Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 386
Healthy volunteers: no

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

Detailed description:
This was a phase 3, multi-center, randomized, double-blind, parallel-group study to demonstrate that bexagliflozin was non-inferior to sitagliptin as add-on therapy in subjects whose T2DM was not adequately controlled by metformin treatment alone. The primary effectiveness endpoint was the change in HbA1c from baseline at week 24.

At the time of screening, all subjects were to have taken metformin at a stable dose of ≥ 1500 mg per day for ≥ 8 weeks and have received diet and exercise counseling. A total of 374 eligible subjects were to be enrolled in the study. Subjects who successfully completed a 1-week run-in and who met all eligibility criteria were to be randomized in a 1:1 ratio to receive once daily double-blind treatment of either active bexagliflozin tablets with placebo sitagliptin tablets or placebo bexagliflozin tablets and active sitagliptin tablets. The study subjects were to continue receiving open-labeled metformin during the entire study at a stable dose and frequency. The treatment period was 24 weeks and was conducted in an outpatient setting.

Randomization was stratified by HbA1c (≤ 8.5% vs. ˃ 8.5%) values. Symptoms and blood sugars related to the occurrence of hyperglycemia, hypoglycemic events or symptoms that could indicate ketoacidosis were to be recorded. Bexagliflozin tablets, 20 mg or placebo, and sitagliptin tablets, 100 mg or placebo, were to be taken once daily at approximately the same time each day either before or after breakfast. Background metformin was to be taken at the same dose and frequency from screening throughout the entire study.

Each subject was advised to return to the clinic at weeks 6, 12, 18 and 24 for efficacy assessment and safety monitoring, including review of AEs and concomitant medication, vital signs, ECG, physical examination and blood and urine specimen collections. Subjects were to return to the clinic for a follow-up exit visit at week 26 or 2 weeks after the last dose of study drugs if subjects withdrew from the study prior to week 24.

Arms:
arm 1: Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for sitagliptin daily for the duration of the study. arm 2: Subjects will receive a sitagliptin tablet, 100 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study.

Interventions: intervention 1: Bexagliflozin intervention 2: Sitagliptin intervention 3: Placebo for sitagliptin intervention 4: Placebo for bexagliflozin
Intervention descriptions: intervention 1: tablets containing 20 mg bexagliflozin intervention 2: tablets containing 100 mg sitagliptin intervention 3: inactive tablets to match the appearance of sitagliptin tablets intervention 4: inactive tablets to match the appearance of bexagliflozin tablets

Protocol document:
Prot_000.pdf: 
 
 
Clinical Trial Protocol: THR-1442-C-423 
Study Title: 
A Phase 3, Randomized, Double-Blind, Active-Controlled Study to 
Evaluate the Effects of Bexagliflozin versus Sitagliptin in Subjects 
with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic 
Control by Metformin 
Study Number: 
THR-1442-C-423 
Study Phase: 
3 
Product Name: 
Bexagliflozin Tablets 
Indication: 
Type 2 Diabetes Mellitus 
Investigators: 
Multicenter study 
EudraCT Number: 
2017-000420-95 
IND Number: 
103822 
Sponsor: 
Theracos Sub, LLC 
Sponsor Contact: 
Lynelle Cortellini, MSc 
Translational Medicine Group 
Massachusetts General Hospital  
185 Cambridge Street, Boston, MA 02114 
Phone:  617-724-8420 
Fax:  617-643-8203 
E-mail: lcortellini@ccib.mgh.harvard.edu  
Medical Monitor: 
Robert Klugman M.D. 
Theracos Sub, LLC 
225 Cedar Hill Road, Suite 200, Marlborough, MA 01752  
Phone: 508-735-9491 
Fax: 617-643-8203 
Email: rklugman@theracos.com 
 
 
Date 
Protocol Version 2.0 
06 April 2017 
 
Confidentiality Statement 
The information in this document is the confidential information of Theracos Sub, LLC 
(“Theracos”) and must not be disclosed, used, or copied except with prior written approval 
from Theracos or to the extent required by applicable laws, rules and regulations. 
 
 
 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 2 of 69 
Global Version 2.0 
TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................12 
1 
INTRODUCTION ...........................................................................................................14 
1.1 
Type 2 Diabetes Mellitus .......................................................................................14 
1.2 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus ...............................15 
2 
STUDY OBJECTIVES ....................................................................................................16 
2.1 
Primary Objective ..................................................................................................16 
2.2 
Key Secondary Objectives .....................................................................................16 
2.3 
Exploratory Objectives ..........................................................................................16 
3 
INVESTIGATIONAL PLAN ..........................................................................................17 
3.1 
Overall Study Design and Plan ..............................................................................17 
3.2 
Research Methods and Procedures ........................................................................17 
3.2.1 
Run-in Period ...............................................................................................17 
3.2.2 
Treatment Period ..........................................................................................18 
3.2.3 
Glycemic Control Monitoring......................................................................19 
3.2.3.1 
Placebo Run-in Period .......................................................................19 
3.2.3.2 
Treatment Period ................................................................................19 
3.2.3.3 
Rescue Medication .............................................................................19 
3.2.4 
Other Safety Monitoring Activities .............................................................20 
3.2.5 
Data and Safety Monitoring Board (DSMB) ...............................................21 
3.2.6 
Major Adverse Cardiovascular Event (MACE) Adjudication .....................21 
3.2.7 
Diabetic Ketoacidosis (DKA) Event Adjudication ......................................21 
3.3 
Rational for Study Design and Procedures ............................................................22 
3.3.1 
Rationale for the Study Design ....................................................................22 
3.3.2 
Rationale for Background Medication and Active Comparator ..................22 
3.3.3 
Rationale for the Dose Selection..................................................................23 
3.4 
Study Duration and Dates ......................................................................................23 
4 
STUDY POPULATION SELECTION ...........................................................................24 
4.1 
Study Population ....................................................................................................24 
4.2 
Inclusion Criteria ...................................................................................................24 
4.3 
Exclusion Criteria ..................................................................................................24 
5 
STUDY TREATMENTS .................................................................................................26 
5.1 
Description of Treatments......................................................................................26 
5.1.1 
Investigational Product ................................................................................26 
5.1.2 
Active Comparator .......................................................................................26 
5.2 
Treatments Administered .......................................................................................26 
5.2.1 
Investigational Product ................................................................................26 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 3 of 69 
Global Version 2.0 
5.2.2 
Active Comparator .......................................................................................26 
5.2.3 
Background Metformin Therapy .................................................................27 
5.3 
Selection and Timing of Dose for Each Patient .....................................................27 
5.3.1 
Bexagliflozin ................................................................................................27 
5.3.2 
Sitagliptin .....................................................................................................27 
5.4 
Method of Assigning Treatment Groups and Study Drugs ...................................27 
5.5 
Blinding..................................................................................................................28 
5.6 
Concomitant Therapy.............................................................................................28 
5.6.1 
Diuretics and Medications for Treatment of Dyslipidemia and 
Hypertension ................................................................................................29 
5.7 
Restrictions ............................................................................................................29 
5.7.1 
Prior Therapy ...............................................................................................29 
5.7.2 
Fluid and Food Intake ..................................................................................29 
5.7.3 
Subject Activity Restrictions .......................................................................30 
5.8 
Treatment Compliance ...........................................................................................30 
5.9 
Packaging and Labeling .........................................................................................30 
5.9.1 
Run-in Kits ...................................................................................................30 
5.9.2 
Bexagliflozin Kit ..........................................................................................30 
5.9.3 
Sitagliptin Kit ...............................................................................................31 
5.10 
Storage and Accountability ....................................................................................31 
5.11 
Investigational Product Retention at Study Site ....................................................31 
6 
STUDY PROCEDURES .................................................................................................32 
6.1 
Informed Consent...................................................................................................32 
6.2 
Screening for I/E Criteria .......................................................................................32 
6.3 
Medical History .....................................................................................................32 
6.3.1 
General Demographics and Characteristics .................................................32 
6.3.2 
Diabetes History...........................................................................................33 
6.3.3 
Cardiovascular Disease History ...................................................................33 
6.3.4 
Medication History ......................................................................................33 
6.4 
Diet and Exercise Counseling ................................................................................33 
6.5 
Physical Examination.............................................................................................33 
6.6 
Abbreviated Physical Examination ........................................................................33 
6.7 
Body Weight ..........................................................................................................34 
6.8 
Vital Signs ..............................................................................................................34 
6.9 
Electrocardiography ...............................................................................................34 
6.10 
Clinical Laboratory Tests .......................................................................................35 
6.10.1 
Laboratory Parameters .................................................................................35 
6.10.2 
Sample Collection, Storage, and Shipping ..................................................35 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 4 of 69 
Global Version 2.0 
6.10.3 
Urinalysis .....................................................................................................35 
6.11 
Laboratory Tests ....................................................................................................37 
6.12 
Diary and Glucometer Dispensation ......................................................................38 
6.13 
Dispensing Run-in Drug ........................................................................................38 
6.14 
Diary and Glucometer Record Review ..................................................................38 
6.15 
Dispensing Investigational Product .......................................................................38 
6.15.1 
Drug Accountability.....................................................................................38 
6.16 
Adverse Events Assessments .................................................................................39 
6.16.1 
Definition of Adverse Events.......................................................................39 
6.16.2 
Eliciting and Reporting AEs ........................................................................40 
6.16.3 
Immediately Reportable AEs .......................................................................41 
6.16.4 
Pregnancy .....................................................................................................41 
6.16.5 
Procedure for Breaking the Blind ................................................................42 
6.16.6 
Follow-up of Non-Serious AEs ...................................................................42 
6.16.7 
Follow-up of Post-Study SAEs ....................................................................42 
6.16.8 
Urinary Tract Infections (UTIs) ...................................................................43 
6.16.9 
Genital Mycotic Infections (GMIs) .............................................................43 
6.16.10 Hepatotoxicity ..............................................................................................43 
6.16.11 Hypoglycemia ..............................................................................................44 
6.16.12 Major Adverse Cardiovascular Event (MACE) ...........................................46 
6.16.13 Diabetic Ketoacidosis (DKA) ......................................................................47 
6.16.14 Amputation ..................................................................................................47 
6.16.15 Pancreatitis ...................................................................................................47 
6.17 
Concomitant Medication Assessments ..................................................................48 
7 
STUDY ACTIVITIES .....................................................................................................49 
7.1 
V1/ Screening.........................................................................................................49 
7.2 
V2/ Run In..............................................................................................................49 
7.3 
V3/ Randomization ................................................................................................49 
7.4 
V4/ 6 weeks............................................................................................................50 
7.5 
V5/ 12 weeks..........................................................................................................50 
7.6 
V6/ 18 weeks..........................................................................................................50 
7.7 
V7/ End of Treatment ............................................................................................50 
7.8 
V8/ Follow up ........................................................................................................51 
7.9 
Early Termination Procedures ...............................................................................51 
8 
QUALITY CONTROL AND ASSURANCE .................................................................52 
9 
PLANNED STATISTICAL METHODS ........................................................................53 
9.1 
General Considerations ..........................................................................................53 
9.2 
Determination of Sample Size ...............................................................................53 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 5 of 69 
Global Version 2.0 
9.3 
Analysis Populations ..............................................................................................54 
9.3.1 
Intention-to-Treat Analysis Set ....................................................................54 
9.3.2 
Safety Analysis Set ......................................................................................54 
9.3.3 
Per Protocol Analysis Set.............................................................................54 
9.4 
Demographics and Baseline Characteristics ..........................................................54 
9.4.1 
Concomitant Medications ............................................................................55 
9.5 
Primary Efficacy Analyses ....................................................................................55 
9.5.1 
Hypotheses for the Primary Endpoint ..........................................................55 
9.5.2 
Statistical Methods for Primary Analyses....................................................55 
9.5.3 
Analysis of Dropouts Pattern .......................................................................56 
9.6 
Secondary Efficacy Analyses ................................................................................56 
9.7 
Other Efficacy Analyses ........................................................................................56 
9.8 
Analysis of Safety ..................................................................................................57 
9.8.1 
Adverse Events ............................................................................................57 
9.8.2 
Adverse Events of Interest ...........................................................................57 
9.8.3 
Clinical and Laboratory Events and Analyses .............................................58 
9.8.4 
Physical Examination...................................................................................58 
9.9 
Interim Analysis .....................................................................................................58 
9.10 
Final Analysis ........................................................................................................58 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................59 
10.1 
Investigators and Study Administrative Structure .................................................59 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................59 
10.3 
Ethical Conduct of the Study .................................................................................59 
10.4 
Subject Information and Consent...........................................................................60 
10.5 
Subject Confidentiality ..........................................................................................60 
10.6 
Study Monitoring ...................................................................................................61 
10.7 
Case Report Forms and Study Records .................................................................61 
10.8 
Data Monitoring Committee ..................................................................................61 
10.9 
Protocol Violations/Deviations ..............................................................................61 
10.10 Access to Source Documentation ..........................................................................62 
10.11 Retention of Data ...................................................................................................62 
10.12 Publication and Disclosure Policy .........................................................................63 
11 REFERENCE LIST .........................................................................................................64 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Treatment Groups and Assigned Treatment ................................................18 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 6 of 69 
Global Version 2.0 
Table 2 
List of Laboratory Tests ...............................................................................37 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................65 
Appendix 2 
Schedule of Clinical Laboratory Tests ...............................................66 
Appendix 3 
Examples of SGLT2 Inhibitors ..........................................................67 
Appendix 4 
Sponsor Signatures.............................................................................68 
Appendix 5 
Investigator’s Signature .....................................................................69 
 
 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 7 of 69 
Global Version 2.0 
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 Sitagliptin in Subjects with Type 2 Diabetes Mellitus Who Have 
Inadequate Glycemic Control by Metformin  
Study Number: THR-1442-C-423 
Study Phase: 3 
Primary Objective:  
The primary efficacy objective is to demonstrate that bexagliflozin is non-inferior to 
sitagliptin by evaluating the treatment effect on hemoglobin A1c (HbA1c) reduction at week 
24 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. sitagliptin on the change in fasting 
plasma glucose (FPG) at week 24 
• 
To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in body 
weight in subjects with baseline body mass index (BMI) ≥ 25 kg/m2 at week 24 
• 
To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in systolic 
blood pressure (SBP) in subjects at week 24 
Exploratory Objectives:  
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in the 
proportion of subjects achieving HbA1c < 7.0% over time 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in HbA1c 
over time 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in fasting 
plasma glucose (FPG) over time  
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in body 
weight over time  
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in SBP over 
time 
Safety Objectives: 
• 
To compare the effects of bexagliflozin with sitagliptin on the incidence of adverse 
events (AE) of interest. AE of interest are urinary tract infections, urosepsis and 
pyelonephritis, genital mycotic infections (GMI), 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(DKA), pancreatitis, amputations, and renal failure events 
• 
To compare the effects of bexagliflozin with sitagliptin on general safety assessments 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 8 of 69 
Global Version 2.0 
including treatment emergent AEs, clinical laboratory findings, 12-lead 
electrocardiograms (ECG) parameters, physical examinations, vital signs including 
orthostatic blood pressure (BP), and use of concomitant medications. 
Study Design:  
THR-1442-C-423 is a phase 3, multi-center, randomized, double-blind, active controlled 
study to evaluate the efficacy and safety of bexagliflozin versus sitagliptin in subjects whose 
T2DM is not well controlled by metformin alone. A total of 374 subjects are planned to be 
randomized in a ratio of 1:1 to receive once daily treatment of bexagliflozin tablets, 20 mg, 
with sitagliptin tablets, placebo (Group 1) or bexagliflozin tablets, placebo, with sitagliptin 
tablets, 100 mg (Group 2) for 24 weeks in an outpatient setting. 
The main eligibility criteria include 1) male or female subjects with T2DM and 2) screening 
HbA1c between 7.0% and 11% (inclusive).  
Qualified subjects must have taken metformin at a stable dose of ≥ 1500 mg/day in addition 
to diet and exercise counseling for at least 8 weeks prior to screening. Study subjects will 
continue taking open-labeled metformin during the entire study. 
All eligible subjects will start a single-blind run-in period by taking placebo bexagliflozin 
and placebo sitagliptin once daily for one week. Subjects who meet all inclusion criteria and 
no exclusion criteria after completion of the run-in period will be eligible for randomization 
and receive investigational products.  
During the treatment period, subjects will receive once daily sitagliptin tablets, 100 mg, and 
bexagliflozin tablets, placebo, or bexagliflozin tablets, 20 mg, and sitagliptin tablets, placebo, 
for 24 weeks. Each subject will be instructed to return to the clinic at weeks 6, 12, 18, and 24 
for efficacy assessment and safety monitoring. Subjects will return to the clinic for a follow-
up exit visit at week 26 or 2 weeks after last dose of study drug if subjects early terminate 
prior to week 24. 
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 right 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 374 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 with a diagnosis of T2DM with HbA1c levels between 7.0% and 11% 
(inclusive) at screening  
4. Subjects whose T2DM is treated with a stable dose of ≥ 1500 mg/day metformin only 
along with diet and exercise counseling for at least 8 weeks prior to screening 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 9 of 69 
Global Version 2.0 
5. Subjects with a 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 
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. Adhere to the investigational product administration requirements as evidenced by 
missing no more than 1 day of placebo run-in medication  
Test Products, Dose, and Mode of Administration: 
Once daily oral administration of bexagliflozin and sitagliptin with or without food taken 
together in the morning  
• 
Group 1: bexagliflozin tablets, 20 mg, and sitagliptin tablets, placebo  
• 
Group 2: bexagliflozin tablets, placebo, and sitagliptin tablets, 100 mg 
Duration of Treatment:  
Eligible subjects will receive a total treatment duration of 25 weeks including 1 week of run-
in medications and 24 weeks of investigational products. 
Efficacy Assessments: 
Primary efficacy assessment: 
• 
Change in HbA1c from baseline at week 24 
Secondary efficacy assessments: 
• 
Change in FPG from baseline at week 24 
• 
Change in body weight in subjects with baseline BMI ≥ 25 kg/m2 at week 24 
• 
Change in SBP in subjects from baseline at week 24 
Other efficacy endpoints: 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in the 
proportion of subjects achieving HbA1c < 7.0% over time 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in HbA1c 
over time 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in (FPG over 
time  
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in body 
weight over time  
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in SBP over 
time 
Safety Endpoints: 
• 
Treatment emergent AEs, including AEs of special interest (genital and urinary tract 
infections, diuretic effects, hepatotoxicity, MACE, hypoglycemia, fractures, malignancy, 
hypersensitivity reactions, hypotensive episodes, acid-base disorders, pancreatitis, 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 10 of 69 
Global Version 2.0 
amputations and renal failure events) 
• 
Laboratory testing, including hematology, serum chemistry, and urinalysis 
• 
Physical examination 
• 
12-lead ECG 
• 
Vital signs 
• 
Concomitant medication use 
Statistical Methods:  
The primary hypothesis is that bexagliflozin is non-inferior to sitagliptin by evaluating the 
treatment effect on HbA1c reduction at week 24 in combination with metformin. The non-
inferiority margin for mean change from baseline at week 24 in HbA1c comparing 
bexagliflozin group with sitagliptin 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 24 in HbA1c comparing bexagliflozin group with sitagliptin 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, region 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 24 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 endpoints 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 be excluded. 
2. Missing data will be imputed via last observation carried forward (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. 
 
