Clinical trial NCT02769481
Conditions: Type 2 Diabetes Mellitus
Sponsor: Theracos
Start date: 2016-08-15; Completion date: 2019-06-14
Enrollment: 426 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Detailed description:
Approximately 420 subjects with inadequately controlled T2DM on metformin will be recruited from North America and Europe. Subjects will be randomly assigned to receive bexagliflozin tablets, 20 mg, or glimepiride capsules, 2, 4 or 6 mg, in a ratio of 1:1 once daily for 96 weeks. Subjects will continue to take metformin for the duration of the study.

Arms: arm 1: Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride daily for the duration of the study. arm 2: Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study.
Interventions: intervention 1: Bexagliflozin intervention 2: Placebo for Bexagliflozin intervention 3: Glimepiride intervention 4: Placebo for Glimepiride
Intervention descriptions: intervention 1: 20 mg, tablet intervention 2: inactive tablet to match active comparator bexagliflozin intervention 3: 2, 4 or 6 mg, capsule intervention 4: inactive capsules to match active comparator glimepiride

Protocol documents:
Prot_000.pdf: 
 
 
Clinical Trial Protocol: THR-1442-C-480 
Study Title: 
A Phase 3, Randomized, Double-Blind, Active-Controlled Study to 
Evaluate the Effects of Bexagliflozin versus Glimepiride in Subjects 
with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic 
Control by Metformin 
Study Number: 
THR-1442-C-480 
Study Phase: 
3 
Product Name: 
Bexagliflozin Tablets 
Indication: 
Type 2 Diabetes Mellitus 
Investigators: 
Multicenter study 
EudraCT Number: 
2016-002013-21 
IND Number: 
103822 
Sponsor: 
Theracos Sub, LLC 
Sponsor Contact: 
Annie Conery, Ph.D. 
Project Manager 
Translational Medicine Group 
Massachusetts General Hospital  
185 Cambridge Street, Boston, MA 02114 
Phone: 1-617-726-5930 
Fax:  617-643-8203 
E-mail: aconery@mgh.harvard.edu  
Medical Monitor: 
J. Paul Lock, M.D. 
Theracos Sub, LLC 
225 Cedar Hill Road, Suite 200, Marlborough, MA 01752 
Phone: 1-508-735-9491 
Fax: 617-643-8203 
E-mail: jplock@theracos.com 
 
 
Date 
Version 3.0: 
27 October 2016 
 
Confidentiality Statement 
The information in this document is the confidential information of Theracos Sub, LLC 
(“Theracos”) and must not be disclosed, used, or copied except with prior written approval 
from Theracos or to the extent required by applicable laws, rules and regulations. 
 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................13 
1 
INTRODUCTION ...........................................................................................................16 
1.1 
Type 2 Diabetes Mellitus .......................................................................................16 
1.2 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus ...............................17 
2 
STUDY OBJECTIVES ....................................................................................................18 
2.1 
Primary Objective ..................................................................................................18 
2.2 
Key Secondary Objectives .....................................................................................18 
2.3 
Exploratory Objectives ..........................................................................................18 
3 
INVESTIGATIONAL PLAN ..........................................................................................20 
3.1 
Overall Study Design and Plan ..............................................................................20 
3.2 
Rationale for Study Design and Control Group .....................................................20 
3.2.1 
Rationale for Background Medication and Active Comparator ..................20 
3.2.2 
Rationale for the Study Design ....................................................................21 
3.2.3 
Rationale for the Dose Selection..................................................................21 
3.3 
Research Methods and Procedures ........................................................................22 
3.3.1 
Wash-out and Run-in Period ........................................................................22 
3.3.2 
Treatment Period ..........................................................................................23 
3.3.2.1 
Glimepiride Dose Titration ................................................................24 
3.3.3 
Glycemic Control Monitoring......................................................................26 
3.3.3.1 
Wash-out Period and Placebo Run-in Period.....................................26 
3.3.3.2 
Treatment Period ................................................................................26 
3.3.3.3 
Intensification of Medical Therapy for Hyperglycemia ....................27 
3.3.4 
Other Safety Monitoring Activities .............................................................28 
3.3.5 
Data and Safety Monitoring Board (DSMB) ...............................................28 
3.3.6 
Major Adverse Cardiovascular Event (MACE) Adjudication .....................29 
3.3.7 
Diabetic Ketoacidosis (DKA) Event Adjudication ......................................29 
3.4 
Study Duration and Dates ......................................................................................29 
4 
STUDY POPULATION SELECTION ...........................................................................30 
4.1 
Study Population ....................................................................................................30 
4.2 
Inclusion Criteria ...................................................................................................30 
4.3 
Exclusion Criteria ..................................................................................................31 
5 
STUDY TREATMENTS .................................................................................................32 
5.1 
Description of Treatments......................................................................................32 
5.1.1 
Investigational Product ................................................................................32 
5.1.2 
Active Comparator .......................................................................................32 


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5.2 
Treatments Administered .......................................................................................32 
5.2.1 
Investigational Product ................................................................................32 
5.2.2 
Active Comparator .......................................................................................32 
5.2.3 
Background Metformin Therapy .................................................................33 
5.2.4 
Diuretics and Medications for Treatment of Dyslipidemia and 
Hypertension ................................................................................................33 
5.3 
Selection and Timing of Dose for Each Patient .....................................................34 
5.3.1 
Bexagliflozin ................................................................................................34 
5.3.2 
Glimepiride ..................................................................................................34 
5.4 
Method of Assigning Treatment Groups and Study Drugs ...................................34 
5.5 
Blinding..................................................................................................................35 
5.6 
Concomitant Therapy.............................................................................................36 
5.7 
Restrictions ............................................................................................................36 
5.7.1 
Prior Therapy ...............................................................................................36 
5.7.2 
Fluid and Food Intake ..................................................................................36 
5.7.3 
Subject Activity Restrictions .......................................................................37 
5.8 
Treatment Compliance ...........................................................................................37 
5.9 
Packaging and Labeling .........................................................................................37 
5.9.1 
Run-in Kits ...................................................................................................37 
5.9.2 
Bexagliflozin Kit ..........................................................................................37 
5.9.3 
Glimepiride Kit ............................................................................................38 
5.10 
Storage and Accountability ....................................................................................38 
5.11 
Investigational Product Retention at Study Site ....................................................38 
6 
STUDY PROCEDURES .................................................................................................39 
6.1 
Informed Consent...................................................................................................39 
6.2 
Screening for I/E Criteria .......................................................................................39 
6.3 
Medical History .....................................................................................................39 
6.3.1 
General Demographics and Characteristics .................................................39 
6.3.2 
Diabetes History...........................................................................................39 
6.3.3 
Cardiovascular Disease History ...................................................................40 
6.3.4 
Medication History ......................................................................................40 
6.4 
Diet and Exercise Counseling ................................................................................40 
6.5 
Physical Examination.............................................................................................40 
6.6 
Abbreviated Physical Examination ........................................................................40 
6.7 
Vital Signs ..............................................................................................................41 
6.8 
Electrocardiography ...............................................................................................41 
6.9 
Clinical Laboratory Tests .......................................................................................42 
6.9.1 
Laboratory Parameters .................................................................................42 


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6.9.2 
Sample Collection, Storage, and Shipping ..................................................42 
6.9.2.1 
Hematology, Blood Chemistry, Serum Lipids, and Glycemic 
Control Assessments ..........................................................................42 
6.9.2.2 
Urinalysis ...........................................................................................42 
6.9.2.3 
Urine Pregnancy Test (UPT) .............................................................43 
6.10 
Diary and Glucometer Dispensation and Review ..................................................44 
6.11 
Dispensing Run-in Drug ........................................................................................45 
6.12 
Diary and Glucometer Record Review ..................................................................45 
6.13 
Dispensing Investigational Product .......................................................................45 
6.13.1 
Dispensing Bexagliflozin .............................................................................45 
6.13.2 
Dispensing Glimepiride ...............................................................................45 
6.14 
Adverse Events Assessments .................................................................................46 
6.14.1 
Definition of Adverse Events.......................................................................46 
6.14.2 
Eliciting and Reporting AEs ........................................................................47 
6.14.3 
Immediately Reportable AEs .......................................................................48 
6.14.4 
Pregnancy .....................................................................................................48 
6.14.5 
Procedure for Breaking the Blind ................................................................49 
6.14.6 
Follow-up of Non-Serious AEs ...................................................................50 
6.14.7 
Follow-up of Post-Study SAEs ....................................................................50 
6.14.8 
Urinary Tract Infections (UTIs) ...................................................................50 
6.14.9 
Genital Mycotic Infections (GMIs) .............................................................51 
6.14.10 Hepatotoxicity ..............................................................................................51 
6.14.11 Hypoglycemia ..............................................................................................52 
6.14.12 Diabetic Ketoacidosis (DKA) ......................................................................54 
6.14.13 Major Adverse Cardiovascular Event (MACE) ...........................................54 
6.14.14 Amputation ..................................................................................................55 
6.15 
Concomitant Medication Assessments ..................................................................55 
6.16 
Healthy-related Quality of Life Assessment ..........................................................55 
6.17 
Removal of Subjects from the Trial or Discontinuation of Investigational 
Product Administration ..........................................................................................56 
6.18 
Appropriateness of Measurements .........................................................................56 
7 
STUDY ACTIVITIES .....................................................................................................57 
7.1 
Screening Period ....................................................................................................57 
7.1.1 
Visit V1 (3 days to 3 weeks for metformin-only group and up to 9 
weeks for metformin-and-OHA group before run-in period) ......................57 
7.2 
Wash-out and Run-in Period (Up to 8 weeks prior to randomization) ..................57 
7.2.1 
Wash-out Period (Visits V2 and V3) ...........................................................57 
7.2.1.1 
Visit V2 (8 weeks prior to randomization) ........................................58 
7.2.1.2 
Visit V3 (6 weeks prior to randomization, off-site phone visit) ........58 


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7.2.2 
Run-in Period ...............................................................................................58 
7.2.2.1 
Visit V4 (2 weeks prior to randomization) ........................................58 
7.2.2.2 
Visit V5 (3 to 5 days prior to randomization) ....................................58 
7.3 
Treatment Period (Day 1 to Week 96) ...................................................................59 
7.3.1 
Visit V6 (Day 1 of Week 1) .........................................................................59 
7.3.2 
Visit V7 (Week 2) ........................................................................................59 
7.3.3 
Visit V8 (Week 4) ........................................................................................59 
7.3.4 
Visit V9 (Week 6) ........................................................................................59 
7.3.5 
Visit V10 (Week 12) ....................................................................................60 
7.3.6 
Visit V11 (Week 24) ....................................................................................60 
7.3.7 
Visit V12 (Week 36) ....................................................................................60 
7.3.8 
Visit V13 (Week 48) ....................................................................................61 
7.3.9 
Visit V14 (week 60) .....................................................................................61 
7.3.10 
Visit V15 (week 72) .....................................................................................61 
7.3.11 
Visit V16 (week 84, off-site phone visit).....................................................61 
7.3.12 
Visit V17 (end of treatment, week 96) .........................................................62 
7.4 
Visit V18 (Exit Visit or Early Termination Visit) .................................................62 
7.4.1 
Visit V18 (week 98 or two weeks after the last dose of investigational 
product is administered or if a subject withdraws consent) .........................62 
7.5 
Discontinuation of Investigational Product Administration ..................................62 
7.6 
Early Termination Procedures ...............................................................................62 
8 
QUALITY CONTROL AND ASSURANCE .................................................................64 
9 
PLANNED STATISTICAL METHODS ........................................................................65 
9.1 
General Considerations ..........................................................................................65 
9.2 
Determination of Sample Size ...............................................................................65 
9.3 
Analysis Populations ..............................................................................................66 
9.3.1 
Intention-to-Treat Analysis set ....................................................................66 
9.3.2 
Safety Analysis Set ......................................................................................66 
9.3.3 
Per Protocol Analysis Set.............................................................................66 
9.4 
Demographics and Baseline Characteristics ..........................................................66 
9.4.1 
Concomitant Medications ............................................................................67 
9.5 
Primary Efficacy Analyses ....................................................................................67 
9.5.1 
Hypotheses for the Primary Endpoint ..........................................................67 
9.5.2 
Statistical Methods for Primary Analyses....................................................67 
9.5.3 
Analysis of Dropouts Pattern .......................................................................68 
9.6 
Secondary Efficacy Analyses ................................................................................68 
9.7 
Other Efficacy Analyses ........................................................................................69 
9.8 
Analysis of Safety ..................................................................................................69 


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9.8.1 
Adverse Events ............................................................................................69 
9.8.2 
Adverse Events of Special Interest ..............................................................69 
9.8.3 
Clinical and Laboratory Events and Analyses .............................................70 
9.8.4 
Physical Examination...................................................................................70 
9.9 
Health Related Quality of Life Assessment ...........................................................70 
9.10 
Interim Analysis .....................................................................................................70 
9.11 
Final Analysis ........................................................................................................70 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................71 
10.1 
Investigators and Study Administrative Structure .................................................71 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................71 
10.3 
Ethical Conduct of the Study .................................................................................71 
10.4 
Subject Information and Consent...........................................................................72 
10.5 
Subject Confidentiality ..........................................................................................72 
10.6 
Study Monitoring ...................................................................................................72 
10.7 
Case Report Forms and Study Records .................................................................73 
10.8 
Data Monitoring Committee ..................................................................................73 
10.9 
Protocol Violations/Deviations ..............................................................................73 
10.10 Access to Source Documentation ..........................................................................74 
10.11 Retention of Data ...................................................................................................74 
10.12 Publication and Disclosure Policy .........................................................................74 
11 REFERENCE LIST .........................................................................................................75 
LIST OF IN-TEXT TABLES 
Table 1. 
Treatment Groups and Assigned Treatment ................................................24 
Table 2. 
Study Drug Dispensation Schedule .............................................................35 
Table 3. 
List of Laboratory Tests ...............................................................................44 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Study Design ................................................................................................20 
Figure 2. 
HbA1c Requirements Prior to Randomization ............................................23 
Figure 3. 
Glimepiride Dose Up-titration Flow Chart ..................................................26 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................76 
Appendix 2 
Schedule of Clinical Laboratory Tests ...............................................77 
Appendix 3 
Sponsor Signatures.............................................................................78 
Appendix 4 
Investigator’s Signature .....................................................................79 


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SYNOPSIS 
Sponsor: 
Theracos Sub, LLC 
Name of Finished Product: Bexagliflozin Tablets  
Name of Active Ingredient: Bexagliflozin 
Study Title: 
A Phase 3, Randomized, Double-Blind, Active-Controlled Study to Evaluate the Effects of 
Bexagliflozin versus Glimepiride in Subjects with Type 2 Diabetes Mellitus Who Have 
Inadequate Glycemic Control by Metformin  
Study Number: THR-1442-C-480 
Study Phase: 3 
Primary Objective:  
The primary efficacy objective is to demonstrate that bexagliflozin is non-inferior to 
glimepiride by evaluating the treatment effect on hemoglobin A1c (HbA1c) reduction at 
week 60 in subjects whose type 2 diabetes mellitus (T2DM) is inadequately controlled by 
metformin. 
Secondary Objectives: 
The key secondary objectives are: 
• To evaluate the treatment effect of bexagliflozin vs. glimepiride on the change in body 
weight in subjects with baseline body mass index (BMI) ≥ 25 kg/m2 at week 60 
• To evaluate the treatment effect of bexagliflozin vs. glimepiride on the change in systolic 
blood pressure (SBP) in subjects with baseline SBP ≥ 140 mmHg at week 60 
• To evaluate the treatment effect of bexagliflozin vs. glimepiride on the difference in 
proportion of subjects with ≥ 1 severe or documented symptomatic hypoglycemia events 
over 96 weeks 
• To evaluate if bexagliflozin is superior to glimepiride on HbA1c reduction at week 60 
Exploratory Objectives:  
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the change in the 
proportion of subjects achieving HbA1c < 7.0% over time 
• To assess the treatment effect of bexagliflozin vs. glimepiride on the change in HbA1c 
over time 
• To evaluate the treatment effect of bexagliflozin vs. glimepiride on the change in fasting 
plasma glucose (FPG) over time 
• To assess the treatment effect of bexagliflozin vs. glimepiride on the change in SBP over 
time 
• To assess the treatment effect of bexagliflozin vs. glimepiride on the change in body 
weight over time 
• To assess the treatment effect of bexagliflozin vs. glimepiride on the difference in 
proportion of subjects with ≥ 1 severe or documented symptomatic hypoglycemia events 
over time 


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Safety Objectives: 
• 
To compare the effects of bexagliflozin vs. glimepiride on the incidence of adverse 
events of interest. Adverse events of interest are urinary tract infections including 
urosepsis and pyelonephritis, genital mycotic infections, diuretic effects including 
hypovolemia, hypotension episodes, hypoglycemia, hepatotoxicity, major adverse 
cardiovascular events (MACE), falls and fractures, malignancies, hypersensitivity 
reactions, acid-base disorders including diabetic ketoacidosis, and renal failure events. 
• 
To compare the effects of bexagliflozin vs. glimepiride on general safety assessments 
including treatment emergent adverse events, clinical laboratory events, 12-lead 
electrocardiograms (ECG) parameters, physical examinations, vital signs including 
orthostatic blood pressure, and use of concomitant medications 
Other Objectives: 
• 
To compare the effects of bexagliflozin vs glimepiride on health-related quality of life 
using a validated instrument EQ-5D-3L. 
Study Design:  
THR-1442-C-480 is a phase 3, multi-center, randomized, double-blind, parallel-group study 
to evaluate the efficacy and safety of bexagliflozin versus glimepiride in subjects T2DM is 
inadequately controlled by metformin. A total of420 subjects are planned to be randomized 
in a ratio of 1:1 to receive once daily treatment of active bexagliflozin with placebo 
glimepiride (Group 1) or placebo bexagliflozin with active glimepiride (Group 2) for 96 
weeks in an outpatient setting. Active treatment in Group 1 will be bexagliflozin tablets, 
20 mg. Active treatment in Group 2 will be glimepiride capsules, 2, 4, or 6 mg. At the time of 
screening, subjects will be taking metformin only (metformin-only) or metformin in addition 
to no more than one additional oral hypoglycemic agent (metformin-and-OHA). Study 
subjects will continue receiving open-labeled metformin background medication during the 
entire study.  
The main eligibility criteria include 1) male or female subjects with T2DM and 2) screening 
HbA1c between 7.0% and 10.5% (inclusive) for subjects who are metformin-only treated, or 
screening HbA1c between 6.5% and 10.0% (inclusive) for subjects who are metformin-and-
OHA treated. 
All eligible subjects must have taken metformin at a stable dose of ≥ 1500 mg/day for at least 
8 weeks prior to screening. Subjects who are metformin-and-OHA treated must be willing to 
undergo a 6-week wash-out of the non-metformin OHA prior to the start of a 2 week run-in 
period. During the wash-out, subjects will discontinue non-metformin OHA and continue 
taking metformin at the dose and frequency taken at screening. 
All eligible subjects who are metformin-only treated or have completed the 6-week wash-out 
period will start a 2-week single-blind run-in period. During the run-in, subjects will receive 
placebo bexagliflozin and placebo glimepiride. Subjects who meet all inclusion criteria and 
no exclusion criteria prior to randomization will be eligible for randomization and receive 


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investigational products.  
During the treatment period, glimepiride will be provided in three dose levels: 2 mg, 4 mg, 
and 6 mg. Placebo glimepiride will also be provided in three dose levels: placebo for 2 mg, 
placebo for 4 mg, and placebo for 6 mg. Subjects will receive the starting dose of 
glimepiride, 2 mg or placebo. Subjects who meet protocol-specified glycemic criteria will 
undergo up-titration of the glimepiride dose at weeks 2, 4, and 6. The dose will be increased 
to the next dosing level if during the proceeding 2 weeks: (1) ≥ 50% of fasting SMBG 
measurements ˃ 110 mg/dL and (2) no severe or documented symptomatic hypoglycemia 
events. Subjects assigned to receive placebo glimepiride, will receive mock titrations of 
glimepiride at weeks 2, 4, and 6 based on the same glycemic criteria. No dose changes of 
glimepiride will occur after 6 weeks of treatment. 
Each subject will be instructed to return to the clinic at weeks 0, 2, 4, 6, 12, 24, 36, 48, 60, 
72, 84 (off-site phone visit) and 96 for efficacy assessment and safety monitoring. Subjects 
will return to the clinic for a follow-up exit visit at week 98 or 2 weeks after last dose of 
study drug if subjects early terminate prior to week 96. 
During the study, 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. In 
the event of administrative changes or other related reasons, the sponsor reserves the rights to 
terminate the study early. There will be no interim analysis; final statistical analysis will be 
performed after all subjects complete the study. 
Study Population and Main Eligibility Criteria: 
A total of 420 eligible subjects are planned for this study. The study population will 
comprise: 
1. Male or female adult subjects ≥ 18 years of age  
2. If subjects are female of childbearing potential, subjects must be negative on the urine 
pregnancy test and agree to abstain from coitus or use contraception during the entire 
study to avoid any possible pregnancy 
3. Subjects who are in one of the two categories: 
a. Metformin-only treated: receive ≥ 1500 mg/day metformin only for at least 8 weeks 
prior to screening  or  
b. Metformin-and-OHA treated: receive ≥ 1500 mg/day metformin for at least 8 weeks 
prior to screening and ≥ 14 days of 1 additional oral hypoglycemia agent (OHA) in 
the 8 weeks prior to screening.  
4. Subjects with a diagnosis of T2DM with HbA1c levels between 7.0% and 10.5% 
(inclusive) at screening if metformin-only treated or with HbA1c levels between 6.5% 
and 10.0% (inclusive) at screening if metformin- and-OHA treated  
5. Subjects with a body mass index (BMI) ≤ 45 kg/m2 at screening 
6. If applicable, taking stable doses of treatment for dyslipidemia and/or hypertension for 30 
days prior to screening. Subjects do not need to be treated for dyslipidemia or 
hypertension to be eligible for the study 


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7. Subjects who are willing and able to return for all clinic visits and to complete all study-
required procedures, including self-monitoring blood glucose (SMBG) measurements 
 
Prior to randomization, all subjects must: 
8. Maintain adequate glycemic control during the washout and run-in periods (fasting 
plasma glucose values are not ≥ 250 mg/dL on consecutive days) 
9. Have an HbA1c between 7.0% and 10.5% (inclusive) at Visit V5 
10. Adhere to the investigational product administration requirements as evidenced by 
missing no more than 2 placebo run-in medication doses of any kind  
 
Test Products, Dose, and Mode of Administration: 
Once daily oral administration of bexagliflozin and glimepiride 
• 
Group 1: bexagliflozin tablets, 20 mg, and glimepiride capsules, placebo  
• 
Group 2: bexagliflozin tablets, placebo, and glimepiride capsules, 2 mg, 4 mg or 6 mg 
 
Duration of Treatment:  
Eligible subjects will receive a total treatment duration of 98 weeks including 2 weeks of 
run-in medications and 96 weeks of investigational products. 
 
Efficacy Assessments: 
Primary efficacy assessment: 
• 
Change in HbA1c from baseline at week 60 
 
Secondary efficacy assessments: 
• 
Change in body weight in subjects with baseline body mass index (BMI) ≥ 25 kg/m2 at 
week 60 
• 
Change in SBP in subjects with baseline SBP ≥ 140 mmHg from baseline at week 60 
• 
Difference in proportion of subjects with ≥ 1 severe or documented symptomatic 
hypoglycemia events over 96 weeks 
• 
Change in HbA1c from baseline at week 60 
 
Other efficacy endpoints: 
• 
Change in proportion of subjects achieving HbA1c < 7.0% over time 
• 
Change in body weight over time 
• 
Change in FPG over time 
• 
Change in SBP over time 
• 
Change in HbA1c over time 
• 
Difference in proportion of subjects with ≥ 1 severe or documented symptomatic 
hypoglycemia events over time 
 


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Safety Endpoints: 
• 
Adverse events, including adverse events of special interest (genital and urinary tract 
infections, diuretic effects, hepatotoxicity, MACE, hypoglycemia, fractures, malignancy, 
hypersensitivity reactions, hypotensive episodes, acid-base disorders, and renal failure 
events) 
• 
Laboratory testing, including hematology, serum chemistry, and urinalysis 
• 
Physical examination 
• 
12-lead ECG 
• 
Vital signs 
• 
Concomitant medication use 
 
Other Assessment: 
Health-related quality of life instrument EQ-5D-3L 
Statistical Methods:  
The primary hypothesis is that bexagliflozin is non-inferior to glimepiride by evaluating the 
treatment effect on HbA1c reduction at week 60 in combination with metformin. The non-
inferiority margin for mean change from baseline at week 60 in HbA1c comparing 
bexagliflozin group with glimepiride group will be 0.35%. Superiority will be declared 
without additional statistical testing when the upper bound of the 95% CI for difference in 
change from baseline at week 60 in HbA1c comparing bexagliflozin group with glimepiride 
group is less than 0. The treatment difference will be examined by using a mixed model 
repeated measures (MMRM) analysis of covariance model (ANCOVA). The model will 
include treatment, visit, treatment-by-visit interaction and randomization stratification factors 
as the fixed effects terms and the baseline HbA1c value as a fixed effect covariate. Least 
squares mean treatment differences between the bexagliflozin group and the comparator 
group at week 60 in change from baseline will be estimated from the model. An unstructured 
covariance will be used to model the within-subject correlation. If the model with the 
unstructured covariance structure does not converge, an autoregressive(1) covariance 
structure will be used. HbA1c values obtained after the start of rescue medication will not be 
excluded from this primary analysis. Primary endpoint will be analyzed on both intention-to-
treat (ITT) and per protocol (PP) analysis sets. 
The MMRM model is one approach to obtain treatment effect estimates in the presence of 
missing data. As sensitivity analyses for missing data, the following will be performed on 
both ITT and PP analysis sets: 
1. 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 imputation techniques; HbA1c values collected after the start of 
rescue medication will not be excluded. 
2. Missing data will be imputed via LOCF, following which the MMRM will be repeated; 
HbA1c values collected after the start of rescue medication will be considered missing. 
3. HbA1c values collected after the start of rescue medication will be considered missing, 


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and the MMRM analyses will be re-performed. 
 
