Clinical trial NCT02956044
Conditions: Type2 Diabetes Mellitus
Sponsor: Theracos
Start date: 2016-11-01; Completion date: 2017-03-01
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to examine the drug-drug interaction in your body when given the study drug, bexagliflozin, with three commonly used ant-diabetic medications, metformin, glimepiride or sitagliptin. The study will also evaluate how safe the study drug is and how well the study drug is tolerated when taken with metformin, glimepiride or sitagliptin.

Detailed description:
A total of 54 healthy subjects were enrolled and assigned to one of three groups of eighteen. Each group participated in one of three open-label, randomized, three treatment period, crossover studies:

* Group 1: Bexagliflozin/metformin drug-drug interaction (DDI)
* Group 2: Bexagliflozin/glimepiride DDI
* Group 3: Bexagliflozin/sitagliptin DDI For each Group, every subject received a single dose of bexagliflozin tablet, 20 mg, alone, a single dose of an oral hypoglycemic agent (OHA) (1000 mg metformin, 2 mg glimepiride, or 100 mg sitagliptin) alone, and the combination of both (bexagliflozin tablet and OHA) alternately in a crossover fashion, with three treatment periods separated by a washout period of at least 7 days. Within each Group, subjects were randomized to one of six treatment sequences in an equal ratio.

To prevent hypoglycemia, subjects assigned to Group 2 (bexagliflozin/glimepiride DDI) received approximately 300 mL of a solution containing 50 g of glucose with study medication at the time of dosing, as well as approximately 75 mL of a solution containing 12.5 g of glucose every 15 minutes for 4 hours post-dose.

For each treatment period in Group 1 (bexagliflozin/metformin DDI) and Group 2 (bexagliflozin/glimepiride DDI), subjects were admitted to the clinic on the day before dosing and stayed in the clinic until 48 h post-dose. For Group 3 (bexagliflozin/sitagliptin DDI), subjects stayed in the clinic until 72 h post-dose.

For all Groups, blood samples for PK analysis were collected in each period prior to dosing (pre-dose) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose. For Group 3, PK blood samples were also collected at 60 and 72 h post-dose. Plasma concentrations of bexagliflozin and OHAs were determined by validated liquid chromatography tandem mass spectrometry (LC MS/MS) assays.

Urine samples for PD analysis were collected in 12 h intervals. For all Groups, urine samples were collected pre-dose (-12 to 0 h) and post-dose at 0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h. For Group 3, additional samples at 48 to 60 h and 60 to 72 h post-dose were collected.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None arm 9: None
Interventions: intervention 1: Bexagliflozin intervention 2: Metformin intervention 3: Glimepiride intervention 4: Sitagliptin
Intervention descriptions: intervention 1: Bexagliflozin tablets, 20 mg intervention 2: 1000 mg metformin intervention 3: 4 mg glimepiride intervention 4: 100 mg sitagliptin

Protocol documents:
Prot_000.pdf: 
Bexagliflozin tablets 
 
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Clinical Trial Protocol: THR-1442-C-453 
 
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Clinical Trial Protocol: THR-1442-C-453 
Study Title: 
A phase 1, open-label, randomized, three-period, crossover study to 
evaluate pharmacokinetic interaction between bexagliflozin tablets and 
metformin, glimepiride, or sitagliptin in healthy subjects 
Study Number: 
THR-1442-C-453 
Study Phase: 
1 
Product Name: 
Bexagliflozin tablets 
IND Number: 
103822 
Indication: 
Type 2 Diabetes Mellitus 
Investigators: 
Single center 
Sponsor: 
Theracos Sub, LLC 
Sponsor Contact: 
Albert Collinson, Ph.D. 
Theracos Sub, LLC. 
225 Cedar Hill Street, Suite 200, Marlborough, MA 01752 
Phone: 508-688-4221 
e-mail: acollinson@theracos.com 
Sponsor Study 
Representative: 
Annie L. Conery, Ph.D. 
185 Cambridge Street, Boston, MA 02114 
Phone: 617-726-5930, Fax: 617-643-8203 
e-mail: aconery@mgh.harvard.edu 
Medical Monitor: 
Mason W. Freeman, MD 
185 Cambridge Street, Boston, MA 02114 
Phone: 617-724-7704, Fax: 617-643-8203 
e-mail: mfreeman@ccib.mgh.harvard.edu 
 
 
Date 
Original Protocol: 
01 September 2016 
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 Sub, LLC.  


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................10 
1 
INTRODUCTION ...........................................................................................................12 
2 
STUDY OBJECTIVES ....................................................................................................13 
2.1 
Primary Objective ..................................................................................................13 
2.2 
Secondary Objective ..............................................................................................13 
3 
INVESTIGATIONAL PLAN ..........................................................................................14 
3.1 
Overall Study Design and Plan ..............................................................................14 
3.2 
Rationale for Study Design and Control Group .....................................................15 
3.2.1 
Rationale for Study Design ..........................................................................15 
3.2.2 
Rationale for Dose Selection .......................................................................15 
3.2.3 
Rationale for PK and PD Sampling Time Points .........................................16 
3.3 
Study Duration and Dates ......................................................................................16 
4 
STUDY POPULATION SELECTION ...........................................................................17 
4.1 
Study Population ....................................................................................................17 
4.2 
Inclusion Criteria ...................................................................................................17 
4.3 
Exclusion Criteria ..................................................................................................17 
5 
STUDY TREATMENTS .................................................................................................19 
5.1 
Description of Treatments......................................................................................19 
5.1.1 
Investigational products ...............................................................................19 
5.1.2 
Oral Hypoglycemic Agents..........................................................................19 
5.1.2.1 
Metformin ..........................................................................................19 
5.1.2.2 
Glimepiride ........................................................................................19 
5.1.2.3 
Sitagliptin ...........................................................................................19 
5.2 
Treatments Administered .......................................................................................19 
5.3 
Selection and Timing of Dose for Each Subject ....................................................20 
5.3.1 
Group 1: Bexagliflozin and Metformin .......................................................20 
5.3.2 
Group 2: Bexagliflozin and Glimepiride .....................................................20 
5.3.3 
Group 3: Bexagliflozin and Sitagliptin ........................................................20 
5.4 
Method of Assigning Subjects to Treatment Groups and Sequences ....................21 
5.5 
Blinding..................................................................................................................21 
5.6 
Concomitant Therapy.............................................................................................21 
5.7 
Restrictions ............................................................................................................21 
5.7.1 
Prior Therapy ...............................................................................................21 
5.7.2 
Fluid and Food Intake ..................................................................................21 
5.7.3 
Subject Activity Restrictions .......................................................................22 


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5.8 
Treatment Compliance ...........................................................................................22 
5.9 
Packaging and Labeling .........................................................................................22 
5.10 
Storage and Accountability ....................................................................................22 
6 
STUDY PROCEDURES .................................................................................................23 
6.1 
Informed Consent...................................................................................................23 
6.2 
Medical History .....................................................................................................23 
6.3 
Physical Examination.............................................................................................24 
6.4 
Vital Signs ..............................................................................................................24 
6.5 
Electrocardiography ...............................................................................................24 
6.6 
Clinical Laboratory Tests .......................................................................................25 
6.6.1 
Laboratory Parameters .................................................................................25 
6.6.2 
Sample Collection, Storage, and Shipping ..................................................26 
6.6.2.1 
Hematology and Blood Chemistry.....................................................26 
6.6.2.2 
Urinalysis ...........................................................................................26 
6.6.2.3 
Urine Collection .................................................................................26 
6.6.2.4 
Plasma Sample Collection for PK ......................................................26 
6.7 
Adverse Events Assessments .................................................................................26 
6.7.1 
Collecting and Reporting Adverse Events ...................................................28 
6.7.2 
Immediately Reportable Adverse Events .....................................................29 
6.7.3 
Pregnancy .....................................................................................................29 
6.7.4 
Follow-up of Adverse Events ......................................................................30 
6.7.4.1 
Follow-up of Non-serious Adverse Events ........................................30 
6.7.4.2 
Follow-up of Post-Study Serious Adverse Events .............................30 
6.7.4.3 
Hepatotoxicity ....................................................................................30 
6.7.4.4 
Hypoglycemia ....................................................................................31 
6.8 
Concomitant Medication Assessments ..................................................................31 
6.9 
Removal of Subjects from the Trial or Discontinuation of Investigational 
Product ...................................................................................................................32 
6.10 
Appropriateness of Measurements .........................................................................33 
7 
STUDY ACTIVITIES .....................................................................................................34 
7.1 
Screening (Days -28 to Day -1) .............................................................................34 
7.2 
Period 1 ..................................................................................................................34 
7.2.1 
Day 0 (Clinic Admission) ............................................................................34 
7.2.2 
Day 1 (Dosing Day): Pre-dose Activities ....................................................35 
7.2.3 
Day 1 (Dosing Day): Dosing .......................................................................35 
7.2.4 
Day 1: Post-dose Activities ..........................................................................36 
7.2.5 
Day 2: Post-dose Activities ..........................................................................36 
7.2.6 
Day 3: Post-dose Activities ..........................................................................36 
7.2.7 
Day 4 (Group 3 Only): Post-dose Activities ................................................37 


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7.3 
Period 2 ..................................................................................................................37 
7.3.1 
Day 7 (Clinic Admission) ............................................................................37 
7.3.2 
Day 8 (Dosing Day): Pre-dose Activities ....................................................37 
7.3.3 
Day 8 (Dosing Day): Dosing .......................................................................38 
7.3.4 
Day 8 (Dosing Day): Post-dose Activities ...................................................38 
7.3.5 
Day 9: Post-dose Activities ..........................................................................38 
7.3.6 
Day 10: Post-dose Activities ........................................................................39 
7.3.7 
Day 11 (Group 3 Only): Post-dose Activities ..............................................39 
7.4 
Period 3 ..................................................................................................................40 
7.4.1 
Day 14 (Clinic Admission) ..........................................................................40 
7.4.2 
Day 15 (Dosing Day): Pre-dose Activities ..................................................40 
7.4.3 
Day 15 (Dosing Day): Dosing .....................................................................40 
7.4.4 
Day 15 (Dosing Day): Post-dose Activities .................................................41 
7.4.5 
Day 16: Post-dose Activities ........................................................................41 
7.4.6 
Day 17: Post-dose Activities ........................................................................41 
7.4.7 
Day 18 (Group 3 Only): Post-dose Activities ..............................................42 
7.5 
Early Termination or Follow-up Procedures .........................................................42 
8 
QUALITY CONTROL AND ASSURANCE .................................................................43 
9 
PLANNED STATISTICAL METHODS ........................................................................44 
9.1 
General Considerations ..........................................................................................44 
9.2 
Determination of Sample Size ...............................................................................44 
9.3 
Analysis Populations ..............................................................................................44 
9.3.1 
Safety Population .........................................................................................44 
9.3.2 
PK Population ..............................................................................................44 
9.3.3 
PD Population ..............................................................................................44 
9.4 
Demographics and Baseline Characteristics ..........................................................44 
9.5 
Pharmacokinetic Analysis ......................................................................................45 
9.5.1 
Calculation of Pharmacokinetic Variables ...................................................45 
9.5.2 
Statistical Analysis of Pharmacokinetic Variables ......................................46 
9.6 
Pharmacodynamic Analysis ...................................................................................46 
9.7 
Safety Analysis ......................................................................................................47 
9.7.1 
Adverse Events ............................................................................................47 
9.7.2 
Hypoglycemia ..............................................................................................47 
9.7.3 
Clinical and Laboratory Events and Analyses .............................................47 
9.7.4 
Concomitant Medications ............................................................................48 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................49 
10.1 
Investigators and Study Administrative Structure .................................................49 


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10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................49 
10.3 
Ethical Conduct of the Study .................................................................................49 
10.4 
Subject Information and Consent...........................................................................50 
10.5 
Subject Confidentiality ..........................................................................................50 
10.6 
Study Monitoring ...................................................................................................50 
10.7 
Case Report Forms and Study Records .................................................................51 
10.8 
Protocol Violations/Deviations ..............................................................................51 
10.9 
Access to Source Documentation ..........................................................................51 
10.10 Retention of Data ...................................................................................................52 
10.11 Publication and Disclosure Policy .........................................................................52 
11 REFERENCE LIST .........................................................................................................53 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Treatment Sequences .................................................................................14 
Table 2. 
Required Laboratory Tests .........................................................................25 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .....................................................................................54 
Appendix 2 
Sponsor Signatures.....................................................................................57 
Appendix 3 
Investigator’s Signature .............................................................................58 
 
 


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SYNOPSIS 
Sponsor: 
Theracos Sub, LLC 
Name of Finished Product: 
Bexagliflozin tablets 
Name of Active Ingredient: 
Bexagliflozin 
Name of Inactive Ingredients: 
Polyethylene oxide, glyceryl behenate, lactose monohydrate, micronized poloxamer 188, 
microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate (vegetable 
grade). The tablets are film-coated with Opadry II Blue with no markings on the tablets. 
Study Title: 
A phase 1, open-label, randomized, three-period, crossover study to evaluate 
pharmacokinetic interaction between bexagliflozin tablets and metformin, glimepiride, or 
sitagliptin in healthy subjects  
Study Number: 
THR-1442-C-453 
Study Phase: 1 
Primary Objective:  
To evaluate the drug-drug interaction of co-administration of bexagliflozin with commonly 
prescribed oral hypoglycemic agents (OHAs) metformin, glimepiride, or sitagliptin on the 
pharmacokinetics (PK) of bexagliflozin and each OHA 
Secondary Objective: 
To evaluate the safety, tolerability, and pharmacodynamics (PD) of bexagliflozin when it is 
co-administered with commonly prescribed OHAs  
Study Design: 
In this study, a total of 54 healthy subjects will be enrolled and assigned to one of three 
groups of eighteen. Each group will participate in one of three open-label, randomized, three-
period, three-treatment crossover studies: 
Group 1: Bexagliflozin/metformin drug-drug interaction (DDI) 
Group 2: Bexagliflozin/glimepiride DDI 
Group 3: Bexagliflozin/sitagliptin DDI 
Within each study, subjects will be randomized to one of six treatment sequences in an equal 
ratio. Each subject will receive a single dose of bexagliflozin tablet, 20 mg, alone, a single 
dose of an OHA (1000 mg metformin, 4 mg glimepiride or 100 mg sitagliptin) alone, and the 
combination of both (bexagliflozin tablet and OHA) alternately in a crossover fashion, with 
three treatment periods separated by a washout period of at least 7 days. 