The effects of bexagliflozin on the changes from baseline at week 24 in FPG, body weight 
and SBP  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, 
MMRM ANCOVA models will be used. A hierarchical testing strategy will be followed to 
preserve experiment-wide alpha at 0.05: 
1. Superiority test of the change in FPG in the bexagliflozin group vs. the sitagliptin group 
at week 24 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 11 of 69 
Global Version 2.0 
2. Superiority test of the change in body weight in subjects with baseline BMI ≥ 25 kg/m2 in 
the bexagliflozin group vs. the  sitagliptin group at week 24 
3. Superiority test of the change in SBP in the bexagliflozin group vs. the sitagliptin group 
at week 24 
 
Additional effects of bexagliflozin versus sitagliptin on the changes in HbA1c, FPG, SBP, 
body weight, and the proportion of subjects who reach an HbA1c < 7%, 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 sitagliptin with respect to the change in 
HbA1c from baseline at week 24 by a margin of 0.35%, assuming an estimated pooled 
standard deviation (SD) 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 8.0% dropout rate, 187 
patients will be randomized in each treatment arm, and the total sample size will be 374 
subjects for this study.  
Statistical analyses and summaries will be performed using SAS® software (SAS Institute, 
Cary, NC).  
Date of Protocol V2.0: 06 April 2017 
Date of Protocol V1.0: 01 February 2017 
 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 12 of 69 
Global Version 2.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
American Diabetes Association 
AE 
adverse event 
ALB 
albumin 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase  
ATC 
Anatomic Therapeutic Chemical classification 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CEC 
cardiovascular endpoint committee 
CI 
confidence interval 
CRF 
case report form 
CRO 
contract research organization 
DKA 
diabetic ketoacidosis  
DPP4 
dipeptidyl peptidase-4 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eGFR 
estimating glomerular filtration rate 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GMI 
genital mycotic infection 
h 
hour 
HbA1c 
hemoglobin A1c 
Hct 
hematocrit 
HDL-C 
high-density lipoprotein cholesterol 
HDPE 
high-density polyethylene 
Hgb 
hemoglobin 
HUA 
hospitalization for unstable angina 
ICH 
International Conference for Harmonisation  
IEC  
Independent Ethics Committee 
IRAE 
immediately reportable adverse event 
IRB 
Institutional Review bBoard 
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 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 13 of 69 
Global Version 2.0 
MCV 
mean corpuscular volume 
MDRD 
modification of diet in renal disease 
MedDRA 
medical dictionary for regulatory activities 
MI 
myocardial infarction 
MMRM 
mixed model repeated measures 
MODY 
maturity–onset diabetes of the young 
N 
number of subjects 
OHA 
oral hypoglycemic agent 
PP 
per protocol 
PR 
time from the beginning of the P wave to the beginning of the QRS complex in 
electrocardiogram 
QRS 
QRS complex the combination of three of the graphical deflections seen on a typical 
electrocardiogram 
QT 
a measure of the time between the start of the Q wave and the end of the T wave in the 
heart's electrical cycle 
RBC 
red blood cell (count) 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SGLT2 
sodium glucose cotransporter 2 
SMBG 
self-monitored blood glucose 
SOP 
standard operating procedure 
SU 
sulfonylurea 
SUSAR 
serious and unexpected suspected adverse event 
TIA 
transient ischemic attack 
T2DM 
type 2 diabetes mellitus 
TC 
total cholesterol 
TEAE 
treatment emergent adverse event 
TG 
triglycerides 
TZD 
thiazolidinedione 
UACR 
urine albumin to creatinine ratio 
UADR 
unexpected adverse drug reaction 
UGE 
urinary glucose excretion 
ULN 
upper limit of normal 
UPT 
urinary pregnancy test 
UTI 
urinary tract infection 
WBC 
white blood cell (count) 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of childbearing potential 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 14 of 69 
Global Version 2.0 
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, 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. DPP4 inhibitors are considered second-line therapy for T2DM in clinical 
practice and are often prescribed with metformin as a combination therapy for treating 
T2DM. Sitagliptin is a DPP-4 inhibitor, which prevents the degradation of incretin. Incretin 
increases insulin production and reduces hepatic glucose production, leading to better 
glucose metabolism. Sitagliptin is primarily excreted unchanged in the urine. DPP4 inhibitors 
can reduce the risk of long-term microvascular complications via effective glycemic control 
and do not have weight gain or increased hypoglycemia risk compared with placebo. 
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 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 15 of 69 
Global Version 2.0 
ions. Individuals with disruptions in SLC5A2, the gene encoding SGLT2, exhibit prominent 
glucosuria in the absence of significant co-morbidities (van den Heuvel, Assink et al. 2002; 
Santer, Kinner et al. 2003). The excretion of glucose in the urine of diabetic subjects in 
amounts comparable to or greater than that seen in individuals harboring loss of function 
mutations in SLC5A2 has the potential to improve fasting and postprandial hyperglycemia 
without increasing insulin secretion, causing weight gain, or inducing hypoglycemia. Several 
SGLT2 inhibitors have demonstrated these clinical benefits, as well as sustained weight loss, 
when used as a monotherapy or in combination with other oral anti-diabetic medications 
including insulin (Nauck 2014; Seufert 2015). 
1.2 
 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus 
Bexagliflozin is a candidate oral hypoglycemic agent (OHA) that is a potent and highly 
specific inhibitor of SGLT2. It was identified following a synthetic program aimed at 
creating molecules with high selectivity and potency for SGLT2 (Zhang, 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. In a 12 week monotherapy study, bexagliflozin 
tablets, 20 mg, showed greater placebo adjusted HbA1c reduction (-0.80%) than 
bexagliflozin, 10 mg (-0.68%), and bexagliflozin, 5 mg (-0.55%). Bexagliflozin 
administration has been well tolerated. The safety and efficacy of bexagliflozin tablets, 
20 mg, were evaluated in a 96-week study that measured reduction in hemoglobin A1c 
(HbA1c) as the primary endpoint. This 96 week study showed bexagliflozin tablets, 20 mg, 
to be superior to placebo in reducing HbA1c.   Details of the pharmacology, efficacy, and 
safety assessments are described in the Investigator’s Brochure. The safety profile supports 
continued evaluation of the treatment effect when used in combination with metformin. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 16 of 69 
Global Version 2.0 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary efficacy objective of this trial is to demonstrate that bexagliflozin is non-inferior 
to sitagliptin by evaluating the treatment effect on HbA1c reduction at week 24 in subjects 
whose T2DM is inadequately controlled by metformin. 
2.2 
Key Secondary Objectives 
• 
To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in fasting 
plasma glucose (FPG) at week 24 
• 
To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in body 
weight in subjects with baseline body mass index (BMI) ≥ 25 kg/m2 at week  24 
• 
To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in systolic 
blood pressure (SBP) in subjects at week 24 
 
2.3 
Exploratory Objectives 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in the 
proportion of subjects achieving HbA1c < 7.0% over time 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in HbA1c 
over time 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in FPG over 
time  
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in body 
weight over time  
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in SBP over 
time 
 
Safety Objectives: 
• 
To compare the effects of bexagliflozin vs. sitagliptin on the incidence of adverse events 
(AE) of interest. AE of interest are urinary tract infections including urosepsis and 
pyelonephritis, genital mycotic infections (GMI), 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 (DKA), amputations, pancreatitis, and renal failure events 
• 
To compare the effects of bexagliflozin vs. sitagliptin on general safety assessments 
including treatment emergent AE, clinical laboratory events, 12-lead electrocardiograms 
(ECG) parameters, physical examinations, vital signs including orthostatic blood 
pressure(BP), and use of concomitant medications 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 17 of 69 
Global Version 2.0 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
THR-1442-C-423 is a phase 3, multi-center, randomized, double-blind, parallel-group study 
and aims to demonstrate that bexagliflozin is non-inferior to sitagliptin 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 24. The study will enroll 
T2DM patients who are treated with only metformin. 
All subjects must have taken metformin at a stable dose of ≥ 1500 mg/day for ≥ 8 weeks 
prior to screening and have received diet and exercise counseling.  
A total of 374 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. Subjects who 
successfully complete a 1-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 sitagliptin tablets (Group 1) or placebo bexagliflozin 
tablets and active sitagliptin tablets (Group 2). Active treatment in Group 1 will be 
bexagliflozin tablets, 20 mg. Active treatment in Group 2 will be sitagliptin tablets, 100 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 24 
weeks and be conducted in an outpatient setting. 
3.2 
Research Methods and Procedures 
3.2.1 
Run-in Period 
All subjects who are eligible at the screening visit will begin a 1 week run-in period. At the 
start of the run-in period, 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. At the start of run-in, subjects will be provided 
with a glucometer and instructions for its daily use. During the run-in, subjects will receive 
placebo bexagliflozin and placebo sitagliptin. Bexagliflozin tablets and sitagliptin tablets will 
be taken with water at the same time everyday. 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:  
1. have fasting blood glucose values ≥ 250 mg/dL on two or more consecutive days, 
accompanied by symptoms of hyperglycemia 
2. omit more than 1 day of run-in medication, or 
3. are deemed inappropriate for the study by the investigator,  
 
Inclusion and exclusion criteria are described in more detail in sections 4.2 and 4.3. 
 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 18 of 69 
Global Version 2.0 
Changes in the dose of treatment for dyslipidemia or hypertension will not be permitted 
during the screening and run-in periods. Management of concomitant medications is 
described in Section 5.6 Concomitant Therapy.  
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 and screen failed.  
3.2.2 
Treatment Period 
The double-blind treatment period will start at randomization and last 24 weeks. A total of 
374 subjects of 187 subjects per group will be randomized in a 1:1 ratio to the two groups as 
shown in Table 1.  
Table 1. 
Treatment Groups and Assigned Treatment 
Treatment Group 
Treatment 
1 
Bexagliflozin tablets, 20 mg, (once daily P.O.) 
Sitagliptin tablets, placebo, (once daily P.O.) 
2 
Bexagliflozin tablets, placebo, (once daily P.O.) 
Sitagliptin tablets, 100 mg, (once daily P.O.) 
 
Randomization will be stratified by HbA1c at Visit V1 (≤ 8.5% vs. ˃ 8.5%) at screening. At 
the start of the treatment period, each subject will be provided with bexagliflozin tablets, 
sitagliptin tablets, and dosing instructions. 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, and sitagliptin tablets, 
100 mg or placebo, will be taken once daily at approximately the same time each day either 
before or after breakfast with approximately one cup (250 mL) of water. Background 
metformin shall be taken at the same dose and frequency from screening throughout the 
entire study.  
Each subject will be instructed to return to the clinic at weeks 6, 12, 18 and 24 for efficacy 
assessment and safety monitoring, including review of AEs and concomitant 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 and 
sitagliptin shall be withheld until after blood is drawn and taken with water at the clinic or 
home. 
Subjects will return to the clinic for a follow-up exit visit at week 26 or 2 weeks after the last 
dose of study drugs if subjects early terminate prior to week 24. Following the exit visit, 
subjects will be advised to see their primary physician to undergo treatment to control their 
diabetes. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 19 of 69 
Global Version 2.0 
3.2.3 
Glycemic Control Monitoring 
3.2.3.1 
Placebo Run-in Period 
During placebo run-in period, subjects will be instructed to determine self-monitored blood 
glucose (SMBG) daily after fasting overnight for approximately 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 the SMBG is ≥ 250 mg/dL on 2 
consecutive days, and is accompanied by symptoms of hyperglycemia. Subjects with clinical 
signs or symptoms of severe hyperglycemia during the run-in period, including weight loss, 
blurred vision, increased thirst, increased urination, or fatigue, should also be excluded. 
3.2.3.2 
Treatment Period 
During the treatment period, subjects will be advised to continue daily, fasting SMBG 
measurements. Subjects should contact the clinic if any fasting SMBG is ≥ 270 mg/dL 
(15 mmol/L) from week 0 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. 
If hyperglycemia is identified through SMBG or FPG measurements, the investigator will 
determine whether the subject has fasted for approximately 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 
may prescribe rescue medication if it is necessary for the well-being of the subject. 
3.2.3.3 
Rescue Medication 
Rescue medication is suggested during the treatment period if, after diet and exercise 
counseling, subjects meet the following glycemic criteria:  
1. More than 3 consecutive, daily, fasting SMBG measures are ≥ 270 mg/dL (15 mmol/L) 
from baseline to week 6, ≥ 240 mg/dL (13.3 mmol/L) from week 6 to week 12, or 
≥ 200 mg/dL (11.1 mmol/L) or HbA1c > 8.0% from week 12 to week 24 
2. Fasting SMBG values are ≥ 250 mg/dL (13.9 mmol/L) and associated with clinical signs 
or symptoms of hyperglycemia (e.g., weight loss, blurred vision, increased thirst, 
increased urination, or fatigue), and the signs or symptoms are severe. 
 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 20 of 69 
Global Version 2.0 
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. Other SGLT2 inhibitors (Appendix 3), DPP-4 
inhibitors, or GLP-1 agonists may not be prescribed. Metformin dose can be increased at the 
discretion of the investigator. SUs and insulins are known to increase the risk of 
hypoglycemia in combination with sitagliptin. As subjects may be taking active sitagliptin, 
investigators should use caution in prescribing these medications. 
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, the study drug can be 
discontinued at the discretion of the investigator. 
If recurrent symptomatic hypoglycemia occurs in subjects who are not prescribed rescue 
medication, the total daily dose of metformin should be decreased at the discretion of the 
investigator. If recurrent symptomatic hypoglycemia continues after decreasing the dose of 
metformin, subjects should be discontinued from the study and treated in accordance with 
local standards of care. 
Subjects who receive rescue medication due to poor glycemic control will continue to receive 
investigational products and 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. 
3.2.4 
Other Safety Monitoring Activities  
The safety monitoring activities will include assessments of vital signs, 12-lead ECG, 
physical examinations, urinalysis, blood chemistry, hematology, AEs, and concomitant 
medication use. The occurrence of blood, liver, or skin disorders will be monitored through 
laboratory testing and evaluation of AE documentation.  
Sitagliptin treatment may increase the risk of developing acute pancreatitis, acute renal 
failure, hypersensitivity reactions, and arthralgia. Subjects experiencing these conditions 
should be immediately discontinued from taking bexagliflozin tablets and sitagliptin tablets 
and treated in accordance with local standards of care until the AE is resolved. The subject 
will be permanently discontinued from participation in the clinical trial if the subject’s 
condition worsens or if the subject starts dialysis or other renal replacement therapies.  If 
discontinued, subjects should be advised to consult with their primary physician for 
managing T2DM.    
Sitagliptin administration should be suspended if estimated glomerular filtration rate (eGFR) 
decreases to < 60 mL/min/1.73 m2 and laboratory values should be retested within 48 h.  


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 21 of 69 
Global Version 2.0 
Sitagliptin dosing may resume if the eGFR returns to ≥ 60 mL/min/1.73 m2.  If eGFR 
remains below 60 mL/min/1.73 m2, the subject should discontinue from participation in the 
clinical trial and be advised to see their primary physician to undergo treatment to control 
their diabetes and other medical conditions. 
AEs of special interest as defined in the statistical analysis plan will include any clinical 
signs and symptoms that indicate adverse experience in the categories listed below. All such 
events must be appropriately documented within source documentation. 
• 
Acid-base disorders including DKA 
• 
Amputations 
• 
Diuretic effects including hypovolemia 
• 
Falls and fractures 
• 
GMI 
• 
Hepatotoxicity 
• 
Hypersensitivity reactions 
• 
Hypoglycemia 
• 
Hypotension episodes 
• 
MACE 
• 
Malignancies 
• 
Pancreatitis 
• 
Renal failure events 
• 
Urinary tract infections including urosepsis and pyelonephritis 
 
3.2.5 
Data and Safety Monitoring Board (DSMB)  
An independent Data and Safety Monitoring Board (DSMB) will monitor overall safety 
information during the bexagliflozin development program. The safety review activity and 
potential risk benefit assessments utilized by the DSMB will be defined in its charter. 
3.2.6 
Major Adverse Cardiovascular Event (MACE) Adjudication  
An independent cardiovascular 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. 
3.2.7 
Diabetic Ketoacidosis (DKA) Event Adjudication  
An independent adjudication committee will be established to review all potential DKA 
under blind. The adjudicated events will be documented and archived. All adjudicated DKA 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 22 of 69 
Global Version 2.0 
events in the bexagliflozin phase 3 program will be pooled at the end of the program and a 
final analysis will be conducted.  
3.3 
Rational for Study Design and Procedures 
3.3.1 
Rationale for the Study Design 
THR-1442-C-423 is designed to assess the non-inferiority of bexagliflozin to sitagliptin as 
add-on therapy to metformin for glycemic control in T2DM subjects. To assess the effect of 
bexagliflozin or sitagliptin 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, 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 unless persistent hypoglycemia occurs during the treatment period.  
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.  
3.3.2 
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. It is a biguanide that decreases hepatic glucose production and 
may improve peripheral glucose uptake and utilization. 
Subjects who have T2DM often require multiple anti-diabetic medications for glycemic 
control. DPP-4 inhibitors are often prescribed with metformin as a combination therapy for 
treating T2DM. DPP-4 inhibitors can reduce the risk of long-term microvascular 
complications via effective glycemic control. Sitagliptin in addition to metformin does not 
have additional risk of hypoglycemia. Sitagliptin is one of the most commonly prescribed 
DPP-4 inhibitors. Thus, it is an appropriate active comparator in the subject population 
studied during the treatment period (24 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. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 23 of 69 
Global Version 2.0 
3.3.3 
Rationale for the Dose Selection 
Bexagliflozin produces a dose-dependent and saturable increase in UGE in healthy 
volunteers and subjects with T2DM. Population pharmacodynamic modeling has indicated 
that bexagliflozin doses of 20 mg result in approximately 90% of the maximal UGE. In a 12-
week dose range finding study, daily administration of 20 mg bexagliflozin was found to 
reduce HbA1c by 0.80% compared to placebo at week 12, a greater reduction than found in 
10 mg and 5 mg cohorts. A higher proportion of patients that have been treated with 
bexagliflozin tablets at 20 mg per day has achieved the target of HbA1c below 7%. FPG 
reduction, weight loss, and decreased systolic and diastolic BPs compared to baseline were 
also observed following 12 weeks of treatment.  In addition, AEs, particularly those 
involving urinary tract infections (UTI) and GMIs, were found to be similar between placebo 
and active agent cohorts. To evaluate the safety and efficacy of bexagliflozin compared to 
sitagliptin for the treatment of subjects with T2DM, bexagliflozin tablets, 20 mg, will be 
administered in this trial. 
3.4 
Study Duration and Dates 
Subjects will be enrolled within 2 weeks of screening. Eligible subjects who provide written 
consent will start a run-in period of 1 week prior to randomization to receive study drugs to 
demonstrate compliance. Subjects who successfully complete the run-in will begin 24 weeks 
of treatment and will be followed for 2 weeks after the last dosing. The study duration from 
screening to follow-up will be no more than 29 weeks overall. For details of the schedule and 
nature of the investigations, see the Schedule of Events in Appendices 1 and 2.  


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 24 of 69 
Global Version 2.0 
4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study population will include approximately 374 subjects whose T2DM is inadequately 
controlled by metformin and who meet all of the inclusion criteria and none of the exclusion 
criteria. Clinical sites in the North America and Europe are anticipated to recruit subjects. 
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 
3. Subjects with a diagnosis of T2DM with HbA1c levels between 7.0% and 11% 
(inclusive) at screening 
4. Subjects whose T2DM is treated with a stable dose of ≥ 1500 mg/day metformin only 
along with diet and exercise counseling for at least 8 weeks prior to screening 
5. Subjects have a 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  
7. Subjects who are willing and able to return for all clinic visits and to complete all study-
required procedures, including SMBG measurements 
 
Prior to randomization, all subjects must: 
8. Adhere to the investigational product administration requirements as evidenced by 
missing no more than 1 day of run-in medications. If run-in medication doses are missed 
for reasons that, in the judgement of the investigator, are appropriate, this requirement 
may be waived 
 
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. Hemoglobinopathy that affects HbA1c measurement 
3. Any contraindication to the safe use of DPP4 therapy or sitagliptin, including known 
hypersensitivity reaction  
4. History of pancreatitis 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 25 of 69 
Global Version 2.0 
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. Triglycerides > 500 mg/dl at Visit V1 
9. 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 
10. eGFR, as calculated by the modification of diet in renal disease study equation (MDRD), 
< 60 mL/min/1.73 m2 at screening. 
11. Uncontrolled hypertension (SBP > 160 mmHg or diastolic BP > 95 mmHg) at Visit V1 
12. Life expectancy < 2 years 
13. History of 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 inhibitor (Appendix 3) 
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 
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 accompanied by clinical signs or symptoms of hyperglycemia prior to 
randomization, including weight loss, blurred vision, increased thirst, increased urination, 
or fatigue 
 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 26 of 69 
Global Version 2.0 
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 
Sitagliptin tablets, 100 mg or placebo, are beige, round, film-coated tablets with “277” on 
one side. 
The following active comparator products will be used for oral administration: 
• 
Sitagliptin tablets, 100 mg: tablets containing 100 mg of sitagliptin 
• 
Sitagliptin tablets, placebo: tablets containing no sitagliptin 
 
5.2 
Treatments Administered 
5.2.1 
Investigational Product 
Bexagliflozin tablets, 20 mg or placebo, should be taken at approximately the same time each 
day, before or after breakfast, with one cup (250 mL) of water. 
On the day of scheduled clinic visits 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 with one cup (250 mL) of water. 
5.2.2 
Active Comparator 
Sitagliptin tablets, 100 mg or placebo, should be taken once daily at the same time as 
bexagliflozin, before or after breakfast, with one cup (250 mL) of water.  
On the day of scheduled clinic visits when there is fasting and blood is to be drawn, 
administration of sitagliptin should be delayed until after blood is drawn and taken in the 
clinic or at home with one cup (250 mL) of water. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 27 of 69 
Global Version 2.0 
5.2.3 
Background Metformin Therapy 
Subjects will continue receiving metformin as background therapy during the entire study 
period at an unchanged dose (≥ 1500 mg/day), time, and frequency as 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. 
Guidance for adjustment to metformin dose is provided in Section 3.2.3. Changes to the dose, 
frequency, or time of administration of metformin should be recorded in the concomitant 
medication log. 
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 at the beginning of the treatment period. All study subjects will be instructed to 
take bexagliflozin tablets once daily in the morning, before or after breakfast, with one cup 
(250 mL) of water. The dose and frequency of bexagliflozin will be unchanged during the 
24-week treatment period.  
On the day of each scheduled clinic visit, subjects must fast for approximately 10 h prior to 
the collection of blood samples. During the fasting period, only water will be permitted.  
5.3.2 
Sitagliptin 
Dosing with sitagliptin tablets, 100 mg or placebo, will be based on randomized assignment 
at the beginning of the treatment period. All study subjects will be instructed to take 
sitagliptin tablets once daily in the morning, before or after breakfast, with one cup (250 mL) 
of water. The dose of sitagliptin will be unchanged during the 24-week treatment period. 
5.4 
Method of Assigning Treatment Groups and Study Drugs 
The study will be conducted at multiple investigative sites and will involve variable numbers 
of subjects at each site. Enrollment will be on a competitive basis, but each site will be 
capped at 30 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 run-in period and meet all study inclusion/exclusion 
requirements will be randomized in a 1:1 ratio to receive active bexagliflozin with placebo 
sitagliptin or active sitagliptin 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 screening (Visit V1) HbA1c (< 8.5% or ≥ 8.5%). The investigator or 
designated staff will log into the IWRS to receive the randomization code and assigned kit 
numbers. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 28 of 69 
Global Version 2.0 
Subject randomization will be deactivated for all sites when the planned number of subjects 
(N) is met. However, if a potential subject has been screened 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 endpoint committee (CEC), and the DKA 
committee will be blinded to the study medications.  
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 
results 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 CEC and DKA adjudication 
committee members until all global investigational studies are completed and final analyses 
to assess cardiovascular and ketoacidosis risks are conducted. 
5.6 
Concomitant Therapy 
During the course of the study, investigators will manage glucose, BP, and lipid levels 
according to local or regional standard of care guidance documents for the management of 
T2DM. Instructions for rescue medication for hyperglycemia are provided in Section 3.2.3.3. 
Subjects will be allowed to take medications or medicinal supplements prescribed to manage 
non-diabetic medical conditions during the study. Any concurrent medication or 
supplemental treatment of other, non-diabetes, medical conditions should be continued at a 
stable dose and frequency for the entire study duration unless there is a clinical reason to 
change the dose or frequency.  
Subjects may receive any medications for AEs that are necessary in the investigators’ 
judgment. Medications prescribed after the informed consent are to be recorded on the CRF. 
The medication name, dose, frequency, route of administration, date(s) of administration, and 
reason for administration must be recorded. This documentation should continue through the 
treatment period and the follow-up period.  


