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Appendix 4 
Congestive Heart Failure Classes 
The New York Heart Association (NYHA) Functional Classification classifies the heart 
failure based on how much the patients are limited during physical activity. 
Table 3. 
NYHA Classification of Heart Failure 
Class 
Functional Capacity:  
How a patient with cardiac disease feels during physical activity 
I 
Patients with cardiac disease but resulting in no limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or 
anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity. They 
are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnea or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be 
present even at rest.  If any physical activity is undertaken, discomfort increases. 
 




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Appendix 6 
Investigator’s Agreement 
Study Title: 
A double blind placebo controlled study to evaluate the effects of 
bexagliflozin on hemoglobin A1c in patients with type 2 diabetes 
and increased risk of cardiovascular adverse events 
Study Number: 
THR-1442-C-476 
Protocol V8.0 Date: 
01 December 2016 
 
I have read the protocol described above. I agree to comply with the International Conference 
on Harmonisation (ICH) Tripartite guideline on Good Clinical Practice (GCP) and all 
applicable regulations and to conduct the study as described in the protocol.  
I agree to ensure that Financial Disclosure Statements will be completed by myself and my 
subinvestigators at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation without 
the prior written consent of Theracos Sub, LLC.  
 
 
Signed: 
 
 
Date:  
 
Clinical Investigator 
 
 


Statistical Analysis Plan  
 
 
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03.007A.02     
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Sponsor Name: 
Theracos Sub, LLC 
Protocol Number and Title: 
 
THR-1442-C-476 A double blind placebo 
controlled study to evaluate the effects of 
bexagliflozin on hemoglobin A1c in patients 
with type 2 diabetes and increased risk of 
cardiovascular adverse events 
Protocol Version and Date: 
Version 8.0, 28 October 2016 
 
 
INC Research Project Code: 
1010225 
Author(s): 
Fang Zhu, Principal Biostatistician 
SAP Version: 
Version 2.0 
SAP Version Date:  
20-Nov-2019 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential property of 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. 


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Revision History 
 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document 
Owner 
Revision Summary 
Version 0.1 
02-Oct-2017 
Fang Zhu 
Initial Release Version 
Version 0.2 
20-Nov-2017 
Fang Zhu 
Update per sponsor comments 
Version 0.3 
15-Dec-2017 
Fang Zhu 
Update per sponsor comments 
Version 1.0 
15-Dec-2017 
Fang Zhu 
Same as above, just update version 
Version 1.1 
30-Aug-2018 
Fang Zhu 
• 
Include additional analysis or summaries 
for subjects who have been prescribed 
insulin or sulfonylurea to control their 
diabetes. 
• 
Update primary analysis for primary 
endpoint using retrieval dropouts 
• 
Change sensitivity analysis of primary 
analysis from jump to reference 
multiple imputations to tipping point 
analysis. 
• 
Change baseline definition for efficacy 
endpoints to be based on first dose of 
study medication to be consistent with 
safety endpoints. Randomization date is 
only used if first dose date is missing. 
Version 1.2 
28-Mar-2019 
Fang Zhu 
• 
Minor correction per comments, e.g. 
model covariates, and other changes to 
make text and shell consistent; 
• 
Removing intensification and relaxation 
adjudication process. Adding definition 
for intensification/relaxation. Unify 
wording of intensification, rescue 
medication; 
• 
Update censoring rule in section 8.2.2.5; 
• 
Update sensitivity analyses for key 
secondary endpoints. 
• 
Update compliance computation for 
unreturned kit. 
• 
Update AE of interest list. 
• 
Adding ECG values inclusion rule. 


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Version # 
Date 
(dd-mmm-yyyy) 
Document 
Owner 
Revision Summary 
Version 1.3 
25-Sep-2019 
Fang Zhu 
• 
Add exploratory endpoints of time to 
hospitalization for a heart failure or a 
cardiovascular death event. 
• 
Add definitions to subsets of subjects 
who have been prescribed insulin and 
subjects who have been prescribed 
sulfonylurea. 
• 
Remove adjudication of rescue 
medication and remove reviewing of 
short course hypoglycemic agent. 
• 
Add rules of intensification of 
hypoglycemic agent related to PRN and 
intensification after relaxation. 
• 
Remove statements that visits after 
Week 48 will not be mapped. 
• 
Remove covariates in multiple 
imputation models based on retrieval 
dropouts due to insufficient number of 
subjects.  
Verion 1.4 
09-Oct-2019 
Fang Zhu 
• 
Update overtime analysis to include all 
post-baseline visits. 
• 
For overtime analysis on HbA1c and FPG, 
use of other hypoglycemic agent is 
added as a covariate. 
• 
Minor updates to wordings and formats. 
Missing abbreviations are added to 
glossary table. 
Version 2.0 
20-Nov-19 
Fang Zhu 
Update DKA analysis to include 
adjudication results. 
 
 




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TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS ............................................................. 9 
2. 
PURPOSE .................................................................................................. 12 
2.1. 
Responsibilities ................................................................................................................. 12 
2.2. 
Timings of Analyses .......................................................................................................... 13 
3. 
STUDY OBJECTIVES ............................................................................... 14 
3.1. 
Primary Objective .............................................................................................................. 14 
3.2. 
Secondary Objectives ....................................................................................................... 14 
3.3. 
Safety Objectives ............................................................................................................... 15 
3.4. 
Other Objectives ................................................................................................................ 15 
3.5. 
Brief Description ................................................................................................................ 15 
3.6. 
Subject Selection ............................................................................................................... 16 
3.6.1. 
Inclusion Criteria ......................................................................................................... 17 
3.6.2. 
Exclusion Criteria ........................................................................................................ 17 
3.7. 
Determination of Sample Size .......................................................................................... 17 
3.8. 
Treatment Assignment & Blinding ................................................................................... 19 
3.8.1. 
Treatment Assignment ................................................................................................ 19 
3.8.2. 
Blinding ........................................................................................................................ 20 
3.9. 
Administration of Study Medication ................................................................................ 20 
3.10. 
Study Procedures and Flowchart ..................................................................................... 21 
4. 
ENDPOINTS .............................................................................................. 27 
4.1. 
Primary Efficacy Endpoint ................................................................................................ 27 
4.2. 
Secondary Efficacy Endpoints ......................................................................................... 27 


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4.3. 
Safety Endpoints ................................................................................................................ 28 
4.4. 
Other Endpoints ................................................................................................................. 28 
5. 
ANALYSIS SETS ....................................................................................... 29 
5.1. 
Screened Analysis Set ...................................................................................................... 29 
5.2. 
Safety Analysis Set ............................................................................................................ 29 
5.3. 
Intention-to-Treat Analysis Set ......................................................................................... 29 
5.4. 
Per Protocol Analysis Set ................................................................................................. 29 
5.5. 
Protocol Deviations ........................................................................................................... 29 
5.6. 
Subsets ............................................................................................................................... 30 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ............................ 31 
6.1. 
General Methods ................................................................................................................ 31 
6.2. 
Key Definitions ................................................................................................................... 31 
6.2.1. 
Baseline Values .......................................................................................................... 31 
6.2.2. 
First Dose Date ........................................................................................................... 31 
6.2.3. 
Study Day .................................................................................................................... 32 
6.2.4. 
Duration ....................................................................................................................... 32 
6.2.5. 
End of Study ................................................................................................................ 32 
6.2.6. 
Patient Years ............................................................................................................... 32 
6.2.7. 
Intensification of Hypoglycemic Agent Use ................................................................. 32 
6.2.8. 
Relaxation of Hypoglycemic Agent Use ...................................................................... 33 
6.3. 
Missing Data ....................................................................................................................... 33 
6.4. 
Analysis Visit Windows ..................................................................................................... 33 
6.5. 
Pooling of Centers ............................................................................................................. 34 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ....................................................................................................... 35 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 35 
7.2. 
Subject Eligibility and Protocol Deviations .................................................................... 35 
7.3. 
Demographic and Other Baseline Characteristics ......................................................... 35 


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7.4. 
Medical History .................................................................................................................. 36 
7.5. 
Medication .......................................................................................................................... 36 
7.5.1. 
Prior Medication .......................................................................................................... 37 
7.5.2. 
Concomitant Medication .............................................................................................. 37 
8. 
EFFICACY ................................................................................................. 38 
8.1. 
Primary Efficacy Endpoint and Analysis ......................................................................... 38 
8.1.1. 
Primary Efficacy Analysis ............................................................................................ 38 
8.1.2. 
Sensitivity Analyses .................................................................................................... 40 
8.1.3. 
Subgroups ................................................................................................................... 41 
8.2. 
Secondary Efficacy Endpoint(s) and Analyses .............................................................. 41 
8.2.1. 
Key secondary efficacy endpoints and analyses ........................................................ 42 
8.2.2. 
Exploratory secondary efficacy endpoints and analyses ............................................ 44 
9. 
SAFETY ..................................................................................................... 47 
9.1. 
Extent of Exposure ............................................................................................................ 48 
9.2. 
Treatment Compliance ...................................................................................................... 48 
9.3. 
Adverse Events .................................................................................................................. 49 
9.3.1. 
Derived Data ............................................................................................................... 49 
9.3.2. 
Data Summarization .................................................................................................... 50 
9.3.3. 
AE of Special Interest .................................................................................................. 51 
9.4. 
Laboratory Evaluations ..................................................................................................... 54 
9.5. 
Vital Signs ........................................................................................................................... 57 
9.6. 
Electrocardiogram ............................................................................................................. 57 
10. 
INTERIM ANALYSES ................................................................................ 59 
11. 
DATA AND SAFETY MONITORING BOARD ........................................... 60 
12. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ......................... 61 
13. 
REFERENCE LIST .................................................................................... 62 
14. 
PROGRAMMING CONSIDERATIONS ...................................................... 63 


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14.1. 
General Considerations .................................................................................................... 64 
14.2. 
Table, Listing, and Figure Format .................................................................................... 64 
14.2.1. 
General ........................................................................................................................ 64 
14.2.2. 
Headers ....................................................................................................................... 64 
14.2.3. 
Display Titles ............................................................................................................... 65 
14.2.4. 
Column Headers ......................................................................................................... 65 
14.2.5. 
Body of the Data Display ............................................................................................. 65 
14.2.6. 
Footnotes .................................................................................................................... 68 
15. 
QUALITY CONTROL ................................................................................. 69 
 
 


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


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Abbreviation 
Description 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IP 
Investigational Product 
ITT 
Intention to Treat 
IVRS 
Interactive Voice Randomization System 
IWRS 
Interactive Web Randomization System 
LDL-C  
Low Density Lipoprotein Cholesterol  
LOCF  
Last Observation Carried Forward  
LVEF 
Left ventricular ejection fraction 
MACE  
Major Adverse Cardiovascular Event  
MCH  
Mean Cell Hemoglobin  
MCHC  
Mean Cell Hematocrit  
MCV  
Mean Cell Volume  
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram  
MI 
Multiple Imputation  
Min 
Minimum 
mL 
Milliliter 
MMRM 
Mixed Model Repeated Measures 
N/A 
Not Applicable 
Na 
Sodium 
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 
PRN 
pro re nata 
PT 
Preferred Term 


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


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives. The current SAP is based on protocol version 8.0. 
2.1. 
RESPONSIBILITIES 
Theracos has designed the study protocol and is responsible for the conduct of the 
study. Covance is responsible for the development and validation of a clinical database 
using the MediData RAVE platform.  
INC Research will perform the statistical analyses and is responsible for the production 
and quality control of all tables, figures and listings. 
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 report, consisting of the information reported in the SAE forms, subject 
characteristics documented in the case report forms, and additional source data such as 
a hospital discharge summary, is recorded in a validated ARGUS database which is 
managed by Covance. Any discrepancies in critical data fields of each SAE report will be 
reconciled between the AUGUS and THR-1442-C-476 clinical databases prior to database 
lock. The SAE coding, analyses and summaries will be based on the final study data 
recorded in the clinical database. Theracos will perform a review of all tables, figures 
and listings before final acceptance. 
An independent Cardiovascular Endpoint Committee (CEC) has been established to 
prospectively adjudicate, in a blinded fashion, suspected cardiovascular events. All 
suspected major adverse cardiovascular events (MACE) reports should also be captured 
as SAEs and every effort will be made to ensure that events recorded as suspected 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 study investigators.  
The independent CEC will receive and adjudicate the following types of events: 
• All deaths 
• Suspected non-fatal myocardial infarction 
• Suspected hospitalization for unstable angina (HUA) 
• Suspected transient ischemic attack (TIA) and stroke 
• Suspected hospitalization for HF (HF) 
• Reported coronary revascularization procedures 


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For study THR-1442-C-476, MACE+ is defined as adjudicated cardiovascular death, non-
fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina. 
An independent DKA adjudicator is to review, in a blinded fashion, all suspected cases 
of acidosis to identify confirmed or probable diabetic ketoacidosis (DKA) according to 
prespecified DKA case definitions. 
2.2. 
TIMINGS OF ANALYSES 
The final analysis of safety and efficacy is planned to be conducted when (i) all 
randomized subjects have either completed at least 52 weeks of treatment or 
withdrawn from the study, and (ii) at least 134 subjects have an adjudicated MACE+ 
event confirmed by the CEC. 
 