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To prevent hypoglycemia, subjects assigned to Group 2 (bexagliflozin/glimepiride DDI) will 
receive 240 mL of a 20% glucose solution in water with study medication at the time of 
dosing, as well as 60 mL of a 20% glucose solution in water every 15 min for 4 hours post-
dose. 
For each treatment period in Group 1 (bexagliflozin/metformin DDI) and Group 2 
(bexagliflozin/glimepiride DDI), subjects will be admitted to the clinic on the day before 
dosing and will stay in the clinic until 48 h post-dose. For Group 3 (bexagliflozin/sitagliptin 
DDI), subjects will be admitted to the clinic on the day before dosing and will stay in the 
clinic until 72 h post-dose. 
For all Groups, blood samples for PK analysis will be collected in each period prior to dosing 
(pre-dose) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose. For Group 3, 
PK blood samples will also be collected at 60 and 72 h post-dose. 
Urine samples for PD analysis will be collected in 12 h intervals. For all Groups, urine 
samples will be collected pre-dose (-12 to 0 h) and post-dose at 0 to 12 h, 12 to 24 h, 24 to 36 
h, and 36 to 48 h. For Group 3, additional samples at 48 to 60 h and 60 to 72 h post-dose will 
be collected. 
Clinical laboratory tests and safety monitoring will be conducted during all treatment 
periods. 
Study Population:  
Approximately 54 healthy male and female subjects are planned to be enrolled. 
Diagnosis and Main Criteria for Inclusion 
1. Male and female subjects who are between 18 to 65 years of age, inclusive, in good 
health based on medical history, physical examination (PE), electrocardiogram (ECG) 
and routine laboratory tests. 
2. Subjects with body-mass index (BMI) between 18.0 kg/m2 and 32.0 kg/m2, inclusive. 
3. Subjects who are non-smokers for at least 3 months prior to screening. 
4. Subjects with adequate venous access at multiple sites in both arms. 
5. Subjects who are willing and able to be confined to the clinical research facility as 
required by the protocol. 
6. Subjects who have the ability to comprehend and who are willing to provide written 
informed consent in accordance with institutional and regulatory guidelines. 
Test Product, Dose, and Mode of Administration: 
Bexagliflozin tablets, 20 mg, single dose per treatment period, oral administration 
Reference Therapy, Dose, and Mode of Administration: 
Metformin, 1000 mg, single dose per treatment period, oral administration 
Glimepiride, 4 mg, single dose per treatment period, oral administration 
Sitagliptin, 100 mg, single dose per treatment period, oral administration 
Duration of Treatment:  
After subjects are screened and randomized, the duration of the study will be up to 22 days 
from the day of initial investigational product administration. There will be 3 treatments 
separated by a washout period of at least 7 days. 


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Pharmacokinetic Assessment: 
The following PK parameters of bexagliflozin and the OHAs will be determined when 
feasible after each subject is dosed with bexagliflozin, an OHA or a combination of both: 
Cmax 
    Maximum observed plasma concentration 
Tmax  
    Time of maximum observed plasma concentration 
Oz           Terminal elimination phase rate constant  
T½           Apparent terminal elimination half-life 
CL/F     Apparent oral clearance  
Vz/F 
    Apparent volume of distribution 
AUC0-t    Area under the plasma concentration-time curve from Time 0 to Time t (time of  
last quantifiable plasma concentration) 
AUC0-∞  Area under the plasma concentration-time curve from Time 0 to infinity 
Pharmacodynamic Assessment: 
Urinary glucose excretion (UGE) will be derived from the urine samples collected in 12-hour 
batches in study subjects administered bexagliflozin or OHA alone or bexagliflozin with an 
OHA in combination. UGEt1-t2 (mg) will be derived from urine volume (Vt1-t2, mL) x glucose 
concentration (mg/dL)/100. 
Safety Assessments: 
• Vital signs 
• Clinical laboratory tests including blood chemistry and hematology parameters 
• Urinalysis  
• Adverse events 
• Concomitant medication use 
Statistical Methods:  
Statistical analysis will be performed using Statistical Analysis Software SAS for Windows® 
(SAS Institute Inc., USA). PK parameters of bexagliflozin will be calculated by non-
compartmental analysis (NCA) of plasma concentration-time data. Non-compartmental 
analysis will be performed using Phoenix® WinNonlin® 6.4 (Certara, USA). To assess the 
effect of OHAs metformin, glimepiride or sitagliptin on the PK of bexagliflozin and vice 
versa, an analyses of variance (ANOVA) using a linear mixed-effects model will be fitted to 
the natural logarithmic transformation of PK parameters of bexagliflozin (Cmax, AUC0-t and 
AUC0-∞). The linear mixed-effects model will include subject as a random effect, and 
treatment, period, and sequence as fixed effects. The 90% confidence intervals will be 
constructed for the (bexagliflozin and OHA in combination) to (bexagliflozin alone) or 
(OHA alone) ratio of the least squares (LS) geometric means of PK parameters (Cmax, AUC0-t 
and AUC0-∞), with 80-125% defined as the lack of interaction boundaries. 
Descriptive statistics for the PK parameters Cmax, Tmax, AUC0-∞, AUC0-t , CL/F, Vz/F, λz and 
T1/2 will be tabulated by treatment. Means, standard deviations, medians, ranges (min, max) 
and geometric means and coefficients of variation will be presented for all PK parameters 


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with exception of Tmax. Medians and ranges will be presented for Tmax. 
Descriptive statistics on the PD parameters will be also performed. The effect of OHA alone, 
bexagliflozin alone and OHA and bexagliflozin in combination on the cumulative UGE of 
healthy subjects will be compared. 
Date of Original Protocol: 01 September 2016 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCextr 
% of AUC0-∞ due to extrapolation from Tlast to infinity 
AUC0-∞ 
area under the plasma concentration-time curve from time 0 to infinity 
AUC0-t 
area under the plasma concentration-time curve from time 0 to time t (time of last 
quantifiable plasma concentration) 
BMI 
body mass index 
BLOQ 
below level of quantification 
BP 
blood pressure 
Cmax 
maximum plasma drug concentration 
Clast 
concentration corresponding to Tlast 
CL/F 
apparent oral clearance 
CRF 
case report form 
CRO 
contract research organization 
DDI 
drug-drug interaction 
DPP-4 
dipeptidyl peptidase 4 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
GMI 
genital mycotic infection 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICH 
International Council on Harmonisation  
IEC 
Independent Ethics Committee 
IRAE 
immediately reportable adverse event 
IRB 
Institutional Review Board 
K2EDTA 
potassium ethylenediaminetetraacetic acid 
LS 
least squares  
λz 
terminal elimination phase rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCA 
non-compartmental analysis 
OHA 
oral hypoglycemic agent 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PE 
physical examination 
PK 
pharmacokinetic 
SAE 
serious adverse event 


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SD 
standard deviation 
SFU 
sulfonylurea 
SGLT2 
sodium glucose cotransporter 2 
SOP 
standard operating procedure 
TEAE 
treatment emergent adverse event 
T1/2 
terminal elimination half life 
Tlast 
time of last measurable concentration 
Tmax 
time to maximum plasma concentration 
T2DM 
type 2 diabetes mellitus 
UGE 
urine glucose excretion 
ULN 
upper limit of normal 
UTI 
urinary tract infection 
Vz/F 
apparent volume of distribution 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of child-bearing potential 
 
 
Definitions of Terms 
Study 
The THR-1442-C-453 study refers to all activities within the protocol. Within THR-1442-C-
453, there are 3 open-label, randomized, three-period, three-treatment crossover studies. 
Each of the 3 studies will enroll a Group of 18 subjects (see Group below). 
Group 
The 54 subjects in the THR-1442-C-453 study will be assigned to one of 3 groups of 18 
subjects. Each Group will be treated with bexagliflozin and one of the three oral 
hypoglycemic agents (OHAs), metformin (Group 1), sitagliptin (Group 2), or glimepiride 
(Group 3). 
Sequence 
Each Group of 18 subjects will be randomized to participate in 1 of 6 treatment sequences 
with 3 subjects in each sequence. Each sequence will have a different order of 3 possible 
treatments: bexagliflozin alone, OHA alone, or bexagliflozin and OHA in combination. 
Period 
Each Sequence will have 3 treatment periods. During each Period, subjects will receive 1 of 
3 possible treatments (bexagliflozin alone, OHA alone, or bexagliflozin and OHA in 
combination). 


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1 
INTRODUCTION 
Diabetes mellitus, a metabolic disease characterized by prolonged hyperglycemia, is one of 
the leading causes of morbidity and mortality worldwide, affecting an estimated 387 million 
people as of 2014 (IDF, 2014). More than 95% of people with diabetes have type 2 diabetes 
mellitus (T2DM) (IDF, 2014).  
Several classes of oral agents are available for treating T2DM, including biguanides, 
sulfonylureas (SFU), or dipeptidyl peptidase-4 (DPP-4) inhibitors. Metformin (a biguanide), 
sitagliptin (an SFU) and glimepiride (a DDP-4 inhibitor) are 3 commonly prescribed oral 
hypoglycemic agents (OHAs) with different mechanism of actions (Tahrani et al., 2016). 
Metformin is the first-line treatment for T2DM that works by increasing insulin sensitivity of 
body tissues and decreasing glucose production by the liver. Sitagliptin causes elevation of 
circulating incretins, which results in enhanced nutrient-induced insulin secretion. 
Glimepiride increases secretion of insulin by the pancreas.  
Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of OHAs that targets the 
renal Na+/glucose transport protein, SGLT2. SGLT2 inhibitors increase excretion of glucose 
in the urine and thereby lower fasting and post-prandial glucose levels. SGLT2 inhibitors 
increase urinary glucose excretion without increasing insulin secretion, causing weight gain, 
or inducing hypoglycemia (Nauck, 2014). 
Bexagliflozin is a candidate OHA that is a potent and highly specific inhibitor of SGLT2. 
(Zhang et al., 2011). Bexagliflozin has been shown to cause dose-dependent increases in 
urinary glucose excretion (UGE) in humans, rats, dogs and monkeys and to reduce HbA1c in 
animal models of T2DM and in diabetic subjects. Detailed information regarding 
bexagliflozin clinical studies and potential risks for study subjects are provided in the 
Investigator’s Brochure. 
Bexagliflozin is cleared predominantly by metabolism to an inactive metabolite, 
bexagliflozin 3-O-glucuronide by uridine diphosphate glucuronosyltransferase isoform 1A9 
(UGT1A9) pathway. 
The aim of the study is to evaluate potential drug-drug interaction (DDI) effects on the 
pharmacokinetics (PK) and pharmacodynamics (PD) of co-administration of bexagliflozin 
with three commonly prescribed OHAs, i.e., metformin, glimepiride, or sitagliptin. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
The primary objective of this study is to evaluate whether drug-drug interactions following 
co-administration of bexagliflozin with commonly prescribed OHAs metformin, glimepiride, 
or sitagliptin result in any change in the PK of bexagliflozin or each of the OHAs. 
2.2 
Secondary Objective 
The secondary objective of this study is to evaluate the safety, tolerability, and PD of 
bexagliflozin following single dose administration of the drug in combination with 
commonly prescribed OHAs. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
In this study, a total of 54 healthy subjects will be enrolled and assigned to three groups of 
eighteen. Each group will participate in one of three open-label, three treatment period, 
crossover studies: 
Group 1: Bexagliflozin/metformin drug-drug interaction (DDI) 
Group 2: Bexagliflozin/glimepiride DDI 
Group 3: Bexagliflozin/sitagliptin DDI 
 
For each Group, every subject will receive a single dose of bexagliflozin tablet, 20 mg, alone, 
a single dose of an OHA (1000 mg metformin, 4 mg glimepiride or 100 mg sitagliptin) alone, 
and the combination of both (bexagliflozin tablet and OHA) alternately in a crossover 
fashion, in three treatment periods separated by a washout period of at least 7 days. Within 
each Group, subjects will be randomized to one of six treatment sequences in an equal ratio 
as shown in Table 1. 
Table 1. 
Treatment Sequences 
Treatment Sequence 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
1 
Bexa alone1 
OHA alone2 
Bexa + OHA 
2 
Bexa alone 
Bexa + OHA 
OHA alone 
3 
OHA alone 
Bexa alone 
Bexa + OHA 
4 
OHA alone 
Bexa + OHA 
Bexa alone 
5 
Bexa + OHA 
OHA alone 
Bexa alone 
6 
Bexa + OHA 
Bexa alone 
OHA alone 
1 
Bexa: bexagliflozin; OHA: oral hypoglycemic agent 
 
To prevent hypoglycemia, subjects assigned to Group 2 will receive a 20% oral glucose 
solution with study medication at the time of dosing, as well as a 20% glucose solution every 
15 min for 4 hours post-dose. 
During each treatment period for Group 1 (bexagliflozin/metformin DDI) and Group 2 
(bexagliflozin/glimepiride DDI), subjects will be admitted to the clinic on the day before 
dosing and will stay in the clinic until 48 h post-dose. For Group 3 (bexagliflozin/sitagliptin 
DDI), subjects will stay in the clinic until 72 h post-dose. 
For Group 1 and 2, blood samples for PK analysis will be collected in each period prior to 
dosing (pre-dose) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose. For 
Group 3, PK blood samples will also be collected at 60 and 72 h post-dose. Plasma 