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 29 of 69 
Global Version 2.0 
5.6.1 
Diuretics and Medications for Treatment of Dyslipidemia and Hypertension 
Subjects who are prescribed diuretics, anti-hypertensive agents, or medications to treat 
dyslipidemia will continue the current dose, frequency, and time of administration of these 
medications throughout the study. Subjects do not need to be treated with dyslipidemia or 
hypertension to be eligible for the study. Adjustment of these medications will not be 
permitted during the screening and run-in periods.  
If a change in diuretics, anti-hypertensive agents, or medications to treat dyslipidemia is 
required during the screening 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.  
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. New diuretic 
medications should not be initiated during the first 2 weeks of the treatment period. The dose 
and frequency of existing diuretic medications should not be changed during the first 2 weeks 
of therapy. Changes to the dose or frequency of anti-hypertensive and diuretic medications 
will be recorded in the concomitant medications log. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
All subjects will continue regimens for medical conditions other than diabetes during the 
study as indicated above. No subject shall have been treated with an investigational drug 
within 30 days of screening 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 any hypoglycemic agents other than 
metformin during the 8 weeks prior to 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, low in simple carbohydrates, and contain 
appropriate caloric intake to maintain weight. Subjects will also be counseled consume 
alcohol in moderation. Subjects with a known history of alcohol abuse should be excluded 
from the study as indicated in Section 4.3. 
Subjects will fast for approximately 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-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 30 of 69 
Global Version 2.0 
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 1 day of 
placebo run-in medication doses has been omitted. If, in the judgement of the investigator, it 
was appropriate for the subject to omit these doses, this requirement may be waived (e.g., if 
the subject was hospitalized overnight during run-in). 
At each visit after the start of the run-in period, the study staff will review 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 sitagliptin tablets, placebo, will 
be provided for the 1-week run-in portion of the study. All investigational product supplies 
will be prepared and labeled according to the requirements of local laws and regulations. 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  
• 
Sitagliptin tablets, placebo, 15 tablets 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 90 count bottle of bexagliflozin tablets, 20 mg or placebo.  


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 31 of 69 
Global Version 2.0 
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 
Sitagliptin Kit 
One sitagliptin kit contains a 90 count bottle of sitagliptin tablets, 100 mg or placebo. 
The label attached to each sitagliptin 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 sitagliptin tablets will be stored at controlled room temperatures of 
below 30°C (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 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-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 32 of 69 
Global Version 2.0 
6 
STUDY PROCEDURES 
The following sections describe procedures that are conducted in the protocol.  The clinical 
investigator must personally conduct or supervise the procedures that are required in the 
protocol.  Study tasks may be delegated to qualified staff after training is completed.  
Procedures that require clinical /medical knowledge must be performed by the investigator or 
qualified sub-investigators. 
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, 
purpose of the study, and the action of the drug, in such a manner that the study subject is 
aware of the potential risks, inconveniences, or AEs that may occur. The investigator 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 the Good Clinical Practice (GCP) guidelines of the 
International Conference for Harmonisation (E6).  
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. He or she should evaluate any 
change to status affecting conformance to inclusion and exclusion criteria at subsequent visits 
prior to randomization. At randomization, the investigator should confirm the run-in drug 
compliance. 
6.3 
Medical History  
The following information will be collected at the screening visit: 
6.3.1 
General Demographics and Characteristics  
• 
Date of birth, age, sex, and race, and whether a female subject is of childbearing potential 
or not 
• 
Significant medical and surgical history, including dates of diagnoses, procedures and 
whether the condition is ongoing, if applicable 
 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 33 of 69 
Global Version 2.0 
6.3.2 
Diabetes History  
• 
History of all medications used to treat diabetes (to be recorded in the concomitant 
medication form), including start date, duration of use, and stop date, if applicable 
• 
History of complications due to diabetes, including nephropathy, retinopathy, 
neuropathy, non-traumatic amputations, and DKA, including date of diagnosis 
• 
Frequency of hypoglycemic events (per week) that are symptomatic or require assistance 
6.3.3 
Cardiovascular Disease History  
History of cardiovascular disease, including presence of angina, congestive heart failure 
(including NYHA classification), known atherosclerotic cardiovascular disease, prior MI, 
transient ischemic attack (TIA) or stroke, and prior cardiac or peripheral re-vascularization 
procedures. The history should include the date of diagnosis and the current status of 
diagnosis (resolved or ongoing). 
6.3.4 
Medication History  
• 
Use of prescribed or non-prescribed medications, including name of medication, 
indications for usage, start and stop dates, dose, and frequency 
• 
Use of supplements, including over the counter drugs, vitamins, herbal preparations, and 
dietary supplements within the past 30 days prior to screening. Each medication history 
will include the agent used, indication for usage, start and stop dates, dose, and frequency 
 
6.4 
Diet and Exercise Counseling  
Subjects will receive counseling regarding appropriate diet and exercise to aid in glycemic 
control based on standards of medical care in diabetes throughout the study. In addition, all 
subjects are encouraged to consume enough liquid to maintain adequate hydration. 
6.5 
Physical Examination  
A complete physical examination will be performed by the investigator at the time points 
indicated in the Schedule of Events (Appendix 1). The examination will include 
measurement of body weight and a general assessment of all body systems, including the 
skin, head, eyes, ears, nose, throat, neck, heart, lungs, abdomen, lymph nodes, vascular 
system and extremities. The body weight must be determined using a scale that is calibrated. 
The same scale should be used for the duration of the study if possible. 
6.6 
Abbreviated Physical Examination  
An abbreviated physical examination will be performed by the investigator at the time points 
indicated in the Schedule of Events (Appendix 1). An abbreviated physical examination will 
include height (only at the screening visit) and general assessment of the skin, heart, lungs 
and abdomen, and extremities. The body weight must be determined using a scale that is 
calibrated. The same scale should be used for the duration of the study if possible. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 34 of 69 
Global Version 2.0 
6.7 
Body Weight 
The body weight will be measured at every visit except visit V2.  The weight must be 
determined using a scale that is calibrated. The same scale should be used for the duration of 
the study, if possible. 
6.8 
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. Only the 
BP measured in the sitting position will be used to determine eligibility. 
Devices designed to measure BP from the finger or wrist may not be used. The left arm and 
same cuff sizes should be used for each measurement at all visits. If the left arm cannot be 
used at the screening visit or during the study for BP measurements, the reason should be 
documented, and the right arm should be used for BP measurements for all subsequent visits. 
At each visit, BP measurements will be obtained using a calibrated sphygmomanometer 
while the subject is in sitting, supine, and standing positions. A single heart rate measurement 
should be taken just prior to the BP evaluation in the sitting, supine, and standing positions.  
All readings are to be entered into the source document and CRF for all subjects. The date 
and time of BP measurements should be captured in the source document and CRF. BP will 
be assessed first in the sitting position. Sitting BP and heart rate will be measured after the 
subject has been sitting for at least 5 minutes with feet on the floor and arm supported at 
heart level.  
After sitting BP measurement has been completed, supine and standing BP will be measured 
to evaluate orthostatic vital signs. Supine and standing BP 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 BP 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.  
6.9 
Electrocardiography  
A 12-lead ECG will be conducted at the time points indicated in the Schedule of Events in 
Appendix 1 and whenever clinically indicated. This procedure should be performed in the 
supine position after at least 10 minutes of rest. ECG parameters to be recorded on the CRF 
are RR interval, PR interval, QRS duration, and QT interval. Each ECG should also be 
assessed by the investigator for signs of ischemia, clinically significant hypertrophy, and 
clinically significant T-wave abnormalities or arrhythmia.  
It is the investigator’s responsibility to review the results of the ECG as they become 
available. For each abnormal ECG result, the investigator shall ascertain if the observation 
represents a clinically significant change from the screening ECG for that individual subject. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 35 of 69 
Global Version 2.0 
This determination does not necessarily need to be made the first time an abnormal result is 
observed. The investigator may repeat the ECG to verify the original result. If the ECG result 
is determined to be a clinically significant and abnormal change from baseline for that 
subject, it is considered to reflect an AE. 
6.10 Clinical Laboratory Tests  
6.10.1 
Laboratory Parameters  
Clinical laboratory tests are listed in Table 2. 
6.10.2 
Sample Collection, Storage, and Shipping  
Blood samples for hematology, chemistry, serum lipids and glycemic control assessments 
will be collected. Subjects will be in a seated or supine position during blood collection. 
Samples will be collected at the time points indicated in the schedule of events in Appendix 1 
and Appendix 2. 
The study staff will contact each subject prior to a scheduled clinic visit to confirm the time 
of the visit and to remind the subject of proper fasting practice. A subject must be queried to 
assess compliance with an approximately 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. 
An investigator can perform additional laboratory testing to diagnose or to follow up an AE 
progression or resolution. Clinical samples should be analyzed in a local laboratory if a fast 
turn-around time is necessary to determine treatment plan.  
6.10.3 
Urinalysis 
Urine samples will be collected routinely at designated clinic visits from a clean 
catch sample. Urinalysis will be performed at the time points indicated in the schedule of 
events (Appendix 1 & Appendix 2). The investigator or study staff should document if pre-
menopausal female subjects are menstruating and note it in the source documents since 
hematuria is likely to be identified on dipstick urinalysis. 
Strips to assess leukocyte esterase and nitrite but not glucose will be provided for immediate 
assessment at the clinical sites. If more than traces of positive results are shown in the 
leukocyte esterase and/or nitrite testing, a urine culture should be performed in a designated 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 36 of 69 
Global Version 2.0 
laboratory regardless of patient reported signs or symptoms. Results of the urinalysis and 
possible urine culture will be documented in the CRFs. 
Urine samples will be transported to the central laboratory for urinalysis. Microscopy will 
be conducted if the subject has a positive result on the leukocyte esterase or nitrite dipstick 
tests to clarify the significance of the finding. Results of glucose measurement in the 
urinalysis must be suppressed from the laboratory reports so the sponsor, investigators, study 
coordinators, pharmacists, study subjects, and the CEC members will remain blinded to the 
dosing assignment. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 37 of 69 
Global Version 2.0 
6.11 Laboratory Tests 
Table 2 
List of Laboratory Tests  
TEST NAME 
SHIPMENT 
Hematology 
Ambient 
• Hematocrit (Hct) 
• Hemoglobin (Hgb) 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin 
concentration (MCHC) 
• Platelet count 
• Mean corpuscular volume (MCV) 
• Red cell distribution width (RDW) 
• Red blood cell (RBC) count  
• White blood cell (WBC) count with differential  
  
Serum Chemistry and Electrolytes  
Ambient 
• Albumin (ALB) 
• Alanine aminotransferase (ALT) 
• Alkaline Phosphatase (ALP) 
• Aspartate aminotransferase (AST) 
• Blood urea nitrogen (BUN) 
• Glucose 
• Bicarbonate (HCO3) 
• Creatinine 
• Chloride (Cl) 
• Total protein 
• Calcium (Ca) 
• Magnesium 
• Phosphorus 
• Potassium (K) 
• Sodium (Na) 
• Total bilirubin 
• Direct bilirubin 
• Uric acid 
Glycemic Control  
Ambient 
• Fasting plasma glucose (FPG) 
• Hemoglobin A1c (HbA1c) 
  
Serum Lipids  
Ambient 
• Total cholesterol (TC) 
• High-density lipoprotein cholesterol 
(HDL-C) 
• Triglycerides (TG) 
• Low-density lipoprotein cholesterol (LDL-C), 
calculated 
• LDL-C, direct 
Urinalysis  
Ambient 
• Appearance 
• Bilirubin 
• Color 
• Glucose 
• Ketones 
• Microscopic examination of sediment  
• UACR 
• Nitrite  
• Occult blood 
• pH 
• Protein 
• Specific gravity 
• Urobilinogen 
• Leukocyte esterase 
Urine Pregnancy Test (WOCBP)   
Local 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 38 of 69 
Global Version 2.0 
6.12 Diary and Glucometer Dispensation  
A glucometer, testing strips, and a glycemic control diary will be provided to each subject at 
the start of the run-in period for SMBG. Subjects will be trained to use the glucometer and 
record any hypoglycemic events in the glycemic control diary. The SMBG record from the 
glucometer and diary entries must be reviewed by the investigator at all subsequent visits. 
During the SMBG training, symptoms that may indicate hypoglycemia, hyperglycemia, or 
ketoacidosis will be reviewed with study subjects. Instructions to contact the clinic when the 
subjects experience potential hypoglycemia or DKA must be provided. 
6.13 Dispensing Run-in Drug  
Each eligible study subject will receive one bottle of sitagliptin run-in drug and one bottle of 
bexagliflozin run-in drug at the visit indicated in Appendix 1. 
Patients should self-administer the first dose of each run-in drug with 1 cup (250 mL) of 
water under observation during the scheduled visit.  
6.14 Diary and Glucometer Record Review  
At each visit after the beginning of run in, the investigator will review the glycemic control 
diary, glucometer record, and symptoms that may indicate potential DKA with the subject 
and record the findings in the CRF. 
6.15 Dispensing Investigational Product  
At randomization and at every 12 weeks of treatment thereafter, each study subject will 
receive two bottles of the investigational product based on the kit number assigned to the 
subject by the IWRS. One bottle will be bexagliflozin, 20 mg or placebo, and the other bottle 
will be sitagliptin, 100 mg or placebo.  Each bottle of the investigational product will provide 
daily dosing for 12 weeks. 
Patients should self-administer the dose of investigational product with one cup (250 mL) of 
water under observation during the scheduled visits, if they have not already taken 
investigational product that day.  
6.15.1 
Drug Accountability 
To ensure adequate recordkeeping, subjects must bring all investigational products to each 
visit. The remaining tablets will be accounted for in the CRF and drug consumption forms. 
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-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 39 of 69 
Global Version 2.0 
6.16 Adverse Events Assessments  
6.16.1 
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 AE (SAE) or reaction is any untoward medical 
occurrence that at any dose:  
• 
results in death  
• 
is life-threatening (NOTE: The term "life-threatening" in this context refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe) 
• 
requires inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity  
• 
is a congenital anomaly/birth defect  
• 
is a medically important event or reaction. Medical and scientific judgment should be 
exercised in deciding whether a situation should be considered serious. Important medical 
events which jeopardize the subject or require intervention to prevent one of the 
outcomes listed above should 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 AE caused by a drug. Adverse reactions 
are a subset of all suspected AEs in which there is a reason to conclude that the drug caused 
the event. 
Unexpected Adverse Drug Reaction (UADR): An adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g. Investigator’s 
Brochure for an unapproved investigational medicinal product). 
Serious and Unexpected Suspected Adverse Reaction (SUSAR): A serious UADR. The 
sponsor must report any suspected SUSAR in an IND safety report (21 CFR 312.32(c)(1)(i)). 
Before submitting an IND safety report, the sponsor needs to ensure that the event meets all 
three of the definitions:  
• 
Suspected adverse reaction  
• 
Serious  
• 
Unexpected  


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 40 of 69 
Global Version 2.0 
 
Severity: AEs will be graded on a 3-point scale and reported as indicated in the CRF. The 
intensity of an AE is defined as follows: 
1 = Mild: event is medically significant but produces no disruption to daily activity 
2 = Moderate: event is medically significant and reduces or affects normal daily activity 
3 = Severe: event is medically significant and results in inability to work or perform 
normal daily activity 
Investigational Product Causality: An assignment made by the investigator based on the 
circumstances of the event and its analysis. Cases with causal relationship classified as 
possible, probable, or definite are defined as related. Cases with causal relationship 
categorized as not likely or unrelated are defined as not related. Relationship of an AE to 
dosing will be assessed as follows: 
• 
Definite: The event responds to withdrawal of the investigational product (dechallenge), 
and recurs with rechallenge by administration of the investigational product  
• 
Probable: There is a reasonable causal relationship between the investigational product 
and the AE. The event responds to dechallenge. Rechallenge is not required 
• 
Possible: There is a reasonable causal relationship between the investigational product 
and the AE. Dechallenge is lacking or dechallenge response is unclear 
• 
Not Likely: There is a temporal relationship to investigational product administration, 
but there is not a reasonable causal relationship between the investigational product and 
the event 
• 
Unrelated: There is not a temporal or causal relationship to investigational product 
administration 
 