 


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3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
To evaluate the placebo-adjusted change in hemoglobin A1c (HbA1c) from baseline after 
24 weeks of exposure to bexagliflozin in type 2 diabetic subjects with increased risk of 
cardiovascular adverse events. 
3.2. 
SECONDARY OBJECTIVES 
The key secondary efficacy objectives of this study are: 
• 
To evaluate the effect of bexagliflozin compared to placebo on the change in 
HbA1c from baseline to week 24 in randomized subjects who have been 
prescribed insulin to control their diabetes; 
• 
To evaluate the effect of bexagliflozin on the change in body weight from 
baseline to week 48 in randomized subjects with a BMI ≥ 25 kg m-2 compared to 
placebo; 
• 
To evaluate the effect of bexagliflozin on the change in systolic blood pressure 
(SBP) from baseline to week 24 in subjects with baseline systolic blood pressure 
≥ 140 mm Hg compared to placebo. 
The other exploratory secondary efficacy objectives are: 
• 
To assess the effect of bexagliflozin treatment on the change in HbA1c versus 
placebo over time; 
• 
To evaluate the effect of bexagliflozin treatment on the change in fasting 
plasma glucose (FPG) versus placebo over time; 
• 
To measure the proportion of subjects requiring an intensification of anti-
diabetic regimen versus placebo over time; 
• 
To measure the proportion of subjects requiring a relaxation of their anti-
diabetic regimen versus placebo over time; 
• 
To measure the incidence of hospitalization for heart failure among all subjects 
and among subjects with a history of heart failure at baseline; 
• 
To compare the time to hospitalization for a heart failure event or a 
cardiovascular death;  


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• 
To assess the effect of bexagliflozin compared to placebo on the change in HbA1c 
from baseline to week 24 in randomized subjects who have been prescribed 
sulfonylurea without insulin to control their diabetes. 
3.3. 
SAFETY OBJECTIVES 
• 
To contribute at least 134 subjects who have experienced at least one 
adjudicated major adverse cardiovascular events (MACE+) to an eventual meta-
analysis that is intended to exclude a hazard ratio of 1.8 or greater for subjects 
exposed to bexagliflozin compared to subjects exposed to placebo/comparator. 
MACE+ is defined as cardiovascular death, non-fatal myocardial infarction, non-
fatal stroke, or hospitalization for unstable angina. 
• 
To evaluate the safety of exposure to bexagliflozin for a minimum of 52 weeks in 
a treatment population that is at elevated risk for major adverse cardiovascular 
events. 
3.4. 
OTHER OBJECTIVES 
• 
Measurement of bexagliflozin plasma concentration as a function of time from 
dosing (sparsely sampled) will be conducted at 30 sites and will include 
approximately 240 subjects. 
• 
Measurement of cardiovascular biomarkers at baseline and at week 12 will be 
performed in an exploratory study of the bexagliflozin treatment effect on 
biomarkers that are relevant to cardiovascular (CV) disease diagnosis and 
prognosis. 
3.5. 
BRIEF DESCRIPTION 
THR-1442-C-476 is a multi-center, randomized, double-blind, placebo-controlled, parallel 
group study. Approximately 1650 subjects with sub-optimally controlled type 2 diabetes 
mellitus (T2DM) and at high risk of CV adverse events will be randomized to bexagliflozin 
tablets, 20 mg, or placebo in a ratio of 2:1 in addition to the background anti-diabetic 
medications. 
Potential participants with suboptimal glycemic control (HbA1c between 7.0 % and 11 %) 
despite treatment as recommended in local guidelines and at high risk of cardiovascular 
adverse events will enter a screening period of up to 3 weeks. Qualified participants will 
enter a single-blind, placebo run-in period to allow for diabetes education and 
optimization of compliance with diet and exercise recommendations. Qualified subjects 
will continue their pre-screening regimen for glycemic control and will be instructed to 
take the run-in medication once daily for 13 ± 2 days. Adjustment of treatment for 
hypertension or dyslipidemia will not be permitted during the screening and run-in periods 


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although initiation of anti-coagulant therapy (if clinically indicated) will be permitted. If 
a change in treatment is required to improve management of hypertension or 
dyslipidemia, the subject may re-enter the screening after the clinical condition and 
treatment regimen have not changed for at least 4 weeks. Subjects who continue to 
qualify for the study and who have demonstrated compliance by missing no more than 1 
dose of the run-in doses as instructed will be randomized to receive the investigational 
product. 
Assignment to treatment arms will be stratified by baseline HbA1c (> or ≤ 9.5%), baseline 
eGFR (eGFR ≥ or < 60 mL min-1 per 1.73 m2), baseline BMI (≥ or < 25 kg m-2) and history of 
heart failure. The study subjects will visit the clinic or complete phone interviews for 
evaluation at 2, 6, 12, 18, 24, 36 and 48 weeks post-randomization with subsequent visits 
scheduled every 24 weeks and a phone interview at 12 weeks after each clinic visit. The 
study duration will be determined by event accumulation. The treatment period will end 
when all randomized subjects have completed at least 52 weeks of treatment and a total 
of 134 subjects have experienced a MACE+. A follow-up visit will take place 4 weeks after 
the conclusion of treatment. 
3.6. 
SUBJECT SELECTION 
The study population will include subjects who have been diagnosed with sub-optimally 
controlled T2DM and who exhibit an elevated risk of cardiovascular events. Subjects with 
either established cardiovascular disease or with multiple cardiovascular risk factors (but 
no documented cardiovascular disease) and having the following attributes will be 
included: 
Group 1: A history of atherosclerotic vascular disease as defined by one or more of the 
following: a) myocardial infarction or ischemic (non-hemorrhagic) stroke > 3 months but 
≤ 5 years prior to screening or b) documented history of coronary, carotid, or peripheral 
arterial revascularization (coronary artery bypass grafting must have occurred ≥ 5 years 
prior to screening) 
Group 2: A history of NYHA class II or class III heart failure (Appendix 4 of the protocol) 
at the time of screening. A history of heart failure is defined as: 
• 
documented left ventricular ejection fraction (LVEF) ≤ 40% and no subsequent 
LVEF > 40% within 6 months of screening, or 
• 
(i) an NT-proBNP >300 pg mL-1 and no evidence of atrial fibrillation/flutter (AF) 
at the time of the screening ECG or an NT-proBNP >900 pg mL-1 and evidence of 
AF at the time of the screening ECG and (ii) either (a) structural heart disease 
documented by report of left atrial enlargement or left ventricular hypertrophy, 
or (b) exhibiting symptom(s) of HF requiring treatment with diuretic(s) for at 
least 30 days prior to screening. 


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Group 3: Age ≥ 55 years with 2 or more of the following: 
a. diabetes duration of ≥ 10 years, 
b. uncontrolled hypertension defined as SBP > 140 mm Hg despite 3 or more 
anti-hypertensive medications, 
c. current smoking, 
d. urine albumin: creatinine ratio (UACR) > 30 mg g-1, 
e. eGFR of 45 to 60 mL min-1 per 1.73 m2, or 
f. HDL < 1 mmol L-1 (38 mg dL-1) 
To ensure that subjects with various cardiovascular risks are adequately represented, a 
minimum of 352 subjects (21%) from each of the three groups will be recruited and ≤ 400 
subjects who have a history of heart failure will be randomized in the study. 
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 
The sample size is based on the required number of MACE+ for the program wide meta-
analysis of bexagliflozin cardiovascular safety assessment, in which non-inferiority of 
bexagliflozin to control will be formally assessed by a hazard ratio analysis. There will be 
no formal non-inferiority statistical testing of MACE+ rate; the only primary endpoint is 
the change in HbA1c from baseline to Week 24. 
The following are the assumptions to have an adequate number of events to appropriately 
power the meta-analysis: 
1. Enrollment will take 1 year. 
2. Every subject is followed for a minimum of 1 years and a maximum of 3 years, except 
for premature withdrawals. 
3. The annual premature withdrawal rate is 6.5%. 
4. The randomization ratio is 2:1 (bexagliflozin vs. placebo). 
5. The primary analysis is non-inferiority of treatment vs. placebo from a hazard ratio 
perspective over a 3 year period, using a non-inferiority margin of 1.8 for MACE+. 
6. A one-sided 0.025 level of significance will be used to assess non-inferiority. 
7. Non-inferiority to placebo for MACE + will be assessed by comparing the upper limit of 


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a one-sided 97.5% CI of the hazard ratio (treatment vs. placebo) to a margin of 1.8; the 
hazard ratio will be calculated from Cox proportional hazards regression. 
8. The actual hazard ratio is an equivalence hazard ratio of 1.00 and the reference group 
monthly hazard rate is 0.00308. 
Under the above assumptions, the observation of 134 events across 1650 randomized 
patients (1100 active and 550 placebo) yields 87% power to detect non-inferiority of 
experimental treatment compared to placebo with respect to MACE+. If the study accrues 
134 MACE+ events before every subject has either been exposed to investigational product 
for at least 52 weeks or withdrawn from the study, the study will continue until all 
subjects either complete the minimum 52 week course of exposure or withdraw. 
If the true hazard ratio is 0.9, the power to claim non-inferiority increases to 93%. This 
should yield sufficient power for the program-wide meta-analysis (in which all 
experimental dose groups will be pooled and considered as one treatment arm), since the 
number of program-wide events will be greater than the number in study THR-1442-C-
476, and since the ratio of the treatment population size to the placebo population size 
will remain approximately 2:1 across the meta-analysis. 
To determine the sample size of THR-1442-C-476 study, the event rates were estimated 
based on a published cardiovascular outcome study (SAVOR; Scirica et al., 2013; Scirica 
et al., 2014a). In the SAVOR study, subjects with T2DM with a baseline HbA1c of 6.5% to 
12.0%, and either a history of established cardiovascular disease or multiple risk factors 
for vascular disease were included. The estimated 2 year event rate of the placebo group 
was 7.2%. Assuming a similar event rate in the THR-1442-C-476 study, a sample size of 
1650 is anticipated to provide 134 MACE+ within a treatment duration of between 2 and 
3 years. The estimated numbers of MACE+ based on the heart failure background are 
shown in Table 1. The projected number of CV deaths from subjects with an HF history 
is anticipated to be ≤50% of the total CV deaths. 
Table 1 Estimated Event Rates in Patients with Cardiovascular Risks1 
Event rate in 2 years  
No prior 
HF (%)  
Prior 
HF (%)  
From 1250 
non-HF  
From 400 
HF  
Total of 
1650 
subjects  
Mortality  
3.5%  
8.8%  
44  
35  
79  
CV death  
2.3%  
7.3%  
29  
29  
58  
Myocardial infarction 
3.2%  
4.5%  
40  
18  
58  
Stroke  
1.0%  
16  
 