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concentrations of bexagliflozin and OHAs will be determined by validated liquid 
chromatography tandem mass spectrometry (LC-MS/MS) assays. 
Urine samples for PD analysis will be collected in 12 h intervals. For Group 1 and 2, urine 
samples will be collected pre-dose (-12 to 0 h) and post-dose at 0 to 12 h, 12 to 24 h, 24 to 36 
h, and 36 to 48 h. For Group 3, additional samples at 48 to 60 h and 60 to 72 h post-dose will 
be collected. 
Clinical laboratory tests and safety monitoring will be conducted during all treatment periods 
as is outlined in Appendix 1 Schedule of Events. 
3.2 
Rationale for Study Design and Control Group 
3.2.1 
Rationale for Study Design 
Each of the 3 Groups within THR-1442-C-453 will participate in a randomized, three-period, 
three-treatment crossover study. This design was chosen to properly separate treatment 
effects from period effects. 
Three commonly prescribed OHAs, metformin, sitagliptin and glimepiride, were chosen for 
the THR-1442-C-453 study.  
Sitagliptin does not undergo extensive metabolism. After oral exposure, the parent drug 
comprises the majority of plasma and urinary drug concentrations (Vincent et al., 2007). 
Sitagliptin metabolites were detected in small amounts and in vitro experiments found that 
CYP3A4 and, to a lesser extent, CYP2C8, were the major CYP isozymes responsible for the 
limited metabolism (Vincent et al., 2007). Metformin also does not undergo significant 
metabolism, and both metformin and sitagliptin are eliminated unchanged in urine via tubular 
secretion and glomerular filtration (Pentikainen et al., 1979). Glimepiride is mainly 
metabolized by CYP2C9 and the metabolites are excreted in urine (Langtry and Balfour, 
1998).  
The metabolic pathway for bexagliflozin is different from that of the 3 OHAs (metformin, 
sitagliptin, and glimepiride), which suggests a low potential for metabolic drug-drug 
interaction between bexagliflozin and the OHAs being tested. In vitro metabolism studies 
demonstrated that bexagliflozin is not a potent inhibitor or inducer of CYP450 enzymes. 
UGT1A9 is principally responsible for the glucuronidation of bexagliflozin. In the urine, 
unchanged parent drug accounted for less than 2% of the dose.  
3.2.2 
Rationale for Dose Selection 
Bexagliflozin produces a dose-dependent, saturable increase in UGE in healthy volunteers 
and diabetic subjects. Population pharmacodynamic modeling has indicated that 
bexagliflozin doses of 20 mg result in 90% of the maximal UGE. In a long term treatment 
study, daily administration of 20 mg bexagliflozin was found to reduce HbA1c by 0.79% 
compared to placebo at week 24. In addition, adverse events (AEs), particularly those 
involving urinary tract infection (UTI) and genital mycotic infection (GMI), were found to be 


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similar between placebo and active agent cohorts. To evaluate the drug-drug interaction of 
co-administration of bexagliflozin with metformin, glimepiride, or sitagliptin, bexagliflozin 
tablets, 20 mg, which is intended to be the commercial product, will be administered in this 
trial. 
The dosages for the OHAs are equivalent to the highest single tablet dose available for each 
OHA (1000 mg metformin, 4 mg glimepiride or 100 mg sitagliptin), and are within 
recommended daily dose ranges. 
3.2.3 
Rationale for PK and PD Sampling Time Points 
The T½ of bexagliflozin is 7.80 to 9.71 h, and T½ of metformin and glimepiride are 4-9 h and 
5-9 h, respectively. Based on the biological half-lives of the study drugs, the PK sampling 
time points for Group 1 (bexagliflozin/metformin DDI) and Group 2 (bexagliflozin/ 
glimepiride DDI) are pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose. 
For Group 3 (bexagliflozin/sitagliptin DDI), two additional PK sampling time points, at 60 
and 72 h post-dose, will be added as the T½ for sitagliptin is 12.4 h. 
Urine samples for PD analysis will be collected in 12 h intervals from -12 h pre-dose to 48 h 
post dose (-12 to 0 h, 0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h) for Groups 1 and 2, 
and additional samples at 48 to 60 h and 60 to 72 h post-dose will be collected for Group 3. 
3.3 
Study Duration and Dates 
Subjects will be screened within 28 days of the planned initiation of investigational product 
dosing. Eligible subjects who consent to the study will be assigned to 1 of 3 Groups. Subjects 
in each Group will be randomly assigned to receive 1 of 6 treatment regimens in a crossover 
fashion with three treatment periods separated by a washout period of at least 7 days. Up to 2 
additional washout days will be allowed. 
For each treatment period in Group 1 (bexagliflozin/metformin DDI) and Group 2 
(bexagliflozin/glimepiride DDI), subjects will be admitted to the clinic on the day before 
dosing (day 0 for treatment period 1, day 7 for treatment period 2 and day 14 for treatment 
period 3) and will stay in the clinic until 48 h post-dose. For Group 3 
(bexagliflozin/sitagliptin DDI), subjects will be admitted on the day before dosing (day 0 for 
treatment period 1, day 7 for treatment period 2 and day 14 for treatment period 3), but will 
stay in the clinic until 72 h post-dose. 
The duration of the overall study from screening until study termination is estimated to be a 
maximum of 50 days. For details of the schedule and nature of the investigations, see the 
Schedule of Events in Appendix 1. 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Fifty-four eligible healthy male and female subjects who consent to participate in this study 
will be enrolled. 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study. 
1. Male and female subjects who are between 18 to 65 years of age, inclusive, in good 
health based on medical history, physical examination (PE), electrocardiogram (ECG) 
and routine laboratory tests. 
2. Subjects with body-mass index (BMI) between 18.0 kg/m2 and 32.0 kg/m2, inclusive. 
3. Subjects who are non-smokers for at least 3 months prior to screening. 
4. Subjects with adequate venous access at multiple sites in both arms. 
5. Subjects who are willing and able to be confined to the clinical research facility as 
required by the protocol. 
6. Subjects who have the ability to comprehend and who are willing to provide written 
informed consent in accordance with institutional and regulatory guidelines. 
 
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Subjects who are determined by the investigator or sub-investigator to be unsuitable for 
participating in the study based on medical conditions or factors that would influence 
adherence to study activities. 
2. Subjects with a clinically significant history of allergy to drugs or latex. 
3. Subjects with a history of alcohol or drug dependence in the last 12 months. 
4. Subjects who have donated 400 mL of whole blood within 56 days, 200 mL of whole 
blood within one month, or donated blood components within 14 days of screening. 
5. Subjects who have used prescription or over-the-counter (OTC) drugs within 14 days 
prior to the first dose. 
6. Subjects who have used vitamin preparations within 7 days or supplements (including St. 
John’s Wort and ginseng) within 14 days prior to the first dose. 
7. Subjects who have undergone strenuous physical activity within 72 hours prior to dosing 
in each period. 
8. Subjects who have been treated with an investigational drug within 30 days or 7 half-
lives of the investigational drug, whichever is longer, prior to the first dose of 
investigational drug in this trial. 


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9. Subjects who had previously received EGT0001474 or bexagliflozin, or any other 
SGLT2 inhibitors within 3 months from screening or have participated in previous 
bexagliflozin clinical trials., regardless of whether they received bexagliflozin or placebo 
in those trials. 
10. Subjects who had previously received OHAs, including metformin, sitagliptin, 
glimepiride or drugs of the same class (i.e. biguanides, DPP-4 inhibitors or 
sulfonylureas), within 3 months of screening. 
11. Subjects whose screening ECG demonstrates any one of the following: heart rate > 100 
bpm, QRS > 120 msec, QTc > 470 msec (corrected by Bazett’s formula), PR > 220 msec 
(a subject with PR > 220 msec will generally be excluded but exceptions may be allowed 
at the discretion of the investigator), or any clinically significant arrhythmia. 
12. Subjects whose sitting blood pressure is above 140/90 mmHg at screening.  If the sitting 
blood pressure at screening is above 140/90 mmHg, one repeat measurement is allowed 
and the subject may be randomized if the repeat screening blood pressure is 140/90 +/-5 
mmHg at the discretion of the Investigator. 
13. Subjects who have a positive result of hepatitis B surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody, urinary drug or urinary cotinine test. 
14. Subjects with known human immunodeficiency virus (HIV) infection. 
15. Subjects who have had a febrile illness within 5 days prior to the first dose of 
investigational drug. 
16. Subjects vaccinated (with the exception of the flu vaccine) within 30 days prior to the 
first dose of investigational drug. 
17. Subjects with estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 or a 
history of kidney transplant. 
18. Male subjects who do not agree to refrain from donating sperm and use appropriate birth 
control such as the use of condoms when engaging in sexual intercourse for a period of 
30 days after discharge from the clinic. 
19. Female subjects of childbearing potential who are not willing to use an adequate method 
of contraception and to not become pregnant for the duration of the study. Female 
subjects who are surgically sterile (hysterectomy, oophorectomy) or postmenopausal 
(absence of menses greater than 12 months and age > 45 years) are eligible if they test 
negative on the urine pregnancy test. 
 


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5 
STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
Investigational products 
Bexagliflozin tablets, 20 mg, are blue caplet-shaped, film-coated tablets that are intended for 
use in investigational studies in humans. The tablets contain excipients designed to promote 
extended release through a gastroretentive mechanism. The active tablets exhibit a greater 
than 75% release of drug substance by 8 hours in simulated gastric fluid in vitro. 
5.1.2 
Oral Hypoglycemic Agents 
Three OHAs that are frequently prescribed in patients with T2DM are included in the study. 
5.1.2.1 
Metformin 
Metformin is a biguanide, which decreases hepatic glucose production and may improve 
peripheral glucose uptake and utilization. After oral administration, metformin is absorbed 
from the gastrointestinal tract. Metformin is excreted unchanged in the urine and does not 
undergo hepatic metabolism or biliary excretion. 
5.1.2.2 
Glimepiride 
Glimepiride is a 2nd generation SFU, which stimulates glucose-independent insulin release 
from the pancreas. After oral administration, glimepiride is absorbed from the 
gastrointestinal tract. Glimepiride is metabolized mostly by hepatic P450 enzyme CYP2C9.  
5.1.2.3 
Sitagliptin 
Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor. After oral administration, sitagliptin 
is absorbed from the gastrointestinal tract. Sitagliptin is metabolized by hepatic P450 enzyme 
CYP3A4 and CYP2C8. 
5.2 
Treatments Administered 
Subjects who consent to be in the study will be assigned to 1 of 3 groups. Each subject will 
receive a single oral dose of bexagliflozin tablet, 20 mg, alone, a single dose of one other 
OHA alone, and the combination of both (bexagliflozin tablet and OHA) alternately in a 
crossover fashion in three treatment periods separated by a washout period of at least 7 days:  
Group 1: Bexagliflozin tablet, 20 mg, and metformin, 1000 mg 
Group 2: Bexagliflozin tablet, 20 mg, and glimepiride, 4 mg 
Group 3: Bexagliflozin tablet, 20 mg, and sitagliptin, 100 mg 
 


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5.3 
Selection and Timing of Dose for Each Subject 
Dosing order with bexagliflozin alone, OHA alone, or bexagliflozin in combination with 
OHA will be based on randomized assignment. Bexagliflozin and OHAs will be 
administered with 240 mL of liquid (water for Group 1 and 3, 20% glucose solution for 
Group 2). If for some reason, a portion of the liquid is not consumed, the reason and the 
amount of remaining liquid will be recorded. 
5.3.1 
Group 1: Bexagliflozin and Metformin 
• Bexagliflozin alone: After an overnight fast of at least 10 hours, a bexagliflozin tablet, 
20 mg, will be administered before the first meal of the day with 240 mL of water. 
• Metformin alone: After an overnight fast of at least 10 hours, metformin, 1000 mg, will 
be administered before the first meal of the day with 240 mL of water.  
• Co-administration of bexagliflozin and metformin: After an overnight fast of at least 
10 hours, a bexagliflozin tablet, 20 mg, and metformin, 1000 mg, will be administered 
before the first meal of the day with 240 mL of water. 
 
5.3.2 
Group 2: Bexagliflozin and Glimepiride 
• Bexagliflozin alone: After an overnight fast of at least 10 hours, a bexagliflozin tablet, 
20 mg, will be administered before the first meal of the day with 240 mL 20% glucose 
solution in water. Subjects will be administered 60 mL of 20% glucose solution in water 
every 15 minutes during the first 4 hours following administration of bexagliflozin. 
• Glimepiride alone: After an overnight fast of at least 10 hours, glimepiride, 4 mg, will 
be administered before the first meal of the day with 240 mL of 20% glucose solution in 
water. Subjects will be administered 60 mL of 20% glucose solution in water every 15 
minutes during the first 4 hours following administration of glimepiride. 
• Co-administration of bexagliflozin and glimepiride: After an overnight fast of at least 
10 hours, a bexagliflozin tablet, 20 mg, and glimepiride, 4 mg, will be administered 
before the first meal of the day with 240 mL of 20% glucose solution in water. Subjects 
will be administered 60 mL of 20% glucose solution in water every 15 minutes during the 
first 4 hours following administration of bexagliflozin and glimepiride. 
 
5.3.3 
Group 3: Bexagliflozin and Sitagliptin 
• Bexagliflozin alone: After an overnight fast of at least 10 hours, a bexagliflozin tablet, 
20 mg, will be administered before the first meal of the day with 240 mL of water. 
• Sitagliptin alone: After an overnight fast of at least 10 hours, sitagliptin, 100 mg, will be 
administered before the first meal of the day with 240 mL of water. 


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• Co-administration of bexagliflozin and sitagliptin: After an overnight fast of at least 
10 hours, a bexagliflozin tablet, 20 mg, and sitagliptin, 100 mg, will be administered 
before the first meal of the day with 240 mL of water. 
 