The effects of bexagliflozin on the changes from baseline at week 60 in body weight and 
systolic blood pressure, the difference in the proportion of subjects with ≥ 1 severe or 
documented symptomatic hypoglycemia events over 96 weeks and the change in HbA1c 
from baseline at week 60 will be tested as key secondary endpoints and will be analyzed in a 
hierarchical testing strategy and only if the primary objective is met. Similar to the primary 
endpoint, ANCOVA models will be used for the continuous secondary endpoints and logistic 
regression model will be used for the binary endpoint. A hierarchical testing strategy will be 
followed to preserve experiment-wide alpha at 0.05: 
1. Superiority test of the change in body weight in subjects with baseline BMI ≥ 25 kg/m2 in 
the bexagliflozin group vs. the glimepiride group at week 60 
2. Superiority test of the change in systolic blood pressure (SBP) in subjects with baseline 
SBP ≥ 140 mmHg in the bexagliflozin group vs. the glimepiride group at week 60 
3. Superiority test of the difference in proportion of subjects with ≥ 1 severe or documented 
symptomatic hypoglycemia event in the bexagliflozin group vs. the glimepiride group 
over 96 weeks 
 
Additional effects of bexagliflozin versus glimepiride on the changes in HbA1c, FPG, SBP, 
body weight, the proportion of subjects who reach an HbA1c  < 7%, and the proportion of 
subjects with ≥ 1 severe or documented symptomatic hypoglycemia events over time, as well 
as the general safety in subjects with T2DM, will be analyzed as exploratory efficacy 
endpoints. These endpoints are considered exploratory and will not be adjusted for 
multiplicity. 
For the primary efficacy endpoint, a minimum of 172 subjects are needed in each treatment 
arm to detect non-inferiority of bexagliflozin to glimepiride with respect to the change in 
HbA1c from baseline at week 60 by a margin of 0.35%, assuming an estimated pooled 
standard deviation of 1.0%. This estimation is based on a one-sided t-test with 90% power at 
a 0.025 level of significance. To allow for an estimated 18.0% dropout rate, 210 patients will 
be randomized in each treatment arm, and the total sample size will be 420 subjects for this 
study.  
Statistical analyses and summaries will be performed using SAS® software (SAS Institute, 
Cary, NC).  


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
American Diabetes Association 
AE 
adverse event 
ALB 
albumin 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase  
ATC 
Anatomic Therapeutic Chemical classification 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CEC 
cardiovascular endpoint committee 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRF 
case report form 
CRO 
contract research organization 
DKA 
diabetic ketoacidosis  
CYP 
cytochrome P450 
DPP4 
dipeptidyl peptidase-4 
DSMB 
data and safety monitoring board 
ECG 
electrocardiogram 
eGFR 
estimating glomerular filtration rate 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP-1 
glucagon-like peptide-1 
GMI 
genital mycotic infection 
h 
hour 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein cholesterol 
HDPE 
high-density polyethylene 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation  


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IEC  
independent ethics committee 
IND 
Investigational New Drug application 
IRAE 
immediately reportable adverse event 
IRB 
institutional review board 
ITT 
intention-to-treat 
IWRS 
Interactive Web Response System  
LDL-C 
low density lipoprotein cholesterol 
LOCF 
last observation carried forward 
MACE 
major adverse cardiovascular event 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDRD 
modification of diet in renal disease 
MedDRA 
medical dictionary for regulatory activities 
MI 
myocardial infarction 
MMRM 
mixed model repeated measures 
MODY 
maturity–onset diabetes of the young 
N 
number of subjects 
NYHA 
New York Heart Association 
OHA 
oral hypoglycemic agent 
PO 
per oral 
PP 
per protocol 
PR 
time from the beginning of the P wave to the beginning of the QRS 
complex in electrocardiogram 
QRS 
QRS complex is a name for the combination of three of the graphical 
deflections seen on a typical electrocardiogram 
QT 
corrected QT interval is a measure of the time between the start of the Q 
wave and the end of the T wave in the heart's electrical cycle 
RBC 
red blood cell (count) 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SGLT2 
sodium glucose cotransporter 2 
SMBG 
self-monitored blood glucose 
SOP 
standard operating procedure 
 SU 
sulfonylurea 
SUSAR 
serious and unexpected suspected adverse event 
T2DM 
type 2 diabetes mellitus 


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TC 
total cholesterol 
TEAE 
treatment emergent adverse event 
TG 
triglycerides 
TZD 
thiazolidinedione 
UACR 
urine albumin to creatinine ratio 
UADR 
unexpected adverse drug reaction 
UGE 
urinary glucose excretion 
ULN 
upper limit of normal 
UPT 
urinary pregnancy test 
UTI 
urinary tract infections 
WBC 
white blood cell (count) 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of childbearing potential 


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1 
INTRODUCTION 
Type 2 diabetes mellitus (T2DM) is one of the leading causes of morbidity and mortality 
worldwide, affecting an estimated 415 million people in 2015. Approximately 187 million of 
those affected are thought to be unaware of their condition and over 80% reside in low- and 
middle-income countries (IDF 2015). 
1.1 
Type 2 Diabetes Mellitus 
T2DM is the predominant form of diabetes and accounts for at least 90% of all diabetes 
cases, which is characterized by insulin resistance and relative or absolute insulin 
insufficiency. Despite the availability of several classes of therapeutics, the number of people 
with diabetes is projected to increase by nearly 55% to over 642 million adults by 2040 (IDF 
2015). Among the debilitating consequences of T2DM are peripheral neuropathy, 
retinopathy, renal failure, peripheral ischemia and exacerbations of cardiovascular disease, 
which result in blindness, amputation, dialysis and death. 
T2DM is a disease strongly linked to increased body fat mass in the majority of cases 
(Schwartz, Fabricatore et al. 2012). Weight loss has been shown to improve glycemic control 
and to reduce the severity of diabetes-associated comorbidities, supporting the view that anti-
diabetic agents that promote weight loss may be particularly beneficial for the treatment of 
the disease (Look, Wing et al. 2013; Scheen and Van Gaal 2014). Several classes of agents 
are available for treating T2DM, including insulin and its secretagogues such as, 
sulfonylureas (SU), PPAR agonists, biguanides, alpha glucosidase inhibitors, glucagon-like 
peptide 1 (GLP-1) receptor agonists, sulfonylureas, meglitinides, dipeptidyl peptidase 4 
(DPP4) inhibitors, and sodium glucose linked transporter 2 inhibitors (SGLT2i).  Metformin 
is the first line medication for treating T2DM; however, as T2DM progresses over time, 
metformin monotherapy is not able to adequately manage hyperglycemia. T2DM patients 
often receive more than one antidiabetic medication after an initial treatment period of 
metformin monotherapy. SU are considered second-line therapy for T2DM in clinical 
practice and are often prescribed with metformin as a combination therapy for treating 
T2DM. SU can reduce the risk of long-term microvascular complications via effective 
glycemic control; however, common side effects include weight gain and increased risk of 
hypoglycemia. The durability of SU treatment can be reduced due to loss of β-cell function 
as T2DM progresses over time. 
The rapid growth rate in the incidence of T2DM has led to an increasing recognition that 
additional therapeutics are needed to provide safe and effective reductions of elevated plasma 
glucose levels. New agents to treat T2DM, either as monotherapy or add-on therapy to other 
anti-diabetic medications, would ideally treat hyperglycemia and avoid common side effects 
of currently available agents, such as weight gain, gastrointestinal disturbance, and 
hypoglycemia. 
The renal Na+/glucose transport protein SGLT2 actively transports extracellular glucose into 
cells using the driving energy of the transmembrane electrochemical potential for sodium 
ions. Individuals with disruptions in SLC5A2, the gene encoding SGLT2, exhibit prominent 


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glucosuria in the absence of significant co-morbidities (van den Heuvel, Assink et al. 2002; 
Santer, Kinner et al. 2003). The excretion of glucose in the urine of diabetic subjects in 
amounts comparable to or greater than that seen in individuals harboring loss of functions 
mutations in SLC5A2 has the potential to improve fasting and postprandial hyperglycemia 
without increasing insulin secretion, causing weight gain, or inducing hypoglycemia. Several 
SGLT2 inhibitors have demonstrated these clinical benefits, as well as sustained weight loss 
when used as a mono-therapy or in combination with other oral anti-diabetic medications 
including insulin (Nauck 2014; Seufert 2015). 
1.2 
 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus 
Bexagliflozin is a candidate oral hypoglycemic agent (OHA) that is a potent and highly 
specific inhibitor of SGLT2. It was identified following a synthetic program aimed at 
creating molecules with high selectivity and potency for SGLT2 (Zhang, Welihinda et al. 
2011). Bexagliflozin has been shown to cause dose-dependent increases in urinary glucose 
excretion (UGE) in humans, rats, dogs and monkeys and to reduce HbA1c in animal models 
of T2DM as well as in diabetic subjects. The safety and efficacy of bexagliflozin capsules, 
20 mg, were evaluated in a 96-week study that measured reduction in hemoglobin A1c as the 
primary endpoint. Adverse event incidences, particularly for urinary tract infection (UTI) and 
genital mycotic infection (GMI), were similar between placebo and active agent cohorts. 
Details of the pharmacology, efficacy, and safety assessments are described in the 
Investigator’s Brochure. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary efficacy objective of this trial is to demonstrate that bexagliflozin is non-inferior 
to glimepiride by evaluating the treatment effect on HbA1c reduction at week 60 in subjects 
whose T2DM is inadequately controlled by metformin. 
2.2 
Key Secondary Objectives 
• 
To evaluate the treatment effect of bexagliflozin vs. glimepiride on the change in body 
weight in subjects with baseline body mass index (BMI) ≥ 25 kg/m2 at week 60 
• 
To evaluate the treatment effect of bexagliflozin vs. glimepiride on the change in systolic 
blood pressure (SBP) in subjects with baseline SBP ≥ 140 mmHg at week 60 
• 
To evaluate the treatment effect of bexagliflozin vs. glimepiride on the difference in 
proportion of subjects with ≥1 severe or documented symptomatic hypoglycemia events 
over 96 weeks 
• 
To evaluate if bexagliflozin is superior to glimepiride on HbA1c reduction at week 60 
 
2.3 
Exploratory Objectives 
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the change in the 
proportion of subjects achieving HbA1c < 7.0% over time 
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the change in HbA1c 
over time 
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the change in fasting 
plasma glucose (FPG) over time  
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the change in SBP over 
time 
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the change in body 
weight over time 
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the difference in 
proportion of subjects with ≥ 1 severe or documented symptomatic hypoglycemia events 
over time 
 
Safety Objectives: 
• 
To compare the effects of bexagliflozin vs. glimepiride on the incidence of adverse 
events of interest. Adverse events of interest are urinary tract infections including 
urosepsis and pyelonephritis, genital mycotic infections, diuretic effects including 
hypovolemia, hypotension episodes, hypoglycemia, hepatotoxicity, major adverse 
cardiovascular events (MACE), falls and fractures, malignancies, hypersensitivity 
reactions, acid-base disorders including diabetic ketoacidosis, and renal failure events. 
• 
To compare the effects of bexagliflozin vs. glimepiride on general safety assessments 
including treatment emergent adverse events, clinical laboratory events, 12-lead 


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electrocardiograms (ECG) parameters, physical examinations, vital signs including 
orthostatic blood pressure, and use of concomitant medications 
 
Other Objectives: 
• 
To compare the effects of bexagliflozin and glimepiride on health-related quality of life 
using a validated instrument EQ-5D-3L 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
THR-1442-C-480 is a phase 3, multi-center, randomized, double-blind, parallel-group study 
and aims to demonstrate that bexagliflozin is non-inferior to glimepiride as add-on therapy in 
subjects whose T2DM is not adequately controlled by metformin treatment. The primary 
efficacy endpoint is the change in HbA1c from baseline at week 60. The study will enroll 
T2DM patients who are treated with only metformin (metformin-only) or who are treated 
with metformin and one additional oral hypoglycemic agent (metformin-and-OHA)  
All subjects must have taken metformin at a stable dose of ≥ 1500 mg/day for ≥ 8 weeks 
prior to screening. Subjects can be eligible for the metformin-only treated group if they have 
received < 14 days of any other antidiabetic medications in the 8 weeks prior to screening. 
Subjects can be eligible for the metformin-and-OHA treated group if they have received ≥ 14 
days of no more than 1 other OHA in the 8 weeks prior to screening; subjects taking any 
other antidiabetic medication (in addition to metformin and the 1 OHA) for < 14 days in the 
8 weeks prior to screening are allowed.  
A total of 420 subjects who meet all the inclusion criteria, none of the exclusion criteria, and 
who consent to participate in the study, are eligible for study enrollment. Metformin-and-
OHA treated subjects will undergo a 6-week washout of the non-metformin OHA prior to the 
start of run-in. Subjects who complete the 2-week run-in and who meet all eligibility criteria 
will be randomized in a 1:1 ratio to receive once daily double-blind treatment of either active 
bexagliflozin tablets with placebo glimepiride capsules (Group 1) or placebo bexagliflozin 
tablets and active glimepiride capsules (Group 2). Active treatment in Group 1 will be 
bexagliflozin tablets, 20 mg. Active treatment in Group 2 will be glimepiride capsules, 2, 4 
or 6 mg. Study subjects will continue receiving open-labeled metformin background 
medication during the entire study at a stable dose and frequency. The treatment period will 
last 96 weeks and be conducted in an outpatient setting (Figure 1).  
 
Figure 1. 
Study Design 
 
3.2 
Rationale for Study Design and Control Group 
3.2.1 
Rationale for Background Medication and Active Comparator 
Metformin is the most commonly prescribed OHA and is recommended as first-line therapy 
for the treatment of T2DM. However, subjects who have T2DM often require multiple anti-


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diabetic medications for glycemic control. Sulfonylureas are often prescribed with metformin 
as a combination therapy for treating T2DM. Sulfonylureas can reduce the risk of long-term 
microvascular complications via effective glycemic control. Yet, common side effects of 
sulfonylureas include weight gain and increased risk of hypoglycemia. Glimepiride is one of 
the most commonly prescribed second-generation sulfonylureas. Thus, it is an appropriate 
active comparator in the subject population studied during the treatment period (96 weeks). 
Bexagliflozin is an SGLT2 inhibitor developed for the treatment of T2DM that reduces 
hyperglycemia via an insulin-independent pathway of inhibiting glucose re-uptake and 
promoting urinary glucose excretion. Individuals treated with metformin and with inadequate 
glycemic control have reduced HbA1c, reduced body weight, and less incidence of 
hypoglycemia when treated with approved SGLT2 inhibitors canagliflozin, dapagliflozin or 
empagliflozin. Thus T2DM subjects on metformin therapy with inadequate glycemic control 
may benefit from combination treatment with bexagliflozin. 
3.2.2 
Rationale for the Study Design 
THR-1442-C-480 is designed to assess the non-inferiority of bexagliflozin to glimepiride as 
add-on therapy to metformin for glycemic control in T2DM subjects. 
To assess the effect of bexagliflozin or glimepiride in addition to an effective dose of 
metformin background therapy, all subjects must be taking a stable dose of ≥ 1500 mg 
metformin daily for at least 8 weeks prior to screening. If a potential subject has taken 
< 1500 mg/day metformin, alone or in combination with 1 other OHA, the subject can enter 
screening once the dose of metformin has been be increased to at least 1500 mg/day for at 
least 8 weeks. Changes in the dose of metformin will not be permitted at any time during the 
study.  
To exclude the possibility that OHAs other than metformin taken prior to study enrollment 
might influence study outcomes, subjects who are metformin-and-OHA treated will undergo 
a 6-week wash-out of the non-metformin OHA prior to the start of run-in. During the wash-
out, subjects will discontinue non-metformin OHA and continue taking metformin at the 
dose and frequency taken at screening. 
Diet and exercise counseling will be provided to all participating subjects to reduce risks of 
worsening diabetic conditions. A monitoring plan and criteria to initiate rescue medications 
are included in the protocol to prevent prolonged hyperglycemia.  
Reduction in HbA1c directly reflects improvement in glycemic control and is considered a 
well-validated surrogate for the long-term microvascular complications of diabetes mellitus. 
Therefore the primary endpoint of change in HbA1c measurement from baseline at 60 weeks 
will reflect the long-term effects of bexagliflozin compared with glimepiride.  
3.2.3 
Rationale for the Dose Selection 
Bexagliflozin produces a dose-dependent, saturable increase in UGE in healthy volunteers 
and diabetic subjects. Population pharmacodynamic modeling has indicated that 


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bexagliflozin doses of 20 mg result in 90% of the maximal UGE. In a long term treatment 
study, daily administration of 20 mg bexagliflozin 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 pressures 
were also observed following 96 weeks of treatment. In addition, adverse events (AEs), 
particularly those involving UTI and GMI, were found to be similar between placebo and 
active agent cohorts. To evaluate the safety and efficacy of bexagliflozin for the treatment of 
subjects with T2DM, bexagliflozin tablets, 20 mg will be administered in this trial. 
Sulfonylureas are known to increase the risk of hypoglycemia. To control hyperglycemia and 
minimize hypoglycemia, subjects randomized to Group 2 will start with glimepiride at 2 mg 
daily and undergo dose up-titration based on protocol-specific criteria during the first 6 
weeks of the study (Section 3.3.2.1).  
3.3 
Research Methods and Procedures 
3.3.1 
Wash-out and Run-in Period 
Subjects who are metformin-and-OHA treated will undergo a 6-week wash-out of the non-
metformin OHA prior to the start of a 2 week run-in period. During the wash-out, subjects 
will discontinue non-metformin OHA and continue taking metformin at the dose and 
frequency taken at screening.  
At the start of the washout, metformin-and-OHA treated subjects will receive diet and 
exercise counseling as well as instructions on contacting the clinic in the event of 
hyperglycemia, hypoglycemia, or symptoms that may suggest ketoacidosis. Study subjects 
will be provided with a glucometer and instructions for its daily use. Two weeks after the 
start of the wash-out period, each subject will participate in a phone interview visit with 
study staff for SMBG data review and general safety evaluation. Subjects who remain 
eligible at the end of the washout period will begin a two-week run-in period.  
Metformin-only treated subjects will not undergo washout; they will proceed directly to the 
start of run-in. At the start of the run-in period, metformin-only treated subjects will receive 
diet and exercise counseling as well as instructions on contacting the clinic in the event of 
hyperglycemia, hypoglycemia, or symptoms that may suggest ketoacidosis. Metformin-and 
OHA treated subjects will receive this information at the start of the washout period. At the 
start of run-in, metformin-only treated subjects will be provided with a glucometer and 
instructions for its daily use.  
All eligible subjects who are metformin-only treated or have successfully completed the 6-
week wash-out period will start a 2-week single-blind run-in period. During the run-in, 
subjects will receive placebo bexagliflozin and placebo glimepiride. Bexagliflozin tablets, 
placebo, will be taken once daily in the morning prior to the first meal and glimepiride 
capsules, placebo, will be taken once daily in the morning with the first meal; the 
medications should be taken with water. Metformin dose and frequency will remain 
unchanged from time of screening throughout the course of the study. 
Subjects will not be eligible for randomization if during the run-in period they:  


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1. have fasting blood glucose values ≥ 250 mg/dL on two or more consecutive days,  
2. omit more than 2 placebo run-in medication doses of any kind, 
3. are deemed inappropriate for the study by the investigator, or  
4. have an HbA1c value ˂ 7.0% or ˃ 10.5% at visit V5. The glycemic control requirement 
based on HbA1c values is outlined in Figure 2.  
 
 
Figure 2. 
HbA1c Requirements Prior to Randomization 
 
Changes in the dose of treatment for dyslipidemia or hypertension will not be permitted 
during the screening and run-in periods.  
If a change in treatment for hypertension or dyslipidemia is deemed necessary by the 
investigator for the well-being of the study subject during the screening or washout periods, 
the subject will be considered as screen failed and discontinue study activities; the subject 
may be re-screened as a new subject after the clinical condition and treatment regimen have 
not changed for at least 30 days. When re-screening, a new subject number will be assigned 
and all screening activities, including informed consent, and assessments will be performed.  
If a change in treatment for hypertension or dyslipidemia is deemed necessary by the 
investigator for the well-being of the study subject during the run-in period, the subject will 
be considered as screen failed and discontinue study activities; there will be no opportunity to 
re-screen for subjects who have started run-in or failed screening.  
3.3.2 
Treatment Period 
The double-blind treatment period will start at randomization and last 96 weeks. A total of 
420 subjects of 210 subjects per group will be randomized in a 1:1 ratio to the two groups as 
shown in Table 1.  


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Table 1. 
Treatment Groups and Assigned Treatment 
Treatment Group 
Treatment 
1 
Bexagliflozin tablets, 20 mg, (once daily P.O.) 
Glimepiride capsules, placebo, (once daily P.O.) 
2 
Bexagliflozin tablets, placebo, (once daily P.O.) 
Glimepiride capsules, 2, 4 or 6 mg, (once daily P.O.) 
 
Randomization will be stratified by HbA1c at Visit V5 (≤ 8.5% vs. ˃ 8.5%), treatment 
background (metformin-only vs. metformin-and-OHA), and baseline estimated glomerular 
filtration rate (eGFR) at screening visit (V1) (eGFR ≥ 90 vs. < 90 and ≥ 60 mL/min/1.73 m2). 
At the start of the treatment period, each subject will be provided with bexagliflozin tablets, 
glimepiride capsules, dosing instructions, and a glycemic control diary in which to record 
SMBG measurements. Symptoms and blood sugars related to the occurrence of 
hyperglycemia, hypoglycemic events or symptoms that may suggest ketoacidosis will be 
recorded. Bexagliflozin tablets, 20 mg or placebo, will be orally administered once daily 
prior to the first meal; glimepiride capsules, 2, 4, or 6 mg or placebo, will be taken once daily 
with the first meal. Background medication metformin shall be taken at an unchanged dose 
and frequency taken at screening throughout the entire study.  
Each subject will be instructed to return to the clinic at weeks 0, 2, 4, 6, 12, 24, 36, 48, 60, 
72, 84 (off-site phone visit) and 96 for efficacy assessment and safety monitoring, including 
review of adverse events and concomitant medication, vital signs, ECG, physical 
examination, and blood and urine specimen collections. On the day of a clinic visit at which 
blood samples are scheduled to be collected, approximately 10 hours (h) fasting must be 
confirmed prior to blood draw. On the day of the scheduled clinic visits at which there is 
fasting and blood is to be drawn, administration of bexagliflozin shall be withheld until after 
blood is drawn and taken with water at the clinic or home prior to the first meal; glimepiride 
shall be withheld and taken with the first meal of the day. 
Subjects will return to the clinic for a follow-up exit visit at week 98 or 2 weeks after the last 
dose of study drugs if subjects early terminate prior to week 96. Following the exit visit, 
subjects will be advised to see their primary physician to undergo treatment to control their 
diabetes. 
3.3.2.1 
Glimepiride Dose Titration  
During the treatment period, glimepiride will be provided in three dose levels: 2 mg, 4 mg, 
and 6 mg. Glimepiride placebo will also be provided.  
Weeks 0 to 6  
Subjects will receive the starting dose of glimepiride at 2 mg or placebo at week 0 (V6).  
At weeks 2, 4 and 6 (scheduled visits V7, V8 and V9, respectively), subjects will return to 
the clinic for the assessment of glimepiride dose up-titration and safety evaluation. If subjects 


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meet the following glycemic criteria in the preceding 2 weeks, glimepiride dose will be 
increased to the next level. 
1. ≥ 50% of documented fasting SMBG measurements ˃ 110 mg/dL (6.1mmol/L) 
2. no severe or documented symptomatic hypoglycemia events 
 
Subjects assigned to receive placebo glimepiride, will receive mock titrations of glimepiride 
at weeks 2, 4, and 6 based on the same glycemic criteria.  
In case of persistent hyperglycemia [more than 3 consecutive daily, fasting SMBG measures 
≥ 270 mg/dL (15mmol/L)] during the treatment period, subjects should contact the clinic and 
schedule the up-titration visit(s) early to receive the next higher dose of glimepiride. 
During weeks 0 to 6, each up-titration visit should be conducted no more than 2 weeks after 
the prior visit. Visits V6 and V9 will always occur at week 0 and week 6, respectively.  
In the case that subjects experience persistent hyperglycemia and up-titration visits are 
scheduled early, if more than two weeks elapse between scheduled visits or an up-titration is 
needed between scheduled visits, an unscheduled visit with the same study procedures and 
tests as the previous scheduled visit will be conducted during the unscheduled visit.  
If subjects do not meet up-titration glycemic criteria, subjects will continue glimepiride at the 
same dose prescribed to them at previous visit. The up-titration schema is demonstrated in 
Figure 3. 
Weeks 7 to 96 
No dose changes in glimepiride will occur after 6 weeks of treatment. Subjects will continue 
receiving glimepiride at the unchanged dose, time, and frequency prescribed to them at 
week 6. 
Down-titration of glimepiride is not allowed during the entire study.  
At the discretion of the investigator, subjects who experience recurring symptomatic 
hypoglycemia or any severe episode of hypoglycemia during the treatment period can 
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*If subjects have persistent hyperglycemia [more than 3 consecutive daily, fasting SMBG measures 
≥ 270 mg/dL (15mmol/L)], subjects should contact the clinic and schedule the up-titration visit(s) 
early to receive the next higher dose of glimepiride 
Figure 3. 
Glimepiride Dose Up-titration Flow Chart 
 
3.3.3 
Glycemic Control Monitoring 
3.3.3.1 
Wash-out Period and Placebo Run-in Period 
During the wash-out and placebo run-in period, subjects will be instructed to determine 
SMBG daily after fasting overnight for a minimum of 10 h. Subjects should contact the clinic 
if any fasting glucose value is ≥ 250 mg/dL (13.9 mmol/L), and the investigator will 
determine whether the participant should attempt to improve diet and exercise to maintain 
glycemic control or if the participant must withdraw from the study and initiate a more 
intense pharmacological regimen for glucose control.  
A subject will be excluded from further participation if his fasting blood glucose is 
≥ 250 mg/dL prior to randomization on 2 or more consecutive days. Subjects with clinical 
signs or symptoms of severe hyperglycemia during the wash-out or run-in periods, including 
weight loss, blurred vision, increased thirst, increased urination, or fatigue, should also be 
excluded. 
3.3.3.2 
Treatment Period 
During the treatment period, subjects will be advised to continue daily, fasting SMBG 
measurements. Subjects should contact the clinic if any fasting SMBG is ≥ 270 mg/dL 
(15 mmol/L) from week baseline to week 6, ≥ 240 mg/dL (13.3 mmol/L) after week 6 to 
week 12, or ≥ 200 mg/dL (11.1 mmol/L) after week 12. Blood glucose values collected via 
SMBG will be evaluated at study visits by the investigator. In addition, hyperglycemia will 
be monitored by FPG at scheduled visits. 