16  
Hospital. for HF  
1.7%  
10.2%  
21  
41  
62  
Hospital. for unstable 
angina  
1.0%  
16  
 
16  
1 Event rate is based on the rate observed for the placebo group in the SAVOR study (Scirica et 
al., 2013; Scirica etal., 2014a) 


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The estimated sample size of 1650 in a 2:1 active to placebo ratio yields 90% power to 
detect a treatment effect of 0.22% in HbA1c reduction assuming the SD is 1.1% and HbA1c 
values from all subjects will be used for the primary efficacy analysis. 
For the key secondary objective to measure change in HbA1c from baseline to week 24 in 
randomized subjects who have been prescribed insulin to control their diabetes, it is 
anticipated that approximately 50% of the randomized subjects will have been prescribed 
insulin to manage their disease. For this key secondary endpoint, a sample size of 800 
subjects will yield >90% power to detect a treatment effect of 0.3% assuming the SD is 
1.1% for a superiority testing at one sided significance level of 0.025. 
3.8. 
TREATMENT ASSIGNMENT & BLINDING 
3.8.1. 
Treatment Assignment 
Potential study subjects will be screened and assigned a subject number. Once all 
screening procedures are completed and the study eligibility is confirmed by the 
investigator, the randomization numbers will be allocated to subjects within the 
appropriate treatment arm by the randomization system. Once a screening or 
randomization number has been assigned, it will never be re-used. No subjects will be 
randomized into the study more than once. If a randomization number has been 
allocated incorrectly, no attempt will be made to remedy the error once study 
medication has been dispensed. The subject will continue with the randomization 
number and study medication. The study staff will notify the Sponsor Contact as soon as 
the error is discovered without disclosing the study medication administered. Admission 
of subsequent eligible subjects will continue using the next unallocated number in the 
sequence. 
The study will be conducted at investigative sites in multiple countries and will likely 
involve variable numbers of subjects at each site. Enrollment will be on a competitive 
basis but each site will be capped at 48 subjects per site. Activation of investigational 
sites in each country will be centrally controlled by a centrally managed Interactive Web 
Response system (IWRS). 
Eligible subjects who complete the run-in period and meet all study inclusion/exclusion 
requirements will be randomized in a 2:1 ratio to receive investigational product. 
Subjects will be assigned to treatment arms in sequential order as they qualify for the 
study, using the IWRS. Randomization will be stratified according to baseline HbA1c (≤ 
9.5% or > 9.5% at screening visit), baseline eGFR (eGFR < 60 or ≥ 60 mL min-1 per 1.73 m2at 
screening), BMI (<25 kg m-2 or ≥ 25 kg m-2) and history of heart failure (yes or no). 
Among the 3 groups of subjects based on the baseline CV risks, a minimum of 352 subjects 
(21%) from each of the three groups will be recruited and ≤ 400 subjects who have a 
history of heart failure can be randomized in the study. If a subject has a history of class 


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II or III heart failure, the subject will be allocated to group 2, regardless of any history of 
atherosclerotic vascular disease or additional cardiovascular risk factors. If a subject does 
not have a heart failure history and has a history of atherosclerotic vascular disease, the 
subject will be allocated to group 1 regardless of other cardiovascular risks. Subject status 
with respect to group assignment criteria will be recorded on the CRF and group 
assignment will be stored in the IWRS. The final group assignment used in the summary 
or analysis will be primarily based on data captured in the IWRS. Subjects will be 
considered as CV risk group 2 if subject is assigned to group 2 on IWRS or satisfied group 
2 criteria on CRF. Otherwise, CV risk group will be determined based on the assignment 
by IWRS.  
3.8.2. 
Blinding 
This is a double-blind placebo-controlled study. The sponsor, investigators, study 
coordinators, pharmacists, study subjects, and the CEC and DKA adjudication committee 
members will be blinded to the composition of the investigational product. Upon 
randomization, each subject will receive a subject randomization number and a drug kit 
assigned to the subject. To maintain blinding of the individual treatment assignments, 
central laboratory glucose urinalysis data will not be made available to any study 
personnel or subjects. 
If knowledge of the investigational product ingredients is needed to manage the 
subject’s condition, the investigator will contact the IWRS to obtain the treatment 
assignment. If unblinding occurs for any reason, the time and reason for breaking the 
blind will be recorded on the case report form (CRF) and the sponsor must be notified 
within 24 h. 
A designated statistician who is not involved in 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 cardiovascular 
endpoint committee (CEC) members until all investigational studies contributing to the 
MACE+ meta-analysis are completed and the meta-analysis has been conducted. 
3.9. 
ADMINISTRATION OF STUDY MEDICATION 
The following investigational products (IP) will be used for oral administration: 
• 
Bexagliflozin tablets, 20 mg: tablets containing 20 mg of bexagliflozin 
• 
Bexagliflozin tablets, placebo: tablets containing no bexagliflozin 


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Bexagliflozin tablets, 20 mg or placebo, should be taken in the morning prior to eating 
or drinking. The tablets should be taken with 250 mL of water. 
Dosing with bexagliflozin tablets, 20 mg or placebo, will be based on randomized 
assignment. All study subjects will be instructed to self-administer tablets once daily in 
the morning prior to eating or drinking; the medication should be taken with water. 
There will be no change of dose during the treatment period. 
On the day of each scheduled clinic visit, subjects must fast for a minimum of 10 hours 
prior to the collection of blood samples. During the fasting period, only water will be 
permitted. The investigational product should be administered at the clinic under 
supervision on the day of visit V2 when the run-in drug is dispensed and on the day of 
visit V3 when the double-blind study drug is dispensed. Only one tablet per day should 
be administered. 
3.10. 
STUDY PROCEDURES AND FLOWCHART 
The study activities at each clinic visit are presented in Table 2 and Table 3. The 
schedule of laboratory tests is presented in Table 4. 
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 a minimum 10 hours fast prior to blood draw to 
ensure the FPG and triglycerides values can be accurately determined. If a subject has 
not fasted for 10 hours, the subject must return as soon as can be arranged (within 1 
week) to provide a specimen after proper fasting. Urine samples will be transported to 
the central lab for urinalysis. 


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Table 2 Schedule of Events from Screening to Week 48 
Procedure  
Screening  
Run-in  
Treatment Period  
Visit number  
V1  
V2  
V3  
V4  
V5  
V6  
V7  
V8  
V9  
V10  
Time to Randomization Visit (weeks)1  
-2 to -5  
-2  
0  
2  
6  
12  
18  
24  
36  
48  
Type of visit2  
C  
C  
C  
P  
C  
C  
P  
C  
C  
C  
Informed Consent  
X  
 
 
 
 
 
 
 
 
 
Screening for I/E criteria  
X  
 
X  
 
 
 
 
 
 
 
Demographics and medical history  
X  
 
 
 
 
 
 
 
 
 
Diet & exercise counseling3  
 
X  
 
 
 
 
 
 
 
 
Physical exam4  
X  
 
X  
 
 
X  
 
X  
X  
X  
Weight and height5  
X  
X  
X  
 
X  
X  
 
X  
X  
X  
Diary & glucometer record review6  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
Dispense Run-in Medication  
 
X  
 
 
 
 
 
 
 
 
Randomization  
 
 
X  
 
 
 
 
 
 
 
Vital signs  
X  
 
X  
 
X  
X  
 
X  
X  
X  
ECG  
X  
 
X  
 
 
 
 
X  
 
X  
Dispense study medication7  
 
 
X  
 
 
X  
 
X  
X  
X  
Blood draw for clinical lab test8  
X  
 
X  
 
X  
X  
 
X  
X  
X  
Population PK sampling9  
 
 
 
 
X  
X  
 
 
 
 
Urine collection10  
X  
 
X  
 
X  
X  
 
X  
X  
X  
AE and potential DKA  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
Con Med  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 


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Table 3 Schedule of Events after Week 48 to End of Study 
Procedure  
Treatment Period  
Follow Up  
Visit number  
V 11, 13, 15, 17, etc.  
V 12, 14, 16, 18, etc.  
EV  
FU  
Time to Randomization Visit (weeks)1  
60, 84, 108, 132, 156, 
etc.  
72, 96, 120, 144, 168, 
etc.  
End of treatment 
visit  
4 weeks after EV  
Type of Visit2  
P  
C  
C  
C  
Informed Consent  
 
 
 
 
Screening for I/E criteria  
 
 
 
 
Demographics and medical history  
 
 
 
 
Diet & exercise counseling3  
 
 
 
 
Physical exam4  
 
X  
X  
X  
Weight and height5  
 
X  
X  
X  
Diary & glucometer record review6  
X  
X  
X  
X  
Dispense Run-in Medication  
 
 
 
 
Randomization  
 
 
 
 
Vital signs  
 
X  
X  
X  
ECG  
 
X  
X  
X  
Dispense study medication7  
 
X  
 
 
Blood draw for clinical lab test8  
 
X  
X  
X  
Population PK sampling9  
 
 
 
 
Urine collection10  
 
X  
X  
X  
AE and potential DKA  
X  
X  
X  
X  
Con Med  
X  
X  
X  
X  
 
 
 


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Footnotes for the Schedules of Events: 
1 
Screening period may last up to 3 weeks (V1 to V2); run-in period is to be 2 weeks (V2); the efficacy assessment period (V3 to V8) 
will be 24 weeks; the total treatment period will be 104 to 156 weeks. A visit window of ± 3 days is allowed for all visits except 
visit V3. Visit V3 is to be scheduled between 13 and 15 days after visit V2 is complete. Visits V4 and V7 will be phone interviews. 
2 
Visits will be conducted as phone interviews (P) or clinic visits (C). 
3 
Diet and exercise counseling will be performed at V2. 
4 
A complete physical examination will be performed by the investigator at V3 prior to randomization and at the follow up visit (FU). 
Abbreviated physical examinations will be performed by the investigator at all other time points, unless clinically indicated. During 
the abbreviated physical examinations, general assessment of the skin, heart, lungs and abdomen will be performed. 
5 
Weight will be determined at all clinic visits and height will be determined at screening visit only (V1). 
6 
Glucometer will be dispensed to each enrolled subject at visit V2. Glycemic control diary will be dispensed at visit V3. Subjects will 
be trained on using glucometer and SMBG recording. SMBG record will be reviewed by the investigator at all subsequent visits 
including both phone interview and clinic visits. 
7 
One bottle of the investigational product will be dispensed between V3 and V8. Two bottles of the investigational product will be 
dispensed between V12 and end of treatment visit EV. 
8 
Blood sample collection and laboratory tests at designated visits are listed in Appendix 2 of the protocol. A minimum fasting time 
of 10 h must be confirmed prior to blood draw. 
9 
PK samples will be drawn in selected subjects in participating trial centers only. The samples will be drawn during the weeks 6, 
and 12. 
10 Urine pregnancy test (UPT) is scheduled for all women at screening and just for WOCBP thereafter. 
 
