Clinical trial NCT02390050
Conditions: Diabetes Mellitus, Type 2
Sponsor: Theracos
Start date: 2015-05-12; Completion date: 2016-06-03
Enrollment: 292 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to investigate the effect of bexagliflozin in lowering hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM). Bexagliflozin is an orally administered drug for the treatment of T2DM and is classified as a Sodium Glucose co-Transporter 2 (SGLT2) Inhibitor. This study was to enroll both treatment naive and those subjects previously treated with one oral hypoglycemic agent (OHA). Approximately 320 subjects eligible for randomization was to receive bexagliflozin tablets, 5, 10, 20 mg or placebo, once daily for 12 weeks in an outpatient setting.

Detailed description:
The study was a phase 2b multicenter, double-blind, placebo-controlled parallel group study to assess the effect of once daily bexagliflozin tablets on HbA1c in either treatment-naïve T2DM subjects or in subjects who were treated with one oral anti-diabetic agent. Treatment naïve subjects were eligible if their HbA1c values were between 7% and 8.5% at the screening visit while subjects who were treated with one oral hypoglycemic agent (OHA) were eligible if their HbA1c value was between 6.5% and 8.5% at screening and underwent a 6 or 10 week washout period. In addition, all eligible subjects underwent a two week placebo run-in period and those who showed good compliance in taking study medication (i.e., missed no more than one dose during the run-in period) during this period and whose HbA1c values were between 7 and 8.5% at the end of the run-in period were eligible for randomization.

Arms: arm 1: Bexagliflozin tablets, 5 mg, once daily by mouth before breakfast arm 2: Bexagliflozin tablets, 10 mg, once daily by mouth before breakfast arm 3: Bexagliflozin tablets, 20 mg, once daily by mouth before breakfast arm 4: Bexagliflozin tablets, placebo, once daily by mouth before breakfast
Interventions: intervention 1: Bexagliflozin tablets intervention 2: Bexagliflozin tablets, placebo
Intervention descriptions: intervention 1: Bexagliflozin tablets are blue caplet-shaped, film-coated tablets that are intended for use in investigational studies in humans. intervention 2: Bexagliflozin tablets, placebo, are blue caplet-shaped, film-coated tablets that are intended for use in investigational studies in humans.

Protocol documents:
Prot_000.pdf: 
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Clinical Trial Protocol: THR-1442-C-449 
 
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Clinical Trial Protocol: THR-1442-C-449 
 
Study Title: 
A Phase 2b, Multi-center, Double-blind, Placebo-controlled, Dose 
Range Finding Study to Evaluate the Effect of Bexagliflozin Tablets on 
HbA1c in Subjects with Type 2 Diabetes Mellitus 
Study Number: 
THR-1442-C-449 
Study Phase: 
2b 
Product Name: 
Bexagliflozin tablets 
Indication: 
Type 2 Diabetes Mellitus 
Investigators: 
Multi-center study 
 
 
Sponsor: 
Theracos, Inc. 
Sponsor Contact: 
Albert Collinson, Ph.D. 
Theracos, Inc. 
225 Cedar Hill Street, Suite 200, Marlborough, MA 01752 
Phone: 508-688-4221 
 
Medical Monitor: Geoffrey Walford, M.D. 
Massachusetts General Hospital 
185 Cambridge Street, Boston, MA 02114 
Phone:  617-643-4986 
Fax:  617-643-3328 
E-mail:  gwalford@partners.org 
 
 
 
Date 
Original Protocol: 
29 September 2014 
Protocol Revision 
16 February 2015 
 
Confidentiality Statement 
The information contained in this protocol is confidential and provided only to the 
investigators, clinical study collaborators, investigational drug managers, study sites and 
institutional review boards participating in the study. The information may, therefore, not be, 
disclosed to any third party except for subjects when receiving their consent, or used for 
purposes other than this study without the written consent of Theracos, Inc.  


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................10 
1 
INTRODUCTION ...........................................................................................................12 
1.1 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus ...............................13 
1.1.1 
Summary of Non-clinical Data with Bexagliflozin .....................................13 
1.1.2 
Summary of Clinical Data with Bexagliflozin.............................................13 
2 
STUDY OBJECTIVES ....................................................................................................14 
2.1 
Primary Objective ..................................................................................................14 
2.2 
Secondary Objectives.............................................................................................14 
3 
INVESTIGATIONAL PLAN ..........................................................................................15 
3.1 
Overall Study Design and Plan ..............................................................................15 
3.2 
Research Methods and Procedures ........................................................................15 
3.2.1 
Washout and Run-in Period .........................................................................15 
3.2.2 
Treatment Period ..........................................................................................17 
3.2.3 
Glycemic Control Monitoring......................................................................17 
3.3 
Rationale for Study Design and Control Group .....................................................20 
3.4 
Study Duration and Dates ......................................................................................21 
4 
STUDY POPULATION SELECTION ...........................................................................22 
4.1 
Study Population ....................................................................................................22 
4.2 
Inclusion Criteria ...................................................................................................22 
4.3 
Exclusion Criteria ..................................................................................................22 
5 
STUDY TREATMENTS .................................................................................................24 
5.1 
Description of Treatments......................................................................................24 
5.1.1 
Investigational Product ................................................................................24 
5.2 
Treatments Administered .......................................................................................24 
5.3 
Selection and Timing of Dose for Each Patient .....................................................24 
5.4 
Method of Assigning Patients to Treatment Groups..............................................24 
5.5 
Blinding..................................................................................................................25 
5.6 
Concomitant Therapy.............................................................................................25 
5.7 
Restrictions ............................................................................................................26 
5.7.1 
Prior Therapy ...............................................................................................26 
5.7.2 
Fluid and Food Intake ..................................................................................26 
5.7.3 
Patient Activity Restrictions ........................................................................26 
5.8 
Treatment Compliance ...........................................................................................27 
5.9 
Packaging and Labeling .........................................................................................27 


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5.9.1 
Run-in Kit ....................................................................................................27 
5.9.2 
Investigational Product Kit ..........................................................................27 
5.10 
Storage and Accountability ....................................................................................27 
5.11 
Investigational Product Retention at Study Site ....................................................27 
6 
STUDY PROCEDURES .................................................................................................29 
6.1 
Informed Consent...................................................................................................29 
6.2 
Medical History .....................................................................................................29 
6.2.1 
General Demographics and Characteristics .................................................29 
6.2.2 
Diabetes History...........................................................................................29 
6.2.3 
Cardiovascular Disease History ...................................................................29 
6.2.4 
Medication History ......................................................................................29 
6.3 
Physical Examination.............................................................................................30 
6.4 
Vital Signs ..............................................................................................................30 
6.4.1 
Blood Pressure and Pulse Measurements ....................................................30 
6.4.2 
Temperature and Respiratory Rate ..............................................................31 
6.5 
Electrocardiography ...............................................................................................31 
6.6 
Diet and Exercise Counseling ................................................................................31 
6.7 
Clinical Laboratory Tests .......................................................................................31 
6.7.1 
Laboratory Parameters .................................................................................31 
6.7.2 
Sample Collection, Storage, and Shipping ..................................................33 
6.7.2.1 
Hematology, Blood Chemistry, Serum Lipids, and Glycemic 
Control Assessments ..........................................................................33 
6.7.3 
Urinalysis .....................................................................................................33 
6.7.4 
Population PK Sampling ..............................................................................34 
6.8 
Dispensing Investigational product........................................................................34 
6.9 
Efficacy Assessments.............................................................................................34 
6.9.1 
HbA1c Determination ..................................................................................34 
6.9.2 
Body Weight ................................................................................................35 
6.9.3 
Blood Pressure .............................................................................................35 
6.10 
Adverse Events Assessments .................................................................................35 
6.10.1 
Eliciting and Reporting Adverse Events ......................................................36 
6.10.2 
Immediately Reportable Adverse Events .....................................................37 
6.10.3 
Pregnancy .....................................................................................................37 
6.10.4 
Procedure for Breaking the Blind ................................................................38 
6.10.5 
Follow-up of Adverse Events ......................................................................38 
6.10.5.1 
Follow-up of Non-serious Adverse Events ........................................38 
6.10.5.2 
Follow-up of Post-Study Serious Adverse Events .............................39 
6.10.6 
Urinary Tract Infections (UTIs) ...................................................................39 


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6.10.7 
Genital Mycotic Infections (GMIs) .............................................................39 
6.10.8 
Hepatotoxicity ..............................................................................................40 
6.10.9 
Hypoglycemia ..............................................................................................40 
6.11 
Concomitant Medication Assessments ..................................................................42 
6.12 
Removal of Patients from the Trial or Discontinuation of Investigational 
Product Administration ..........................................................................................43 
6.13 
Appropriateness of Measurements .........................................................................43 
7 
STUDY ACTIVITIES .....................................................................................................44 
7.1 
Screening (Up to 15 weeks prior to randomization, visit S1) ................................44 
7.2 
Washout and Run-in Periods (Up to 12 weeks prior to randomization) ................44 
7.2.1 
Washout of OHA (Visits S2 and S3) ...........................................................44 
7.2.1.1 
Visit S2 (subjects taking one OHA)...................................................45 
7.2.1.2 
Visit S3 – Phone interview (subjects in washout) .............................45 
7.2.2 
Run-in Period: ..............................................................................................45 
7.2.2.1 
Visit S4 (Week -2) .............................................................................45 
7.2.2.2 
Visit S5 (Days -3 to -5) ......................................................................46 
7.3 
Treatment Period (week 1 to week 12) ..................................................................46 
7.3.1 
Visit V1 (Day 1 of week 1) ..........................................................................46 
7.3.2 
Visit V2 (week 2) .........................................................................................46 
7.3.3 
Visit V3 (week 6) .........................................................................................47 
7.3.4 
Visit V4 (week 12) .......................................................................................47 
7.4 
Exit Visit or Early Termination Visit .....................................................................48 
7.4.1 
Visit V5 (week 14 or two weeks after the last dose of investigational 
product if a subject early terminates) ...........................................................48 
7.5 
Early Termination Procedures ...............................................................................48 
8 
QUALITY CONTROL AND ASSURANCE .................................................................48 
9 
PLANNED STATISTICAL METHODS ........................................................................49 
9.1 
General Considerations ..........................................................................................49 
9.1.1 
Handling Dropouts, and Missing Data.........................................................49 
9.1.2 
Multiple Comparisons / Multiplicity ...........................................................50 
9.2 
Determination of Sample Size ...............................................................................50 
9.3 
Analysis Populations ..............................................................................................50 
9.3.1 
Full Analysis Set ..........................................................................................50 
9.3.2 
Safety Analysis Set ......................................................................................50 
9.3.3 
Per Protocol Analysis Set.............................................................................51 
9.4 
Demographics and Baseline Characteristics ..........................................................51 
9.5 
Analysis of Efficacy ...............................................................................................51 
9.6 
Analysis of Safety ..................................................................................................52 
9.6.1 
Adverse Events ............................................................................................52 


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9.6.2 
Adverse Events of Special Interest ..............................................................53 
9.6.3 
Clinical and Laboratory Events and Analyses .............................................53 
9.6.4 
Physical Examination...................................................................................54 
9.6.5 
Concomitant Medications ............................................................................54 
9.7 
Interim Analysis .....................................................................................................54 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................55 
10.1 
Investigators and Study Administrative Structure .................................................55 
10.2 
Institutional Review Board or Independent Ethics Committee Approval .............55 
10.3 
Ethical Conduct of the Study .................................................................................55 
10.4 
Subject Information and Consent...........................................................................56 
10.5 
Subject Confidentiality ..........................................................................................56 
10.6 
Study Monitoring ...................................................................................................56 
10.7 
Case Report Forms and Study Records .................................................................57 
10.8 
Data and Safety Monitoring Board ........................................................................57 
10.9 
Protocol Violations/Deviations ..............................................................................57 
10.10 Access to Source Documentation ..........................................................................57 
10.11 Retention of Data ...................................................................................................58 
10.12 Publication and Disclosure Policy .........................................................................58 
11 REFERENCE LIST .........................................................................................................59 
 
LIST OF IN-TEXT TABLES 
Table 1. 
List of Laboratory Tests ...............................................................................32 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Glycemic Control Requirements Prior to Randomization ...........................16 
Figure 2. 
Dose related glucosuria in healthy Japanese subjects ..................................21 
Figure 3. 
THR-1442-C-449 Study Design ..................................................................21 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................60 
Appendix 2 
Schedule of Laboratory Tests ............................................................62 
Appendix 3 
Estimating Glomerular Filtration Rate...............................................63 
Appendix 4 
Sponsor Signatures.............................................................................64 
Appendix 5 
Investigator’s Signature .....................................................................65 
 
 


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Clinical Trial Protocol: THR-1442-C-449 
 
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SYNOPSIS 
Sponsor: 
Theracos, Inc. 
Name of Finished Product: 
Bexagliflozin tablets  
Name of Active Ingredient: 
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)-benzyl)phenyl)-6-
(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol 
Code name: EGT0001442 
 
Study Title: 
A Phase 2b, Multi-center, Double-blind, Placebo-controlled, Dose Range Finding Study to 
Evaluate the Effect of Bexagliflozin Tablets on HbA1c in Subjects with Type 2 Diabetes 
Mellitus  
Study Number: 
THR-1442-C-449 
Study Phase: 2b 
Primary Objective:  
The primary objective of this study is to identify dose(s) for further clinical study through the 
comparison of HbA1c change from baseline in each active group that will receive 
bexagliflozin tablets, 5 mg, 10 mg, or 20 mg, to the placebo group over 12 weeks of 
treatment. 
Secondary Objectives: 
• To assess the change in HbA1c over time 
• To assess the efficacy of bexagliflozin tablets in lowering FPG as a function of time 
• To assess the efficacy of bexagliflozin based on the proportion of subjects who reach the 
American Diabetes Association (ADA) and the Japan Diabetes Society target HbA1c of 
<7% 
• To assess the effect of bexagliflozin on systolic and diastolic blood pressure over time 
• To assess the effect of bexagliflozin on body weight over time 
• To assess the safety of bexagliflozin in subjects with T2DM 
 
Other endpoint: 
Population pharmacokinetic evaluation of bexagliflozin plasma concentration 
 
Study Design: 
THR-1442-C-449 is a phase 2b multicenter, double-blind, placebo-controlled parallel group 
study to assess the effect of once daily bexagliflozin tablets on HbA1c in either treatment-
naïve type 2 diabetic subjects or in subjects who have been treated with one oral anti-diabetic 


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Clinical Trial Protocol: THR-1442-C-449 
 
16 February 2015 
 
 
 
 
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agent.  To be eligible, a prospective subject of either gender must have T2DM and an HbA1c 
value between 7% and 8.5% at the screening visit if treatment naïve or an HbA1c value 
between 6.5% and 8.5% if currently treated with one oral hypoglycemic agent and willing to 
undergo a 6 or 10 week washout.   
All eligible subjects who are treatment naïve or who have completed the washout will start a 
2 week placebo run-in period.  Subjects who are deemed compliant in taking the run-in 
medication (i.e., miss no more than one dose during the run-in period) and have HbA1c 
between 7 and 8.5% at the end of the run-in period will be eligible for randomization and will 
receive investigational product. 
Approximately 320 subjects divided equally into 4 groups will be randomly assigned to take 
oral bexagliflozin tablets, 5 mg, 10 mg, 20 mg, or placebo, once daily for 12 weeks in an out-
patient setting.  Subjects with hyperglycemia based on fasting blood glucose levels may 
receive approved anti-diabetic medication. 
Subjects will visit their study sites at weeks 2, 6, and 12 for safety and efficacy evaluation, 
with a follow-up visit at week 14. 
Measurement of bexagliflozin plasma concentration over time (sparsely sampled) will also 
be conducted at 20 centers and will include approximately 240 study subjects as part of a 
bexagliflozin population PK study. 
 
Study Population:  
Approximately 320 diabetic subjects will be randomized.   
Prospective subjects must be: 
1. Men or women ≥ 20 years of age at screening. Women of childbearing potential must test 
negative by urine pregnancy test and agree to abstain from coitus or use contraception 
during the entire study period to avoid any possible pregnancy.  Females who are 
surgically sterile (by reason of hysterectomy or oophorectomy) or postmenopausal (most 
recent menses more than 12 months prior to screening) are eligible if they test negative 
by urine pregnancy test.  
2. Treatment naïve (i.e., have never received prescription anti-diabetic medications or have 
received no more than 14 days of prescription medications for diabetes in the 12 weeks 
prior to enrollment) or currently taking one OHA in combination with diet and exercise 
3. Diagnosed with T2DM with HbA1c levels at screening between 7.0% and 8.5% 
(inclusive) if treatment naïve or with HbA1c levels between 6.5 and 8.5% (inclusive) if 
on one oral anti-diabetic medication 
4. Currently having a body mass index (BMI) ≤ 40 kg/m2 
5. Taking stable doses of medication for hypertension or hyperlipidemia as determined by 
adherence to a regimen that has not changed for at least 30 days prior to screening (if 


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applicable) 
6. Able to comprehend the study participation requirements and willing to provide written 
informed consent in accordance with institutional and regulatory guidelines 
7. Able to maintain adequate glycemic control at the run-in visit (for subjects who complete 
the washout) 
8. Having an HbA1c between 7.0 and 8.5% (inclusive) prior to randomization (day -3 to -5):  
9. Capable of adhering to the investigational product administration requirements as 
evidenced by omission of no more than one dose of run-in medication 
 
Test Product, Dose, and Mode of Administration:  
Bexagliflozin tablets, 5, 10, 20 mg or placebo, once daily by mouth before breakfast 
Duration of Treatment:  
12 weeks 
Efficacy Assessments: 
Primary efficacy assessment: 
• Change in HbA1c over 12 weeks of treatment 
 
Secondary efficacy assessments: 
• Change in HbA1c over time  
• Proportion of subjects with HbA1c <7%  
• Change in body weight over time 
• Change in FPG over time 
• Change in systolic and diastolic blood pressure over time 
 
Samples for population PK analysis will be collected and the required plasma concentrations 
determined.  The PK parameters will be assessed separately as part of the population PK 
analysis. 
 
Safety Assessments:  
Safety will be assessed based on an analysis of the adverse events record; of laboratory data, 
including hematology, serum chemistry, urinalysis, urinary electrolytes and creatinine; of 
electrocardiograms (ECGs), vital signs and physical examinations; and of concomitant 
medication use. 
Statistical Methods:  
Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], Q1, median, Q3, minimum, and maximum) for continuous variables, and 
frequency and percentage for categorical and ordinal variables.  If there are missing values, 
the number missing will be presented, but without a percentage.  All data collected will be 
included in by-subject data listings. 
For the primary endpoint of HbA1c change from baseline over 12 weeks of treatment, a 


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mixed model repeated measures (MMRM) analysis of covariance model (ANCOVA) with 
baseline HbA1c as a covariate will be fitted on the available data, incorporating all visits at 
which HbA1c was measured from each subject including the scheduled visits at weeks 2, 6, 
and 12 as well as the unscheduled visits for measurement of HbA1c. Treatment, study center, 
and stratification factor for randomization (treatment naïve versus taking one OHA at 
baseline) will be applied as fixed effects, as will study week and study week-by-treatment 
interaction. From this model, an estimate of the treatment difference at week 12 will be 
generated, as will an assessment of whether this estimate is significantly different when 
comparing placebo with each dose of bexagliflozin at a two-sided 0.05 level of significance. 
An unstructured within-patient covariance structure will be assumed. HbA1c values obtained 
after the start of rescue medication will be excluded from this primary analysis.  
The MMRM model is one approach to obtain treatment effect estimates in the presence of 
missing data. As sensitivity analyses for missing data, the following will be performed: 
1. Missing HbA1c data (for weeks 2, 6, or 12) will be imputed via multiple imputation, 
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 be considered missing. 
2. Missing HbA1c data will be imputed via LOCF, following which the MMRM will be 
repeated; HbA1c values collected after the start of rescue medication will be considered 
missing. 
3. HbA1c values collected after the start of rescue medication will NOT be considered 
missing, and the MMRM analyses will be re-performed. 
 
The effect of bexagliflozin on fasting blood glucose, blood pressure, body weight, change in 
HbA1c over time, and proportion of subjects who reach HbA1c < 7% will be evaluated as 
secondary endpoints. These endpoints are considered exploratory and will not be adjusted for 
multiplicity.  
Safety and tolerability of bexagliflozin in subjects with T2DM will also be assessed 
descriptively.  Data summaries will be produced for AEs, physical exam results, vital signs, 
ECG results, and clinical lab results including serum chemistry, hematology, serum lipids, 
glycemic control parameters and urinalysis. 
Date of Original Approved Protocol: 29 September 2014 
Date of Revised Protocol: 16 February 2015 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
American Diabetic Association 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomic therapeutic chemical 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CK 
Creatinine kinase 
CRF 
Case report form 
CRO 
Contract research organization 
CV 
Cardiovascular 
DPP4 
Dipeptidyl peptidase 4 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
FAS 
Full analysis set 
FPG 
Fasting plasma glucose 
-GTP 
Gamma-glutamyl transferase  
GCP 
Good Clinical Practice 
GLP-1 
Glucagon-like peptide-1 
h 
Hour 
HbA1c 
Glycated hemoglobin 
HBsAg 
Hepatitis B surface antigen  
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
HDPE 
High density polyethylene 
HF 
Heart failure 
Hgb 
Hemoglobin 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICCR 
In country caretaker representative 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  


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IRAE 
Immediately reportable adverse event 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive web response system 
LDH 
Lactic dehydrogenase 
MACE 
Major adverse cardiovascular event 
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 
NYHA 
New York Heart Association 
OHA 
Oral hypoglycemic agent 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
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 
T2DM 
Type 2 diabetes mellitus 
TEAE 
Treatment emergent adverse event 
TIA 
Transient ischemic attack 
UACR 
Urine albumin-to-creatinine ratio 
UGE 
Urinary glucose excretion 
ULN 
Upper limit of normal 
UPT 
Urine pregnancy test 
UTI 
Urinary tract infection 
WOCBP 
Woman of child bearing potential 
WHO-DD 
World Health Organization Drug Dictionary 
 


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1 
INTRODUCTION 
Type 2 diabetes mellitus (T2DM) is one of the leading causes of morbidity and mortality 
worldwide, affecting an estimated 387 million people in 2014 and reaching epidemic 
proportions in nearly all countries in the world.  Approximately 179 million of those affected 
are estimated to be unaware of their condition and over 80% reside in low- and middle-
income countries (International Diabetes Foundation, 2014).  T2DM accounts for at least 
90% of all diabetes cases. Despite the availability of several classes of therapeutics, the 
number of people with T2DM is projected to increase by 55% to over 590 million adults by 
2035.  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 of insulin resistance and is strongly linked to increased body fat mass in 
the majority of cases (Schwartz et al., 2012).  Weight loss has been shown to improve 
glycemic control and to reduce the severity of diabetes-associated comorbidities, supporting 
the view that anti-diabetic agents that promote weight loss may be particularly beneficial for 
the treatment of the disease (Look et al., 2013; Scheen and Van Gaal, 2014).   
Asian populations may be particularly at risk for the adverse consequences of increased body 
mass. Metabolic syndrome, a presentation of diabetes with comorbid hypertension and 
dyslipidemia, increases more rapidly with increasing weight among Asians than among non-
Asians and it has been proposed that the BMI ranges that define the overweight and obese 
categories should be lower in Asian populations than in non-Asian populations (Palaniappan 
et al., 2011).  
Several classes of agents are available for treating T2DM, including insulin and its 
secretagogues, PPAR agonists, biguanides, alpha glucosidase inhibitors, glucagon-like 
peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP4) inhibitors.  However, 
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 will ideally reduce hyperglycemia and avoid 
common side effects of currently available agents, such as weight gain, gastrointestinal 
disturbances, and hypoglycemia. 
The renal Na+/glucose transport protein SGLT2 actively transports extracellular glucose into 
cells using the driving energy of the transmembrane electrochemical potential for sodium 
ions.  Individuals with disruptions in SLC5A2, the gene encoding SGLT2, exhibit prominent 
glucosuria in the absence of significant co-morbidities (Santer et al., 2003; van den Heuvel et 
al., 2002).  The excretion of glucose in the urine of diabetic subjects in amounts comparable 
to or greater than that seen in individuals harboring loss of functions mutations in SLC5A2 
has the potential to improve both fasting and postprandial hyperglycemia without increasing 
insulin secretion, causing weight gain, or inducing hypoglycemia. 