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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 SMBG or 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 treatment period, hyperglycemia should be managed first with diet and exercise 
counseling. If hyperglycemia continues after diet and exercise counseling, the investigator 
should intensify medical therapy if it is necessary for the well-being of the subject. Options 
for intensification of medical therapy will vary during the study, including up-titration of 
glimepiride dose (weeks 0-6) and addition of rescue medication (see below, Intensification of 
Medical Therapy for Hyperglycemia).  
3.3.3.3 
Intensification of Medical Therapy for Hyperglycemia 
During the entire treatment period, a review of diet and exercise counseling is suggested 
prior to prescription of rescue medication in the absence of specific medical indications for 
rescue medication.  
Intensification of medical therapy for hyperglycemia is suggested during the treatment period 
if, after diet and exercise counseling, subjects meet the following glycemic criteria:  
1. More than 3 consecutive, daily, fasting SMBG measures are ≥ 270 mg/dL (15 mmol/L) 
from baseline to week 6, ≥ 240 mg/dL (13.3 mmol/L) after week 6 to week 12, or 
≥ 200 mg/dL (11.1 mmol/L) after week 12 to week 96 
2. Fasting SMBG values are ≥ 250 mg/dL (13.9 mmol/L) and associated with clinical signs 
or symptoms of hyperglycemia (e.g., weight loss, blurred vision, increased thirst, or 
increased urination, or fatigue), and the signs or symptoms are severe 
 
From week 0 to week 6, up-titrating glimepiride dose to next higher level should be 
considered prior to prescribing rescue medication for hyperglycemia. If necessary, increases 
in glimepiride dosing can occur before the scheduled study visits. The criteria for glimepiride 
up-titration are provided in Section 3.3.2.1. After glimepiride up-titration to the maximal 
level, rescue medication should be initiated for treating hyperglycemia based on 
investigator’s assessment. 
After week 6 of treatment, no further increases in glimepiride will occur. Therefore, from 
weeks 7 to 96, rescue medication for hyperglycemia should be prescribed by the investigator 
when deemed necessary for the well-being of the subject. 
If a rescue medication for hyperglycemia is to be prescribed, a blood sample must be drawn 
prior to the administration of the rescue medication so that a final HbA1c value can be 
ascribed to the latest date upon which the subject’s glycemic control will be impacted by the 
rescue medication. 
The investigator may provide rescue treatment with any approved medication for diabetes 
that is not otherwise contraindicated, with the exception of SGLT2 inhibitor, sulfonylurea 


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and metformin, as all study subjects will already be taking metformin and may be taking 
active SGLT2 inhibitor or glimepiride through study participation.  
If hypoglycemia occurs in any subject who has been prescribed rescue medication for 
hyperglycemia during the study, the total daily dose of the rescue medication should be 
reduced 50% or more at the discretion of the investigator. If recurrent symptomatic 
hypoglycemia occurs after discontinuation of the rescue medication or in subjects who are 
not prescribed rescue medication, study drug can be discontinued at the discretion of the 
investigator. 
Subjects who receive rescue medication due to poor glycemic control will continue to receive 
investigational products and standard of care per investigator decision, according to current 
treatment guidelines. Following the exit visit, subjects will be advised to see their primary 
physician to undergo treatment to control their diabetes. 
3.3.4 
Other Safety Monitoring Activities  
The safety monitoring activities will include assessments of vital signs, 12-lead ECG, 
physical examinations, urinalysis, blood chemistry, hematology, adverse events, and 
concomitant medication use. The occurrence of blood, liver, or skin disorders will be 
monitored through laboratory testing and evaluation of adverse event documentation.  
Adverse events of special interest as defined in the statistical analysis plan will include any 
clinical signs and symptoms that indicate adverse experience in the categories listed below. 
All such events must be appropriately documented within source documentation. 
• 
Genital mycotic infection 
• 
Urinary tract infections including urosepsis and pyelonephritis 
• 
Acid-base disorders including diabetic ketoacidosis 
• 
Diuretic effects including hypovolemia 
• 
Hypotension episodes 
• 
Hepatotoxicity 
• 
MACE 
• 
Hypoglycemia 
• 
Falls and fractures 
• 
Malignancies 
• 
Hypersensitivity reactions 
• 
Renal failure events 
• 
Amputation 
 
3.3.5 
Data and Safety Monitoring Board (DSMB)  
An independent Data and Safety Monitoring Board (DSMB) will monitor overall safety 
information during the bexagliflozin development program. The safety review activity and 
potential risk benefit assessments utilized by the DSMB will be defined in its charter. 


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3.3.6 
Major Adverse Cardiovascular Event (MACE) Adjudication  
An independent cardiovascular adjudication committee has been established to review, under 
blind, all potential cardiovascular events occurring during the study. The events of interest 
include cardiovascular mortality, myocardial infarction (MI), stroke, hospitalization for acute 
coronary syndromes, urgent revascularization procedures, and other possible serious 
cardiovascular events. The adjudicated events will be documented and archived to allow a 
meta-analysis to be performed at a later time. No separate cardiovascular risk assessment will 
be performed based on events in the study population of the current protocol. 
3.3.7 
Diabetic Ketoacidosis (DKA) Event Adjudication  
An independent adjudication committee will be established to review all potential diabetic 
ketoacidosis events under blind. The adjudicated events will be documented and archived. 
All adjudicated DKA events in the bexagliflozin phase 3 program will be pooled at the end of 
the program and a final analysis will be conducted.  
3.4 
Study Duration and Dates 
Subjects will be screened within 3 weeks of enrollment. Eligible subjects who provide 
written consent will start a wash-out and run-in period of 2 or 8 weeks prior to randomization 
to receive study drugs. Subjects will receive 2 weeks of run-in medication and 96 weeks of 
treatment and will be followed for 2 weeks after the last dosing. The study duration from 
screening to follow-up will be no more than 109 weeks overall. For details of the schedule 
and nature of the investigations, see the Schedule of Events in Appendices 1 and 2.  


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study population will include approximately 420 subjects whose T2DM is inadequately 
controlled by metformin and who meet all of the inclusion criteria, none of the exclusion 
criteria. Clinical sites in the North America and Europe are anticipated to recruit subjects. 
Clinical sites in other continents may also participate in the trial. 
4.2 
Inclusion Criteria 
Prospective subjects must be: 
1. Male or female adult subjects ≥ 18 years of age 
2. If subjects are female of childbearing potential, subjects must be negative on the urine 
pregnancy test and agree to abstain from coitus or use contraception during the entire 
study to avoid any possible pregnancy.  
3. Subjects who are in one of the two categories: 
 
a) Metformin-only treated: receive ≥ 1500 mg/day metformin only for at least 8 
weeks prior to screening  or  
b) Metformin-and-OHA treated: receive ≥ 1500 mg/day metformin for at least 8 
weeks prior to screening and ≥ 14 days of 1 additional oral hypoglycemia 
agent (OHA) in the 8 weeks prior to screening.  
4. Subjects with a diagnosis of T2DM with HbA1c levels between 7.0% and 10.5% 
(inclusive) at screening if metformin-only treated or with HbA1c levels between 6.5% 
and 10.0% (inclusive) at screening if metformin-and-OHA treated  
5. Subjects have a body mass index (BMI) ≤ 45 kg/m2 at screening 
6. If applicable, taking stable doses of treatment for dyslipidemia and/or hypertension for 30 
days prior to screening. Subjects do not need to be treated with dyslipidemia or 
hypertension to be eligible for the study. 
7. Subjects who are willing and able to return for all clinic visits and to complete all study-
required procedures, including self-monitoring blood glucose (SMBG) measurements 
 
Prior to randomization, all subjects must: 
8. Maintain adequate glycemic control during the washout and run-in periods (fasting 
plasma glucose values are not ≥ 250 mg/dL on consecutive days) 
9. Have an HbA1c between 7.0% and 10.5% (inclusive) at Visit V5  
10. Adhere to the investigational product administration requirements as evidenced by 
missing no more than 2 doses of run-in medications 
 


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4.3 
Exclusion Criteria 
Subjects 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. Current use of injected therapy for treatment of diabetes (insulin or glucagon-like 
peptide-1 (GLP-1) receptor agonist therapy) or a thiazolidinedione (TZD) 
3. Hemoglobinopathy that affects HbA1c measurement 
4. Any contraindication to the safe use of sulfonylurea therapy, glimepiride or metformin, 
including known hypersensitivity reaction  
5. Genitourinary tract infection within 6 weeks of screening or history of ≥ 3 genitourinary 
infections requiring treatment within 6 months from screening 
6. 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) 
7. History of alcohol or illicit drug abuse in the past 2 years 
8. 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 
9. Estimated glomerular filtration rate (eGFR), as calculated by the modification of diet in 
renal disease study equation (MDRD), < 60 mL/min/1.73 m2 at screening. 
10. Uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood 
pressure > 95 mmHg) at Visit V1 
11. History of human immunodeficiency virus (HIV) infection 
12. Life expectancy < 2 years 
13. History of myocardial infarction (MI), unstable angina, stroke, or hospitalization for heart 
failure within 3 months of screening 
14. History of treatment with an investigational drug within 30 days or within 7 half-lives of 
the investigational drug, whichever is longer 
15. Previous treatment with bexagliflozin or EGT0001474 study drug (run-in or double-blind 
investigational product) 
16. Currently or within 3 months of taking any SGLT2  
17. Currently participating in another interventional trial 
18. Prior renal transplantation or evidence of nephrotic syndrome (defined as a urine 
albumin-to-creatinine ratio (UACR) > 1500 mg/g at screening). 
19. Any condition, disease, disorder, or clinically relevant abnormality that, in the opinion of 
the primary investigator, would jeopardize the subject’s appropriate participation in this 
study or obscure the effects of treatment including condition or co-morbidity for which 
the use of metformin or any planned or existing second diabetes therapy is 
contraindicated 
20. Female subjects who are pregnant or nursing. 
21. Two or more consecutive SMBG measures ≥ 250 mg/dL (13.9 mmol/L) prior to 
randomization or severe clinical signs or symptoms of hyperglycemia prior to 
randomization, including weight loss, blurred vision, increased thirst, or increased 
urination, or fatigue. 


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5 
STUDY TREATMENTS 
5.1 
Description of Treatments 
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 
 
5.1.2 
Active Comparator 
Glimepiride capsules, 2 mg, 4 mg, 6 mg or placebo, are orange colored capsules. 
The following investigational drugs will be used for oral administration: 
• 
Glimepiride capsules, 2 mg: capsules containing 2 mg of glimepiride  
• 
Glimepiride capsules, 4 mg: capsules containing 4 mg of glimepiride  
• 
Glimepiride capsules, 6 mg: capsules containing 6 mg of glimepiride  
• 
Glimepiride capsules, placebo: capsules containing no glimepiride 
 
5.2 
Treatments Administered 
5.2.1 
Investigational Product 
Bexagliflozin tablets, 20 mg or placebo, should be taken once daily with 250 mL of water in 
the morning prior to the first meal.  
On the day of scheduled clinic visits when there is fasting and blood is to be drawn, 
administration of bexagliflozin should  be delayed until after blood is drawn and taken in the 
clinic or at home prior to the first meal with 250 mL of water. 
5.2.2 
Active Comparator 
Glimepiride is a second generation sulfonylurea, which stimulates glucose-independent 
insulin release from the pancreas. After oral administration, glimepiride is absorbed from the 
GI tract. Glimepiride is metabolized mostly by hepatic P450 enzyme CYP2C9. 


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Glimepiride capsules, 2, 4 or 6 mg or placebo, should be taken once daily with the first meal. 
On the day of scheduled clinic visits when there is fasting and blood is to be drawn, 
administration of glimepiride shall be withheld until the first meal. 
5.2.3 
Background Metformin Therapy 
Metformin is commonly prescribed as the first-line agent for treating T2DM. It is a biguanide 
that decreases hepatic glucose production and may improve peripheral glucose uptake and 
utilization. After oral administration, metformin is absorbed from the gastrointestinal (GI) 
tract, and it is excreted unchanged in the urine and does not undergo hepatic metabolism or 
biliary excretion.  
Any OHA other than metformin taken by study subjects prior to screening will be 
discontinued at the start of the wash-out period. Subjects will continue receiving metformin 
as background therapy during the entire study period at an unchanged dose (≥ 1500 mg/day), 
time, and frequency that is prescribed to subjects prior to screening.  
The dose, frequency, and time of administration 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 metformin should be recorded in 
the concomitant medication log. 
5.2.4 
Diuretics and Medications for Treatment of Dyslipidemia and Hypertension 
Subjects who are prescribed diuretics, anti-hypertensive agents, or medications to treat 
dyslipidemia medications to treat hypertension or dyslipidemia will continue the current 
dose, frequency, and time of administration of these medications throughout the study. 
Adjustment of these medications will not be permitted during the screening, washout and 
run-in periods.  
If a change in diuretics, anti-hypertensive agents, or medications to treat dyslipidemia is 
required during the screening or wash-out period, the subject will discontinue study activities 
and may be re-screened after the clinical condition and treatment regimen have been stable 
for at least 30 days.  
Subjects who start the run-in period or screen fail for any reason, including adjustment of 
diuretics, anti-hypertensive agents, or medications to treat dyslipidemia, will not be allowed 
for re-screening.  
If a subject re-enters screening after treatment adjustment, a new subject number will be 
assigned. During the treatment period, adjustments in the treatment for hypertension or 
dyslipidemia are permitted if required for the well-being of the subject. If it is medically 
necessary to alter blood pressure medications during the treatment period, new diuretic 
medications should not be initiated and the dose and frequency of existing diuretic 
medications should not be changed during the first 2 weeks of therapy. Changes to the dose 
or frequency of anti-hypertensive and diuretic medications will be recorded in the 
concomitant medications log. 


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5.3 
Selection and Timing of Dose for Each Patient 
5.3.1 
Bexagliflozin 
Dosing with bexagliflozin tablets, 20 mg or placebo, will be based on randomized 
assignment. All study subjects will be instructed to take bexagliflozin tablets once daily in 
the morning prior to the first meal; bexagliflozin tablets should be taken once daily P.O. with 
250 mL water. There will be no change of dose and frequency during the 96-week treatment 
period.  
On the day of each scheduled clinic visit, subjects must fast for approximately 10 h prior to 
the collection of blood samples. During the fasting period, only water will be permitted.  
5.3.2 
Glimepiride 
Dosing with glimepiride capsules or placebo, will be based on randomized assignment at the 
beginning of the treatment period. The dose of glimepiride may be increased during the first 
6 weeks of treatment according to the protocol-specific criteria (Section 3.3.2.1). From weeks 
7 to 96, subjects will continue receiving glimepiride at the dose prescribed to them at week 6. 
Down titration of glimepiride will not be permitted during the entire study period. 
5.4 
Method of Assigning Treatment Groups and Study Drugs 
The study will be conducted at multiple investigative sites 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 40 randomized subjects. Activation of investigational sites in each country will 
be centrally controlled by an Interactive Web Response System (IWRS). 
Eligible subjects who complete the wash-out and run-in period and meet all study 
inclusion/exclusion requirements will be randomized in a 1:1 ratio to receive active 
bexagliflozin with placebo glimepiride or active glimepiride with placebo bexagliflozin. 
Subjects will be assigned to treatment groups in sequential order as they qualify for the study. 
Randomization will be stratified according to baseline (Visit V5) HbA1c (< 8.5% or ≥ 8.5%), 
treatment background (metformin-only or metformin-and-OHA), and Visit V5 eGFR (≥ 90 
or ˂ 90 and ≥ 60 mL/min/1.73 m2). 
The investigator or designated staff will log in to the IWRS to receive the following 
information: 


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Table 2. 
Study Drug Dispensation Schedule 
Visit 
Unique ID 
Run-in Drugs 
Bexagliflozin Tablets 
(no. of kits) 
Glimepiride Capsules (no. 
of kits) 
V1 
Subject no. 
 
 
 
V4 
 
bexagliflozin & 
glimepiride 
 
 
V6 
Randomization 
no. 
 
20 mg or placebo (1) 
2 mg or placebo (1) 
V7 to V91 
 
 
 
4 mg, 6 mg or placebo (1) 
V10 to V14 
 
 
20 mg or placebo (1) 
2, 4 or 6 mg or placebo 
assigned at Week 6 (1) 
V15 
 
 
20 mg or placebo (2) 
2, 4 or 6 mg or placebo 
assigned at Week 6 (2) 
1 
The investigator will select the glimepiride dose based on clinical assessment. The up-titration of 
glimepiride dosing can occur before the scheduled study visits in the case of persistent hyperglycemia. The 
guidance for glimepiride up-titration is outlined in Section 3.3.2.1. 
 
Subject randomization will be deactivated for all sites when the planned number of subjects 
is met. However, if a potential subject is in wash-out already and wishes to continue with the 
study, the subject will be allowed to continue and, if eligible, to be randomized. 
5.5 
Blinding 
This is a double-blind, double dummy study. The sponsor, investigators, study coordinators, 
pharmacists, study subjects, the cardiovascular adjudication committee and the diabetic 
ketoacidosis committee will be blinded to the study medication.  
To maintain blinding of the individual treatment assignment, the results of urinary glucose 
testing will not be made available to any study personnel or subjects. If knowledge of the test 
substance is needed to manage a subject’s condition, the investigator will contact the IWRS 
to obtain the treatment assignment. If unblinding occurs for any reason, the time and reason 
for breaking the blind will be recorded on the case report form (CRF) and the sponsor must 
be notified within 24 h.  
A designated statistician who is not involved with the study operation will hold the treatment 
codes. The unblinded treatment information can be provided to the DSMB to facilitate the 
evaluation of any clinically important increase in the rate of a serious suspected adverse 
reaction or to the designated safety contact when the treatment information is required to 
determine if an expedited safety report must be submitted to regulatory agencies.  
The treatment assignment will continue to be withheld from the cardiovascular adjudication 
committee and diabetic ketoacidosis adjudication committee members until all global 
investigational studies are completed and final analyses to assess cardiovascular and 
ketoacidosis risks are conducted. 


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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. Instructions for intensification of medical therapy for hyperglycemia 
are provided in Section 3.3.3.3. Instructions and requirements for adjustment to diuretics and 
treatment for dyslipidemia and hypertension are provided in Section 5.2.4. Subjects will be 
allowed to take medications or medicinal supplements prescribed to manage non-diabetic 
medical conditions during the study. Any concurrent medication or supplemental treatment 
of other, non-diabetes, medical conditions should be continued at a stable dose and frequency 
for the entire study duration unless there is a clinical reason to change the dose or frequency.  
Subjects may receive any medications for adverse events that are necessary in the 
investigators’ judgment. Concomitant medications prescribed at the time of the wash-out and 
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 
period and the follow-up period.  
Any medication prescribed to a subject after enrollment and prior to randomization, 
including contraceptives, must be recorded in the CRF. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
All subjects will continue regimens for medical conditions other than diabetes during the 
study as indicated above. No subject shall have been treated with an investigational drug 
within 30 days of screening or within a period equal to less than 7 half-lives of the 
investigational drug, whichever is longer. No subject shall have been treated with an SGLT2 
inhibitor within 3 months of screening. Subjects taking insulin or GLP-1 receptor agonists or 
a TZD at the time of screening are not eligible for this study. 
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. For example, the recommended diet 
might be low in saturated fat, high in fiber, and low in simple carbohydrates and contain 
appropriate caloric intake to maintain weight.  
Subjects will fast for approximately 10 h prior to the scheduled blood sample draws. During 
fasting, only water will be permitted. 


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5.7.3 
Subject Activity Restrictions 
Throughout the study period, subjects are counseled and encouraged to engage in a level of 
physical activity that is appropriate for their physical condition. For those without specific 
restrictions or limitations, at least 150 min/week of moderate activity is advised by the 
American Diabetes Association (ADA) (American Diabetes, 2014). Alternatively, local 
regulatory guidelines may be used. 
5.8 
Treatment Compliance 
Subjects will be provided with dosing instructions when the investigational products are 
dispensed. Subjects will also be instructed to bring their medications with them at every visit. 
During the run-in period, subjects will be excluded from randomization if more than 2 
placebo run-in medication doses of any kind have been omitted.  
At each visit the study staff will review SMBG diary and medications 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 products will be provided to the pharmacist or designated site personnel in 
high-density polyethylene (HDPE) bottles of 90 tablets enclosed with a child-resistant cap. A 
bottle of 15 bexagliflozin tablets, placebo, and a bottle of 15 glimepiride capsules, placebo, 
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. The pharmacist or designated site personnel will dispense the investigational 
products for each subject according to randomization assignment.  
5.9.1 
Run-in Kits 
Two types of run-in kits are provided: 
• 
Bexagliflozin tablets, placebo, 15 tablets per bottle;  
• 
Glimepiride capsules, placebo, 15 capsules per bottle. 
 
The label attached to each run-in kit will contain the protocol number, product identification, 
kit number, batch number, expiration date, subject number, investigator name, storage 
condition, directions for use, sponsor’s name and address, and the investigational drug 
caution statement. 
5.9.2 
Bexagliflozin Kit 
One bexagliflozin kit contains a bottle of 90 counts of bexagliflozin tablets, 20 mg or 
placebo.  


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The label attached to each bexagliflozin kit will contain the protocol number, product 
identification, kit number, batch number, expiration date, subject number, investigator name, 
storage condition, directions for use, sponsor’s name and address, and the investigational 
drug caution statement. 
5.9.3 
Glimepiride Kit 
One glimepiride kit contains a 90 count bottle of one of the following products: 
• 
Glimepiride capsules, 2 mg or placebo 
• 
Glimepiride capsules, 4 mg or placebo 
• 
Glimepiride capsules, 6 mg or placebo 
 
The label attached to each glimepiride kit will contain the protocol number, product 
identification, kit number, batch number, expiration date, subject number, investigator name, 
storage condition, directions for use, sponsor’s name and address, and the investigational 
drug caution statement. 
5.10 Storage and Accountability 
Bexagliflozin tablets and glimepiride capsules will be stored at controlled room temperatures 
of 15°C to 30°C (59°F to 86°F). 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. The investigational 
products should be stored at controlled room temperature until ready for dispensing to study 
subjects. The trial staff must record the amount of investigational products dispensed to each 
subject on the dosing record. To ensure adequate recordkeeping, subjects must bring all 
investigational products to each visit. The remaining tablets and capsules will be accounted 
for in the CRF and drug consumption forms. The procedures for obtaining drug resupply will 
be provided by the sponsor. All unused drug must be returned to a sponsor-designated depot 
after drug accountability is verified by the sponsor or its designee.  


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


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


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


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is determined to be a clinically significant and abnormal change from baseline for that 
subject, it is considered to reflect an AE. 
 
6.9 
Clinical Laboratory Tests 
6.9.1 
Laboratory Parameters 
Clinical laboratory tests are listed in Table 3. 
6.9.2 
Sample Collection, Storage, and Shipping 
6.9.2.1 
Hematology, Blood Chemistry, Serum Lipids, and Glycemic Control 
Assessments  
Blood samples for hematology, chemistry, serum lipids and glycemic control assessments 
will be collected. Subjects will be in a seated or supine position during blood collection. 
Samples will be collected at the time points indicated in the schedule of events in Appendix 1 
and Appendix 2. 
The study staff will contact each subject prior to a scheduled clinic visit to confirm the time 
of the visit and to remind the subject of proper fasting practice. A subject must be queried to 
assess compliance with an approximately 10 h fast prior to blood draw to ensure the FPG and 
triglycerides values can be accurately determined. If a subject has not fasted for 
approximately 10 h, the subject must return as soon as can be arranged (within 1 week) to 
provide a specimen after proper fasting. 
Low-density lipoprotein-cholesterol (LDL-C) will be calculated by the Friedewald equation. 
If triglycerides are > 400 mg/dL, the calculated LDL-C value is invalid by this equation and 
will be set as missing. Direct LDL-C will be determined in subjects whose triglycerides are 
> 350 mg/dL at screening visit. All subsequent LDL-C of these subjects will be determined 
by the same direct LDL-C measurements only. 
6.9.2.2 
Urinalysis  
Urine samples will be collected routinely at designated clinic visits from a clean catch 
sample. Urinalysis will be performed at the time points indicated in the schedule of events 
(Appendix 1 and Appendix 2). Investigator or staff should document if pre-menopausal 
female subjects are menstruating and note it in the source documents since hematuria is 
likely to be identified on dipstick urinalysis. 
Urine samples will be transported to the central laboratory for urinalysis. Microscopy will be 
conducted if the subject has a positive result on the leukocyte esterase or nitrite dipstick tests 
to clarify the significance of the finding. Results of glucose measurement in the urinalysis 
must be suppressed from the laboratory reports so the sponsor, investigators, study 
coordinators, pharmacists, study subjects, the cardiovascular endpoint committee (CEC) 
members and (diabetic ketoacidosis) DKA adjudication committee members will remain 
blinded to the dosing assignment. 


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


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Table 3. 
List of Laboratory Tests 
Test Name (sample volume) 
 
Hematology (2 mL blood) 
 
• Mean corpuscular hemoglobin 
(MCH) 
• Mean corpuscular hemoglobin 
concentration (MCHC) 
• Mean corpuscular volume (MCV) 
• White blood cell (WBC) count 
with differential  
• RBC Morphology 
• Red blood cell (RBC) count  
• Hematocrit (Hct) 
• Hemoglobin (Hgb) 
• Platelet count  
Serum Chemistry and Electrolytes (3 mL serum) 
 
• Albumin (ALB) 
• ALT 
• AST 
• Blood urea nitrogen (BUN) 
• Creatinine  
• Uric acid 
• Calcium (Ca) 
• Magnesium 
• Phosphorus 
• Potassium (K) 
• Sodium (Na) 
• Total Protein 
• Glucose 
• Bicarbonate (HCO3) 
• Chloride (Cl) 
• Total bilirubin 
• Direct bilirubin  
 
Glycemic Control (2 mL plasma, 2 mL blood) 
• FPG 
• HbA1c 
 
Serum Lipids  
 
• Total cholesterol (TC) 
• High-density lipoprotein cholesterol 
(HDL-C) 
• Low-density lipoprotein 
cholesterol (LDL-C), calculated, 
or  
• LDL-C, direct (if applicable) 
• Triglycerides (TG) 
Urinalysis 
• Appearance 
• Bilirubin 
• Color 
• Glucose (blinded) 
• Ketones 
• Microscopic examination of 
sediment 
• Nitrite  
• Leukocyte esterase  
• Occult blood 
• pH 
• Protein 
• Specific gravity 
• Urobilinogen 
 
Renal Functional Test 
• UACR 
 
 
Urine Pregnancy Test 
 
 
6.10 Diary and Glucometer Dispensation and Review  
A glucometer, testing strips, and a glycemic control diary will be provided to each 
metformin-and-OHA treated subject at the start of wash-out and each metformin-only treated 
subject at the start of run-in. Subjects will be trained to use the glucometer and record any 
events in the glycemic control diary. Study subjects may continue using their own 
glucometer, if applicable, if the device has a function for glucose value storage for at least 
180 days and the glucose values must be downloadable so that SMGB records can be kept for 


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the evaluation by the investigator. The SMBG record from the glucometer and diary entries 
must be reviewed by the investigator at all subsequent visits including both phone interview 
and clinic visits. 
During the SMBG training, symptoms that may indicate hypoglycemia, hyperglycemia, or 
ketoacidosis will be reviewed with study subjects. Instructions to contact the clinic when the 
subjects experience potential hypoglycemia or diabetic ketoacidosis must be provided. 
6.11 Dispensing Run-in Drug  
Each eligible study subject will receive 1 bottle of bexagliflozin, placebo run-in drug and 1 
bottle of glimepiride, placebo run-in drug based on the scheduled visit outlined in 
Appendix  1.  
6.12 Diary and Glucometer Record Review  
Review SMBG and glycemic control record. 
6.13 Dispensing Investigational Product  
6.13.1 
Dispensing Bexagliflozin 
At randomization and at every 12 weeks of treatment thereafter, each study subject will 
receive 1 bottle of bexagliflozin tablets, 20 mg or placebo, based on the kit number assigned 
to the subject by the IWRS. At visit V15, two bottles of bexagliflozin tablets will be 
dispensed for dosing between week 72 and week 96.  
6.13.2 
Dispensing Glimepiride 
Weeks 0 to 6 
• 
Each subject will receive 1 bottle of glimepiride capsules, 2 mg or placebo, at 
randomization. 
• 
During weeks 2 to 6 post-randomization, the investigator will select the glimepiride dose 
based on clinical assessment. The guidance for glimepiride up-titration is outlined in 
Section 3.3.2.1. If subjects meet up-titration criteria, a bottle of glimepiride, 4 mg, 6 mg 
or placebo, will be dispensed. If subjects do not meet up-titration criteria, subjects will 
continue the glimepiride prescribed to them at the previous visit. The up-titration of 
glimepiride dosing can occur before the scheduled study visits in the case of persistent 
hyperglycemia.  
 