6.16.2 
Eliciting and Reporting AEs  
After a subject consents to participation in the study, the investigator will periodically assess 
subjects for the occurrence of AEs. To avoid bias in collecting information about AEs, the 
investigator should ask subjects the following question: "How have you felt since you were 
last checked?" All AEs (serious and non-serious) reported by the subject must be recorded in 
the source documents and CRFs. 
It is the investigator's responsibility to review the results of all laboratory tests as they 
become available. For each abnormal laboratory test result, the investigator needs to ascertain 
if this is a clinically significant change from baseline for that individual subject. This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed. The investigator may repeat the laboratory test or request additional tests 
to verify the results of the original laboratory tests. If the laboratory value is determined to be 
a clinically significant and abnormal change from baseline for that subject, this is considered 
a laboratory AE. 
In addition, the sponsor’s Medical Monitor or its designated personnel must be notified 
immediately by telephone, email, or fax of any immediately reportable AEs (IRAE) 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 41 of 69 
Global Version 2.0 
according to the procedure outlined below. Special attention should be paid to recording 
hospitalization and concomitant medications. 
6.16.3 
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 its representative within 24 hours of knowledge of the event. 
Non-serious events that require discontinuation of investigational product (including 
laboratory abnormalities) should be reported to the sponsor within 3 working days. The CRF 
AE form should be completed as directed by 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. 
6.16.4 
Pregnancy  
Women of childbearing potential (WOCBP) who are sexually active must use an effective 
method of birth control during the course of the study, in a manner such that risk of failure is 
minimized. 
Before enrolling WOCBP in this clinical trial, investigators must review guidelines about 
study participation for WOCBP. The topics should generally include: 
• 
General information 
• 
Informed consent form 
• 
Pregnancy prevention information 
• 
Drug interactions with hormonal contraceptives 
• 
Contraceptives in current use 
• 
Guidelines for the follow-up of a reported pregnancy 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy. The 
subject must sign an informed consent form confirming that the above-mentioned risk factors 
and that the consequences were discussed with her. 
During the study, all WOCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (e.g. missed or late menstrual cycle). 
If a subject or investigator suspects that the subject may be pregnant prior to investigational 
product administration, the investigational product administration must be withheld until the 
results of serum pregnancy tests are available. If the pregnancy is confirmed, the subject must 
not receive the investigational product and must not be enrolled or remain in the study. If 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 42 of 69 
Global Version 2.0 
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 a sponsor Medical 
Monitor or designated personnel. The investigator must notify the Medical Monitor within 3 
working days of any female subject who becomes pregnant. This reporting requirement will 
continue until 4 weeks after the last investigational product exposure.  
The investigator must record the event on the Pregnancy Surveillance Form and forward it to 
sponsor’s Medical Monitor. 
Protocol required procedures for 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. 
6.16.5 
Procedure for Breaking the Blind  
As indicated in Section 5.5 above, the sponsor, medical monitor, study coordinators, 
pharmacists, study subjects, and the CEC members will be blinded to the treatment 
assignment during the study period. The investigator should also remain blinded to the 
subject treatment during the entire study unless knowledge of the subject’s treatment is 
required for clinical care and safety. The Emergency Code Break module in the IWRS is 
used for such situations. The investigator must confirm the intention to unblind the subject’s 
treatment to obtain the dose information in IWRS. Upon completion of the unblinding, the 
system will send an alert to designated study team members that an unblinding event has 
occurred. Documentation of breaking the blind should be recorded in the subject’s medical 
record with the date and time the blind was broken, and the names of the personnel 
requesting and authorizing unblinding. The treatment assignment will continue to be 
withheld from the CEC members until all phase 3 studies are completed. 
6.16.6 
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. 
6.16.7 
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 6.16.2. 
These may include unresolved previously reported SAEs, or new SAEs. The investigator 
should follow these SAEs until the events are resolved, or the subject is lost to follow-up. 
Resolution means the subject has returned to the baseline state of health, or the investigator 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 43 of 69 
Global Version 2.0 
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. 
6.16.8 
Urinary Tract Infections (UTIs)  
Events potentially representing UTIs, including cystitis, urethritis, pyelonephritis, or 
urosepsis, should be carefully evaluated. 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 
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.  
6.16.9 
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. 
6.16.10 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 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 44 of 69 
Global Version 2.0 
• 
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 hours to confirm the hepatic enzyme 
elevation. Testing should be repeated based on the clinical situation at least every 96 hours (4 
days) until ALT and AST return to < 2.5 x ULN or until the liver function test results are 
stable and significant changes are not expected anymore. Study medication should be 
stopped and the event should be reported as a laboratory AE within the CRF if the enzyme 
elevation is confirmed or worsening.  
Should it be determined that the etiology is an unrelated acute or chronic medical condition 
(e.g.; NASH, Hepatitis A) and the return of LFT abnormalities to normal is unlikely during 
the course of the illness, further testing and follow up is at the investigator’s discretion. 
Hepatotoxicity will be diagnosed and entered as an AE should any of the following occur: 
• 
ALT or AST > 8 x ULN 
• 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or INR > 1.5 
• 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
 
In the event of hepatotoxicity, investigational product should be permanently discontinued. 
The investigator is encouraged to consult with the Medical Monitor regarding diagnostic 
evaluation for the hepatic enzyme elevations. Consultation with a hepatologist may also be 
appropriate in some circumstances. 
6.16.11 Hypoglycemia  
Events of hypoglycemia or potentially representing hypoglycemia should be carefully 
evaluated.  
All subjects will be provided with a glucometer for recording blood glucose measurements 
and a diary to record 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, if appropriate, consume 
carbohydrates to treat hypoglycemia.  
The subject will be expected to record the following information for each hypoglycemic 
event in the glycemic control diary: 
• 
Signs and symptoms attributed to hypoglycemia and the time and date on which they 
occurred  


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 45 of 69 
Global Version 2.0 
• 
SMBG reading at the time of the signs and symptoms attributed to hypoglycemia 
• 
Time elapsed from the most recent meal to the onset of signs and symptoms 
• 
Duration, intensity, and type of any exercise within the 24 h prior to the signs and 
symptoms 
• 
Type of treatment used (e.g., juice, crackers) for the signs and symptoms and whether 
assistance was required from another person to administer the treatment 
• 
SMBG reading 15 minutes after treatment with carbohydrate and the time at which this 
was measured 
• 
Whether or not the signs and symptoms attributed to hypoglycemia resolved after blood 
glucose returned to normal 
 
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: 
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 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 46 of 69 
Global Version 2.0 
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. 
6.16.12 Major Adverse Cardiovascular Event (MACE)  
Evaluation of MACE will be undertaken across the development program for bexagliflozin. 
All MACE reports should also be captured as SAEs and every effort will be made to ensure 
that events recorded as MACE are coded in a similar manner within the safety database. The 
SAE listing will also be reviewed periodically by the CEC members to identify potential 
MACE that may not have been reported by the site investigators. All subjects will be 
followed by investigators for MACE for the duration of the study even if study medication 
has been permanently withdrawn. 
The independent CEC will receive and adjudicate the following events.  
 
All deaths 
 
Suspected non-fatal MI 
 
Suspected hospitalization for unstable angina (HUA) 
 
Suspected TIA and stroke  
 
Suspected hospitalization for heart failure (HF) 
 
Reported coronary revascularization procedure 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 47 of 69 
Global Version 2.0 
6.16.13 Diabetic Ketoacidosis (DKA)  
DKA is a serious, acute complication of diabetes and can be life-threatening. Subjects will be 
educated on the signs and symptoms of DKA and 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, 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. 
Laboratory values should be 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.  The investigator should collect the data necessary for the completion of 
the DKA CRF.  
If symptoms suggestive of DKA may have occurred but are not ongoing, investigator should 
review available data in order to complete the DKA CRF. The investigator may also perform 
laboratory assessment using local resources if necessary for clinical care.  
6.16.14 Amputation 
Amputation and related AEs will be recorded in a dedicated CRF. During each study visit, 
the investigator should query the subject for any amputation and related AEs 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. Subjects with history of amputation, or 
risk factors for amputation should be counseled to seek preventive care to prevent further 
complications. Such risk factors include peripheral vascular disease and diabetic neuropathy. 
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.  
6.16.15 Pancreatitis 
Subjects should be informed that persistent severe abdominal pain, sometimes radiating to 
the back or accompanied by vomiting, is the symptom of acute pancreatitis. Subjects must 
contact the clinic immediately if they experience these symptoms. The investigator should 
observe carefully for signs and symptoms of pancreatitis. Laboratory testing, including 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 48 of 69 
Global Version 2.0 
amylase and lipase, should be performed using local resources if necessary for diagnosis and 
clinical care. If pancreatitis is suspected, administration of study products should be 
discontinued promptly and appropriate management should be initiated. Diagnosis of 
pancreatitis must be documented in the CRF. 
6.17 Concomitant Medication Assessments  
A concomitant medication is any medication that the subject has been taking prior to 
enrollment and that the subject is expected to continue to take for some portion of the trial, as 
well as any medication other than the investigational product that the subject takes during the 
course of the trial. Changes in dose and/or frequency from therapies taken prior to 
randomization and their rationale must be recorded in the CRF. 
The medications or treatment for controlling hyperglycemia must be recorded as concomitant 
medications in the CRF. Any medication given to treat hyperglycemia and continued for 
more than 2 weeks is considered a rescue therapy and should be recorded in the concomitant 
medication log. 
All prescription and over-the-counter medications, including vitamins and herbal 
supplements, that subjects receive during the trial must be documented on the CRF. This 
documentation should continue until the subjects complete the study.  
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A table of concomitant medications based on the anatomic 
therapeutic chemical classification (ATC) and preferred name will be produced. A listing of 
concomitant medications will include all medications taken by any subjects during the course 
of the study. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 49 of 69 
Global Version 2.0 
7 
STUDY ACTIVITIES 
The study activities at each clinic visit listed below are presented in Appendix 1. The 
required laboratory tests scheduled at each visit are listed in Appendix 2. Detailed study 
procedures are described in Section 6.  
A visit window of ± 3 days is allowed for all visits except visit V3. Visit 3 is the day of 
randomization and the basis for the visit window.  
7.1 
V1/ Screening  
• 
Explain the content of the informed consent materials to the subject and collect signed 
informed consent 
• 
Collect needed information and evaluate conformance to inclusion and exclusion criteria 
• 
Obtain Medical History and Demographic Information 
• 
Perform an abbreviated physical examination 
• 
Measure vital signs, including BPs and heart rate 
• 
Measure weight 
• 
Perform a 12-lead ECG measurement 
• 
Draw blood if an approximately 10-h fast has been completed by the subject as described 
in section _Sample_Collection,_Storage,6.10.2.  The specific laboratory tests scheduled 
for this visit are listed in Appendix 2 
• 
Collect a clean-catch, mid-stream urine sample 
 
7.2 
V2/ Run In  
• 
Counsel subject on appropriate diet and exercise 
• 
Dispense glucometer and instruct subject in SMBG determination and recording 
• 
Dispense two run-in kits for run-in period 
• 
Assess AEs 
• 
Record concomitant medications 
 
7.3 
V3/ Randomization  
• 
Collect needed information and evaluate conformance to inclusion and exclusion criteria 
• 
Perform a complete physical examination 
• 
Measure vital signs, including BPs and heart rate 
• 
Measure weight 
• 
Perform a 12-lead ECG measurement 
• 
Draw blood if an approximately 10 h fast has been completed by the subject as described 
in section 6.10.2.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Review SMBG and glycemic control record 
• 
Record drug accountability, collect run-in product bottles 
• 
Dispense investigational product based on randomization 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 50 of 69 
Global Version 2.0 
• 
Assess AEs 
• 
Record concomitant medications 
 
7.4 
V4/ 6 weeks  
• 
Measure vital signs, including BPs and heart rate 
• 
Measure weight 
• 
Draw blood if an approximately 10-h fast has been completed by the subject as described 
in section 6.10.2.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Review SMBG and glycemic control record 
• 
Record drug accountability 
• 
Assess AEs  
• 
Record concomitant medications 
 
7.5 
V5/ 12 weeks  
• 
Measure vital signs, including BPs and heart rate 
• 
Measure weight 
• 
Draw blood if an approximately 10-h fast has been completed by the subject as described 
in section 6.10.2.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Review SMBG and glycemic control record 
• 
Record drug accountability and collect previous investigational product bottles 
• 
Dispense investigational product based on randomization 
• 
Assess AEs  
• 
Record concomitant medications 
 
7.6 
V6/ 18 weeks  
• 
Measure vital signs, including BPs and heart rate 
• 
Measure weight 
• 
Draw blood if an approximately 10-h fast has been completed by the subject as described 
in section 6.10.2.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Review SMBG and glycemic control record 
• 
Record drug accountability 
• 
Assess AEs  
• 
Record concomitant medications 
 
7.7 
V7/ End of Treatment  
• 
Perform an abbreviated physical examination 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 51 of 69 
Global Version 2.0 
• 
Measure vital signs, including BPs and heart rate 
• 
Measure weight 
• 
Perform a 12-lead ECG measurement 
• 
Draw blood if an approximately 10-h fast has been completed by the subject as described 
in section 6.10.2.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Review SMBG and glycemic control record 
• 
Record drug accountability and collect previous investigational product bottles 
• 
Assess AEs  
• 
Record concomitant medications 
 
7.8 
V8/ Follow up  
• 
Perform a complete physical examination 
• 
Measure vital signs, including BPs and heart rate 
• 
Measure weight 
• 
Perform a 12-lead ECG measurement 
• 
Draw blood if an approximately 10-h fast has been completed by the subject as described 
in section 6.10.2.  The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• 
Collect a clean-catch, mid-stream urine sample 
• 
Review SMBG and glycemic control record 
• 
Assess AEs  
• 
Record concomitant medications 
 
7.9 
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 
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-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 52 of 69 
Global Version 2.0 
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-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 53 of 69 
Global Version 2.0 
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 sitagliptin 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 24 in HbA1c comparing 
bexagliflozin group with sitagliptin 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 FPG in the bexagliflozin group vs. the sitagliptin group 
at week 24 
2. Superiority test of the change in body weight in subjects with baseline BMI ≥ 25 kg/m2 in 
the bexagliflozin group vs. the  sitagliptin group at week 24 
3. Superiority test of the change in SBP in the bexagliflozin group vs. the sitagliptin group 
at week 24 
 
The exploratory efficacy objectives and safety objectives will be analyzed descriptively. 
9.2 
Determination of Sample Size 
Approximate total 374 subjects will be randomized and equally allocated to receive 
bexagliflozin tablets (20 mg) + sitagliptin tablets (placebo), or bexagliflozin tablets (placebo) 
+ sitagliptin tablets (100 mg) 
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 24 in HbA1c 
comparing bexagliflozin group to sitagliptin group will be 0.35% 
2. The pooled SD for the change from baseline to week 24 in HbA1c for bexagliflozin 
group and sitagliptin group will be 1.0% 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 54 of 69 
Global Version 2.0 
 
Under the above assumptions, an estimated sample size of 172 patients is needed in each 
treatment arm to detect non-inferiority of bexagliflozin to sitagliptin with respect to change 
in HbA1c at week 24 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 187 per arm has been selected to 
account for approximate 8% drop-out rate and to allow adequate safety evaluation. The total 
sample size for this study will be 374 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 30 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, BP, body weight, BMI, 
FPG level, eGFR, duration of diabetes and prior anti-diabetic treatment status at screening 
(including type of therapy used [metformin, SU, DPP-4 inhibitor, alpha-glucosidase inhibitor 
etc.). In general, baseline measurement is defined as the last measurement prior to the first 
dose of double-blind medication. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 55 of 69 
Global Version 2.0 
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 24 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, region 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 24 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 sitagliptin treatment. Superiority of bexagliflozin group over 
sitagliptin group at week 24 in HbA1c change from baseline will be declared if the upper 
bound of 95% CI is less than 0.  


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 56 of 69 
Global Version 2.0 
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. 
1. 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. 
2. 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 8%. 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 in FPG in the bexagliflozin group vs. the 
sitagliptin group at week 24, similar to the primary endpoint analysis method, MMRM 
ANCOVA will be implemented (values obtained after the start of rescue medication will not 
be excluded in the analysis). The model will include treatment, visit, treatment-by-visit 
interaction, region and the baseline FPG 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 body weight for subjects with baseline BMI ≥ 25 kg/m2 in the bexagliflozin 
group vs. the sitagliptin group at week 24, and the change in SBP in the bexagliflozin group 
compared with sitagliptin group at week 24 will be analyzed using the same method. 
All analyses will be conducted in ITT analysis set. A hierarchical testing procedure will be 
applied to above three endpoints in the sequence provided in Section 9.1. 
9.7 
Other Efficacy Analyses 
Changes in HbA1c, FPG, SBP, and body weight for all subjects during the treatment period 
will be summarized descriptively by each time point (i.e., Weeks 6, 12, 18, 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 at different time points.  


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 57 of 69 
Global Version 2.0 
Cumulative summary on the proportion of subjects achieving HbA1c < 7% will be presented 
over time. Generalized estimation equation (GEE) logistic regression 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 AE will 
be considered those to be at least possibly related to the study treatments based on the 
investigators assessment.  
The number and percentage of subjects reporting serious AEs, and the number and 
percentage of subjects reporting AEs leading to treatment discontinuation will also be 
summarized for each treatment group by MedDRA system organ class and preferred term. 
9.8.2 
Adverse Events of Interest 
AE of interest include UTI, GMI, diuretic effects, hypotension episodes, hypoglycemia, 
hepatotoxicity, MACE, falls and fractures, malignancy, hypersensitivity reactions, 
pancreatitis, amputations and renal failure events. These AEs of interest except DKA, MACE 
and amputations will be prospectively identified based on the MedDRA preferred terms in 
the AE log by a medical expert prior to the data base lock and unblinding of the individual 
subject treatment assignment. The list of AE of interest will be confirmed in a peer review 
process. DKA and MACE will be identified by the investigator and documented in the CRF, 
and subsequently adjudicated by seperate independent committees. Adjudicated results will 
be used for summary.  Amputation events will be recorded in the procedures and amputation 
CRF.   
The number and percentage of subjects experienced TEAE of  interest will be summarized 
for each treatment group by types of events. The incidence rate of AE of 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. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 58 of 69 
Global Version 2.0 
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 
Interim Analysis 
No interim analysis will be performed during this study. 
9.10 Final Analysis 
After all subjects have completed the planned 24 weeks of blinded study treatment and the 
subsequent follow-up visit, 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-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 59 of 69 
Global Version 2.0 
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. 
The clinical investigator must personally conduct or supervise the procedures that are 
required in the protocol.  Procedures that require clinical or medical knowledge must be 
performed by the investigators or qualified sub-investigators.   The investigator may delegate 
tasks to any individual to whom a task is delegated is qualified by education, training, and 
experience (and local licensure where relevant). The investigator must maintain a list of the 
appropriately qualified persons to whom significant trial-related duties have been delegated. 
This list should also describe the delegated tasks and maintain records of  the training that 
individuals have received that qualifies them to perform delegated tasks (e.g., individual’s 
CV, certifications), and identify the dates of involvement in the study.  No study-related 
procedures should be conducted unless the delegated individual has adequate training on the 
protocol and assigned task 
10.2 Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
The study protocol, informed consent document, relevant supporting information, and all 
types of subject recruitment or advertisement information must be submitted to the 
independent review board (IRB) or independent ethics committee (IEC) for review and must 
be approved by the sponsor and the IRB/IEC before the study is initiated. Any amendments 
or addenda to the protocol must also be approved by the IRB/IEC prior to implementing 
changes in the study. The investigator is responsible for keeping the IRB/IEC informed of the 
progress of the study and of any changes made to the protocol as deemed appropriate, but in 
any case at least once a year. The investigator must also keep the IRB/IEC informed of any 
SAEs occurring to subjects under 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 GCP guidelines (E6) and the guiding principles detailed in the Declaration of Helsinki. 
The study will also be carried out in keeping with applicable local laws and regulations. An 
inspection by the sponsor representatives and/or their designee and/or other authorized 
regulatory authorities representatives may occur at any time. The investigator must agree to 
the inspection of study-related records by the regulatory authority/sponsor representatives, 
and must allow direct access to source documents to the regulatory authority/sponsor 
representatives. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 60 of 69 
Global Version 2.0 
The investigator is responsible for complying with the protocol and all appropriate 
regulations and guidelines governing global clinical research. Additionally, he/she is 
responsible for ensuring that all participating staff members are adequately trained and 
competent to perform his/her assigned tasks. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator may implement a 
deviation from or a change of the protocol to eliminate any immediate hazards to the trial 
subjects without prior IRB/IEC or sponsor approval/favorable opinion. As soon as possible, 
the implemented deviation or change, the reasons for it, and if appropriate, the proposed 
protocol amendment should be submitted to the IRB/IEC and sponsor. 
Any deviations from the protocol must be fully explained and documented by the 
investigator. The circumstances, action taken, and impact of the deviation on the trial must be 
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 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 61 of 69 
Global Version 2.0 
protocol will be posted on clinicaltrials.gov and any local regulatory registry websites, as 
required by regulation. 
Subject names and other identifiers, such as photographs, audio, or videotapes, may not be 
disclosed in any publication without prior written authorization from the subject. 
10.6 Study Monitoring 
An authorized sponsor representative will conduct site visits to inspect study data, subjects’ 
medical records, and CRFs in accordance with ICH guidelines, GCP, and the respective 
national and local government regulations and guidelines. 
The investigator will permit authorized representatives of the sponsor and the respective 
national or local health authorities, other authorized regulatory authorities, and IRB/IEC to 
inspect facilities and records relevant to this study. 
10.7 Case Report Forms and Study Records 
For each subject consented, a CRF, in paper or electronic format, will be supplied and 
maintained by the CRO staff and signed by the investigator or authorized designee to indicate 
that he/she has reviewed and agrees with the entered data. This also applies to those subjects 
who fail to complete the trial. The reason a subject is withdrawn must be recorded in the 
CRF. 
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 
designee’s SOPs. 
10.8 Data Monitoring Committee 
An independent DSMB will monitor overall safety information during the bexagliflozin 
development program. The safety review activity and potential risk benefit assessments 
utilized by the DSMB will be defined in its charter. 
10.9 Protocol Violations/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 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 62 of 69 
Global Version 2.0 
procedure, etc. Protocol violations will reported in the final clinical study report, whereas 
protocol deviations may be mentioned but are not required to be reported. 
It is important to conduct the study according to the protocol. Protocol deviation waivers will 
not be prospectively granted by the sponsor. If minor protocol deviations occur, the 
investigator must decide the most appropriate way to proceed with study activities and 
should consult the study representative for assistance. If major protocol deviations occur, the 
sponsor’s Medical Monitor must be notified immediately so that a decision about whether to 
keep the subject in the study can be made. 
Only when an emergency occurs that requires a departure from the protocol for an individual 
subject can there be a departure without the sponsor’s pre-approval. The nature and reasons 
for the protocol deviation/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. 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 63 of 69 
Global Version 2.0 
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-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 64 of 69 
Global Version 2.0 
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-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 65 of 69 
Global Version 2.0 
Appendix 1 
Schedule of Events 
Procedure 
Screening 
Run-in 
Treatment 
Follow-up 
Visit Number 
V1/ 
Screening 
V2/ 
Run In 
V3/ 
Randomization 
V4/ 
6 weeks 
V5/ 
12 weeks 
V6/ 
18 weeks 
V7/ End of 
Treatment 
V8/ 
Follow up 
Time to Randomization 
-3 
-1 
0 
6 
12 
18 
24 
26 
Informed Consent 
X 
 