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1.1 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus 
Bexagliflozin (previously identified as EGT0001442), is a potent and highly specific 
inhibitor of the SGLT2 with an in vitro IC50 of 2 nM or 0.9 ng/mL and a 2435-fold selectivity 
for human SGLT2 compared with SGLT1.  Bexagliflozin elicits a prominent and predictable 
glucosuria in laboratory animals and human subjects.   
1.1.1 
Summary of Non-clinical Data with Bexagliflozin 
The potential adverse effects of bexagliflozin have been evaluated in studies of non-clinical 
safety pharmacology, acute and chronic general toxicology, genotoxicity, acute and chronic 
reproductive toxicity and two-year carcinogenicity. Repeat dose toxicity studies have found 
exacerbation of chronic progressive nephropathy and gastric irritation, including sporadic 
ulceration, at the lowest observable dose level in male rats, as well as signs of reversible 
cardiac inflammation and abdominal distension at a dose level of 200 mg/kg in monkeys.  
Details of the adverse findings are provided in the Investigator’s Brochure. 
1.1.2 
Summary of Clinical Data with Bexagliflozin 
Theracos has completed eight phase 1 studies to evaluate safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD) and drug metabolism in healthy subjects, 
subjects with T2DM, and diabetic subjects with renal impairment. Details of the 
pharmacology, efficacy, and safety assessments are described in the Investigator’s Brochure 
and summarized in the following sections. 
Bexagliflozin exhibits high permeability and is a weak Pgp substrate and inhibitor.  It 
produces dose-proportional exposures in humans and animals.  Metabolism in humans is 
most similar to that in monkeys, and the principal pathway for biotransformation in humans 
is glucuronide formation.  The majority of bexagliflozin and related metabolites are excreted 
within 48 to 72 h in humans, rats and monkeys, and there is no evidence of accumulation.  
Bexagliflozin is neither a significant inducer nor inhibitor of cytochrome P450 isozymes 
relevant for drug-drug interactions. 
In the course of bexagliflozin therapeutic development, several formulations have been 
evaluated.  Immediate release capsule formulations have been used in the initial clinical 
pharmacology and phase 2 studies.  A program to develop an extended release tablet 
formulation that would reduce daily variation in the concentration of the compound was 
carried out and resulted in the identification of a mucoadhesive formulation with the desired 
properties. The drug products exhibit a greater than 75% release of drug substance by 8 h in 
simulated gastric fluid in vitro. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to identify the optimal dose(s) through the comparison 
of mean HbA1c change in subjects who receive bexagliflozin tablets, 5 mg, 10 mg, 20 mg, or 
placebo, after 12 weeks of treatment. 
2.2 
Secondary Objectives  
The secondary objectives of this study are the following: 
• To assess the change in HbA1c over time 
• To assess the efficacy of bexagliflozin tablets in lowering fasting plasma glucose (FPG) 
over time 
• To assess the efficacy of bexagliflozin based on the proportion of subjects who reach the 
American Diabetes Association (ADA) and the Japan Diabetes Society target HbA1c of 
<7% 
• To assess the effect of bexagliflozin on systolic and diastolic blood pressure over time 
• To assess the effect of bexagliflozin on body weight over time 
• To assess the safety of bexagliflozin in subjects with T2DM 
 
Other exploratory objective includes: 
• Population pharmacokinetic evaluation of bexagliflozin plasma concentration 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
THR-1442-C-449 is a phase 2b multicenter, double-blind, placebo-controlled, dose range 
finding study to assess the efficacy and safety of once daily bexagliflozin in either treatment-
naïve type 2 diabetic subjects or subjects previously treated with one oral hypoglycemic 
agent (OHA).  The primary efficacy endpoint will be placebo-adjusted reduction in HbA1c, 
measured after 12 weeks of treatment.  Treatment naïve subjects are those who have never 
received prescription anti-diabetic medications or who have received no more than 14 days 
of prescription medications for diabetes in the 12 weeks prior to enrollment.  The study will 
enroll men and women with T2DM and with HbA1c between 7% and 8.5% (inclusive) at the 
screening visit (for subjects who are treatment naïve) or with T2DM and with HbA1c 
between 6.5% and 8.5% (inclusive) at screening visit (for subjects who have received one 
OHA and who are willing and able to undergo a washout period.)   
Approximately 400 subjects who meet all the inclusion criteria, none of the exclusion 
criteria, and who consent to participate in the study are eligible to be enrolled to complete a 6 
to 10 week washout if needed and a 2 week placebo run-in period prior to being randomized.  
Subjects who can adhere to the run-in medication dosing schedule (i.e., miss no more than 
one dosage in 2 weeks) and who have HbA1c between 7 and 8.5% at baseline (visit S5) will 
be eligible for randomization and receive investigational product. A 20% screen fail rate is 
expected by the end of run-in, leading to approximately 320 subjects eligible for 
randomization to receive oral bexagliflozin tablets, 5, 10, 20 mg or placebo once daily for 12 
weeks in an outpatient setting.  Subjects who experience hyperglycemia during the study may 
receive approved anti-diabetic medication. Subjects will visit their study site at weeks 2, 6, 
and 12 for safety and efficacy evaluation, with a follow up visit at week 14. 
Measurement of bexagliflozin plasma concentration over time (sparsely sampled) will be 
conducted at 20 centers and will include approximately 240 subjects who consent to 
participate the PK study. Three samples from each subject will be drawn at weeks 2, 6, or 12. 
3.2 
Research Methods and Procedures 
3.2.1 
Washout and Run-in Period 
Eligible subjects who are not treatment naïve will discontinue their current OHA and enter a 
6- or 10-week washout.  Those who are taking any OHA except a thiazolidinedione will 
discontinue the medication for 6 weeks.  Subjects who are taking a thiazolidinedione will 
discontinue the medication for 10 weeks.  At the start of the washout, each subject will be 
provided with diet and exercise counseling, a glucometer, a glycemic control diary in which 
to record daily fasting self-monitored blood glucose (SMBG) measurements and instructions 
regarding the appropriate circumstances under which a call to the clinic to register an 
observation of hyperglycemia should be made (see Glycemic Control below). Two weeks 
after the start of the washout period each subject will participate in a phone interview with 
study staff for SMBG data review and general safety evaluation.  Subjects who remain 


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eligible at the end of the 6 or 10 week washout period will proceed to a 2-week placebo run-
in period. Subjects will be ineligible if they exhibit fasting blood glucose values ≥ 250 mg/dL 
on two consecutive days during the wash-out period.  
Eligible subjects who are treatment naïve will not require a washout period and will proceed 
to the run-in period. These subjects will be provided with diet and exercise counseling, a 
glucometer, and a glycemic control diary in which to record daily fasting SMBG 
measurements at the start of the 2-week placebo run-in period. 
Treatment naïve subjects and subjects on background OHA who complete the washout will 
enter a 2-week single-blind placebo run-in period. Each subject will be provided with 
placebo run-in drug, dosing instructions, and instructions regarding the appropriate 
circumstances under which a call to the clinic to register an observation of hyperglycemia 
should be made (see Glycemic Control below). During the run-in, a placebo tablet should be 
taken daily in the morning prior to eating or drinking; the medication should be taken with 
water. 
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, 2) omit more 
than one of the daily doses of placebo, 3) are deemed inappropriate for the study by the 
investigator, or 4) on day -3 to day -5 prior to randomization, have HbA1c value < 7.0% or > 
8.5%.  The glycemic control requirement based on HbA1c values is outlined in Figure 1. 
 
Figure 1. 
Glycemic Control Requirements Prior to Randomization 
 
Approximately 320 eligible subjects will be randomized in equal ratio. Randomization will 
be stratified by the background anti-diabetes treatment status (treatment naïve or taking one 
OHA).  
An assessment of bexagliflozin pharmacokinetics will also be conducted at 20 centers to 
include approximately 240 subjects. Samples will be taken during weeks 2, 6, or 12. 


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3.2.2 
Treatment Period 
The 12- week treatment period will start at randomization.  At the start of the treatment 
period each subject will be provided with the investigational products, dosing instructions, 
and a glycemic control diary in which to record SMBG measurements.  Information related 
to the occurrence of hyperglycemic or hypoglycemic events will be recorded.  The 
investigational products will be orally administered in the morning prior to eating or 
drinking; the medication should be taken with water.  Rescue medication for hyperglycemia 
will be allowed when deemed medically necessary by the investigator. 
Each subject will be instructed to return to the clinic at weeks 2, 6, and 12 for safety and 
efficacy evaluations including review of adverse events and concomitant medications, vital 
signs, ECG, physical examination, and blood and urine specimen collections.  On the day of 
the clinic visit a minimum fasting period of 10 hours (h) must be confirmed prior to blood 
draw.  
Subjects will return to the clinic for a follow-up exit visit at week 14 or 2 weeks after the last 
dose of investigational product. Following the exit visit, subjects will be advised to see their 
primary physician to undergo treatment to control their diabetes.  The duration of 
participation for each subject is up to 29 weeks based on the treatment status of each 
potential subject. 
3.2.3 
Glycemic Control Monitoring 
WASHOUT AND PLACEBO RUN-IN PERIODS 
During the washout and placebo run-in period subjects will be instructed to determine SMBG 
daily after fasting overnight for a minimum of 10 h.  If the fasting blood glucose is ≥ 250 
mg/dL (13.9 mmol/L) the subject should contact the clinic within 24 h 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.  The participant will be excluded 
from further participation if fasting blood glucose values are ≥250 mg/dL prior to 
randomization on 2 or more consecutive days. Subjects with SMBG clinical signs or 
symptoms of hyperglycemia during the washout or run-in periods, including weight loss, 
blurred vision, increased thirst, increased urination, or fatigue should be excluded. 
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 1 to week 6 or ≥ 240 mg/dL (13.3 mmol/L) from week 6 to week 12. 
Fasting blood glucose values collected via SMBG will be evaluated at study visits by the 
investigator. In addition, hyperglycemia will be monitored by FPG measurement at each 
study visit. 


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If hyperglycemia is identified through SMBG or FPG measurements, the investigator will 
determine whether the subject had fasted for a minimum of 10 h prior to the morning blood 
draw to ensure that the FPG value is truly a fasting sample.  If proper fasting had not 
occurred, the subject will be asked to return for a repeat blood test within a week.  
During the 12 weeks of the treatment period, hyperglycemia should be managed first with 
diet and exercise counseling and should be managed with changes in the medical therapy 
only if the investigator feels it is necessary for the well-being of the subject (see below, 
Prescription of Rescue Medication). 
If a concomitant medication for hyperglycemia is to be prescribed, a 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 was taking investigational product as the 
sole therapy. 
PRESCRIPTION OF RESCUE MEDICATION 
Rescue medication for hyperglycemia should be prescribed by the investigator at any time it 
is deemed necessary for the well-being of the subject.  During the 12 week treatment period, 
a review of diet and exercise counseling is suggested prior to prescription of rescue 
medication in the absence of specific medical indications for rescue medication.  Rescue 
medication is suggested if, after a review of diet and exercise counselling:  
1. more than 3 consecutive, daily, fasting SMBG measures are ≥ 270 mg/dL (15 mmol/L) 
from week 1 to week 6, or ≥ 240 mg/dL (13.3 mmol/L) from week 6 to week 12 
2. fasting SMBG values are ≥ 250 mg/dL (13.9 mmol/L) and associated with clinical signs 
or symptoms of hyperglycemia (e.g. weight loss, blurred vision, increased thirst, or 
increased urination, or fatigue), and the signs or symptoms are severe 
 
The investigator may provide rescue treatment with any approved medication for diabetes 
that is not otherwise contraindicated, with the exception of an SGLT2 inhibitor, as study 
subjects may already be taking a drug in that class as a consequence of being randomized to 
receive bexagliflozin.  
Subjects who receive rescue medication due to poor glycemic control will continue to receive 
investigational product 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. 
If hypoglycemia occurs in any subject prescribed rescue medication for hyperglycemia 
during the study, the total daily dose of the rescue medication should be reduced 50% or 
more at the discretion of the investigator. 


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OTHER SAFETY MONITORING ACTIVITIES 
The safety monitoring activities will include assessment of vital signs, physical 
examinations, urinalysis, blood chemistry, hematology, adverse events, and concomitant 
medication use.  The occurrence of blood, liver, or skin disorders will be monitored through 
laboratory testing and evaluation of adverse event documentation.   
Adverse events of special interest as defined in the statistical analysis plan will include any 
clinical signs and symptoms that indicate adverse experience in the categories listed below.  
All such events must be appropriately documented within source documentation. 
• Genital mycotic infections 
• Urinary tract infections including urosepsis and pyelonephritis 
• Diuretic effects including hypovolemia 
• Hypotension episodes 
• Hepatotoxicity 
• MACE 
• Hypoglycemia 
• Falls and fractures 
• Malignancies 
• Hypersensitivity reactions 
• Acid-base disorders 
• Renal failure events 
 
DATA AND SAFETY MONITORING BOARD 
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 are defined in its charter. 
MAJOR ADVERSE CARDIOVASCULAR EVENT 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. 


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3.3 
Rationale for Study Design and Control Group 
THR-1442-C-449 is designed to evaluate the efficacy and safety of bexagliflozin tablets at 5 
mg, 10 mg, and 20 mg strengths in the treatment of subjects with T2DM.  A randomized, 
double-blind study reduces bias and confounding by unmeasured factors and is the most 
suitable design to evaluate a new agent as a monotherapy in diabetic subjects.  Under the 
close monitoring detailed in this study, placebo is the appropriate control treatment in the 
subject population studied during the 12-week treatment period. In order to exclude the 
possibility that a subject’s HbA1c level at 12 weeks is determined by medications taken prior 
to the study, up to an 8 or 12 week combined washout and run-in period will be implemented 
prior to randomization.  All subjects will receive a placebo in the last 2 weeks prior to 
randomization to allow compliance with the dosing regimen to be monitored.  Subjects with 
FPG levels ≥ 250 mg/dL at randomization will be excluded as a safety measure.  Diet and 
exercise counseling will be provided to all participating subjects to reduce risks of worsening 
diabetic conditions or prolonged hyperglycemia. 
Results from published data in individuals with genetic mutations in SLC5A2, the gene 
encoding SGLT2, and in subjects that have been treated with other SGLT2 inhibitors, and 
from previous clinical studies in healthy or diabetic subjects treated with bexagliflozin, 
indicate that the risk of induced hypoglycemia as a consequence of the loss of SGLT2 
activity should be minimal. 
Reduction in HbA1c directly reflects improvement in glycemic control and is a well 
validated surrogate for the risk of long-term microvascular complications of T2DM. HbA1c 
reflects mean glycemic control over 2 to 3 months, and therefore the primary endpoint of 
HbA1c measurement at 12 weeks will reflect the impact of bexagliflozin compared to the 
placebo. Previous non-clinical and clinical study data have suggested that the glucosuria and 
changes in HbA1c are likely to be less correlated when the baseline HbA1c is high but more 
correlated when the HbA1c is modestly elevated. To better demonstrate the dose relatedness 
of the treatment effect, a baseline HbA1c value of 7% to 8.5% is included in this protocol to 
allow clinical dose selection. Near maximal glucosuria should be safe for the treatment of 
minimal diabetes since hypoglycemia has never occurred in trials with healthy subjects.  
A previously completed clinical study in Japanese subjects demonstrated that a single dose of 
bexagliflozin of 3, 10, 30, or 90 mg strength resulted in a dose-dependent glucosuria from 3 
mg to 30 mg with no incremental effect from 30 mg to 90 mg (Figure 2).  This protocol is 
designed to assess the effect of bexagliflozin on HbA1c at 12 weeks.  Strengths of 5, 10, and 
20 mg will be tested.   


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Figure 2. 
Dose related glucosuria in healthy Japanese subjects 
 
3.4 
Study Duration and Dates 
Diabetic subjects will be screened within 3 weeks of enrollment.  Eligible subjects who 
provide written consent will start a 2 to 12 week washout and run-in period prior to 
randomization to receive investigational product. Subjects will receive 12 weeks of treatment 
and be followed for 2 weeks after the last dose. The study duration from screening to follow-
up will be 16 weeks and up to 29 weeks overall (Figure 3). For details of the schedule and 
nature of the investigations, see the Schedule of Events in Appendix 1. 
 
Figure 3. 
THR-1442-C-449 Study Design 
 
0
20
40
60
80
100
3
10
30
90
UGE g/24 h 
Dose in mg 
UGE, Japanese Healthy Subjects 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study population will include approximately 320 subjects diagnosed with T2DM who are 
inadequately controlled by diet and exercise or by treatment with a single oral anti-diabetic 
agent and who have an HbA1c level between 7% and 8.5% at the time of randomization. 
Clinical sites in the US and in Japan are anticipated to recruit subjects.  Clinical sites in other 
countries may also participate in the trial. 
4.2 
Inclusion Criteria 
Prospective subjects must be: 
1. Men or women ≥ 20 years of age at screening. Women of childbearing potential must test 
negative by urine pregnancy test and agree to abstain from coitus or use contraception 
during the entire study period to avoid any possible pregnancy.  Females who are 
surgically sterile (by reason of hysterectomy or oophorectomy) or postmenopausal (most 
recent menses more than 12 months prior to screening) are eligible if they test negative 
by urine pregnancy test.  
2. Treatment naïve (i.e., have never received prescription anti-diabetic medications or have 
received no more than 14 days of prescription medications for diabetes in the 12 weeks 
prior to enrollment) or currently taking one OHA in combination with diet and exercise 
3. Diagnosed with T2DM with HbA1c levels at screening between 7.0% and 8.5% 
(inclusive) if treatment naïve or with HbA1c levels between 6.5 and 8.5% (inclusive) if 
on one oral anti-diabetic medication 
4. Currently having a body mass index (BMI) ≤ 40 kg/m2 
5. Taking stable doses of medication for hypertension or hyperlipidemia as determined by 
adherence to a regimen that has not changed for at least 30 days prior to screening (if 
applicable) 
6. Able to comprehend the study participation requirements and willing to provide written 
informed consent in accordance with institutional and regulatory guidelines 
7. Able to maintain adequate glycemic control at the run-in visit (for subjects who complete 
the washout) 
8. Having an HbA1c between 7.0 and 8.5% (inclusive) prior to randomization (day -3 to -5) 
9. Capable of adhering to the investigational product administration requirements as 
evidenced by omission of no more than one dose of run-in medication 
 
4.3 
Exclusion Criteria 
Subjects who exhibit any of the following characteristics will be excluded from the study: 


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1. A diagnosis of type 1 diabetes mellitus or maturity–onset diabetes of the young (MODY) 
2. Current use of parenteral therapy for treatment of diabetes (insulin or glucagon-like 
peptide-1 (GLP-1) receptor agonist therapy) 
3. Pregnancy or current breastfeeding status 
4. Hemoglobinopathy or carrier status for hemoglobin alleles that affect HbA1c 
measurement 
5. Genitourinary tract infection (e.g. urinary tract infection, vaginitis, balanitis) within 6 
weeks of screening or history of ≥3 genitourinary infections requiring treatment within 6 
months of screening 
6. Estimated glomerular filtration rate (eGFR), as calculated by the modification of diet in 
renal disease study equation (MDRD), < 60 mL/min/1.73 m2 at screening (Appendix 2) 
7. Uncontrolled hypertension (average of two sitting measurements of systolic blood 
pressure >160 mmHg or diastolic blood pressure > 95 mmHg) at screening 
8. A positive result on hepatitis B surface antigen (HBsAg), hepatitis C (HCV), or positive 
result from screen for drugs of abuse 
9. History of human immunodeficiency virus (HIV) infection 
10. Life expectancy < 2 years 
11. History of New York Heart Association (NYHA) Class 4 heart failure within 3 months of 
screening 
12. History of MI, unstable angina, stroke, or hospitalization for heart failure within 3 months 
of screening 
13. History of treatment with an investigational drug within 30 days or within 7 half lives of 
the investigational drug, whichever is longer 
14. Previous treatment with bexagliflozin or EGT0001474 
15. Currently or within 6 months of taking any SGLT2 inhibitors from screening 
16. Currently participating in another interventional trial 
17. Not able to comply with the study scheduled visits 
18. Affected by any condition, disease, disorder, or clinically relevant abnormality that, in the 
opinion of the investigator, would jeopardize the subject’s appropriate participation in 
this study or obscure the effects of treatment 
19. ALT or AST ≥ 2.5 x upper limit of normal (ULN) or total bilirubin ≥ 1.5 x ULN with the 
exception of isolated Gilbert’s syndrome at screening 
20. Exhibiting fasting plasma glucose ≥ 250 mg/dL (13.9 mmol/L) on two or more 
consecutive days prior to randomization or exhibiting severe clinical signs or symptoms 
of hyperglycemia during the washout or run-in periods, including weight loss, blurred 
vision, increased thirst, or increased urination, or fatigue 
21. FPG ≥ 250 mg/dL at randomization 
22. Prior renal transplantation or evidence of nephrotic syndrome, defined as a urine 
albumin-to-creatinine ratio (UACR) > 2000 mg/g at screening 
 


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5 
STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
Investigational Product 
Bexagliflozin tablets, 5 mg, 10 mg, 20 mg, and 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 
drug products exhibit a greater than 75% release of drug substance by 8 h in simulated gastric 
fluid in vitro. 
The following investigational drugs will be used for oral administration: 
• Bexagliflozin tablets, 5 mg: tablets containing 5 mg of bexagliflozin 
• Bexagliflozin tablets, 10 mg: tablets containing 10 mg of bexagliflozin 
• Bexagliflozin tablets, 20 mg: tablets containing 20 mg of bexagliflozin 
• Bexagliflozin tablets, placebo: tablets containing no bexagliflozin 
 
5.2 
Treatments Administered 
Bexagliflozin tablets should be taken in the morning prior to eating or drinking. The 
medication should be taken with water. 
5.3 
Selection and Timing of Dose for Each Patient 
Prior clinical experience has shown bexagliflozin tablets in strengths up to 90 mg per tablet 
are safe and well tolerated.  The highest planned dosage of 20 mg per day is not expected to 
produce serious drug-related adverse events.  Doses of 10 mg and 30 mg bexagliflozin in the 
tablet formulation have produced near saturation of UGE and statistically significant FPG 
lowering activity in prior studies.  The dose strengths of 5, 10, and 20 mg have been selected 
to evaluate safety and efficacy of bexagliflozin. 
Dosing with bexagliflozin tablets, 5, 10, 20 mg or placebo, will be based on randomized 
assignment.  All study subjects will be instructed to self-administer one tablet with water 
every morning prior to eating or drinking.  There will be no change of dose during the 12-
week treatment period. 
5.4 
Method of Assigning Patients to Treatment Groups 
Eligible subjects who complete the run-in period and meet all study inclusion/exclusion 
requirements will be randomized in a 1:1:1:1 ratio to receive investigational product 
according to a computer-generated randomization schedule.  Subjects will be assigned to 
treatment groups in sequential order as they qualify for the study, using a centrally located 
and managed IWRS. Randomization will be stratified according to background anti-diabetic 
treatment status (treatment naïve or taking one OHA). 