Weeks 7 to 96 
• 
From weeks 7 to 12, each subject will continue taking glimepiride prescribed to them at 
week 6.  
• 
At week 12 and at every 12 weeks of treatment thereafter, each study subject will receive 
1 bottle of glimepiride capsules, 2mg, 4 mg, 6 mg or placebo, based on the kit number 


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assigned to the subject by the IWRS. At visit V15, two bottles of glimepiride capsules 
will be dispensed for dosing between week 72 and week 96.  
 
6.14 Adverse Events Assessments  
6.14.1 
Definition of Adverse Events 
Adverse event (AE): Any untoward medical occurrence in a subject administered a 
pharmaceutical product that does not necessarily have a causal relationship with the 
treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not it is considered related to the medicinal product use. 
Serious adverse event (SAE): A serious adverse event (experience) or reaction is any 
untoward medical occurrence that at any dose:  
1. results in death,  
2. is life-threatening, (NOTE: The term "life-threatening" in this context refers to an event 
in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe.) 
3. requires inpatient hospitalization or prolongation of existing hospitalization,  
4. results in persistent or significant disability/incapacity, 
5. is a congenital anomaly/birth defect, or  
6. is a medically important event or reaction. Medical and scientific judgment should be 
exercised in deciding whether other situations should be considered serious such as 
important medical events that might not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above. These should also usually be 
considered serious. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalization, or development of drug dependency or drug abuse.  
 
Adverse Reaction: An adverse reaction means any adverse event caused by a drug. Adverse 
reactions are a subset of all suspected adverse events in which there is a reason to conclude 
that the drug caused the event. 
Unexpected Adverse Drug Reaction (UADR): An adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (see the Investigator’s 
Brochure for an unapproved investigational medicinal product). 
Serious and Unexpected Suspected Adverse Reaction (SUSAR): The sponsor must report 
in an Investigational New Drug (IND) safety report any suspected adverse reaction to study 
treatment (including active comparators) that is both serious and unexpected (21 CFR 


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312.32(c)(1)(i)). Before submitting an IND safety report, the sponsor needs to ensure that the 
event meets all three of the definitions:  
• Suspected adverse reaction  
• Serious  
• Unexpected  
 
Severity: AEs will be graded on a 3-point scale and reported as indicated in the CRF. The 
intensity of an adverse experience is defined as follows: 
1 = Mild: event is medically significant but produces no disruption to daily activity; 
2 = Moderate: event is medically significant and reduces or affects normal daily activity; 
3 = Severe: event is medically significant and results in inability to work or perform normal 
daily activity. 
Investigational Product Causality: An assignment will be 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. 
6.14.2 
Eliciting and Reporting AEs  
The investigator will periodically assess each subject for the occurrence of AEs after the 
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. 


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It is the investigators responsibility to review the results of all laboratory tests as they 
become available. For each abnormal laboratory test result the investigator needs to ascertain 
if the result is a clinically significant change from baseline for that individual subject. This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed. The investigator may repeat the laboratory test or request additional tests 
to verify the results of the original laboratory tests. If the laboratory value is determined to be 
a clinically significant and an abnormal change from baseline for that subject, the result is 
considered a laboratory AE. 
Hypoglycemia is defined as any FPG or SMBG value ≤ 70 mg/dL and documented as 
described in Section 6.14.11. 
Any increase in liver function tests (AST, ALT, or bilirubin) greater than 3 times the ULN 
for the laboratory utilized will automatically be considered a laboratory AE unless the 
investigator specifically designates otherwise. In addition, investigators are reminded that 
any increase in liver function test values that fall below this threshold may be considered 
clinically significant and entered as an AE if the change is determined to be clinically 
significant. 
In addition, the sponsor’s Medical Monitor or its designated personnel must be notified 
immediately by telephone, email, or fax of any immediately reportable AEs (IRAE) 
according to the procedure outlined below. Special attention should be paid to recording 
hospitalization and concomitant medications. 
6.14.3 
Immediately Reportable AEs  
The investigator must report any SAE to the sponsor or its representative immediately after 
the investigator becomes aware of the event. An SAE form should be completed and sent to 
the sponsor or representative 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. The CRF 
AE form should be completed and sent to the sponsor. 
Subjects experiencing an SAE should be followed clinically until their health has returned to 
baseline status or no further improvement in condition can be expected with further care. It is 
expected that the investigator will provide or arrange appropriate supportive care for the 
subject. 
6.14.4 
Pregnancy  
WOCBP who are sexually active must use an effective method of birth control during the 
course of the study, in a manner such that risk of failure is minimized. 
Before enrolling WOCBP in this clinical trial, investigators must review guidelines about 
study participation for WOCBP. The topics should generally include: 


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• General information 
• Informed consent form 
• Pregnancy prevention information 
• Drug interactions with hormonal contraceptives 
• Contraceptives in current use 
• Guidelines for the follow-up of a reported pregnancy 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy. The 
subject must sign an informed consent form stating the above-mentioned risk factors and that 
the consequences were discussed with her. 
During the study, all WOCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (e.g., missed or late menstrual cycle). 
If a subject or investigator suspects that the subject may be pregnant prior to investigational 
product administration, the investigational product administration must be withheld until the 
results of serum pregnancy tests are available. If the pregnancy is confirmed, the subject must 
not receive the investigational product and must not be enrolled or remain in the study. If 
pregnancy is suspected while the subject is receiving study treatment, the investigational 
product must be withheld immediately until the result of the pregnancy test is known. If 
pregnancy is confirmed, the investigational product will be permanently discontinued and the 
subject will be withdrawn from the trial. (Exceptions to study discontinuation may be 
considered for life-threatening conditions only after consultations with the sponsor Medical 
Monitor or designated personnel.) The investigator must notify the Medical Monitor within 3 
working days of any female subject who becomes pregnant. This reporting requirement will 
continue until 4 weeks after the last investigational product exposure.  
The investigator must record the event on the Pregnancy Surveillance Form and forward it to 
sponsor’s Medical Monitor 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. 
6.14.5 
Procedure for Breaking the Blind  
As indicated in Section 5.5 above, the sponsor, medical monitor, study coordinators, 
pharmacists, study subjects, the CEC members and DKA adjudication committee members 
will be blinded to the treatment assignment during the study period. The investigator should 
also remain blinded to the subject treatment during the entire study unless knowledge of the 
subject’s treatment is required for clinical care and safety. The Emergency Code Break 
module in the IWRS is used for such situations. The investigator must confirm the intention 
to unblind the subject’s treatment to obtain the dose information in IWRS. Upon completion 


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of the unblinding, the system will send an alert to designated study team members that an 
unblinding event has occurred. Documentation of breaking the blind should be recorded in 
the subject’s medical record with the date and time the blind was broken, and the names of 
the personnel requesting and authorizing unblinding. The treatment assignment will continue 
to be withheld from the CEC members. 
6.14.6 
Follow-up of Non-Serious AEs  
Non-serious AEs that are identified on the last scheduled contact must be recorded in the AE 
CRF with the current status noted. All non-serious events that are ongoing at the time will be 
recorded as ongoing in the CRF. 
6.14.7 
Follow-up of Post-Study SAEs  
SAEs that are identified on the last scheduled contact must be recorded on the AE CRF page 
and reported to the sponsor according to the reporting procedures outlined in Section 6.14. 
These may include unresolved previously reported SAEs, or new SAEs. The investigator 
should follow these SAEs until the events are resolved, or the subject is lost to follow-up. 
Resolution means the subject has returned to the baseline state of health, or the investigator 
does not expect any further improvement or worsening of the subject’s condition. The 
investigator should continue to report any significant follow-up information to the sponsor 
until the event has been resolved.  
Any new SAEs reported by the subject to the investigator that occur after the last scheduled 
contact, and are determined by the investigator to be reasonably associated with the use of 
the investigational product, should be reported to the sponsor or designated personnel. This 
may include SAEs that are captured on follow-up telephone contact or at any other time point 
after the defined study period (i.e., up to last scheduled contact). The investigator should 
follow SAEs identified after the last scheduled contact until the events are resolved, or the 
subject is lost to follow-up. The investigator should continue to report any significant follow-
up information to the sponsor until the event has been resolved. This study requires that 
subjects be actively monitored for SAEs for at least 4 weeks after the last treatment. 
6.14.8 
Urinary Tract Infections (UTIs)  
Events potentially representing UTIs, including cystitis, urethritis, pyelonephritis, or 
urosepsis, should be carefully evaluated and documentation of signs, symptoms, culture 
results for infectious agent, and treatment should be undertaken when appropriate.  
The investigator should query the subject at every clinical visit for symptoms that may be 
related to a UTI and, if appropriate, document these events as symptomatic UTI in the CRF 
unless an alternative diagnosis is present. In addition, a clean catch urine sample 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 will be performed at the central laboratory. A positive 


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urine culture will be defined as one with ≥ 105 CFU of any species. The investigator may 
also perform a urine culture using local resources if necessary for clinical care.  
6.14.9 
Genital Mycotic Infections (GMIs) 
The investigator will query the subjects for signs or symptoms that may represent a GMI at 
all clinic visits. GMIs will be diagnosed based on symptoms and, if appropriate, physical 
exam and laboratory findings. Investigators must exclude the possibility of sexually 
transmitted infections before diagnosing GMI. Diagnosis of GMIs must be documented in 
the CRF. 
6.14.10 Hepatotoxicity  
If plasma AST and/or ALT concentrations > 3 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 
• 
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 discontinued. If no 
alternative cause of hepatotoxicity to the study drug is identified, the study drug should not 
be restarted. If an alternative cause of hepatotoxicity is identified, study drug administration 
may be resumed after the liver function testing returns to baseline and any related symptoms 
have resolved. If the liver function abnormalities or related symptoms recur after dosing is 
resumed, the study drug dosing 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. 


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6.14.11 Hypoglycemia  
Events of hypoglycemia or potentially representing hypoglycemia should be carefully 
evaluated.  
All subjects will be provided with a glucometer and diary for recording blood glucose 
measurements and signs and symptoms of hypoglycemia. During the study the subject is 
expected to record daily SMBG readings and all signs and symptoms that may potentially 
reflect hypoglycemia. In the event of such signs or symptoms, the subject is expected to 
check the blood glucose if it is reasonably safe to do so, and consume carbohydrates, if 
appropriate, to treat hypoglycemia.  
The subject will be expected to record in the glycemic control diary the following 
information for each hypoglycemic event: 
1. Signs and symptoms attributed to hypoglycemia and the time and date on which they 
occurred  
2. SMBG reading at the time of the signs and symptoms attributed to hypoglycemia 
3. Time elapsed from the most recent meal to the onset of signs and symptoms 
4. Duration, intensity, and type of any exercise within the 24 h prior to the signs and 
symptoms 
5. Type of treatment used (e.g., juice, crackers) for the signs and symptoms and whether 
assistance was required from another person to administer the treatment 
6. SMBG reading 15 minutes after treatment with carbohydrate and the time at which 
this was measured 
7. Whether or not the signs and symptoms attributed to hypoglycemia resolved after 
blood glucose returned to normal. 
 
Subjects are encouraged to call the study clinic should signs and symptoms potentially 
related to hypoglycemia occur. 
At each study visit, the investigator is expected to review the glucometer and glycemic 
control diary with particular attention to any SMBG value ≤ 70 mg/dL and any recorded 
signs or symptoms potentially related to hypoglycemia. In addition, the investigator should 
query the subject with regard to the occurrence of signs and symptoms potentially related to 
hypoglycemia even if none are recorded in the diary.  
In the event of a blood glucose value ≤ 70 mg/dL or signs and symptoms potentially related 
to hypoglycemia, the investigator should complete the supplemental CRF which will include 
data from the glycemic control diary and action items to reduce future hypoglycemia 
episodes.  
Hypoglycemia events will be recorded in the hypoglycemia log under 5 categories: 


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1. Severe hypoglycemia: an event requiring assistance by another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose 
measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration. All such 
events should be recorded as SAEs in the CRF. 
2. Documented symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by a measured plasma glucose concentration ≤ 70 mg/dL 
(3.9 mmol/L).  
3. Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of 
hypoglycemia but with a measured blood glucose concentration ≤70 mg/dL 
(3.9 mmol/L).  
4. Probable symptomatic hypoglycemia: an event during which symptoms of hypoglycemia 
are not accompanied by a blood glucose determination but that is presumably caused by a 
blood glucose concentration ≤ 70 mg/dL (3.9 mmol/L). 
5. Relative hypoglycemia: An event during which the person with diabetes reports any of 
the typical symptoms of hypoglycemia, and interprets those as indicative of 
hypoglycemia, but with a measured plasma glucose concentration > 70 mg/dL 
(3.9 mmol/L). 
 
While each event meeting the criteria above will be entered into the hypoglycemia log, only 
critical 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 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. 


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6.14.12 Diabetic Ketoacidosis (DKA) 
DKA is a serious, acute complication of diabetes and can be life-threatening. Subjects will be 
educated on the signs and symptoms of DKA and are required to call the study clinic and 
seek treatment should such signs and symptoms occur. 
During the clinical trial period, potential DKA will be monitored by the routine measurement 
of urinary ketones and assessment for signs or symptoms of acidosis at every clinic visit. 
Clinical presentations, such as difficulty breathing, abdominal pain, nausea, vomiting, 
lethargy, or a fruity smell in the breath, or laboratory values that suggest clinically significant 
acidosis should be documented. Treatment of DKA should be provided when appropriate.  
If ongoing symptoms or signs suggest a possible DKA, the investigator should perform 
relevant laboratory testing while directing appropriate medical care for the subject. If DKA is 
suspected, regardless of the blood glucose level, the following assessments should be done 
immediately: physical exam and serum glucose, bicarbonate, electrolytes, and serum ketones 
measured STAT at a local laboratory. If ketoacidosis is likely, investigational product 
administration should be discontinued and immediate appropriate medical therapy, including 
insulin, should be initiated. A glucose infusion may be provided if necessary to avoid 
hypoglycemia during insulin therapy. Insulin treatment should continue until resolution of 
the ketoacidosis and stabilization of the subject’s clinical condition. Investigational product 
administration may be resumed following stabilization of the subject’s condition. 
Investigator should collect the data necessary for the completion of the DKA CRF. 
If symptoms suggestive of DKA may have occurred but are not ongoing, investigator should 
review available data in order to complete the DKA CRF. The investigator may also perform 
laboratory assessment using local resources if necessary for clinical care. 
6.14.13 Major Adverse Cardiovascular Event (MACE) 
Evaluation of MACE will be undertaken across the development program for bexagliflozin. 
All MACE reports should also be captured as SAEs and every effort will be made to ensure 
that events recorded as MACE are coded in a similar manner within the safety database. The 
SAE listing will also be reviewed periodically by the CEC members to identify potential 
MACE that may not have been reported by the site investigators. All subjects will be 
followed by investigators for MACE for the duration of the study even if study medication 
has been permanently withdrawn. 
The independent CEC will receive and adjudicate the following events.  
 
All deaths 
 
Suspected non-fatal myocardial infarction (MI) 
 
Suspected hospitalization for unstable angina (HUA) 
 
Suspected transient ischemic attack (TIA) and stroke  
 
Suspected hospitalization for heart failure (HF) 
 
Reported coronary revascularization procedure 


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6.14.14 Amputation 
Amputation and related adverse events will be recorded in a case report form. During each 
study visit, the investigator should query the subject for any amputation and related adverse 
events and procedures. Investigators are reminded to counsel appropriate foot care to avoid 
cuts or sores and to treat even minor cuts or sores to prevent infection and ulceration. Patients 
who have had a previous amputation should be closely monitored. Special attention may be 
appropriate for patients who are also receiving thiazide diuretics as these have been shown to 
increase the risk of amputation in diabetics.  
6.15 Concomitant Medication Assessments 
A concomitant medication is any medication that the subject has been taking prior to 
enrollment and that the subject is expected to continue to take for some portion of the trial, as 
well as any medication other than the investigational product that the subject takes during the 
course of the trial. 
The medications or treatment for controlling hypoglycemia must be recorded as concomitant 
medications in the CRF. Any medication given to treat hyperglycemia and continued for 
more than 2 weeks is considered a rescue therapy and should be recorded in the concomitant 
medication log. 
Changes from baseline anti-hypertensive and anti-hyperlipidemia therapies and their 
rationale must be recorded in the CRF. 
All prescription and over-the-counter medications, including vitamins and herbal 
supplements, that subjects receive during the trial must be documented on the CRF. This 
documentation should continue until the subjects complete the study.  
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A table of concomitant medications based on the anatomic 
therapeutic chemical classification (ATC) and preferred name will be produced. A listing of 
concomitant medications will include all medications taken by any subjects during the course 
of the study. 
6.16 Healthy-related Quality of Life Assessment 
EQ-5D-3L is a multi-attribute utility instrument for measuring preferences associated with an 
individual’s health state. The instrument includes a visual analog scale and a descriptive 
system with 5 dimensions (mobility, self-care, usual activity, pain/discomfort, 
anxiety/depression), each of which has 3 levels (no problem, some problem, extreme 
problem). 
Enrolled subjects will complete the EQ-5D-3L questionnaire independently at clinic Visits 
V6, V11, V14 and V17. EQ-5D-3L should be completed prior to other scheduled procedures 
at those visits.  


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6.17 Removal of Subjects 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 investigator 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.  
Participation in a clinical trial is voluntary. A subject can withdraw from the study at any 
time. The sponsor may terminate the study for medical or administrative reasons. An 
investigator may decline to participate in the conduct of the study if either the investigator or 
the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) determines that, 
based on good medical judgment, immediate cessation is appropriate for subject safety. If a 
decision is made to withdraw a subject from the study, no further investigational product 
should be administered. Even if the subject discontinues 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 adverse event has occurred, 
3. A clinically significant change in a laboratory parameter has occurred, 
4. The sponsor or investigator 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 7.6. 
Subjects who withdraw from the study will not be replaced. 
6.18 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 
of risk of microvascular complications and is widely used as a measurement for the 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 V6. Visit V6 is the day of 
randomization and is the basis for all subsequent visit windows.  
7.1 
Screening Period 
7.1.1 
Visit V1 (3 days to 3 weeks for metformin-only group and up to 9 weeks for 
metformin-and-OHA group before run-in period) 
The screening can be performed from 3 days to 3 weeks before the start of the wash-out 
period for subjects who are metformin-and-OHA treated and 3 days to 3 weeks before the 
start of the run-in period for subjects who are metformin-only treated. 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 6.9.2.1. 
• 
Obtain medical history and demographic information 
• 
Perform an abbreviated physical examination and record body weight and height 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Perform a 12-lead ECG measurement 
• 
Draw blood if a minimum 10 h fast has been completed by the subject as described in 
Section 6.9.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 
• 
Collect a clean-catch, mid-stream urine sample 
 
7.2 
Wash-out and Run-in Period (Up to 8 weeks prior to 
randomization) 
The wash-out and run-in period is required for any enrolled subject who is taking metformin 
and one additional OHA. Eligible subjects who are taking metformin only will enter the run-
in period directly. 
7.2.1 
Wash-out Period (Visits V2 and V3) 
Two visits will be conducted during the wash-out period. V2 is an on-site clinic visit. At V3 
each subject will be evaluated by the investigator or study staff via a phone interview. 


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7.2.1.1 
Visit V2 (8 weeks prior to randomization) 
• 
Evaluate inclusion and exclusion criteria based on the information collected at the 
screening visit. Verify compliant fasting status as described in Section 6.9.2.1. 
• 
Counsel subject on appropriate diet and exercise (for subjects who are metformin-and-
OHA treated) 
• 
Dispense glucometer and instruct subject in SMBG determination and recording (for 
subjects who are metformin-and-OHA treated) 
• 
Start wash-out and discontinue the non-metformin OHA  
• 
Assess adverse events and potential DKA 
• 
Record pre-treatment medications 
 
7.2.1.2 
Visit V3 (6 weeks prior to randomization, off-site phone visit) 
• 
Review SMBG and glycemic control record 
• 
Assess adverse events and potential DKA 
• 
Record pre-treatment medications 
 
7.2.2 
Run-in Period  
7.2.2.1 
Visit V4 (2 weeks prior to randomization) 
• 
Counsel subject on appropriate diet and exercise (for subjects who receive metformin 
only and do not need a washout) 
• 
Dispense glucometer and instruct subject in SMBG determination and recording (for 
subjects who receive metformin-only) 
• 
Review SMBG and glycemic control record (for subjects who receive metformin + 1 
OHA) 
• 
Dispense run-in kits for run-in period 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Assess adverse events and potential DKA 
• 
Record pre-treatment medications 
 
7.2.2.2 
Visit V5 (3 to 5 days prior to randomization) 
• 
Evaluate inclusion and exclusion criteria based on the information collected at the 
screening visit. Verify compliant fasting status as described in Section 6.9.2.1. 
• 
Perform a complete physical examination and record body weight 
• 
Review SMBG and glycemic control record 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Perform a 12-lead ECG measurement 
• 
Draw blood if a minimum 10 h fast has been completed by the subject as described in 
Section 6.9.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Assess adverse events and potential DKA 
• 
Record pre-treatment medications 


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7.3 
Treatment Period (Day 1 to Week 96) 
At the end of the run-in period, subjects who have successfully completed run-in period and 
continue to meet the inclusion/exclusion criteria will be randomized and enter the treatment 
period. 
7.3.1 
Visit V6 (Day 1 of Week 1) 
Visit V6, day of randomization, must be conducted after the HbA1c value from the sample of 
Visit V5 is available for eligibility confirmation.  
• 
Complete EQ-5D-3L  questionnaire  
• 
Review SMBG and glycemic control record 
• 
Collect used run-in medications and dispense investigational products based on 
randomization 
• 
Assess adverse events and potential DKA 
• 
Record concomitant medications 
 
7.3.2 
Visit V7 (Week 2) 
• 
Review SMBG and glycemic control record 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Collect used study medication, if applicable, and dispense glimepiride based on up-
titration criteria assessment  
• 
Assess adverse events and potential DKA 
• 
Record concomitant medications 
 
7.3.3 
Visit V8 (Week 4) 
• 
Review SMBG and glycemic control record 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Collect used study medication, if applicable, and dispense glimepiride based on up-
titration criteria assessment  
• 
Assess adverse events and potential DKA 
• 
Record  concomitant medications 
 
7.3.4 
Visit V9 (Week 6) 
• 
Perform an abbreviated physical examination and record body weight 
• 
Review SMBG and glycemic control record 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Collect used study medication, if applicable, and dispense glimepiride based on up-
titration criteria assessment  
• 
Draw blood if a minimum 10 h fast has been completed by the subject as described in 
Section 6.9.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 


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• 
Collect a clean-catch, mid-stream urine sample 
• 
Assess adverse events and potential DKA 
• 
Record concomitant medications 
 
7.3.5 
Visit V10 (Week 12) 
• 
Review SMBG and glycemic control record 
• 
Record body weight 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Collect used study medications and dispense investigational products  
• 
Draw blood if a minimum 10 h fast has been completed by the subject as described in 
Section 6.9.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Assess adverse events and potential DKA 
• 
Record concomitant medications 
 
7.3.6 
Visit V11 (Week 24) 
• 
Complete EQ-5D-3L questionnaire  
• 
Perform an abbreviated physical examination and record body weight 
• 
Review SMBG and glycemic control record 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Perform a 12-lead ECG measurement 
• 
Collect used study medications and dispense investigational products  
• 
Draw blood if a minimum 10 h fast has been completed by the subject as described in 
Section 6.9.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Assess adverse events and potential DKA 
• 
Record  concomitant medications 
 
7.3.7 
Visit V12 (Week 36) 
• 
Perform an abbreviated physical examination and record body weight 
• 
Review SMBG and glycemic control record 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Collect used study medications and dispense investigational products  
• 
Draw blood if a minimum 10 h fast has been completed by the subject as described in 
Section 6.9.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Assess adverse events and potential DKA 
• 
Record concomitant medications 
 


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7.3.8 
Visit V13 (Week 48) 
• 
Perform an abbreviated examination and record body weight 
• 
Review SMBG and glycemic control record 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Collect used study medications and dispense investigational products 
• 
Draw blood if a minimum 10 h fast has been completed by the subject as described in 
Section 6.9.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Assess adverse events and potential DKA 
• 
Record concomitant medications 
 
7.3.9 
Visit V14 (week 60) 
• 
Complete EQ-5D-3L questionnaire  
• 
Perform a complete physical examination and record body weight 
• 
Review SMBG and glycemic control record 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Perform a 12-lead ECG measurement 
• 
Collect used study medications and dispense investigational products  
• 
Draw blood if a minimum 10 h fast has been completed by the subject as described in 
Section 6.9.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Assess adverse events and potential DKA 
• 
Record concomitant medications 
 
7.3.10 
Visit V15 (week 72) 
• 
Perform an abbreviated physical examination and record body weight 
• 
Review SMBG and glycemic control record 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Collect used study medications and dispense investigational products  
• 
Draw blood if a minimum 10 h fast has been completed by the subject as described in 
Section 6.9.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Assess adverse events and potential DKA 
• 
Record concomitant medications 
 
7.3.11 
Visit V16 (week 84, off-site phone visit) 
• 
Review SMBG and glycemic control record 
• 
Assess adverse events and potential DKA 
• 
Record concomitant medications 


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7.3.12 
Visit V17 (end of treatment, week 96) 
• 
Complete EQ-5D-3L questionnaire  
• 
Perform an abbreviated physical examination and record body weight 
• 
Review SMBG and glycemic control record 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Perform a 12-lead ECG measurement 
• 
Draw blood if a minimum 10 h fast has been completed by the subject as described in 
Section 6.9.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 
• 
Collect a clean-catch, mid-stream urine sample. 
• 
Collect used investigational products 
• 
Assess adverse events and potential DKA 
• 
Record concomitant medications 
 