 


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Table 4 Schedule of Laboratory Tests 
Procedure  
Screening  
Treatment  
Follow 
up  
Visit Number  
V1  
V3  
V5  
V6  
V8, 9, 10  
V 12, 14, 
16, 18, 
etc.  
EV  
FU  
Time to Randomization Visit 
(weeks)  
 
0  
6  
12  
24, 36, 48  
every 24 
weeks  
End of 
treatment  
 
Hematology1  
X  
X  
 
X  
X  
X  
X  
X  
Serum chemistry electrolytes1  
X  
X  
 
X  
X  
X  
X  
X  
Fasting Plasma Glucose1  
X  
X  
X  
X  
X  
X  
X  
X  
HbA1c1  
X  
X  
X  
X  
X  
X  
X  
X  
Lipids1, 2  
X  
X  
 
X  
X  
X  
X  
X  
Urinalysis3  
X  
X  
X  
X  
X  
X  
X  
X  
UACR4  
X  
X  
 
 
X  
X  
X  
 
Infectious disease testing5  
X  
 
 
 
 
 
 
 
Urine pregnancy test (UPT) 6  
X  
X  
X  
X  
X  
X  
X  
X  
PK sampling7  
 
 
X  
X  
 
 
 
 
Biomarker sampling  
 
X  
 
X  
 
 
 
 
NT-proBNP sampling8  
X  
 
 
 
 
 
 
 
1 
Blood for clinical chemistry and hematology will be drawn after 10 h of fasting prior to breakfast (i.e. only water is allowed). 
2 
LDL-C will be calculated by the Friedewald equation. At screening, the calculated LDL-C value is invalid by this equation and will 
be set as missing if triglycerides are > 400 mg dL-1. Direct LDL-C will be determined in subjects whose baseline triglycerides are > 
350 mg dL-1. All subsequent LDL-C of these subjects will be determined by the same direct LDL-C measurements only. 
3 
Urine samples will be collected at all clinic visits. Glucose in the urinalysis results must be suppressed from the laboratory report 
so the dosing blind can be maintained. Testing strips with only the leucocytes and nitrate will be provided for immediate 
assessment at the sites. 
4 
UACR will be determined at screening V1, V3, and every 24 weeks until the end of treatment visit is conducted. 
5 
Infectious disease testing will be conducted at screening only. HIV testing will be conducted at screening in Canada. 


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6 
UPT will be performed for WOCBP at all clinic visits. For surgically sterile or post- menopausal women, it will only be done at Visit 
V1. 
7 
Samples for the PK analysis will be drawn at weeks 6 and/or 12 from 240 subjects who consent to the PK study in participating trial 
centers. 
8 
Samples for NT-proBNP evaluation will be drawn within 1 h of the ECG measurement during the screening (V1) visit for Group 2 
subjects with undocumented ejection fraction or documented left ventricular ejection fraction (LVEF) > 40%.


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4. 
ENDPOINTS 
4.1. 
PRIMARY EFFICACY ENDPOINT 
• 
Change in HbA1c from baseline to week 24, compared to placebo 
4.2. 
SECONDARY EFFICACY ENDPOINTS 
The key secondary efficacy endpoints include: 
• 
Change in HbA1c from baseline to week 24 in randomized subjects who have been 
prescribed insulin to control their diabetes 
• 
Change in body weight from baseline to week 48 in subjects with a BMI 
≥ 25 kg m-2  
• 
Change in SBP from baseline to week 24 in subjects with baseline systolic blood 
pressure ≥ 140 mm Hg 
The exploratory secondary efficacy endpoints include: 
• 
Change from baseline in HbA1c over time 
• 
Change from baseline in FPG over time 
• 
Change from baseline in body weight over time 
• 
Change from baseline in SBP over time 
• 
Requirement of additional anti-diabetic medications, including insulin; and time 
to first use of additional anti-diabetic medication 
• 
Requirement of reduced anti-diabetic medications, including insulin dose over 
time; and time to first reduced anti-diabetic medications 
• 
Hospitalization for heart failure in all subjects and in subjects with a history of 
heart failure 
• 
Time to hospitalization for heart failure in subjects in all subjects and in 
subjects with a history of heart failure 
• 
Time to hospitalization for heart failure or cardiovascular death in all subjects 
and in subjects with a history of heart failure 
• 
Change in HbA1c from baseline to week 24 in randomized subjects who have 
been prescribed sulfonylurea without insulin to control their diabetes 


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4.3. 
SAFETY ENDPOINTS  
The key safety endpoints include: 
• 
A 5-point composite endpoint of CV death, non-fatal myocardial infarction, non-
fatal stroke, hospitalization for unstable angina, or coronary revascularization 
• 
A 6-point composite endpoint of CV death, non-fatal myocardial infarction, non-
fatal stroke, hospitalization for unstable angina, coronary revascularization or 
hospitalization for heart failure 
• 
Individual events including all-cause mortality, CV death, fatal and non-fatal 
myocardial infarction, fatal and non-fatal stroke, hospitalization for unstable 
angina, hospitalization for CHF, or coronary revascularization. Both first events 
and total events, taking account of repeat events will be examined 
• 
Change in eGFR from baseline 
• 
Change in UACR from baseline 
• 
Incidence of adverse events of interest. Adverse events of interest including 
urinary tract infections (UTI), pyelonephritis urosepsis, genital mycotic 
infections (GMI), diuretic effects including hypovolemia, hypotension episodes, 
hypoglycemia, hepatotoxicity, fractures, malignancies, hypersensitivity 
reactions, acid-base disorders including diabetic ketoacidosis, rash, renal failure 
events, and amputations  
Other safety endpoints include: 
• 
Adverse events 
• 
Clinical laboratory events 
• 
Physical examinations 
• 
Vital signs including orthostatic blood pressure 
• 
Use of concomitant medications 
4.4. 
OTHER ENDPOINTS  
Samples for population PK analysis will be collected and the plasma concentration of 
bexagliflozin determined. The PK parameters will be assessed separately as part of the 
population PK analysis. Biomarker samples will be collected. The biomarker analysis will 
be performed separately. These analyses will not be discussed in this SAP. 
 


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5. 
ANALYSIS SETS 
5.1. 
SCREENED ANALYSIS SET 
The screened analysis set will include all subjects who have signed the informed 
consent forms and completed the eligibility screening prior to randomization. The 
screened population will consist of both enrolled subjects and subjects who do not meet 
the eligibility criteria. Unless specified otherwise, this population will be used for 
summaries of subject disposition. 
5.2. 
SAFETY ANALYSIS SET 
All subjects who are randomized and take at least one dose of the double-blind IPs will 
be included in the Safety Analysis Set. Safety analyses will be based on the medication 
that was actually dispensed to each subject. This is the primary analysis set for safety. 
If a randomization error causes a subject in the placebo arm to receive active drug 
inadvertently, the subject will be considered exposed to active drug and will be 
analyzed accordingly in the Safety Analysis Set. If a subject in the active arm receives 
placebo inadvertently but receives active drug subsequently, the subject will be 
considered exposed to active drug and will be analyzed accordingly. 
5.3. 
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 by the IWRS. 
5.4. 
PER PROTOCOL ANALYSIS SET  
The Per Protocol (PP) Analysis Set will include all subjects in the ITT who meet the 
study eligibility requirements and have no major protocol deviations that will affect the 
validity of the efficacy measurements. Detailed protocol deviations that may result in 
subject or visit exclusion from the PP Analysis Set are described in Section 5.5. The 
subject assignment to the PP analysis set will be determined prior to database lock. The 
PP Analysis Set will serve as the secondary set for efficacy assessment. 
5.5. 
PROTOCOL DEVIATIONS 
Protocol deviations will be captured during monitoring visits. Major protocol deviations 
that could affect the primary and secondary variables, in the opinion of the medical 
monitor, will be considered when determining a subject’s eligibility for the PP 
population. Table 5 describes some possible types of major protocol deviations. All 
protocol deviations will be reviewed and determined as major or minor before database 
lock. 


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Table 5 
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] 
 
 
 
Dosing Non-Compliance  
 
 
Dosing Non-Compliance 
-Subject missed more than 50% of the 
investigational product doses between 
week 12 and week 24 
Subject exclusion 
 
5.6. 
SUBSETS 
Subsets below will be repeated for selected analyses: 
• 
Subjects who have been prescribed insulin: This subset includes all subjects who 
are taking insulin (ATC class 3 is A10A - INSULINS AND ANALOGUES FOR INJECTION, 
LONG-ACTING) on the day that the subject took the first dose of the study 
medication. This subset will be used in the baseline demographics, analyses of 
primary and key secondary efficacy endpoints, adverse event, clinical lab, and 
vital signs in addition to all subjects. 
• 
Subjects who have been prescribed sulfonylurea: This subset includes all subjects 
who are taking sulfonylurea (ATC class 4 is A10BB – SULFONYLUREAS) and not 
taking insulin on the day that the subject took the first dose of the study 
medication. This subset will be used in the analysis for primary and key secondary 
efficacy endpoints, adverse event, clinical lab, and vital signs in addition to all 
subjects. 
• 
Subjects with a history of heart failure: This subset includes all subjects who 
indicate they had a history of congestive heart failure at screening on CRF 
cardiovascular disease history page. This subset is primarily used in the analyses 
on heart failure related exploratory endpoints. 


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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
The proposed statistical methodology and analyses are in accordance with the principles 
outlined by the ICH E9 guidelines. All statistical analyses will be conducted using SAS 
statistical software version 9.3 or higher.  
Tables, listings and figures (TLFs) will be produced in accordance with the principles 
outlined by the ICH E3 guidelines. For most summary statistics, data will be analyzed by 
the following treatment arms: Bexagliflozin 20 mg and Placebo. All available data from 
subjects who signed an informed consent will be presented in the subject listings.  
Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], Q1, median, Q3, minimum and maximum) for continuous variables, and 
frequency and percentage of subjects for categorical and ordinal variables, unless 
otherwise specified.  
Unless otherwise specified, all statistical tests will be one-tailed using a 0.025 level of 
significance. All confidence intervals (CIs) will be two-sided 95% CIs. 
The analysis visit window will be assigned to data collection. One selected data point 
per visit will appear in summary tables and figures. Refer to section 6.4 for details. All 
visit assessment data will be included in shift tables and will appear in the subject 
listings. 
No data imputation will be applied for missing values, unless otherwise specified.  
6.2. 
KEY DEFINITIONS 
6.2.1. 
Baseline Values 
Baseline is defined as the last non-missing value on or prior to the day of the first dose 
of double-blind study medication.  If the first dose date is missing, the last non-missing 
value on or prior to the randomization date will be used. 
6.2.2. 
First Dose Date 
Two “first dose dates” will be required – one for the Run-In period and one for the 
double-blind treatment period. The first dose date for the Run-In period will be the 
date of administration of the first dose of single-blind placebo tablets during the Run-In 
period. The first dose date for the double-blind treatment period will be the date that 
the first dose of randomized, double-blind study drug is administered. Both first dose 


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dates will be obtained from the eCRF. Study analyses will use the double-blind 
treatment period first dose date.  
6.2.3. 
Study Day 
Study Day is the number of days starting from the first administration of double-blind 
study drug, which is counted as Study Day 1. If the assessment date is after the date of 
the first double-blind study drug, the study day is calculated as date of 
assessment - date of the first dose administration+1. If the assessment date is prior to 
the date of the first double-blind study drug, the study day is calculated as date of 
assessment - date of the first dose administration. 
6.2.4. 
Duration 
Duration of double-blind treatment will be determined as Double-Blind Duration = 
Double-Blind Last Dose Date minus Double-Blind First Dose Date plus 1. Duration of 
Run-In period will be determined as Duration = Last Dose Date in the run-in period 
minus First Dose Date in the run-in period plus 1. 
6.2.5. 
End of Study 
The end of study is defined as the date of final contact as entered on the End of Study 
page of the eCRF. Any missing date of last contact on the End-of-Study eCRF will be 
imputed as the date of last contact recorded in the database.  
6.2.6. 
Patient Years 
Patient years are calculated as sum of the duration from first dose of double-blind 
treatment 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. 
6.2.7. 
Intensification of Hypoglycemic Agent Use 
Intensification of hypoglycemic therapies should be considered if one or more of the 
following: 
1. A new oral hypoglycemic therapy is added to the prior medication. 
2. An increase of dose in any of the prior oral therapies. 
3. A new injectable non-insulin hypoglycemic therapy is added to the prior medication. 
4. An insulin therapy is initiated in addition or in place of oral hypoglycemic therapy 
(ies). 
5. An increase of ≥ 5 units total daily dose of insulin any time during the treatment 
period 
The following scenarios are NOT considered intensification: 
1. A replacement of a sulfonylurea or insulin with an injectable GLP-1 agonist; 