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The study will be conducted at multiple investigative sites and will likely involve variable 
numbers of subjects at each site.  Enrollment will be on a competitive basis but each site will 
be capped at 32 subjects.  Activation of investigational sites will be centrally controlled by 
IWRS.  Subject randomization will be deactivated for all sites when the planned number of 
subjects is met.  However, if a potential subject is in the washout period and wishes to 
participate in the study, the subject will be allowed to continue and, if eligible, to be 
randomized. 
5.5 
Blinding 
This is a double-blind placebo-controlled study.  The sponsor, investigators, study 
coordinators, pharmacists, study subjects, and the cardiovascular adjudication committee 
members will be blinded to the study medication.  Upon randomization, each subject will 
receive a subject randomization number and a drug kit assigned to the subject.  To maintain 
blinding of the individual treatment assignment, the results of urinary glucose testing will not 
be made available to any study personnel or subjects.  
If knowledge of the treatment is needed to manage the subject’s condition, the investigator 
will contact the IWRS to obtain the treatment assignment.  If unblinding occurs for any 
reason, the time and reason for breaking the blind will be recorded on the case report form 
(CRF) and the sponsor must be notified within 24 h.  
A designated statistician who is not involved with the study operation will hold the treatment 
codes.  The unblinded treatment information can be provided to the DSMB to facilitate the 
evaluation of any clinically important increase in the rate of a serious suspected adverse 
reaction or to the designated safety contact when the treatment information is required to 
determine if an expedited safety report must be submitted to regulatory agencies.   
The treatment assignment will continue to be withheld from the cardiovascular adjudication 
committee members until all global investigational studies are completed and a meta-analysis 
to assess cardiovascular risk is conducted. 
5.6 
Concomitant Therapy 
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.  
During the run-in period, blood pressure medications can be altered to optimize blood 
pressure control at the discretion of the investigator. Blood pressure medications should not 
be altered during the treatment period unless it is medically necessary to do so. If it is 
medically necessary to alter blood pressure medications during the treatment period, new 
diuretic medications should not be initiated and the dose and frequency of existing diuretic 
medications should not be altered.  


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Subjects with hyperglycemia during the treatment period will review diet and exercise 
counseling and/or receive rescue medication at the discretion of the investigator during the 
study. Anti-diabetic therapies prescribed to subjects for the purpose of treating 
hyperglycemia will be considered rescue medications (see Prescribing Rescue Medication, 
above). A blood sample will be collected to measure the last HbA1c value prior to 
administration of any rescue medications. The rescue medications must be recorded as 
concomitant medications in the CRF. 
Subjects may receive any medications for adverse events that are necessary in the 
investigators’ judgments. Concomitant medications prescribed at the time of the run-in 
period and during the study are to be recorded on the CRF. The medication name, dose, 
frequency, route of administration, date(s) of administration and reason for administration 
must be recorded. This documentation should continue through the treatment period and the 
follow up period.  
Any medication prescribed to a subject after enrollment and prior to randomization, 
including contraceptives, must be recorded in the CRF. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
All subjects will continue regimens for medical conditions other than diabetes during the 
study as indicated above. No subject shall have been treated with an investigational drug 
within 30 days of screening or within a period equal to less than 7 half-lives of the 
investigational drug, whichever is longer. No subject shall have been treated with an SGLT2 
inhibitor within 6 months of screening. Subjects taking insulin or GLP-1 receptor agonists 
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. The diet should be low in saturated 
fat, high in fiber, and low in simple carbohydrates and should contain appropriate caloric 
content to maintain weight.  Subjects will fast for a minimum of 10 h prior to the scheduled 
blood sample draws. During fasting, only water will be permitted. 
5.7.3 
Patient Activity Restrictions 
Throughout the study period, subjects are to be counseled and encouraged to engage in a 
level of physical activity that is appropriate for their physical condition.  For those without 
specific restrictions or limitations, at least 150 min/week of moderate activity is advised by 
the American Diabetes Association (American Diabetes, 2014) and an amount of exercise to 
balance energy intake in food by the Japanese Diabetes Association (JapanDiabetesSociety, 
2012). 


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5.8 
Treatment Compliance 
Subjects will be provided with dosing instructions when the investigational product is 
dispensed.  Subjects will also be instructed to bring their medication with them at every visit.  
During the run-in period, subjects will be excluded from randomization if more than one 
dose has been omitted. 
At each visit the study staff will review SMBG diary and medication use with the subject and 
record the drug consumption in the CRF. Reasons for non- adherence will also be recorded in 
the protocol deviation log if applicable. 
5.9 
Packaging and Labeling 
The finished products are packaged in HDPE bottles with a child resistant cap. There are two 
types of investigational products. 
5.9.1 
Run-in Kit 
One run-in kit contains a bottle of 15 bexagliflozin tablets, placebo. 
The label attached to each run-in kit will contain the protocol number, product identification, 
lot number, subject number, storage condition, sponsor’s name and address, and the 
investigational drug caution statement. 
5.9.2 
Investigational Product Kit 
One investigational product kit contains a bottle of 90 bexagliflozin tablets, 5 mg, 10 mg, 20 
mg, or placebo. 
The label attached to each investigational product kit will contain the following information: 
the kit number, protocol number, product identification, blinded batch number, subject 
number, storage conditions, sponsor’s name and address, CRO or ICCR name and address, 
investigator’s name, and the investigational drug caution statement. 
5.10 Storage and Accountability 
Bexagliflozin tablets will be stored at controlled room temperatures of 15°C to 30°C (59°F to 
86°F). The rescue medications will be stored in conditions specified in the manufacturers’ 
prescribing information.  The sponsor will notify the sites of the process for returning unused 
drug. 
5.11 Investigational Product Retention at Study Site 
The investigational products should be stored in a secure area with limited access at 
controlled room temperature until ready for dispensing to study subjects. The drug storage 
facility must comply with the medication storage instructions. The trial staff must record the 
amount of investigational product dispensed to each subject on the dosing record. To ensure 


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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. At the completion of 
the trial, all unused drug must be returned to a sponsor-designated depot after drug 
accounting is verified by the sponsor or its designee. 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All subjects will be informed of the nature and purpose of the study and their written 
informed consent will be obtained during the pre-study screening procedures. A copy of the 
informed consent forms, including subject information, will be provided to each subject. The 
investigator must 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.  
6.2 
Medical History 
The following information will be collected at the screening visit: 
6.2.1 
General Demographics and Characteristics 
1. Date of birth, age, sex, and race, and whether a female subject is of childbearing potential 
or not 
2. Significant medical and surgical history, including dates of diagnoses and procedures and 
whether the condition is ongoing, if applicable. 
 
6.2.2 
Diabetes History 
1. History of all medications used to treat diabetes (to be recorded in the concomitant 
medication form), including start date, duration of use, and stop date, if applicable. 
2. History of complications due to diabetes, including nephropathy, retinopathy, 
neuropathy, non-traumatic amputations, and diabetic ketoacidosis, including date of 
diagnosis 
3. Frequency of hypoglycemic events (per week) that are symptomatic or require assistance. 
 
6.2.3 
Cardiovascular Disease History 
History of cardiovascular disease including presence of angina, congestive heart failure 
(classification, if present), known atherosclerotic cardiovascular disease, prior MI, 
cerebrovascular ischemia (TIA or stroke/cerebrovascular accident) and prior cardiac or 
peripheral re-vascularization procedures.  
History should include date of diagnosis and current status of diagnosis (resolved or 
ongoing). 
6.2.4 
Medication History 
1. Use of prescribed or non-prescribed medications, including name of medication, 
indications for usage, start and stop dates, dose, and frequency 
2. Use of supplements, including over the counter drugs, vitamins, herbal medicine, and 
dietary supplements within the past 30 days prior to screening.  A medication history will 


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include the medication used, indication for usage, start and stop dates, dose, and 
frequency.  
 
6.3 
Physical Examination 
A complete physical examination will be performed by the investigator at screening and at 
the last study visit.  A complete physical examination will include measurement of body 
weight and height (height will be measured only at screening), general assessment of all body 
systems including the skin, head, eyes (including fundoscopic exam), ears, nose, throat, neck, 
heart, lungs, abdomen, lymph nodes, and extremities (including Achilles tendon reflex and 
foot exam). The fundoscopic examination should be characterized as normal or abnormal 
with description of any detected abnormality. The Achilles tendon reflex should be graded as 
normal or abnormal.  The foot exam should assess skin and toenail lesions and be 
documented as normal or abnormal with description of any detected abnormality. 
An abbreviated physical examination will include general assessment of the skin, heart, lungs 
and abdomen.  Abbreviated physical examinations will be performed by the investigator at 
all other time points as defined in the Schedule of Events, unless clinically indicated. 
The body weight must be determined at clinical visits specified in the Schedule of Events 
(Appendix 1) using a scale that is calibrated regularly.   
6.4 
Vital Signs 
Vital signs will be measured as indicated in the Schedule of Events (Appendix 1) and will 
include supine, sitting and standing blood pressure (BP) measurements, pulse, temperature 
and respiratory rate.   
6.4.1 
Blood Pressure and Pulse Measurements 
Devices designed to measure BP from the finger or wrist may not be used. The left arm and 
same cuff sizes should be used for each measurement at all visits.  If the left arm cannot be 
used for BP measurements, the reason should be documented, and the right arm should be 
used for BP measurements at all study visits.   
At each visit, BP measurements will be obtained using a calibrated sphygmomanometer 
while the subject is in sitting, supine, and standing positions.  A single pulse 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 pulse 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 evaluated orthostatic vital signs. Supine and standing blood pressure measures will not be 


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used to determine eligibility for the study. First, the subject will lie flat for 5 minutes and 
have pulse and supine blood pressure measured using the same equipment and arm as 
described for sitting BP. Once the supine BP measurement is complete, the subject will 
stand. Standing BP and pulse 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.  
6.4.2 
Temperature and Respiratory Rate 
Oral, axillary, or ear temperatures are acceptable but they must be taken from the same 
measurement site during the study.  The subject should be advised to rest after strenuous 
physical activity prior to a temperature measurement. When taking the temperature orally, 
the subject must not have eaten, drunk, or smoked anything in at least the previous 15 to 20 
minutes, as the temperature of the food, drink, or smoke can dramatically affect the reading.  
Respiratory rate should be measured after at least 5 minutes of rest. 
6.5 
Electrocardiography 
A 12-lead electrocardiogram (ECG) will be conducted as listed 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 measured will be the RR 
interval, PR interval, QRS duration, and QT, P-wave axis, and QRS-axis. Each ECG should 
also be assessed by the investigator for signs of ischemia, clinically significant hypertrophy, 
and clinically significant T-wave abnormalities.  
It is the investigator’s responsibility to review the results of the ECG as they become 
available. For each abnormal ECG result, the investigator needs to ascertain if this is 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, this is considered an AE. 
6.6 
Diet and Exercise Counseling 
Subjects will receive counseling regarding an appropriate diet and exercise to aid in glycemic 
control based on standards of medical care in diabetes throughout the study. In addition, all 
subjects are encouraged to consume enough non-sweetened liquids to maintain adequate 
hydration. 
6.7 
Clinical Laboratory Tests 
6.7.1 
Laboratory Parameters 
Subjects will be in a seated or supine position during blood collection.  Each laboratory test 
is outlined in Table 1 and the schedule is provided in Appendix 1.   


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Table 1. 
List of Laboratory Tests 
Test Name 
 
Blood or urine  
Vol. (mL) 
Shipment  
Hematology1 
2 (blood) 
Ambient 
- 
Hematocrit (Hct) 
- 
Hemoglobin (Hgb) 
- 
Mean corpuscular hemoglobin 
(MCH) 
- 
Mean corpuscular hemoglobin 
concentration (MCHC) 
- 
Mean corpuscular volume 
(MCV) 
- 
Platelet count 
- 
Red blood cell (RBC) count  
- 
White blood cell (WBC) 
count with differential  
 
 
Serum Chemistry and Electrolytes1, 2 
 
10 (serum)  
Ambient 
- 
Albumin (ALB) 
- 
Alanine aminotransferase (ALT) 
- 
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,1 
 
 
Ambient 
- 
Fasting plasma glucose (FPG) 
- 
Hemoglobin A1c (HbA1c) 
 
2 (plasma) 
2 (blood) 
 
Serum Lipids 1, 3 
 
6 (serum) 
Ambient 
- 
Total cholesterol (TC) 
- 
High-density lipoprotein cholesterol 
(HDL-C) 
- 
Triglycerides (TG) 
- 
Low-density lipoprotein 
cholesterol (LDL-C), 
calculated 
- 
LDL-C, direct5 
 
 
Urinalysis4 
 
10 (urine) 
Ambient 
- 
Appearance 
- 
Bilirubin 
- 
Color 
- 
Glucose 
- 
Ketones 
 
- 
Nitrite  
- 
Occult blood 
- 
pH 
- 
Protein 
- 
Specific gravity 
- 
Urobilinogen 
- 
Leukocyte esterase 
 
 
Urine drug screen5 
 
10 (urine) 
Ambient 
- 
Amphetamines 
- 
Barbiturates 
- 
Cocaine Metabolites 
- 
Opiates 
- 
Benzodiazepines 
- 
Cannabinoids 
 
 
Infectious Disease Testing6 
 
6 (serum)  
 
- 
HBsAg 
- 
HCV 
 
 
Urine pregnancy test (WOCBP)7  
 
2 (urine) 
Local 
Population PK Sampling8 
 
6 (plasma) 
Frozen 
- 
Bexagliflozin plasma level 
 
 
 
1. Blood for clinical chemistry and hematology will be drawn after at least 10 h of fasting prior to 
breakfast (i.e. only water is allowed, no caloric intake).   
2. Lactate dehydrogenase (LDH), gamma-glutamyl transferase (γ-GTP), creatinine kinase (CK), 


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Test Name 
 
Blood or urine  
Vol. (mL) 
Shipment  
and alkaline phosphatase (ALP) are not required routinely but will be included when clinically 
indicated. 
3. LDL-C will be calculated by the Friedewald equation. If triglycerides are > 400 mg/dL, the 
calculated LDL-C value is invalid by this equation and will be set as missing. Direct LDL-C will 
be determined in subjects whose baseline triglycerides are > 300 mg/dL. All subsequent LDL-C 
of these subjects will be determined by the same direct LDL-C measurements only. 
4. Urinalysis will be collected routinely at all clinic visits except S3 and V1 from a clean catch 
sample. Glucose results in the urinalysis reports must be suppressed so the dosing blind can be 
maintained.  Testing strips with only the leucocytes and nitrate will be provided for immediate 
assessment at the clinical sites. 
5. Urine drug screen will be performed on screening visit only. Drug abuse screening includes 
amphetamines, barbiturates, cocaine metabolites, opiates, benzodiazepines, and cannabinoids.   
6. Infectious disease testing will be conducted at screening only. 
7. Urine pregnancy test (UPT) will be performed for WOCBP at all clinic visits, except Visits S3 
and V1. For surgically sterile or post- menopausal women, it will only be done at Visit S1. 
8. Blood samples for the population PK analysis will be drawn at or during the weeks of V2, V3 or 
V4 from 240 randomly selected subjects in participating trial centers. 
 
 
 
6.7.2 
Sample Collection, Storage, and Shipping 
6.7.2.1 
Hematology, Blood Chemistry, Serum Lipids, and Glycemic Control 
Assessments 
Blood samples for hematology, chemistry, serum lipids and glycemic control assessments 
will be collected.  Timing of collection is described in Section 7 and the Schedule of Events 
(see 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 the proper fasting procedure.  A subject must be 
queried to assess compliance with a minimum 10 h fast prior to blood draw to ensure the 
FPG and triglycerides values can be accurately determined.  If a subject has not fasted for at 
least 10 h, the subject must return as soon as can be arranged (within 7 days) to provide a 
specimen after proper fasting.  If the 10 h fasting sample is not collected within 7 days of the 
initially scheduled visit, the FPG will be considered missing. 
6.7.3 
Urinalysis 
Urine samples will be collected per the schedule outlined in Section 7.  
Investigator or staff should document if pre-menopausal female subjects are menstruating 
and note it in the source documents since hematuria is likely to be identified on dipstick 
urinalysis. 


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Urinalysis strips that assess leukocyte esterase and nitrite and that do not report the presence 
or absence of glucose will be provided for immediate assessment at the clinical sites. Urine 
samples will also be transported to the central laboratory. 
Urine culture and microscopy will be conducted at the central lab if the subject has a positive 
result on the leukocyte esterase or nitrite dipstick tests at the clinical site. Dipstick urinalysis 
will also be conducted at the central laboratory for assessment of parameters not measured at 
the clinical site. Positive leukocyte esterase or nitrite results recorded from the central 
laboratory dipstick measurement will not trigger urine culture and microscopy.  
6.7.4 
Population PK Sampling 
Blood samples for the population PK analysis will be drawn when the subjects return to the 
clinic during weeks 2, 6, or 12 from 240 selected subjects in participating trial centers. One 
blood sample will be drawn at each of the 3 time points from each subject for a total of 3 
postdose samples per subject. Approximately 120 subjects will be sampled at 0.25-1 h, 7-10 
h, and 20-24 h post dose. Another 120 subjects will be sampled at 1.5-3 h, 3.5-6.5 h and 7-10 
h postdose. The sampling time should take into consideration the study subject availability 
and can be on any of the days during the week of the specified clinical visits.  The precise 
dosing time and sample draw time must be recorded. 
Two mL (2 mL) of whole venous blood will be collected from a peripheral vein. Samples 
will be placed in tubes containing K2EDTA, stored on ice, and centrifuged under 
refrigeration for at least ten minutes at 3,000 rpm. After centrifugation, plasma will be 
removed and stored frozen in 3 aliquots of 200 L at or below -20° C.  Processed frozen 
plasma samples will be transferred on dry ice to the analytical laboratory and will be stored at 
or below -20o C until analysis.  
Plasma concentrations of bexagliflozin will be determined by a validated LC-MS/MS 
method. Approximately 540 measurements of bexagliflozin plasma concentrations will be 
collected from an estimated 180 subjects who will have received active drug in this study. 
6.8 
Dispensing Investigational product 
Each study subject will receive 1 run-in kit at visit S4 and 1 investigational product kit at 
visits V1 (week 1). 
6.9 
Efficacy Assessments 
6.9.1 
HbA1c Determination 
The HbA1c values will be determined in a central laboratory using a method that is certified 
by the National Glycohemoglobin Standardization Program (NGSP) and standardized to the 
Diabetes Control and Complications Trial (DCCT) reference assay. 


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6.9.2 
Body Weight 
Total body weight will be determined in clinical visits as described in Section 6.3. 
6.9.3 
Blood Pressure 
Systolic and diastolic blood pressure will be determined as described in the vital signs section 
(Section 6.4). 
6.10 Adverse Events Assessments 
Adverse event (AE): Any untoward medical occurrence experienced by a subject 
administered an investigational product. An AE does not necessarily have a causal 
relationship with treatment. An AE can therefore be any unfavorable and unintended accident, 
sign (including an abnormal laboratory finding), symptom, or disease occurring during the 
period of use of an investigational product or the period of follow-up, whether or not related 
to the investigational product. 
Serious adverse event (SAE): Any event that results in any of the following outcomes: 
1. Death 
2. A life-threatening event, i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred (this does not include an event that, 
had it occurred in a more severe form, might have caused death) 
3. A persistent or significant disability/incapacity 
4. An event that requires hospitalization or prolongs hospitalization 
5. A congenital anomaly/birth defect 
6. Any other medically significant events that, based upon appropriate medical judgment, 
may harm the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above, e.g. allergic bronchospasm requiring intensive treatment in an 
emergency room or home; blood dyscrasias or convulsions that do not result in 
hospitalization; or the development of drug dependency or drug abuse. 
 