7.4 
Visit V18 (Exit Visit or Early Termination Visit) 
7.4.1 
Visit V18 (week 98 or two weeks after the last dose of investigational 
product is administered or if a subject withdraws consent) 
• 
Perform a complete physical examination and record body weight 
• 
Review SMBG and glycemic control record 
• 
Measure vital signs, including blood pressures and heart rate 
• 
Draw blood if a minimum 10 h fast has been completed by the subject as described in 
Section 6.9.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2. 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Collect used investigational products if early termination 
• 
Assess adverse events and potential DKA 
• 
Record concomitant medications 
 
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 
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 products should have a 
follow-up examination, including a complete physical examination, vital signs, ECG, and 


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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 (SOPs) of the contract research organization 
(CRO) and the sponsor. Review procedures will be implemented at the CRO for all 
documents that are generated in relation to the study. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The following sections provide a summary of the planned analysis of the trial but a complete 
statistical analysis plan will be developed as a separate document and will be the final plan. 
All statistical analyses will be performed using SAS Version 9.2 or higher. 
In general, descriptive statistics (number of subjects [N], mean, standard deviation [SD], Q1, 
median, Q3, minimum and maximum) will be presented for continuous variables, and 
frequency and percentage for categorical variables.  
The primary efficacy non-inferiority test will be one-sided at 0.025 significance level. The 
upper bound of the 95% confidence interval (CI) on the difference of HbA1c reduction 
between bexagliflozin and glimepiride will be used to determine the study’s conclusion. That 
is, if the upper bound of the CI is within 0.35%, then the primary objective of the study is 
met. Superiority will be declared without additional statistical testing when the upper bound 
of the 95% CI for the difference in change from baseline at week 60 in HbA1c comparing 
bexagliflozin group with glimepiride group is less than 0.  
The secondary efficacy objectives will be tested at two-sided 0.05 significance level 
following a sequential testing procedure to control the overall type I error of 0.05. The 
secondary efficacy endpoints will be tested only if the primary efficacy assessment achieves 
significance, and following the hierarchy as below: 
1. Superiority test of the change in body weight in subjects with baseline BMI ≥ 25 kg/m2 in 
the bexagliflozin group compared with glimepiride group at week 60 
2. Superiority test of the change in SBP in subjects with baseline SBP ≥140 mmHg in the 
bexagliflozin group compared with glimepiride group at week 60 
3. Superiority test of the difference in  proportion of subjects with ≥1 severe or documented 
symptomatic hypoglycemia events in the bexagliflozin group compared with glimepiride 
group over 96 weeks 
 
The exploratory efficacy objectives and safety objectives will be analyzed descriptively. 
9.2 
Determination of Sample Size 
Approximate total 420 subjects will be randomized and equally allocated to receive 
bexagliflozin tablets 20 mg or placebo, and glimepiride capsules, 2 mg, 4 mg, 6 mg or 
placebo. 
The sample size calculation for this study is based on a two group t-test with a one-sided 
significance at the 0.025 level and the following assumptions: 
1. The non-inferiority limit (margin) for mean change from baseline to week 60 in HbA1c 
comparing bexagliflozin group to glimepiride group will be 0.35% 


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2. The pooled standard deviation for the change from baseline to week 60 in HbA1c for 
bexagliflozin group and glimepiride group will be 1.0% 
 
Under the above assumptions, an estimated sample size of 172 patients is needed in each 
treatment arm to detect non-inferiority of bexagliflozin to glimepiride with respect to change 
in HbA1c at week 60 from baseline. This estimation is based on a one-sided t-test with 90% 
power at a 0.025 level of significance. A sample size of 210 per arm has been selected to 
account for approximate 18% drop-out rate and to allow adequate safety evaluation. The total 
sample size for this study will be 420 subjects. 
This study will be conducted at multiple investigative sites and will likely involve various 
numbers of subjects at each site. Enrollment will be on a competitive basis, but will be 
capped at 40 subjects from each site. 
9.3 
Analysis Populations  
9.3.1 
Intention-to-Treat Analysis set 
All subjects who are randomized regardless of treatment adherence or availability of follow-
up data will be included in the intention-to-treat analysis set (ITT). All analyses of the ITT 
will be based on each subject’s randomized assigned treatment. The ITT analysis set will 
serve as the primary set for the efficacy analyses. 
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 taken by each subject.  The Safety Analysis Set is the primary analysis set 
for safety evaluation. 
9.3.3 
Per Protocol Analysis Set 
The Per Protocol (PP) Analysis Set will include all subjects in the ITT who meet the study 
eligibility requirements and have no major protocol deviations that affect the validity of the 
efficacy measurements. Protocol deviations that may result in subject exclusion from the PP 
Analysis Set will be detailed in the Statistical Analysis Plan. The 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 assessments. 
9.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively based on the ITT 
and PP analysis set for each treatment group as well as for all subjects combined. Key 
variables include age, gender, race, ethnicity, baseline HbA1c values, blood pressure, body 
weight, body mass index (BMI in kg/m2), fasting plasma glucose level, eGFR, duration of 
diabetes and prior anti-diabetic treatment status at screening (including type of therapy used 
[metformin, sulfonylurea, DPP-4 inhibitor, alpha-glucosidase inhibitor etc.]). In general, 


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baseline measurement is defined as the last measurement prior to the first dose of double-
blind medication. 
9.4.1 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD), and include medications that are either started prior to the study treatment and 
continue to be taken during the study treatment period, or medications started after the start of 
study treatment. Concomitant medications will be summarized by ATC term and by treatment 
groups.  
9.5 
Primary Efficacy Analyses 
9.5.1 
Hypotheses for the Primary Endpoint 
The null and alternative hypotheses for the primary endpoint are:  
H0: µ bexagliflozin - µ comparator > δ 
Ha: µ bexagliflozin - µ comparator ≤ δ 
Where µ bexagliflozin and µ comparator represent the mean change in HbA1c at week 60 from 
baseline for bexagliflozin and comparator groups, respectively. Non-inferiority margin δ is 
chosen to be 0.35% using clinical judgment, with reference to relevant regulatory guidance. 
9.5.2 
Statistical Methods for Primary Analyses 
For the primary endpoint, the treatment difference will be examined by using a mixed model 
repeated measures (MMRM) analysis of covariance model (ANCOVA). The model will 
include treatment, visit, treatment-by-visit interaction and randomization stratification factors 
as the fixed effects terms and the baseline HbA1c value as a fixed effect covariate. Least 
squares mean treatment differences between the bexagliflozin group and the comparator 
group at week 60 will be estimated from the model. An unstructured covariance will be used 
to model the within-subject correlation. If the model with the unstructured covariance 
structure does not converge, an autoregressive(1) covariance structure will be used.  
HbA1c values obtained after the start of rescue medication will not be excluded in the 
analysis. These analyses will be conducted on both ITT (primary) and PP analysis sets, and 
conclusions can be considered more robust when both approaches support the non-inferiority 
of the treatment. 
In non-inferiority analysis, a CI is calculated to estimate the range of values in which the 
treatment difference is likely to lie. This CI is used to provide the basis for drawing the 
study’s conclusions. In this specific test, if the 95% CI lies below the specified non-
inferiority margin 0.35%, the results would lead to a conclusion of non-inferiority of 
bexagliflozin treatment to glimepiride treatment. Superiority of bexagliflozin group over 


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glimepiride group at week 60 in HbA1c change from baseline will be declared if the upper 
bound of 95% CI is less than 0.  
Sensitivity analyses will also be performed as the following, and these analyses will be 
conducted for ITT and PP analysis sets. 
1. 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 MI techniques; HbA1c values collected after the start of rescue medication 
will not be excluded. 
2. Missing data will be imputed via LOCF, following which the MMRM will be repeated; 
HbA1c values collected after the start of rescue medication will be considered missing. 
3. HbA1c values collected after the start of rescue medication will be considered missing, 
and the MMRM analyses will be re-performed. 
 
9.5.3 
Analysis of Dropouts Pattern 
The early termination rate is estimated to be 18%. To the extent possible, attempts will be 
made to minimize the amount of missing data through measures planned in the study 
conduct. 
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. 
9.6 
Secondary Efficacy Analyses 
To assess the treatment effect on the change of body weight in subjects with baseline BMI ≥ 
25 kg/m2 at week 60, an analysis of covariance model (ANCOVA) will be implemented 
using all available data at week 60 (values obtained after the start of rescue medication will 
not be excluded in the analysis). The model will include treatment, randomization 
stratification factors, and the baseline weight value as fixed effects/covariates. Least squares 
mean treatment differences between the bexagliflozin group and the comparator group will 
be estimated from the model. The corresponding 95% CI and p-value will be provided. 
The change in systolic blood pressure (SBP) in subjects with baseline SBP ≥ 140 mmHg in 
the bexagliflozin group compared with glimepiride group at week 60 will be analyzed using 
the same method. 
The difference in proportion of subjects with ≥ 1 severe or documented symptomatic 
hypoglycemia events in the bexagliflozin group compared with glimepiride group over 96 
weeks will be analyzed using logistic regression model which includes terms of treatment, 
randomization stratification. Odd ratio estimates, 95% two-sided confidence intervals and p-
values for the treatment difference will be provided. 


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All analyses will be conducted in ITT analysis set. A hierarchical testing procedure will be 
applied to above three endpoints in the sequence provided above. 
9.7 
Other Efficacy Analyses 
Changes in FPG, SBP/DBP, and body weight for all subjects during the treatment period will be 
summarized descriptively by each time point (i.e., Weeks 2, 4, 6, 12, 24, …, etc.). In addition, 
these endpoints may be analyzed using a similar MMRM model as used for the primary analysis 
of HbA1c to compare two treatment groups.  
Cumulative summary on the proportion of subjects achieving HbA1c < 7%, and the proportion of 
subjects with documented hypoglycemia event will be presented over time. Generalized 
estimation equation (GEE) method may be utilized for assessment of treatment effects. 
Analyses will be conducted using ITT analysis set. 
9.8 
Analysis of Safety 
Safety data include AEs, physical exam results, vital signs, ECG results, and clinical lab results 
including serum chemistry, hematology, serum lipids, glycemic control parameters and 
urinalysis. Observed data will be summarized by treatment using safety analysis set.  
9.8.1 
Adverse Events 
AEs will be mapped to preferred term and body system using the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. AEs that begin at or after the first 
administration of double-blind study medication or existing AEs that worsen in severity after 
the first dose of double-blind study medication are considered treatment emergent AEs 
(TEAE). The number and percentage of subjects reporting TEAEs will be summarized for 
each treatment group by MedDRA system organ class and preferred term. Further summaries 
by severity, and by relationship to study treatment will also be provided. Drug-related 
adverse events will be considered those to be at least possibly related to the study treatments 
based on the investigators assessment.  
The number and percentage of subjects reporting serious AEs, and the number and 
percentage of subjects reporting AEs leading to treatment discontinuation will also be 
summarized for each treatment group by MedDRA system organ class and preferred term. 
9.8.2 
Adverse Events of Special Interest 
AE of special interest include UTI, GMI, diuretic effects, hepatotoxicity, cardiovascular 
events, hypoglycemia, fracture, malignancy, hypersensitivity reactions, hypotensive 
episodes, DKA, renal failure events, and amputation. These AEs of special interest will be 
prospectively identified based on the MedDRA preferred terms in the adverse event log by a 
medical expert prior to the data base lock and unblinding of the individual subject treatment 
assignment. The list of adverse events of special interest will be confirmed in a peer review 
process.  


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The number and percentage of subjects experienced TEAE of special interest will be 
summarized for each treatment group by types of events. The incidence rate of adverse 
events of special interest per 100 patient years will also be summarized. Additional analyses 
will be specified in the statistical analysis plan to evaluate other event associated safety 
parameters and potential risks in subpopulations based on age, gender, or other baseline 
characteristics. 
9.8.3 
Clinical and Laboratory Events and Analyses 
Clinical laboratory (see Section 6 for a complete list), vital signs, and 12-lead ECG will be 
measured at scheduled visits (see Appendix 1). These data will be summarized as actual 
values and changes from baseline by treatment for each visit for selected parameters.  
Laboratory data will be classified as low, normal or high relative to the parameter’s reference 
range. Laboratory abnormalities for each treatment will also be summarized with shift tables 
for selected parameters.  
9.8.4 
Physical Examination 
Physical examination findings will be presented in a by subject listing. 
9.9 
Health Related Quality of Life Assessment 
Descriptive statistics will be calculated for each item of the questionnaire, the EQ-5D-3L 
index score and visual analog score. Both actual values and changes from baseline will be 
summarized by treatment group for each visit. In addition, the changes from baseline in index 
score and visual analog score will be assessed for treatment effect using MMRM method. 
Similar to efficacy endpoints, the model will include treatment, visit, treatment-by-visit 
interaction and randomization stratification factors as the fixed effects terms and the baseline 
EQ-5D-3L index score (or visual analog score) as a fixed effect covariate. 
9.10 Interim Analysis 
No interim analysis will be performed during this study. 
9.11 Final Analysis 
After all subjects have completed the planned 60 weeks of blinded study treatment and the 
subsequent safety extension and follow-up periods, the final analysis of the clinical study will be 
completed. At this time, the database will be cleaned and locked, and the treatment codes will be 
unblinded. 


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
Information regarding key personnel involved in the conduct of the study, including names 
and contact details of participating investigators, monitors, clinical laboratories, and technical 
departments and/or institutions, as well as information on members of additional study 
committees, will be found in the study files of the investigational site. 
10.2 Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
The study protocol, informed consent document, relevant supporting information, and all 
types of subject recruitment or advertisement information must be submitted to the IRB/IEC 
for review and must be approved by the sponsor and the IRB/IEC before the study is 
initiated. Any amendments or addenda to the protocol must also be approved by the IRB/IEC 
prior to implementing changes in the study. The investigator is responsible for keeping the 
IRB/IEC informed of the progress of the study and of any changes made to the protocol as 
deemed appropriate, but in any case at least once a year. The investigator must also keep the 
IRB/IEC informed of any SAEs occurring to subjects under their supervision. 
10.3 Ethical Conduct of the Study 
The procedures set out in this protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the sponsor and investigator follow 
ICH 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 local regulations or 
institutional policy. 
Written informed consent must be obtained before any study-specific procedure takes place. 
Participation in the study and date of informed consent given by the subject should be 
documented appropriately in the subject’s files. A copy of the signed informed consent form 
must be provided to the subject. If applicable, it will be provided in a certified translation in 
the language understood by the subject, 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 paper or electronic format, will be 
supplied and maintained by the CRO staff and signed by the investigator or authorized 
designee to indicate that he/she has reviewed and agrees with the entered data. This also 
applies to those subjects who fail to complete the trial. The reason a subject is withdrawn 
must be recorded in the case report form. 
Entries made in the CRF must be verifiable against source documents. Source documents are 
defined as all medical records, medical notes, laboratory results, ECG traces and any 
additional document other than the CRF that has original subject information contained 
within it. 
All CRFs and source documents should be completed following GCP and the Sponsor or its 
designees standard operating procedures. 
10.8 Data Monitoring Committee 
An independent Data and Safety Monitoring Board (DSMB) will monitor overall safety 
information during the bexagliflozin development program. The safety review activity and 
potential risk benefit assessments utilized by the DSMB will be defined in its charter. 
10.9 Protocol Violations/Deviations 
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 


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


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


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Appendix 1 
Schedule of Events 
 
Screening 
Wash-out 
Run-in 
Efficacy Assessment 
Safety Extension 
Follow-
up 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
Time to Randomization Visit (wk) 
-11 
-8 
-6 
-2 
-0.5 
0 
2 
4 
6 
12 
24 
36 
48 
60 
72 
84 
96 
98 
Off-site phone visit 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
 
EQ-5D-3L 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Screening for I/E criteria 
X 
X 
 
X 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
Diet & exercise counseling 
X 
X 
 
 
 
 
 
Physical exam 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Abbreviated physical exam 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
Record height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record body weight 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Dispense diary & glucometer 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary & glucometer record review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Start wash-out 
X 
 
 
 
 
 
 
Dispense Run-in Medication 
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
Vital signs 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
ECG 
X 
 
X 
 
X 
X 
 
 
X 
 
Discontinue non-metformin OHA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense bexagliflozin 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense glimepiride 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Blood draw for clinical lab test 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Urine collection 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
AE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Med 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Appendix 2 
Schedule of Clinical Laboratory Tests 
 
 
Screening 
Wash-out 
Run-in 
Efficacy Assessment 
Safety Extension 
Follow-
up 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
Time to Randomization Visit (weeks) 
-11 
-8 
-6 
-2 
-0.5 
0 
2 
4 
6 
12 
24 
36 
48 
60 
72 
84 
96 
98 
Hematology 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Serum chemistry electrolytes 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Fasting Plasma Glucose 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
HbA1c 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Lipids 
X 
X 
 
X 
 
X 
 
 
X 
X 
Urinalysis 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Urine pregnancy test (UPT) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 






Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 79 of 79 
Version 3.0  (Global) 
Appendix 4 
Investigator’s Signature 
Study Title: 
A Phase 3, Randomized, Double-Blind, Active-Controlled Study to 
Evaluate the Effects of Bexagliflozin versus Glimepiride in Subjects 
with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic 
Control by Metformin 
Study Number: 
THR-1442-C-480 
V3.0 Final Date: 
27 October 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 

SAP_001.pdf: 
Statistical Analysis Plan 
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Version 1.0 
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1007777A 
 
This document is proprietary and confidential to INC Research LLC. 
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Sponsor Name: 
Theracos Sub, LLC 
Protocol Number and Title: 
 
THR-1442-C-480 A Phase 3, Randomized, 
Double-Blind, Active-Controlled Study to 
Evaluate the Effects of Bexagliflozin versus 
Glimepiride in Subjects with Type 2 Diabetes 
Mellitus Who Have Inadequate Glycemic 
Control by Metformin 
Protocol Version and Date: 
Version 3.0, 27 October 2016 
 
 
INC Research Project Code: 
1007777A 
Author(s): 
Fang Zhu, Principal Biostatistician 
SAP Version: 
Final Version 1.0 
SAP Version Date:  
24-Jun-2019 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Theracos Sub, LLC. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Theracos Sub, LLC.  However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation, INC Research should be notified 
promptly. 


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Revision History 
 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
0.1 
28-Jul-2016 
Fang Zhu 
Initial draft 
0.2 
3-Feb-2016 
Fang Zhu 
Update based on sponsor 
comments 
0.3 
1-Aug-2018 
Fang Zhu 
Update per SAP for THR-1442-
C-419 and THR-1442-C-423 
0.4 
29-Jan-2019 
Fang Zhu 
Update per comments 
0.5 
14-Mar-2019 
Fang Zhu 
Update per comments 
1.0 
24-Jun-2019 
Fang Zhu 
Updates includes: 
1. Correct WHO-DD 
version; 
2. Update the offset in 
section 8.2.4 for 
subjects used rescue 
medication; 
3. Add rule to compute 
compliance when 
some bottles 
dispensed are not 
returned; 
4. Add EQ-5D-3L score. 
 
 
 




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TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS ............................................................ 8 
2. 
PURPOSE ..................................................................................................... 11 
2.1. 
Responsibilities ................................................................................................................. 11 
2.2. 
Timings of Analyses .......................................................................................................... 11 
3. 
STUDY OBJECTIVES ................................................................................... 12 
3.1. 
Primary Objective .............................................................................................................. 12 
3.2. 
Secondary Objectives ....................................................................................................... 12 
3.3. 
Exploratory efficacy objectives: ....................................................................................... 12 
3.4. 
Safety Objectives ............................................................................................................... 13 
3.5. 
Other Objectives ................................................................................................................ 13 
3.6. 
Brief Description ................................................................................................................ 13 
3.7. 
Subject Selection ............................................................................................................... 14 
3.7.1. 
Inclusion Criteria ......................................................................................................... 14 
3.7.2. 
Exclusion Criteria ........................................................................................................ 14 
3.8. 
Determination of Sample Size .......................................................................................... 15 
3.9. 
Treatment Assignment & Blinding ................................................................................... 15 
3.9.1. 
Treatment Assignment ................................................................................................ 15 
3.9.2. 
Blinding ........................................................................................................................ 16 
3.10. 
Administration of Study Medication ................................................................................ 16 
3.11. 
Study Procedures and Flowchart ..................................................................................... 17 
4. 
ENDPOINTS .................................................................................................. 20 
4.1. 
Primary Efficacy Endpoint ................................................................................................ 20 


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4.2. 
Secondary Efficacy Endpoints ......................................................................................... 20 
4.3. 
Other Efficacy Endpoints .................................................................................................. 20 
4.4. 
Safety Endpoints ................................................................................................................ 20 
4.5. 
Other Endpoints ................................................................................................................. 21 
5. 
ANALYSIS SETS .......................................................................................... 22 
5.1. 
Screened Analysis Set ...................................................................................................... 22 
5.2. 
Safety Analysis Set ............................................................................................................ 22 
5.3. 
Intention-to-Treat Analysis Set ......................................................................................... 22 
5.4. 
Per Protocol Analysis Set ................................................................................................. 22 
5.5. 
Protocol Deviations ........................................................................................................... 22 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 24 
6.1. 
General Methods ................................................................................................................ 24 
6.2. 
Key Definitions ................................................................................................................... 24 
6.2.1. 
Baseline Values .......................................................................................................... 24 
6.2.2. 
First Dose Date ........................................................................................................... 24 
6.2.3. 
Study Day .................................................................................................................... 25 
6.2.4. 
Duration ....................................................................................................................... 25 
6.2.5. 
End of Study ................................................................................................................ 25 
6.2.6. 
Patient Years ............................................................................................................... 25 
6.3. 
Missing Data ....................................................................................................................... 25 
6.4. 
Analysis Visit Windows ..................................................................................................... 25 
6.5. 
Pooling of Centers ............................................................................................................. 26 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ....................................................................................................... 28 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 28 
7.2. 
Subject Eligibility and Protocol Deviations .................................................................... 28 
7.3. 
Demographic and Other Baseline Characteristics ......................................................... 28 


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7.4. 
Medical History .................................................................................................................. 29 
7.5. 
Medication .......................................................................................................................... 29 
7.5.1. 
Prior Medication .......................................................................................................... 30 
7.5.2. 
Concomitant Medication .............................................................................................. 30 
8. 
EFFICACY ..................................................................................................... 31 
8.1. 
Primary Efficacy Endpoint and Analysis ......................................................................... 31 
8.1.1. 
Primary Efficacy Analysis ............................................................................................ 31 
8.1.2. 
Sensitivity Analyses .................................................................................................... 33 
8.1.3. 
Subgroups ................................................................................................................... 34 
8.2. 
Secondary Efficacy Endpoint(s) and Analyses .............................................................. 35 
8.2.1. 
Change in body weight in subjects with baseline body mass index (BMI) ≥ 25 kg/m2 
at week 60 .................................................................................................................................... 35 
8.2.2. 
Change in SBP in subjects with baseline SBP ≥ 140 mmHg from baseline at week 60
 
35 
8.2.3. 
Difference in proportion of subjects with ≥ 1 severe or documented symptomatic 
hypoglycemia event over 96 weeks ............................................................................................. 36 
8.2.4. 
Sensitivity analysis ...................................................................................................... 36 
8.3. 
Exploratory efficacy endpoints and analyses ................................................................ 37 
8.3.1. 
Changes from baseline in HbA1c, body weight, SBP, and in FPG over time .............. 37 
8.3.2. 
Proportions of subjects with HbA1c of < 7% and the proportion of subjects with ≥ 1 
severe or documented symptomatic hypoglycemia events over time .......................................... 37 
9. 
SAFETY ......................................................................................................... 39 
9.1. 
Extent of Exposure ............................................................................................................ 39 
9.2. 
Treatment Compliance ...................................................................................................... 39 
9.3. 
Adverse Events .................................................................................................................. 40 
9.3.1. 
Derived Data ............................................................................................................... 41 
9.3.2. 
Data Summarization .................................................................................................... 41 
9.3.3. 
AE of Special Interest .................................................................................................. 42 
9.4. 
Laboratory Evaluations ..................................................................................................... 44 
9.5. 
Vital Signs ........................................................................................................................... 47 
9.6. 
Electrocardiogram ............................................................................................................. 47 
9.7. 
Physical Examination ........................................................................................................ 48 


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10. 
HEALTH RELATED QUALITY OF LIFE ASSESSMENT .......................... 49 
11. 
INTERIM ANALYSES ................................................................................ 50 
12. 
DATA AND SAFETY MONITORING BOARD ........................................... 50 
13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ......................... 50 
14. 
REFERENCE LIST .................................................................................... 51 
15. 
PROGRAMMING CONSIDERATIONS ...................................................... 52 
15.1. 
General Considerations .................................................................................................... 53 
15.2. 
Table, Listing, and Figure Format .................................................................................... 53 
15.2.1. 
General ........................................................................................................................ 53 
15.2.2. 
Headers ....................................................................................................................... 53 
15.2.3. 
Display Titles ............................................................................................................... 54 
15.2.4. 
Column Headers ......................................................................................................... 54 
15.2.5. 
Body of the Data Display ............................................................................................. 54 
15.2.6. 
Footnotes .................................................................................................................... 57 
16. 
QUALITY CONTROL ................................................................................. 58 
17. 
INDEX OF TABLES ................................................................................... 59 
18. 
INDEX OF FIGURES ................................................................................. 63 
19. 
INDEX OF LISTINGS ................................................................................. 64 
20. 
MOCK-UPS ................................................................................................ 66 
21. 
APPENDICES ............................................................................................ 66 
 
 


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


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


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Abbreviation 
Description 
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 
SS 
Safety Set 
T2DM 
Type 2 Diabetes Mellitus 
TC 
Total Cholesterol 
TEAE 
Treatment Emergent Adverse Event 
TG 
Triglycerides 
TLF 
Table, Listing And Figure 
TZD 
Thiazolidinedione 
UACR 
Urine Albumin To Creatinine Ratio  
UGE  
Urine Glucose Excretion  
ULN 
Upper Limit of Normal 
UPT  
Urine Pregnancy Test  
UTI 
Urinary Tract Infection 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives.   
2.1. 
RESPONSIBILITIES 
Theracos has designed the study protocol and is responsible for the conduct of the 
study.  INC Research is responsible for the development and validation of a clinical 
database using MediData RAVE platform.   
INC Research will perform the statistical analyses and are responsible for the production 
and quality control of all tables, figures and listings. 
Adverse events that have met the seriousness criteria defined in the protocol are reported 
on the serious adverse event (SAE) forms using MediData RAVE platform.  An SAE case, 
consists of the information reported in the SAE forms, subject characteristics documented 
in the case report forms (CRF), 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 will be reconciled between the ARGUS 
and THR-1442-C-480 clinical database prior to database lock.  The SAE coding, analyses 
and summaries are based on the final study data recorded in the clinical database. 
Detailed serious adverse event follow-up data will be reported from ARGUS database and 
not included this report. 
Theracos will perform review of all tables, figures and listings before the finalization. 
2.2. 
TIMINGS OF ANALYSES 
The final analysis of safety and efficacy is planned after all subjects have completed the 
96 weeks of treatment period and a two-week post-dose follow-up period.  The 
treatment assignment is blinded to all study personnel throughout the 96-week 
treatment and the two-week follow-up periods. The database will be cleaned and 
locked followed by the unblinding of subject treatment codes. 
 
