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
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Theracos

 
 
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. 
 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 2 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 3 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 4 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 5 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 6 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 7 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 8 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 9 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 10 of 79 
Version 3.0  (Global) 
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 
 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 11 of 79 
Version 3.0  (Global) 
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, 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 12 of 79 
Version 3.0  (Global) 
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).  

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 13 of 79 
Version 3.0  (Global) 
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  

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 14 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 15 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 16 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 17 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 18 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 19 of 79 
Version 3.0  (Global) 
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 
 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 20 of 79 
Version 3.0  (Global) 
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-

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 21 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 22 of 79 
Version 3.0  (Global) 
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:  

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 23 of 79 
Version 3.0  (Global) 
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.  

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 24 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 25 of 79 
Version 3.0  (Global) 
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 
discontinue study drug.  

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 26 of 79 
Version 3.0  (Global) 
 
*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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 27 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 28 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 29 of 79 
Version 3.0  (Global) 
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.  

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 30 of 79 
Version 3.0  (Global) 
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 
 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 31 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 32 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 33 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 34 of 79 
Version 3.0  (Global) 
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: 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 35 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 36 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 37 of 79 
Version 3.0  (Global) 
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.  

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 38 of 79 
Version 3.0  (Global) 
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.  

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 39 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 40 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 41 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 42 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 43 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 44 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 45 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 46 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 47 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 48 of 79 
Version 3.0  (Global) 
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: 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 49 of 79 
Version 3.0  (Global) 
• 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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 50 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 51 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 52 of 79 
Version 3.0  (Global) 
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: 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 53 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 54 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 55 of 79 
Version 3.0  (Global) 
 
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.  

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 56 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 57 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 58 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 59 of 79 
Version 3.0  (Global) 
 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 60 of 79 
Version 3.0  (Global) 
• 
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 
 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 61 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 62 of 79 
Version 3.0  (Global) 
 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 63 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 64 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 65 of 79 
Version 3.0  (Global) 
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% 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 66 of 79 
Version 3.0  (Global) 
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, 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 67 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 68 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 69 of 79 
Version 3.0  (Global) 
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.  

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 70 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 71 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 72 of 79 
Version 3.0  (Global) 
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. 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 73 of 79 
Version 3.0  (Global) 
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 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 74 of 79 
Version 3.0  (Global) 
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. 
 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 75 of 79 
Version 3.0  (Global) 
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. 
 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 76 of 79 
Version 3.0  (Global) 
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 
 

Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-480 
 
27 October 2016  
 
 
 
 
Confidential 
Page 77 of 79 
Version 3.0  (Global) 
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