Non-serious adverse events are all events that do not meet the criteria for a serious adverse 
event. 
Immediately Reportable Adverse Event (IRAE): Any serious adverse event or any 
adverse event that necessitates discontinuation of investigational product, including 
pregnancy. 
Clinical Laboratory Changes: 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 


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value is determined to be a clinically significant and abnormal change from baseline for that 
subject, this is considered an AE. 
Hypoglycemia is defined as any FPG or SMBG value ≤ 70 mg/dL and documented as 
described in Section 6.10.9. 
Any increase in liver function tests (AST, ALT, or bilirubin) greater than 3 times the ULN 
for the laboratory utilized will be considered a clinical laboratory adverse event. 
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on the 
CRF.  The intensity of an adverse experience is defined as follows: 
1 = Mild: discomfort noticed, but no disruption to daily activity; 
2 = Moderate: discomfort sufficient to reduce or affect normal daily activity; 
3 = Severe: 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 adverse 
event 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 unclear. 
Not Likely: There is a temporal relationship to investigational product administration, but 
there is not a reasonable causal relationship between the investigational product and the 
event. 
Unrelated: There is not a temporal or causal relationship to investigational product 
administration. 
6.10.1 
Eliciting and Reporting Adverse Events 
The investigator will periodically assess subjects for the occurrence of adverse events.  To 
avoid bias in collecting information about adverse events, the investigator should ask 
subjects the following question: "How have you felt since you were last checked?"  All 
adverse events (serious and non-serious) reported by the subject must be recorded on the 
source documents and CRFs provided by the sponsor.   


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In addition, the sponsor’s Medical Monitor or its designated personnel must be notified 
immediately by telephone, email, or fax of any immediately reportable adverse events 
(IRAE)_according to the procedure outlined below. Special attention should be paid to 
recording hospitalization and concomitant medications. 
6.10.2 
Immediately Reportable Adverse Events 
The investigator must report any serious adverse event (SAE), by telephone, email, or fax, to 
Theracos or its representative immediately after the investigator becomes aware of the event.  
An SAE form should be completed and sent by email or fax or overnight courier to the 
sponsor within 24 h of knowledge of the event. 
Non-serious events that require discontinuation of investigational product (including 
laboratory abnormalities) should be reported to Theracos within 3 working days.  The IRAE 
form should be completed and sent by email or fax or overnight courier 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. 
6.10.3 
Pregnancy 
Women of childbearing potential (WOCBP) who are sexually active must use an effective 
method of birth control during the course of the study, in a manner such that risk of failure is 
minimized.   
Before enrolling WOCBP in this clinical trial, investigators must review guidelines about 
study participation for WOCBP.  The topics should generally include: 
1. General information 
2. Informed consent form 
3. Pregnancy prevention information 
4. Drug interactions with hormonal contraceptives. 
5. Contraceptives in current use. 
6. Guidelines for the follow-up of a reported pregnancy. 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy.  The 
subject must sign an informed consent form stating the above-mentioned risk factors and that 
the consequences were discussed with her. 
During the study, all WOCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (e.g. missed or late menstrual cycle). 
If a subject or investigator suspects that the subject may be pregnant prior to investigational 
product administration, the investigational product administration must be withheld until the 


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results of serum pregnancy tests are available.  If the pregnancy is confirmed, the subject 
must not receive the investigational product and must not remain or be enrolled in the study.  
If pregnancy is suspected while the subject is receiving study treatment, the investigational 
product must be withheld immediately until the result of the pregnancy is known.  If 
pregnancy is confirmed, the investigational product will be permanently discontinued and the 
subject will be withdrawn from the trial.  [Exceptions to study discontinuation may be 
considered for life-threatening conditions only after consultations with a Theracos Medical 
Monitor or designated personnel.] 
The investigator must immediately notify the Medical Monitor of any female subject who 
becomes pregnant within 30 days after investigational product exposure.  The investigator 
must record the event on the Pregnancy Surveillance form and forward it to Theracos clinical 
or designated personnel. 
Protocol required procedures for study discontinuation and follow-up must be performed on 
the subject unless contraindicated by pregnancy (e.g., x-ray studies).  Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator must report to Theracos, on the appropriate Pregnancy Surveillance form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome.  Infants will be followed for a minimum of six months. 
6.10.4 
Procedure for Breaking the Blind 
As indicated in Section 5.5 above, the sponsor, study coordinators, pharmacists, study 
subjects, and the cardiovascular adjudication committee members will be blinded to the 
treatment assignment during the study period.  The investigator should also remain blinded to 
the subject treatment during the entire study unless knowledge of the subject’s treatment is 
required for clinical care and safety.  The Emergency Code Break module in the IWRS is 
used for such situations.  The investigator must confirm the intention to unblind the subject’s 
treatment to obtain the dose information in IWRS.  Upon completion 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 cardiovascular adjudication committee members until all phase 3 studies 
are completed. 
6.10.5 
Follow-up of Adverse Events  
6.10.5.1 
Follow-up of Non-serious Adverse Events 
Non-serious AEs that are identified on the last scheduled contact must be recorded on the AE 
CRF with the current status noted.  All non-serious AEs that are ongoing at the time will be 
recorded as ongoing on the CRF. 


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6.10.5.2 
Follow-up of Post-Study Serious Adverse Events 
SAEs that are identified on the last scheduled contact must be recorded on the AE CRF page 
and reported to Theracos according to the reporting procedures outlined in Section 6.10.2.  
These may include unresolved previously reported SAEs, or new SAEs. The investigator 
should follow these SAEs until the events are resolved, or the subject is lost to follow-up.  
Resolution means the subject has returned to the baseline state of health, or the investigator 
does not expect any further improvement or worsening of the subject’s condition.  The 
investigator should continue to report any significant follow-up information to Theracos 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 Theracos 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 at least 14 days after the last treatment. 
6.10.6 
Urinary Tract Infections (UTIs) 
Events potentially representing UTIs, including cystitis, urethritis, pyelonephritis, or 
urosepsis, should be carefully evaluated and documentation of signs, symptoms, culture 
results for infectious agent, and treatment should be undertaken when appropriate.  
The investigator should query the subject at every clinical visit for symptoms that may be 
related to a UTI and, if appropriate, document these events as symptomatic UTI in the CRF 
unless an alternative diagnosis is present. In addition, a clean catch urine sample will be 
obtained at all clinical visits and a urinalysis will be performed on that sample at every 
clinical visit. A positive urinalysis will be defined as one with detectable leukocyte esterase 
and/or nitrites. If the subject reports symptoms consistent with a UTI or the urinalysis at the 
clinical site is positive, a urine culture will be performed at the central laboratory. A positive 
urine culture will be defined as one with ≥ 105 CFU of any species. The investigator may also 
perform a urine culture using local resources if necessary for clinical care.  
6.10.7 
Genital Mycotic Infections (GMIs) 
The investigator will query the subjects for signs or symptoms that may represent a GMI at 
all clinical 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. 


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6.10.8 
Hepatotoxicity 
If plasma AST and/or ALT concentrations > 3 x ULN are detected, the investigator will 
record in the source documents the date corresponding to the date of the laboratory 
abnormality; the type, frequency, and dose of any concurrent medications or supplements 
taken by the subject within the 14 days of the detected abnormality; and any symptoms or 
change in physical exam that have occurred since the prior assessment.  The investigator 
should perform additional laboratory and imaging tests to attempt to establish the cause of 
the AST and ALT elevations, including ruling out any potential contribution from bone or 
muscle etiologies. 
Any clinically significant increase in hepatic enzymes and specifically any ALT or AST >3x 
ULN requires immediate repeat test within 48 to 72 h to confirm the hepatic enzyme 
elevation and should be repeated based on the clinical situation at least every 96 h (4 days) 
until ALT and AST return to < 2.5 x ULN.  Study medication should be stopped and the 
event should be reported as a laboratory adverse event within the CRF if the enzyme 
elevation is confirmed or worsening.  
Hepatotoxicity will be diagnosed and entered as an AE should any of the following occur: 
• ALT or AST > 8 x ULN; 
• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or INR > 1.5 
• ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
 
In the event of hepatotoxicity, investigational product should be permanently discontinued.  
The investigator is encouraged to consult with the Medical Monitor regarding diagnostic 
evaluation for the hepatic enzyme elevations. Consultation with a hepatologist may also be 
appropriate in some circumstances. 
6.10.9 
Hypoglycemia 
Events of hypoglycemia or potentially representing hypoglycemia should be carefully 
evaluated.  
All subjects will be provided with a glucometer and diary for recording blood glucose 
measurements and signs and symptoms of hypoglycemia.  During the study the subject is 
expected to record daily SMBG readings and all signs and symptoms that may potentially 
reflect hypoglycemia. In the event of such signs or symptoms, the subject is expected to 
check the blood glucose if it is reasonably safe to do so, and consume carbohydrates, if 
appropriate, to treat hypoglycemia.  
The subject will be expected to record in the glycemic control diary the following 
information for each hypoglycemic event: 


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1. Signs and symptoms attributed to hypoglycemia and the time and date on which they 
occurred  
2. SMBG reading at the time of the signs and symptoms attributed to hypoglycemia 
3. Time elapsed from the most recent meal to the onset of  signs and symptoms 
4. Duration, intensity, and type of any exercise within the 24 h prior to the signs and 
symptoms 
5. Type of treatment used (e.g., juice, crackers) for the signs and symptoms and whether 
assistance was required from another person to administer the treatment 
6. SMBG reading 15 minutes after treatment with carbohydrate and the time at which this 
was measured 
7. Whether or not the signs and symptoms attributed to hypoglycemia resolved after blood 
glucose returned to normal. 
 
Subjects are encouraged to call the study clinic should signs and symptoms potentially 
related to hypoglycemia occur. 
At each study visit, the investigator is expected to review the glucometer and glycemic 
control diary with particular attention to any SMBG value ≤ 70 mg/dL and any recorded 
signs or symptoms potentially related 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 serious adverse events 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). 


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5. Relative hypoglycemia: An event during which the person with diabetes reports any of 
the typical symptoms of hypoglycemia, and interprets those as indicative of 
hypoglycemia, but with a measured plasma glucose concentration > 70 mg/dL (3.9 
mmol/L). 
 
While each event meeting the criteria above will be entered into the hypoglycemia log, only 
critical hypoglycemia, documented symptomatic hypoglycemia, asymptomatic 
hypoglycemia, and probable hypoglycemia will be entered as AEs.  
In the event of asymptomatic hypoglycemia, the investigator should review the signs and 
symptoms of hypoglycemia with the subject to elicit a complete description and should 
review proper glucometer technique to ensure that the low glucose value is not due to 
improper use of the glucometer. 
The investigator should be alert 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. 
6.11 Concomitant Medication Assessments 
A concomitant medication is any medication that the subject has been taking prior to 
enrollment and that the subject is expected to continue to take for some portion of the trial, as 
well as any medication other than the investigational product that the subject takes during the 
course of the trial.  
The medications or treatment for controlling hypoglycemia must be recorded as concomitant 
medications in the CRF.  Any medication given to treat hyperglycemia is considered a rescue 
therapy and should be recorded in the concomitant medication log. 
Changes from baseline anti-hypertensive therapy and their rationale must be recorded in the 
CRF. 
All prescription and over-the-counter medications, including vitamins and herbal 
supplements, that subjects receive during the trial must be documented 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 


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therapeutic chemical classification (ATC) and preferred name will be produced.  A listing of 
concomitant medications will include all medications taken by any subjects during the course 
of the study. 
6.12 Removal of Patients from the Trial or Discontinuation of 
Investigational Product Administration 
The investigator must emphasize to potential subjects the importance of continued 
participation for the full duration of the trial during the informed consent process. Potential 
subjects should be informed that the trial procedures will allow additional medications to 
control hyperglycemia or other adverse conditions. It is also important to emphasize that 
missing data and missed visits could affect the entire trial. If subjects are dissatisfied with the 
conduct of the trial but have not withdrawn, the investigator should make an effort to address 
their concerns and retain them in the trial if possible. In doing so, investigators must be 
careful that the efforts do not cross over into coercion. Investigator should encourage a 
subject to remain in the study even if the investigational product administration is stopped so 
that safety information can be collected. 
Participation in a clinical trial is voluntary.  A subject can withdraw from the study at any 
time.  The sponsor or investigator may terminate the study for medical or administrative 
reasons.  If a decision is made to withdraw a subject from the study, no further 
investigational product should be administered.  Even if the subject discontinues study 
medication, every attempt should be made to complete all required study evaluations and 
procedures.  Reasons for all withdrawals should be recorded on the CRF.  Examples of 
reasons for withdrawal include:   
1. A protocol violation has occurred, 
2. A serious or intolerable adverse event has occurred, 
3. A clinically significant change in a laboratory parameter has occurred,  
4. The sponsor or investigator terminates the study, or 
5. The patient requests to be withdrawn from the study. 
 
Subjects who do not complete the study but who have received investigational product 
should have a follow-up examination, including a physical examination, vital signs, ECG and 
clinical laboratory tests according to Section 7. 
Subjects who withdraw from the study will not be replaced. 
6.13 Appropriateness of Measurements 
The percentage of HbA1c is a widely used measure of chronic glycemia, reflecting average 
blood glucose levels over a 2- to 3-month period of time. It is an accepted surrogate marker 
for risk of microvascular complications and is widely used as a measurement for the 
adequacy of glycemic management. Other study procedures and measurements in this 
protocol are widely used and generally recognized as reliable, accurate, and relevant for 
subjects with T2DM. 


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7 
STUDY ACTIVITIES 
The study activities at each clinic visit listed below are presented in Appendix 1.  The 
required laboratory tests scheduled at each visit are listed in Appendix 2.  Detailed study 
procedures are described in Section 6. 
A visit window of ± 3 days is allowed for all visits except visit V1.  Visit V1 is to be 
scheduled 3 days after visit S5 is complete and can be extended to 5 days depending on 
HbA1c value availability. 
7.1 
Screening (Up to 15 weeks prior to randomization, visit S1) 
The screening can be performed from 3 weeks to 3 days before the start of the washout 
period for subjects who are taking background OHA or 3 weeks to 3 days before the start of 
the run-in period for subjects who are treatment naïve.  At the screening visit the study 
investigator will: 
• Explain the content of informed consent to the subject and collect signed informed 
consent 
• Obtain medical history and demographic information 
• Perform a complete physical examination including height and weight 
• Measure vital signs, including blood pressures, pulse, temperature, and respiratory rate  
• Perform a 12-lead ECG measurement 
• Draw blood if a minimum 10-h fast has been completed by the subject as described in 
Section 6.7.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• Collect a clean-catch, mid-stream urine sample for drug abuse screening, urinalysis, and 
for UPT for all females 
• Evaluate the subject’s suitability for enrollment according to the inclusion and exclusion 
criteria based on the information collected.  
 
7.2 
Washout and Run-in Periods (Up to 12 weeks prior to 
randomization) 
The washout and run-in period is required for all enrolled subjects who are taking an OHA. 
Enrolled treatment naïve subjects will not require any washout and will enter the run-in 
period. 
7.2.1 
Washout of OHA (Visits S2 and S3) 
Two visits will be conducted during the washout period.  Visit S2 is a clinic visit. At Visit S3 
each subject will be evaluated by the investigator or study staff via a phone interview 2 
weeks after washout starts; there will be no on-site evaluation at Visit S3. 


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7.2.1.1 
Visit S2 (subjects taking one OHA)  
At the S2 visit the study investigator will: 
• Evaluate inclusion/exclusion criteria for eligibility  
• Counsel subject on appropriate diet and exercise 
• Dispense glucometer and train subject in SMBG determination and recording 
• Discontinue the OHA for 10 weeks if a subject is taking a TZD; discontinue the OHA for 
6 weeks if a subject is taking a non-TZD OHA 
• Collect clean-catch, mid-stream urine for urinalysis and UPT for women of child bearing 
potential. 
• Assess pre-treatment signs and symptoms and record pre-treatment concomitant 
medications. 
 
7.2.1.2 
Visit S3 – Phone interview (subjects in washout) 
At the S3 visit the study investigator will: 
• Review daily SMBG and glycemic control record for each day during the prior 2 weeks 
• Assess any signs and symptoms of severe hyperglycemia, including increased urination, 
increased thirst, weight loss, and changes in vision 
• Assess pre-treatment signs and symptoms and record pre-treatment concomitant 
medications. 
 
7.2.2 
Run-in Period:  
7.2.2.1 
Visit S4 (Week -2) 
At the S4 visit the study investigator will: 
• Counsel subject on appropriate diet and exercise (for subjects who are treatment naïve 
and do not require washout) 
• Dispense glucometer and instruct subject in SMBG determination and recording (for 
subjects who are treatment naïve and do not require washout) 
• Review glycemic control diary and SMBG (for subjects who complete 6 or 10 weeks of 
washout) 
• Measure vital signs, including blood pressures, pulse, temperature, and respiratory rate 
• Collect clean-catch, mid-stream urine sample for urinalysis and UPT for women of child 
bearing potential. 
• Dispense run-in kit for run-in period 
• Assess pre-treatment signs and symptoms and record pre-treatment concomitant 
medications. 
 


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7.2.2.2 
Visit S5 (Days -3 to -5) 
At the S5 visit the study investigator will: 
• Confirm inclusion/exclusion criteria for eligibility and review run-in drug compliance 
• Perform an abbreviated physical examination including weight 
• Review glycemic control diary and SMBG results 
• Measure vital signs, including blood pressures, pulse, temperature, and respiratory rate 
• Perform a 12-lead ECG measurement 
• Draw blood from subject if a fast of 10 h or greater has been completed as described in 
Section 6.7.2.1. The specific laboratory tests scheduled for this visit are listed in 
Appendix 2 
• Collect clean-catch, mid-stream urine sample for urinalysis and UPT for women of child 
bearing potential. 
• Assess pre-treatment signs and symptoms and record pre-treatment concomitant 
medications. 
 
7.3 
Treatment Period (week 1 to week 12) 
At the end of the run-in period, subjects who have successfully completed run-in period and 
continue to meet inclusion/exclusion criteria will be randomized and enter the treatment 
period. 
7.3.1 
Visit V1 (Day 1 of week 1) 
Visit 1, day of randomization, must be conducted after the HbA1c value from the sample of 
S5 visit is available for eligibility confirmation.  
At the V1 visit the study investigator will: 
• Confirm HbA1c value of 7.0 to 8.5% based on the S5 sample results 
• Review SMBG and glycemic control record 
• Dispense investigational product based on randomization 
• Assess adverse events and record concomitant medications 
 
7.3.2 
Visit V2 (week 2) 
At the V2 visit the study investigator will: 
• Review SMBG and glycemic control record  
• Measure vital signs, including blood pressures, pulse, temperature, and respiratory rate 
• Draw blood from subjects who have fasted a minimum of 10 h as described in Section 
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• Collect blood specimens for sparse PK sampling from selected subjects in participating 
centers 
• Collect clean-catch, mid-stream urine sample for urinalysis in all subjects and for UPT 
for women of child bearing potential 
• Assess adverse events and record concomitant medications 
 
7.3.3 
Visit V3 (week 6) 
At the V3 visit the study investigator will: 
• Review SMBG and glycemic control record  
• Measure vital signs, including blood pressures, pulse, temperature, and respiratory rate 
• Draw blood from subjects who have fasted a minimum of 10 h as described in Section 
6.7.2.1. The specific laboratory tests scheduled for this visit are listed in Appendix 2 
• Collect blood specimens for sparse PK sampling from selected subjects in participating 
centers 
• Collect clean-catch, mid-stream urine sample for urinalysis in all subjects and for UPT 
for women of child bearing potential 
• Assess adverse events and record concomitant medications. 
 
7.3.4 
Visit V4 (week 12) 
At the V4 visit the study investigator will: 
• Review SMBG and glycemic control record  
• Perform an abbreviated physical examination including weight 
• Measure vital signs, including blood pressures, pulse, temperature, and respiratory rate 
• Perform a 12-lead ECG measurement 
• Draw blood from subjects who have fasted a minimum of 10 h as described in Section 
6.7.2.1. The specific laboratory tests scheduled for this visit are listed in Appendix 2 
• Collect blood specimens for sparse PK sampling from selected subjects in participating 
centers 
• Collect clean-catch, mid-stream urine sample for urinalysis in all subjects and for UPT 
for women of child bearing potential 
• Retrieve remaining study medication and record the number of remaining tablets 
• Assess adverse events and record concomitant medications. 
 


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7.4 
Exit Visit or Early Termination Visit 
7.4.1 
Visit V5 (week 14 or two weeks after the last dose of investigational product 
if a subject early terminates) 
At the V5 visit the study investigator will: 
• Review SMBG and glycemic control record 
• Perform a complete physical examination including weight 
• Measure vital signs, including blood pressures, pulse, temperature, and respiratory rate 
• Perform a12-lead ECG measurement 
• Draw blood from subjects who have fasted a minimum of 10 h as described in Section 
6.7.2.1.  The specific laboratory tests scheduled for this visit are listed in Appendix 2  
• Collect clean-catch, mid-stream urine sample for urinalysis in all subjects and for UPT 
for women of child bearing potential 
• Assess adverse events and record concomitant medications: If subjects have an ongoing 
serious adverse event, the subject should be followed until the adverse event is resolved 
or returns to baseline.  All possible attempts should be made to document resolution of 
acute and chronic toxicities. 
 
7.5 
Early Termination Procedures 
Subjects removed from the study due to drug related toxicity will be followed until resolution 
or stabilization of the adverse event.  The sponsor must be notified in the event that a subject 
withdraws or has been withdrawn from the study.  
Subjects who withdraw consent and have received investigational product will have a follow-
up examination, including a complete physical examination, vital signs, ECG, and clinical 
laboratory tests (hematology, serum chemistry, and glycemic control).  
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 SOPs of the CRO and the sponsor.  Review procedures will be implemented at 
the CRO for all documents that are generated in relation to the study. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
All statistical analyses will be performed using Version 9.4 or later of Statistical Analysis 
Software (SAS®). 
Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], Q1, median, Q3, minimum, and maximum) for continuous variables, and 
frequency and percentage for categorical and ordinal variables.  If there are missing values, 
the number missing will be presented, but without a percentage.   All data collected will be 
included in by-subject data listings. 
Unless otherwise specified, all tests will be two-tailed using a 0.05 level of significance.  All 
confidence intervals (CIs) will be two-sided 95% confidence intervals.     
9.1.1 
Handling Dropouts, and Missing Data 
Discontinuation criteria are explained in Section 6.12.  Subjects who discontinue will not be 
replaced.  To the extent possible, attempts will be made to minimize the amount of missing 
data through measures planned in the study conduct.  But if missing data are present for the 
primary efficacy endpoint, they will be handled using a multiple imputation approach.  The 
imputation method is as follows: 
As the primary analysis, only available data will be analyzed and data obtained after rescue 
will be excluded and considered as missing.   The following sensitivity analyses will be 
conducted: 
• Missing endpoint information (including data obtained after rescue) will be imputed via 
multiple imputation linear regression approach. A total of 10 imputed datasets will be 
generated, and the primary efficacy endpoint analysis described below will be carried out 
on each imputed dataset; the analyses results will be combined across the 10 datasets 
using the standard techniques for multiple imputed data sets in order to yield overall 
treatment comparison results on the imputed data. 
• Missing endpoint data will also be handled based on the last observation carried forward 
(LOCF) technique.  The last non-missing observation for a subject (i.e., excluding data 
obtained after rescue) will be carried forward for analysis. 
• Data collected after the start of rescue medication will NOT be considered missing, and 
the primary efficacy endpoint analyses will be performed based on all observed data. 
 