 


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3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
The primary efficacy objective of this trial is to demonstrate that bexagliflozin is 
non-inferior to glimepiride by evaluating the treatment effect on Hemoglobin A1C 
(HbA1c) reduction at week 60 in subjects whose type 2 diabetes mellitus (T2DM) is 
inadequately controlled by metformin.  
3.2. 
SECONDARY OBJECTIVES 
• 
To evaluate the treatment effect of bexagliflozin vs. glimepiride on the change 
in body weight in subjects with baseline body mass index (BMI) ≥ 25 kg/m2 at 
week 60 
• 
To evaluate the treatment effect of bexagliflozin vs. glimepiride on the change 
in systolic blood pressure (SBP) in subjects with baseline SBP ≥ 140 mmHg at 
week 60 
• 
To evaluate the treatment effect of bexagliflozin vs. glimepiride on the 
difference in proportion of subjects with ≥1 severe or documented symptomatic 
hypoglycemia events over 96 weeks 
• 
To evaluate if bexagliflozin is superior to glimepiride on HbA1c reduction at 
week 60 
3.3. 
EXPLORATORY EFFICACY OBJECTIVES: 
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the change in 
the proportion of subjects achieving HbA1c < 7.0% over time 
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the change in 
HbA1c over time 
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the change in 
fasting plasma glucose (FPG) over time 
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the change in 
SBP over time 
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the change in 
body weight over time 
• 
To assess the treatment effect of bexagliflozin vs. glimepiride on the difference 
in proportion of subjects with ≥ 1 severe or documented symptomatic 
hypoglycemia events over time 


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3.4. 
SAFETY OBJECTIVES 
• 
To compare the effects of bexagliflozin vs. glimepiride on the incidence of 
adverse events of interest. Adverse events of interest are urinary tract infections 
(UTI), pyelonephritis urosepsis, genital mycotic infections (GMI), diuretic effects 
including hypovolemia, hypotension episodes, hypoglycemia, hepatotoxicity, 
major adverse cardiovascular events (MACE), fractures, malignancies, 
hypersensitivity reactions, acid-base disorders including diabetic ketoacidosis, 
rash, and renal failure events 
• 
To compare the effects of bexagliflozin vs. glimepiride on general safety 
assessments including treatment emergent adverse events, clinical laboratory 
events, 12-lead electrocardiograms (ECG) parameters, physical examinations, 
vital signs including orthostatic blood pressure, and use of concomitant 
medications 
3.5. 
OTHER OBJECTIVES 
• 
To compare the effects of bexagliflozin and glimepiride on health-related quality 
of life using a validated instrument EQ-5D-3L 
3.6. 
BRIEF DESCRIPTION 
THR-1442-C-480 is a phase 3, multi-center, randomized, double-blind, active-controlled 
study and aims to demonstrate that bexagliflozin is non-inferior to glimepiride as 
add-on therapy in subjects whose T2DM is not adequately controlled by metformin 
treatment. The primary efficacy endpoint is the change in HbA1c from baseline at week 
60. The study will enroll T2DM patients who are treated with only metformin 
(metformin-only) or who are treated with metformin and one additional oral 
hypoglycemic agent (metformin-and-oral hypoglycemic agent [OHA]). 
All subjects must have taken metformin at a stable dose of ≥ 1500 mg/day for ≥ 8 weeks 
prior to screening. Subjects can be eligible for the metformin-only treated group if they 
have received < 14 days of any other antidiabetic medications in the 8 weeks prior to 
screening.  Subjects can be eligible for the metformin-and-OHA treated group if they 
have received ≥ 14 days of no more than 1 other OHA in the 8 weeks prior to screening; 
subjects taking any other antidiabetic medication (in addition to metformin and the 
1 OHA) for < 14 days in the 8 weeks prior to screening are allowed. 
A total of 420 subjects who meet all the inclusion criteria, none of the exclusion 
criteria, and who consent to participate in the study are eligible for study enrollment. 
Metformin-and-OHA treated subjects will undergo a 6-week washout of the 
non-metformin OHA prior to the start of run-in. Subjects who complete the 2-week 
run-in and who meet all eligibility criteria will be randomized in a 1:1 ratio to receive 


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once daily double-blind treatment of either active bexagliflozin tablets with placebo 
glimepiride capsules (Group 1) or placebo bexagliflozin tablets and active glimepiride 
capsules (Group 2). Active treatment in Group 1 will be bexagliflozin tablets, 20 mg. 
Active treatment in Group 2 will be glimepiride capsules, 2, 4, or 6 mg. Study subjects 
will continue receiving open-labeled metformin background medication during the 
entire study at a stable dose and frequency. The treatment period will last 96 weeks 
and be conducted in an outpatient setting (Figure 1). 
Figure 1 
Study Design 
 
3.7. 
SUBJECT SELECTION 
The study population will include approximately 420 subjects whose T2DM is 
inadequately controlled by metformin and who meet all of the inclusion criteria, none 
of the exclusion criteria. Clinical sites in the North America and Europe are anticipated 
to recruit subjects. Clinical sites in other continents may also participate in the trial. 
3.7.1. 
Inclusion Criteria 
Refer to protocol Section 4.2 for a list of inclusion criteria. 
3.7.2. 
Exclusion Criteria 
 Refer to protocol section 4.3 for a list of exclusion criteria. 
 


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3.8. 
DETERMINATION OF SAMPLE SIZE 
An approximate total of 420 subjects will be randomized and equally allocated to 
receive: 
• 
bexagliflozin tablets, 20 mg and glimepiride, placebo capsules (referred to as 
bexagliflozin group in this document)  
• 
bexagliflozin tablets, placebo and glimepiride capsules, 2 mg, 4 mg, or 6 mg 
(referred to as glimepiride group in this document). 
The sample size calculation for this study is based on a two group t-test with a 
one-sided significance at the 0.025 level and the following assumptions: 
• 
The non-inferiority limit (margin) for mean change from baseline to week 60 in 
HbA1c comparing bexagliflozin group to glimepiride group will be 0.35% 
• 
The standard deviation for the change from baseline to week 60 in HbA1c for 
bexagliflozin group and glimepiride group will be 1.0% 
Under the above assumptions, an estimated sample size of 172 subjects is needed in 
each treatment arm to determine non-inferiority of bexagliflozin to glimepiride with 
respect to change in HbA1c at week 60 from baseline. This estimation is based on a 
one-sided t-test with 90% power at a 0.025 level of significance. A sample size of 210 
per arm has been selected to account for approximate 18% drop-out rate and to allow 
adequate safety evaluation. The total sample size for this study will be 420 subjects. 
3.9. 
TREATMENT ASSIGNMENT & BLINDING 
3.9.1. 
Treatment Assignment 
The study will be conducted at multiple investigative sites and will likely involve various 
numbers of subjects at each site. The study will have a competitive enrollment but the 
number of randomized subjects from each site will be capped at 40. Activation of 
investigational sites will be centrally controlled by an Interactive Web Response System 
(IWRS).  Subject randomization will be deactivated for all sites when the planned 
number of subjects is met. However, if a potential subject is in wash-out already and 
wishes to continue with the study, the subject will be allowed to continue and, if 
eligible, to be randomized. 
Eligible subjects who have completed the wash-out of oral hypoglycemic agent other 
than metformin and have met all study inclusion/exclusion requirements are to be 
randomized in a 1:1 ratio to receive active bexagliflozin with placebo glimepiride or 
active glimepiride with placebo bexagliflozin.  Subjects will be assigned to treatment 
groups in sequential order as they qualify for the study. Randomization will be stratified 
according to baseline (Visit V5) HbA1c (< 8.5% or ≥ 8.5%), treatment background 


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(metformin-only or metformin-and-OHA), and Visit V5 eGFR (≥ 90 or ˂ 90 and 
≥ 60 mL/min/1.73 m2). 
3.9.2. 
Blinding 
This is a double-blind, double dummy study. The sponsor, investigators, study 
coordinators, pharmacists, study subjects, the cardiovascular adjudication committee 
and the diabetic ketoacidosis committee will be blinded to the study medication.  
To maintain blinding of the individual treatment assignment, the results of urinary 
glucose testing will not be made available to any study personnel or subjects. If 
knowledge of the test substance is needed to manage a subject’s condition, the 
investigator will contact the IWRS to obtain the treatment assignment. If unblinding 
occurs for any reason, the time and reason for breaking the blind will be recorded on 
the case report form (CRF) and the sponsor must be notified within 24 hours. 
A designated statistician who is not involved with the study operation will hold the 
treatment codes. The unblinded treatment information can be provided to the Data and 
Safety Monitoring Board (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 
adjudication committee and diabetic ketoacidosis adjudication committee members 
until all global investigational studies are completed and final analyses to assess 
cardiovascular and ketoacidosis risks are conducted. 
3.10. 
ADMINISTRATION OF STUDY MEDICATION 
The following investigational products will be used for oral administration: 
• 
Bexagliflozin tablets, 20 mg: tablets containing 20 mg of bexagliflozin 
• 
Bexagliflozin tablets, placebo: tablets containing no bexagliflozin 
Active comparator will be: 
• 
Glimepiride capsules, 2 mg: capsules containing 2 mg of glimepiride 
• 
Glimepiride capsules, 4 mg: capsules containing 4 mg of glimepiride 
• 
Glimepiride capsules, 6 mg: capsules containing 6 mg of glimepiride 
• 
Glimepiride capsules, placebo: capsules containing no glimepiride 
Bexagliflozin tablets, 20 mg or placebo, should be taken with 250 mL of water in the 
morning prior to eating or drinking.  On the day of scheduled clinic visits when there is 


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fasting and blood is to be drawn, administration of bexagliflozin should be delayed until 
after blood is drawn and taken in the clinic or at home prior to the first meal with 250 
mL of water. 
Glimepiride capsules, 2, 4 or 6 mg or placebo, should be taken once daily with the first 
meal.  On the day of scheduled clinic visits when there is fasting and blood is to be 
drawn, administration of glimepiride shall be withheld until the first meal. 
3.11. 
STUDY PROCEDURES AND FLOWCHART 
The activities that must be performed at each clinic visit listed below are presented in 
Table 1.  
A visit window of ± 3 days is allowed for all visits except Visit 6. V6 is the day of 
randomization and the basis for the visit window. 
The study staff will contact each subject prior to a scheduled clinic visit to confirm the 
time of the visit and to remind the subject of proper fasting practice. A subject must be 
queried to assess compliance with an approximately 10 hours fast prior to blood draw to 
ensure the FPG and triglycerides values can be accurately determined. If a subject has 
not fasted for approximately 10 hours, the subject must return as soon as can be 
arranged (within 1 week) to provide a specimen after proper fasting. Blood samples will 
be transported to the central lab for analysis. 


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Table 1 
Schedule of Events 
 
Screeni
ng  
Wash-out  
Run-in  
Efficacy Assessment  
Safety Extension  Follow
-up  
Visit number  
V1  
V2  
V3  
V4  
V5  
V6  
V7  
V8  
V9  
V10  V11  V12  V13  V14  V15  V16  V17  
V18  
Time to Randomization Visit 
(wk)  
-11  
-8  
-6  
-2  
-0.5  
0  
2  
4  
6  
12  
24  
36  
48  
60  
72  
84  
96  
98  
Off-site phone visit  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
Informed Consent  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-3L  
 
 
 
 
 
X  
 
 
 
 
X  
 
 
X  
 
 
X  
 
Screening for I/E criteria  
X  
X  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical 
history  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diet & exercise counseling  
 
X  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam  
 
 
 
 
X  
 
 
 
 
 
 
 
 
X  
 
 
 
X  
Abbreviated physical exam  
X  
 
 
 
 
 
 
 
X  
 
X  
X  
X  
 
X  
 
X  
 
Record height  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record body weight  
X  
 
 
 
X  
 
 
 
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
Dispense diary & glucometer  
 
X  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary & glucometer record 
review  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Start wash-out  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Run-in Medication  
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
X  
 
 
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
ECG  
X  
 
 
 
X  
 
 
 
 
 
X  
 
 
X  
 
 
X  
 
Discontinue non-metformin 
OHA  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense bexagliflozin  
 
 
 
 
 
X  
 
 
 
X  
X  
X  
X  
X  
X  
 
 
 
Dispense glimepiride  
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 


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Screeni
ng  
Wash-out  
Run-in  
Efficacy Assessment  
Safety Extension  Follow
-up  
Visit number  
V1  
V2  
V3  
V4  
V5  
V6  
V7  
V8  
V9  
V10  V11  V12  V13  V14  V15  V16  V17  
V18  
Time to Randomization Visit 
(wk)  
-11  
-8  
-6  
-2  
-0.5  
0  
2  
4  
6  
12  
24  
36  
48  
60  
72  
84  
96  
98  
Blood draw for clinical lab test  
X  
 
 
 
X  
 
 
 
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
Urine collection  
X  
 
 
 
X  
 
 
 
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
AE  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Con Med  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Hematology  
X  
 
 
 
X  
 
 
 
X  
 
X  
 
X  
X  
 
 
X  
X  
Serum chemistry electrolytes  
X  
 
 
 
X  
 
 
 
X  
 
X  
 
X  
X  
 
 
X  
X  
Fasting Plasma Glucose  
X  
 
 
 
X  
 
 
 
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
HbA1c  
X  
 
 
 
X  
 
 
 
 
X  
X  
X  
X  
X  
X  
 
X  
X  
Lipids  
X  
 
 
 
X  
 
 
 
 
 
X  
 
 
X  
 
 
X  
X  
Urinalysis  
X  
 
 
 
X  
 
 
 
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
Urine pregnancy test (UPT)  
X  
 
 
 
X  
 
 
 
X  
X  
X  
X  
X  
X  
X  
 
X  
X  


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4. 
ENDPOINTS 
4.1. 
PRIMARY EFFICACY ENDPOINT 
• 
Change from baseline to week 60 in HbA1c compared to glimepiride 
4.2. 
SECONDARY EFFICACY ENDPOINTS 
• 
Change from baseline to week 60 in body weight in subjects with baseline body 
mass index (BMI) ≥ 25 kg/m2  
• 
Change from baseline to week 60 in SBP in subjects with baseline SBP 
≥ 140 mmHg  
• 
Difference in proportion of subjects with ≥ 1 severe or documented symptomatic 
hypoglycemia events over 96 weeks 
• 
Change from baseline to week 60 in HbA1c  
4.3. 
OTHER EFFICACY ENDPOINTS 
• 
Change over time in proportion of subjects achieving HbA1c < 7.0%  
• 
Change over time in body weight  
• 
Change over time in FPG  
• 
Change over time in SBP  
• 
Change over time in HbA1c  
• 
Difference in proportion of subjects with ≥ 1 severe or documented symptomatic 
hypoglycemia events over time 
4.4. 
SAFETY ENDPOINTS  
• 
Adverse events of interest are UTI, pyelonephritis urosepsis, GMI, diuretic 
effects including hypovolemia, hypotension episodes, hypoglycemia, 
hepatotoxicity, MACE, fractures, malignancies, hypersensitivity reactions, 
acid-base disorders including diabetic ketoacidosis, rash, and renal failure events 
• 
Laboratory testing, including hematology, serum chemistry, and urinalysis 
• 
Physical examination 
• 
12-lead ECG 
• 
Vital signs 
• Concomitant medication use 


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4.5. 
OTHER ENDPOINTS 
• 
Health-related quality of life instrument, EQ-5D-3L 
 
 


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5. 
ANALYSIS SETS 
5.1. 
SCREENED ANALYSIS SET 
The Screened Analysis Set will include all subjects screened for eligibility prior to 
randomization. The screened population will include screen failures. Unless specified 
otherwise, this population will be used for summaries of subject disposition. 
5.2. 
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 taken first.  The Safety Analysis Set is the primary analysis set 
for safety evaluation. 
 
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 (ITT) Analysis Set.  All analyses 
of the ITT Analysis Set will be based on each subject’s randomized assigned treatment.  
The ITT analysis set will serve as the primary set for the efficacy analyses. 
 
5.4. 
PER PROTOCOL ANALYSIS SET  
The Per Protocol (PP) Analysis Set will include all subjects in the ITT Analysis Set who 
meet the study eligibility requirements and have no major protocol deviations that 
affect the validity of the efficacy measurements.  Detailed protocol deviations that may 
result in subject exclusion from the PP Analysis Set are described in Section 5.5.  The PP 
Analysis Set will serve as the secondary set for efficacy assessment. 
 
5.5. 
PROTOCOL DEVIATIONS 
Protocol deviations will be captured during monitoring visits and recorded in CRF.  
Deviation will be classified into each of the 9 categories: enrollment criteria, 
non-compliance, laboratory, dosing, visit schedule, visit/procedure requirement, 
concomitant medication, informed consent, and other.  Date and details of the 
deviation will be recorded.  The list of deviation will be reviewed before unblinding and 
major protocol deviations that, in the opinion of the medical monitor, will be 
determined in the ongoing bases. The list of major protocol deviations will be further 
reviewed before database lock in the unblinded fashion and the deviations that could 
affect the primary and secondary variables will be determined.  Some possible types of 
major protocol deviations are showing in Table 2.  
 
 


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Table 2 
Some Possible Types of Major Protocol Deviations That Lead to 
Subject or Visit Exclusion from PP analysis set. 
Category  
Criteria 
Exclusion 
Inclusion/Exclusion 
Criteria  
 
 
Ineligible subject is enrolled  - Subjects not satisfying HbA1c inclusion criteria  
- Subjects not satisfying eGFR inclusion criteria 
(inclusion #4 and #7) 
- Treated with SGLT2 within 3 months of 
screening 
 
Subject exclusion 
Prior or Concomitant 
Medication Restrictions  
 
 
Use of another SGLT2 
inhibitor  
Use of an SGLT2 inhibitor, sulfonylurea, or 
additional metformin as the rescue medication 
for hyperglycemia  
Visit exclusion 
[exclude data post 
rescue medication 
starts] 
Randomization/Blinding  
 
 
Unblinding  
Blind was broken (requested in IWRS)  
Visit exclusion 
[exclude data post 
blind broken] 
Dosing and Compliance  
 
 
Dosing Non-Compliance 
Subject missed more than 20% of the 
investigational product doses for the 60 weeks 
of efficacy assessment period or missed more 
than 50% between week 48 and week 60 
Subject exclusion 
 
 
 
 
 


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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
Statistical methodology and analyses are in accordance with the principles outlined by 
the ICH E9 guidelines.  All statistical analyses will be conducted using SAS statistical 
software version 9.3 or higher.  
Tables, listings and figures (TLFs) will be produced in accordance with the principles 
outlined by the ICH E3 guidelines.  For most summary statistics, data will be analyzed 
by the following treatment groups:  Bexagliflozin 20 mg; Glimepiride; and total of all 
treatment groups.   
Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], Q1, median, Q3, minimum, and maximum) for continuous variables, and 
frequency and percentage of subjects for categorical and ordinal variables, unless 
otherwise specified.  
All 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 appear in the subject listings. 
No data imputation will be applied for missing values, unless otherwise specified.  
6.2. 
KEY DEFINITIONS 
6.2.1. 
Baseline Values 
For subject who is dosed, baseline is defined as the last non-missing value on or prior to 
the first dose of double-blind study medication. For subject who is not dosed, baseline 
is defined as the last non-missing value on or prior to the randomization date. 
 
6.2.2. 
First Dose Date 
Two “first dose dates” will be required, one for the Run-In period and one for the 
double-blind treatment period.  The first dose date for the Run-In period will be the 
date of administration of the first dose of single-blind placebo tablets during the Run-In 
period.  The first dose date for the double-blind treatment period will be the date that 
the first dose of randomized, double-blind study drug is administered.  Both first dose 


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dates will be obtained from the CRF.  Study analyses will use the double-blind 
treatment period first dose date.   
6.2.3. 
Study Day 
Study Day is the number of days starting from the first administration of double-blind 
study drug, which is counted as Study Day 1.  If the assessment date is after the date of 
the first double-blind medication, the study day is calculated as date of assessment - 
date of the first dose administration+1.  If the assessment date is prior to the date of 
the first double-blind medication, the study day is calculated as date of assessment - 
date of the first dose administration. 
6.2.4. 
Duration 
Duration of double-blind treatment will be determined as Double-Blind Duration = 
Double-Blind Last Dose Date - Double-Blind First Dose Date plus 1.  Duration of Run-In 
period will be determined as 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 CRF.   
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. 
6.3. 
MISSING DATA 
The handling of missing or incomplete data is described for each endpoint and data type 
(as needed) in Sections 7 to 10.   
6.4. 
ANALYSIS VISIT WINDOWS 
Table 3 shows how data will be mapped to analysis visits prior to selection of records 
for analysis. All post-baseline visits, including unscheduled and early termination visits, 
will be mapped.  After mapping the data to the analysis visits, the following rules will 
apply unless other handling is specified for a particular analysis.  
• 
If multiple records are available within a single analysis visit window, the record 
closest to the planned assessment day will be selected for analysis.  


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• 
If 2 records are equidistant from the target day, then the later record will be 
selected.  
• 
If a subject has no record in an analysis window, the subject will be considered 
missing at that visit. 
Table 3 
Analysis Visit Windows 
Data type 
Study Day Window 
Scheduled day   
Scheduled 
Visit/Week 
Body Weight, HbA1c, 
Fasting Plasma 
Glucose, Lab data 
(including Lipids), 
EQ-5D-3L 
Day  2 - 63 
Day 42 
Visit 9/Week 6 
Day 64 – 125 
Day 84 
Visit 10/Week 12 
Day 126 – 209 
Day 168 
Visit 11/Week 24 
Day 210 - 293 
Day 252 
Visit 12/Week 36 
Day 294 - 377 
Day 336 
Visit 13/Week 48 
Day 378 – 461 
Day 420 
Visit 14/Week 60 
Day 462 – 587 
Day 504 
Visit 15/Week 72 
> 587 
Day 672 
Visit 17/Week 96 
Vital signs (except 
for height and 
weight 
Day 2 - 21 
Day 14 
Visit 7/Week 2 
Day 22 - 35 
Day 28 
Visit 8/Week 4 
Day 36 - 63 
Day 42 
Visit 9/Week 6 
Day 64 – 125 
Day 84 
Visit 10/Week 12 
Day 126 – 209 
Day 168 
Visit 11/Week 24 
Day 210 - 293 
Day 252 
Visit 12/Week 36 
Day 294 - 377 
Day 336 
Visit 13/Week 48 
Day 378 – 461 
Day 420 
Visit 14/Week 60 
Day 462 – 587 
Day 504 
Visit 15/Week 72 
> 587 
Day 672 
Visit 17/Week 96 
ECG 
Day  2 - 294 
Day 168 
Visit 11/Week 24 
Day 295 – 546 
Day 420 
Visit 14/Week 60 
> 546 
Day 672 
Visit 17/Week 96 
* Week 96 is the end of treatment visit for those subjects completing the study per 
protocol. For endpoint of lab and vital sign, the first collection after assigned Week 96 
and > 7 days from Week 96 visit will be considered as Week 98 visit.  
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 the ITT and PP populations for 
analysis that contain region as a model effect.  The tables below show which countries 
comprise each of the regions to be used in analysis.   
 


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Region 
Country 
Europe 
Germany 
Poland  
Spain 
North 
America 
United States 
 
 
 


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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition data will be listed. A disposition table will present, by treatment 
group and overall, the number and/or percentage of subjects who signed the informed 
consent and entered the study (i.e., were screened, screen failed prior to Run-in, 
screen failed during the Day -14 to Day -1 Run-in, and randomized), complete the study 
drug dosing, discontinued study drug dosing, completed the study, and discontinued 
from the study after randomization.  The reasons for early withdrawal after 
randomization will be summarized.   
Assignment to the analysis sets (safety, ITT, and PP) will be summarized.  
7.2. 
SUBJECT ELIGIBILITY AND PROTOCOL DEVIATIONS 
All subjects, including screen failure subjects, who violate the Inclusion/exclusion 
criteria will be listed.  Reason for screen failure will be summarized. 
Deviations that could affect the primary and secondary variables will be considered 
when determining a subject’s eligibility for the PP population. The number and percent 
of subjects who had any major deviation and each type of major protocol deviation will 
be tabulated for the ITT Analysis Set.  All deviation term and class will be listed. 
7.3. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic characteristics include age, gender, race, ethnicity and country of 
investigational site. Baseline characteristics include baseline HbA1c values, blood 
pressure, height, body weight, BMI, FPG, eGFR, eGFR at baseline categories (≥ 90 or ˂ 
90 mL/min/1.73 m2), duration of diabetes from diagnosis to the date of informed 
consent, and prior anti-diabetic treatment status at screening (including type of therapy 
used [metformin, sulfonylurea, DPP-4 inhibitor, alpha-glucosidase inhibitor etc.]). 
Randomization stratification related factors will be summarized based on data collected 
on CRF or by lab.  They include HbA1c values at baseline (< 8.5% vs. ≥ 8.5%), background 
anti-diabetic treatment status (metformin-only or metformin-and-OHA), eGFR at 
screening, and eGFR at screening categories (≥ 90 or ˂ 90 and ≥ 60 mL/min/1.73 m2). 
Stratification factors from IWRS will be summarized.  Summary descriptive statistics by 
treatment will include counts and percentages for discrete variables and estimation of 
means, standard deviations, medians, inter-quartile range (Q1, Q3), minimum, and 
maximum for continuous variables. Subjects’ baseline demographic and personal 
baseline characteristics will be summarized by treatment group and overall for subjects 
in the Safety, ITT, and PP Analysis Set. Subject age at screening visit collected on CRF 
will be used. 


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Demographics data and randomization stratification factors will be presented in a data 
listing.  Prior treatment will be listed along with all medications. 
7.4. 
MEDICAL HISTORY 
Significant medical and surgical history, including dates of diagnoses and procedures 
and whether the condition is ongoing, if applicable, will be collected. Each condition 
will be recorded as a verbatim term, date of onset, date resolved, and a checkbox that 
indicates ongoing conditions.  Significant surgical and medical history will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) Version 19.0. 
Medical and surgical history will be summarized for the Safety Analysis Set by treatment 
group, system organ class (SOC), and MedDRA preferred term (PT), overall. Subject data 
will be listed. 
Subject diabetes and cardiovascular diseases history will be summarized for all 
categorical variables by frequency and percentage.  Listing will be provided. 
7.5. 
MEDICATION 
All prescription and over-the-counter medications, including vitamins and herbal 
supplements, that subjects receive during the trial must be documented on the CRF. 
The medication name, dose, frequency, route of administration, date(s) of 
administration and reason for administration must be recorded. This documentation 
should continue through the treatment period and the follow up period. Changes from 
baseline anti-hypertensive therapy and their rationale must be recorded in the CRF.  
All medication will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) version Enhanced B2 format.  Preferred drug name, Anatomical/Therapeutic/ 
Chemical (ATC) class will be reported for inclusion in the database.   
Medication summaries based on ATC level 2, and the preferred drug names will be 
produced for the Safety Analysis Set. The summaries will present, by treatment group, 
the frequency and percentage of subjects who used any medication in an ATC class, or 
any medication based on a single preferred drug name. Subjects will be counted only 
once for each medication class and each preferred drug name.  
For subject listings, medications will be reported based on ATC class and PT; multiple 
medications for an individual subject will be listed by start date and then by stop date, 
from earliest to latest medications.  