5.4 
Method of Assigning Subjects to Treatment Groups and 
Sequences 
A total of 54 healthy subjects will be enrolled and assigned to one of three groups of 
eighteen. Each group of eighteen will be randomized to 1 of 6 possible treatment sequences. 
Subjects who discontinue the study early will not be replaced.  
5.5 
Blinding 
This is an open-label study. 
5.6 
Concomitant Therapy 
The participants are not allowed to take any prescription or non-prescription drugs, or dietary 
supplements at any time during the 14 days prior to first drug administration and for the 
duration of all three study periods. Vitamins can be taken up to 7 days prior to first study 
drug administration.  No other concomitant medications are permitted with the exception of 
those required for treatment of an AE. Subjects may receive any medications for AEs that are 
necessary to control or minimize the likelihood of more serious adverse events in the 
investigators’ judgment. 
Concomitant medications administered at the time of randomization and during the study are 
to be recorded on the case report form (CRF). The medication name, dose, frequency, route 
of administration, date(s) of administration and reason for administration must be recorded. 
This documentation should continue until the end of the last study period. Medications that a 
subject receives after entering the study and prior to randomization must be recorded in the 
CRF. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
No study subject shall have been dosed with any SGLT2 inhibitor within 3 months prior to 
the screening, nor with an investigational drug within 30 days or 7 half-lives, or used any 
prescription medication or herbal supplements within 14 days prior to the first dose of study 
medication. 
5.7.2 
Fluid and Food Intake  
An overnight fast of at least 10 h prior to dosing is required. Water is permitted during the 
fasting period up to 1 hour prior to and after the administration of each investigational 


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product administration. Adequate hydration is encouraged during each study period. Food 
can be consumed 4 h after dosing. 
• Bexagliflozin will be taken before the first meal of the day with 240 mL of water, except 
during Group 2 (bexagliflozin/glimepiride DDI) when bexagliflozin will be administered 
with 240 mL 20% glucose solution in water and 60 mL 20% glucose solution in water 
every 15 minutes during the first 4 hours following administration of bexagliflozin.  
• Metformin will be taken before the first meal of the day with 240 mL of water.  
• Glimepiride will be taken before the first meal of the day with 240 mL 20% glucose 
solution in water and 60 mL of 20% glucose solution in water will be provided every 15 
minutes during the first 4 hours following administration of glimepiride. 
• Sitagliptin will be taken before the first meal of the day with 240 mL of water. 
 
5.7.3 
Subject Activity Restrictions 
Light physical activity is permitted. Subjects should not perform strenuous activity which 
could result in elevations of muscle creatine kinase levels. Smoking during the study is 
prohibited. 
5.8 
Treatment Compliance 
To ensure compliance, all medication dosing will be supervised by the Investigator or 
qualified staff in the clinic. The exact times of dosing will be recorded in the CRFs, including 
a record of checks followed by hand mouth inspection. 
5.9 
Packaging and Labeling 
Bexagliflozin tablets, 20 mg, are packaged in high density polyethylene bottles sealed with a 
child resistant closure. The product is packaged with 90 tablets per bottle. 
Investigational product bottles will be labeled with protocol number, drug name and strength, 
lot number, sponsor’s name, storage condition, and the investigational drug caution 
statement. 
5.10 Storage and Accountability 
Drug supplies should be stored at controlled room temperature (15° to 30°C) in a secure area 
with access limited to authorized personnel. The sponsor will perform an ongoing inventory 
of study products. The responsible pharmacist must keep a careful inventory of drug 
shipments received and the number of tablets dispensed per study subject. A full 
reconciliation of drug inventory will be performed at the end of the study and the results of 
this inventory must be recorded in the Drug Accountability Form. Empty and partially used 
bottles may be discarded after use according to the study sites’ regulations for the disposal of 
investigational drug substances at study close out, after the Drug Accountability Form is 
completed. 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Before each subject is enrolled in the clinical study, written informed consent will be 
obtained from the subjects according to the regulatory and legal requirements. As part of this 
procedure, the investigator or designee must explain orally and in writing the nature, duration, 
and purpose of the study, and the action of the drug in such a manner that the study subject is 
aware of the potential risks, inconveniences, or AEs that may occur. The investigator should 
educate potential subjects about the scientific importance of their data and the vital role that 
their participation has for the outcome of the entire study. The subject must be informed that 
he/she is free to withdraw from the study at any time. He/she will receive all information that 
is required by federal regulations and International Council on Harmonisation (ICH) 
guidelines. 
The informed consent document must be signed and dated. One copy will be given to the 
subjects, and the investigator will retain a copy as part of the clinical study records. The 
investigator will not undertake any investigation specifically required for the clinical study 
until written consent has been obtained. The terms of the consent and when it was obtained 
must also be documented. 
6.2 
Medical History 
The following information will be collected at the screening visit: 
• Demographic information including age, sex, and race. 
• Significant medical, surgical history and timeframe of the history relative to study 
screening, if applicable. 
• Clinically significant history of allergy including drugs and latex. 
• History of smoking in the last 3 months, and alcohol or drug dependence, or abuse in the 
last 12 months. 
• Any blood donation within 56 days or blood component donation within 14 days. 
• Use of any medications including OTC drugs, or dietary supplements in the last 14 days. 
Use of any vitamins in the last 7 days. 
• History of vaccination (except the flu vaccine) within 30 days prior to the first dose of 
study medication. 
• History of diagnosis with HIV, hepatitis B or hepatitis C. 
• Use of any investigational drug in the previous 30 days or 7 half-lives, whichever time 
frame is longer. 
• Prior exposure to bexagliflozin (or EGT0001474), or any other SGLT2 inhibitors in the 
last 3 months. 


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• Prior exposure to metformin, sitagliptin, glimepiride, or drugs of the same class 
(biguanides, DPP-4 inhibitors, or sulfonylureas) in the last 3 months. 
 
6.3 
Physical Examination 
The investigator or designated qualified individual will perform the PEs. A complete PE will 
be performed at screening and on the last day of period 3 prior to discharge. Partial PEs will 
be performed at scheduled visits. 
A complete PE will include measurement of body weight and height (height will be 
measured only at screening), general assessment of all body systems including the skin, head, 
eyes, ears, nose, throat, neck, lungs, heart, abdomen, lymph nodes, and extremities. A partial 
PE will include body weight and an update of the general assessment of the skin, heart, lungs 
and abdomen. 
6.4 
Vital Signs 
Vitals signs, including pulse, systolic and diastolic blood pressure (BP), respiration rate, and 
oral temperature, will be measured at the scheduled visits described in Appendix 1.  
Vital signs should be measured prior to blood draws. 
Pulse, systolic and diastolic BP should be measured in a seated position after a subject has 
been sitting for 5 minutes. 
Respiration rate should be measured after at least 5 minutes of rest.  
BP measures will be obtained using a calibrated sphygmomanometer. Devices designed to 
measure BP from the finger or wrist may not be used. 
6.5 
Electrocardiography 
A 12-lead ECG will be conducted as listed in Appendix 1 and whenever clinically indicated. 
This procedure should be performed in the supine position after at least 5 minutes of rest. 
ECG parameters measured will be the RR interval, PR interval, QRS duration, and QT. Each 
ECG should also be assessed by the investigator for signs of ischemia, clinically significant 
hypertrophy, and clinically significant T-wave abnormalities. 
It is the investigator or designee’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 an abnormal change 
from baseline for that subject, this is considered an AE. 


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6.6 
Clinical Laboratory Tests 
6.6.1 
Laboratory Parameters 
Subjects will be in a seated or in a supine position during blood collection. Clinical blood 
chemistry and hematology tests will be performed at the scheduled visits (Appendix 1). 
Blood samples should be drawn after overnight fasting prior to breakfast. The details of the 
required laboratory tests are listed in Table 2. 
Table 2. 
Required Laboratory Tests 
Test Name 
 
mL (sample) 
Hematology 
4.0 (blood) 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration  
Mean corpuscular volume 
Platelet count 
Red blood cell count  
White blood cell count with differential  
 
Serum Chemistry and Electrolytes 
 
5.0 (serum) 
Albumin 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Blood urea nitrogen 
Glucose 
Bicarbonate 
Creatinine 
Chloride 
Total protein 
Calcium 
Magnesium 
Phosphorus 
Potassium  
Sodium  
Total bilirubin 
Direct bilirubin 
Uric acid 
 
Serum Lipids 
 
3.5 (serum) 
Total cholesterol 
High-density lipoprotein cholesterol 
Triglycerides 
Low-density lipoprotein cholesterol, 
calculated 
 
 
Urinalysis 
 
20 (urine) 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Microscopic examination of sediment  
Nitrite  
pH 
Protein 
Specific gravity 
Urobilinogen 
Leukocyte esterase 
 
Urine Collection (in 12-h batches) 
Glucose 
Creatinine 
 
 
All (urine) 
Urine Drug Screen 
 
10 (urine) 
Amphetamines 
Barbiturates 
Cocaine Metabolites 
Cotinine 
Opiates 
Benzodiazepines 
Cannabinoids 
 
Urine Pregnancy Test (Female only) 
 
5 (urine) 
Infectious Disease Testing 
 
5.0 (serum) 
Hepatitis B surface antigen (HBsAg) 
Hepatitis C virus (HCV)  
 


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6.6.2 
Sample Collection, Storage, and Shipping 
6.6.2.1 
Hematology and Blood Chemistry 
Blood samples for hematology and chemistry will be collected. Timing of the collection is 
described in Appendix 1. 
6.6.2.2 
Urinalysis 
Clean-catch, midstream urine samples will be collected per schedule outlined in Section 7 
and in Appendix 1. Dipstick urinalysis will be conducted. Microscopy will be obtained if the 
subject has a positive result on any of the dipstick tests that require microscopic follow-up to 
clarify their significance. In addition, urinalysis will be performed from a clean-catch urine 
sample at any time in subjects with symptoms of UTI or pyelonephritis. 
6.6.2.3 
Urine Collection 
Pre-dose urine samples must be collected from -12 to 0 h for baseline measurement. Subjects 
will empty their bladders prior to dosing. Post-dose urine will be collected without 
preservative in four (4) batches for Groups 1 and 2 at 0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 
to 48 h collections.  Post-dose urine will be collected in six (6) batches for Group 3 at 0 to 12 
h, 12 to 24 h, 24 to 36 h, and 36 to 48 h, 48 to 60 h and 60 to 72 h. Urine must be refrigerated 
at 2-8oC during collection. After collection, the total volume of each batch and collection 
time will be recorded. A 20 mL aliquot will be prepared from well mixed urine collections. 
The samples will be analyzed for urinary glucose (for PD analysis) and creatinine. 
6.6.2.4 
Plasma Sample Collection for PK  
Whole venous blood samples of 5 mL will be collected from a peripheral vein in each period 
at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose for Group 1 
and 2.  PK blood samples will be collected at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 
16, 24, 36, 48, 60 and 72 h post-dose for Group 3.  Blood samples will be collected in tubes 
containing potassium ethylenediaminetetraacetic acid (K2EDTA) and stored on ice until 
centrifuged under refrigeration for at least 10 min at 3,000 rpm. After centrifugation, plasma 
will be removed, divided into 2 aliquots of approximately 1 mL, frozen and stored at or 
below -20°C.  Plasma should be processed and frozen within 2 h of blood collection. 
Processed frozen plasma samples will be transferred on dry ice to the analytical laboratory 
and will be stored at or below -20oC until analysis. 
6.7 
Adverse Events Assessments 
Adverse Event (AE): Any untoward medical occurrence in clinical investigation subject 
administered a pharmaceutical product. An AE does not necessarily have to have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of 


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an investigational product, whether or not it is considered related to the investigational 
product. 
Serious Adverse Event (SAE): A serious adverse event (experience) or reaction is any 
untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening (NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the patient was at risk of death at the time of the event and does not 
refer to an event which hypothetically might have caused death if it were more severe.), 
• requires inpatient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, 
• is an important medical event. 
 
An important medical event is an event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
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. 
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 this laboratory 
value is determined to be an abnormal change from baseline for that subject, this is 
considered an AE. 
Hypoglycemia will be defined as any fasting plasma glucose (FPG) value < 70 mg/dL and 
documented as described in Section 6.7.4.4. 
Any increase in liver function tests (aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), or bilirubin) greater than 3 times the upper limit of normal (ULN) 
for the laboratory utilized will be considered a clinical laboratory adverse event. 


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An increase in creatinine from baseline by 0.5 mg/dL or more will be reported as a 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: The site and database should ask for the causality 
relative to the study compound. Relationship of an adverse event to dosing will be assessed 
as follows: 
Definite: There is a reasonable causal relationship between the investigational product and 
the AE when the event responds to withdrawal of the investigational product (dechallenge), 
and recurs with administration of the investigational product (rechallenge). 
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 no temporal or causal relationship to investigational product 
administration. 
6.7.1 
Collecting and Reporting Adverse Events 
Adverse event collection will begin on the first clinical admission day (Day 0). 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. 
In addition, Theracos’ Medical Monitor or its designated personnel must be notified 
immediately by telephone or fax of any immediately reportable adverse events according to 
the procedure outlined below. Special attention should be paid to recording hospitalization 
and concomitant medications. 


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6.7.2 
Immediately Reportable Adverse Events 
The investigator must report any serious SAE, by telephone, email, or fax, to Theracos or its 
representative immediately after the investigator becomes aware of the event. An IRAE 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 until all parameters have returned to normal, or have otherwise been 
explained. It is expected that the investigator will provide or arrange appropriate supportive 
care for the subject. 
6.7.3 
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 
results of serum pregnancy tests are available. If the pregnancy is confirmed, the subject must 
not receive the investigational product and must not remain in or be enrolled in the study. 