For all other endpoints, the missing data will not be imputed and only the observed data will 
be used in the analyses. 
The number, timing, pattern, reason for and possible implications of missing values in 
efficacy and safety assessments will be investigated.  The dropout patterns may be assessed 
by graphical methods. 


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9.1.2 
Multiple Comparisons / Multiplicity 
The primary objective of this study is to identify the effect of bexagliflozin tablets in three 
strengths on the placebo-corrected change in HbA1c from baseline after 12 weeks of 
treatment.  All secondary endpoints are considered exploratory and adjustment for multiple 
endpoints will not be performed. 
9.2 
Determination of Sample Size 
Approximately 320 subjects will be randomized and equally allocated to receive 
bexagliflozin tablets, 5 mg, 10 mg, 20 mg, or placebo.   
The sample size calculation for this study is based on a two group t-test with a two-sided 
significance at the 5% level and the following assumptions:  
1) The placebo-corrected population mean change from baseline to Week 12 in HbA1c 
in the highest dose group of 20 mg will be -0.5%.  
2) The pooled standard deviation for the change from baseline to Week 12 in HbA1c for 
the active and placebo groups will be 0.9%. 
 
Under the above assumptions, an estimated sample size of 70 evaluable subjects per 
treatment arm yields approximately 90% power to detect a treatment difference between 
bexagliflozin and placebo. A sample size of 80 per arm has been selected to account for a 
potential drop-out and to allow adequate safety evaluation.  The total sample size for this 
study will be 320 subjects. 
This study will be conducted at multiple investigative sites and will likely involve variable 
numbers of subjects at each site.  Enrollment will be on a competitive basis but will be 
capped at 32 subjects from each site. 
9.3 
Analysis Populations  
9.3.1 
Full Analysis Set 
All subjects who are randomized, take at least one dose of double-blind study medication, 
and have at least one post-randomization HbA1c measurement will be included in the Full 
Analysis Set (FAS).  All analyses of the FAS will be based on each subject’s randomized 
assigned treatment. 
9.3.2 
Safety Analysis Set 
All subjects who are randomized and take at least one dose of double-blind study medication 
will be included in the Safety Analysis Set.  Safety analyses will be based on the medication 
that was actually dispensed to each subject. 


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9.3.3 
Per Protocol Analysis Set 
The Per Protocol (PP) Analysis Set will include all subjects in the FAS who meet the study 
eligibility requirements and have no major protocol deviations that 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. 
9.4 
Demographics and Baseline Characteristics 
Demographic characteristics include age, gender, race, ethnicity, and study center.  Baseline 
characteristics include baseline HbA1c values, blood pressure, body weight, body mass index 
(BMI in kg/m2), fasting plasma glucose level, and prior anti-diabetic treatment status 
(whether treatment naïve or not).  Summary statistics by treatment group will include counts 
and percentages for discrete variables, and means, SD, Q1, medians, Q3, minimum and 
maximum for continuous variables.  
9.5 
Analysis of Efficacy 
All efficacy analyses will be performed based on the FAS.  The primary endpoint analysis 
will also be conducted using the PP Analysis Set.  
For the primary endpoint of HbA1c change from baseline over 12 weeks of treatment, the 
MMRM analysis of covariance model (ANCOVA) with baseline HbA1c as a covariate will 
be fitted to the available data, incorporating all visits at which HbA1c was measured for each 
subject including the scheduled visits at weeks 2, 6, and 12 as well as the unscheduled visits 
for measurement of HbA1c (NationalResearchCouncil, 2010). Treatment, study center, and 
stratification factor for randomization (treatment naïve versus taking one OHA at baseline) 
will be applied as fixed effects, as will study week and study week-by-treatment interaction. 
From this model, an estimate of the treatment difference at week 12 will be generated, as will 
an assessment of whether this estimate is significantly different when comparing placebo 
with each dose of bexagliflozin at a two-sided 0.05 level of significance. An unstructured 
within-patient covariance structure will be assumed. HbA1c values obtained after the start of 
rescue medication will be excluded from this primary analysis.  
The MMRM model is one approach to obtain treatment effect estimates in the presence of 
missing data. As sensitivity analyses for missing data, the following will be performed: 
3) Missing HbA1c data (for weeks 2, 6, or 12) will be imputed via multiple imputation 
(MI), following which the MMRM will be repeated on the complete datasets with 
results combined across complete datasets using standard MI techniques; HbA1c 
values collected after the start of rescue medication will be considered missing. 
4) Missing HbA1c data will be imputed via LOCF, following which the MMRM will be 
repeated; HbA1c values collected after the start of rescue medication will be 
considered missing. 
5) HbA1c values collected after the start of rescue medication will NOT be considered 
missing, and the MMRM analyses will be re-performed. 
 


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For the primary efficacy model, a test for a significant baseline-by-treatment interaction will 
be performed in a separate model, using a 0.100 alpha level.  If the baseline-by-treatment 
interaction is significant, then the ANCOVA assumptions are violated and an analysis of 
variance (ANOVA) model will be used instead, omitting the baseline covariate.   
A treatment by study center interaction effect will be added to the MMRM ANCOVA (or 
ANOVA) model used for the analyses of the primary efficacy variable.  If a statistically 
significant treatment by study center interaction effect is noted using a 0.1 level of 
significance, then separate analyses will be performed for each study center.   
In addition to the week 12 comparisons, the change from baseline to week 2 and week 6 will 
also be analyzed from the same MMRM ANCOVA model using 95% CIs for the between-
group mean changes.  The secondary efficacy endpoint, changes in HbA1c over time will be 
assessed descriptively using graphical methods 
To examine the dose response, tests for linear and quadratic dose-response relationships 
between the doses (0 [placebo], 5, 10 and 20 mg bexagliflozin) and the change from baseline 
in HbA1c at week 12 will be conducted using a general linear model and appropriate 
orthogonal polynomial contrasts. 
Fasting plasma glucose, systolic and diastolic blood pressure, and weight will be analyzed 
using the same MMRM ANCOVA model used in the primary efficacy analysis.   
For each subject, the post-baseline HbA1c values on or before week 12 will be assigned to a 
category of < 7% or ≥ 7%.  Incidences of reduction of HbA1c to < 7% will be analyzed using 
a logistic regression model with effects for treatment, study center and baseline 
HbA1c.  Odds ratio and the corresponding 95% CI will also be presented. 
9.6 
Analysis of Safety 
All safety analyses will be conducted based on the Safety Analysis Set. 
Safety data will include AEs, physical exam results, vital signs, ECG results, and clinical lab 
measurements of serum chemistry, hematology, serum lipids, glycemic control parameters 
and urine specimens.  Observed data will be listed by subject and summarized using 
descriptive statistics by treatment group based on the Safety Analysis Set. 
9.6.1 
Adverse Events 
Adverse events will be mapped to preferred term and body system using the Medical 
Dictionary for Regulatory Activities (MedDRA). AEs that begin after the first administration 
of investigational products or existing AEs that worsen after the first dose of  study 
medication are considered treatment emergent AEs (TEAEs).  TEAEs will be assigned to the 
run-in period or the double blind randomization period in the same manner.  The number and 
percentage of subjects reporting TEAEs will be summarized for each treatment group by 
MedDRA system organ class and preferred term, then by severity, and by relationship to 
study treatment.  Drug-related AEs will be considered those to be at least possibly related to 


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investigational product based on the investigator’s 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  
Adverse event listings will be provided for the following subsets: 
1. All TEAEs 
2. All TEAEs at least possibly related to bexagliflozin 
3. Serious AEs (if any) 
4. AEs leading to treatment discontinuation (if any) 
 
9.6.2 
Adverse Events of Special Interest  
Adverse events of special interest include the following categories: 
• Genital mycotic infections 
• Urinary tract infections including urosepsis and pyelonephritis 
• Diuretic effects including hypovolemia 
• Hypotension episodes 
• Hepatotoxicity 
• MACE 
• Hypoglycemia 
• Falls and fractures 
• Malignancies 
• Hypersensitivity reactions 
• Acid-base disorders 
• Renal failure events 
 
AEs of special interest will be defined programmatically based on MedDRA system organ 
class and preferred term which will be predefined by a blinded medical reviewer and will be 
specified in the Statistical Analysis Plan. 
Event terms, signs, and symptoms will be documented in the listings.  The number and 
percentage of subjects who have experienced TEAEs of special interest will be summarized 
for each treatment group by type of AE. 
9.6.3 
Clinical and Laboratory Events and Analyses 
Clinical and laboratory parameters will be measured at baseline, during the treatment period 
and at follow-up.  These variables include vital signs (blood pressure, pulse, respiration rate, 
and temperature), clinical laboratory outcomes (see Section 6.7 for a complete list) and ECG 
data. They will be summarized as changes from baseline. 


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Laboratory data will be classified as low, normal or high relative to the parameter’s reference 
range. Laboratory abnormalities for each treatment will also be summarized with shift tables. 
Abnormalities as well as percent changes from baseline in the clinical and laboratory 
assessment will be listed. 
9.6.4 
Physical Examination 
Physical examination findings including body weight will be collected at baseline and during 
the treatment period, safety extension phase and at follow-up. Abnormal findings at each 
visit will be tabulated as incidences by body system. 
9.6.5 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A by-subject listing of concomitant medications will include all 
medications taken during the study regardless of the timing for the start of the medication. 
All medications started prior to the administration of the investigational product will be 
included in the data but will be identified as prior in the listing. Only the concomitant 
medication use will be summarized. 
9.7 
Interim Analysis 
There will be no interim analysis. The final analysis will be performed after all subjects have 
completed the follow up assessments and all subject data have been cleaned and locked in the 
study database. 
An independent Data and Safety Monitoring Board (DSMB) will monitor the safety of the 
subjects in this study.  The objectives of the DSMB are to assess drug safety and to allow for 
protocol modification or early stopping due to safety concerns. 


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
Information regarding key personnel involved in the conduct of the study, including names 
and contact details of participating investigators, monitors, clinical laboratories, and technical 
departments and/or institutions, as well as information on members of additional study 
committees, will be found in the study files of the investigational site. 
10.2 Institutional Review Board or Independent Ethics Committee 
Approval 
The study protocol, informed consent document, relevant supporting information, and all 
types of subject recruitment or advertisement information must be submitted to the 
Institutional 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 
Good Clinical Practice Guidelines and the guiding principles detailed in the Declaration of 
Helsinki. The study will also be carried out in keeping with applicable local laws and 
regulations. An inspection by the sponsor representatives and/or their designee and/or other 
authorized regulatory authorities representatives may occur at any time. The investigator 
must agree to the inspection of study-related records by the regulatory authority/sponsor 
representatives, and must allow direct access to source documents to the regulatory 
authority/sponsor representatives. 
The investigator is responsible for complying with the protocol and all appropriate 
regulations and guidelines governing global clinical research. Additionally, he/she is 
responsible for ensuring that all participating staff members are adequately trained and 
competent to perform his/her assigned tasks. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator may implement a 
deviation from or a change of the protocol to eliminate any immediate hazards to the trial 
subjects without prior IRB/IEC or sponsor approval/favorable opinion. As soon as possible, 
the implemented deviation or change, the reasons for it, and if appropriate, the proposed 
protocol amendment should be submitted to the IRB/IEC and sponsor. 


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Any deviations from the protocol must be fully explained and documented by the 
investigator. The circumstances, action taken, and impact of the deviation on the trial must be 
communicated by the principal investigator to the designated medical monitor. Any 
subsequent actions will be assessed by the designated medical monitor and documented. 
10.4 Subject Information and Consent 
Prior to the beginning of the study, the investigator must have received from the Ethics 
Committee (EC) 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 Good Clinical Practices (GCP) Guidelines (E6), in 
addition to, any other elements required by Japan regulations or institutional policy. 
Written informed consent must be obtained before any study-specific procedure takes place.  
Participation in the study and date of informed consent given by the subject should be 
documented appropriately in the subject’s files. A copy of the signed informed consent form 
must be provided to the subject. If applicable, it will be provided in a certified translation in 
the language understood by the subject, if not English.  Signed consent forms must remain in 
each subject’s study file and must be available for verification by study monitors at any time. 
10.5 Subject Confidentiality 
The information obtained during the conduct of this clinical study is confidential, and 
disclosure to third parties other than those noted below is prohibited. Information obtained 
during the conduct of this study will be used by the sponsor in connection with the 
development of the investigational product. The study investigator is obliged to provide the 
sponsor with complete test results and all data developed in this study. Subject-specific 
information may be provided to other appropriate medical personnel only with the subject’s 
permission. To ensure compliance with current ICH guidelines, data generated by this study 
must be available for inspection upon request by representatives of national and local health 
authorities, the sponsor, and the IRB/IEC for each study site. Study information from this 
protocol will be posted on clinicaltrials.gov and any local regulatory registry websites, as 
required by regulation. 
Subject names and other identifiers, such as photographs, audio, or videotapes, may not be 
disclosed in any publication without prior written authorization from the subject. 
10.6 Study Monitoring 
An authorized sponsor representative will conduct site visits to inspect study data, subjects’ 
medical records, and CRFs in accordance with ICH guidelines, GCPs, and the respective 
national and local government regulations and guidelines. 


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The investigator will permit authorized representatives of the sponsor and the respective 
national or local health authorities, other authorized regulatory authorities, and IRB/IEC to 
inspect facilities and records relevant to this study. 
10.7 Case Report Forms and Study Records 
For each subject consented, a case report form (CRF), in electronic format, will be supplied 
and maintained by the 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 for subject withdrawal must be recorded in 
the case report form. 
Entries made in the CRF must be verifiable against source documents. Source documents are 
defined as all medical records, medical notes, laboratory results, ECG traces and any 
additional document other than the CRF that has original subject information contained 
within it. 
All CRFs and source documents should be completed following GCPs and the CRO’s 
standard operating procedures. 
10.8 Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will monitor overall safety 
information during the bexagliflozin development program. The safety review activity and 
potential risk benefit assessments utilized by the DSMB will be defined in its charter. 
10.9 Protocol Violations/Deviations 
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 if an emergency occurs that requires a departure from the protocol for an individual 
subject can there be a departure without the sponsor’s pre-approval. The nature and reasons 
for the protocol deviation will be recorded in the subject’s CRF, and the principal 
investigator must notify the Sponsor. 
Protocol violations/deviations 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. 


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


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11 REFERENCE LIST 
American Diabetes, A. (2014). Standards of medical care in diabetes--2014. Diabetes Care 
37 Suppl 1, S14-80. 
JapanDiabetesSociety (2012). Treatment Guidance for Diabetes 2012-2013. 
Look, A.R.G., Wing, R.R., Bolin, P., Brancati, F.L., Bray, G.A., Clark, J.M., Coday, M., 
Crow, R.S., Curtis, J.M., Egan, C.M., et al. (2013). Cardiovascular effects of intensive 
lifestyle intervention in type 2 diabetes. The New England journal of medicine 369, 145-154. 
Matsuo, S., Imai, E., Horio, M., Yasuda, Y., Tomita, K., Nitta, K., Yamagata, K., Tomino, 
Y., Yokoyama, H., Hishida, A., et al. (2009). Revised equations for estimated GFR from 
serum creatinine in Japan. American journal of kidney diseases : the official journal of the 
National Kidney Foundation 53, 982-992. 
NationalResearchCouncil (2010). The Prevention and Treatment of Missing Data in Clinical 
Trials. In 978-0-309-15814-5, N.R. Council, ed., pp. 162. 
Palaniappan, L.P., Wong, E.C., Shin, J.J., Fortmann, S.P., and Lauderdale, D.S. (2011). 
Asian Americans have greater prevalence of metabolic syndrome despite lower body mass 
index. International journal of obesity 35, 393-400. 
Santer, R., Kinner, M., Lassen, C.L., Schneppenheim, R., Eggert, P., Bald, M., Brodehl, J., 
Daschner, M., Ehrich, J.H., Kemper, M., et al. (2003). Molecular analysis of the SGLT2 gene 
in patients with renal glucosuria. J Am Soc Nephrol 14, 2873-2882. 
Scheen, A.J., and Van Gaal, L.F. (2014). Combating the dual burden: therapeutic targeting of 
common pathways in obesity and type 2 diabetes. The lancet Diabetes & endocrinology 2, 
911-922. 
Schwartz, S., Fabricatore, A.N., and Diamond, A. (2012). Weight reduction in diabetes. 
Advances in experimental medicine and biology 771, 438-458. 
van den Heuvel, L.P., Assink, K., Willemsen, M., and Monnens, L. (2002). Autosomal 
recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter 
(SGLT2). Hum Genet 111, 544-547. 
 
 
 
 


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Appendix 1 
Schedule of Events 
 
Screen-
ing 
Washout 
Run-in 
Treatment 
Follo
w Up 
Visit number 
S1 
S2 
S3 
S4 
S5 
V1 
V2 
V3 
V4 
V5 
Time to Randomization (weeks)1 
up to 15 
weeks 
-12 
or -8 
-10 
or -6 
-2 
-0.5 
0 
2 
6 
12 
14 
Informed Consent 
X 
 
 
Screening for I/E criteria 
X 
X 
 
X 
Demographics and medical history 
X 
 
 
Diet & exercise counseling2 
X 
X 
 
Physical exam3 
X 
 
 
 
X 
 
 
 
X 
X 
Body weight 
X 
X 
 
 
X 
 
X 
X 
X 
X 
Diary & glucometer record review4 
X 
X 
X 
X 
X 
X 
X 
X 
Start washout 
X 
 
 
Dispense Run-in Medication 
X 
 
 
Randomization 
 
 
X 
Vital signs 
X 
X 
X 
 
X 
X 
X 
X 
ECG 
X 
 
X 
X 
X 
Dispense study medication5 
 
 
X 
Blood draw for clinical lab test6 
X 
 
X 
X 
X 
X 
X 
Population PK sampling 
 
 
 
 
 
 
X 
X 
X 
 
Urine collection7 
X 
X 
X 
X 
X 
X 
X 
X 
AE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Med 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 
Screening period may last up to 3 weeks; washout period will be 10 weeks for subjects on a TZD 
or 6 weeks for subjects on other OHA, which includes a clinic visit (S2) and a phone interview 
(S3); run-in period is to be 2 weeks (S4 to S5); the treatment period (V1 to V4) will be 12 weeks.  
A visit window of ± 3 days is allowed for all visits except visit V1.  Visit V1 is to be scheduled at 3 
days after visit S5 and can be extended to 5 days pending on HbA1c value availability. 
2 
Counseling will be performed at S2 for washout and at S4 for treatment naïve subjects. 
3 
A complete physical examination will be performed by the investigator at screening (S1) and at 
the termination visit (V5).  Abbreviated physical examinations will be performed by the 
investigator at all other time points, unless clinically indicated.  General assessment of the skin, 
heart, lungs and abdomen will be performed. 
4 
Glucometer and diary will be dispensed to each enrolled subject at visit S2 (for subjects 
undergoing washout) or S4 (for subjects not undergoing washout), and subjects will be trained in 
glucometer use and SMBG recording. The SMBG record will be reviewed by the investigator at 
all subsequent visits. 
5 
At visit V1, an investigational product kit will be dispensed; subjects should bring in their study 
medication to be checked on visits V2, V3, and V4. 
6 
Blood sample collection and laboratory tests at designated visits are listed in Appendix 2.  A 
minimum fasting time of 10 h must be confirmed prior to blood draw. 
7 
UPT is scheduled for all women at screening and for WOCBP thereafter. 


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Appendix 2 
Schedule of Laboratory Tests 
  
Screen
ing 
Washout 
Run-in 
Treatment Period 
FU 
Visit Number 
S1 
S2 
S3 
S4 
S5 
V1 
V2 
V3 
V4 
V5 
Time to Randomization (weeks) 
up to 3 
wks 
-12 or 
-8 
-10 
or -6 
-2 
0.5 
0 
2 
6 
12 
14 
Hematology1 
X 
  
  
  
X 
  
X 
  
X 
X 
Serum chemistry electrolytes1 
X 
  
  
  
X 
  
X 
  
X 
X 
Fasting Plasma Glucose1 
X 
  
  
X 
  
X 
X 
X 
X 
HbA1c 
X 
  
  
X 
  
X 
X 
X 
X 
Lipids2 
X 
  
  
  
X 
  
  
  
X 
X 
Infectious disease testing3 
X 
  
  
  
  
  
  
  
  
  
Urine drug screen4 
X 
  
  
  
  
  
  
  
  
  
Urinalysis5, 6 
X 
X 
  
X  
X 
  
X 
X 
 X 
X 
Urine pregnancy test (UPT)7 
X 
 X 
 
X  
X 
  
X 
X 
X 
X 
PK sampling8 
 
 
 
 
 
 
X 
X 
X 
 
Total blood drawn (mL) without PK 
28 
0 
0 
0 
22 
0 
16 
4 
22 
22 
Total blood drawn (mL) with PK 
28 
0 
0 
0 
22 
0 
18 
6 
24 
22 
1. Blood for clinical chemistry and hematology will be drawn after 10 h of fasting prior to 
breakfast (i.e. only water is allowed, no caloric intake).   
2. LDL-C will be calculated by the Friedewald equation. If triglycerides are > 400 mg/dL, the 
calculated LDL-C value is invalid by this equation and will be set as missing. Direct LDL-C will 
be determined in subjects whose baseline triglycerides are > 300 mg/dL.  All subsequent LDL-C 
of these subjects will be determined by the same direct LDL-C measurements only. 
3. Infectious disease testing will be conducted at screening only. 
4. Urine drug screen will be performed on screening visit only. Drug abuse screening includes 
amphetamines, barbiturates, cocaine metabolites, opiates, benzodiazepines, and cannabinoids.   
5. Urinalysis will be collected routinely at all clinic visits except S2 from a clean catch sample. 
Glucose in the urinalysis results must be suppressed from the laboratory report so the dosing 
blind can be maintained.  Testing strips with only the leucocytes and nitrate will be provided for 
immediate assessment at the clinical sites. 
6. UACR will be determined at screening only.  
7. Urine pregnancy test (UPT) will be performed for WOCBP at all clinic visits, except Visits S2. 
For surgically sterile or post- menopausal women, it will only be done at Visit S1. 
8. Blood samples for the population PK analysis will be drawn at or during the week of V2, V3, or 
V4 from 240 randomly selected subjects in participating trial centers. 
 