 
 
 
 
 
 
Screening for I/E Criteria 
X 
 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Diet and Exercise Counseling 
 
X 
 
 
 
 
 
 
Physical Examination 
 
 
X 
 
 
 
 
X 
Abbreviated Physical Examination 
X 
 
 
 
 
 
X 
 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
X 
Measure Weight 
X 
 
X 
X 
X 
X 
X 
X 
Electrocardiography 
X 
 
X 
 
 
 
X 
X 
Clinical Laboratory Tests 
X 
 
X 
X 
X 
X 
X 
X 
Diary and Glucometer Dispensation 
 
X 
 
 
 
 
 
 
Dispensing Run-in Drug 
 
X 
 
 
 
 
 
 
Diary and Glucometer Record Review 
 
 
X 
X 
X 
X 
X 
X 
Dispensing Investigational Product 
 
 
X 
 
X 
 
 
 
Adverse Events Assessments 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication Assessments 
 
X 
X 
X 
X 
X 
X 
X 
 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 66 of 69 
Global Version 2.0 
Appendix 2 
Schedule of Clinical Laboratory Tests 
Procedure 
Screening 
Run-in 
Treatment 
Follow-up 
Visit number 
V1/ 
Screening 
V2/ 
Run In 
V3/Randomi-
zation 
V4/ 
6 weeks 
V5/ 
12 weeks 
V6/ 
18 weeks 
V7/ End of 
Treatment 
V8/ Follow 
up 
Time to Randomization Visit (weeks)  
-3 
-1 
0 
6 
12 
18 
24 
26 
Hematology 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry and Electrolytes 
X 
X 
X 
X 
X 
X 
X 
Glycemic Control 
X 
X 
X 
X 
X 
X 
X 
Serum Lipids 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
Infectious Disease Testing 
X 
Urine Pregnancy Test (WOCBP) 
X 
X 
X 
X 
X 
X 
X 
 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 67 of 69 
Global Version 2.0 
Appendix 3 
Examples of SGLT2 Inhibitors 
The following medications are prohibited during the study. Other SGLT2 inhibitors that may 
be approved for the treatment of T2DM during the THR-1442-C-423 study will also be 
prohibited as a concomitant medication in this protocol. 
Generic Name 
Trade Name 
canagliflozin 
Invokana™ 
canagliflozin plus metformin 
Invokamet™ 
dapagliflozin 
Farxiga™ or Forxiga™ 
empagliflozin 
Jardiance® 
empagliflozin plus linagliptin 
Glyxambi® 
empagliflozin/metformin HCl 
Synjardy 
dapagliflozin/metformin HCl 
extended release tablet 
Xigduo XR 
 


Apr 18 2017 1:03PM 
HP LASERJET FAX 
n~x.agltflo~'J~t '1'abl.eN 
rllol<'al l\·iall'rotocot: THrt- 1442·C·4Z:< 
·-··~· 
·--·-···-~ -···-.. ··~ 
l1lw:llC('I:< ~u\'1, t,Lc 
06 ArrllZOI? 
•• 
----·-·----·---.. ~ 
----"~ 
....... _ 
.. ~·· ________ ,,, 
-
..... ,_ 
.. y·~ _,______ 
,,,, ____ ~ ···----
Appendix4 
Sponsl)r Signatums 
Study T.itlt:1~ 
,<\ J•htmc 3, R!IJ.t<)"mized, lJoub!o Blind, Actlvc·C<"ll.rol.k•d Study to 
1.-:;yjlluatc tho El'!oN• <Jfll<>:<.agl.l!] dn vor.,,t> SltagiJrn:~l m Subjects 
with Type 2 lli•bote.o M~!Jiu•s Whn llaw frmde<Jttllte Olyoemlc 
Control by Mc:tfiwuti• 
lltudy Nnntb•n 
Vl,l) Fin111 Dntc: 
lHR· 144~1-lc-42.1 
or, April 2(117 
'l1t!s cJ ittlCii.l ~!udy protuc!ll Willi ~ubjoctto orltlcnl. t~vicw nd hil~ boot.> approv•'<i by tho 
•poii~0-1, Hte fbi lowing par11011Ml L'Oillrlbt.tte.rl l<:• writing a. dl<)r appt"O\'ing lhi~ p!X1I.OMI: 
Signoo:JL~¢- ----·--·-····--
Adrbn ll1mc •· 
P~<,tooc>l Orlgiontw: 
1\'f:!~Mch~ Kotl• Ovmm~l U>s~>it!~l 
c:m:~~uJhuU: f~ll' 
1'I'bti:J'UC.()S Sub,. LLC 
Slgncd:_r~U1 _____ .=frl:~_ __ 
Robert K 1"~111'~'" M.D. 
Mud!oal MorJlt<>~· 
C<>n~III11U1t lk>l' "lll<::rnc<JO S<tl>, Lt,C 
Co.nfideutlill 
J) tc: 
t-( /il /17 
~ -------·-----------·----------
' 
p. 1 


Bexagliflozin Tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-423 
 
06 April 2017  
 
 
 
 
Confidential 
Page 69 of 69 
Global Version 2.0 
Appendix 5 
Investigator’s Signature 
Study Title: 
A Phase 3, Randomized, Double-Blind, Active-Controlled Study to 
Evaluate the Effects of Bexagliflozin versus Sitagliptin in Subjects 
with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic 
Control by Metformin 
Study Number: 
THR-1442-C-423 
V2.0 Final Date: 
06 April 2017 
I have read the protocol described above. I agree to comply with the International Conference 
on Harmonisation (ICH) Tripartite guideline on Good Clinical Practice (GCP) and all 
applicable regulations and to conduct the study as described in the protocol.  
I agree to ensure that Financial Disclosure Statements will be completed by me and my sub-
investigators at the start of the study and for up to 1 year after the study is completed, if there 
are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation without 
the prior written consent of Theracos Sub, LLC.  
 
 
Signed: 
 
 
Date:  
 
Clinical Investigator 

SAP_001.pdf: 
Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 1 of 53 
Sponsor Name: 
Theracos Sub, LLC 
Protocol Number and Title: 
 
A Phase 3, Randomized, Double-Blind, Active-
Controlled Study to Evaluate the Effects of 
Bexagliflozin versus Sitagliptin in Subjects 
with Type 2 Diabetes Mellitus Who Have 
Inadequate Glycemic Control by Metformin 
Protocol Version and Date: 
Version 2.0, 06 April 2017 
 
 
INC Research Project Code: 
1007779 
Author(s): 
Lu Wang, Biostatistician II 
SAP Version: 
Version 1.0 
SAP Version Date:  
28-Feb-2018 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Theracos Sub, LLC. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Theracos Sub, LLC. However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation, INC Research should be notified 
promptly. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 2 of 53 
Revision History 
 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
Version 0.1 
24-Jan-2018 
Lu Wang 
Initial Release Version 
Version 0.2 
06-Feb-2018 
Lu Wang 
Update to Address Sponsor 
Comments 
Version 1.0 
28-Feb-2018 
Lu Wang 
Update to Address Sponsor 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 4 of 53 
TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................ 8 
2. 
PURPOSE ..................................................................................................... 11 
2.1. 
Responsibilities ................................................................................................................. 11 
2.2. 
Timings of Analyses .......................................................................................................... 11 
3. 
STUDY OBJECTIVES ................................................................................... 12 
3.1. 
Primary Objective .............................................................................................................. 12 
3.2. 
Key Secondary Objectives ................................................................................................ 12 
3.3. 
Safety Objectives ............................................................................................................... 12 
3.4. 
Brief Description ................................................................................................................ 13 
3.5. 
Subject Selection ............................................................................................................... 13 
3.5.1. 
Inclusion Criteria ......................................................................................................... 14 
3.5.2. 
Exclusion Criteria ........................................................................................................ 14 
3.6. 
Determination of Sample Size .......................................................................................... 14 
3.7. 
Treatment Assignment & Blinding ................................................................................... 15 
3.7.1. 
Treatment Assignment ................................................................................................ 15 
3.7.2. 
Blinding ........................................................................................................................ 15 
3.8. 
Administration of Study Medication ................................................................................ 15 
3.9. 
Study Procedures and Flowchart ..................................................................................... 16 
4. 
ENDPOINTS .................................................................................................. 19 
4.1. 
Primary Efficacy Endpoint ................................................................................................ 19 
4.2. 
Secondary Efficacy Endpoints ......................................................................................... 19 
4.3. 
Safety Endpoints ................................................................................................................ 19 
5. 
ANALYSIS SETS .......................................................................................... 20 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 5 of 53 
5.1. 
Screened Analysis Set ...................................................................................................... 20 
5.2. 
Safety Analysis Set ............................................................................................................ 20 
5.3. 
Intention to Treat Analysis Set ......................................................................................... 20 
5.4. 
Per Protocol Analysis Set ................................................................................................. 20 
5.5. 
Protocol Deviations ........................................................................................................... 20 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 22 
6.1. 
General Methods ................................................................................................................ 22 
6.2. 
Key Definitions ................................................................................................................... 22 
6.2.1. 
Baseline Values .......................................................................................................... 22 
6.2.2. 
First Dose Date ........................................................................................................... 22 
6.2.3. 
Study Day .................................................................................................................... 23 
6.2.4. 
Duration ....................................................................................................................... 23 
6.2.5. 
End of Study ................................................................................................................ 23 
6.3. 
Missing Data ....................................................................................................................... 23 
6.4. 
Analysis Visit Windows ..................................................................................................... 23 
6.5. 
Pooling of Centers ............................................................................................................. 24 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ....................................................................................................... 25 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 25 
7.2. 
Subject Eligiblity and Protocol Deviations...................................................................... 25 
7.3. 
Demographic and Other Baseline Characteristics ......................................................... 25 
7.4. 
Medical History .................................................................................................................. 26 
7.5. 
Medication .......................................................................................................................... 26 
7.5.1. 
Prior Medication .......................................................................................................... 26 
7.5.2. 
Concomitant Medication .............................................................................................. 27 
8. 
EFFICACY ..................................................................................................... 28 
8.1. 
Primary Efficacy Endpoint and Analysis ......................................................................... 28 
8.1.1. 
Primary Efficacy Analysis ............................................................................................ 28 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 6 of 53 
8.1.2. 
Sensitivity Analyses .................................................................................................... 29 
8.1.3. 
Subgroups ................................................................................................................... 32 
8.2. 
Secondary Efficacy Endpoint(s) and Analyses .............................................................. 32 
8.2.1. 
Change in FPG in the bexagliflozin group vs. the sitagliptin group at week 24 .......... 32 
8.2.2. 
Change in body weight in subjects with baseline body mass index (BMI) ≥ 25 kg/m2 in 
the bexagliflozin group vs. the sitagliptin group at week 24 ......................................................... 33 
8.2.3. 
Change in SBP in the bexagliflozin group vs. the sitagliptin group at week 24 .......... 33 
8.2.4. 
Sensitivity analysis ...................................................................................................... 33 
8.3.1. 
Change from baseline in HbA1c, SBP, Body weight, and in FPG over time .............. 34 
8.3.2. 
Proportions of subjects with HbA1c of < 7% over time ............................................... 34 
9. 
SAFETY ......................................................................................................... 35 
9.1. 
Extent of Exposure ............................................................................................................ 35 
9.2. 
Treatment Compliance ...................................................................................................... 36 
9.3. 
Adverse Events .................................................................................................................. 36 
9.3.1. 
Derived Data ............................................................................................................... 37 
9.3.2. 
Data Summarization .................................................................................................... 37 
9.3.3. 
AE of Special Interest .................................................................................................. 38 
9.4. 
Laboratory Evaluations ..................................................................................................... 40 
9.5. 
Vital Signs ........................................................................................................................... 43 
9.6. 
Electrocardiogram ............................................................................................................. 43 
9.7. 
Physical Examination ........................................................................................................ 43 
10. 
INTERIM ANALYSES ................................................................................ 45 
11. 
DATA AND SAFETY MONITORING BOARD ........................................... 45 
12. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ......................... 45 
13. 
REFERENCE LIST .................................................................................... 46 
14. 
PROGRAMMING CONSIDERATIONS ...................................................... 47 
14.1. 
General Considerations .................................................................................................... 47 
14.2. 
Table, Listing, and Figure Format .................................................................................... 48 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 7 of 53 
14.2.1. 
General ........................................................................................................................ 48 
14.2.2. 
Headers ....................................................................................................................... 48 
14.2.3. 
Display Titles ............................................................................................................... 49 
14.2.4. 
Column Headers ......................................................................................................... 49 
14.2.5. 
Body of the Data Display ............................................................................................. 49 
14.2.6. 
Footnotes .................................................................................................................... 52 
15. 
QUALITY CONTROL ................................................................................. 52 
16. 
INDEX OF TABLES ................................................................................... 53 
17. 
INDEX OF FIGURES ................................................................................. 53 
18. 
INDEX OF LISTINGS ................................................................................. 53 
19. 
MOCK-UPS ................................................................................................ 53 
20. 
APPENDICES ............................................................................................ 53 
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 8 of 53 
1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass index 
BP 
Blood Pressure 
CEC 
Cardiovascular Endpoint Committee 
CI 
Confidence Interval 
CRF 
Case Report Form 
DKA 
Diabetic Ketoacidosis 
dL  
Deciliter 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimating Glomerular Filtration Rate 
FPG 
Fasting Plasma Glucose 
GEE 
Generalized Estimating Equation 
GMI 
Genital Mycotic Infection 
HbA1c 
Hemoglobin A1c 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ITT 
Intention to Treat 
IWRS 
Interactive Web Randomization System 
LDL-C  
Low Density Lipoprotein Cholesterol  
LOCF  
Last Observation Carried Forward  
LS 
Least Squares 
MACE  
Major Adverse Cardiovascular Event  


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 9 of 53 
Abbreviation 
Description 
MAR 
Missing at Random 
MCAR 
Missing Completely at Random 
MCMC 
Monte Carlo Markov Chain 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram  
mL 
Milliliter 
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing not at Random 
N/A 
Not Applicable 
Na 
Sodium 
PP 
Per Protocol  
PR 
Time from the beginning of the P wave to the beginning of the QRS 
complex in electrocardiogram 
PT 
Preferred Term 
Q1 
1st Quartile 
Q3 
3rd Quartile 
QRS 
Graphical deflections corresponding to ventricular depolarization in 
a typical electrocardiogram 
QTc 
Time between the start of the Q wave and the end of the T wave in 
the ECG, corrected for heart rate 
RR 
Time between the start of one R wave and the start of the next R 
wave in the ECG 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
Standard International System of Units 
SMBG 
Self-Monitored Blood Glucose 
SOC 
System Organ Class 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 10 of 53 
Abbreviation 
Description 
SOP 
Standard Operating Procedure 
T2DM 
Type 2 Diabetes Mellitus 
TEAE 
Treatment-emergent Adverse Event 
TLF 
Table, Listing And Figure 
UACR 
Urine Albumin To Creatinine Ratio  
UTI 
Urinary Tract Infection 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 11 of 53 
2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives. 
2.1. 
RESPONSIBILITIES 
Theracos has designed the study protocol and is responsible for the conduct of the 
study. INC Research is responsible for the development and validation of a clinical 
database using MediData RAVE platform. 
INC Research will perform the statistical analyses and are responsible for the production 
and quality control of all tables, figures and listings (TLFs). 
Adverse events that have met the seriousness criteria defined in the protocol are 
reported on the serious adverse event (SAE) forms using the MediData RAVE platform. 
An SAE case consists of the information reported in the SAE forms, subject 
characteristics documented in the case report forms, and additional source data such as 
hospital discharge summaries. Each SAE case is recorded in a validated ARGUS database 
which is managed by Covance. Any discrepancies in critical data fields of each SAE will 
be reconciled between the AUGUS and THR-1442-C-423 clinical database prior to 
database lock. The SAE coding, analyses and summaries are based on the final study 
data recorded in the clinical database. Detailed serious adverse event follow-up data 
will be reported from the ARGUS database and are not included in this report. 
Theracos will perform review of all tables, figures and listings before the finalization. 
2.2. 
TIMINGS OF ANALYSES 
The final analysis of safety and efficacy is planned after all subjects complete the 
planned 24 weeks of blinded study treatment and the subsequent follow-up period or 
terminate early from the study. 
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 12 of 53 
3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
To demonstrate that bexagliflozin is non-inferior to sitagliptin by evaluating the 
treatment effect on hemoglobin A1c (HbA1c) reduction at week 24 in subjects whose 
type 2 diabetes mellitus (T2DM) is not adequately controlled by metformin. 
3.2. 
KEY SECONDARY OBJECTIVES 
The key secondary efficacy objectives of this study are: 
• 
To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in 
fasting plasma glucose (FPG) at week 24. 
 
• 
To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in 
body weight in subjects with baseline body mass index (BMI) ≥ 25 kg/m2 at 
week 24. 
 
• 
To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in 
systolic blood pressure (SBP) in subjects at week 24. 
 
The other exploratory secondary efficacy objectives are: 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in 
the proportion of subjects achieving HbA1c < 7.0 % over time. 
 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in 
HbA1c over time. 
 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in 
FPG over time. 
 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in 
body weight over time. 
 
• 
To assess the treatment effect of bexagliflozin vs. sitagliptin on the change in 
SBP over time. 
 
3.3. 
SAFETY OBJECTIVES 
• 
To compare the effects of bexagliflozin with sitagliptin on the incidence of 
adverse events (AE) of interest. AE of interest are urinary tract infections (UTI) 
including urosepsis and pyelonephritis, genital mycotic infections (GMI), diuretic 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 13 of 53 
effects including hypovolemia, hypotension episodes, hypoglycemia, 
hepatotoxicity, major adverse cardiovascular events (MACE), falls and fractures, 
malignancies, hypersensitivity reactions, acid-base disorders including diabetic 
ketoacidosis (DKA), amputations, pancreatitis, and renal failure events. 
 