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The investigator must notify the Medical Monitor within 3 working days of the receipt of 
information that any female subject who has become pregnant.  
The investigator must record the event on the Pregnancy Surveillance Form and forward it to 
the sponsor’s clinical or designated personnel. 
6.7.4 
Follow-up of Adverse Events 
6.7.4.1 
Follow-up of Non-serious Adverse Events 
Non-serious adverse events that are identified on the last scheduled contact must be recorded 
on the AE CRF with the current status noted. All non-serious events that are ongoing at the 
time will be recorded as ongoing on the CRF. 
6.7.4.2 
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 6.7.1. 
These may include unresolved previously reported SAEs, or new SAEs. The investigator 
should follow these subjects until the events are resolved, or the subject is lost to follow-up. 
Resolution means the subject has returned to the baseline state of health, or the investigator 
does not expect any further improvement or worsening of the subject’s condition. The 
investigator should continue to report any significant follow-up information to 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 Medical Monitor or the sponsor’s 
designated personnel. These may include SAEs that are captured on follow-up telephone 
contact or at any other time point after the defined study period (i.e., up to last scheduled 
contact). The investigator should follow subjects with SAEs identified after the last 
scheduled contact until the events are resolved, or the subject is lost to follow-up. The 
investigator should continue to report any significant follow-up information to the Sponsor 
until the event has been resolved. This study requires that subjects be actively monitored for 
SAEs for at least 14 days after discharge from the study. 
6.7.4.3 
Hepatotoxicity 
Any clinically significant increase in hepatic enzymes and specifically ALT or AST ≥ 3x 
ULN requires immediate repeat test within 48 to 72 h to confirm the hepatic enzyme 
elevation. Study medication should be stopped and the event should be reported as an 
adverse event within the CRF if the enzyme elevation is confirmed or worsening. Potential 
contributors to hepatic enzyme elevation should be evaluated by the investigator. The 
investigator is encouraged to consult with the Medical Monitor regarding ongoing diagnostic 
workup. 


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Investigational product should be permanently discontinued if any of the following criteria is 
met: 
• ALT or AST > 8xULN, 
• ALT or AST > 3xULN and (total bilirubin > 2xULN or INR > 1.5), 
• ALT or AST > 3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
 
6.7.4.4 
Hypoglycemia 
Hypoglycemia will be recorded under 5 categories: 
• Critical hypoglycemia: An event requiring assistance of another person to actively 
administer carbohydrate, glucagons, 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. 
• 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). 
• Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration ≤ 70 mg/dL 
(3.9 mmol/L). 
• Probable symptomatic hypoglycemia: An event during which symptoms of hypoglycemia 
are not accompanied by a plasma glucose determination but that was presumably caused 
by a plasma glucose concentration ≤ 70 mg/dL (3.9 mmol/L). 
• 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). 
 
6.8 
Concomitant Medication Assessments 
A concomitant medication is any medication the subject enters the trial taking and is 
expected to continue taking for some portion of the trial, as well as any medication the 
subject takes during the course of the trial. 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 are 
discharged. 


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Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A table of concomitant medications based on the anatomic 
therapeutic chemical classification 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. 
Concomitant medications administered 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 until 
discharge from the study. 
6.9 
Removal of Subjects from the Trial or Discontinuation of 
Investigational Product 
The investigator must emphasize to potential subjects the importance of continued 
participation for the full duration of the trial during the informed consent process. 
Participation in the study is voluntary. A participant has the right to withdraw from the study 
at any moment for any reason. The investigator will be informed immediately. 
The investigator has the right to terminate participation of a subject in case it is difficult to 
obtain blood samples, in case of violation of the protocol or in case of severe or serious 
adverse events. 
In case a subject withdraws from the study, the study monitor will be informed immediately. 
If there is a medical reason for withdrawal, the volunteer should remain under the 
supervision of the medical investigator until satisfactory health returns. 
Subjects who discontinue the active dosing phase of the study due to adverse event(s) or 
other safety concerns will not be replaced. 
When the decision is made to discontinue a subject’s participation in the study, no further 
investigational product medication should be administered. Every attempt should be made to 
complete all required study evaluations and procedures. Reasons for all withdrawals should 
be recorded on the CRF. 
The investigator may withdraw a subject from the THR-1442-C-453 trial for any of the 
following reasons: 
• A protocol violation occurs, or 
• A serious or intolerable adverse event occurs, or 
• A clinically significant change in a laboratory parameter occurs, or 
• The sponsor or investigator terminates the study, or 
• The subject requests to be discontinued from the study. 
 


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Subjects who do not complete the study but who have received investigational product 
should have a follow-up examination, including a complete physical examination, vital signs, 
ECG and clinical laboratory tests if clinically indicated according to Section 7. 
6.10 Appropriateness of Measurements 
PK and safety parameters in this protocol are standard assessments and are widely used and 
generally recognized as reliable, accurate, and relevant measurements. 
Determination of urinary glucose is a non-invasive and quantitative method that allows 
immediate assessment of the PD effects of an SGLT2 inhibitor. 


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7 
STUDY ACTIVITIES 
7.1 
Screening (Days -28 to Day -1) 
During the screening period, the following information will be gathered and the indicated 
procedures will be performed: 
• Content of informed consent will be explained to the subject and the signed informed 
consent collected. 
• Medical history and demographic information will be obtained. 
• Physical examination will be conducted, including height and weight measurements as 
described in Section 6.3. 
• Vital signs will be measured, including pulse, temperature, respiratory rate, and blood 
pressure taken in the sitting position after at least 5 min of rest as described in Section 
6.4. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest as described 
in Section 6.5. 
• Clean-catch, mid-stream urine will be collected for urinalysis as described in Section 
6.6.2.2. If urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent 
for microscopic evaluation and culture. 
• Urine screen will be conducted for drug abuse and cotinine. If the drug screen is 
conducted more than 5 days pre-dose, the drug screen must be repeated prior to dosing. 
Drug abuse testing includes amphetamines, barbiturates, cocaine metabolites, opiates, 
benzodiazepines, and cannabinoids. 
• All female subjects will receive urine pregnancy test. 
• Blood will be drawn for hematology, serum chemistry, and serology as detailed in 
Section 6.6.2.1. 
• Inclusion/exclusion criteria will be evaluated based on the information collected at the 
screening examination. 
 
7.2 
Period 1 
7.2.1 
Day 0 (Clinic Admission) 
The following information will be gathered and the indicated procedures will be performed: 
• If screening was conducted more than five days prior to dosing, the inclusion and 
exclusion criteria must be confirmed and a urine drug screen performed. 
• All female subjects will receive urine pregnancy test. 
• Partial PE will be performed as described in Section 6.3. 


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• If the subject is still eligible based on the study inclusion and exclusion criteria, the 
subject will be admitted and randomized into the study. 
• Concomitant medications and adverse event information will be collected as appropriate. 
• Pre-dose urine collection in 12 h batches will begin with the -12 h to 0 h batch for 
baseline analysis of creatinine and for UGE (PD) analysis as described in Section 6.6.2.3. 
 
7.2.2 
Day 1 (Dosing Day): Pre-dose Activities 
The following information will be gathered and the indicated procedures will be performed 
pre-dose: 
• Vital signs will be recorded pre-dose. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest pre-dose. 
• Pre-dose urine will be collected until 0 h (-12 h to 0 h batch) for baseline UGE and 
creatinine analysis as described in Section 6.6.2.3. 
• Urine sample will be collected for pre-dose urinalysis as described in Section 6.6.2.2. If 
urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for 
microscopic evaluation and culture. 
• Pre-dose blood will be drawn for hematology, and serum chemistry as detailed in Section 
6.6.2.1. 
• Pre-dose plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4. 
• Pre-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.2.3 
Day 1 (Dosing Day): Dosing 
• For Group 1 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
alone, metformin, 1000 mg, alone or bexagliflozin and metformin in combination will be 
administered prior to first meal of the day as detailed in Section 5.3.1. 
• For Group 2 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
alone, glimepiride, 4 mg, alone or bexagliflozin and glimepiride in combination will be 
administered prior to first meal of the day with glucose solution as detailed in Section 
5.3.2. 
• For Group 3 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
alone, sitagliptin, 100 mg, alone or bexagliflozin and sitagliptin in combination will be 
administered prior to first meal of the day as detailed in Section 5.3.3. 
 


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7.2.4 
Day 1: Post-dose Activities 
• Vital signs will be recorded at 4 h post-dose. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest at 4 h post-
dose. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 0.5, 1, 2, 
3, 4, 5, 6, 8, 10, 12, 16 h post-dose.   
• Urine for analysis of creatinine and UGE will be collected in 12 h batches at 0 to 12 h 
and 12 to 24 h post-dose as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.2.5 
Day 2: Post-dose Activities 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 24 and 36 
h post-dose.   
• Urine for analysis of creatinine and UGE will be collected in 12 h batches 12 to 24 h, 24 
to 36 h and 36 to 48 h as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.2.6 
Day 3: Post-dose Activities 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 48 h post-
dose for all Groups and additionally at 60 h post-dose for Group 3.   
• Urine for analysis of creatinine and UGE will be collected in 12 h batches at 36 to 48 h 
post-dose for all Groups and additionally at 48 to 60 h and 60 to 72 h post-dose for Group 
3 as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
• For Group 1 and 2, vital signs will be recorded at 48 h post-dose. 
• For Group 1 and 2, urine will be collected for urinalysis as described in Section 6.6.2.2. 
• For Group 1 and 2, blood will be drawn for hematology and serum chemistry as detailed 
in Section 6.6.2.1. 
• For Group 1 and 2, the subject will be discharged after completion of all activities and 
scheduled for admission for Period 2. 
 


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7.2.7 
Day 4 (Group 3 Only): Post-dose Activities 
• Vital signs will be recorded at 72 h post-dose. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 72 h post-
dose.   
• Urine for analysis of creatinine and UGE will be collected in 12 h batches at 60 to 72 h 
post-dose as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
• Urine will be collected for urinalysis as described in Section 6.6.2.2. 
• Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
• Subject will be discharged after completion of all activities and scheduled for admission 
for Period 2. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the study termination day except for PK and PD sample collection must be completed. The 
reason for termination must be entered onto the case report form. 
7.3 
Period 2 
7.3.1 
Day 7 (Clinic Admission) 
The following information will be gathered and the indicated procedures will be performed: 
• All female subjects will receive urine pregnancy test. 
• If the subject is still eligible based on the study inclusion and exclusion criteria, the 
subject will be admitted. 
• Concomitant medications and adverse event information will be collected as appropriate. 
• Pre-dose urine collection in 12 h batches will begin with the -12 h to 0 h batch for 
baseline analysis of creatinine and for UGE (PD) analysis as described in Section 6.6.2.3. 
 
7.3.2 
Day 8 (Dosing Day): Pre-dose Activities 
The following information will be gathered and the indicated procedures will be performed 
pre-dose: 
• Vital signs will be recorded pre-dose. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest pre-dose. 
• Pre-dose urine will be collected until 0 h (-12 h to 0 h batch) for baseline UGE and 
creatinine analysis as described in Section 6.6.2.3. 


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• Urine sample will be collected for pre-dose urinalysis as described in Section 6.6.2.2. If 
urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for 
microscopic evaluation and culture. 
• Pre-dose blood will be drawn for hematology, and serum chemistry as detailed in Section 
6.6.2.1. 
• Pre-dose plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4. 
• Pre-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.3.3 
Day 8 (Dosing Day): Dosing 
• For Group 1 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
alone, metformin, 1000 mg, alone or bexagliflozin and metformin in combination will be 
administered prior to first meal of the day as detailed in Section 5.3.1. 
• For Group 2 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
alone, glimepiride, 4 mg, alone or bexagliflozin and glimepiride in combination will be 
administered prior to first meal of the day with glucose solution as detailed in Section 
5.3.2. 
• For Group 3 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
alone, sitagliptin, 100 mg, alone or bexagliflozin and sitagliptin in combination will be 
administered prior to first meal of the day as detailed in Section 5.3.3. 
 
7.3.4 
Day 8 (Dosing Day): Post-dose Activities 
• Vital signs will be recorded at 4 h post-dose. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest at 4 h post-
dose. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 0.5, 1, 2, 
3, 4, 5, 6, 8, 10, 12, 16 h post-dose.   
• Urine for analysis of creatinine and UGE will be collected in 12 h batches at 0 to 12 h 
and 12 to 24 h post-dose as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.3.5 
Day 9: Post-dose Activities 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 24 and 36 
h post-dose.   


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• Urine for analysis of creatinine and UGE will be collected in 12 h batches 12 to 24 h, 24 
to 36 h and 36 to 48 h as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.3.6 
Day 10: Post-dose Activities 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 48 h post-
dose for all Groups and additionally at 60 h post-dose for Group 3.   
• Urine for analysis of creatinine and UGE will be collected in 12 h batches at 36 to 48 h 
post-dose for all Groups and additionally at 48 to 60 h and 60 to 72 h post-dose for Group 
3 as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
• For Group 1 and 2, vital signs will be recorded at 48 h post-dose. 
• For Group 1 and 2, urine will be collected for urinalysis as described in Section 6.6.2.2. 
• For Group 1 and 2, blood will be drawn for hematology and serum chemistry as detailed 
in Section 6.6.2.1. 
• For Group 1 and 2, the subject will be discharged after completion of all activities and 
scheduled for admission for Period 3. 
 
7.3.7 
Day 11 (Group 3 Only): Post-dose Activities 
• Vital signs will be recorded at 72 h post-dose. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 72 h post-
dose.   
• Urine for analysis of creatinine and UGE will be collected in 12 h batches at 60 to 72 h 
post-dose as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
• Urine will be collected for urinalysis as described in Section 6.6.2.2. 
• Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
• Subject will be discharged after completion of all activities and scheduled for admission 
for Period 3. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the study termination day except for PK and PD sample collection must be completed. The 
reason for termination must be entered onto the case report form. 