 


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Appendix 3 
Estimating Glomerular Filtration Rate 
The equation for estimating glomerular filtration rate (GFR) from serum creatinine is the 
isotope dilution mass spectrometry (IDMS)-traceable Modification of Diet in Renal Disease 
(MDRD) Study equation. This eGFR calculator applies serum creatinine (Scr) reported in 
mg/dL. 
The eGFR for non-Japanese subjects should be calculated based on following equation  
eGFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 × (Age)-0.203 x (0.742 if female) x (1.212 if 
African American)  
The eGFR for Japanese subjects should be calculated based on following equation (Matsuo et 
al., 2009) : 
eGFR (mL/min/1.73 m2) = 194 × (Scr)-1.094 × (Age)-0.287× (0.739 if female) 
 




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Appendix 5 
Investigator’s Signature 
Study Title: 
A Phase 2b, Multi-center, Double-blind, Placebo-controlled, Dose 
Range Finding Study to Evaluate the Effect of Bexagliflozin Tablets 
on HbA1c in Subjects with Type 2 Diabetes Mellitus 
Study Number: 
THR-1442-C-449 
Final Date: 
16 February 2015 
I have read the protocol described above. I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  
 
 
Signed: 
 
 
Date:  
 
Principal Investigator 
 
 
 
 

SAP_001.pdf: 
 
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Theracos Sub, LLC. 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 2b, Multi-center, Double-blind, Placebo-controlled, Dose Range Finding 
Study to Evaluate the Effect of Bexagliflozin Tablets on HbA1c in Subjects with 
Type 2 Diabetes Mellitus 
 
THR-1442-C-449 
 
 
 
SAP Version: 
Date of Statistical Analysis Plan: 
 
 
 
Version 1 
 
 
21 October 2015 
 
 
 
 
 
 
 
 
 




 
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DOCUMENT HISTORY 
Version 
Author 
Description 
1.0  
Monica Massaro 
New Document 
 
 
 


 
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Table of Contents 
1 
INTRODUCTION .............................................................................................. 10 
2 
STUDY SUMMARY.......................................................................................... 10 
2.1 
STUDY OBJECTIVES ................................................................................ 10 
2.2 
STUDY DESIGN ......................................................................................... 11 
2.2.1 
Number of Subjects............................................................................... 11 
2.2.2 
Randomization and Blinding Procedures.............................................. 12 
2.2.3 
Efficacy Assessments............................................................................ 12 
2.2.4 
Safety Assessments ............................................................................... 13 
2.2.5 
Other Assessments ................................................................................ 13 
3 
STATISTICAL METHODS ............................................................................... 17 
3.1 
General Methods .......................................................................................... 17 
3.1.1 
Computing Environment ....................................................................... 17 
3.1.2 
Reporting of Numerical Values ............................................................ 17 
3.1.3 
Significance Level ................................................................................ 17 
3.1.4 
Multiplicity ........................................................................................... 17 
3.1.5 
Baseline and Change from Baseline ..................................................... 18 
3.1.6 
Study Day.............................................................................................. 18 
3.1.7 
Handling of Missing/Incomplete Values .............................................. 18 
3.1.8 
Methods of Pooling Data ...................................................................... 18 
3.1.9 
Analysis Visit Windows ....................................................................... 18 
3.2 
Analysis Populations and Subgroups ........................................................... 19 


 
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3.2.1 
Definition of Analysis Populations ....................................................... 19 
3.2.2 
Definition of Subgroups ........................................................................ 21 
3.3 
Analysis Variables........................................................................................ 21 
3.3.1 
Primary Efficacy Variable .................................................................... 21 
3.3.2 
Secondary Efficacy Variables ............................................................... 21 
3.3.3 
Safety Variables .................................................................................... 21 
3.3.4 
Other Variables ..................................................................................... 21 
3.4 
Subjects Disposition and Evaluability ......................................................... 22 
3.4.1 
Subject Disposition ............................................................................... 22 
3.4.2 
Protocol Deviations ............................................................................... 22 
3.5 
Demographics and Baseline Characteristics ................................................ 23 
3.5.1 
Demographics ....................................................................................... 23 
3.5.2 
Screening Characteristics ...................................................................... 23 
3.5.3 
Disease Characteristics ......................................................................... 23 
3.5.4 
Medical History .................................................................................... 23 
3.6 
Prior and Concomitant Medications ............................................................. 24 
3.7 
Treatment Compliance and Exposure .......................................................... 25 
3.7.1 
Compliance with Study Treatment ....................................................... 25 
3.7.2 
Exposure to Study Treatment................................................................ 25 
3.8 
Efficacy Analysis ......................................................................................... 26 
3.8.1 
Primary Efficacy Endpoint(s) ............................................................... 26 
3.8.2 
Secondary Efficacy Endpoints .............................................................. 29 


 
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3.9 
Safety Analysis ............................................................................................. 29 
3.9.1 
Adverse Events ..................................................................................... 29 
3.9.2 
Clinical Laboratory Evaluation ............................................................. 33 
3.9.3 
Vital Signs ............................................................................................. 34 
3.9.4 
ECG....................................................................................................... 34 
3.9.5 
Physical Examination and Body Weight .............................................. 35 
3.10 
Independent Data Monitoring Committee ................................................ 35 
4 
Programming Specifications ............................................................................... 36 
5 
List of Tables, Figures and Listings .................................................................... 38 
5.1 
List of Tables ................................................................................................ 38 
5.2 
List of Figures .............................................................................................. 42 
5.3 
List of Listings ............................................................................................. 43 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Full Term 
ADA 
American Diabetes Association 
AE 
Adverse Event 
AIC 
Akaike’s Information Criteria 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic Therapeutic Class 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CA 
Calcium 
CI 
Confidence Interval 
Cl 
Chloride 
CSR 
Clinical Study Report 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FPG 
Fasting Plasma Glucose 
GMI 
Genital Mycotic Infection 


 
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Abbreviation 
Full Term 
HbA1c 
Hemoglobin A1c 
HCO3 
Bicarbonate 
HDL-C 
High-density Lipoprotein Cholesterol 
ICF 
Informed Consent Form 
IDMC 
Independent Data Monitoring Committee 
IWRS 
Interactive Web Response System 
K 
Potassium 
LDL-C 
Low-density Lipoprotein Cholesterol 
LOCF 
Last Observation Carried Forward 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary of Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Model Repeated Measures 
Na 
Sodium 
NYHA 
New York Health Association 
OHA 
Oral Hypoglycemic Agent 
PK 
Pharmacokinetic 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 


 
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Abbreviation 
Full Term 
RBC 
Red Blood Cell 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
T2DM 
Type 2 Diabetes Mellitus 
TC 
Total Cholesterol 
TG 
Triglycerides 
TEAE 
Treatment-Emergent Adverse Event 
UN 
Unstructured 
UTI 
Urinary Tract Infections 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
Women of Childbearing Potential 


 
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1 INTRODUCTION 
Study THR-1442-C-449 is a Phase 2b, multi-center, double-blind, placebo-controlled, 
dose range finding study.  The goals of the study are to evaluate the efficacy and 
safety of once daily bexagliflozin at 5 mg, 10 mg and 20 mg strengths compared to 
placebo in either treatment-naïve type 2 diabetic subjects or subjects previously 
treated with one oral hypoglycemic agent (OHA) and to identify the optimal dose(s) 
for further clinical study.   
The statistical analysis plan (SAP) contains a detailed description of the data 
presentations and statistical analyses that will be included in the clinical study report 
(CSR) for Protocol THR-1442-C-449.  The statistical methods and analyses described 
here are based on those presented in Section 9 of the study protocol (Version 2: 16 
February 2015).   
Blood samples for a population pharmacokinetic (PK) analysis will be collected and 
the required plasma concentration determined, however, the PK parameters will be 
assessed separately as a population PK analysis (i.e., the population PK analysis will 
not be described in this SAP). 
2 STUDY SUMMARY 
2.1 
STUDY OBJECTIVES 
Primary Objective 
 To identify dose(s) of bexaglifloxin for further clinical study through the 
comparison of hemoglobin A1c (HbA1c) change from baseline in each active 
group that will receive bexagliflozin tablets, 5 mg, 10 mg or 20 mg, to the 
placebo group over 12 weeks of treatment 
Secondary Objectives 
 To assess the change in HbA1c over time 
 To assess the efficacy of bexagliflozin in lowering fasting plasma glucose 
(FPG) as a function of time 
 To assess the efficacy of bexagliflozin based on the proportion of subjects 
who reach the American Diabetes Association (ADA) and the Japan Diabetes 
Society target HbA1c of <7% 
 To assess the effect of bexagliflozin on systolic and diastolic blood pressure 
over time  


 
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 To assess the effect of bexagliflozin on body weight over time 
 To assess the safety of bexagliflozin in subjects with type 2 diabetes mellitus 
(T2DM) 
Other Exploratory Objective 
 Population PK evaluation of bexagliflozin plasma concentration 
2.2 
STUDY DESIGN 
A brief summary of the main study design features and assessments to be performed 
is presented here.  Refer to Section 3 of the study protocol for complete details. 
This is a Phase 2b, multi-center, double-blind, placebo-controlled parallel group, dose 
range finding study of once daily bexagliflozin tablets in either treatment-naïve type 2 
diabetes subjects or subjects previously treated with one OHA.  Treatment-naïve 
subjects are those who have never received prescription anti-diabetic medications or 
who have received no more than 14 days of prescription medications for diabetes in 
the 12 weeks prior to enrollment.  Subjects who meet all of the inclusion criteria, 
none of the exclusion criteria and who consent to participate in the study are eligible 
to be enrolled to complete a 6 to 10 week washout (only required if the subject is not 
treatment naïve), and a 2 week placebo run-in period prior to being randomized.  
Subjects who can adhere to the run-in medication dosing scheduled (i.e., miss no 
more than one dosage in 2 weeks) and who have HbA1c between 7 and 8.5% at 
baseline will be eligible for randomization.  Eligible subjects will be randomized to 
receive oral bexagliflozin tablets, 5, 10, 20 mg or placebo, once daily for 12 weeks in 
an outpatient setting.  Subjects will visit their study site at weeks 2, 6 and 12 for 
safety and efficacy evaluation, with a follow up visit at week 14.      
2.2.1 Number of Subjects 
Approximately 320 subjects will be randomized into this study, with approximately 
80 subjects in the placebo group and 80 subjects in each of the three bexagliflozin 
treatment groups (5 mg, 10 mg and 20 mg).  
The study will be conducted at multiple investigative sites and will likely involve 
variable numbers of subjects at each site.  Enrollment will be on a competitive basis 
but each site will be capped at 32 subjects.  Activation of investigational sites will be 
centrally controlled by interactive web response system (IWRS).  Subject 
randomization will be deactivated for all sites when the planned number of subjects is 
met.  However, if a potential subject is in the washout period and wishes to 
participate in the study, the subject will be allowed to continue and, if eligible, to be 
randomized.    


 
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2.2.2 Randomization and Blinding Procedures 
Eligible subjects, who sign the informed consent form (ICF), complete the run-in 
period and meet all inclusion/exclusion requirements will be randomized in a 1:1:1:1 
ratio on Day 1 (Visit 1 – Treatment Phase) to receive investigational product 
according to a computer-generated randomization schedule.  Subjects will be 
assigned to treatment groups in sequential order as they qualify for the study, using a 
centrally located and managed IWRS.  Randomization will be stratified according to 
background anti-diabetic treatment status (treatment naïve or taking one OHA). Upon 
randomization, each subject will receive a subject randomization number and a drug 
kit assignment.      
This is a double-blind, placebo-controlled study.  The sponsor, investigators, study 
coordinators, pharmacists, study subjects and the cardiovascular adjudication 
committee members will be blinded to the study medication.  To maintain blinding of 
the individual treatment assignment, the results of urinary glucose testing will not be 
made available to any study personnel or subjects.   
If knowledge of the treatment is needed to manage the subject’s condition, the 
investigator will contact the IWRS to obtain the treatment assignment.  If unblinding 
occurs for any reason, the time and reason for breaking the blind will be recorded on 
the electronic case report form (eCRF) and the sponsor must be notified within 24 
hours.   
A designated statistician who is not involved with the study operation will hold the 
treatment codes.  The unblinded treatment information can be provided to the Data 
Safety Monitoring Board (DSMB) to facilitate the evaluation of any clinically 
important increase in the rate of a serious suspected adverse reaction or to the 
designated safety contact when the treatment information is required to determine if 
an expedited safety report must be submitted to regulatory agencies.  
The treatment assignment will continue to be withheld from the cardiovascular 
adjudication committee members until all global investigational studies are completed 
and a meta-analysis to assess cardiovascular risk is conducted.     
2.2.3 Efficacy Assessments 
Efficacy assessments will include blood draws for a glycemic control laboratory 
panel, including HbA1c and FPG, body weight, and systolic and diastolic blood 
pressure (BP). 
Blood samples for HbA1c and FPG will be obtained at Screening (Visit S1), Run-in 
(Visit S5), Treatment Period Visits 2, 3, 4 and Follow-up Visit 5.  Body weight will 
be measured at Screening (Visit S1), Washout (Visit S2), Run-in (Visit S5), 
Treatment Period Visits 2, 3, 4 and Follow-up Visit 5.  Supine, sitting and standing 


 
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BP measurements will be obtained at Screening (Visit S1), Run-in (Visits S4 and S5), 
Treatment Period Visits 2, 3, 4 and Follow-up Visit 5. 
2.2.4 Safety Assessments 
Adverse event (AE) occurrences will be recorded throughout the study.  For non-
serious AEs, documentation will start from the time the subject signs the ICF until the 
last scheduled contact.  For serious adverse events (SAEs), documentation will start 
from the time the subject signs the ICF through 14 days after the last treatment, or for 
ongoing events, until the event is resolved or the subject is lost to follow-up.  Careful 
evaluation and documentation of the following potential adverse events of special 
interest, as outlined in Sections 6.10.6 through 6.10.9 of the Protocol, will also occur 
throughout the study: urinary tract infections (UTIs), genital mycotic infections 
(GMIs), hepatotoxicity and hypoglycemia. 
A complete physical examination will be performed at Screening (Visit S1) and at the 
Follow-up Visit 5.  Unless clinically indicated, an abbreviated physical examination 
will be performed at Run-in (Visit S5) and Treatment Period Visit 4.  Vital sign 
measurements (supine, sitting and standing blood pressure, pulse, temperature and 
respiratory rate) will be performed at Screening (Visit S1), Run-in (Visits S4 and S5) 
and Treatment Period Visits 2, 3, 4 and Follow-up Visit 5.  A 12-lead 
electrocardiogram (ECG) will be conducted at Screening (Visit S1), Run-in (Visit 
S5), Treatment Period Visit 4, Follow-up Visit 5 and whenever clinically indicated.  
ECG measurements include RR interval, PR interval, QRS duration, QTcB, P wave 
axis and QRS axis, overall interpretation.  Each ECG should also be assessed by the 
investigator for signs of ischemia, clinically significant hypertrophy, and clinically 
significant T-wave abnormalities. 
Clinical laboratory tests, including hematology, serum chemistry and electrolytes, 
lipids, infectious disease testing, urine drug screen, urinalysis and urine pregnancy 
test [women of childbearing potential (WOCBP) only], will all be obtained at 
Screening (Visit S1).  Hematology, serum chemistry and electrolytes samples will 
also be obtained at Run-in (Visit S5), Treatment Period Visits 2, 4 and Follow-up 
Visit 5.  Serum lipids will be obtained at Run-in (Visit S5), Treatment Period Visit 4 
and Follow-up Visit 5.  Urinalysis and urine pregnancy test (WOCBP only) will be 
obtained at Washout (S2), Run-in (Visits S4 and S5), Treatment Period Visits 2, 3, 4 
and Follow-up Visit 5.            
2.2.5 Other Assessments 
Other assessments include concomitant medication use throughout the study and 
compliance with study drug administration.  Compliance is reviewed at each visit 
after investigational product has been dispensed.  In addition, for subjects who fail to 


 
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complete the study (through follow-up) or treatment, the reason for study or treatment 
discontinuation will be recorded. 
Blood samples for the population PK analysis will be drawn at Treatment Period 
Visits 2, 3 and 4.     
. 
 
 


 
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Table 1.  Schedule of Events 
 
Screen
-ing 
Washout 
Run-in 
Treatment 
Follow 
Up 
Visit number 
S1 
S2 
S3 
S4 
S5 
V1 
V2 
V3 
V4 
V5 
Time to Randomization (weeks)1 
up to 
15 
weeks 
-12 
or -8 
-10 
or -6 
-2 
-0.5 
0 
2 
6 
12 
14 
Informed Consent 
X 
 
 
Screening for I/E criteria 
X 
X 
 
X 
Demographics and medical history 
X 
 
 
Diet & exercise counseling2 
X 
X 
 
Physical exam3 
X 
 
 
 
X 
 
 
 
X 
X 
Body weight 
X 
X 
 
 
X 
 
X 
X 
X 
X 
Diary & glucometer record review4 
X 
X 
X 
X 
X 
X 
X 
X 
Start washout 
X 
 
 
Dispense Run-in Medication 
X 
 
 
Randomization 
 
 
X 
Vital signs 
X 
X 
X 
 
X 
X 
X 
X 
ECG 
X 
 
X 
X 
X 
Dispense study medication5 
 
 
X 
Blood draw for clinical lab test6 
X 
 
X 
X 
X 
X 
X 
Population PK sampling 
 
 
 
 
 
 
X 
X 
X 
 
Urine collection7 
X 
X 
X 
X 
X 
X 
X 
X 
AE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Med 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 
Screening period may last up to 3 weeks; washout period will be 10 weeks for subjects on a TZD or 6 weeks 
for subjects on other OHA, which includes a clinic visit (S2) and a phone interview (S3); run-in period is to 
be 2 weeks (S4 to S5); the treatment period (V1 to V4) will be 12 weeks.  A visit window of ± 3 days is 
allowed for all visits except visit V1.  Visit V1 is to be scheduled at 3 days after visit S5 and can be extended 
to 5 days pending on HbA1c value availability. 
2 
Counseling will be performed at S2 for washout and at S4 for treatment naïve subjects. 
3 
A complete physical examination will be performed by the investigator at screening (S1) and at the 
termination visit (V5).  Abbreviated physical examinations will be performed by the investigator at all other 
time points, unless clinically indicated.  General assessment of the skin, heart, lungs and abdomen will be 
performed. 
4 
Glucometer and diary will be dispensed to each enrolled subject at visit S2 (for subjects undergoing 
washout) or S4 (for subjects not undergoing washout), and subjects will be trained in glucometer use and 
SMBG recording. The SMBG record will be reviewed by the investigator at all subsequent visits. 
5 
At visit V1, an investigational product kit will be dispensed; subjects should bring in their study medication 
to be checked on visits V2, V3, and V4. 


 
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6 
Blood sample collection and laboratory tests at designated visits are listed in Appendix 2 of the Protocol.  A 
minimum fasting time of 10 h must be confirmed prior to blood draw. 
7 
UPT is scheduled for all women at screening and for WOCBP thereafter. 


 
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3 STATISTICAL METHODS  
3.1 
General Methods 
3.1.1 Computing Environment 
All statistical analyses will be performed using SAS® Version 9.4 or higher.   
3.1.2 Reporting of Numerical Values 
All clinical study data will be presented in subject data listings.  Data summaries will 
use descriptive statistics (number of subjects [n], mean, standard deviation [SD], first 
quartile [Q1], median, third quartile [Q3], minimum and maximum) for continuous 
variables, and frequency and percentage for categorical and ordinal variables.  If there 
are missing values, the number of missing will be presented, but without a 
percentage.   
Means, medians and confidence intervals (CIs) will be reported to one decimal place 
more than what is reported on the eCRF or by the laboratory/vendor.  Standard 
deviations will be reported to two decimal places more than what is reported in the 
data.  Interquartile range values (Q1 and Q3) and minimum and maximum values will 
be reported to the same number of decimal places displayed on the eCRF or by the 
laboratory/vendor.   
P-values will be reported to four decimals.   
3.1.3 Significance Level 
Inferential treatment comparisons on efficacy endpoints will be declared statistically 
significant at the 0.050 level using two-tailed tests.  There will be no adjustments 
made for multiple comparisons.  Tests for interaction will be declared statistically 
significant at the 0.100 level. 
All confidence intervals will be two-sided 95% CIs.        
3.1.4 Multiplicity 
The primary objective of this study is to identify the effect of bexagliflozin tablets in 
three strengths on the placebo-corrected change from baseline in HbA1c after 12 
weeks of treatment.  All secondary endpoints are considered exploratory and 
adjustment for multiple endpoints and multiple comparisons within each endpoint 
will not be performed.   