• 
To compare the effects of bexagliflozin with sitagliptin on general safety 
assessments including treatment emergent AEs, clinical laboratory findings, 12-
lead electrocardiograms (ECG) parameters, physical examinations, vital signs 
including orthostatic blood pressure (BP), and use of concomitant medications. 
3.4. 
BRIEF DESCRIPTION 
THR-1442-C-423 is a phase 3, multi-center, randomized, double-blind, parallel-group 
study and aims to demonstrate that bexagliflozin is non-inferior to sitagliptin as an add-
on therapy in subjects whose T2DM is not adequately controlled by metformin 
treatment. A total of 374 subjects are planned to be randomized in a ratio of 1:1 to 
receive once daily treatment of bexagliflozin tablets, 20 mg, with sitagliptin tablets, 
placebo (Group 1) or bexagliflozin tablets, placebo, with sitagliptin tablets, 100 mg 
(Group 2) for 24 weeks in an outpatient setting. The main eligibility criteria include 1) 
male or female subjects with T2DM and 2) screening HbA1c between 7.0% and 11% 
(inclusive). 
Qualified subjects must have taken metformin at a stable dose of ≥ 1500 mg/day in 
addition to diet and exercise counseling for at least 8 weeks prior to screening. Study 
subjects will continue taking open-labeled metformin during the entire study. 
All eligible subjects will start a single-blind run-in period by taking placebo bexagliflozin 
and placebo sitagliptin once daily for one week. Subjects who meet all inclusion criteria 
and no exclusion criteria after completion of the run-in period will be eligible for 
randomization and receive investigational products. 
During the treatment period, subjects will receive once daily sitagliptin tablets 100 mg 
with dummy placebo bexagliflorzin, or bexagliflozin tablets 20 mg with dummy placebo 
sitagliptin tablets, for 24 weeks. Each subject will be instructed to return to the clinic 
at weeks 6, 12, 18, and 24 for efficacy assessment and safety monitoring. Subjects will 
return to the clinic for a follow-up exit visit at week 26 or 2 weeks after last dose of 
study drug if subjects early terminate prior to week 24. 
3.5. 
SUBJECT SELECTION 
The study population will include approximately 374 subjects whose T2DM is 
inadequately controlled by metformin and who meet all of the inclusion criteria and 
none of the exclusion criteria. Clinical sites in the North America, Europe and Japan are 
anticipated to recruit subjects. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 14 of 53 
3.5.1. 
Inclusion Criteria 
Refer to protocol section 4.2 for inclusion criteria. 
3.5.2. 
Exclusion Criteria 
Refer to protocol section 4.3 for exclusion criteria. 
3.6. 
DETERMINATION OF SAMPLE SIZE 
Approximately 374 subjects will be randomized 1:1 to bexagliflozin tablets (20 mg) + 
sitagliptin tablets (placebo), or bexagliflozin tablets (placebo) + sitagliptin tablets (100 
mg). The sample size calculation for this study was based on a two group t-test with a 
one-sided significance test at the 2.5% level and the following assumptions: 
1. The non-inferiority limit (margin) for mean change from baseline to week 24 in HbA1c 
comparing bexagliflozin group to sitagliptin group will be 0.35%. The proposed non-
inferiority margin of 0.35% was based on a published clinical trial that demonstrated the 
effectiveness of sitagliptin, 100 mg, on HbA1c reduction in subjects with type 2 
diabetes mellitus (Charbonnel, et al, 2006; Diabetes Care, 29, 2638). The sitagliptin 
study included male and female adult subjects with T2DM diagnosis and inadequate 
glycemic control defined by an HbA1c ≥ 7.0% and ≤ 10% while taking metformin 
monotherapy at a stable dose of ≥ 1500 mg per day. In THR-1442-C-423 study, the 
eligibility included the same criteria except the HbA1c range was between 7.0% to 11%. 
Baseline HbA1c values in the sitagliptin study was 8.03 ± 0.82% in the placebo arm and 
7.96 ± 0.81% in the active arm, respectively. This is nearly identical to the overall 
baseline mean HbA1c of 7.99 ± 0.868% in the THR-1442-C-423 subject population. A 
placebo adjusted least-squares mean (95% CI) treatment effect of reduction from 
baseline in HbA1c was -0.65% (-0.77 to -0.53). The clinical meaningful margin is 
selected to be approximately half of sitagliptin effect, 0.35% reduction. That is, if the 
upper bound of 95% CI of the difference between sitagliptin and bexagliflozin is less 
than the chosen margin of 0.35%, the study would demonstrate that the effect of 
sitagliptin is preserved in the bexagliflozin treatment arm. 
2. The pooled SD for the change from baseline to week 24 in HbA1c for bexagliflozin 
group and sitagliptin 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 sitagliptin with respect 
to change in HbA1c at week 24 from baseline. This estimation is based on a one-sided t-
test with 90% power at a 2.5% level of significance. A sample size of 187 per arm has 
been selected to account for approximate 8% drop-out rate and to allow adequate 
safety evaluation. The total sample size for this study will be 374 subjects. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 15 of 53 
3.7. 
TREATMENT ASSIGNMENT & BLINDING 
3.7.1. 
Treatment Assignment 
The study will be conducted at multiple investigative sites and will involve variable 
numbers of subjects at each site. Enrollment will be on a competitive basis, but each 
site will be capped at 30 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 run-in period and meet all study inclusion/exclusion 
requirements will be randomized in a 1:1 ratio to receive active bexagliflozin with 
placebo sitagliptin or active sitagliptin 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 screening (Visit V1) HbA1c (< 8.5% or ≥ 
8.5%). The investigator or designated staff will log into the IWRS to receive the 
randomization code and assigned kit numbers. 
3.7.2. 
Blinding 
This is a double-blind, double-dummy study. The sponsor, investigators, study 
coordinators, pharmacists, study subjects, the cardiovascular endpoint committee 
(CEC), and the DKA committee will be blinded to the study medications. 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 
results 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 Data and Safety Monitoring Board (DSMB) to 
facilitate the evaluation of any clinically important increase in the rate of a serious 
suspected adverse reaction or to the designated safety contact when the treatment 
information is required to determine if an expedited safety report must be submitted to 
regulatory agencies. The treatment assignment will continue to be withheld from the 
CEC and DKA adjudication committee members until all global investigational studies 
are completed and final analyses to assess cardiovascular and ketoacidosis risks are 
conducted. 
3.8. 
ADMINISTRATION OF STUDY MEDICATION 
 The following investigational products will be used for oral administration: 
• 
Bexagliflozin tablets, 20 mg: tablets containing 20 mg of bexagliflozin 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 16 of 53 
• 
Bexagliflozin tablets, placebo: tablets containing no bexagliflozin 
 
The following active comparator products will be used for oral administration: 
• 
Sitagliptin tablets, 100 mg: tablets containing 100 mg of sitagliptin 
• 
Sitagliptin tablets, placebo: tablets containing no sitagliptin 
Bexagliflozin tablets, 20 mg or placebo, should be taken at approximately the same 
time each day, before or after breakfast, with one cup (250 mL) of water. 
On the day of scheduled clinic visits 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 with one cup (250 mL) of water. 
Sitagliptin tablets, 100 mg or placebo, should be taken once daily at the same time as 
bexagliflozin, before or after breakfast, with one cup (250 mL) of water. 
On the day of scheduled clinic visits when there is fasting and blood is to be drawn, 
administration of sitagliptin should be delayed until after blood is drawn and taken in 
the clinic or at home with one cup (250 mL) of water. 
 
3.9. 
STUDY PROCEDURES AND FLOWCHART 
The activities that must be performed at each clinic visit are presented in Table 1. The 
required laboratory tests scheduled at each visit are listed in Table 2. 
A visit window of ± 3 days is allowed for all visits except Visit 3. Visit 3 is the day of 
randomization and the basis for the visit window. 
The study staff will contact each subject prior to a scheduled clinic visit to confirm the 
time of the visit and to remind the subject of proper fasting practice. A subject must be 
queried to assess compliance with an approximately 10 hours fast prior to blood draw to 
ensure the FPG and triglycerides values can be accurately determined. If a subject has 
not fasted for approximately 10 hours, the subject must return as soon as can be 
arranged (within 1 week) to provide a specimen after proper fasting. Blood samples will 
be transported to the central lab for analysis. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 17 of 53 
Table 1    Schedule of Events 
Procedure  
Screening  
Run-in  
Treatment  
Follow-up  
Visit Number  
V1/ 
Screening  
V2/ 
 Run In  
V3/ 
Randomization  
V4/  
6 weeks  
V5/ 
 12 weeks  
V6/  
18 
weeks  
V7/ End of 
Treatment  
V8/  
Follow up  
Time to Randomization  
-3  
-1  
0  
6  
12  
18  
24  
26  
Informed Consent  
X  
 
 
 
 
 
 
 
Screening for I/E Criteria  
X  
 
X  
 
 
 
 
 
Medical History  
X  
 
 
 
 
 
 
 
Diet and Exercise Counseling  
 
X  
 
 
 
 
 
 
Physical Examination  
 
 
X  
 
 
 
 
X  
Abbreviated Physical Examination  
X  
 
 
 
 
 
X  
 
Vital Signs  
X  
 
X  
X  
X  
X  
X  
X  
Measure Weight  
X  
 
X  
X  
X  
X  
X  
X  
Electrocardiography  
X  
 
X  
 
 
 
X  
X  
Clinical Laboratory Tests  
X  
 
X  
X  
X  
X  
X  
X  
Diary and Glucometer Dispensation  
 
X  
 
 
 
 
 
 
Dispensing Run-in Drug  
 
X  
 
 
 
 
 
 
Diary and Glucometer Record Review  
 
 
X  
X  
X  
X  
X  
X  
Dispensing Investigational Product  
 
 
X  
 
X  
 
 
 
Adverse Events Assessments  
 
X  
X  
X  
X  
X  
X  
X  
Concomitant Medication Assessments  
 
X  
X  
X  
X  
X  
X  
X  
 
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC 
Page 18 of 53 
Table 2    Schedule of Clinical Laboratory Tests 
 
Screening  
Run-in  
Treatment  
Follow-up  
Visit number  
V1/ 
Screening  
V2/ Run In  
V3/Randomi-
zation  
V4/  
6 weeks  
V5/  
12 weeks  
V6/ 
 18 weeks  
V7/ End of 
Treatment  
V8/ 
Follow up  
Time to Randomization Visit (weeks)  -3  
-1  
0  
6  
12  
18  
24  
26  
Hematology  
X  
 
X  
X  
X  
X  
X  
X  
Serum Chemistry and Electrolytes  
X  
 
X  
X  
X  
X  
X  
X  
Glycemic Control  
X  
 
X  
X  
X  
X  
X  
X  
Serum Lipids  
X  
 
X  
 
X  
 
X  
X  
Urinalysis  
X  
 
X  
X  
X  
X  
X  
X  
Infectious Disease Testing  
X  
 
 
 
 
 
 
 
Urine Pregnancy Test (WOCBP)  
X  
 
X  
X  
X  
X  
X  
X  


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 19 of 53 
4. 
ENDPOINTS 
4.1. 
PRIMARY EFFICACY ENDPOINT 
• 
Change in HbA1c from baseline at week 24 
4.2. 
SECONDARY EFFICACY ENDPOINTS 
The key secondary efficacy endpoints include: 
• 
Change in FPG from baseline at week 24  
• 
Change in body weight in subjects with baseline BMI ≥ 25 kg/m2 at week 24 
• 
Change in SBP from baseline at week 24 
The exploratory secondary efficacy endpoints include: 
• 
Proportion of subjects with HbA1c of < 7% over time 
• 
Change from baseline in HbA1c over time 
• 
Change from baseline in FPG over time 
• 
Change from baseline in body weight over time 
• 
Change from baseline in SBP over time 
4.3. 
SAFETY ENDPOINTS  
• 
AEs 
• 
AE of special interest 
• 
Clinical laboratory results 
• 
Physical exam results 
• 
Vital signs 
• 
ECG results 
• 
Medication use 
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 20 of 53 
5. 
ANALYSIS SETS 
5.1. 
SCREENED ANALYSIS SET 
The Screened Analysis Set will include all subjects screened for eligibility prior to 
randomization. The screened population will include screen failures. Unless specified 
otherwise, this population will be used for summaries of subject disposition. 
5.2. 
 SAFETY ANALYSIS SET  
All subjects who are randomized and take at least one dose of each double-blind study 
medications will be included in the Safety Analysis Set. Safety analyses will be based on 
the medications that were taken first. The Safety Analysis Set is the primary analysis set 
for safety evaluation. 
5.3. 
INTENTION TO TREAT ANALYSIS SET  
All subjects who are randomized regardless of treatment adherence or availability of 
follow up data will be included in the Intention to Treat (ITT) Analysis Set. All analyses 
of the ITT Analysis Set will be based on each subject’s randomized assigned treatment. 
The ITT analysis set will serve as the primary set for the efficacy analyses. 
5.4. 
PER PROTOCOL ANALYSIS SET  
The Per Protocol (PP) Analysis Set will include all subjects in the ITT who meet the 
study eligibility requirements and have no major protocol deviations that affect the 
validity of the efficacy measurements. Protocol deviations that may result in subject or 
visit exclusion from the PP Analysis Set are described in Section 5.5. The PP analysis set 
will serve as the secondary set for efficacy assessment. 
5.5. 
PROTOCOL DEVIATIONS 
Protocol deviations will be captured during monitoring visits and recorded in CRF. 
Deviation will be classified into each of the 9 categories: enrollment criteria, 
non-compliance, laboratory, dosing, visit schedule, visit/procedure requirement, 
concomitant medication, informed consent, and other. Date and details of the deviation 
will be recorded. The list of deviation will be reviewed before unblinding and major 
protocol deviations that, in the opinion of the medical monitor, could affect the 
primary and secondary variables will be determined. Some possible types of major 
protocol deviations are showing in Table 3. 
  
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 21 of 53 
Table 3    Some Possible Types of Major Protocol Deviations 
Category  
Criteria 
Exclusion 
Inclusion/Exclusion Criteria  
 
 
Ineligible subject is enrolled  
- Subjects not satisfying HbA1c inclusion 
criteria  
- Treated with SGLT2 within 3 months of 
screening 
 
Subject exclusion 
Prior or Concomitant 
Medication Restrictions  
 
 
Use of another SGLT2 inhibitor  
Use of an SGLT2 inhibitor as the rescue 
medication for hyperglycemia  
Visit exclusion [exclude 
data post SGLT2 starts] 
Use of new Diuretic medication 
Initiate of new diuretic medication within 12 
weeks
Visit exclusion [exclude 
data post initiation of a 
new diuretic] 
 of randomization 
Randomization/Blinding  
 
 
Unblinding  
Blind was broken (requested in IWRS)  
Visit exclusion [exclude 
data post blind broken] 
Dosing Non-Compliance 
-Subject missed more than 50% of the 
investigational product doses between week 12 
and week 24 
Subject exclusion 
 
 
 
 
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 22 of 53 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
Statistical methodology and analyses are in accordance with the principles outlined by 
the International Conference on Harmonization (ICH) E9 guidelines. All statistical 
analyses will be conducted using SAS statistical software version 9.3 or higher. 
Tables, listings and figures (TLFs) will be produced in accordance with the principles 
outlined by the ICH E3 guidelines. For most summary statistics, data will be analyzed by 
the following treatment groups: Bexagliflozin 20 mg; Sitagliptin 100 mg. 
Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], 1st quartile [Q1], median, 3rd quartile [Q3], minimum and maximum) for 
continuous variables, and frequency and percentage of subjects for categorical and 
ordinal variables, unless otherwise specified.  
Unless otherwise specified, all statistical tests will be one-sided using a 0.025 level of 
significance. All confidence intervals (CIs) will be two-sided 95% CIs. 
The analysis visit window will be assigned to data collection. One selected data point 
per visit will appear in summary tables and figures. Refer to section 6.4 for details. All 
visit assessment data will be included in shift tables and will appear in the subject 
listings. 
No data imputation will be applied for missing values, unless otherwise specified. 
6.2. 
KEY DEFINITIONS 
6.2.1. 
Baseline Values 
For subject who is dosed, baseline is defined as the last non-missing value on or prior to 
the first dose of double-blind study medication. For subject who is not dosed, baseline 
is defined as the last non-missing value on or prior to the randomization date. 
6.2.2. 
First Dose Date 
Two “first dose dates” will be required – one for the Run-In period and one for the 
double-blind treatment period. The first dose date for the Run-In period will be the 
date of administration of the first dose of single-blind placebo tablets during the Run-In 
period. The first dose date for the double-blind treatment period will be the date that 
the first dose of randomized, double-blind study drug is administered. Both first dose 
dates will be obtained from the electronic case report form (eCRF). Study analyses will 
use the double-blind treatment period first dose date. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 23 of 53 
6.2.3. 
Study Day 
Study Day is the number of days starting from the first administration of double-blind 
study drug, which is counted as Study Day 1. If the assessment date is after the date of 
the first double-blind medication, the study day is calculated as date of assessment - 
date of the first dose administration+1. If the assessment date is prior to the date of the 
first double-blind medication, the study day is calculated as date of assessment - date 
of the first dose administration. 
6.2.4. 
Duration 
Duration of double-blind treatment will be determined as Double-Blind duration = 
Double-Blind last dose date minus Double-Blind first dose date plus 1. Duration of Run-In 
period will be determined as Duration = last dose date in the run-in period minus first 
dose date in the run-in period plus 1. 
6.2.5. 
End of Study 
The end of study is defined as the date of final contact as entered on the End of Study 
page of the eCRF. 
6.2.6. 
Patient Years 
Patient years are calculated as sum of the duration from first dose of double-blind 
treatment to the end of study / 365.25 of all subjects in the specified analysis set and 
treatment arm. This is used as the denominator of the computation of incidence rate. 
6.3. 
MISSING DATA 
The handling of missing or incomplete data is described for each endpoint and 
data type (as needed) in Section 7 to 9. 
6.4. 
ANALYSIS VISIT WINDOWS 
Table 4 shows how data will be mapped to analysis visits prior to selection of records 
for analysis. All post-baseline visits, including unscheduled and early termination visits, 
will be mapped. After mapping the data to the analysis visits, the following rules will 
apply unless other handling is specified for a particular analysis. 
• 
If multiple records are available within a single analysis visit window, the record 
closest to the planned assessment day will be selected for analysis. 
• 
If 2 records are equidistant from the target day, then the later record will be 
selected. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 24 of 53 
• 
If a subject has no record in an analysis window, the subject will be considered 
missing at that visit. 
Table 4    Analysis Visit Windows 
Study Day Window 
Scheduled day  
Scheduled Visit/Week 
Day 1 - 63 
Day 42 
Visit 4/Week 6 
Day 64 – 105 
Day 84 
Visit 5/Week 12 
Day 106 - 147 
Day 126 
Visit 6/Week 18 
>= Day 148 
Day 168 or (Last dose date + 
1), select the less one 
Visit 7/Week 24 
* Week 24 is the end of treatment visit for those subjects completing the study per protocol. For 
endpoints of lab, vital sign and ECG, the first collection after assigned Week 24 and > 7 days 
from Week 24 visit will be considered as Week 26 visit. All data summary will base on the 
mapped visit. 
6.5. 
POOLING OF CENTERS 
Subjects will not be pooled based on site size, but rather by region, to ensure a 
sufficient number of subjects per treatment arm in both ITT and PP populations for 
analysis that contain region as a model effect.  
Region 
Country 
North 
America 
United States 
Europe 
Czech Rep 
Hungary 
Poland 
Spain 
Asia 
Japan 
 
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 25 of 53 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition data will be listed. A disposition table will present, by treatment 
group and overall, the number and/or percentage of subjects who signed the informed 
consent and entered the study (i.e., were screened, screen failed prior to Run-in, 
screen failed during the Day -7 to Day -1 Run-in, and randomized), completed the study 
drug, discontinued study drug, completed the study, and discontinued from the study 
after randomization. The reasons for early withdrawal after randomization will be 
summarized. A separate table will display the number of subjects who met eligibility 
criteria at screening and Run-in period but withdrew prior to randomization 
(non-randomized subjects) with a summary of the reasons for withdrawal prior to 
randomization. 
Assignment to the analysis sets (safety, ITT, and PP) will be summarized. 
7.2. 
SUBJECT ELIGIBLITY AND PROTOCOL DEVIATIONS 
All subjects, including screen failure subjects, who violate the Inclusion/exclusion 
criteria will be listed. Reason for screen failure will be summarized. 
Deviations that could affect the primary and secondary variables will be considered 
when determining a subject’s eligibility for the PP population. The number and percent 
of subjects who had any major deviation and each type of major protocol deviation will 
be tabulated for the ITT Analysis Set. 
7.3. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic characteristics include age, gender, race and ethnicity. Subject age will 
be calculated from the date of informed consent date. Baseline characteristics will 
include HbA1c, baseline HbA1c group (≤ 8.5% vs. ˃ 8.5%) at Visit 1, blood pressure, body 
weight, BMI, FPG, eGFR, duration of diabetes from diagnosis to the date of informed 
consent, and prior anti-diabetic treatment status at screening (including type of therapy 
used, such as metformin, SU, DPP-4 inhibitor, alpha-glucosidase inhibitor, etc.). 
Descriptive summary statistics by treatment will include counts and percentages for 
discrete variables and estimation of means, standard deviations, medians, inter-quartile 
range (Q1, Q3), minimum, and maximum for continuous variables. Subjects’ baseline 
demographic and baseline characteristics will be summarized by treatment group and 
overall for subjects in the safety, ITT, and PP analysis set.  