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7.4 
Period 3 
7.4.1 
Day 14 (Clinic Admission) 
The following information will be gathered and the indicated procedures will be performed: 
• All female subjects will receive urine pregnancy test. 
• If the subject is still eligible based on the study inclusion and exclusion criteria, the 
subject will be admitted. 
• Concomitant medications and adverse event information will be collected as appropriate. 
• Pre-dose urine collection in 12 h batches will begin with the -12 h to 0 h batch for 
baseline analysis of creatinine and for UGE (PD) analysis as described in Section 6.6.2.3. 
 
7.4.2 
Day 15 (Dosing Day): Pre-dose Activities 
The following information will be gathered and the indicated procedures will be performed 
pre-dose: 
• Vital signs will be recorded pre-dose. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest pre-dose. 
• Pre-dose urine will be collected until 0 h (-12 h to 0 h batch) for baseline UGE creatinine 
analysis as described in Section 6.6.2.3. 
• Urine sample will be collected for pre-dose urinalysis as described in Section 6.6.2.2. If 
urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for 
microscopic evaluation and culture. 
• Pre-dose blood will be drawn for hematology, and serum chemistry as detailed in Section 
6.6.2.1. 
• Pre-dose plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4. 
• Pre-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.4.3 
Day 15 (Dosing Day): Dosing 
• For Group 1 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
alone, metformin, 1000 mg, alone or bexagliflozin and metformin in combination will be 
administered prior to first meal of the day as detailed in Section 5.3.1. 
• For Group 2 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
alone, glimepiride, 4 mg, alone or bexagliflozin and glimepiride in combination will be 
administered prior to first meal of the day with glucose solution as detailed in Section 
5.3.2. 


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• For Group 3 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
alone, sitagliptin, 100 mg, alone or bexagliflozin and sitagliptin in combination will be 
administered prior to first meal of the day as detailed in Section 5.3.3. 
 
7.4.4 
Day 15 (Dosing Day): Post-dose Activities 
• Vital signs will be recorded at 4 h post-dose. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest at 4 h post-
dose. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 0.5, 1, 2, 
3, 4, 5, 6, 8, 10, 12, 16 h post-dose.   
• Urine for analysis of creatinine and UGE will be collected in 12 h batches at 0 to 12 h 
and 12 to 24 h post-dose as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.4.5 
Day 16: Post-dose Activities 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 24 and 36 
h post-dose.   
• Urine for analysis of creatinine and UGE will be collected in 12 h batches 12 to 24 h, 24 
to 36 h and 36 to 48 h as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.4.6 
Day 17: Post-dose Activities 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 48 h post-
dose for all Groups and additionally at 60 h post-dose for Group 3.   
• Urine for analysis of creatinine and UGE will be collected in 12 h batches at 36 to 48 h 
post-dose for all Groups and additionally at 48 to 60 h and 60 to 72 h post-dose for Group 
3 as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
• For Group 1 and 2, vital signs will be recorded at 48 h post-dose. 
• For Group 1 and 2, urine will be collected for urinalysis as described in Section 6.6.2.2. 
• For Group 1 and 2, blood will be drawn for hematology and serum chemistry as detailed 
in Section 6.6.2.1. 


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• For Group 1 and 2, a physical examination will be conducted as described in Section 6.3. 
• For Group 1 and 2, a 12-lead ECG will be taken in the supine position after at least 5 min 
of rest as described in Section 6.5. 
• For Group 1 and 2, the subject will be discharged after completion of all activities. 
 
7.4.7 
Day 18 (Group 3 Only): Post-dose Activities 
• Vital signs will be recorded at 72 h post-dose. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 72 h post-
dose.   
• Urine for analysis of creatinine and UGE will be collected in 12 h batches at 60 to 72 h 
post-dose as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
• Urine will be collected for urinalysis as described in Section 6.6.2.2. 
• Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
• Physical examination will be conducted as described in Section 6.3. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest as described 
in Section 6.5. 
• Subject will be discharged after completion of all activities. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the study termination day except for PK and PD sample collection must be completed. The 
reason for termination must be entered onto the case report form. 
7.5 
Early Termination or Follow-up Procedures 
Subjects who have completed study activities or have withdrawn consent and have received 
investigational product should have a follow-up examination if clinically indicated, including 
a complete physical examination, vital signs, ECG, and clinical laboratory tests (hematology, 
and serum chemistry). The sponsor must be notified in the event that a subject withdraws or 
has been withdrawn from the study. 
 


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8 
QUALITY CONTROL AND ASSURANCE 
The clinical research facility will be monitored by the study monitor to ensure correct 
performance of the study procedures and assure that the study will be conducted according to 
the protocol and relevant regulatory requirements. CRF entries will be verified with the 
source documentation. 
Quality control principles will be applied throughout the performance of this study by 
following the standard operating procedure (SOPs) of the contract research organization 
(CRO) and the sponsor. Review procedures will be implemented at the CRO for all 
documents that are generated in relation to the study. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The statistical evaluation of PK parameters will be conducted by the designated CRO. A 
detailed Statistical and Analytical Plan will be generated prior to any PK, PD or statistical 
analysis of the data. Statistical analysis will be performed using Statistical Analysis Software 
SAS for Windows® (SAS Institute Inc., USA). Non-compartmental analysis will be 
performed using Phoenix®WinNonlin® 6.4 (Certara, USA). 
9.2 
Determination of Sample Size 
The sample size for this study is not based upon formal statistical consideration. The sample 
size is considered adequate to characterize the PK of bexagliflozin and OHAs, to assess 
potential drug-drug interactions, and to provide safety and tolerability data on bexagliflozin 
when administered alone and in combination with OHAs. 
9.3 
Analysis Populations 
9.3.1 
Safety Population 
The Safety Population will include all randomized subjects who received at least one dose of 
investigational product. Subjects will be analyzed according to the treatment received. 
9.3.2 
PK Population 
The PK Population will include all randomized subjects who receive at least one dose of 
investigational product and who have sufficient plasma bexagliflozin and OHA 
measurements to derive PK parameters following dosing. The PK Population will be used to 
summarize the PK parameters. 
9.3.3 
PD Population 
The PD Population will include all randomized subjects who receive at least one dose of 
investigational product and will have had at least 2 batches of 12 h urine collection from 
which to calculate UGE measurement following dosing. The PD Population will be used to 
summarize the PD parameters. 
9.4 
Demographics and Baseline Characteristics 
Baseline characteristics will be summarized for all subjects in the Safety, PK and PD 
Populations. Descriptive statistics will be performed. 


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9.5 
Pharmacokinetic Analysis 
9.5.1 
Calculation of Pharmacokinetic Variables 
A non-compartmental analysis will be used to calculate the PK parameters of bexagliflozin, 
metformin, glimepiride and sitagliptin individually and the combination of bexagliflozin with 
each tested OHA using the software Phoenix® WinNonlin® 6.4 (Certara, USA). From the 
plasma bexagliflozin concentration-time data, the following PK parameters will be estimated 
for each subject where feasible. 
Cmax:  
Maximum observed plasma concentration 
Tmax:  
Time of maximum observed plasma concentration 
Oz:  
 
Terminal elimination phase rate constant 
T½:  
 
Apparent terminal elimination half life 
CL/F:  
Apparent oral clearance 
Vz/F:  
Apparent volume of distribution 
AUC0-t: 
Area under the plasma concentration-time curve from Time 0 to Time t (time of 
last quantifiable plasma concentration) 
AUC0-∞: 
Area under the plasma concentration-time curve from Time 0 to infinity 
Cmax and Tmax will be obtained directly from experimental observations. If multiple maxima 
occur at equal concentrations, the first temporal value will be taken as the Cmax and Tmax. 
The apparent terminal elimination half-life, T1/2, where determinable, will be calculated as 
the natural log of 2 divided by the terminal phase rate constant, λz. The number of data points 
included in the regression will be determined by visual inspection, but a minimum of three 
data points in the terminal phase, excluding Cmax, is required to estimate λz. In order for the 
selection to take place the adjusted r2 value reported in Phoenix®WinNonlin® must be ≥ 0.7.  
AUC0-t and AUC0-∞ will be calculated using the linear trapezoidal linear interpolation 
method, using actual elapsed time values. If the actual collection time is unknown the 
nominal collection time may be used for the purposes of PK parameter estimation. For the 
purpose of calculating AUC, all missing values will be treated as missing in the PK analysis 
and excluded from analysis except when they occur at pre-dose where they will be set to 
zero. All values that were below the limit of quantitation (BLOQ) prior to Tmax will be set to 
zero. BLOQ values that occur after Tmax will be set to missing. When ≥ 2 consecutive plasma 
concentrations BLOQ are encountered after Tmax, these and all subsequent values will be 
excluded from the analysis.  
AUC0-∞ will be calculated according to the following equation: 
AUC0-∞= AUClast + (Clast / λz), where Clast is the last temporal quantifiable plasma 
concentration corresponding to Tlast. 


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The proportion of AUC0-∞ due to extrapolation (AUCextr) will be calculated and expressed as 
a percentage. AUC0-∞ values will be considered unreliable estimates if the AUCextr is greater 
than 20%. 
CL/F will be calculated as Dose/AUC0-∞. 
Vz/F will be calculated as Dose/(λz × AUC0-∞). 
T½ will be calculated as 0.693/λz. 
Descriptive statistics for the plasma concentrations of bexagliflozin, metformin, glimepiride 
and sitagliptin by Treatment and Timepoint will be provided. A listing of plasma 
concentrations by Subject Number, Treatment Period and Timepoint will also be provided. 
9.5.2 
Statistical Analysis of Pharmacokinetic Variables 
To assess the effect of OHAs metformin, glimepiride or sitagliptin on the PK of bexagliflozin 
and vice versa, an analyses of variance (ANOVA) using a linear mixed-effects model will be 
fitted to the natural logarithmic transformation of PK parameters of bexagliflozin (Cmax, 
AUC0-t and AUC0-∞). The linear mixed-effects model will include subject as a random effect, 
and treatment, period, and sequence as fixed effects. The 90% confidence intervals will be 
constructed for the (bexagliflozin and OHA in combination) to (bexagliflozin alone) or 
(OHA alone) ratio of the least squares (LS) geometric means of PK parameters (Cmax, AUC0-t 
and AUC0-∞), with 80-125% defined as the lack of interaction boundaries. 
Descriptive statistics for the PK parameters Cmax, Tmax, AUC0-∞ , AUC0-t , CL/F, Vz/F, λz, and 
T1/2 will be tabulated by treatment. Means, standard deviations, medians, ranges (min, max) 
and geometric means and coefficients of variation will be presented for all PK parameters 
with the exception of Tmax. Medians and ranges will be presented for Tmax.  
A listing of derived PK parameters of bexagliflozin by Subject ID and Treatment Period will 
be provided.  
9.6 
Pharmacodynamic Analysis 
Urinary glucose excretion will be determined as a PD parameter at baseline and up to 72 h 
post-dose. The drug-drug interaction effect between bexagliflozin and OHAs will be 
evaluated by comparing the mean cumulative UGE between subjects taking bexagliflozin or 
OHA alone and bexagliflozin and OHA in combination. 
Descriptive statistics on the PD parameters will be performed. The effect of an OHA on the 
cumulative UGE between subjects administered bexagliflozin alone or in combination with 
an OHA will be compared. The PD parameters, UGE and UGE normalized by urinary 
creatinine, including UGEt1-t2, in 12-hour and 24 –hour increments, and total 24-hour UGE, 
will be determined. UGEt1-t2 (mg) will be derived from urine volume (Vt1-t2, mL) × glucose 
concentration (mg/dL) / 100. UGE will be listed and summarized by treatment arm using 
descriptive statistics. 


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9.7 
Safety Analysis 
Safety data will include AEs, PE results, vital signs, ECG results, and clinical lab results, 
including serum chemistry, hematology, and urinalysis. Observed data will be described as 
counts and percentages for discrete variables and estimation of means, standard deviations 
(SDs), medians, inter-quartile range, minimum and maximum for continuous metrics. All 
subjects in the Safety Population will be included in the safety analyses. All safety data will 
be presented in by-subject listings and included in the clinical trial report. 
9.7.1 
Adverse Events 
Adverse events will be mapped to preferred term and body system using the Medical 
Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects 
reporting adverse events will be determined by relationship to treatment and by severity of 
the event. Drug-related adverse events will be considered those to be possibly related to 
bexagliflozin administration. 
Adverse event listings will be provided for the following subsets: 
• all treatment emergent AEs (TEAEs). 
• all TEAEs at least possibly related to bexagliflozin. 
• serious TEAEs (if any). 
• TEAEs leading to study discontinuation (if any). 
 
AEs are dosing emergent if they occur on or after bexagliflozin administration. TEAEs will 
be considered at least possibly related to bexagliflozin based on the investigator’s 
assessment. Only TEAEs will be tabulated in summary tables. If the AE(s) onset date-time or 
date occurs after the first dose up until right before the next dose, the AE(s) will be assigned 
to the first treatment. Any AE(s) that occur after the second dose up until the follow-up visit 
will be assigned to the second treatment. 
Tabulations will display TEAEs by severity and relationship to bexagliflozin. 
9.7.2 
Hypoglycemia 
Hypoglycemia as defined in Section 6.7.4.4 will be presented in listings and summarized. 
9.7.3 
Clinical and Laboratory Events and Analyses 
Clinical and laboratory metrics are measured at baseline (pre-dose measurement of each 
period) and during the treatment periods (Appendix 1). These variables include vital signs 
(blood pressure, respiration, temperature), clinical laboratory results (see Section 6.6 for a 
complete list), and ECGs. 


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Serum chemistry, hematology, and urinalysis (quantitative parameters) data will be 
summarized for each treatment period. Summaries for change from baseline will be 
presented for these laboratory tests.  
ECG results will be summarized as changes from baseline in intervals. Abnormalities as well 
as changes from previous assessment will be listed. 
9.7.4 
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. 