 
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3.1.5 Baseline and Change from Baseline 
Baseline is defined as the last non-missing value obtained immediately prior to 
administration of the first dose.  For each post-baseline value, change from baseline 
will be calculated by subtracting the baseline assessment value from the post-baseline 
assessment for each subject (i.e., post-baseline assessment – baseline assessment). 
3.1.6 Study Day 
Subjects will be randomized and the first dose of investigational product during the 
Treatment Period will be considered Day 1.  Study day for event dates prior to 
randomization and first dose will be determined as Study Day = (Event Date – 
Treatment Period First Dose Date).  Study day for events after randomization and 
treatment period first dose will be determined as Study Day = (Event Date – 
Treatment Period First Dose Date) + 1. 
3.1.7 Handling of Missing/Incomplete Values 
To the extent possible, attempts will be made to minimize the amount of missing data 
through measures planned in the study conduct.  However, if missing data are present 
for the primary efficacy endpoint, HbA1c, they will be handled using a multiple 
imputation approach, as a part of a sensitivity analysis, as described in Section 3.8.1 
of the SAP.  For all other endpoints, the missing data will not be imputed and only the 
observed data will be used for analyses.  The number, timing, pattern, reason for and 
possible implications of missing values in efficacy and safety assessments will be 
investigated.  The dropout patterns may be assessed by graphical methods (e.g., 
Kaplan-Meier plot for time to drop-out).   
Rules for handling missing dates are outlined within applicable sections. 
3.1.8 Methods of Pooling Data 
Pooling of subjects from different study centers may be done to ensure a sufficient 
number of subjects per treatment arm for analyses that include study center as a 
model effect.  Therefore, pooling will be done in the case where there is at least one 
study center with fewer than 5 subjects in the per protocol analysis set per treatment 
arm.  Study centers will be pooled based on geographical region (i.e., closest 
geographical site) within each country.  Study center pooling will be determined 
during a blinded review of the data prior to database lock. 
3.1.9 Analysis Visit Windows 
Visit windows for study conduct are specified in footnote 1 of Table 1: Schedule of 
Events.  Treatment period visits are planned for Day 1, Randomization (V1: Week 0), 


 
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Day 15 (V2: Week 2), Day 43 (V3: Week 6) and Day 85 (V4: Week 12).  There is 
also a scheduled follow-up visit at Day 99 (V5: Week 14).  A visit window of ±3 days 
is allowed for all visits except for Week 0.  Week 0 (Study Day 1, Randomization) is 
to be scheduled at 3 days after the last run-in visit (Visit S5) and can be extended to 5 
days pending on HbA1c value availability. 
For any unscheduled visits, Table 2 will be used to map the unscheduled assessments 
to the analysis visits prior to selection of records for analysis 
Table 2: Nominal (Targeted) Time Points and Analysis Visit Windows 
Assessment 
Nominal (Targeted) Time 
Point 
Analysis Visit Window 
(Interval in Study Days) 
Baseline Assessments 
Week 0 (Study Day 1) 
≤ Day 1 
 
 
 
Post-Baseline Assessments 
Week 2 (Study Day 15) 
Day 8 through Day 22 
 
Week 6 (Study Day 43) 
Day 36 through Day 50 
 
Week 12 (Study Day 85) 
Day 78 through Day 92 
 
Week 14 (Study Day 99) 
Day 93 through Day 105 
After mapping the data to the analysis visits, the following rules will apply unless 
otherwise 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 first record will be 
selected. 
 If a subject has no record in an analysis window, the subject will be 
considered missing at that time point. 
For subjects withdrawing early, the end of study data (early termination visit) will be 
mapped according to the analysis visit windows in Table 2 for summarization and 
analysis.  However, if the visit does not fall within any of the analysis visit windows 
then the visit will be mapped to the next scheduled time point.     
3.2 
Analysis Populations and Subgroups 
3.2.1 Definition of Analysis Populations 
All Enrolled 
All subjects who signed an informed consent form will be included in the all enrolled 
analysis set. 


 
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Full Analysis Set 
All subjects who are randomized, take at least one dose of double-blind study 
medication, and have at least one post-randomization HbA1c measurement will be 
included in the full analysis set.  All analyses of the full analysis set will be based on 
each subject’s randomized assigned treatment. 
Intent-to-Treat Analysis Set 
All subjects who are randomized will be included in the intent-to-treat analysis set.  
All analyses of the intent-to-treat analysis set will be based on each subject’s 
randomized assigned treatment.   
Safety Analysis Set 
All subjects who are randomized and take at least one dose of double-blind study 
medication will be included in the safety analysis set.  Safety analyses will be based 
on the medication that was actually dispensed to each subject. 
Per Protocol Analysis Set 
The per protocol (PP) analysis set will include all subjects in the full analysis set who 
meet the study eligibility requirements as defined in Section 4 of the study protocol 
and have no major protocol deviations that affect the validity of the efficacy 
measurements.  All analyses of the per protocol analysis set will be based on each 
subject’s randomized assigned treatment.  Major protocol deviations are defined as: 
 Study drug compliance <80% 
 Missing baseline or Week 12 HbA1c measurement 
 Received prohibited medication including SGLT2 inhibitor, insulin or GLP-1 
receptor agonists 
 Randomization error 
 Inappropriate unblinding (i.e., blind was broken (requested in IWRS) in 
absence of medical emergency or blind broken by unauthorized site 
personnel) 
 Subject was dispensed with incorrect study medication  
Subject exclusions will be determined on a case-by-case basis during a blinded 
review of the data prior to database lock.  In addition, a blinded review of 
concomitant medications will be performed to further identify any other potential 
restricted medications.   


 
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3.2.2 Definition of Subgroups 
Consistency of treatment effects across country (USA versus Japan) will be examined 
through the addition of a treatment-by-country interaction term to the statistical 
model for the primary efficacy endpoint.  This is described in Section 3.8.1 of the 
SAP.  No other subgroup analyses are planned. 
3.3 
Analysis Variables 
3.3.1 Primary Efficacy Variable 
 Change in HbA1c from baseline to Week 12 
3.3.2 Secondary Efficacy Variables 
 Change in HbA1c from baseline over time 
 Change in FPG from baseline over time 
 Percentage of subjects with HbA1c <7% post-baseline 
 Change in systolic and diastolic blood pressure from baseline over time 
 Change in body weight from baseline over time 
3.3.3 Safety Variables 
 Incidence of adverse events 
 Percentage of subjects with a hypoglycemic event post-baseline 
 Change in clinical laboratory parameters from baseline to each post-baseline 
assessment  
 Shift in clinical laboratory parameters from baseline to each post-baseline 
assessment  
 Change in vital sign measurements from baseline to each post-baseline 
assessment 
 Change in ECG parameters from baseline to each post-baseline assessment 
3.3.4 Other Variables 
 Incidence of discontinuations and reasons for discontinuations from the study 
and, separately, from treatment 
 Incidence of concomitant medications used 


 
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 Number of weeks on study drug 
 Percentage of study drug taken relative to the planned dose 
3.4 
Subjects Disposition and Evaluability 
3.4.1 Subject Disposition 
Subject disposition will be summarized overall (all subjects) and then separately by 
country (USA and Japan).  The overall number of subjects screened will be presented.  
The number of subjects randomized to treatment (intent-to-treat analysis set) and the 
number of subjects evaluated for safety (safety analysis set) will be presented by 
treatment group and overall.  The number and percentage of subjects evaluated for 
efficacy (full and per protocol analysis sets) will be presented by treatment group and 
overall.  The numbers and percentages of subjects completing and not completing the 
study through follow-up as well as the reasons for study discontinuations will be 
tabulated by treatment group and overall.  In addition, the number and percentage of 
subjects completing and not completing treatment through week 12 as well as reasons 
for treatment discontinuations will be presented by treatment group and overall. 
The demographic information for screen failures and run-in failures as well as reasons 
for their failures will be listed.   
Screen failures are subjects who sign the informed consent but who have failed 
screening (e.g., subject did not meet eligibility criteria, subject withdrew consent) at 
Screening (Visit S1), Washout (Visit S2) or at the Phone Interview (Visit S3).  
Subjects who did not have study medication dispensed at the start of the Run-in 
Period (Visit S4) are also considered screen failures.   
A run-in failure is defined as a subject who signs the informed consent but is deemed 
ineligible for the study (e.g., subject did not meet entry criteria, subject withdrew 
consent) after start of the Run-in Period but prior to randomization (Visit S5). 
3.4.2 Protocol Deviations 
All protocol deviations will be shown in a subject listing by treatment group. Subjects 
with major deviations identified as exclusions from the per-protocol analysis set will 
be indicated in the listing.   


 
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3.5 
Demographics and Baseline Characteristics 
If the full and intent-to-treat analysis sets are different from the safety analysis set 
then demographic and baseline characteristic analyses will be repeated using the full 
and intent-to-treat analysis sets.   
3.5.1 Demographics  
Subject demographics including age, gender, race, ethnicity, country and study center 
will be summarized by treatment group and overall for the safety analysis set.   
Descriptive statistics will be provided for age (years).  Frequencies and percentages 
will be tabulated for gender, race, ethnicity, country and study center. 
3.5.2 Screening Characteristics 
Subject baseline characteristics including screening body weight, height and body 
mass index (BMI) will be summarized by treatment group and overall for the safety 
analysis set.   
Descriptive statistics will be provided for screening body weight (kg), height (cm) 
and BMI (kg/m2).   
3.5.3 Disease Characteristics 
Subject disease characteristics including prior anti-diabetic treatment status, disease 
duration since diagnosis and episodes of symptomatic hypoglycemia per week will be 
summarized by treatment group and overall for the safety analysis set.   
Descriptive statistics will be provided for disease duration since diagnosis (years).  
Disease duration is based on the year of first diagnosis and the year of informed 
consent signature (i.e., year of informed consent signature – year of first diagnosis).  
A value of 0 year means that the subject was diagnosed in the same year when 
informed consent was signed.  Frequencies and percentages will be tabulated for prior 
anti-diabetic treatment status (whether treatment naïve or not) and for how many 
episodes of symptomatic hypoglycemia per week a subject experienced on average 
over the past year (0, 1, 2, 3 and more than 3).   
3.5.4 Medical History 
All significant medical and surgical history conditions will be coded using the 
Medical Dictionary of Regulatory Activities (MedDRA, Version 17.0) and will be 
classified by MedDRA system organ class (SOC) and preferred term (PT).  Medical 
and surgical history conditions will be included in a subject data listing.  Type 2 


 
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diabetes history and cardiovascular disease history will also be included in subject 
data listings.   
3.6 
Prior and Concomitant Medications 
All medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD, Version B2 June 2014).  A concomitant medication is defined as any 
medication that the subject has taken prior to enrollment and that the subject is 
expected to continue to take for some portion of the study as well as any medication 
other than the double-blind study medication that the subject takes during the course 
of the study.  Medications used for controlling hypoglycemia will be recorded as 
concomitant medications in the eCRF. 
Medications started prior to administration of the double-blind study medication will 
be identified as prior medications and included in a subject data listing only.  
Medications ongoing during the treatment period or started on or after administration 
of double-blind study medication will be summarized for the safety analysis set.  The 
number and percentage of subjects who took at least one medication during the 
double-blind period as well as the number and percentage of subjects who took each 
type of medication will be presented for each treatment group and all active treatment 
groups combined.  Medications will be listed according to their WHO-DD anatomic 
therapeutic chemical (ATC) class level 4 and preferred drug name within ATC class 
level 4 by decreasing frequency of incidence for all active treatment groups 
combined. 
 Rescue Medications 
Any medication given to treat hyperglycemia is considered a rescue therapy 
only if it is continued for 2 weeks or longer.  Rescue medications will be 
identified by review of  concomitant medication data, specifically the WHO-
DD preferred drug name, indication field and duration of use (start and stop 
dates), during a blinded review of the data prior to database lock.  Missing or 
partial start and stop dates for rescue medications taken during the double-
blind treatment period are not expected, however if there are missing or partial 
start dates for rescue medications the same rules for handling missing or 
partial adverse event start dates will be applied (see Section 3.9.1).  Missing or 
partial stop dates for rescue medications will not be imputed.  Unless it is 
obvious from review of the partial stop date that the medication given to treat 
hyperglycemia could not have continued for 2 weeks or longer, it will be 
considered a rescue medication.  Medications given to treat hyperglycemia 
with missing stop dates will be considered rescue medications. 


 
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Time to administration of first rescue medications will be summarized for the 
safety analysis set.  Time to rescue medication use is derived by [(date of 
rescue medication – date of first study medication dose) +1 day] / 7.  The 
number and percentage of subjects who took at least one rescue medication 
during the double-blind period as well as the number and percentage of 
subjects who took their first rescue medication during the intervals of <=2 
weeks, >2 weeks - <=6 weeks, >6 weeks - <=12 weeks and > 12 weeks from 
administration of first double-blind study drug will be tabulated by treatment 
group and all active treatment groups combined. 
3.7 
Treatment Compliance and Exposure 
3.7.1 Compliance with Study Treatment 
Compliance rates during the treatment period will be derived with the following 
formula: 
100*((Total number of tablets dispensed – Total number of tablets returned) / 
(Expected number of tablets to be taken over a subject’s extent of exposure in days)) 
Expected number of tablets to be taken over a subject’s extent of exposure is based on 
the date of first study medication dose and the date of last study medication dose [i.e., 
(date of last study medication dose – date of first study medication dose) +1].  If a 
subject is lost to follow-up, and therefore does not have a date of last study 
medication dose, the last visit date will be used as the date of last study dose to 
determine the expected number of tablets to be taken and it will be assumed that the 
subject did not take any tablets since the last visit date.   
Compliance rates will be presented for the safety analysis set using summary statistics 
and percentage for the frequency distributions (0-<20%, 20-<40%, 40-<60%, 60-
<80%, 80-<100%, 100-≤120%) by treatment group and overall. 
3.7.2 Exposure to Study Treatment 
Treatment duration (weeks on treatment) will be described in the safety analysis set 
using summary statistics.  Treatment duration will be calculated as follows: [(date of 
last study medication dose – date of first study medication dose) + 1 day] / 7.  
Summaries will also include the number and percentage of subjects who were 
exposed for at least 2, >2 - ≤6, >6 - ≤12, and >12 - ≤13 weeks. 
If the last dose date is unknown, the date of the last visit will be used. 


 
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3.8 
Efficacy Analysis 
Unless otherwise specified, all efficacy analyses will be performed using the full 
analysis set. 
3.8.1 Primary Efficacy Endpoint(s) 
The primary endpoint is HbA1c change from baseline through 12 weeks, and the 
primary analysis is based on the available data and data obtained after rescue will be 
excluded and considered missing.  Mixed model repeated measures (MMRM) 
analysis of covariance model (ANCOVA) with baseline HbA1c as a covariate will be 
fit to the available data, incorporating all visits at which HbA1c was measured for 
each subject including scheduled visits at Weeks 2, 6, and 12 as well as unscheduled 
visits for measurements of HbA1c.  Treatment (placebo, 5 mg, 10 mg, 20 mg), study 
center, prior anti-diabetic treatment status, study visit and treatment-by-visit 
interaction will be applied as fixed effects and subject as a random effect.   
A normal distribution will be assumed for the built-in probability distribution.  Model 
assumption will be checked.  An unstructured (UN) within-subject covariance 
structure will also be assumed.  The Kenward-Roger approximation will be used to 
estimate the denominator degrees of freedom.   
Sample SAS code for this analysis is as follows: 
proc mixed data=temp method=reml covtest; 
 
class subject visit treat prior center; 
model change = visit treat prior center baseline visit*treat / 
solution ddfm=KENWARDROGER;  
repeated visit / subject=subject type=un; 
 
lsmeans visit*treat / diff=all cl alpha=0.05; 
run; 
In the case that this covariance matrix is not an appropriate estimate, other covariance 
structures (e.g., compound symmetry) will be considered and ultimately determined 
through graphical tools (i.e., plot of changes in covariance and correlation among 
residuals on the same subject over lag between times of observation) and information 
criteria [e.g., Akaike’s Information Criteria (AIC)].  
Descriptive statistics will be presented for the observed measurements as well as for 
change from baseline by treatment group and visit overall (all subjects) and by 
country.     
Least squares (LS) means and the corresponding standard errors (SE) of the change 
from baseline over time will be presented by treatment. In addition, the time profile of 
these LS mean and SE values will be presented graphically. 


 
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Least squares means and the corresponding standard errors for the difference in the 
changes from baseline over time between each bexagliflozin dose group and placebo 
will also be presented. Two-sided 95% CIs for the difference in these changes 
between each active dose and placebo will be generated. P-values from the model 
effects and key comparisons (i.e., treatment difference at Week 12) will be presented. 
 Sensitivity Analyses 
The same MMRM model and methods as outlined above for the primary 
analysis will be repeated using the per protocol analysis set.   
Missing Data 
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 sensitivity analyses will be performed on the primary efficacy 
variable for the full analysis set: 
1) HbA1c values collected after start of rescue medication will be considered 
missing.  Missing HbA1c data (for Weeks 2, 6, or 12) will be imputed 
through multiple imputation (MI) linear regression methods which 
assumes a monotone missing data pattern.  If the missing data pattern does 
not follow a monotone missing data then the Markov Chain Monte Carlo 
(MCMC) method will be used.  The covariates to be included in the 
imputation linear regression model are treatment, center, age, gender, race, 
BMI, prior anti-diabetic treatment status as well as previous visit HbA1c 
values.  A total of 10 imputed datasets will be generated and then analyzed 
using the MMRM methods as outlined above for the primary analysis.  
The point and variance estimates from each of these 10 analyses will be 
calculated.  These analyses results will be combined across the 10 datasets 
using the standard techniques for multiple imputed data sets through SAS 
PROC MIANALYZE in order to yield overall treatment comparison 
results on imputed data.   
 
2) Missing HbA1c data will be imputed through last observation carried 
forward (LOCF), where a subject’s prior post-baseline non-missing 
observation will be imputed for any missing post-baseline visit for which 
there is a prior non-missing value, and then analyzed using the MMRM 
methods as outlined above for the primary analysis.  HbA1c values 
collected after the start of rescue medication will be considered missing. 
 
3) HbA1c values collected after the start of rescue medication will NOT be 
considered missing, and the MMRM methods as outlined above for the 
primary analysis will be re-performed. 


 
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Dropout patterns may be assessed by graphical methods (e.g., Kaplan-Meier 
plot for time to drop-out). 
 Tests for Interaction 
For the primary efficacy model, specifically the MMRM ANCOVA model, a 
test for a significant treatment-by-baseline interaction will be performed in a 
separate model.  If the treatment-by-baseline interaction is significant at an 
alpha=0.100, then an analysis of variance (ANOVA) model will be used 
instead, removing the baseline covariate. 
A treatment-by-study center interaction term will be added to the MMRM 
ANCOVA (or ANOVA) model used for the analyses of the primary efficacy 
variable.  If a statistically significant treatment-by-study center interaction 
effect is observed at a 0.100 level, then separate analyses may be performed 
for each study center.   
A treatment-by-country interaction term will be added to the MMRM 
ANCOVA (or ANOVA) model used for the analyses of the primary efficacy 
variable.  A statistically significant treatment-by-country interaction effect 
will be declared at the 0.100 level.  Separate analyses will be performed for 
each country.    
Note that significant interactions, if only quantitative (and not qualitative) in 
nature, will not necessarily preclude data being pooled across the baseline 
covariate or across study centers for the primary analysis.  
 Dose Response 
A dose response analysis on the change from baseline in HbA1c to Week 12 
for the full analysis set will be conducted.  Mean change from baseline in 
HbA1c to Week 12 (on vertical axis) will be presented graphically by dose 
group (on horizontal axis).  Assessments of linear and quadratic dose-response 
trends across dose groups will be constructed using the MMRM ANCOVA 
model used for the primary efficacy analysis with appropriate orthogonal 
polynomial contrasts.  P-values for each orthogonal polynomial contrast will 
be presented.  To account for the unequal spacing of the dose levels (0, 5, 10 
and 20), the coefficients to be used for the contrasts are as follows: 
Linear: 
-0.591608 
-0.253546 
0.0845154 0.7606388 
Quadratic: 
0.5640761 -0.322329 
-0.644658 
0.4029115 
The coefficients are derived based on the statistical method from Robson, D.S. 
1959: A simple method for constructing orthogonal polynomials when the 
independent variable is unequally spaced.  Biometrics 15(2): 187-191. 


 
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Additional models may be considered if the dose response curve appears to be 
highly influenced by any single dose group.   
3.8.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints, fasting plasma glucose, sitting systolic and 
diastolic blood pressure and weight, will be analyzed using the same MMRM 
ANCOVA model used for the primary efficacy analysis on the full analysis set.  In 
addition, for each secondary efficacy endpoint, the least squares means and standard 
errors of the change from baseline over time by treatment group will be presented 
graphically.  Sensitivity analyses will not be performed on the secondary efficacy 
endpoints.     
For each subject, post-baseline HbA1c values will be reviewed and subjects with at 
least one post-baseline HbA1c value <7% will be flagged.  HbA1c values obtained 
after start of rescue medication will be excluded from this analysis.  The number and 
percentage of subjects with at least one HbA1c value <7% will be summarized by 
treatment group for the full analysis set.  A logistic model will be used to characterize 
treatment differences in the proportions of subjects with at least one post-baseline 
HbA1c value <7%.  For this model, the dependent variable will take values of 
1=’<7%’ or 0=’≥7%’ and the predictor variables will include treatment, study center, 
baseline HbA1c and prior anti-diabetic treatment status.  Odds ratio for the treatment 
difference versus placebo, its 95% confidence interval and the associated p-value will 
be presented.   
3.9 
Safety Analysis 
Safety analyses will be conducted using the safety analysis set.   
3.9.1 Adverse Events 
All adverse events will be coded using the MedDRA Version 17.0 and will be 
classified by MedDRA SOC and PT.  Analyses of adverse events will be performed 
using the safety analysis set. 
AEs that started on or after the first dose of study medication or worsened after the 
first dose of study medication are considered treatment-emergent AEs (TEAEs).  
TEAEs will be assigned to the run-in period or the double-blind period in the same 
manner.  TEAEs occurring during the run-in period will be listed only.    
For all summaries, SOCs and PTs within SOC will be presented by decreasing 
frequency of incidence for all active treatment groups combined. 