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 26 of 53 
7.4. 
MEDICAL HISTORY 
Significant medical and surgical history, including dates of diagnoses and procedures 
and whether the condition is ongoing, if applicable, will be collected. Each condition 
will be recorded as a verbatim term, date of onset, date resolved, and a checkbox that 
indicates ongoing conditions. Significant surgical and medical history will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) version 19.0. 
Medical and surgical history will be summarized for the Safety Analysis Set by treatment 
group, system organ class (SOC), and MedDRA preferred term (PT), overall. Subject data 
will be listed. 
Subject diabetes and cardiovascular diseases history will be summarized for all 
categorical variables by frequency and percentage. Listing will be provided. 
7.5. 
MEDICATION 
All prescription and over-the-counter medications, including vitamins and herbal 
supplements, that subjects receive during the trial must be documented on the CRF. 
The medication name, dose, frequency, route of administration, date(s) of 
administration and reason for administration must be recorded. This documentation 
should continue through the treatment period and the follow up period. 
All medication will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) version March 2016. Preferred drug name, Anatomical Therapeutic Chemical 
(ATC) class will be reported for inclusion in the database.  
Medication summaries based on ATC level 2, and the preferred drug names will be 
produced for the Safety Analysis Set. The summaries will present, by treatment group, 
the frequency and percentage of subjects who used any medication in an ATC class, or 
any medication based on a single preferred drug name. Medication summaries will be 
sorted by descending total frequency of ATC class and by PT within ATC class. Subjects 
will be counted only once for each medication class and each preferred drug name. 
For subject listings, ATC class and PT of the medications will be reported; multiple 
medications for an individual subject will be listed by start date and then by stop date, 
from earliest to latest medications. 
7.5.1. 
Prior Medication 
Any medication stopped prior to the first dose of the double-blind treatment period will 
be considered a prior medication. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 27 of 53 
No summary for prior medication will be presented. Prior and concomitant medications 
will be presented together on a single listing. Prior medication will be indicated in the 
listing. 
7.5.2. 
Concomitant Medication 
A concomitant medication is any medication that the subject has been taking prior to 
the first dose of double-blind study medication and that the subject is expected to 
continue to take for some portion of the study treatment period, as well as any 
medication other than the investigational product that the subject takes during the 
double-blind treatment period and follow up period of the study. In the case of 
completely missing stop date, medication will be assumed to be concomitant. If a 
medication can be considered as both prior and concomitant due to partial stop date, it 
will be considered as concomitant. 
Any medication a subject takes to treat hyperglycemia after the first dose of double-
blind study drug starts and continues for more than 2 weeks before study treatment 
stops is considered a rescue therapy and should be recorded in the concomitant 
medication log. Increase total daily dose of metformin, the background hypoglycemic 
therapy, is also considered rescue medication if the dose is intensified during the 
double-blind treatment period for more than 2 weeks before study treatment stops. All 
medication given to treat hyperglycemia will be recorded in CRF. 
Concomitant medications will be presented in a summary table as well as in a subject 
listing. Rescue medications will be summarized in a separate table and will be indicated 
in the same listing. 
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 28 of 53 
8. 
EFFICACY 
Efficacy data include HbA1c, FPG, body weight, and SBP. For subject who is dosed, 
changes from baseline will be calculated as the post-treatment value minus the last 
non-missing value on or prior to the first dose of double-blind study medication. For 
subject who is not dosed, changes from baseline will be calculated as the post-
treatment value minus the last non-missing value on or prior to the randomization date. 
All continuous efficacy data will be summarized for observed and change values by 
treatment and visit. Proportion of subjects with HbA1c of < 7% will be summarized by 
frequency and proportion by treatment and visit. 
8.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
The primary efficacy hypothesis is that bexagliflozin reduces HbA1c after 24 weeks of 
treatment when compared to sitagliptin. 
8.1.1. 
Primary Efficacy Analysis 
Let μBexagliflozon and μsitagliptin represent the mean changes from baseline in HbA1c at 
Week 24 for bexagliflozin and sitagliptin arms, respectively. The following hypotheses 
will be tested: 
H0: μ bexagliflozin - μ sitagliptin > δ 
Ha: μ bexagliflozin - μ sitagliptin ≤ δ 
This hypothesis will be tested based on ITT analysis set using all observed data and a 
mixed model repeated measures (MMRM) approach. The MMRM model will include 
treatment, visit, treatment-by-visit interaction, region and the baseline HbA1c value as 
a fixed effect covariate. The analysis will evaluate the mean change from baseline in 
HbA1c over the 24-week double-blind treatment period. An unstructured covariance will 
be used to model the within-subject correlation. The Kenward-Roger approximation will 
be used to estimate denominator degrees of freedom. If the model with the 
unstructured covariance structure does not converge, an autoregressive(1) covariance 
structure will be used. HbA1c values obtained after the start of rescue medication will 
not be excluded from the analysis. 
Based on the MMRM model, the treatment and treatment-by-visit interaction terms 
allow for comparisons of the treatment groups at each visit, and over week 6 to 
week 24. Least squares (LS) mean treatment differences between the bexagliflozin 
group and the sitagliptin group at week 24 will be estimated from the model with their 
two-sided 95 % CIs presented. 
Descriptive statistics (n, mean, Q1, median, Q3, SD, minimum, and maximum) will be 
reported by treatment group and visit, along with the LS means, differences between LS 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 29 of 53 
means, a 2-sided 95% confidence interval for each difference from the model effects. In 
addition, the LS means with standard errors (SEs) of the change from baseline over time 
and difference between treatment groups with 95% CIs will be presented graphically for 
the ITT population. 
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 sitagliptin treatment. Superiority of bexagliflozin group over 
sitagliptin group at week 24 in HbA1c change from baseline will be declared if the upper 
bound of 95% CI is less than 0. 
For supportive analyses, the primary efficacy endpoint will be analyzed with observed 
available data using the PP analysis set in a similar manner as above. 
8.1.2. 
Sensitivity Analyses 
Randomized subjects who withdraw consent to participate in the study will not be 
replaced. The early termination rate is estimated to be 8%. To the extent possible, 
attempts will be made to minimize the amount of missing data through measures 
planned in the study conduct. 
To investigate the possible implications of missing values in efficacy assessments, the 
number, timing, pattern, and reason for the missing value will be summarized. The 
reason for withdrawn will be reviewed. If there are missing values for the primary 
analysis, only available data will be analyzed and data obtained after rescue will not be 
excluded. To account for subjects for whom the post-baseline endpoint (ie, at the time 
when the last post-baseline double-blind assessment was performed) occurs at a time 
point before Week 24, a MMRM approach will be used as the primary method (as 
described in the previous section). It is assumed that the majority of the missing values 
will be one of the following, and in such situations, likelihood-base methods like MMRM 
are appropriate and widely accepted (Little et al, 2002):  
• 
“Missing Completely at Random (MCAR)” (ie, probability of an observation being 
missing does not depend on observed or unobserved measurements) or 
• 
“Missing at Random (MAR)” (ie, probability of an observation being missing 
depends only on observed measurements) 
The dropout patterns will be assessed by a Kaplan-Meier plot of time to discontinuation 
by treatment group to assess whether they differ between treatment groups. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 30 of 53 
 The following sensitivity analyses will be conducted: 
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 imputations techniques; HbA1c values collected 
after the start of rescue medication will not be excluded. A pattern-mixture model 
will be used to explore the impact of the missing data. Imputation will be conducted 
within each treatment arm and subgroup (treatment completer vs. treatment 
terminated early) under the assumption that non-adherent subjects with missing 
data will follow the same trajectory of non-adherent subjects with values observed. 
All efforts will be made to retain subjects in the study. If treatment is discontinued, 
subjects are encouraged to remain in the study and complete all scheduled visits, 
including final follow-up visit. However, with all efforts, insufficient values may be 
available for reliable imputation. This analysis will be performed only if ≥3% of 
subjects in each treatment arm completed scheduled week 24 visit after treatment 
is stopped. For this analysis, the following three-step approach outlined below will 
be used: 
a. Non-monotone (intermediate visits) missing data will be imputed first using the 
Monte Carlo Markov Chain (MCMC) method under the MAR assumption in all 
treatment arms (using the MCMC statement in PROC MI). Multiple chains option 
(CHAIN=MULTIPLE option in the MCMC statement of PROC MI) will be used. For 
the non-monotone imputation of the HbA1c missing data, a multivariate normal 
model will be used including variables for the HbA1c at baseline and all 
post-baseline visits within each treatment group. 
b. After the non-monotone missing data have been imputed, the remaining 
monotone missing data will be imputed within each treatment arm and 
subgroup, defined by whether subject completed 24 week of study treatment, 
using regression approach. The predictors for the regression imputation model at 
any time point will be region, and HbA1c at all previous time points, including 
baseline. Imputations will be performed using a sequence of regression-based 
imputations (using PROC MI statement MONOTONE REG) at each post-baseline 
time point.  
c. Imputed data in each of the multiple imputed datasets will be analyzed using the 
same mixed model for repeated measures as in the primary analysis. The results 
from all imputed datasets will be combined using the Rubin’s combination rule 
(PROC MIANALYZE). 
The number of imputation will be determined using the method described by 
White, et.al., 2011. We will use Bodner’s approximation to estimate the fraction of 
missing information (FMI) as the proportion of the incomplete cases in the data. 
Since the parameter of interest is the mean changes from baseline in HbA1c at 
Week 24 for bexagliflozin and sitagliptin groups, FMI will be approximated using the 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 31 of 53 
proportion of subjects missing Week 24 values. As indicated by Bodner, this is a 
very conservative approach and will work with FMI≤0.5. The number of imputations 
m will be determined to provide sufficient level of reproducibility using formula: 
m≥100×FMI 
as recommended by White. The Monte Carlo error of the p-value using m 
imputation datasets will be approximately 0.01 when the true p-value is 0.05, and 
0.02 when the true p-value is 0.1. 
At least 10 datasets will be imputed. We will examine the FMI estimated from the 
combined results. If it is much larger than our initial approximation, a considerable 
volatility is observed from the imputed datasets. In this case, we will increase the 
number of m using the estimated FMI. 
2) Additionally, the impact of the data after the start of rescue medication will be 
evaluated. HbA1c values collected after the start of rescue medication will be 
considered missing, and the MMRM analyses will be performed. Same statistics 
provided for the primary analysis will be presented. 
3) Tipping point analysis will be conducted. Data after rescue medication will be 
considered as missing. Following steps will be followed: 
a. Create monotone missing data as step a in 1); 
b. Regression approach under MAR will be used to generate complete datasets. The 
predictors for the regression imputation model at any time point will be region, 
treatment, and HbA1c at all previous time points, including baseline. The first 
imputed values will be penalized or rewarded based on the treatment subject 
received: 
o Subjects in the bexagliflozin group: missing value will be analyzed assuming 
the treatment effect is worsened by δ1 (where δ = 0.1 to 0.5, in step of 0.1) 
compared to the subjects who have no missing value in the reduction of 
HbA1c value; 
o Subjects in the sitagliptin group: missing value will be analyzed assuming the 
treatment effect is better by δ2 (where δ = 0.1 to 0.5, in step of 0.1) 
compared to the subjects who have no missing value in the reduction of 
HbA1c value; 
The penalty or reward will not be applied to the values from later time points as 
these values are penalized or rewarded through regression on previous time 
points. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 32 of 53 
c. Imputed datasets will be analyzed and results combined as step c in 1). 
For each combination of (δ1, δ2), 100 imputed datasets will be obtained. These 25 
combinations will be separately analyzed to explore under which condition when the 
null hypothesis can no longer having evidence to be rejected. 
8.1.3. 
Subgroups 
The primary efficacy endpoint will be summarized and analyzed by the following 
subgroups using MMRM model: 
• 
Age (<65 years or ≥65 years), adjusted by region and baseline HbA1c value; 
• 
Gender (male or female), adjusted by region and baseline HbA1c value; 
• 
Race (Asian; Black of African American; White or Caucasian; Other), adjusted by 
region and baseline HbA1c value; 
• 
Baseline HbA1c (>8.5% or ≤ 8.5%), adjusted by region; 
• 
Region (North America, or Europe, or Asia Pacific), adjusted by baseline HbA1c 
value. 
8.2. 
SECONDARY EFFICACY ENDPOINT(S) AND ANALYSES 
The secondary endpoints will only be tested when the non-inferiority of the primary 
efficacy assessment is established at one-sided significance level of 0.025. To control 
the overall type I error of 0.025 one-sided, the secondary efficacy objectives will be 
tested at one-sided 0.025 significance level following the hierarchy sequence as below: 
• 
Superiority test of the change in FPG in the bexagliflozin group vs. the sitagliptin 
group at week 24. 
• 
Superiority test of the change in body weight in subjects with baseline body mass 
index (BMI) ≥ 25 kg/m2 in the bexagliflozin group vs. the sitagliptin group at 
week 24. 
• 
Superiority test of the change in SBP in the bexagliflozin group vs. the sitagliptin 
group at week 24. 
Analysis for secondary endpoints will be based on ITT analysis set and repeated for PP 
analysis set. 
8.2.1. 
Change in FPG in the bexagliflozin group vs. the sitagliptin group at 
week 24 
This will be tested if the non-inferiority of HbA1c has been concluded based on ITT 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 33 of 53 
analysis set. Data after rescue medication will not be excluded. The comparison of 
change in FPG between randomized treatments at week 24 will be carried out using the 
similar MMRM model as in section 8.1.1. The model will include terms for treatment, 
visit, treatment-by-visit interaction, region as fixed effects and the corresponding 
baseline FPG value as covariate. Treatment comparison p-values and difference at week 
24 will be estimated from the model, with the two-sided 95 % CIs of the treatment 
difference also presented. If the inferiority of HbA1c is not established, the nominal 
p-value will not be used for inferential purposes. Summary table will be presented and 
figures will be displayed for ITT analysis set. 
8.2.2. 
Change in body weight in subjects with baseline body mass index 
(BMI) ≥ 25 kg/m2 in the bexagliflozin group vs. the sitagliptin group 
at week 24 
This will be tested if the non-inferiority of HbA1c has been concluded and the previous 
secondary efficacy endpoint of FPG reduction is in favor of bexagliflozin significantly. 
Change from baseline in body weight at week 24 will be analyzed in a similar manner as 
change in FPG, Section 8.2.1, based on ITT analysis set for all subjects. Baseline body 
weight will be used as a covariate. Region and baseline HbA1c value will also be used as 
fixed effects. Summary table will be presented and figures will be displayed for ITT 
analysis set. 
8.2.3. 
Change in SBP in the bexagliflozin group vs. the sitagliptin group at 
week 24 
This will be tested if the non-inferiority of HbA1c has been concluded and the previous 
secondary efficacy endpoints (reduction in FPG and body weight) are significant in favor 
of bexagliflozin. Change from baseline in SBP at week 24 will be analyzed in a similar 
manner as change in FPG, Section 8.2.1, based on ITT analysis set for all subjects. 
Baseline SBP will be used as a covariate. Region and baseline HbA1c value will also be 
used as fixed effects. Summary table will be presented and figures will be displayed for 
ITT analysis set. 
8.2.4. 
Sensitivity analysis 
For all secondary analyses of FPG, body weight and SBP, missing data will be imputed 
via multiple imputations, following which the MMRM will be repeated on the complete 
datasets with results combined across complete datasets using standard multiple 
imputations techniques; Values collected after the start of rescue medication will be 
considered missing. Imputation steps include: 
a. Create monotone missing data as step a in 1) of section 8.1.2; 
b. Regression approach under MAR will be used to generate complete datasets. The 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 34 of 53 
predictors for the regression imputation model at any time point will be region, 
treatment, and values at all previous time points, including baseline. Values at 
each visit will be imputed sequentially. The first imputed values for subjects in 
bexagliflozin arm will be penalized by the mean improvement at week 24 on that 
endpoint (i.e. the mean change from baseline at week 24). Imputed values for 
subjects in sitaglipin will not be penalized. Imputed values after the first missing 
value will be penalized through regression on first penalized value. 
c. Imputed datasets will be analyzed and results combined as in step c in 1) in 
section 8.1.2. 
8.3. 
EXPLORATORY EFFICACY ENDPOINTS AND ANALYSES 
All endpoints in this section are exploratory. No sensitivity analysis and adjustment for 
multiple comparisons will be conducted. Nominal p-values will be used to examine any 
trends in these endpoints. 
8.3.1. 
Change from baseline in HbA1c, SBP, Body weight, and in FPG over 
time 
The schedule of HbA1c, FPG, body weight, and SBP/DBP can be found in Table 1. The 
absolute value and change from baseline in HbA1c, FPG, body weight and SBP during the 
double-blind treatment period will be summarized by descriptive statistics at each visit. 
Change from baseline in HbA1c will be analyzed as part of primary efficacy analysis 
(Section 8.1.1). Change from baseline in SBP, body weight and FPG will be analyzed as 
part of key secondary analysis (Section 8.2.1, 8.2.2, and 8.2.3). LS means for each 
treatment and the difference between treatments will be estimated at each visit. The 
corresponding p-values will also be presented. 
All values for follow-up visits will be listed. 
8.3.2. 
Proportions of subjects with HbA1c of < 7% over time 
Summary on the proportion of subjects achieving HbA1c < 7% at each visit will be 
presented over time. It will be analyzed using Generalized Estimating Equation (GEE) 
logistic regression. The fixed effect will include region, treatment, visit, treatment-by-
visit interaction and baseline HbA1c. An unstructured correlation structure will be used 
(or autoregressive (1) if the model with the unstructured structure does not converge). 
The odds ratios of bexagliflozin group over the sitagliptin group at each visit will be 
estimated from LS means based on the model with the corresponding p-values and their 
two-sided 95 % CIs presented. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 35 of 53 
9. 
SAFETY 
The analysis population used for safety analyses will be the Safety Analysis Set. Safety 
data include AEs; physical examination results; vital signs, including blood pressures; 
ECG results; and clinical laboratory results, including serum chemistry, hematology, 
serum lipids, and urinalysis. 
Observed data will be summarized by treatment group as counts and percentages for 
discrete variables and means, standard deviations, medians, inter-quartile range, 
minimum, and maximum for continuous variables. All subjects who are randomized and 
receive at least one dose of double-blind study medication will be included in the safety 
analysis. All safety data will be presented in by-subject listings and included in the 
clinical trial report. 
9.1. 
EXTENT OF EXPOSURE 
Study drug exposure will include: 
• 
Treatment duration by treatment group 
• 
Total dose received by treatment group 
Treatment duration of tablets (in weeks) is calculated as (the date of the last dose of 
study drug – the date of the first dose of study drug + 1) / 7 and rounded to 1 decimal 
place. 
The specific definitions of the first dose and last dose dates of study drug are given 
below: 
• 
First dose date: The date of the first dose of study treatment during the 
double-blind treatment period obtained from the study drug exposure CRF. 
• 
Last dose date: The date of the last dose of study medication in the 24 week 
treatment period for subjects who have completed the study or discontinued 
early. Total dose received will be calculated as number of tablets dispensed – 
number of tablets returned. 
Summary statistics for treatment duration (in weeks) and total dose received, as well as 
a frequency summary of treatment duration categories (e.g., < 1, 1 - < 6 weeks), will be 
provided. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 36 of 53 
9.2. 
TREATMENT COMPLIANCE  
Subjects will be provided with dosing instructions each time study medication is 
dispensed. Subjects will also be instructed to bring their medication with them to every 
visit. During the run-in period, subjects will be considered compliant in investigational 
product administration by missing no more than one day of run-in medication. Subjects 
who are not compliant during the run-in period will be excluded from randomization. If, 
in the judgment of the investigator, it was appropriate for the subject to omit these 
doses, this requirement may be waived (e.g., if the subject was hospitalized overnight 
during run-in). 
At each visit after the start of the run-in period, the study staff will review the 
self-monitored blood glucose (SMBG) control diary and medication use with the subject 
and record the drug consumption in the CRF. Reasons for non-adherence will also be 
recorded in the protocol deviation log if applicable. 
Compliance in the run-in and double-blind phase is calculated for as follows: 
• 
Percent compliance = (number of tablets taken / number of tablets should have 
taken) x 100. 
• 
Number of tablets taken = number of tablets dispensed – number of tablets 
returned. 
• 
Number of tablets should have taken = (number of tablets supposed to take in a 
day) x (number of exposure days). 
• 
Number of exposure days = last dose date – first dose date + 1. 
If any of the bottles dispensed is not returned, it will not be possible to compute the 
compliance. In this case, the number of tablets taken and compliance will be 
considered as missing. Summary statistics for tablet compliance (%) will be provided by 
treatment group for the double-blind treatment period. A frequency summary of 
compliance will also be presented with the following categories: < 75%, 75-<100%, 
100-120%, and > 120%. 
9.3. 
ADVERSE EVENTS 
Adverse events will be collected and recorded from the time a subject signs the 
Informed Consent Form (ICF) to the last scheduled contact. And new 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 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 37 of 53 
to report any significant follow-up information to the sponsor until the event has been 
resolved. This study requires that subjects be actively monitored for SAEs for at least 4 
weeks after the last treatment. 
For all AEs, preferred AE terms and system organ class SOC will be coded using 
terminology from the MedDRA, version 19.0. 
A Treatment-emergent Adverse Event (TEAE) is defined as an AE that begin after the 
first administration of double-blind study medication or existing AEs that worsen after 
the first dose of double-blind study medication. All reported AEs will be listed, but only 
TEAEs will be summarized in tables. 
Drug-related AEs will be considered those to be possibly, probably and definitely related 
to study medication administration based on the investigators assessment. 
Unless otherwise specified, AEs will be summarized by SOC and PT, with SOCs and PTs 
within SOCs presented in descending order of subject incidence. 
9.3.1. 
Derived Data 
AE onset day is calculated as (date of AE start – date of double-blind first dose + 1) if it 
is after the first dose of study drug. AE onset day is calculated as (date of AE start – 
date of double-blind first dose) if it is before the first dose of study drug. The onset day 
will be missing if the start date is missing. 
9.3.2. 
Data Summarization  
AE summary tables are listed below: 
• 
An overall summary of the number and percentage of subjects reporting any 
TEAEs, serious TEAEs, treatment-related TEAEs, serious treatment-related TEAE, 
any TEAEs leading to treatment discontinuation, any TEAEs leading to subject 
discontinuation and TEAEs leading to death.  
• 
TEAEs overall and by SOC and PT 
• 
TEAEs by severity, overall and by SOC and PT 
• 
Serious TEAEs, overall and by system organ class and preferred term 
• 
TEAEs by relationship to study treatment, overall and by system organ class and 
preferred term 
• 
TEAEs leading to treatment discontinuation, overall and by SOC and PT 
• 
TEAEs leading to study discontinuation, overall and by SOC and PT 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 38 of 53 
• 
Most common TEAEs. Most common TEAEs are defined as TEAEs that occur in 
> 5% of the subjects in either of the treatment groups. 
For summary tables, subjects having more than 1 event with the same PT will be 
counted once for that term. Subjects having more than 1 event with the same SOC will 
be counted once for each event and once for that SOC. For tabulations by severity, only 
a subject’s most severe event within the category (e.g. overall, SOC, PT) will be 
counted; similarly, for tabulations by relationship, only a subject’s most related event 
within a category will be counted. The denominator for percentages will be the number 
of subjects in the Safety Analysis Set for the given treatment group (i.e., the N’s for the 
columns). 
Listings will be provided for all AEs and the following subsets: 
• 
All TEAEs 
• 
All TEAEs at least possibly related to study medication 
• 
Serious AEs 
• 
AEs leading to treatment discontinuation 
• 
AEs leading to death 
9.3.3. 
AE of Special Interest 
AE of special interest includes UTI, GMI, diuretic effects, hypotension episodes, 
hypoglycemia, hepatotoxicity, MACE, falls and fractures, malignancy, hypersensitivity 
reactions, pancreatitis, amputations and renal failure events. These AEs of interest 
except DKA, MACE and amputations will be prospectively identified based on the 
MedDRA preferred terms in the AE log by a medical expert prior to the data base lock 
and unblinding of the individual subject treatment assignment. The list of AE of interest 
will be confirmed in a peer review process. DKA and MACE will be identified by the 
investigator and documented in the CRF, and subsequently adjudicated by separate 
independent committees. Adjudicated results will be used for summary. Amputation 
events will be recorded in the procedures and amputation CRF. Cardiovascular events, 
hypoglycemia events by severity, and amputations will be summarized separately. 
9.3.3.1. 
AE of special interest identified by PTs 
Cardiovascular events considered as MACE by investigator will be submitted to an 
independent CEC for adjudication. The events of interest include cardiovascular 
mortality, MI, stroke, hospitalization for acute coronary syndromes, urgent 
revascularization procedures, and other possible serious cardiovascular events. Other AE 
of special interest will be identified from the PTs. The number and percentage of 
subjects experiencing these TEAEs of special interest will be summarized for each 
treatment group by type of event. The incidence rate of AE of special interest per 100 
patient years will also be summarized. Each category of events will be displayed in a 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 39 of 53 
separate listing.  
9.3.3.2. Hypoglycemic Events 
Hypoglycemic event categories include: 
Category 
Description 
Severe 
Assistance required and blood glucose ≤70 mg/dL or no value 
available but responded to glucose treatment 
Documented 
Symptomatic 
Blood glucose ≤70 mg/dL and typical symptoms of hypoglycemia 
Asymptomatic 
Blood glucose ≤70 mg/dL and no typical symptoms of hypoglycemia 
Probable 
Symptomatic 
Typical symptoms of hypoglycemia and no value available but 
responded to glucose treatment 
Relative 
Typical symptoms of hypoglycemia and blood glucose >70 mg/dL 
 