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7.5.1. 
Prior Medication 
Any medication with a stop date prior to or on first dose date for the double-blind 
treatment period will be considered a prior medication.   
No summary for prior medication will be presented.  Prior and concomitant medications 
will be presented together on a single listing.  The listing will be ordered by subject 
number and medication start/end dates. Prior medication will be flagged.   
7.5.2. 
Concomitant Medication 
A concomitant medication is any medication that the subject has taken in any time 
during the study treatment period.  In the case of completely missing stop date, 
medication will be assumed to be concomitant. 
All medication should be recorded in the concomitant medication log.  Any medication 
given to treat hyperglycemia and continued for more than 2 weeks during the efficacy 
evaluation period of 60 weeks is considered a rescue therapy. Increase total daily dose of 
metformin, the background hypoglycemic therapy, during the treatment period is not 
allowed. However, if the dose of metformin is intensified during the double-blind 
treatment period for more than 2 weeks before the week 60 assessment, or study 
treatment stops if subject dropped out before week 60, it is also considered as rescue 
medication. All medications given to treat hyperglycemia will be recorded as concomitant 
medications in CRF. 
Concomitant medications will be presented in a summary table as well as in a subject 
listing.  Rescue medications will be summarized in a separate table and flagged in the 
same listing. 
 
 


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8. 
EFFICACY 
Efficacy data include HbA1c, FPG, body weight, SBP, and hypoglycemia event.  
8.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
The primary efficacy hypothesis is that bexagliflozin is non-inferior to glimepiride in 
reducing HbA1c after 60 weeks of treatment. For all analysis of primary efficacy 
endpoint, all post-baseline values up to week 60 will be used. All visits, including visits 
after 60 weeks, will be summarized. 
8.1.1. 
Primary Efficacy Analysis 
Let μbexagliflozon and μGlimepiride represent the mean changes from baseline in HbA1c at Week 
60 for bexagliflozin and comparator groups, respectively. The following hypotheses will 
be tested: 
H0: μbexagliflozon – μGlimepirider > δ versus  
H1: μbexagliflozon – μGlimepirider ≤ δ 
Non-inferiority margin δ is chosen to be 0.35% using clinical judgment, with reference 
to relevant regulatory guidance, and justified by published glimepiride efficacy study 
(Charpentier et al. 2001).  
This hypothesis will be tested based on ITT analysis set. Missing data will be imputed via 
multiple imputations, following which the MMRM will be repeated on the complete 
datasets with results combined across complete datasets using standard multiple 
imputations techniques; HbA1c values collected after the start of rescue medication will 
not be excluded. A pattern-mixture model will be used to explore the impact of the 
missing data. Imputation will be conducted within each treatment arm and subgroup 
(treatment completer vs. treatment terminated early) under the assumption that non-
adherent subjects with missing data will follow the same trajectory of non-adherent 
subjects with values observed. All efforts will be made to retain subjects in the study. If 
treatment is discontinued, subjects are encouraged to remain in the study and complete 
all scheduled visits, including final follow-up visit. However, with all efforts, insufficient 
values may be available for reliable imputation. This analysis will be performed only if 
≥3% (approximately 6) of subjects in each treatment arm completed scheduled week 60 
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: 
1. Non-monotone (intermediate visits) missing data will be imputed first using the 
Monte Carlo Markov Chain (MCMC) method under the MAR assumption in all 


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treatment arms (using the MCMC statement in PROC MI). Multiple chains option 
(CHAIN=MULTIPLE option in the MCMC statement of PROC MI) will be used. For 
the non-monotone imputation of the HbA1c missing data, a multivariate normal 
model will be used including variables for the HbA1c at baseline and all 
post-baseline visits within each treatment group. Five hundred imputed datasets 
will be generated.  
2. 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 60 week of study treatment, 
using regression approach. The predictors for the regression imputation model at 
any time point will be region, treatment background (metformin only or 
metformin and OHA), baseline eGRF (≥ 90 or < 90 ml/min/1.73 m2), and HbA1c at 
all previous time points, including baseline. Imputations will be performed using 
a sequence of regression-based imputations (using PROC MI statement 
MONOTONE REG) at each post-baseline time point.  
3. 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 region, terms for treatment background (metformin only or metformin 
and OHA), baseline eGRF (≥ 90 or < 90 ml/min/1.73 m2), treatment, visit, 
treatment-by-visit interaction, and the baseline HbA1c value, as a fixed effect 
covariate. The analysis will evaluate the mean change from baseline in HbA1c 
over the 60-week double blind treatment period. An unstructured covariance will 
be used to model the within subject correlation. The Kenward Roger 
approximation will be used to estimate denominator degrees of freedom. If the 
model with the unstructured covariance structure does not converge, an 
autoregressive(1) covariance structure will be used. HbA1c values obtained after 
the start of rescue medication will not be excluded from the analysis. The 
treatment and treatment by visit interaction terms allow for comparisons of the 
treatment groups at each visit, and over week 12 to week 60. Least squares (LS) 
mean treatment differences between the bexagliflozin group and the placebo 
group at week 60 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 60 values from treatment discontinued subjects are available for 
imputation, MMRM analysis as in step 3 will be performed using all available data. 
Sample SAS code will be provided in Appendix. 
In non-inferiority analysis, a CI is calculated to estimate the range of values in which 
the treatment difference is likely to lie.  This CI is used to provide the basis for drawing 
the study’s conclusions.  In this specific test, if the 95% CI lies below the specified 
non-inferiority margin 0.35%, the results would lead to a conclusion of non-inferiority of 


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bexagliflozin treatment to glimepiride treatment.  Lower HbA1c value indicates 
improvement on subject diabetes condition.  Larger decrease would indicate better 
treatment effect of bexagliflozin compared to glimepiride.  Hence, superiority of 
bexagliflozin group over glimepiride group at week 60 in HbA1c change from baseline 
will be declared if the upper bound of 95% CI is less than 0. 
Descriptive statistics (n, mean, Q1, median, Q3, SD, minimum, and maximum) will be 
reported by treatment group and visit, along with the least squares means, differences 
between LS means, a 2-sided 95% confidence interval for each difference, p-values from 
the model effects. In addition, the LS means with standard errors of the change from 
baseline over time and difference between treatment groups with 95% will be presented 
graphically for the ITT population.   
For supportive analyses, regardless of having sufficient week 24 values from treatment 
discontinued subjects are available for imputation or not, MMRM analysis will be 
performed using all available data. The primary efficacy endpoint will also be analyzed 
with all observed available data using MMRM method for the PP analysis set.  
8.1.2. 
Sensitivity Analyses 
Randomized subjects who withdraw consent to participate in the study will not be 
replaced. The early withdrawal rate is estimated to be 18%.  To the extent possible, 
attempts will be made to minimize the amount of missing data through measures 
planned in the study conduct. 
To investigate the possible implications of missing values in efficacy assessments, the 
number, timing, pattern, and reason for the missing value will be summarized.  The 
reason for withdrawal will be reviewed. If there are missing values for the primary 
analysis described in section 8.1.1, only available data will be analyzed and data 
obtained after rescue will not be excluded.   
The dropout patterns will be assessed by a Kaplan-Meier plot of time to discontinuation 
by treatment group to assess whether they differ between treatment groups.   
To evaluate the impact from missing data and rescue medication, the following 
sensitivity analyses will be conducted: 
1) Tipping point analysis will be conducted. Data after rescue medication will be 
considered as missing. The following steps will be implemented: 
a. Create monotone missing data as step a in the primary analysis in 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, 


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treatment background (metformin only or metformin and OHA), baseline eGRF (≥ 
90 or < 90 ml/min/1.73 m2), treatment, and HbA1c at all previous time points, 
including baseline. The first imputed values will be penalized or rewarded based 
on the treatment subject received: 
o Subjects in the bexagliflozin group: missing value will be analyzed assuming 
the treatment effect is worsened by δ1 (where δ1 = 0.1 to 0.5, in step of 0.1) 
compared to the subjects who have no missing value in the reduction of 
HbA1c value; 
o Subjects in the glimepiride group: missing value will be analyzed assuming 
the treatment effect is better by δ2 (where δ2 = 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; 
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 3 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) Additionally, the impact of the data after the start of rescue medication will be 
evaluated. HbA1c values collected after the start of rescue medication will be 
considered missing, and the MMRM analyses will be performed. Same statistics 
provided for the primary analysis will be presented. 
8.1.3. 
Subgroups 
Descriptive and MMRM model comparison using all available data for the primary 
endpoint will be repeated by subgroups.  The nominal p-value will be presented without 
adjustment to the multiple comparisons.  They are not used for inferential purpose.  
The subgroups include: 
• 
Age (< 65 years or ≥ 65 years) 
• 
Gender (male or female) 
• 
Race (white or Caucasian; black or African-American; other) 
• 
Baseline HbA1c (< 8.5% or ≥ 8. 5%) 
• 
Treatment background (metformin-only or metformin-and-OHA) 
• 
Baseline eGFR (≥ 90 or < 90 mL/min/1.73m2) 


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• 
Region 
8.2. 
SECONDARY EFFICACY ENDPOINT(S) AND ANALYSES 
The secondary endpoints will only be tested when the non-inferiority of the primary 
efficacy assessment is established at one-sided significance level of 0.025.  To control 
the overall type I error of 0.05, the secondary efficacy objectives will be tested at 
one-sided 0.025 significance level following the sequence below:   
• 
Superiority test of the change in body weight in subjects with baseline body mass 
index (BMI) ≥ 25 kg/m2 at week 60. 
• 
Superiority test of the change in SBP in subjects with baseline SBP ≥ 140 mmHg 
from baseline at week 60.  
• 
Superiority test of the difference in proportion of subjects with ≥ 1 severe or 
documented symptomatic hypoglycemia events over 96 weeks 
Analysis for secondary endpoints will be based on ITT analysis set and repeated for PP 
analysis set. For body weight and SBP, all post-baseline values up to week 60 will be 
used for model analysis. All values will be summarized.  
8.2.1. 
Change in body weight in subjects with baseline body mass index 
(BMI) ≥ 25 kg/m2 at week 60 
This will be tested if the non-inferiority of HbA1c and the previous secondary efficacy 
endpoints are significant. Data after rescue medication will not be excluded.  The 
comparison of change in body weight between randomized treatments at week 60 will 
be carried out using the similar MMRM model as section 8.1.1 using all available data. 
The model will include terms for region, treatment, baseline HbA1c as continuous 
variable, treatment background (metformin-only or metformin-and-OHA), and baseline 
eGFR (≥ 90 or ˂ 90 mL/min/1.73 m2) as fixed effects and the corresponding baseline 
weight value as covariate. Treatment comparison p-values and difference at week 60 
will be estimated from the model, with the two-sided 95 % CIs of the treatment 
difference also presented.  If the superiority of HbA1c is not established, the nominal 
p-value will not be used for inferential purposes. Summary table will be presented and 
figures will be displayed for ITT population. 
8.2.2. 
Change in SBP in subjects with baseline SBP ≥ 140 mmHg from 
baseline at week 60 
This will be tested if the change from baseline body weight is significantly different 
between bexagliflozin and glimepiride groups based on ITT analysis set for subjects with 
a BMI ≥ 25 kg/m2.  Change from baseline in SBP at week 60 will be analyzed in a similar 
manner as change in body weight, Section 8.2.1, based on ITT analysis set for all 


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subjects. Baseline SBP will be used in place of baseline weight.  Summary table will be 
presented and figures will be displayed for ITT population. 
8.2.3. 
Difference in proportion of subjects with ≥ 1 severe or 
documented symptomatic hypoglycemia event over 96 weeks 
This will be formally tested if the previous secondary efficacy endpoints are significant.  
Events after the start of rescue medication will be counted.  Descriptive statistics of 
frequency and percentage will be provided.  Logistic regression model will be used, with 
region, treatment, baseline HbA1c, treatment background (metformin-only or 
metformin-and-OHA), and baseline eGFR (≥ 90 or ˂ 90 mL/min/1.73 m2) as fixed 
effects.  Odd ratio estimates, 95% two-sided confidence intervals and p-values for the 
treatment difference will be provided.  Summary table will be presented and figures 
will be displayed for ITT population. 
8.2.4. 
Sensitivity analysis 
For all secondary analysis 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; Values collected after the start of rescue medication will be 
considered missing. 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, 
treatment background (metformin only or metformin and OHA), baseline eGRF (≥ 
90 or < 90 ml/min/1.73 m2), 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 at week 60 on that endpoint (i.e. the mean change from baseline 
at week 60). Imputed values for subjects in glimepiride 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. 
For the sensitivity analyses of proportion of subjects with hypoglycemia event, to 
account for subject discontinuation, incidence rate will be analyzed using negative 
binomial regression model. Data collected after the start of rescue medication will be 
considered as missing.  The number of severe or documented symptomatic 


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hypoglycemia events will be used as outcome. Model will include region, treatment 
background (metformin only or metformin and OHA), baseline eGRF (≥ 90 or < 90 
ml/min/1.73 m2), treatment, and baseline HbA1c as fixed effect and the logarithm of 
the duration from first dose of double-blind treatment to date of week 96 visit as 
offset. If subject discontinued before week 96 visit, the date of discontinuation will be 
used. If subject used rescue medication, the last date before rescue medication will be 
used. The adjusted mean incidence over 96 weeks, 95% CI for each treatment arm, the 
risk ratio, 95% CI, and p-value will be presented.  
8.3. 
EXPLORATORY EFFICACY ENDPOINTS AND ANALYSES 
All endpoints in this section are exploratory.  No sensitivity analysis and adjustment for 
multiple comparisons will be conducted.  Nominal p-values will be used to examine any 
trends in these endpoints.  
8.3.1. 
Changes from baseline in HbA1c, body weight, SBP, and in FPG over 
time 
The schedule of HbA1c, FPG, body weight, and SBP/DBP can be found in Table 1.  The 
absolute value and change from baseline in HbA1c, FPG, body weight and SBP/DBP 
during the double-blind treatment period will be summarized by descriptive statistics at 
each visit.  Change from baseline in HbA1c will be analyzed as part of primary efficacy 
analysis.  The change from baseline in body weight for subjects with baseline BMI ≥ 25 
kg/m2, SBP for subject with baseline SBP ≥ 140 mmHg, SBP for all subjects, and FPG will 
be analyzed using the MMRM ANCOVA model from primary analysis as a template 
(Section 8.1.1).  The fixed effect for change from baseline in body weight and SBP will 
include region, baseline HbA1c as continuous variable, treatment background 
(metformin-only or metformin-and-OHA), and baseline eGFR (≥ 90 or ˂ 90 mL/min/1.73 
m2), treatment, visit, and treatment-by-visit. The change from baseline in FPG will 
include region, treatment background (metformin-only or metformin-and-OHA), and 
baseline eGFR (≥ 90 or ˂ 90 mL/min/1.73 m2), treatment, visit, and treatment-by-visit. 
The appropriate baseline values will be used as covariate.  LS means for each treatment 
and the difference between treatments will be estimated at each visit and across all 
post-baseline visits.  The corresponding p-values will also be presented. 
8.3.2. 
Proportions of subjects with HbA1c of < 7% and the proportion of 
subjects with ≥ 1 severe or documented symptomatic 
hypoglycemia events over time  
Summary on the proportion of subjects achieving HbA1c < 7% at each visit and the 
proportion of subjects with documented hypoglycemia event during each 12-week visit 
interval will be presented over time.  They will be analyzed using generalized 
estimating equation (GEE) logistic regression.  The fixed effect will include region, 
treatment background (metformin-only or metformin-and-OHA), baseline eGFR (≥ 90 or 


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˂ 90 mL/min/1.73 m2) and baseline HbA1c, treatment, visit, and treatment-by-visit.  An 
unstructured correlation structure will be used (or autoregressive(1) if the model with 
the unstructured structure does not converge).  The LS mean proportion for each 
treatment will be estimated at each post-baseline visit and across all post-baseline 
visits.  The odds ratios of bexagliflozin group over the glimepiride group at each visit 
and across all post-baseline time points will be estimated from LS means based on the 
model with the corresponding p-values and their two-sided 95 % CIs presented. Sample 
SAS code will be provided in Appendix. 
 
 


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9. 
SAFETY 
The Safety Analysis Set will be used for analyzing the safety parameters. Safety data 
include AEs; physical examination results; vital signs; ECG results; and clinical 
laboratory results, including serum chemistry, hematology, serum lipids, and urinalysis.  
Observed data will be summarized by treatment group as counts and percentages for 
discrete variables and means, standard deviations, medians, minimum, and maximum 
for continuous variables. All subjects who are randomized and receive at least one dose 
of double-blind study medication will be included in the safety analysis. All safety data 
will be presented in by-subject listings and included in the clinical trial report.  
9.1. 
EXTENT OF EXPOSURE 
Study drug exposure will include: 
• 
Treatment duration by treatment group 
• 
Total dose taken by treatment group 
Treatment duration of tablets/capsules (in weeks) is calculated as (the date of the last 
dose of study drug – the date of the first dose of double-blind study drug + 1) / 7 and 
rounded to 1 decimal place.  For glimepiride, this includes doses taken during up-
titration period. The exposure will be summarized for bexagliflozin tablets, 20 mg or 
glimepiride, 2, 4, or 6 mg. 
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, all 
medication will be considered as completely taken. If a subject withdrew early, and the 
last kit dispensed is 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 a frequency summary of 
treatment duration categories (e.g., >=1 Day, >=6 weeks), will be provided. 
9.2. 
TREATMENT COMPLIANCE  
Subjects will be provided with dosing instructions each time study medication is 
dispensed. Subjects will also be instructed to bring their medication with them to every 
visit. During the run-in period, subjects will be considered compliant in investigational 
product administration by missing no more than two doses of run-in medication. 
Subjects who are not compliant during the run-in period will be excluded from 
randomization. 


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At each visit the study staff will review the self-monitored blood glucose (SMBG) control 
diary, glucometer data and medication use with the subject and record the drug 
consumption in the CRF. Reasons for non-adherence will also be recorded in the 
protocol deviation log if applicable. 
Compliance in the double-blind phase is calculated for as follows: 
• 
Percent compliance = (number of tablets or capsules taken / number of tablets 
should have taken) x 100. 
• 
Number of tablets taken = number of tablets dispensed – number of tablets 
returned. 
• 
Number of tablets should have taken = (number of tablets supposed to take in a 
day) x (number of exposure days). 
• 
Number of exposure days = last dose date – first dose date + 1. 
In case of the unreturned bottles: 
• 
If subjects completed the study, all the unreturned bottles will be assumed to be 
completely consumed.  
• 
If subjects discontinued, the unreturned bottles will be assumed to be 
completely consumed if a) unreturned bottles are not from the last visit, or b) if 
only one of the two bottles dispensed from week 60 or week 72 is not returned. 
• 
If subjects discontinued and all bottles from the last visit are not returned (e.g. 
lost to follow-up), subjects will be assumed to consume the medication as 
expected: 
Number of tablets assumed taken=last dose date – date bottles dispensed +1; 
Summary statistics for tablet or capsule compliance (%) will be provided by treatment 
group for the double-blind treatment period. The compliance will only be summarized 
for non-placebo tablets/capsule.  A frequency summary of compliance will also be 
presented with the following categories: < 75%, 75% -< 100%, 100%- ≤ 120%, and > 120%. 
9.3. 
ADVERSE EVENTS 
Adverse events will be collected and recorded from the time a subject signs the 
informed consent form (ICF) to the last scheduled contact.  And new serious adverse 
events (SAE) reported by the subject to the investigator that occur after the last 
scheduled contact, and are determined by the investigator to be reasonably associated 
with the use of the investigational product, should be reported to the sponsor or 
designated personnel. This may include SAEs that are captured on follow-up telephone 


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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 
19.0.  
A treatment-emergent adverse event (TEAE) is defined as an AE that begin after the 
first administration of double-blind study medication or existing AEs that worsen after 
the first dose of double-blind study medication.  All reported AEs will be listed, but only 
TEAEs will be summarized in tables.  
Drug-related AEs will be considered those to be possibly, probably and definitely related 
to bexagliflozin administration based on the investigators assessment. 
Unless otherwise specified, AEs will be summarized by SOC and PT, with SOCs presented 
in the standard international order and PTs within SOCs presented in descending order 
of subject incidence. 
9.3.1. 
Derived Data 
AE onset day is calculated as (date of AE start – date of double-blind first dose + 1).  
The onset day will be missing if the start date is missing or partially missing.   
9.3.2. 
Data Summarization  
AE summary tables are listed below: 
• 
An overall summary of the number and percentage of subjects reporting any 
TEAEs, serious TEAEs, treatment-related TEAEs, serious 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 


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• 
TEAEs by relationship to study treatment, overall and by system organ class and 
preferred term 
• 
TEAEs leading to treatment discontinuation, overall and by SOC and PT 
• 
TEAEs leading to study discontinuation, overall and by SOC and PT 
• 
Most common TEAEs.  Most common TEAEs are defined as TEAEs that occur in 
> 5% of the subjects in either of the treatment groups.  
• 
Serious treatment-related TEAEs, overall and by SOC and PT. 
For summary tables, subjects having more than 1 event with the same PT will be 
counted once for that term.  Subjects having more than 1 event with the same SOC will 
be counted once for each event and once for that SOC.  For tabulations by severity, 
only a subject’s most severe event within the category (e.g. overall, SOC, PT) will be 
counted; similarly, for tabulations by relationship, only a subject’s most related event 
within a category will be counted.  The denominator for percentages will be the number 
of subjects in the Safety Analysis Set for the given treatment group (i.e., the N’s for the 
columns).   
Listings will be provided for all AEs and the following subsets: 
• 
All TEAEs at least possibly related to study treatment 
• 
Serious AEs 
• 
AEs leading to treatment discontinuation 
• 
AEs leading to death.  
Additional information will be collected for diabetic ketoacidosis (DKA).  These data will 
be listed. 
9.3.3. 
AE of Special Interest 
AE of special interest include UTI, pyelonephritis urosepsis, GMI, diuretic effects 
including hypovolemia, hypotension episodes, hypoglycemia, hepatotoxicity, MACE, 
fractures, malignancies, hypersensitivity reactions, acid-base disorders including 
diabetic ketoacidosis, rash, and renal failure events. These AEs of special interest, 
except for cardiovascular events and amputations, will be prospectively identified 
based on the MedDRA PTs in the AEs log by a medical expert prior to the data base lock 
and unblinding of the individual subject treatment assignment. The list of AEs of special 
interest will be confirmed in a peer review process.  Cardiovascular events, 
hypoglycemia events by severity, and amputations will be summarized separately. 


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9.3.3.1. 
AE of special interest identified by PTs 
Cardiovascular events considered as MACE by investigator will be submitted to an 
independent Cardiovascular Endpoint Committee (CEC) for adjudication.  The events of 
interest include all-cause mortality, cardiovascular mortality, MI, stroke, hospitalization 
for acute coronary syndromes, urgent revascularization procedures, and other possible 
serious cardiovascular events.  Other AE of special interest will be identified from the 
PTs. The number and percentage of subjects experiencing these TEAEs of special 
interest will be summarized for each treatment group by type of event. The incidence 
rate of AE of special interest per 100 patient years will also be summarized.  Each 
category of events will be displayed in a listing.   
9.3.3.2. Hypoglycemic Events 
Hypoglycemic event categories include: 
Category 
Description 
Severe 
Assistance required and blood glucose ≤70 mg/dL or no value available 
but responded to glucose treatment 
Documented 
Symptomatic 
Blood glucose ≤70 mg/dL and typical symptoms of hypoglycemia 
Asymptomatic 
Blood glucose ≤70 mg/dL and no typical symptoms of hypoglycemia 
Probable 
Symptomatic 
Typical symptoms of hypoglycemia and no value available but 
responded to glucose treatment 
Relative 
Typical symptoms of hypoglycemia and blood glucose >70 mg/dL 
 
While each event meeting the criteria above will be entered into the hypoglycemia log, 
only critical (severe) hypoglycemia, documented symptomatic hypoglycemia, 
asymptomatic hypoglycemia, and probable hypoglycemia will be entered as AEs.  
The number and percentage will be summarized by treatment for: 
• 
Each category of hypoglycemic events; 
• 
Any severe or documented hypoglycemic events. 
9.3.3.3. 
Revascularization and Amputations 
Revascularization and amputations information are collected in a separate form.  
Frequency and percentage will be summarized for: 
• 
Type of cardiovascular related procedures –or amputation 
• 
Subjects with any amputation 
• 
Conditions that resulted in amputation 


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• 
Location of amputation 
Only procedures performed after the first dose of double-blind study drug will be 
summarized. 
9.4. 
LABORATORY EVALUATIONS 
Laboratory tests will include hematology panel, chemistry panel, serum lipids, and 
urinalysis testing. Hematology and chemistry will be performed at the following time 
points: at the screening visit (Week - 11), on baseline visit (Day -3 to -5), and at weeks 
6, 24, 48, 60, 96, and 98.  Urinalysis will be performed at the following time points: at 
the screening visit (Week - 11), on baseline visit (Day -3 to -5), and at weeks 6, 12, 24, 
36, 48, 60, 72, 96 and 98.  Serum lipids will be performed at the screening visit 
(Week - 11), on baseline visit (Day -3 to -5), and on weeks 24, 60, 96, and 98. Renal 
functional testing by UACR will be determined at the screening visit, on baseline visit 
and at Week 60. The study staff will contact each subject prior to a scheduled clinic 
visit to confirm the time of the visit and to remind the subject of proper fasting 
practice. A subject must be queried to assess compliance with an approximately 10-hour 
fast prior to blood draw to ensure the FPG and triglycerides values can be accurately 
determined. If a subject has not fasted for approximately 10 hours, the subject must 
return as soon as can be arranged (within 1 week) to provide a specimen after proper 
fasting. A list of laboratory tests is included in Table 4. 
Low density lipoprotein cholesterol (LDL-C) will be calculated by the Friedewald 
equation. If triglycerides are > 400 mg/dL, the calculated LDL-C value is invalid by this 
equation and will be set as missing. The following algorithm will be used to obtain LDL-
C values for the analyses: 
1. Select subjects (based on the SI unit) who had screening triglycerides >3.4 or 
>350 based on the conventional unit 
2. Take the LDL – direct measurement values only, throughout the study visits for 
those subjects 
3. If screening triglycerides > 350 and no direct LDL-C values have been 
determined, take the calculated.   
Among those subjects who have screening triglycerides >350 and have both calculated 
and direct LDL values, only take the direct LDL. 
Urinalysis microscopy will be conducted if the subject has a positive result on the 
leukocyte esterase or nitrite dipstick tests to clarify the significance of the finding. 
Results of glucose measurement in the urinalysis must be suppressed from the 
laboratory reports so the sponsor, investigators, study coordinators, pharmacists, study 
subjects, and the CEC members will remain blinded to the dosing assignment.  
The baseline value will be the latest value obtained prior to Day 1.  Change from 


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baseline for all continuous parameters will be calculated as the post-baseline value 
minus the baseline value.  
Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], median, minimum and maximum) for continuous variables, and 
frequency and percentage of subjects for categorical and ordinal variables 
Observed values (in SI units) and change from baseline over time will be summarized by 
treatment group.  Laboratory data will be classified as low, normal, or high relative to 
the parameter’s reference range. Laboratory abnormalities for each treatment will also 
be summarized with shift tables for selected parameters.  
 