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2. An increase of < 5 unit of insulin total daily dose; 
3. Any increase of the therapy use after the last day of investigational product 
administration; 
4. Insulin dose usage as needed or pro re nata (PRN) will be considered the same dose;  
5. A short course treatment of insulin or other therapies to manage an acute illness.  
6. An intensification after relaxation will not be considered as intensification. 
6.2.8. 
Relaxation of Hypoglycemic Agent Use 
Relaxation of hypoglycemic therapies should be considered if one or more of the 
following: 
1. Stop or decrease dose of one or more oral hypoglycemic therapies occur during the 
double-blind treatment period; 
2. A decrease of ≥ 5 unit total daily dose of insulin any time during the treatment 
period. 
The following scenarios are NOT considered relaxation: 
1. A decrease of hypoglycemic therapies after an intensification of hypoglycemic 
therapy use. 
2. Stopping of a short course of hypoglycemic therapy use. 
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 8.2.2.6.  
6.4. 
ANALYSIS VISIT WINDOWS 
Table 6 shows how data will be mapped to visit number 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 visits, the following rules will apply unless other handling 
is specified for a particular analysis.  
• 
If multiple records are available within a single 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 data will be considered 
missing at that visit. 
Table 6 
Analysis Visit Windows 


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Study Day Window 
Scheduled day  
Scheduled Visit/Week 
Day 1 - 63 
Day 42 
Visit 5/Week 6 
Day 64 – 105 
Day 84 
Visit 6/Week 12 
Day 106 - 147 
Day 126 
Visit 7/Week 18 
Day 148 - 210 
Day 168 
Visit 8/Week 24 
Day 211 - 294 
Day 252 
Visit 9/Week 36 
Day 295 - 420 
Day 336 
Visit 10/Week 48 
Day (xx*7-83) – minimum 
(xx*7+84, End of Treatment 
Visit date) 
Day (xx*7) 
Visit /Week xx, where xx is 
every 24 weeks. 
> End of Treatment Visit 
date + 7 
End of Treatment Visit + 28 
Follow-up Visit 
If there are multiple end of treatment visits, the one closest to the last dose date will 
be used. If multiple records are equidistant from the last dose date, the later one will 
be used. Analysis visit windows will be used for all lab, vital sign, and ECG data. 
6.5. 
POOLING OF CENTERS 
Subjects will not be pooled based on site size, but rather by region, to ensure a 
sufficient number of subjects per treatment arm in both ITT and PP populations for 
analysis that contain region as a model effect. The table below shows which countries 
comprise each of the regions to be used in analysis.  
Region 
Country 
Europe 
Czech Republic 
Denmark 
Netherlands 
Poland 
Russian Federation 
North America 
 
United States 
Canada 
Mexico 
Asia Pacific 
Republic of Korea 
Taiwan, Province of China 
 
 
 


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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition data will be listed. A disposition table will present, by treatment 
arm and overall, the number and/or percentage of subjects who signed the informed 
consent and entered the study (i.e., were screened, screen failed prior to Run-in, 
screen failed during the Run-in, and randomized), completed study drug through week 
24, completed the study drug, withdrew from the study, completed the study, and 
discontinued treatment after randomization. The reasons for early withdrawal after 
randomization will be summarized.  
Attempts will be made to collect vital status information that is allowed by local 
guidelines in subjects who discontinued participation in the study after randomization. 
The number of subjects for whom vital status has been determined will be presented.  
Assignment to the analysis sets (safety, ITT, and PP) will be summarized.  
All dispositions will be summarized for all subjects, subjects who has been prescribed 
insulin or sulfonylurea, and by subgroups: CV risk groups. 
7.2. 
SUBJECT ELIGIBILITY AND PROTOCOL DEVIATIONS 
All subjects, including screen failure subjects, who do not meet the Inclusion/exclusion 
criteria, will be listed. Reasons 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, country of 
investigational site and CV history. Baseline characteristics will include baseline HbA1c, 
baseline HbA1c categories (< 9.5% or ≥ 9.5%), baseline eGFR, baseline eGFR categories (< 
60 or ≥ 60 mL min-1 per 1.73 m2), blood pressure (systolic and diastolic), body weight, 
FPG, stratification factors recorded at screening visit in IWRS: including HbA1c (< 9.5% or 
≥ 9.5%), eGFR (< 60 or ≥ 60 mL min-1 per 1.73 m2), body mass index (BMI < 25 kg m-2 or 
BMI ≥ 25 kg m-2) and history of heart failure (yes or no), cardiovascular risk factors and 
subcategories, and type of hypertensive medication and hypoglycemic agents used by 
ATC class 4. Hypertensive medication includes any medication in ATC level 2 class of 
C02, C07, C08, C09, and C03. For Group 2 subjects, NT-proBNP values will be 


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determined at the screening visit in subjects who consent to participate in the study 
under protocol amendment 8. Ejection fraction is reported for Group 2 subjects. 
Ejection fraction will be summarized for Group 2 subjects.  
 
Summary descriptive statistics by treatment will include counts and percentages for 
discrete variables and means, standard deviations, medians, inter-quartile range (Q1, 
Q3), minimum, and maximum for continuous variables. Subjects’ baseline demographic 
and personal baseline characteristics will be summarized by treatment arm and overall 
for subjects in the safety, ITT, and PP analysis set. Subject age will be the age at date 
of informed consent collected from CRF. Summary for demographics will be repeated 
for region, CV groups, and tables based on safety and ITT analysis set will be repeated 
for insulin use and sulfonylurea use subgroups. 
 
7.4. 
MEDICAL HISTORY 
Significant medical and surgical history, including dates of diagnoses and procedures 
and whether the condition is ongoing, if applicable, will be collected. Each condition 
will be recorded as a verbatim term, date of onset, date resolved, and a checkbox that 
indicates ongoing conditions. Significant surgical and medical history will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1. 
Medical and surgical history will be summarized for the Safety Analysis Set by treatment 
arm, system organ class (SOC), and MedDRA preferred term (PT), overall.  
Subject diabetes and cardiovascular diseases history will be summarized for statistical 
treatment as categorical variables by frequency and percentage, for all subjects and by 
insulin use, sulfonylurea use.  
7.5. 
MEDICATION 
All prescription and over-the-counter medications, including vitamins and herbal 
supplements, that subjects receive during the trial must be documented on the CRF. 
The medication name, dose, frequency, route of administration, date(s) of 
administration and reason for administration must be recorded. This documentation 
should continue through the treatment period and the follow up period. Changes from 
baseline anti-hypertensive therapy and their rationale must be recorded in the CRF.  
All medication will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) version B2Enhanced March 2016. The preferred drug name and 
Anatomical/Therapeutic/ Chemical (ATC) class will be reported for inclusion in the 
database.  


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Medication summaries based on ATC level 2, and the preferred drug names will be 
produced for the Safety Analysis Set. The summaries will present, by treatment arm, 
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 start date and an end date prior to or on the first dose date for 
the double-blind treatment period will be considered a prior medication. 
Prior and concomitant medications will be presented together on a single listing. The 
listing will be ordered by subject number, and medication start/end dates. Prior 
medication will be identified in the listing.   
7.5.2. 
Concomitant Medication 
A concomitant medication is any medication that the subject has taken in any time 
during the study treatment period. In the case of a missing stop date, medication will 
be assumed to be concomitant.  
All medications must be recorded in the CRF medication log.  
Concomitant medications will be presented in a summary table as well as in a subject 
listing.  
 
 


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8. 
EFFICACY 
Efficacy data include HbA1c, FPG, body weight, and blood pressure. All changes from 
baseline will be calculated as the post-treatment value minus the baseline value. All 
continuous efficacy data will be summarized for observed and change values by 
treatment and visit. The proportion of subjects requiring an intensification of anti-
diabetic regimen, proportion of subjects requiring a relaxation of anti-diabetic regimen, 
incidence of and time to hospitalization for heart failure will be summarized by 
frequency, and the proportion by treatment and visit. 
8.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
The primary efficacy hypothesis is that bexagliflozin reduces HbA1c after 24 weeks of 
treatment when compared to placebo. 
8.1.1. 
Primary Efficacy Analysis 
Let μBexagliflozon and μPBO represent the mean changes from baseline in HbA1c at Week 24 
for bexagliflozin and placebo arms, respectively. The following hypotheses will be 
tested: 
H0: μ bexagliflozin - μ placebo ≥ 0 
Ha: μ bexagliflozin - μ placebo < 0 
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 intensification of hypoglycemic agent 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 at least 5 
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 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, region, visit, treatment, 
treatment-by-visit interaction, baseline eGFR categories (<60 or 
≥60 mL min-1  per 1.73 m2), baseline BMI (< or ≥25 kg m-2), and history of heart 
failure (yes or no), insulin use or not, as fixed effects and the corresponding 
baseline HbA1c 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 intensification of hypoglycemic agent 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 arm and all observed visits. The least squares means, differences 
between LS means, a 2-sided 95% confidence interval for each difference, and p-values 
from the model effects up to week 24 visit will be presented. In addition, the observed 
change from baseline for all available visits with standard errors, LS means with 


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standard errors of the change from baseline over time and difference between 
treatment arms with 95% will be presented graphically for the ITT population.  
For supportive analyses, the primary efficacy endpoint will be analyzed with observed 
available data using the PP analysis set in a similar manner as above. 
8.1.2. 
Sensitivity Analyses 
Randomized subjects who withdraw consent to participate in the study will not be 
replaced. The early termination rate is estimated to be 6.5% annually. To the extent 
possible, attempts will be made to minimize the amount of missing data through 
measures planned in the study conduct, but if data are missing for the primary 
endpoints and the first key secondary endpoint (change in HbA1c for subjects who have 
been prescribed insulin), the number, timing, pattern, and reason for the missing value 
will be summarized. The reason for missing values will be evaluated to investigate 
possible implications of missing values for efficacy assessments. The dropout patterns 
will be assessed by Kaplan-Meier plots, if applicable, to assess whether they differ 
between treatment arms. If there are missing values for the primary and key secondary 
analysis, all observed data will be analyzed and data obtained after rescue will not be 
excluded. 
To evaluate the impact from missing data and intensification of hypoglycemic agent, 
the following sensitivity analyses will be conducted: 
1) Tipping point analysis will be conducted. Data after intensification of hypoglycemic 
agent will be considered as missing. Following steps will be followed: 
a. Create monotone missing data as step a in section 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 region, baseline eGFR categories (<60 or 
≥60 mL min-1per 1.73 m2), baseline BMI category (< 25 kg m-2 or 
≥ 25 kg m-2), history of heart failure (yes or no), insulin use or not, 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; 


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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; 
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 
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) Furthermore, data that are missing or after intensification of hypoglycemic agent 
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 will be summarized and analyzed by the following 
subgroups: 
• 
Age (<65 years or ≥65 years) 
• 
Gender (male or female) 
• 
Race (White or Caucasian; Black or African-American; American Indian or Alaska 
native; Asian; Other) 
• 
Baseline HbA1c (>8.5% or ≤ 8.5%) 
• 
Baseline eGFR (<60 or ≥60 mL min-1 per 1.73 m2) 
• 
Subject cardiovascular disease history or risk factors groups (Group 1; Group 2; 
or Group 3) 
• 
Region (Europe, North America, or Asia Pacific) 
8.2. 
SECONDARY EFFICACY ENDPOINT(S) AND ANALYSES 
The key secondary efficacy endpoints include: 
• 
Change in HbA1c from baseline to week 24 in randomized subjects who have 
been prescribed insulin to control their diabetes.  