 
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Handling of Missing or Partial Start Dates for Adverse Events 
Rules for handling incomplete or missing adverse event start dates are addressed 
below (stop dates will not be imputed). Once implemented, the adverse event start 
date will be used to identify treatment-emergent adverse events for both run-in and 
double-blind treatment periods.   
In the unusual case that the month portion of an adverse event start date is missing but 
the day portion is not missing, the day portion will be assumed to be missing.  
Likewise, in the case where the year portion of an adverse event start date is missing 
but the month and/or day portion is not missing, the month and/or day portion will be 
assumed to be missing. All missing portion(s) of the date will be handled using the 
same rules:  
 In the event that the day portion (and only the day portion) of the date is 
missing:  
o If the adverse event started in the same month and year as the first 
dose date, the adverse event start date will be assumed to be the first 
dose date.  
o Otherwise, the adverse event start date will be assumed to be the last 
day of the given month and year, e.g., XX–DEC-2005 would be 31-
DEC-2005 where XX represents an unknown day.  
 In the event that the day and month portions (and only the day and month 
portions) of the date are missing: 
o If the adverse event started in the same year as the first dose date, the 
adverse event start date will be assumed to be the first dose date.  
o Otherwise, the adverse event start date will be assumed to be last 
month and day
 of the given year, e.g., XX–XXX-2005 would be 31-
DEC-2005 where XX represents an unknown day and XXX represents 
an unknown month.  
 In the event that the day, month, and year portions of the adverse event start 
date are missing, it will be assumed to be the first dose date.  
 If the adverse event start date has been imputed using the rules above, then the 
adverse event start date must be compared with the adverse event stop date to 
ensure the logical ordering of dates.  If the imputed adverse event start date is 
after the non-missing adverse event stop date, then the imputed start date will 
be reset as the stop date.  
3.9.1.1 Overall Summary of AEs 
An overall summary of TEAEs will be presented by treatment group and for all active 
treatment groups combined.  The number and percentage of subjects who experienced 


 
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at least one TEAE, at least one severe TEAE, at least one treatment-related TEAE, at 
least one serious TEAE, at least one treatment-related serious TEAE, at least one 
TEAE leading to study drug discontinuation, at least one TEAE leading to study 
withdrawal and at least one TEAE leading to death will be displayed.  Treatment-
related TEAEs are events with a study drug causality of ‘possible’, ‘probable’ or 
‘definite.’   
3.9.1.2 AE Incidences 
The incidence of TEAEs will be presented by treatment group and for all active 
treatment groups combined.  The number and percentage of subjects who experienced 
at least one TEAE as well as the number and percentage of subjects who experienced 
each specific SOC and PT will be presented.  For this analysis, if a subject has more 
than one occurrence of the same PT, then the PT will be counted only once for that 
subject.  Similarly, if a subject has more than one occurrence of the same PT within a 
SOC, the subject will be counted only once in that SOC.  
A summary table by PT will be presented using the same methods as described above 
for the by SOC and PT summary table. 
All TEAEs will be included in a subject listing.   
3.9.1.3 Maximum Severity 
The incidence of TEAEs will be presented by maximum severity and by treatment 
group and for all active treatment groups combined.  For this analysis, if a subject 
experiences more than one occurrence of the same PT, the subject will be counted 
only once under the maximum severity at which it was experienced (mild, moderate, 
severe).  TEAEs with missing severity will be counted as severe.       
3.9.1.4 Related AEs 
The incidence of drug-related TEAEs will be presented by treatment group and for all 
active treatment groups combined.  Related TEAEs are those with a ‘possible’, 
‘probable’ or ‘definite’ relationship to treatment.  TEAEs with missing relationship 
will be counted as related.  For this analysis, if a subject has more than one 
occurrence of the same PT, then the PT will be counted only once for that subject.  
Similarly, if a subject has more than one occurrence of the same PT within a SOC, the 
subject will be counted only once in that SOC.    
3.9.1.5 Deaths, Serious AEs and AEs That Led to Discontinuation 
Subject data listings of fatal AEs, serious AEs, AEs that led to treatment 
discontinuation and AEs that led to study withdrawal will be presented.    


 
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3.9.1.6 AEs of Special Interest 
Adverse events of special interest include the following categories: 
 Genital mycotic infections 
 Urinary tract infections including urosepsis and pyelonephritis 
 Diuretic effects including hypovolemia 
 Hypotension episodes 
 Hepatotoxicity 
 Major Adverse Cardiovascular Event (MACE) 
 Hypoglycemia 
 Falls and fractures 
 Malignancies 
 Hypersensitivity reactions 
 Acid-base disorders 
 Renal failure events 
All AEs of special interest will be identified by appropriate MedDRA preferred term 
during a blinded review of the data.   
The incidence of TEAEs of special interest by treatment group and for all active 
treatment groups combined will be presented separately for each category.  The 
number and percentage of subjects who experienced at least one TEAE of special 
interest as well as the number and percentage of subjects who experienced each 
specific SOC and PT will be presented.  For this analysis, if a subject has more than 
one occurrence of the same PT, then the PT will be counted only once for that 
subject.  Similarly, if a subject has more than one occurrence of the same PT within a 
SOC, the subject will be counted only once in that SOC.  
3.9.1.7 Hypoglycemia 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 
 


 
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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.  
Subjects will be dichotomized into two categories, having a hypoglycemic event 
during the double-blind period (i.e., meeting one of the above categories) or not 
having a hypoglycemic event during the double-blind period.  The number and 
percentage of subjects in each category will be summarized by treatment group for 
the safety analysis set.  For this analysis, if a subject experiences more than one 
occurrence of a hypoglycemic event, the subject will be counted only once under the 
maximum severity at which it was experienced (‘relative’, ‘probable symptomatic’, 
‘asymptomatic’, ‘documented symptomatic’, ‘severe’).  A logistic model will be used 
to characterize treatment differences in the proportions of subjects with at least one 
hypoglycemic event.  For this model, the dependent variable will take values of 
1=’Event’ or 0=’No Event’ and the predictor variables will include treatment, study 
center, baseline FPG and prior anti-diabetic treatment status   Odds ratio for the 
treatment difference versus placebo, its 95% confidence interval and the associated p-
value will be presented.   
3.9.2 Clinical Laboratory Evaluation 
A list of clinical laboratory tests is given in Table 3.   
Table 3. 
List of Laboratory Tests 
Hematology 
- Hematocrit  
- Hemoglobin 
- Mean corpuscular hemoglobin 
- Mean corpuscular hemoglobin 
concentration (MCHC) 
- Mean corpuscular volume 
- Platelet count 
- Red blood cell (RBC) count 
- White blood cell (WBC) 
count with differential 
Serum Chemistry and 
Electrolytes 
- Albumin 
- Alanine aminotransferase (ALT) 
- 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 
- Fasting plasma glucose (FPG) 
- Hemoglobin A1c (HbA1c) 
 
Serum Lipids 
- Total cholesterol (TC) 
- High-density lipoprotein 
cholesterol (HDL-C) 
- Triglycerides (TG) 
- Low-density lipoprotein 
cholesterol (LDL-C), 
calculated 
- LDL-C, direct5 
Urinalysis1 
- Appearance 
- Bilirubin 
- Nitrite 
- Occult blood 


 
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- Color 
- Glucose 
- Ketones 
- pH 
- Protein 
- Specific gravity 
- Urobilinogen 
- Leukocyte esterase 
Urine Drug Screen1 
- Amphetamines 
- Barbiturates 
- Cocaine Metabolites 
- Opiates 
- Benzodiazepines 
- Cannabinoids 
Infectious Disease 
Testing1 
- HBsAg 
- HCV 
1 Urinalysis, urine drug screen parameters and infectious disease testing parameters will be listed only. 
Continuous laboratory data will be examined for trends using descriptive statistics of 
changes from baseline to each planned post-baseline visit.  These data will also be 
categorized as low, normal or high based on the reference ranges of the central 
laboratory.  The number and percentage of subjects with indicated shifts relative to 
the laboratory normal ranges (low, normal, high) in their results from baseline to each 
post-baseline visit will be presented by category for all applicable laboratory 
parameters listed in Table 3.  The analyses will be performed using the safety analysis 
set and presented by treatment group. 
A separate listing for all clinically significant laboratory abnormalities will be 
provided.     
3.9.3 Vital Signs  
Descriptive statistics will be presented for orthostatic systolic and diastolic blood 
pressure (mmHg), orthostatic pulse (beats per minute), systolic and diastolic blood 
pressure (mmHg), pulse (beats per minute), temperature (Celsius) and respiratory rate 
(breaths/min) at each visit.  For each parameter, descriptive statistics on the change 
from baseline to each planned post-baseline visit will be presented by treatment group 
for the safety analysis set.   
Orthostatic systolic and diastolic blood pressure will be calculated as supine 
measurement – standing measurement.  Orthostatic pulse will be calculated as supine 
measurement – standing measurement.   
All vital sign results will be included in a subject listing.   
3.9.4 ECG 
Descriptive statistics will be presented for RR interval (msec), PR interval (msec), 
QRS duration (msec), QTcB (msec), P wave axis (degrees) and QRS axis (degrees) 
for each planned visit.  For each parameter, descriptive statistics on change from 
baseline to each post-baseline visit will be presented by treatment group for the safety 
analysis set. 


 
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All ECG findings will be included in a subject listing.     
3.9.5 Physical Examination and Body Weight 
Physical exam findings and body weight will be included in a subject listing.   
3.10 Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC) will be established to review 
unblinded safety data on a regular basis and to make appropriate recommendations 
regarding the conduct of the trial.  The study drug assignment will remain blinded to 
the sponsor, study team, investigators, study coordinators, pharmacists and study 
subjects for the course of the study.  A designated unblinded statistical programming 
team at PROMETRIKA that is not involved with study operations will prepare the 
unblinded tables and listings.  The selected tables and listings to be provided to 
IDMC members have a single asterisk (*) next to the table or listing title in Section 5 
of this SAP.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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4 Programming Specifications 
It is suggested that computer-generated table output adhere to the following 
specifications. 
1. Unless otherwise specified, all computer-generated tables and listings should be 
produced in landscape mode using SAS ODS to create RTF output which can be 
imported by Microsoft Word in table format. All output should have the 
following two-line header at the upper left margin: 
Theracos Sub, LLC. 
THR-1442-C-449 
and the following header at the upper right margin: 
Page x of y 
2.  Each table should be identified by in a sequential numeric order, and the table 
designation should be centered above the title. A decimal system within the 
numeric numbering (i.e., x.y and x.y.z) should be used to identify tables, listings 
and figures with related contents. The title is centered in initial capital characters 
and should include the analysis set analyzed (e.g. Safety Analysis Set). The title 
and table designation are single-spaced, but are separated from the table by at 
least a double space. 
Table No. 
 
First Line of Title 
Second Line of Title (if needed) 
Analysis Set Analyzed 
 
3.  Column headings should be in proper case. 
4.  For variables with numeric values, include “unit” in column heading when 
appropriate. 
5.  Footnotes should be single spaced, but separated by at least a double space from 
the bottom line of the table. The notes are aligned vertically by the left vertical 
border of the table. All output should have at least the footnote about the program 
name and date of the program run.   
[1] Footnote 1 
[2] Footnote 2 
[3] Footnote 3 
PROGRAM: program file name                             DDMMMYYYY HH:MM 
6.  Unless specified otherwise, all data listings should be sorted by subject number 
with the study center, and by visit date within subject, where appropriate. 
7.  For tables that summarize categorical (discrete) data, a Missing category should 
be added to any parameters for which information is not available for any subject. 


 
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8.  Unless otherwise specified, the estimated mean, median, first and third quartiles 
(Q1 and Q3, respectively) for a set of values should be printed out to one more 
decimal place than the raw (observed) data and rounded appropriately. Standard 
errors (or standard deviations) should be printed out to two additional decimal 
places than the raw (observed) data and rounded appropriately. For example, for 
age (with raw data in whole years): 
 
n 
 
     xx 
 
Mean (SD) 
xx.x (xx.xx) 
 
Median  
    xx.x 
 
Q1, Q3  
 xx.x, xx.x 
 
Min, Max 
   xx, xx 
 
9.  The p-values will be printed in the tables rounded appropriately to 4 decimal 
places and formatted as '0.xxxx'. P-values less than 0.0001 will be formatted in 
the tables as '<0.0001'. 
10. All fractional numeric values should be printed with a zero to the left of the 
decimal point (e.g., 0.12, 0.3). 
11. Unless otherwise specified, percentage values should be printed with one digit to 
the right of the decimal point (e.g., 12.8, 5.4).  
12. Missing descriptive statistics due to non-estimability in tables, as well as missing 
data in subject listings should be represented 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.  
13. Dates printed as a result in the table, listing, or graph should be printed in SAS 
DATE9. format (“DDMONYYYY”: 01 JUL 2002). Missing portions of dates 
should be represented on subject listings as dashes (-- JUL 1999). Dates that are 
missing because they are not applicable for the subject should be listed as “N/A”, 
unless otherwise specified. 


 
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5 List of Tables, Figures and Listings 
5.1 
List of Tables 
 
Table 
Number 
Table Title 
Analysis Set 
Disposition, Demographics, Baseline Characteristics, Compliance and Exposure 
14.1.1* 
Subject Disposition 
All Enrolled Subjects 
14.1.2.1* 
Demographics, Screening and Disease 
Characteristics 
Safety Analysis Set 
14.1.2.2# 
Demographics, Screening and Disease 
Characteristics 
Intent-to-Treat Analysis 
Set 
14.1.2.3# 
Demographics, Screening and Disease 
Characteristics 
Full Analysis Set 
14.1.3.1 
Summary of Concomitant Medications 
Safety Analysis Set 
14.1.3.2 
Summary of Rescue Medications for 
Hyperglycemia 
Safety Analysis Set 
14.1.4 
Summary of Study Treatment Duration 
and Compliance 
Safety Analysis Set 
Primary Endpoints 
14.2.1.1.1* 
Summary of HbA1c (%) by Visit: 
Observed and Changes from Baseline 
Full Analysis Set 
14.2.1.1.2 
Summary of HbA1c (%) by Visit: 
Observed and Changes from Baseline 
Per Protocol Analysis 
Set 
14.2.1.2.1 
Mixed Model Repeated-Measure 
(MMRM) Analysis of HbA1c (%): 
Change from Baseline and Dose 
Response, Overall Model for Primary 
Analysis and Sensitivity Analyses 
 
14.2.1.2.2 
Least Squares Summary Mixed Model 
Repeated-Measures (MMRM) Analysis 
of HbA1c (%): Change from Baseline, 
Excluding HbA1c Data Obtained After 
Rescue Medication (Primary Analysis) 
Full Analysis Set 
14.2.1.2.3 
Least Squares Summary Mixed Model 
Repeated-Measures (MMRM) Analysis 
of HbA1c (%): Change from Baseline, 
Using Multiple Imputation (Sensitivity 
Analysis 1) 
Full Analysis Set 


 
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Table 
Number 
Table Title 
Analysis Set 
14.2.1.2.4 
Least Squares Summary Mixed Model 
Repeated-Measures (MMRM) Analysis 
of HbA1c (%): Change from Baseline, 
Using Last Observation Carried 
Forward (Sensitivity Analysis 2) 
Full Analysis Set 
14.2.1.2.5 
Least Squares Summary Mixed Model 
Repeated-Measures (MMRM) Analysis 
of HbA1c (%): Change from Baseline, 
HbA1c Data Obtained After Rescue 
Medication Considered (Sensitivity 
Analysis 3) 
Full Analysis Set 
14.2.1.2.6 
Least Squares Summary Mixed Model 
Repeated-Measures (MMRM) Analysis 
of HbA1c (%): Change from Baseline, 
Excluding HbA1c Data Obtained After 
Rescue Medication Considered 
(Sensitivity Analysis 4) 
Per Protocol Analysis 
Set 
Secondary Endpoints 
14.2.2.1* 
Summary of Fasting Plasma Glucose 
(mmol/L) by Visit: Observed and 
Change from Baseline 
Full Analysis Set 
14.2.2.2 
Mixed Model Repeated-Measure 
(MMRM) Analysis of Fasting Plasma 
Glucose (mmol/L): Change from 
Baseline 
Full Analysis Set 
14.2.2.3 
Least Squares Summary Mixed Model 
Repeated-Measure (MMRM) Analysis 
of Fasting Plasma Glucose (mmol/L): 
Change from Baseline 
Full Analysis Set 
14.2.3.1 
Summary of Sitting Systolic Blood 
Pressure (mmHg) by Visit: Observed 
and Change from Baseline 
Full Analysis Set 
14.2.3.2 
Mixed Model Repeated-Measure 
(MMRM) Analysis of Sitting Systolic 
Blood Pressure (mmHg): Change from 
Baseline 
Full Analysis Set 


 
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Table 
Number 
Table Title 
Analysis Set 
14.2.3.3 
Least Squares Summary Mixed Model 
Repeated-Measure (MMRM) Analysis 
of Sitting Systolic Blood Pressure 
(mmHg): Change from Baseline 
Full Analysis Set 
14.2.4.1 
Summary of Sitting Diastolic Blood 
Pressure (mmHg) by Visit: Observed 
and Change from Baseline 
Full Analysis Set 
14.2.4.2 
Mixed Model Repeated-Measure 
(MMRM) Analysis of Sitting Diastolic 
Blood Pressure (mmHg): Change from 
Baseline 
Full Analysis Set 
14.2.4.3 
Least Squares Summary Mixed Model 
Repeated-Measure (MMRM) Analysis 
of Sitting Diastolic Blood Pressure 
(mmHg): Change from Baseline 
Full Analysis Set 
14.2.5.1 
Summary of Body Weight (kg) by Visit: 
Observed and Change from Baseline  
Full Analysis Set 
14.2.5.2 
Mixed Model Repeated-Measure 
(MMRM) Analysis of Body Weight 
(kg): Change from Baseline 
Full Analysis Set 
14.2.5.3 
Least Squares Summary Mixed Model 
Repeated-Measure (MMRM) Analysis 
of Weight (kg): Change from Baseline 
Full Analysis Set 
14.2.6 
Logistic Regression Analysis of Subject 
Achieving Post-baseline HbA1c <7%, 
Excluding HbA1c Data Obtained After 
Rescue Medication 
Full Analysis Set 
Safety Endpoints – Adverse Events 
14.3.1.1 
Overall Summary of Treatment 
Emergent Adverse Events 
Safety Analysis Set 
14.3.1.2 
Summary of Treatment Emergent 
Adverse Events by MedDRA System 
Organ Class and Preferred Term 
Safety Analysis Set 
14.3.1.3 
Summary of Treatment Emergent 
Adverse Events by MedDRA System 
Organ Class, Preferred Term and 
Maximum Severity 
Safety Analysis Set 


 
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Table 
Number 
Table Title 
Analysis Set 
14.3.1.4 
Summary of Related Treatment 
Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term  
Safety Analysis Set 
14.3.2 
Summary of Treatment Emergent 
Adverse Events of Special Interest by 
MedDRA System Organ Class and 
Preferred Term 
Safety Analysis Set 
14.3.3 
Summary of Hypoglycemic Events by 
Category and Logistic Regression 
Analysis of Subjects with a Post-
baseline Hypoglycemic Event 
Safety Analysis Set 
Safety Endpoints – Clinical Laboratory 
14.3.4.1.1* 
Summary of Hematology: Observed and 
Change from Baseline by Visit 
Safety Analysis Set 
14.3.4.1.2* 
Shift from Baseline in Hematology 
Laboratory Parameters 
Safety Analysis Set 
14.3.4.2.1* 
Summary of Serum Chemistry, 
Electrolytes, Glycemic Control and 
Serum Lipid Laboratory Parameters: 
Observed and Change from Baseline by 
Visit 
Safety Analysis Set 
14.3.4.2.2* 
Shift from Baseline in Serum 
Chemistry, Electrolytes, Glycemic 
Control and Serum Lipid Laboratory 
Parameters  
Safety Analysis Set 
Safety Endpoints – Vital Signs and 12-Lead ECG  
14.3.5* 
Summary of Vital Signs: Observed and 
Change from Baseline by Visit 
Safety Analysis Set 
14.3.6 
Summary of 12-Lead 
Electrocardiogram: Observed and 
Change from Baseline by Visit 
Safety Analysis Set 
* Table is to be provided to the IDMC.  For Table 14.1.2.1, disease characteristics 
will not be included.  For Table 14.3.4, only the following lab parameters will be 
included: ALT, AST, Creatinine, Bicarbonate and Hemoglobin.  For Table 14.3.5, 
only orthostatic systolic and diastolic blood pressure will be included.     
# Only performed if intent-to-treat analysis set and/or full analysis set are different 
    from the safety analysis set. 


 
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5.2 
List of Figures 
Figure 
Number 
Figure Title 
Analysis Set 
Primary Endpoints 
14.2.1.1 
Mean HbA1c (+/- SE) over Time by 
Treatment Group 
Full Analysis Set 
14.2.1.2 
Dose Response Analysis of HbA1c: Change 
from Baseline to Week 12 
Full Analysis Set 
Secondary Endpoints 
14.2.2.1 
Mean FPG (+/- SE) over Time by 
Treatment Group 
Full Analysis Set 
14.2.2.2 
Mean Sitting Systolic Blood Pressure (+/- 
SE) over Time by Treatment Group 
Full Analysis Set 
14.2.2.3 
Mean Sitting Diastolic Blood Pressure (+/- 
SE) over Time by Treatment Group 
Full Analysis Set 
14.2.2.4 
Mean Body Weight (+/- SE) over Time by 
Treatment Group 
Full Analysis Set 
 


 
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5.3 
List of Listings 
Listing 
Number 
Listing Title 
Analysis Set 
16.1.7 
Subject Randomization Schedule and Treatment 
Assignments  
 
16.2.1* 
Subject Disposition 
All Subjects 
16.2.2 
Protocol Deviations 
All Subjects 
16.2.3.1 
Informed Consent and Re-enrollment 
All Subjects 
16.2.3.2 
Inclusion and Exclusion Criteria 
All Subjects 
16.2.4* 
Demographics 
All Subjects 
16.2.5.1 
Significant Medical and Surgical History 
All Subjects 
16.2.5.2* 
Type 2 Diabetes and Cardiovascular Disease History 
All Subjects 
16.2.6.1 
Study Drug Accountability 
All Subjects 
16.2.6.2 
Study Drug Exposure and Compliance 
All Subjects 
16.2.7.1*# 
Adverse Events 
All Subjects 
16.2.7.2# 
Serious Adverse Events 
All Subjects 
16.2.7.3 
Adverse Events Leading to Treatment Discontinuation 
All Subjects 
16.2.7.4 
Adverse Events Leading to Study Discontinuation 
All Subjects 
16.2.7.5 
Adverse Events Leading to Death 
All Subjects 
16.2.8.1 
Clinical Laboratory Tests: Hematology 
All Subjects 
16.2.8.2 
Clinical Laboratory Tests: Serum Chemistry, 
Electrolytes, Glycemic Control and Serum Lipids 
All Subjects 
16.2.8.3 
Clinical Laboratory Tests: Urinalysis, Urine Drug 
Screen and Infectious Disease Testing 
All Subjects 
16.2.8.4 
Clinically Significant Laboratory Abnormalities 
All Subjects 
16.2.9 
Pregnancy Test 
All Subjects 
16.2.10 
Vital Signs 
All Subjects 
16.2.11 
12-Lead Electrocardiograms 
All Subjects 
16.2.12 
Physical Examination and Body Weight 
All Subjects 
16.2.13 
Concomitant Medications 
All Subjects 
16.2.14 
Phone Interview 
All Subjects 
16.2.15 
Blood Sample Collection for Population 
Pharmacokinetics 
All Subjects 
16.2.16 
Hypoglycemic Events 
All Subjects 
16.2.17 
Screen and Run-in Failures 
All Subjects 
* Listing is to be provided to the IDMC.   


 
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# Adverse events from subjects who failed during run-in period will be included in 
this listing. The listing will be presented by run-in failures and randomized 
subjects.