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


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9.5. 
VITAL SIGNS  
Vital signs will be measured at the screening visit (Week -11), both visits of run-in 
(Week -2 and Day -3 to -5), and at weeks 2, 4, 6, 12, 24, 36, 48, and 60. Measurements 
of vital signs will include measurement of supine, sitting and standing blood pressure 
(BP) measurements, and heart rate. Only the BP measured in the sitting position will be 
used to determine eligibility.  Orthostatic systolic and diastolic BP will be calculated as 
supine measurement – standing measurement.  
For BP, pulse rate, and respiration rate, observed values and change from baseline will 
be summarized by treatment group and mapped visit using descriptive statistics (n, mean 
and median, standard deviation, minimum and maximum).  BP summary will include 
supine, sitting, standing and orthostatic BP.  Safety analysis set will be used for table 
summary.   
9.6. 
ELECTROCARDIOGRAM  
A 12-lead electrocardiogram (ECG) will be conducted at the screening visit (Day - 11), 
on baseline visit (Day -3 to -5), at weeks 24, 60, and 96. ECG parameters measured will 
be the RR interval, PR interval, QRS duration, QT interval, and QTcB. Each ECG should 
also be assessed by the investigator for signs of ischemia, clinically significant 
hypertrophy, and clinically significant T-wave abnormalities or arrhythmia. 
If a subject’s ECG parameters cannot be determined due to pacemaker placement or 
atrial fibrillation, the ECG parameters will be considered missing.  Any machine 
generated values such as 0 or 9999 will be excluded from the analyses. 
For each abnormal ECG result, the investigator shall ascertain if the observation 
represents a clinically significant change from the screening ECG for that individual 
subject (this determination, however, does not necessarily need to be made the first 
time an abnormal result is observed. The investigator may repeat the ECG to verify the 
results of the original result). If the ECG result is determined to be a clinically 
significant and abnormal change from baseline for that subject, it is considered an AE. 
For the ECG parameters, observed values and change from baseline from scheduled 
visits will be summarized with descriptive statistics by treatment group and overall at 
each visit.  The maximum change from baseline from scheduled visits will also be 
provided for ECG parameters. 
For the ECG overall assessment, the number and percentage of subjects in each overall 
assessment category (normal, abnormal but not clinically significant, abnormal and 
clinically significant, missing) will be presented by treatment group and overall at each 
visit.   


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9.7. 
PHYSICAL EXAMINATION 
A complete physical examination will be conducted at the baseline visit (Day -3 to -5) and 
at weeks 60, and 98. The examination will include measurement of body weight, and a 
general assessment of all body systems including the skin, head, eyes, ears, nose, throat, 
neck, heart, lungs, abdomen, lymph nodes, and extremities.  An abbreviated physical 
examination will be conducted at screening visit 1 (Week -11) and at weeks 6, 24, 36, 48, 
72, and 96 or clinically indicated.  The examination will include body weight and height 
(height will be measured only at screening), and general assessment of the skin, heart, 
lungs and abdomen. Physical examination findings will be presented in a by-subject 
listing.  
 
 


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10. 
HEALTH RELATED QUALITY OF LIFE ASSESSMENT 
Health related quality of life will be assessed by EQ-5D-3L.  It will be performed on 
Day 1, Weeks 24, 60, and 96.   
The EQ-5D is a standardized measure of health status developed by the EuroQol Group 
in order to provide a measure of health for clinical and economic appraisal.  The 
questionnaire consists of 2 components: the EQ-5D descriptive system and the EQ visual 
analogue scale (EQ VAS).  The EQ-5D descriptive system is comprised of the following 
five dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression; each dimension has 5 possible responses scored from 1 (unimpaired) 
to 5 (most impaired).  The EQ VAS records the respondent’s self-rated overall health on 
a vertical, visual analogue scale where the endpoints are labeled, “Best imaginable 
health state” and “Worst imaginable health state”. Health states in the EQ-5D-3L can 
be converted into a single index value, where index values are presented in the country 
specific value sets to facilitate the calculation of quality-adjusted life years (QALYs). 
EQ-5D-3L value sets can be used to obtain the EQ-5D-3L index values based on the UK 
version. The index score in this version range from -0.594 to 1 with higher score 
indicating better quality of life.  To compute the value of any health state, first of all a 
value of 1 is assigned for the 11111 status (without health problems in any dimension). 
If the status is different to 11111, the constant value is subtracted (see below table). 
Later, if at least one moderate problem (value of 2 reported in the database) is 
reported in any of the dimensions, the correspondent dimension value is subtracted. 
The same procedure is followed when there is at least one extreme problem (value of 3 
reported in the database), but multiplying by 2 the appropriate constant value. Finally, 
if at least one extreme problem is reported then the N3 value is subtracted. 
Parameter 
Coefficient 
(UK) 
Constant 
-0.081 
Mobility=2 
Mobility=3 
-0.069 
-0.314 
Self care=2 
Self care=3 
-0.104 
-0.214 
Usual activities=2 
Usual activities=3 
-0.036 
-0.094 
Pain/discomfort=2 
Pain/discomfort=3 
-0.123 
-0.386 
Anxiety/Depr.=2 
Anxiety/Depr.=3 
-0.071 
-0.236 
N3 
-0.269 
 


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Descriptive statistics will be presented for each item of the questionnaire, the EQ-5D-3L 
index score and VAS for ITT analysis.  Both actual values and changes from baseline will 
be summarized by treatment group for each visit.  In addition, the treatment effect for 
change from baseline in index score and VAS will be assessed using the MMRM model in 
Section 8.1.1 as template.  The model will include treatment, visit, treatment-by-visit 
interaction and randomization stratification factors, including baseline HbA1c, as the 
fixed effects terms and the baseline EQ-5D-3L index score (or VAS) as covariate. All 
analysis will be based on ITT analysis set.  
11. 
INTERIM ANALYSES 
No interim analyses are planned. 
12. 
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. 
13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
In all analysis models, continuous HbA1c at baseline is used as fixed affect, in place of 
randomization stratification factor of HbA1c group at baseline.  In all models, eGFR at 
baseline category is used as fixed effect, in place of randomization stratification factor 
of eGFR at screening. 
Primary analysis of the primary endpoint was MMRM using available data in the protocol. 
In SAP, a “retrieved dropout” analysis is used for handling missing data is used as primary 
analysis if data allows. Retrieve dropouts are subjects who discontinued treatment but 
still had their efficacy measurements at the planned visit. Sensitivity analysis of LOCF is 
planned in the protocol, but removed in SAP since LOCF does not add more information 
on sensitivity in addition to tipping point analysis. 
 


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14. 
REFERENCE LIST 
https://www.economicsnetwork.ac.uk/health/EQ_5D_index_calculator.xls; 
Szende, 
Oppe, Devlin (ed.): EQ-5D Value Sets: Inventory, comparative review, and user guide.  
Charpentier G, Fleury F, Kabir M, Vaur L, Halimi S. Improved glycaemic control by addition 
of glimepiride to metformin monotherapy in Type 2 diabetic patients. Diabetic Medicine 
2001, 18, 828-834 
 
 


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15. 
PROGRAMMING CONSIDERATIONS 
The following conventions will hold for programming of outputs: 
• 
SAS® Version 9.3 or higher will be used for programming and production 
• 
The format of the table shells will be followed as closely as possible; however, in 
the course of programming and familiarization with the database, some changes may 
become necessary.  All changes will be documented.  Major changes will be documented 
through a formal amendment to this document.  
• 
Patients in this study will be identified as “Subjects.” 
• 
Descriptive statistics will be displayed in the following order: 
n 
Mean 
Standard deviation (SD) 
Q1 
Median 
Q3 
Minimum (Min) 
Maximum (Max) 
• 
Decimal places: For summary statistics, the minimum and maximum will be 
reported with the same number of decimal places as the collected measure, the mean, 
LS mean (if applicable) and median will have 1 more decimal place than the measure 
collected, and the SD and confidence interval (CI) will have 2 more decimal places than 
the collected measure.  For frequency distributions, percentages will be reported to 1 
decimal place.  For p-values, 4 decimal places will be reported or the SAS® p-value 
format of “< 0.0001” or “> 0.9999” will be reported.  
• 
Unless otherwise noted, the denominator for percentages is the number of 
subjects in the applicable analysis population and treatment group.  
• 
If the frequency for a particular table cell is zero, then “0”, properly aligned, 
will be displayed (i.e. “0 (0.0%)” will not be displayed.) 
• 
Non-numeric values:  Where variables are recorded using < or > (e.g., “< 10”, 
“> 10”, “≥ 10”, or “≤ 10”) the numeric portion of the result will be used (e.g. < 10, 
≤ 10, > 10, and ≥ 10 become 10) for summary; the actual recorded results, (e.g. “< 10” 
or “> 10”) will appear in listings. 


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15.1. 
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 
 
15.2. 
TABLE, LISTING, AND FIGURE FORMAT 
15.2.1. 
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. 
 
15.2.2. 
Headers 
• 
All output should have the following header at the top left of each page: 
Theracos Sub, LLC 
Protocol Number: THR-1442-C-480       
• 
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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15.2.3. 
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 
 
15.2.4. 
Column Headers 
• 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values will be presented in a separate comparison column (if applicable).  
• 
For numeric variables, include “unit” in column or row heading when appropriate. 
• 
Analysis set sizes will be presented for each treatment group in the column heading 
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set. 
• 
The order of treatments in the tables and listings will be active treatment first, then 
placebo, followed by a total column (if applicable). 
15.2.5. 
Body of the Data Display 
15.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 


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


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displayed and percentages equating to 100% should be presented as 100%, without 
any decimal places.  
• 
Tabular display of data for concomitant and rescue medications should be presented 
by treatment class with the highest occurrence in the total column in decreasing 
order.  Tabular display of data for medical history and adverse event data should be 
presented by the SOC using internationally agreed order.  Within the drug class and 
SOC, medical history (by preferred term), drugs (by ATC1 code), and adverse events 
(by preferred term) should be displayed in decreasing order in the total column. If 
incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics which cannot be estimated should be 
reported as “-”. 
• 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
• 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
• 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page.  The overall summary statistics for the subheading should only be 
output on the first relevant page. 
15.2.5.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 
• 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
• 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
• 
Units will be included where available 


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15.2.5.4. 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. 
15.2.6. 
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’). 
 
 


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16. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. INC Research SOP 03.010 and 
03.013 provide an overview of the development of such SAS programs. 
INC Research SOP 03.009 describes the quality control procedures that are performed for 
all SAS programs and output. Quality control is defined here as the operational techniques 
and activities undertaken to verify that the SAS programs produce the proper clinical trial 
output by checking for their logic, efficiency and commenting and by review of the 
produced output. 
 
 


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17. 
INDEX OF TABLES 
Number 
Title 
Table 14.1.1.1 
Subject Disposition (Screened Analysis Set) 
Table 14.1.1.2 
Reasons for Screen Failure (Non-randomized Subjects) 
Table 14.1.2 
Summary of Major Protocol Deviations  (ITT Analysis Set) 
Table 14.1.3.1 
Demographics and Baseline Characteristics  (Safety Analysis Set) 
Table 14.1.3.2 
Demographics and Baseline Characteristics  (ITT Analysis Set) 
Table 14.1.3.3 
Demographics and Baseline Characteristics  (PP Analysis Set) 
Table 14.1.4.1 
Summary of Significant Medical and Surgical History by System Organ 
Class and Preferred Term (Safety Analysis Set) 
Table 14.1.4.2 
Summary of Type 2 Diabetes History (Safety Analysis Set) 
Table 14.1.4.3 
Summary of Cardiovascular History  (Safety Analysis Set) 
Table 14.1.5.1  
Summary of Concomitant Medications  (Safety Analysis Set) 
Table 14.1.5.2  
Summary of Hyperglycemia Rescue Medications  (Safety Analysis Set) 
Table 14.1.6. 
Study Drug Exposure and Compliance during Double-Blind Treatment 
Period (Safety Analysis Set) 
Table 14.2.1.1.1 
Multiple Imputation for Change from Baseline in HbA1c (%) Including 
Observations Obtained after Rescue Medication  (ITT Analysis Set) 
Table 14.2.1.1.2 
Analysis of Change from Baseline in HbA1c (%) at Week 60 (ITT 
Analysis Set) 
Table 14.2.1.2 
Analysis of Change from Baseline in HbA1c (%) at Week 60  (PP 
Analysis Set) 
Table 14.2.1.3.1 
Summary of Reason for Missing Values by Visit- Change from Baseline 
in HbA1c (%)  (ITT Analysis Set) 
Table 14.2.1.3.2 
Missing Data Pattern - Change from Baseline in HbA1c (%) (ITT 
Analysis Set) 
Table 14.2.1.4.1 
Sensitivity Analysis 1: Analysis of Change from Baseline in HbA1c (%) 
Excluding Observations Obtained after Rescue Medication  (ITT 
Analysis Set) 
Table 14.2.1.4.2 
Sensitivity Analysis 2: Tipping Point Analysis of Change from Baseline 
in HbA1c (%) Excluding Observations Obtained after Rescue 
Medication 
Table 14.2.1.5 
Analysis of Change from Baseline in HbA1c (%) Over Time  (ITT 
Analysis Set) 
Table 14.2.1.6 
Analysis of Change from Baseline in HbA1c (%) at Week 60 by Age  
(ITT Analysis Set) 


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Table 14.2.1.7 
Analysis of Change from Baseline in HbA1c (%) at Week 60 by Gender  
(ITT Analysis Set) 
Table 14.2.1.8 
Analysis of Change from Baseline in HbA1c (%) at Week 60 by Race  
(ITT Analysis Set) 
Table 14.2.1.9 
Analysis of Change from Baseline in HbA1c (%) at Week 60 by Baseline 
HbA1c Category  (ITT Analysis Set) 
Table 14.2.1.10 
Analysis of Change from Baseline in HbA1c (%) at Week 60 by 
Background Treatment Status  (ITT Analysis Set) 
Table 14.2.1.11 
Analysis of Change from Baseline in HbA1c (%) at Week 60 by Baseline 
eGFR (ITT Analysis Set) 
Table 14.2.1.12 
Analysis of Change from Baseline in HbA1c (%) at Week 60 by Region 
(ITT Analysis Set) 
Table 14.2.2.1 
Analysis of Change from Baseline in Body Weight (kg) at Week 60 for 
Subjects with BMI ≥ 25 kg/m2 (ITT Analysis Set) 
Table 14.2.2.2 
Analysis of Change from Baseline in Body Weight (kg) at Week 60 for 
Subjects with BMI ≥ 25 kg/m2 (PP Analysis Set) 
Table 14.2.2.3 
Sensitivity Analysis: Multiple Imputation for Change from Baseline in 
Body Weight (kg) at Week 60 for Subjects with BMI ≥ 25 kg/m2 
Excluding Observations Obtained after Rescue Medication 
Table 14.2.2.4 
Analysis of Change from Baseline in Body Weight (kg) for Subjects 
with BMI ≥ 25 kg/m2 over Time (ITT Analysis Set) 
Table 14.2.3.1 
Analysis of Change from Baseline in SBP (mmHg) at Week 60 for 
Subjects with Baseline SBP ≥ 140 mmHg  (ITT Analysis Set) 
Table 14.2.3.2 
Analysis of Change from Baseline in SBP (mmHg) at Week 60 for 
Subjects with Baseline SBP ≥ 140 mmHg  (PP Analysis Set) 
Table 14.2.3.3 
Sensitivity Analysis: Multiple Imputation for Change from Baseline in 
SBP (mmHg) for Subjects with Baseline SBP ≥ 140 Excluding 
Observations Obtained After Rescue Medication  (ITT Analysis Set) 
Table 14.2.3.4 
Analysis for Change from Baseline in SBP (mmHg) for Subjects with 
Baseline SBP ≥ 130 over Time (ITT Analysis Set) 
Table 14.2.3.5 
Analysis for Change from Baseline in SBP (mmHg) for All Subjects over 
Time (ITT Analysis Set) 
Table 14.2.4.1 
Summary of Proportion of Subjects with ≥1 Severe or Documented 
Symptomatic Hypoglycemia Event over 96 Weeks  (ITT Analysis Set) 
Table 14.2.4.2 
Summary of Proportion of Subjects with ≥1 Severe or Documented 
Symptomatic Hypoglycemia Event over 96 Weeks  (PP Analysis Set) 
Table 14.2.4.3 
Sensitivity Analysis: Incidence Rate of Severe or Documented 
Symptomatic Hypoglycemia Event over 96 Weeks  (ITT Analysis Set) 
Table 14.2.4.4 
Summary of Proportion of Subjects with ≥1 Severe or Documented 
Symptomatic Hypoglycemia Event over Time  (ITT Analysis Set) 
Table 14.2.5 
Analysis of Change from Baseline in FPG (mmol/L) Over Time  (ITT 
Analysis Set) 


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Table 14.2.6 
Summary of Proportion of Subjects with HbA1c < 7% Over Time  (ITT 
Analysis Set) 
Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events  (Safety 
Analysis Set) 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term   (Safety Analysis Set) 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Maximum Severity  (Safety Analysis Set) 
Table 14.3.1.4 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Relationship to Study Drug  (Safety Analysis Set) 
Table 14.3.1.5 
Most Common Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term  (Safety Analysis Set) 
Table 14.3.1.6 
Treatment-Emergent Serious Adverse Events by System Organ Class 
and Preferred Term  (Safety Analysis Set) 
Table 14.3.1.7 
Serious Treatment-Emergent Treatment Related Adverse Events by 
System Organ Class, Preferred Term and Relationship to Study Drug  
(Safety Analysis Set) 
Table 14.3.1.8 
Summary of Treatment Emergent Adverse Events Leading to 
Treatment Discontinuation by System Organ Class and Preferred Term  
(Safety Analysis Set) 
Table 14.3.1.9 
Summary of Treatment Emergent Adverse Events Leading to Study 
Discontinuation by System Organ Class and Preferred Term   (Safety 
Analysis Set) 
Table 14.3.1.10 
 Summary of Treatment Emergent Adverse Events of Interest  (Safety 
Analysis Set) 
Table 14.3.1.11 
Summary of Treatment Emergent Hypoglycemia Events   (Safety 
Analysis Set) 
Table 14.3.1.12 
 
Summary of Revascularization and Amputations  (Safety Analysis Set) 
Table 14.3.2.1 
List of Serious Adverse Events  (Safety Analysis Set) 
Table 14.3.2.2 
List of Adverse Events Leading to Treatment Discontinuation  (Safety 
Analysis Set) 
Table 14.3.2.3 
List of Adverse Events Leading to Death  (Safety Analysis Set) 
Table 14.3.4.1 
Summary of Hematology: Results and Change from Baseline by Visit  
(Safety Analysis Set) 
Table 14.3.4.2 
Shift in Clinical Laboratory Values: Hematology   (Safety Analysis Set) 
Table 14.3.4.3 
Summary of Serum Chemistry: Results and Change from Baseline by 
Visit (Safety Analysis Set) 


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Table 14.3.4.4 
Shift in Clinical Laboratory Values: Serum Chemistry  (Safety Analysis 
Set) 
Table 14.3.4.5 
Summary of Urinalysis: Results and Change from Baseline by 
Visit - Continuous Variables  (Safety Analysis Set) 
Table 14.3.4.6 
Summary of Urinalysis Results by Visit - Categorical Variables  (Safety 
Analysis Set) 
Table 14.3.4.7 
Shift in Clinical Laboratory Values: Urinalysis   (Safety Analysis Set) 
Table 14.3.5  
Summary of Vital Signs: Results and Change from Baseline by Visit  
(Safety Analysis Set) 
Table 14.3.6.1 
Summary of 12-Lead ECG Investigator Overall Assessment by Visit  
(Safety Analysis Set) 
Table 14.3.6.2 
Summary of 12-Lead ECG Parameters by Visit: Results and Change 
from Baseline   (Safety Analysis Set) 
Table 14.4.1 
Analysis of Change from Baseline in EQ-5D-3L Index Score over Time 
(ITT Analysis Set) 
Table 14.4.2 
Analysis of Change from Baseline in EQ-5D-3L VAS Score over Time 
(ITT Analysis Set) 
Table 14.4.3 
Summary of EQ-5D-3L Item Scores: Results and Change from Baseline 
by Visit (ITT Analysis Set) 
 
 


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18. 
INDEX OF FIGURES 
Number 
Title 
Figure 14.1.1 
Kaplan-Meier Plot of Time to Discontinuation by Week 96  (ITT 
Analysis Set) 
Figure 14.2.1.1 
Multiple Imputation LS Mean Difference (95% CI) in Change from 
Baseline in HbA1c (%)  Including Observations Obtained After Rescue 
Medication  (ITT Analysis Set) 
Figure 14.2.1.2 
LS Mean (± SE) Change from Baseline in HbA1c (%) (ITT Analysis Set) 
Figure 14.2.1.3 
LS Mean Difference (95% CI) in Change from Baseline in HbA1c (%) 
(ITT Analysis Set) 
Figure 14.2.1.4 
LS Mean (± SE) Change from Baseline in HbA1c (%) (PP Analysis Set) 
Figure 14.2.1.5 
LS Mean Difference (95% CI) in Change from Baseline in HbA1c (%) (PP 
Analysis Set) 
Figure 14.2.1.6 
Sensitivity Analysis 1: LS Mean Difference (95% CI) in Change from 
Baseline in HbA1c (%)  Excluding Observations Obtained After Rescue 
Medication  (ITT Analysis Set) 
Figure 14.2.1.7 
Sensitivity Analysis 2: Tipping Point Analysis of Change from Baseline 
in HbA1c (%) Excluding Observations Obtained after Rescue  (ITT 
Analysis Set) 
Figure 14.2.1.8 
Subgroup Analysis of Change from Baseline in HbA1c (%) Excluding 
Observations Obtained after Rescue  (ITT Analysis Set) 
Figure 14.2.2 
 LS Mean (± SE) Change from Baseline in Body Weight (kg) Over Time 
for Subjects with BMI ≥ 25 kg/m2 (ITT Analysis Set) 
Figure 14.2.3 
 LS Mean (± SE) Change from Baseline in SBP (mmHg) Over Time for 
Subjects with Baseline SBP ≥ 140 mmHg (ITT Analysis Set) 
Figure 14.2.4 
Proportion of Subjects with ≥1 Severe or Documented Symptomatic 
Hypoglycemia Event over 96 Weeks  
(ITT Analysis Set) 
Figure 14.2.5 
LS Mean (± SE) Change from Baseline in Fasting Plasma Glucose 
(mmol/L) (ITT Analysis Set) 
Figure 14.2.6 
Proportion of Subjects with HbA1c < 7% Over Time(ITT Analysis Set) 
Figure 14.3.1 
Mean (± SE) Change from Baseline in Laboratory Parameters Over 
Time  (Safety Analysis Set) 
 
 
 


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19. 
INDEX OF LISTINGS 
Number 
Title 
Listing 16.2.1.1 
Subject Disposition 
Listing 16.2.1.2 
Subject Discontinuation 
Listing 16.2.2 
Protocol Deviation 
Listing 16.2.3.1 
Analysis Sets (All Randomized Subjects) 
Listing 16.2.3.2 
Subjects Who Did Not Meet Inclusion/Exclusion Criteria 
Listing 16.2.4.1 
Demographics 
Listing 16.2.4.2 
Significant Medical and Surgical History (Safety Analysis Set)  
Listing 16.2.4.3 
Type 2 Diabetes History (Safety Analysis Set) 
Listing 16.2.4.4 
Cardiovascular Disease History (Safety Analysis Set) 
Listing 16.2.4.5 
Prior and Concomitant Medications (Safety Analysis Set) 
Listing 16.2.5.1.1 
Study Drug Accountability – Bexagliflozin (Safety Analysis Set) 
Listing 16.2.5.1.2 
Study Drug Accountability and Up-Titration – Glimpepiride (Safety 
Analysis Set) 
Listing 16.2.5.2 
Study Drug Exposure and Compliance (Safety Analysis Set) 
Listing 16.2.6.1 
Glycemic Control Tests: HbA1c (%) (ITT Analysis Set) 
Listing 16.2.6.2 
Glycemic Control Tests: Fasting Plasma Glucose (mmol/L) (ITT 
Analysis Set) 
Listing 16.2.6.3 
Hypoglycemia Events (ITT Analysis Set) 
Listing 16.2.6.4 
Weight (kg) (ITT Analysis Set) 
Listing 16.2.7.1  
Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.1 
Adverse Events of Interest (Safety Analysis Set)  


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Listing 16.2.7.2.2 
Major Adverse Cardiovascular Events  
(Safety Analysis Set)) 
Listing 16.2.7.2.3 
Revascularization and Amputations  (Safety Analysis Set) 
Listing 16.2.7.3.1 
DKA Symptoms Assessment (Safety Analysis Set) 
Listing 16.2.7.3.2 
Suspected DKA Assessment (Safety Analysis Set) 
Listing 16.2.7.3.3 
Suspected DKA Clinic/Hospital Report (Safety Analysis Set) 
Listing 16.2.7.3.4 
Suspected DKA Outpatient Clinic  (Safety Analysis Set) 
Listing 16.2.7.3.5 
Suspected DKA Hospitalization (Safety Analysis Set) 
Listing 16.2.8.1 
Urine Pregnancy Test (Safety Analysis Set) 
Listing 16.2.9.1 
12-Lead Electrocardiogram (Safety Analysis Set) 
Listing 16.2.9.2 
Physical Examination (Safety Analysis Set) 
Listing 16.2.10 
EQ-5D-3L Scores (ITT Analysis Set) 
 
 
 


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20. 
MOCK-UPS 
 
Attachment 1: Planned Table Shells 
Attachment 2: Planned Listing Shells  
Attachment 3: Planned Figure Shells 
21. 
APPENDICES 
Attachment 4: Appendix.