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• 
Change in body weight from baseline to week 48 in subjects with BMI ≥ 25 kg m-
2  
• 
Change in SBP from baseline to week 24 in subjects with baseline systolic blood 
pressure ≥ 140 mm Hg 
The exploratory efficacy endpoints include: 
• 
Change in HbA1c from baseline to week 24 in randomized subjects who have 
been prescribed sulfonylurea to control their diabetes 
• 
Change from baseline in HbA1c over time 
• 
Change from baseline in FPG over time 
• 
Change from baseline in body weight over time 
• 
Change from baseline in SBP over time 
• 
Requirement of additional anti-diabetic medications, including insulin; and time 
to first use of additional anti-diabetic medication 
• 
Requirement of reduced anti-diabetic medications, including insulin dose over 
time 
• 
Hospitalization for heart failure in all subjects and in subjects with a history of 
heart failure, identified on cardiovascular history CRF page. 
• 
Time to hospitalization for heart failure in all subjects and in subjects with a 
history of heart failure 
• 
Time to hospitalization for heart failure or cardiovascular death in all subjects 
and in subjects with a history of heart failure 
8.2.1. 
Key secondary efficacy endpoints and analyses 
A hierarchical testing procedure will be applied to these endpoints in the sequence of 
key secondary endpoints provided above. These key secondary endpoints will only be 
tested sequentially when significant treatment differences are established for the 
primary efficacy endpoint in the comparisons between the bexagliflozin and placebo 
groups. 
Analysis for key secondary endpoints will be based on the ITT analysis set and repeated 
for the PP analysis set.  
8.2.1.1. 
Change in HbA1c from baseline to week 24 in randomized subjects 
who have been prescribed insulin to control their diabetes 
This will be tested if the primary efficacy endpoint is significant. Change from baseline 
in HbA1c at week 24 will be analyzed using the MMRM ANCOVA model with unstructured 


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covariance assumption. The model will include terms for treatment, baseline eGFR 
categories (<60 or ≥60 mL min-1 per 1.73 m2), baseline BMI (< or ≥25 kg m-2), and history 
of heart failure (yes or no), visit, treatment-by-visit interaction, and region as fixed 
effects and the corresponding baseline HbA1c value as an additional fixed effect 
covariate. Data up to week 24 for subjects who have been prescribed insulin to control 
their diabetes will be used. Treatment comparison p-values and difference at week 24 
will be estimated from the model, with the two-sided 95% CIs of the treatment 
difference also presented. If the model does not converge with the unstructured 
correlation assumption, an autoregressive AR(1) model will be used. If AR(1) does not 
converge, a compound symmetry model will be used. 
Subgroup analysis will be conducted by baseline HbA1c category and baseline eGFR 
categories. 
8.2.1.2. 
Change in body weight from baseline to week 48 in subjects with 
BMI≥ 25 kg m-2 
This will be tested if the primary efficacy endpoint and the key secondary 
endpoint-change from baseline HbA1c, overall and in subjects prescribed with insulin, 
are significantly different between bexagliflozin and placebo groups based on ITT 
analysis set. Change from baseline in body weight at week 48 will be analyzed using the 
MMRM ANCOVA model with unstructured covariance assumption. The model will include 
terms for treatment, visit, treatment-by-visit interaction, baseline HbA1c, region, 
baseline eGFR categories (<60 or ≥60 mL min-1 per 1.73 m2), baseline BMI (< or ≥25 kg m-
2), and history of heart failure (yes or no), insulin use or not as fixed effects and the 
corresponding baseline body weight value as an additional fixed effect covariate. 
Treatment comparison p-values and difference at week 48 will be estimated from the 
model, with the two-sided 95% CIs of the treatment difference also presented. If the 
model does not converge with the unstructured correlation assumption, an 
autoregressive AR(1) model will be used. If the primary hypothesis or treatment effect 
on HbA1c for subjects prescribed with insulin is not significant, the nominal p-value will 
not be used for inferential purposes. Analysis will also be conducted for subjects who 
have been prescribed insulin or sulfonylurea to control their diabetes. 
8.2.1.3. 
Change in SBP from baseline to week 24 in subjects with baseline 
SBP ≥ 140 mm Hg 
This will be tested if the primary efficacy endpoint and the key secondary endpoints – 
change from baseline HbA1c for subjects prescribed with insulin, and change from 
baseline body weight are significant. Change from baseline in sitting SBP at week 24 will 
be analyzed using the MMRM ANCOVA model with unstructured covariance assumption. 
The model will include terms for treatment, region, baseline eGFR categories (<60 or 
≥60 mL min-1 per 1.73 m2), baseline BMI (< or ≥25 kg m-2), and history of heart failure 
(yes or no), insulin use or not, visit, treatment-by-visit interaction, baseline HbA1c as 


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fixed effects and the baseline SBP value as an additional fixed effect covariate. Data 
used for this analysis includes change from baseline in SBP for all visits up to week 24 
and for all subjects with baseline SBP ≥ 140 mm Hg. Treatment comparison p-values and 
difference at week 24 will be estimated from the model, with the two-sided 95% CIs of 
the treatment difference also presented. If the model does not converge with the 
unstructured correlation assumption, an autoregressive AR(1) model will be used. If the 
primary hypothesis on change of HbA1c, treatment effect on HbA1c for subjects 
prescribed with insulin, or change of weight from baseline to week 48 is not significant, 
the nominal p-value will not be used for inferential purposes. Analysis will also be 
conducted for subjects who have been prescribed insulin or sulfonylurea to control their 
diabetes. 
8.2.1.4. 
Sensitivity analysis 
Same sensitivity analysis as described in section 8.1.2 for HbA1c in randomized subjects 
will be used for subjects who have been prescribed insulin to control their diabetes. For 
other secondary analyses of body weight and SBP, 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. Imputation steps include: 
a. Create monotone missing data as step a of section 8.1.1 with 100 imputed 
datasets; 
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 region, 
baseline eGRF (≥ 60 or < 60 mL min-1 [1.73m]-2), baseline BMI (< or ≥25 kg m-2), 
and history of heart failure (yes or no), insulin use or not, baseline HbA1c, 
treatment, and values at all previous time points, including baseline. Values at 
each visit will be imputed sequentially. The first imputed values for subjects in 
bexagliflozin arm will be penalized by the mean improvement of bexagliflozin on 
SBP at week 24 (i.e. the mean change from baseline at week 24) or on body 
weight at week 48 (i.e. the mean change from baseline at week 48). Imputed 
values for subjects in placebo will not be penalized. Imputed values after the 
first missing value will be penalized through regression on first penalized value. 
c. Imputed datasets will be analyzed and results combined as in step c in section 
8.1.1. 
8.2.2. 
Exploratory secondary efficacy endpoints and analyses 
All endpoints in this section are exploratory. No sensitivity analyses and adjustment for 
multiple comparisons will be conducted. Nominal p-values will be used to examine any 
trends in these endpoints.  


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8.2.2.1. 
Change in HbA1c from baseline to week 24 in randomized subjects 
who have been prescribed sulfonylurea to control their diabetes 
Same MMRM ANCOVA model as in section 8.1.1 will be used for this analysis. Analysis 
will be conducted based on ITT and PP analysis set. Same sensitivity analysis as in 
section 8.1.2 will be repeated. Subgroup analysis will be conducted by baseline HbA1c 
category and baseline eGFR categories. 
8.2.2.2. 
Changes from baseline in HbA1c and FPG over time 
Of interest is the difference between treatments on these two endpoints across all 
post-baseline time points with sufficient number of values. If for any treatment arm, 
less than 20 subjects completed the assessment in the analysis visit window, the visit 
will not be included in the analysis. Both endpoints will be analyzed using MMRM model 
with the change from baseline values across all post-baseline visits used as dependent 
variable. The fixed effect will include baseline eGRF (≥ 60 or < 60 mL min-1 [1.73m]-2), 
baseline BMI (< or ≥25 kg m-2), and history of heart failure (yes or no), insulin use or not, 
treatment, visit, treatment and visit interaction, other hypoglycemic agent use (no 
change, after relaxation, or after intensification), treatment and other hypoglycemic 
agent use interaction, and baseline value.  For each endpoint, treatment difference in 
least squares means will be estimated by visit from the model with the corresponding 
p-values and the two-sided 95% CIs of the difference between treatments. 
Analysis of HbA1c over time will also be conducted for subjects who have been 
prescribed insulin or sulfonylurea to control their diabetes. 
8.2.2.3. 
Changes from baseline in SBP and weight over time 
Both endpoints will be analyzed using MMRM model with the change from baseline 
values across all post-baseline visits used as dependent variable. The fixed effect will 
include baseline eGRF (≥ 60 or < 60 mL min-1 [1.73m]-2), baseline BMI (< or ≥25 kg m-2), 
and history of heart failure (yes or no), insulin use or not, treatment, visit, treatment 
and visit interaction, and baseline value.  For each endpoint, treatment difference in 
least squares means will be estimated by visit from the model with the corresponding 
p-values and the two-sided 95% CIs of the difference between treatments. 
8.2.2.4. 
Proportions of subjects with intensification and relaxation of 
hypoglycemic agent (i.e. requirement of additional anti-diabetic 
medications and with requirement of reduced anti-diabetic 
medications)  
These endpoints will be analyzed using logistic regression. The model will include terms 
for treatment, region, baseline eGFR categories (<60 or ≥60 mL min-1 per 1.73 m2 ), 
baseline BMI (< or ≥25 kg m-2), and history of heart failure (yes or no), insulin use or not, 


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and baseline HbA1c. The LS mean proportions and the two-sided 95% CI for each 
treatment will be presented. Also, odds ratio of treatment difference of bexagliflozin 
group over the placebo group will be estimated from the model with the corresponding 
p-values and their two-sided 95% CIs presented. Analysis will also be conducted for 
subjects who have been prescribed insulin or sulfonylurea to control their diabetes. 
8.2.2.5. 
Proportions of subjects with hospitalization of heart failure in all 
subjects, with hospitalization of heart failure in subjects with a 
history of heart failure  
These endpoints will be analyzed using logistic regression. The model will include terms 
for treatment, region, baseline eGFR categories (<60 or ≥60 mL min-1 per 1.73 m2), 
baseline BMI (< or ≥25 kg m-2), history of heart failure (yes or no), insulin use or not, and 
baseline HbA1c. Odds ratios will be estimated from the model with the corresponding 
p-values and their two-sided 95% CIs. The odds ratios of bexagliflozin group over the 
placebo group will be estimated from LS means based on the model with the 
corresponding p-values and their two-sided 95 % CIs presented. 
8.2.2.6. 
Time to first use of intensification or relaxation of hypoglycemic 
agent  
Kaplan-Meier plots will be prepared for these endpoints by treatment. These endpoints 
will be analyzed using Cox proportional hazards models  with treatment, region, 
baseline eGFR categories (<60 or ≥60 mL min-1 per 1.73 m2), baseline BMI (< or ≥25 kg m-
2), history of heart failure (yes or no), insulin use or not, and baseline HbA1c as the 
covariates. Maximum likelihood with ties method of Breslow will be used. The hazard 
ratio of the endpoint, p-value with its two-sided 95% CIs presented. Subjects who 
withdraw from the trial and have post-baseline assessments will be censored at the last 
contact date. Subjects who have no follow-up event data will be censored at the date 
of randomization + 1 day. Analysis will also be conducted for subjects who have been 
prescribed insulin or sulfonylurea to control their diabetes. Time to first intensification 
of hypoglycemic agent will also be conducted for subjects who have been prescribed 
insulin or sulfonylurea to control their diabetes. 
8.2.2.7. 
Time to hospitalization for heart failure and time to cardiovascular 
death or hospitalization for a heart failure event in all subjects and 
in subjects with a history of heart failure 
Same analyses in Section 8.2.2.6 will be conducted. History of heart failure will not be 
used in the analysis model in subjects with a history of heart failure.  
 
 
 


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9. 
SAFETY 
The safety endpoint of the program-wide meta-analysis is the hazard ratio for the time 
to first occurrence of adjusted MACE+. The analysis of this endpoint will not be 
discussed in this SAP.  
The other safety endpoints include: 
• 
Time to a 5-point composite adjudicated endpoint of CV death, non-fatal 
myocardial infarction, non-fatal stroke, hospitalization for unstable angina, 
or coronary revascularization 
• 
Time to a 6-point composite adjudicated endpoint of CV death, non-fatal 
myocardial infarction, non-fatal stroke, hospitalization for unstable angina, 
hospitalization for heart failure, and coronary revascularization; and time to 
onset of event 
• 
Time to individual events including all-cause mortality, CV death, non-fatal 
MI, non-fatal stroke, transient ischemic attack, hospitalization for unstable 
angina, hospitalization for heart failure, and coronary revascularization; and 
time to onset of each event 
• 
Incidence of treatment emergent AEs (TEAEs) of interest 
• 
Incidence of amputations 
• 
Change from baseline in eGFR by study visit 
• 
Change from baseline in UACR by study visit 
Note that analysis for time to event endpoints (ie, first 3 bullets as listed above) will be 
included in a meta analysis plan, and not be included in this SAP. 
Additional safety endpoints will also include: 
• 
Incidence of all TEAEs 
• 
Change from baseline as well as shift in clinical laboratory findings 
• 
Change from baseline in vital signs measurements including orthostatic blood 
pressure 
• 
Incidence of abnormal physical examination findings by body system 
• 
Incidence of concomitant medication use 
The analysis population used for safety analyses will be the Safety Analysis Set. 
 