While each event meeting the criteria above will be entered into the hypoglycemia log, 
only critical (severe) hypoglycemia, documented symptomatic hypoglycemia, 
asymptomatic hypoglycemia, and probable hypoglycemia will be entered as AEs. 
The number and percentage will be summarized by treatment for: 
• 
Each category of hypoglycemic events; 
• 
Any severe or documented hypoglycemic events. 
9.3.3.3. 
Major Adverse Cardiovascular Events 
Cardiovascular events considered as MACE by investigator will be submitted to an 
independent CEC for adjudication. The events of interest include cardiovascular 
mortality, MI, stroke, hospitalization for acute coronary syndromes, urgent 
revascularization procedures, and other possible serious cardiovascular events. The 
number, percentage and incidence rate per 100 patient years of suspected MACE and 
adjudicated MACE will be summarized for each treatment group. Adjudicated MACE will 
be further summarized by PTs. 
9.3.3.4. 
Revascularization and Amputations 
Revascularization and amputations information are collected in a separate form. 
Frequency and percentage will be summarized for: 
• 
Type of procedures –cardiovascular related or amputation 
• 
Subjects with any amputation 
• 
Conditions that resulted in amputation 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 40 of 53 
• 
Location of amputation 
Only procedures performed after the first dose of double-blind study drug will be 
summarized. 
9.4. 
LABORATORY EVALUATIONS 
Laboratory tests will include hematology panel, chemistry panel, serum lipids, and 
urinalysis testing. Hematology, chemistry, and urinalysis will be performed at the 
following time points: at the screening visit, on randomization visit, and at week 6, 12, 
18, 24, and 26. Serum lipids will be performed at the screening visit, on randomization 
visit, and on week 12 and 24, and 26. The study staff will contact each subject prior to 
a scheduled clinic visit to confirm the time of the visit and to remind the subject of 
proper fasting practice. A subject must be queried to assess compliance with an 
approximately 10-hour fast prior to blood draw to ensure the FPG and triglycerides 
values can be accurately determined. If a subject has not fasted for approximately 10 
hours, the subject must return as soon as can be arranged (within 1 week) to provide a 
specimen after proper fasting. A list of laboratory tests is included in Table 5. 
Low density lipoprotein cholesterol (LDL-C) will be calculated by the Friedewald 
equation. If triglycerides are > 400 mg/dL, the calculated LDL-C value is invalid by this 
equation and will be set as missing. Direct LDL-C will be determined in subjects whose 
triglycerides are > 350 mg/dL at screening visit. All subsequent LDL-C of these subjects 
will be determined by the same direct LDL-C measurements only. If triglycerides are 
>350 mg/dL, a reflex test will be performed based on direct LDL measurement. The 
following algorithm will be used to obtain LDL-C values for the analyses: 
1. Select subjects (based on the SI unit) who had screening triglycerides >3.4 or 
>350 based on the conventional unit 
2. Take the LDL – direct measurement values only, throughout the study visits for 
those subjects 
3. If screening triglycerides > 350 and no direct LDL-C values have been 
determined, take the calculated.  
Among those subjects who have screening triglycerides >350 and have both calculated 
and direct LDL values, only take the direct LDL. 
Urinalysis microscopy will be conducted if the subject has a positive result on the 
leukocyte esterase or nitrite dipstick tests to clarify the significance of the finding. 
Results of glucose measurement in the urinalysis must be suppressed from the 
laboratory reports so the sponsor, investigators, study coordinators, pharmacists, study 
subjects, and the CEC members will remain blinded to the dosing assignment. 
All continues variables will be summarized by number of subjects [n], mean, SD, Q1, 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 41 of 53 
median, Q3, minimum and maximum and categorical variables will be summarized by 
frequency and percentage. 
All scheduled and unscheduled results will be considered in tables that assess maximum 
grade or toxicity.  
Observed values (in SI units) and change from baseline over time will be summarized by 
treatment group. Laboratory data will be classified as low, normal, or high relative to 
the parameter’s reference range. Laboratory abnormalities for each treatment will also 
be summarized with shift tables for selected parameters. 
All laboratory data will be listed. For hematology, chemistry, and serum lipids, columns 
will be included for normal ranges and individual abnormal laboratory values will be 
flagged and clinical significance will be indicated. A listing for the microscopic 
examination will be provided for subjects who have a positive result from the urinalysis 
dipstick evaluation.  
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 42 of 53 
Table 5    List of Laboratory Tests 
TEST NAME  
SHIPMENT  
Hematology  
Ambient  
• Hematocrit (Hct) 
• Hemoglobin (Hgb)  
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin 
      concentration (MCHC) 
• Platelet count  
• Mean corpuscular volume (MCV) 
• Red cell distribution width (RDW) 
• Red blood cell (RBC) count 
• White blood cell (WBC) count with differential 
Serum Chemistry and Electrolytes  
Ambient  
• Albumin (ALB) 
• Alanine aminotransferase (ALT) 
• Alkaline Phosphatase (ALP)  
• Aspartate aminotransferase (AST)  
• Blood urea nitrogen (BUN) 
• Glucose 
• Bicarbonate (HCO3) 
• Creatinine 
• Chloride (Cl)  
• Total protein  
• Calcium (Ca)  
• Magnesium  
• Phosphorus  
• Potassium (K)  
• Sodium (Na)  
• Total bilirubin  
• Direct bilirubin  
• Uric acid 
Glycemic Control  
Ambient  
• Fasting plasma glucose (FPG) 
• Hemoglobin A1c (HbA1c)  
Serum Lipids  
Ambient  
• Total cholesterol (TC)  
• High-density lipoprotein cholesterol 
      (HDL-C) • Triglycerides (TG)  
• Low-density lipoprotein cholesterol (LDL-C), 
       calculated  
• LDL-C, direct 
Urinalysis  
Ambient  
• Appearance  
• Bilirubin  
• Color  
• Glucose  
• Ketones  
• Microscopic examination of sediment  
• UACR  
• Nitrite  
• Occult blood  
• pH • Protein  
• Specific gravity  
• Urobilinogen  
• Leukocyte esterase 
Urine Pregnancy Test (WOCBP)  
Local  
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 43 of 53 
9.5. 
VITAL SIGNS  
Vital signs will be measured at the screening visit, on randomization visit, and at week 
6, 12, 18, 24, and 26. Measurements of vital signs will include measurement of supine, 
sitting and standing BP measurements, and heart rate. Only the BP measured in the 
sitting position will be used to determine eligibility. Orthostatic systolic and diastolic BP 
will be calculated as supine measurement – standing measurement. 
For BP and heart rate, observed values and change from baseline will be summarized by 
treatment group and mapped visit using descriptive statistics (n, mean and median, 
standard deviation, Q1, and Q3, minimum and maximum). For BP, supine, sitting, 
standing, and orthostatic BP will be summarized. Subjects vital sign measurements, 
including scheduled and unscheduled visits, will be listed. 
9.6. 
ELECTROCARDIOGRAM  
A 12-lead ECG will be conducted at the screening visit, on randomization visit, at 
week 24, and at week 26. ECG parameters measured will be the RR interval, PR 
interval, QRS duration, and QT interval. Each ECG should also be assessed by the 
investigator for signs of ischemia, clinically significant hypertrophy, and clinically 
significant T-wave abnormalities or arrhythmia. 
For each abnormal ECG result, the investigator shall ascertain if the observation 
represents a clinically significant change from the screening ECG for that individual 
subject (this determination, however, does not necessarily need to be made the first 
time an abnormal result is observed. The investigator may repeat the ECG to verify the 
results of the original result). If the ECG result is determined to be a clinically 
significant and abnormal change from baseline for that subject, it is considered an AE. 
For the ECG parameters, observed values and change from baseline from scheduled 
visits will be summarized with descriptive statistics by treatment group and overall at 
each visit. The maximum change from baseline from scheduled visits will also be 
provided for ECG parameters. 
For the ECG overall assessment, the number and percentage of subjects in each overall 
assessment category (normal, abnormal but not clinically significant, abnormal and 
clinically significant, missing) will be presented by treatment group and overall at each 
visit. 
9.7. 
PHYSICAL EXAMINATION 
A complete physical examination will be conducted at the randomization visit and at 
week 26. The examination will include measurement of body weight, and a general 
assessment of all body systems including the skin, head, eyes, ears, nose, throat, neck, 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 44 of 53 
heart, lungs, abdomen, lymph nodes, and extremities. An abbreviated physical 
examination will be conducted at screening visit and at week 24, or clinically indicated. 
The examination will include body weight and height (height will be measured only at 
screening), and general assessment of the skin, heart, lungs and abdomen. Physical 
examination findings will be presented in a by-subject listing. 
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 45 of 53 
10. 
INTERIM ANALYSES 
No interim analyses are planned. 
11. 
DATA AND SAFETY MONITORING BOARD 
An independent DSMB will review descriptive summaries of accumulating safety, subject 
disposition and limited efficacy data every 6 months, or a frequency recommended by 
the DSMB. 
A designated statistician who is not involved with the study operation will hold the 
treatment codes. The unblinded treatment information can be provided to the DSMB to 
facilitate the evaluation of any clinically important increase in the rate of a serious 
suspected adverse reaction or to the designated safety contact when the treatment 
information is required to determine if an expedited safety report must be submitted to 
regulatory agencies. The data outputs for this review will be created by an unblinded 
team. Personnel involved in the conduct of the study will not participate in the 
preparation of these outputs, receive the data, or participate in the unblinded portions 
of the DSMB meetings. More details will be provided for DSMB charter and DSMB SAP. 
12. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
Protocol section 9.3.2 states “Safety analyses will be based on the medication that was 
actually taken by each subject.” SAP is changed to use ‘Safety analyses will be based on 
the medication that was taken first.’ in section 5.2.  
Protocol section 9.5.2 includes sensitivity analysis using LOCF. This has been removed 
after tipping point analysis is added, as LOCF is redundant.  
Protocol section 9.7 states ‘Cumulative summary on the proportion of subjects 
achieving HbA1c < 7% will be presented over time’. SAP is changed to summarize the 
proportion of subjects achieving HbA1c < 7% at each visit in section 8.3.2. 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 46 of 53 
13. 
REFERENCE LIST 
Little, R., Yau, L. Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs. 
Biometrics, 1996; 52: 1324—1333. 
Ratitch, B., O’Kelly, M. Implementation of Pattern-Mixture Models using Standard 
SAS/STAT Procedures. Pharmasug 2011 – Paper SP04, PHARMASUG. 
Bodner TE. What improves with increased missing data imputations? Structural Equation 
Modeling: A Multidisciplinary Journal 2008; 15: 651—675. 
White IR., Royston P., Wood AM. Multiple imputation using chained equations: Issues 
and guidance for practice. Statistics in Medicine 2011; 30: 377—399. 
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 47 of 53 
14. 
PROGRAMMING CONSIDERATIONS 
The following conventions will hold for programming of outputs: 
• 
SAS® Version 9.4 will be used for programming and production 
• 
The format of the table shells will be followed as closely as possible; however, in 
the course of programming and familiarization with the database, some changes 
may become necessary. All changes will be documented. Major changes will be 
documented through a formal amendment to this document. 
• 
Patients in this study will be identified as “Subjects.” 
• 
Descriptive statistics will be displayed in the following order: 
n 
Mean 
Standard deviation (SD) 
Q1, Q3 
Median 
Minimum, Maximum 
• 
Decimal places: For summary statistics, the minimum and maximum will be reported 
with the same number of decimal places as the collected measure, the mean, LS 
mean (if applicable) and median will have 1 more decimal place than the measure 
collected, and the SD and confidence interval (CI) will have 2 more decimal places 
than the collected measure. For frequency distributions, percentages will be 
reported to 1 decimal place. For p-values, 4 decimal places will be reported or the 
SAS® p-value format of “< 0.0001” or “> 0.9999” will be reported. 
• 
Unless otherwise noted, the denominator for percentages is the number of subjects 
in the applicable analysis population and treatment group. 
• 
If the frequency for a particular table cell is zero, then “0”, properly aligned, will 
be displayed (i.e. “0 (0.0%)” will not be displayed.) 
• 
Non-numeric values: Where variables are recorded using < (e.g., “< 10” or “≤ 10”) 
the numeric portion of the result will be used (e.g., < 10 and ≤ 10 becomes 10) for 
summary; where variables are recorded using > (e.g., “> 10” or “ ≥ 10”) the numeric 
portion of the result will be used (e.g. > 10 and ≥ 10 become 10) for summary; the 
actual recorded results, (e.g. “< 10” or “> 10”) will appear in listings. 
14.1. 
GENERAL CONSIDERATIONS 
• 
A separate SAS program will be created for each output. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 48 of 53 
• 
Output files will be delivered in Word format. 
• 
Numbering of TFLs will follow ICH E3 guidance 
14.2. 
TABLE, LISTING, AND FIGURE FORMAT 
14.2.1. 
General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size 9  
• 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
• 
Headers and footers for figures will be in Courier New font, size 9. 
• 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and 
programmer-supplied formats, as appropriate. 
14.2.2. 
Headers 
• 
All output should have the following header at the top left of each page: 
Theracos Sub, LLC 
Protocol Number: THR-1442-C-423 
• 
Draft or Final in top right corner. 
• 
All output should have Page n of N at the top of each page. TLFs should be internally 
paginated in relation to the total length (i.e., the page number should appear 
sequentially as page n of N, where N is the total number of pages in the table). 
• 
The date output was generated should appear along with the program name as a 
footer on each page. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 49 of 53 
14.2.3. 
Display Titles 
• 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination. A decimal system (x.y and x.y.z) should be 
used to identify TLFs with related contents. The title is centered. The analysis set 
should be identified on the line immediately following the title. The title and table 
designation are single spaced. A solid line spanning the margins will separate the 
display titles from the column headers. There will be 1 blank line between the last 
title and the solid line. 
 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Set 
 
14.2.4. 
Column Headers 
• 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters. 
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values will be presented in a separate comparison column (if applicable). 
• 
For numeric variables, include “unit” in column or row heading when appropriate. 
• 
Analysis set sizes will be presented for each treatment group in the column heading 
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set. 
• 
The order of treatments in the tables and listings will be active treatment first, then 
active control, followed by a total column (if applicable). 
14.2.5. 
Body of the Data Display 
14.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 50 of 53 
14.2.5.2. Table Conventions 
• 
Units will be included where available 
• 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
• 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 
• 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects. 
• 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 
n 
 XX 
Mean 
XXX.X 
SD 
  X.XX 
Q1 
XXX.X 
Median 
XXX.X 
Q3 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
• 
P-values should be output in the format: “0.xxxx”, where xxxx is the value rounded 
to 4 decimal places. Any p-value less than 0.0001 will be presented as <0.0001. If 
the p-value is returned as >0.9999 then present as >0.9999 
• 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). If the rounded 
percentage is 0.0, display as '<0.1'. Unless otherwise noted, for all percentages, the 
number of subjects in the analysis set for the treatment group who have an 
observation will be the denominator. Percentages after zero counts should not be 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 51 of 53 
displayed and percentages equating to 100% should be presented as 100%, without 
any decimal places. 
• 
Tabular display of data for concomitant and rescue medications should be presented 
by treatment class with the highest occurrence in the total column in decreasing 
order. Tabular display of data for medical history and adverse event data should be 
presented by the SOC using descending order. Within the drug class and SOC, 
medical history (by preferred term), drugs (by ATC2 code), and adverse events (by 
preferred term) should be displayed in decreasing order in the total column. If 
incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics which cannot be estimated should be 
reported as “-”. 
• 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
• 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
• 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page. The overall summary statistics for the subheading should only be 
output on the first relevant page. 
14.2.5.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 
• 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
• 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
• 
Units will be included where available 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 52 of 53 
14.2.5.4. Figure Conventions 
• 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis. 
14.2.6. 
Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from the 
footnotes. 
• 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
• 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
• 
Subject specific footnotes should be avoided, where possible. 
• 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page. 
• 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas Listing source: 16.x.y.z’). 
 
15. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. INC Research SOP 03.010 
and 03.013 provide an overview of the development of such SAS programs. 
INC Research SOP 03.009 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the 
proper clinical trial output by checking for their logic, efficiency and commenting and 
by review of the produced output. 
 
 


Statistical Analysis Plan 
Theracos Sub, LLC 
Version 1.0 
THR-1442-C-423 
 
1007779 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02   
 INC Research © LLC                             Page 53 of 53 
16. 
INDEX OF TABLES 
17. 
INDEX OF FIGURES 
18. 
INDEX OF LISTINGS 
19. 
MOCK-UPS 
Attachment 1: Planned Table Shells 
Attachment 2: Planned Listing Shells  
Attachment 3: Planned Figure Shells 
20. 
APPENDICES