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
Information regarding key personnel involved in the conduct of the study, including names 
and contact details of participating investigators, monitors, clinical laboratories, and technical 
departments and/or institutions, as well as information on members of additional study 
committees, will be found in the study files of the investigational site. 
10.2 Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
The study protocol, informed consent document, relevant supporting information, and all 
types of subject recruitment or advertisement information must be submitted to the IRB/IEC 
for review and must be approved by the sponsor and the IRB/IEC before the study is 
initiated. Any amendments or addenda to the protocol must also be approved by the IRB/IEC 
prior to implementing changes in the study. The investigator is responsible for keeping the 
IRB/IEC informed of the progress of the study and of any changes made to the protocol as 
deemed appropriate. The investigator must also keep the IRB/IEC informed of any SAEs 
occurring to subjects under their supervision. 
10.3 Ethical Conduct of the Study 
The procedures set out in this protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the sponsor and investigator follow 
Good Clinical Practice (GCP) Guidelines and the guiding principles detailed in the 
Declaration of Helsinki. The study will also be carried out in keeping with applicable local 
laws and regulations. An inspection by the sponsor representatives and/or their designee 
and/or healthy authority 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 head of the investigational site, IRB (via the 
head of the investigational site)/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 
The investigator will draft the informed consent form based on the protocol and CRO’s draft 
informed consent form. The sponsor will review the investigator’s draft informed consent 
form prior to submission to the IRB/IEC and the final IRB/IEC approved document must be 
provided to the sponsor for regulatory purposes. 
Prior to the beginning of the study, the investigator must have received from the IEC or IRB 
the written approval or favorable opinion of the informed consent form and any other written 
information to be provided to subjects. The written approval of the IRB/IEC together with 
the approved subject information and informed consent forms must be filed. The informed 
consent form must contain all elements required by the Federal Drug Administration under 
21 Code of Federal Regulations Part 50 and the ICH GCP Guidelines (E6), in addition to, 
any other elements required by regulations or institutional policy. 
Written informed consent must be obtained before any study-specific procedure takes place. 
Participation in the study and date of informed consent given by the subject should be 
documented appropriately in the subject’s files. A copy of the signed informed consent form 
must be provided to the subject. If applicable, it will be provided in a certified translation in 
the language understood by the subject, if not English. Signed consent forms must remain in 
each subject’s study file and must be available for verification by study monitors at any time. 
10.5 Subject Confidentiality 
The information obtained during the conduct of this clinical study is confidential, and 
disclosure to third parties other than those noted below is prohibited. Information obtained 
during the conduct of this study will be used by the sponsor in connection with the 
development of the investigational product. The study investigator is obliged to provide the 
sponsor with complete test results and all data developed in this study. Subject-specific 
information may be provided to other appropriate medical personnel only with the subject’s 
permission. To ensure compliance with current ICH guidelines, data generated by this study 
must be available for inspection upon request by representatives of national and local health 
authorities, the sponsor, and the IRB/IEC for each study site. 
Subject names and other identifiers, such as photographs, audio, or videotapes, may not be 
disclosed in any publication without prior written authorization from the subject. 
10.6 Study Monitoring 
An authorized sponsor representative will conduct site visits to inspect study data, subjects’ 
medical records, and CRFs in accordance with ICH guidelines, GCPs, and the respective 
national and local government regulations and guidelines. 


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The investigator will permit authorized representatives of the sponsor and the respective 
national or local health authorities, other authorized regulatory authorities, and IRB/IEC to 
inspect facilities and records relevant to this study. 
10.7 Case Report Forms and Study Records 
For each subject consented, a case report form (CRF), in paper or electronic format, will be 
supplied and maintained by the CRO staff and signed by the investigator or authorized 
designee to indicate that he/she has reviewed and agrees with the entered data. This also 
applies to those subjects who fail to complete the trial. The reason a subject is withdrawn 
must be recorded in the case report form. 
Entries made in the CRF must be verifiable against source documents. Source documents are 
defined as all medical records, medical notes, laboratory results, ECG traces and any 
additional document other than the CRF that has original subject information contained 
within it. 
All CRFs and source documents should be completed following GCPs and the CRO’s 
standard operating procedures. 
10.8 Protocol Violations/Deviations 
It is important to conduct the study according to the protocol. Protocol deviations will not be 
prospectively granted by the sponsor. If deviations occur, such as a visit or sampling window 
being missed, the investigator must decide whether to proceed, for example, whether or not 
to complete the visit or sample collection outside of the protocol-defined window. The 
sponsor’s medical monitor must be notified immediately when protocol deviations are 
discovered so that a decision about whether to keep the subject in the study can be made. 
Only when an emergency occurs that requires a departure from the protocol for an individual 
subject will there be such 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 must be reported in the final study report. 
10.9 Access to Source Documentation 
Authorized sponsor representatives will conduct site visits to inspect study data, subjects’ 
medical records, and CRFs in accordance with ICH guidelines, GCPs, and the respective 
local and national government regulations and guidelines. 
The investigator will permit authorized representatives of the sponsor and the respective 
national or local health authorities, other authorized regulatory authorities, and IRB/IEC to 
inspect facilities and records relevant to this study. 


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The 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. 
10.10 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. 
10.11 Publication and Disclosure Policy 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor, who may utilize the data in various ways, such as 
for submission to government regulatory authorities or disclosure to other investigators. 
No publication or disclosure of study results will be permitted except as specified in a 
separate, written agreement between Theracos Sub, LLC and the investigator. If results of 
this study are reported in medical journals or at meetings, all subjects’ identities will remain 
confidential. 


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11 REFERENCE LIST 
IDF (2014). International Diabetes Federation Diabetes Atlas, 6th Edition. 
 
Langtry, H.D., and Balfour, J.A. (1998). Glimepiride. A review of its use in the management 
of type 2 diabetes mellitus. Drugs 55, 563-584. 
 
Nauck, M.A. (2014). Update on developments with SGLT2 inhibitors in the management of 
type 2 diabetes. Drug design, development and therapy 8, 1335-1380. 
 
Pentikainen, P.J., Neuvonen, P.J., and Penttila, A. (1979). Pharmacokinetics of metformin 
after intravenous and oral administration to man. European journal of clinical pharmacology 
16, 195-202. 
 
Tahrani, A.A., Barnett, A.H., and Bailey, C.J. (2016). Pharmacology and therapeutic 
implications of current drugs for type 2 diabetes mellitus. Nature reviews Endocrinology. 
 
Vincent, S.H., Reed, J.R., Bergman, A.J., Elmore, C.S., Zhu, B., Xu, S., Ebel, D., Larson, P.,  
Zeng, W., Chen, L., et al. (2007). Metabolism and excretion of the dipeptidyl peptidase 4 
inhibitor [14C]sitagliptin in humans. Drug metabolism and disposition: the biological fate of  
chemicals 35, 533-538. 
 
Zhang, W., Welihinda, A., Mechanic, J., Ding, H., Zhu, L., Lu, Y., Deng, Z., Sheng, Z., Lv, 
B., Chen, Y., et al. (2011). EGT1442, a potent and selective SGLT2 inhibitor, attenuates 
blood glucose and HbA(1c) levels in db/db mice and prolongs the survival of stroke-prone 
rats. Pharmacol Res 63, 284-293. 
 


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Appendix 1 
Schedule of Events 
A. SCHEDULE OF EVENTS FOR STUDY 1: BEXAGLIFLOZIN AND METFORMIN DRUG-DRUG INTERACTION 
 
Screening 
Period 1 
Period 2 
Period 3 
Study activity 
D -28 
to -1 
D0 
D1 
pre-
dose 
D1 
post-
dose 
D2 
D3 
D71 
D8 
pre-
dose 
D8 
post-
dose 
D9 
D10 
D141 
D15 
pre-
dose 
D15 
post-
dose 
D16 
D17 
Informed consent form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening for I/E 
criteria 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Physical examination2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission/discharge 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
Vital signs3 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
ECG4 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
X 
Urinalysis5 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Blood draw for clinical 
lab tests6 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Blood sample for PK7 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urine collection for PD8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Adverse event and 
concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study completion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 
The admission day for Period 2 and 3 will be 4-6 days after discharge from the previous Period. 
2 
A complete physical examination will be performed at screening and day 17 prior to discharge. A partial physical exam will be performed on admission day of Period 1. 
3 
On days 1, 8 and 15, vital signs will be determined at pre-dose and at 4 h and 48 h (day 3, 10 and 17) post-dose. 
4 
ECG data will be recorded at screening, on days 1, 8 and 15 at pre-dose and at 4 h post-dose, at the study termination visit and when clinically indicated. 
5 
Urine samples will be collected for urinalysis at screening, pre-dose and prior to discharge. If urine is dipstick positive for leukocyte esterase or nitrites, sample will be sent for microscopic 
evaluation and culture. Urine drug screen will only be performed at screening, and if it is conducted more than 5 days prior to dosing, screening shall be repeated.  
6 
Blood samples will be drawn for clinical laboratory tests at screening, pre-dose and prior to discharge. Clinical laboratory tests are listed in Table 2. 
7 
Plasma samples for PK analysis will be collected as described in Section 6.6.2.4. 
8 
Urine collection for the evaluation of urinary glucose and creatinine are described in Section 6.6.2.3. 
 


Bexagliflozin tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-453 
 
01 September 2016  
 
 
 
 
Confidential 
Page 55 of 58 
B. SCHEDULE OF EVENTS FOR STUDY 2: BEXAGLIFLOZIN AND GLIMEPIRIDE DRUG-DRUG INTERACTION 
 
Screening 
Period 1 
Period 2 
Period 3 
Study activity 
D -28 
to -1 
D0 
D1 
pre-
dose 
D1 
post-
dose 
D2 
D3 
D71 
D8 
pre-
dose 
D8 
post-
dose 
D9 
D10 
D141 
D15 
pre-
dose 
D15 
post-
dose 
D16 
D17 
Informed consent form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening for I/E 
criteria 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Physical examination2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission/discharge 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
Vital signs3 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
ECG4 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
X 
Urinalysis5 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Blood draw for clinical 
lab tests6 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Blood sample for PK7 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urine collection for PD8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Adverse event and 
concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study completion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 
The admission day for Period 2 and 3 will be 4-6 days after discharge from the previous Period. 
2 
A complete physical examination will be performed at screening and day 17 prior to discharge. A partial physical exam will be performed on admission day of Period 1. 
3 
On days 1, 8 and 15, vital signs will be determined at pre-dose and at 4 h and 48 h (day 3, 10 and 17) post-dose. 
4 
ECG data will be recorded at screening, on days 1, 8 and 15 at pre-dose and at 4 h post-dose, at the study termination visit and when clinically indicated. 
5 
Urine samples will be collected for urinalysis at screening, pre-dose and prior to discharge. If urine is dipstick positive for leukocyte esterase or nitrites, sample will be sent for microscopic 
evaluation and culture. Urine drug screen will only be performed at screening, and if it is conducted more than 5 days prior to dosing, screening shall be repeated.  
6 
Blood samples will be drawn for clinical laboratory tests at screening, pre-dose and prior to discharge. Clinical laboratory tests are listed in Table 2. 
7 
Plasma samples for PK analysis will be collected as described in Section 6.6.2.4. 
8 
Urine collection for the evaluation of urinary glucose and creatinine are described in Section 6.6.2.3. 
 
 


Bexagliflozin tablets 
 
Theracos Sub, LLC 
Clinical Trial Protocol: THR-1442-C-453 
 
01 September 2016  
 
 
 
 
Confidential 
Page 56 of 58 
C. SCHEDULE OF EVENTS FOR STUDY 3: BEXAGLIFLOZIN AND SITAGLIPTIN DRUG-DRUG INTERACTION 
 
Screening 
Period 1 
Period 2 
Period 3 
Study activity 
D -28 
to -1 
D0 
D1 
pre-
dose 
D1 
post-
dose 
D2 
D3 
D4 
D71 
D8 
pre-
dose 
D8 
post-
dose 
D9 
D10 
D11 
D141 
D15 
pre-
dose 
D15 
post-
dose 
D16 
D17 
D18 
Informed consent form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening for I/E 
criteria 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Physical examination2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission/discharge 
 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
Vital signs3 
X 
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
ECG4 
X 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
X 
Urinalysis5 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
Blood draw for clinical 
lab tests6 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
Blood sample for PK7 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Urine collection for PD8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Adverse event and 
concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study completion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 
The admission day for Period 2 and 3 will be 4-6 days after discharge from the previous Period. 
2 
A complete physical examination will be performed at screening and day 17 prior to discharge. A partial physical exam will be performed on admission day of Period 1. 
3 
On days 1, 8 and 15, vital signs will be determined at pre-dose and at 4 h and 72 h (day 4, 11 and 18) post-dose. 
4 
ECG data will be recorded at screening, on days 1, 8 and 15 at pre-dose and at 4 h post-dose, at the study termination visit and when clinically indicated. 
5 
Urine samples will be collected for urinalysis at screening, pre-dose and prior to discharge. If urine is dipstick positive for leukocyte esterase or nitrites, sample will be sent 
for microscopic evaluation and culture. Urine drug screen will only be performed at screening, and if it is conducted more than 5 days prior to dosing, screening shall be 
repeated.  
6 
Blood samples will be drawn for clinical laboratory tests at screening, pre-dose and prior to discharge. Clinical laboratory tests are listed in Table 2. 
7 
Plasma samples for PK analysis will be collected as described in Section 6.6.2.4. 
8 
Urine collection for the evaluation of urinary glucose and creatinine are described in Section 6.6.2.3. 