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9.1. 
EXTENT OF EXPOSURE 
Study drug exposure will include: 
• 
Treatment duration by treatment arm 
• 
Total dose received by treatment arm 
Treatment duration (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.  
Total dose taken will be calculated as number of tablets/capsules dispensed – number 
of tablets/capsules, including all doses for glimepiride, returned. For unreturned 
bottles, if subject has completed the study, all study medications are considered as 
completely taken. If a subject withdrew early, and it is not the last kit dispensed, or if 
2 kits are dispensed and only one is not returned, all medications will be considered as 
completely taken. If a subject withdrew early, and all kits dispensed are the last visit 
are not returned, the number taken is considered as what expected from date of 
dispense to the date of last dose date. Summary statistics for total dose taken will be 
provided by treatment group for the double-blind treatment period. 
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. Summary will also be conducted for subjects who have been prescribed insulin 
or sulfonylurea to control their diabetes. 
9.2. 
TREATMENT COMPLIANCE  
Subjects will be provided with dosing instructions each time study medication is 
dispensed. Subjects will also be instructed to bring their medication with them to every 
visit. During the run-in period, subjects will be considered compliant in investigational 
product administration by missing no more than one dose of run-in medication. Subjects 
who are not compliant during the run-in period will be excluded from randomization. 
At each visit the study staff will review the self-monitored blood glucose (SMBG) 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 double-blind phase is calculated for as follows: 
• 
Percent compliance = (number of tablets taken / number of tablets that should have 
been taken) x 100. 
• 
Number of tablets taken = number of tablets dispensed – number of tablets 
returned. 


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• 
Number of tablets that should have been taken = number of exposure days. 
• 
Number of exposure days = last dose date – first dose date + 1. 
Summary statistics for tablet compliance (%) will be provided by treatment arm for the 
double-blind treatment period. A frequency summary of compliance will also be 
presented with the following categories: < 75%, 75-<100%, 100-120%, and > 120%. 
Summary will also be conducted for subjects who have been prescribed insulin or 
sulfonylurea to control their diabetes. 
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. Any new serious adverse 
event (SAE) reported by the subject to the investigator that occur after the last 
scheduled contact, and are determined by the investigator to be reasonably associated 
with the use of the investigational product, should be reported to the sponsor or 
designated personnel. This may include SAEs that are captured on follow-up telephone 
contact or at any other time point after the defined study period (i.e., up to last 
scheduled contact). The investigator should follow SAEs identified after the last 
scheduled contact until the events are resolved, or the subject is lost to follow-up. The 
investigator should continue to report any significant follow-up information to the 
sponsor until the event has been resolved. This study requires that subjects be actively 
monitored for SAEs for at least 4 weeks after the last treatment.  
For all AEs, preferred AE terms and system organ class (SOC) will be coded using 
terminology from the Medical Dictionary for Regulatory Activities (MedDRA), version 
18.1.  
A treatment-emergent adverse event (TEAE) is defined as an AE that begins after the 
first administration of double-blind study medication or an existing AE that worsens 
after the first dose of double-blind study medication. All reported AEs will be listed, but 
only TEAEs will be summarized in tables.  
Drug-related AEs will be considered those to be possibly, probably and definitely related 
to bexagliflozin administration based on the investigators’ assessment. 
Unless otherwise specified, AEs will be summarized by SOC and PT, with SOCs and PTs 
within SOCs presented in descending order of subject incidence. 
9.3.1. 
Derived Data 
AE onset day is calculated as (date of AE start – date of double-blind first dose + 1). The 
onset day will be missing if the start date is missing or partially missing.  


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9.3.2. 
Data Summarization  
AE summary tables are listed below: 
• 
An overall summary of the number and percentage of subjects reporting any 
TEAEs, serious TEAEs, treatment-related TEAEs, serious treatment-related TEAE, 
any TEAEs leading to treatment discontinuation, any TEAEs leading to subject 
discontinuation and TEAEs leading to death.  
• 
TEAEs overall and by SOC and PT 
• 
TEAEs by severity, overall and by SOC and PT 
• 
Serious TEAEs, overall and by system organ class and preferred term 
• 
TEAEs by relationship to study treatment, overall and by system organ class and 
preferred term 
• 
TEAEs leading to treatment discontinuation, overall and by SOC and PT 
• 
TEAEs leading to study discontinuation, overall and by SOC and PT 
• 
Most common TEAEs. Most common TEAEs are defined as TEAEs that occur in 
> 3% of the subjects in either of the treatment arms.  
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 arm (i.e., the N’s for the 
columns).  
Table below will also be presented for subjects who have been prescribed insulin or 
sulfonylurea to control their diabetes: 
• 
An overall summary of the number and percentage of subjects reporting any 
TEAEs, serious TEAEs, treatment-related TEAEs, serious treatment-related TEAE, 
any TEAEs leading to treatment discontinuation, any TEAEs leading to subject 
discontinuation and TEAEs leading to death.  
• 
TEAEs overall and by SOC and PT 
• 
Serious TEAEs, 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.  


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Listings will be provided for all AEs and the following subsets: 
• 
Serious AEs 
• 
AEs leading to treatment discontinuation 
• 
AEs leading to death.  
AE leading to treatment discontinuation and death will be presented for subjects who 
have been prescribed insulin or sulfonylurea to control their diabetes. 
9.3.3. 
AE of Special Interest 
AEs of special interest include UTI, pyelonephritis urosepsis, GMI, diuretic effects 
including hypovolemia, hypotension episodes, hypoglycemia, hepatotoxicity, 
cardiovascular events, fractures, malignancies, hypersensitivity reactions, acid-base 
disorders including diabetic ketoacidosis (DKA), rash, and renal failure events. These 
AEs of special interest, except for DKA, cardiovascular events and amputations, will be 
prospectively identified based on the MedDRA PTs in the AEs log by a medical expert 
prior to the data base lock and unblinding of the individual subject treatment 
assignment. The list of AEs of special interest will be confirmed in a peer review 
process.  Cardiovascular events and DKA will be adjudicated and the confirmed MACE 
events (See Section 9.3.3.3), and confirmed or possible DKA events (See Section 9.3.3.5) 
will be summarized in the same AE of special interest table. The hypoglycemia events 
by severity, and amputations will be summarized separately. 
9.3.3.1. 
AE of special interest identified by PTs 
The number and percentage of subjects experiencing TEAEs of special interest will be 
summarized for each treatment arm by type of event. The incidence rate of AE of 
special interest per 100 patient years will also be summarized. It will be calculated as 
the total number of AEs / total patient years in specific treatment arm (or total) * 100. 
Each category of events will be displayed in a separate listing. Summary will also be 
conducted for subjects who have been prescribed insulin or sulfonylurea to control their 
diabetes 
9.3.3.2. 
Hypoglycemic Events 
Hypoglycemic event categories include: 
Category 
Description 
Severe 
Assistance required and blood glucose ≤70 mg dL-1 or no value available 
but responded to glucose treatment 
Documented 
Symptomatic 
Blood glucose ≤70 mg dL-1 and typical symptoms of hypoglycemia 
Asymptomatic 
Blood glucose ≤70 mg dL-1 and no typical symptoms of hypoglycemia 


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Category 
Description 
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-1 
 
Although 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 event; 
• 
Severe or documented hypoglycemic events. 
Summary will also be conducted for subjects who have been prescribed insulin or 
sulfonylurea to control their diabetes 
9.3.3.3. 
Cardiovascular Events 
The events of interest include any protocol defined MACE event of cardiovascular 
mortality, non-fatal MI, non-fatal stroke, transient ischemic attack, hospitalization for 
unstable angina, hospitalization for heart failure, and coronary revascularization. 
Cardiovascular events considered as any events under protocol defined MACE event by 
the investigator will be submitted to an independent CEC for adjudication. The number, 
percentage and incidence rate per 100 patient years of the adjudicated MACE will be 
summarized for each treatment arm. Adjudicated MACE will be further summarized by 
PTs. MACE will be summarized in the same table of AE of special interest. 
9.3.3.4. 
Revascularization and Amputations 
Revascularization and amputation information is collected in a separate form. 
Frequency and percentage will be summarized for: 
• 
Type of procedures – cardiovascular-related or amputation 
• 
Subjects with any amputation 
• 
Condition that resulted in amputation 
• 
Location of amputation 
Only procedures performed after the first dose of double-blind study drug will be 
summarized. Summary will also be conducted for subjects who have been prescribed 
insulin or sulfonylurea to control their diabetes. 


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9.3.3.5. 
Diabetic Ketoacidosis  
During the clinical trial period, potential DKA will be monitored by the measurement of 
urinary ketones and assessment for signs or symptoms of acidosis at each clinic visit. 
Clinical presentations or laboratory values that suggest acidosis are to be documented 
in the DKA CRF.  A data package of a suspected DKA case will be provided to the blinded 
DKA adjudicator. A DKA adjudication form will be completed and event assigned to one 
of the 5 categories by the independent DKA adjudicator based on clinical data and 
specified case definitions as outlined below. 
Table 7. 
DKA Case Definitions 
Case Term 
Case Definitions 
Confirmed 
DKA 
• an episode consisting of symptoms of DKA with ketonuria or 
ketonemia, AND 
• with one or more biochemical findings of acidosis, which responds 
to fluid replenishment and, if needed, insulin 
 
Probable DKA 
• an episode consisting of moderate or severe symptoms of DKA, 
which responds to fluid replenishment and, if needed, insulin OR  
• an episode consisting of moderate or severe symptoms of DKA, 
moderate or large ketonuria and/or ketonemia without one or 
more biochemical findings of acidosis, which responds to fluid 
replenishment and/or insulin 
Possible DKA 
• an episode consisting of mild to moderate symptoms of DKA, 
ketosis not measured or ketonuria moderate or less, condition self-
managed, resolves with or without change in diabetic medications; 
OR 
• an episode of 4+ or greater (40 mg/dL or greater) ketonuria with 
mild symptoms of DKA; OR  
• an episode of 5+ or greater (80 mg/dL or greater) ketonuria 
without symptoms of DKA 
 
Unlikely DKA 
• an episode consisting of mild symptoms of DKA with urine ketones 
measured small or negative; or a measurement of moderate (2+) 
or less ketonuria without symptoms 
Indeterminate 
DKA 
• mild to moderate symptoms of DKA without measurement of 
ketosis; self-managed and/or self-resolving 
 


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Additional potential DKA cases may be identified by the adjudicator when reviewing 
serious adverse event listing or programmatically based on AEs of special interest 
preferred term list which includes relevant acidosis terms in the MedDRA dictionary. A 
data package will be generated and submitted to the DKA adjudicator prior to study 
completion and treatment assignment unblinded. All suspected DKA will be presented in 
a by-subject listing. Events adjudicated to be “Confirmed DKA” and “Probable DKA” will 
be summarized in the AEs of special interest table. 
9.4. 
LABORATORY EVALUATIONS 
Laboratory tests will include hematology panel, chemistry panel, serum lipids, and 
urinalysis testing. Hematology, chemistry, serum lipids, and urinalysis will be performed 
at the following time points: at the screening visit (Week –2 to -5), at week 0, 6, 12, 24, 
36, 48 from screening to week 48, at every 24 weeks after week 48 to end of study, at 
end of treatment visit and follow up (4 weeks after end of treatment visit) visit. Renal 
functional testing by UACR will be determined at screening visit (Week –2 to -5), at 
week 0, 24, 36, 48 from screening to week 48, at every 24 weeks after week 48 to end 
of study and end of treatment visit. The study staff will contact each subject prior to a 
scheduled clinic visit to confirm the time of the visit and to remind the subject of 
proper fasting practice. A subject must be queried to assess compliance with an 
approximately 10-hour fast prior to blood draw to ensure the FPG and triglycerides 
values can be accurately determined. If a subject has not fasted for approximately 10 
hours, the subject must return as soon as can be arranged (within 1 week) to provide a 
specimen after proper fasting. A list of laboratory tests is included in Table 8. 
Low density lipoprotein cholesterol (LDL-C) will be calculated by the Friedewald 
equation. Direct LDL-C will be determined in subjects whose triglycerides are 
> 350 mg dL-1 at the screening visit. All subsequent LDL-C of these subjects will be 
determined by direct LDL-C measurements only. The following algorithm will be used to 
obtain LDL-C values for the analyses: 
1. Select subjects (based on the SI unit) who have screening triglycerides >3.4 mM 
or >350 mg dL-1 based on the laboratory value reported  
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 adjudication committee members will remain blinded to the dosing 
assignment.  
The baseline value for all laboratory tests will be the latest value obtained on or 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. 
Observed values (in SI units) and change from baseline over time will be summarized by 
treatment arm. 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. 
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.  
Urine albumin/creatinine ratio (UACR) will be summarized and analyzed separately. 
Descriptive statistics for geometric mean, geometric coefficient of variation (gCV), 
median, Q1, Q3, minimum, and maximum of UACR values will be presented at 
screening, baseline, and all post-baseline scheduled visits for all subjects and for 
baseline macroalbuminuria subjects (>300 mg g-1). UACR data is left-skewed and will be 
natural log transformed first. Change in log transformed UACR from baseline to week 24 
will be analyzed by ANCOVA model. The fixed effect will include region, baseline HbA1c 
level as continuous variable, region, baseline eGFR categories (<60 or 
≥60 mL min-1 per 1.73 m2), baseline BMI (< or ≥25 kg m-2), history of heart failure (yes or 
no), insulin use or not, and treatment. The log transformed baseline values will be used 
as covariate. Analysis will be repeated for baseline macroalbuminuria subjects. LS 
means for each treatment will be estimated at week 24. The adjusted geometric mean 
ratio of relative change from baseline in UACR (the ratio of the week 24 geometric 
mean and baseline geometric mean) and the corresponding two sided 95% CI by 
treatment arm will be calculated as the antilog of the LS mean and 95% CI of log 
transformed values, converted to percentage.  
Biomarker evaluation is an exploratory study that will be analyzed and reported in a 
separate report. The biomarker results will not be included in the subject listing or 
summarized in the THR-1442-C-476 study report. Summary and shift table of 
hematology, summary of urinalysis, and analysis table of UACR will also be conducted 
for subjects who have been prescribed insulin or sulfonylurea to control their diabetes. 
 
 


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Table 8 List of Laboratory Tests 
Test Name 
 
Blood or urine  
Vol. (mL) 
Shipment 
Hematology1  
 
2 (blood)  
Ambient  
Hematocrit (Hct)  
Mean corpuscular volume  
 
 
Hemoglobin (Hgb)  
(MCV)  
 
 
Mean corpuscular hemoglobin (MCH)  Red cell distribution width  
 
 
Mean corpuscular hemoglobin 
concentration  
(RDW)  
 
 
(MCHC)  
Red blood cell (RBC) count  
 
 
Platelet count  
White blood cell (WBC) 
count with differential  
 
 
Serum Chemistry and Electrolytes 
 
5 (serum)  
Ambient  
Albumin (ALB)  
Total protein  
 
 
Alanine aminotransferase (ALT)  
Calcium (Ca)  
 
 
Aspartate aminotransferase (AST)  
Magnesium  
 
 
Alkaline phosphatase (ALK)  
Phosphorus  
 
 
Blood urea nitrogen (BUN)  
Potassium (K)  
 
 
Glucose  
Sodium (Na)  
 
 
Bicarbonate (HCO3)  
Total bilirubin  
 
 
Creatinine  
Direct bilirubin  
 
 
Chloride (Cl)  
Uric acid  
 
 
Glycemic Control 
 
 
Ambient  
Fasting plasma glucose (FPG)  
 
2 (plasma)  
 
Hemoglobin A1c (HbA1c)  
 
2 (blood)  
 
Serum Lipids 1, 2  
 
6 (serum)  
Ambient  
Total cholesterol (TC)  
Low-density lipoprotein  
 
 
High-density lipoprotein cholesterol 
(HDL-C)  
cholesterol (LDL-C),  
 
 
Triglycerides (TG)  
calculated  
 
 
 
LDL-C, direct  
 
 
Urinalysis3  
 
10 (urine)  
Ambient  
Appearance  
Nitrite  
 
 
Bilirubin  
Occult blood  
 
 
Color  
pH  
 
 
Glucose  
Protein  
 
 
Ketones  
Specific gravity  
 
 
Microscopic examination of 
sediment  
Urobilinogen  
 
 
UACR  
Leukocyte esterase  
 
 
Infectious Disease Testing 
 
9 (serum)  
Ambient  
HBsAg  
HCV  
 
 
HIV (Canada only)  
 
 
 
Urine pregnancy test (WOCBP) 
2 (urine)  
Local  
Population PK Sampling 
2 (plasma)  
Frozen  
Bexagliflozin plasma level  
 
 
Biomarker evaluation 
5 (serum)  
Ambient  
NT-proBNP evaluation (select Group 2 subjects) 
5 (serum)  
Ambient  


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9.5. 
VITAL SIGNS  
Vital signs will be measured at the screening visit (Week –2 to -5), at week 0, 6, 12, 24, 
36, 48 from screening to week 48, at every 24 weeks after week 48 to end of study, at 
end of treatment visit and follow up (4 weeks after end of treatment visit) visit. 
Measurements of vital signs will include measurement of supine, sitting and standing 
blood pressure (BP) measurements, and heart rate. Only the BP measured in the sitting 
position will be used to determine eligibility. Orthostatic systolic and diastolic BP will 
be calculated as supine measurement – standing measurement.  
For BP, pulse rate, and respiration rate, observed values and change from baseline will 
be summarized by treatment arm and nominal visit using descriptive statistics (n, mean 
and median, standard deviation, Q1, and Q3, minimum and maximum). For BP, supine, 
sitting, standing, and orthostatic BP will be summarized. Summary will also be conducted 
for subjects who have been prescribed insulin or sulfonylurea to control their diabetes. 
9.6. 
ELECTROCARDIOGRAM  
A 12-lead electrocardiogram (ECG) will be conducted at the screening visit (Week –2 
to -5), at week 0, 6, 12, 24, 36, 48 from screening to week 48, at every 24 weeks after 
week 48 to end of study, at end of treatment visit and follow up (4 weeks after end of 
treatment visit) visit. 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 negative values, 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 treatment arm 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 


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clinically significant, missing) will be presented by treatment arm and overall at each 
visit.  
 


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10. 
INTERIM ANALYSES 
No interim analyses are planned. 


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11. 
DATA AND SAFETY MONITORING BOARD 
An independent data and safety monitoring board (DSMB) will review descriptive 
summaries of accumulating safety, subject disposition and limited efficacy data every 6 
months, or a frequency recommended by the DSMB.  
A designated statistician who is not involved with the study operation will hold the 
treatment codes. The unblinded treatment information can be provided to the DSMB to 
facilitate the evaluation of any clinically important increase in the rate of a serious 
suspected adverse reaction or to the designated safety contact when the treatment 
information is required to determine if an expedited safety report must be submitted to 
regulatory agencies. The data outputs for this review will be created by an unblinded 
team. Personnel involved in the conduct of the study will not participate in the 
preparation of these outputs, receive the data, or participate in the unblinded portions 
of the DSMB meetings. More details will be provided for DSMB charter and DSMB SAP. 


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12. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
In protocol, per protocol Analysis Set will include all subjects in the Full Analysis Set (FAS) 
who meet the study eligibility requirements and have no major protocol deviations that 
will affect the validity of the efficacy measurements. FAS is changed to ITT.  
In all analysis models, randomization stratification factors are used as covariates in the 
protocol. In SAP, baseline eGFR group and continuous baseline HbA1c are used, instead of 
screening eGFR groups and screening HbA1c groups. 
In protocol, primary analysis of the primary endpoint is MMRM using all available data. 
This has been updated to use imputed data based on retrieval dropout subjects.  
Exploratory object below is added: 
• 
To compare the time to hospitalization for a heart failure event or a 
cardiovascular death.  
• 
To assess the effect of bexagliflozin compared to placebo on the change in HbA1c 
from baseline to week 24 in randomized subjects who have been prescribed 
sulfonylurea without insulin to control their diabetes. 
Exploratory endpoint below is added: 
• 
Time to hospitalization for heart failure or cardiovascular death in subjects in all 
subjects and in subjects with a history of heart failure. 
• 
Change in HbA1c from baseline to week 24 in randomized subjects who have 
been prescribed sulfonylurea without insulin to control their diabetes. 
 


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13. 
REFERENCE LIST 
Scirica, B.M., Bhatt, D.L., Braunwald, E., Steg, P.G., Davidson, J., Hirshberg, B., Ohman, 
P., Frederich, R., Wiviott, S.D., Hoffman, E.B., et al. (2013). Saxagliptin and 
cardiovascular outcomes in patients with type 2 diabetes mellitus. The New England 
journal of medicine 369, 1317-1326. 
 
 


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14. 
PROGRAMMING CONSIDERATIONS 
The following conventions will hold for programming of outputs: 
• 
SAS® Version 9.4 or higher will be used for programming and production 
• 
The format of the table shells will be followed as closely as possible; however, in 
the course of programming and familiarization with the database, some changes may 
become necessary. All changes will be documented. Major changes will be documented 
through a formal amendment to this document.  
• 
Patients in this study will be identified as “Subjects.” 
• 
Descriptive statistics will be displayed in the following order: 
n 
Mean 
Standard deviation (SD) 
Q1 
Median 
Q3 
Minimum  
Maximum  
• 
Decimal places: For summary statistics, the minimum and maximum will be 
reported with the same number of decimal places as the collected measure, the mean, 
LS mean (if applicable) and median will have 1 more decimal place than the measure 
collected, and the SD and confidence interval (CI) will have 2 more decimal places than 
the collected measure. For frequency distributions, percentages will be reported to 1 
decimal place. For p-values, 4 decimal places will be reported or the SAS® p-value 
format of “< 0.0001” or “> 0.9999” will be reported.  
• 
Unless otherwise noted, the denominator for percentages is the number of 
subjects in the applicable analysis population and treatment arm.  
• 
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”, “> 10” or “≥ 10”) the numeric portion of the result will be used for summary; the 
actual recorded results, (e.g. “< 10” or “> 10”) will appear in listings. 


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14.1. 
GENERAL CONSIDERATIONS 
• 
A separate SAS program will be created for each output. 
• 
Output files will be delivered in Word format. 
• 
Numbering of TFLs will follow ICH E3 guidance 
 
14.2. 
TABLE, LISTING, AND FIGURE FORMAT 
14.2.1. 
General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size 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-476   
 
• 
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 arm 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 arm 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. 


Statistical Analysis Plan 
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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 arms 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 arm who have an 
observation will be the denominator. Percentages after zero counts should not be 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 2.0 
THR-1442-C-476 
 
1010225 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC                                                          Page 67 of 69 
displayed and percentages equating to 100% should be presented as 100%, without 
any decimal places.  
• 
Tabular display of data for concomitant and intensification of hypoglycemic agent 
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 arm (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 arms 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 


Statistical Analysis Plan 
Theracos Sub, LLC 
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THR-1442-C-476 
 
1010225 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
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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’). 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 2.0 
THR-1442-C-476 
 
1010225 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC                                                          Page 69 of 69 
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.