SAP_001.pdf: 
 
Statistical Analysis Plan 
Protocol Number: THR-1442-C-453 
Last Revision Date: 07-Apr-2017 
 
Final 
Page 1 of 34 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Trial Sponsor: 
Protocol Number: 
Theracos Sub, LLC. 
THR-1442-C-453 
IND Number: 
103822 
Investigational Drug: 
Indication: 
Bexagliflozin Tablets 
Type 2 Diabetes Mellitus 
Dosage Form/Strength: 
Tablets/20 mg - Bexagliflozin 
 
 
Protocol Title:  A Phase 1, Open-label, Randomized, Three-Period, Crossover Study to Evaluate 
Pharmacokinetic Interaction Between Bexagliflozin Tablets and Metformin, Glimepiride, or Sitagliptin 
in Healthy Subjects 
 
 
 
 
Last Revision Date: 
07-Apr-2017 
 
 
The information contained in this statistical analysis plan is confidential and provided only to 
Theracos Sub, LLC. Therefore, the information may not be disclosed to, used, or copied by any 
third party without the written consent of Theracos Sub, LLC or to the extent required by 
applicable laws, rules and regulations. 
 




 
Statistical Analysis Plan 
Protocol No: THR-1442-C-453 
Last Revision Date: 07-Apr-2017 
 
Final 
Page 3 of 34 
CONFIDENTIAL 
 
CHANGE LOG FOR CHANGES MADE AFTER THE INITIAL APPROVAL 
 
 
Revision 
Date** 
 
Section(s) 
Modified 
 
Brief Description of Revision(s) or 
Reason(s) for Revision 
Modifications Reviewed and 
Approved by* 
Sponsor, Everest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*   Provide person’s initial and last name. 
** Update the Last Revision Dates on the cover page and the document header. 
 
 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-453 
Last Revision Date: 07-Apr-2017 
 
Final 
Page 4 of 34 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION .......................................................................................................................................... 10 
2. 
STUDY OBJECTIVES................................................................................................................................... 10 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................. 10 
2.2 
SECONDARY OBJECTIVES .......................................................................................................................... 11 
3. 
STUDY DESIGN ............................................................................................................................................ 11 
3.1 
STUDY DESIGN .......................................................................................................................................... 11 
3.2 
RANDOMIZATION ...................................................................................................................................... 12 
3.3 
HYPOTHESIS TESTING ............................................................................................................................... 12 
3.4 
INTERIM ANALYSIS ................................................................................................................................... 12 
3.5 
SAMPLE SIZE ............................................................................................................................................. 12 
3.6 
SCHEDULE OF ASSESSMENTS AND STUDY PROCEDURES ........................................................................... 12 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE ............................................................................. 17 
5. 
ANALYSIS POPULATIONS ........................................................................................................................ 17 
5.1 
SAFETY POPULATION ................................................................................................................................ 17 
5.2 
PHARMACOKINETIC POPULATION.............................................................................................................. 17 
5.3 
PHARMACODYNAMIC POPULATION ........................................................................................................... 17 
6. 
SPECIFICATION OF ENDPOINTS AND VARIABLES .......................................................................... 17 
6.1 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 17 
6.1.1 
Study Day and Visit Window Definitions ................................................................................ 18 
6.2 
PHARMACOKINETICS/PHARMACODYNAMICS ............................................................................................ 19 
6.3 
SAFETY ..................................................................................................................................................... 20 
6.3.1 
Study Day and Visit Window Definitions ................................................................................ 20 
6.3.2 
Extent of Exposure to Study Medication .................................................................................. 20 
6.3.3 
Adverse Events (AEs) ............................................................................................................... 20 
6.3.4 
Laboratory Data ........................................................................................................................ 22 
6.3.5 
Vital Signs ................................................................................................................................ 24 
6.3.6 
Electrocardiogram..................................................................................................................... 24 
6.3.7 
Physical Examination ............................................................................................................... 24 
6.3.8 
Pregnancy Test ......................................................................................................................... 24 
6.3.9 
Concomitant Medications/Treatments ...................................................................................... 24 
7. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES .............................................................. 25 
7.1 
GENERAL CONSIDERATIONS ...................................................................................................................... 25 
7.2 
PHARMACOKINETIC ANALYSES ................................................................................................................. 26 
7.3 
PHARMACODYNAMIC ANALYSES .............................................................................................................. 27 
8. 
STATISTICAL ANALYSIS .......................................................................................................................... 28 
8.1 
GENERAL DATA HANDLING RULES AND DEFINITIONS .............................................................................. 28 
8.2 
SUBJECT DISPOSITION ............................................................................................................................... 28 
8.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 28 
8.4 
SAFETY ANALYSES ................................................................................................................................... 29 
8.4.1 
Adverse Events ......................................................................................................................... 29 
8.4.2 
Laboratory Data ........................................................................................................................ 29 
8.4.3 
Vital Signs ................................................................................................................................ 29 
8.4.4 
Electrocardiogram (ECG) ......................................................................................................... 30 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-453 
Last Revision Date: 07-Apr-2017 
 
Final 
Page 5 of 34 
CONFIDENTIAL 
 
8.4.5 
Physical examinations .............................................................................................................. 30 
8.4.6 
Pregnancy Test ......................................................................................................................... 30 
9. 
ANALYSES PERFORMED BEFORE DATABASE CLOSURE .............................................................. 30 
10. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL ......................................................... 30 
11. 
STATISTICAL SOFTWARE ........................................................................................................................ 30 
12. 
REFERENCES ............................................................................................................................................... 30 
13. 
APPENDIX 1   DATA HANDLING RULES ............................................................................................... 31 
14. 
APPENDIX 2   SAS CODE FOR STATISTICAL ANALYSES ................................................................. 32 
15. 
APPENDIX 3   REFERENCE RANGES AND CLINICALLY RELEVANT CHANGES FROM 
BASELINE FOR MARKED LABORATORY ABNORMALITIES ......................................................... 33 
16. 
APPENDIX 4   MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS) .............................................. 34 
 
 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-453 
Last Revision Date: 07-Apr-2017 
 
Final 
Page 6 of 34 
CONFIDENTIAL 
 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
ALB 
albumin 
ALT 
alanine aminotransferase 
ANOVA 
analyses of variance 
AST 
aspartate aminotransferase 
ATC 
anatomic therapeutic class 
AUC 
area under the plasma concentration-time curve 
AUCextr 
extrapolated area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve from Time 0 to infinity 
AUC0-t 
area under the plasma concentration-time curve from Time 0 to Time t 
BLOQ 
below the limit of quantitation 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Ca 
calcium 
Cl 
chloride 
Clast 
concentration corresponding to Tlast 
CL/F 
apparent oral clearance 
cm 
centimeter 
Cmax 
maximum observed plasma concentration 
CRF 
case report form 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
dL 
deciliter 
DM 
data management 
 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-453 
Last Revision Date: 07-Apr-2017 
 
Final 
Page 7 of 34 
CONFIDENTIAL 
 
Abbreviation 
Term 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
FPG 
fasting plasma glucose 
h 
hour(s) 
HBsAg 
hepatitis B surface antigen 
HCO3 
Bicarbonate 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein cholesterol 
Hgb 
hemoglobin 
ICF 
informed consent form 
IRAE 
immediately reportable adverse event 
K 
potassium 
kg 
kilogram 
KR 
Kenward-Roger 
L 
liter 
λz 
terminal elimination phase rate constant 
LDL-C 
low density lipoprotein cholesterol 
LLN 
lower limit of normal 
LS 
least square 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minute 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-453 
Last Revision Date: 07-Apr-2017 
 
Final 
Page 8 of 34 
CONFIDENTIAL 
 
 
Abbreviation 
Term 
mL 
milliliter 
msec 
millisecond 
Na 
sodium 
NCA 
non compartmental analysis 
NTR 
not treatment related, includes unrelated 
OHA 
oral hypoglycemic agent 
OTC 
over the counter 
PCS 
potentially clinically significant 
PD 
pharmacodynamic 
PE 
physical examination 
PK 
pharmacokinetic 
PR 
The period that extends from the beginning of the P wave (the onset of atrial 
depolarization) until the beginning of the QRS complex (the onset of ventricular 
depolarization). 
PT 
preferred term 
QA 
quality assurance 
QC 
quality control 
QRS 
The combination of three of the graphical deflections seen on a typical 
electrocardiogram. 
QT 
Time from electrocardiogram Q wave to the end of the T wave corresponding to 
the electrical system 
QTcB 
QT corrected using Bazetts formula [QT/(RR1/2)] 
RBC 
red blood cell (count) 
REML 
restricted maximum likelihood 
RR interval 
intra-beat interval  
SAE 
serious adverse event 
SAP 
statistical analysis plan 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-453 
Last Revision Date: 07-Apr-2017 
 
Final 
Page 9 of 34 
CONFIDENTIAL 
 
Abbreviation 
Term 
SAS 
statistical analysis software 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
T½ 
apparent terminal elimination half-life 
TC 
total cholesterol 
TEAE 
treatment emergent adverse event 
TG 
triglycerides 
Tlast 
time of last measurable (positive) concentration 
TLF 
table, listing, figure 
Tmax 
time of maximum observed plasma concentration 
TR 
Treatment related - includes definitely, probably, possibly, and not likely related 
T-wave 
repolarization of the ventricles 
UGE 
urine glucose excretion 
ULN 
upper limit of normal (value) 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell (count) 
WHO-DD 
World Health Organization Drug Dictionary 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-453 
Last Revision Date: 07-Apr-2017 
 
Final 
Page 10 of 34 
CONFIDENTIAL 
 
1. INTRODUCTION 
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary and analysis 
of data collected within the scope of Theracos Sub LLC protocol Ammendment #1 THR-1442-C-453 
dated 29-Oct 2016. As with any SAP, the proposed methods and approaches to the data analysis should 
be deemed as flexible. The analysis of the data should allow changes in the plan to the extent that 
deviations from the original plan would provide a more reliable and valid analysis of the data. As such, 
the statistical analysis to a certain degree is iterative since much of the planning is based on assumptions 
that require verification. The purpose of this plan is to provide general guidelines from which the analysis 
will proceed. Nevertheless, deviations from these guidelines must be substantiated by a sound statistical 
rationale. 
This SAP should be read in conjunction with the study protocol and the Case Report Forms (CRFs). This 
version of the SAP has been developed using the final version of the protocol mentioned above and the 
final version of the annotated CRFs dated 21-NOV-2016. 
The SAP details the analysis of the data collected in the study and the presentation of the results of the 
analyses. The table, listing, and figure (TLF) shells are displayed in a companion document which 
provides information on the layout of the data displays. 
All statistical analyses will be performed using SAS® version 9.4. Adverse events will be coded using the 
latest version of the Medical Dictionary for Regulatory Activities (MedDRA version 19.1 or newer). 
This is a phase 1, open-label, randomized, three-period, crossover study to evaluate pharmacokinetic (PK) 
interaction between bexagliflozin tablets and metformin, glimepiride, or sitagliptin in healthy subjects. A 
total of 54 healthy subjects will be enrolled and assigned to three groups of eighteen. Each group will 
participate in one of three open-label, three treatment period, crossover studies: 
Group 1: Bexagliflozin/metformin drug-drug interaction (DDI) 
Group 2: Bexagliflozin/glimepiride DDI 
Group 3 Bexagliflozin/sitagliptin DDI 
For each group, every subject will receive a single dose of bexagliflozin, 20 mg, alone, a single dose of an 
oral hypoglycemic agent (OHA) (1000 mg metformin, 2 mg glimepiride or 100 mg sitagliptin) alone, and 
the combination of both (bexagliflozin along with OHA) alternatively in a crossover fashion, in three 
treatment periods separated by a washout period of at least 7 days. Within each group, subjects will be 
randomized to one of six treatment sequences in an equal ratio. 
(See Protocol Sections 3.1 to 3.3 for details). 
2. STUDY OBJECTIVES 
2.1 Primary Objective 
To evaluate whether drug-drug interactions following co-administration of bexagliflozin with commonly 
prescribed OHAs metformin, glimepiride, or sitagliptin result in any change in the PK of bexagliflozin or 
each of the OHAs. 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-453 
Last Revision Date: 07-Apr-2017 
 
Final 
Page 11 of 34 
CONFIDENTIAL 
 
2.2 Secondary Objectives 
To evaluate the safety, tolerability, and pharmacodynamics (PD) of bexagliflozin following single dose 
administration of the drug in combination with commonly prescribed OHAs. 
3. STUDY DESIGN 
3.1 Study Design 
This is a phase 1, open-label, randomized, three-period, crossover study to evaluate PK interaction 
between bexagliflozin tablets and metformin, glimepiride, or sitagliptin in healthy subjects. Fifty-four 
(54) eligible healthy subjects will be enrolled and assigned to three groups of eighteen. Each group will 
participate in one of three open-label, three treatment period, crossover studies: 
Group 1: Bexagliflozin/metformin DDI 
Group 2: Bexagliflozin/glimepiride DDI 
Group 3 Bexagliflozin/sitagliptin DDI 
For each group, every subject will receive a single dose of bexagliflozin tablet, 20 mg, alone, a single 
dose of an OHA (1000 mg metformin, 2 mg glimepiride, or 100 mg sitagliptin) alone, and the 
combination of both (bexagliflozin tablet and OHA) alternatively in a crossover fashion, in three 
treatment periods separated by a washout period of at least 7 days. Within each group, subjects will be 
randomized to one of six treatment sequences in an equal ratio as shown in Table 1 below. 
Table 1 
Treatment Sequence 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
1 
Bexa alone1 
OHA alone2 
Bexa + OHA 
2 
Bexa alone 
Bexa + OHA 
OHA alone 
3 
OHA alone 
Bexa alone 
Bexa + OHA 
4 
OHA alone 
Bexa + OHA 
Bexa alone 
5 
Bexa + OHA 
OHA alone 
Bexa alone 
6 
Bexa + OHA 
Bexa alone 
OHA alone 
1. 
Bexa: bexagliflozin; OHA = oral hypoglycemic agent. 
To prevent hypoglycemia, subjects assigned to Group 2 will receive approximately 300 mL of a solution 
containing 50 g of glucose with study medication at the time of dosing, as well as approximately 75 mL 
of a solution containing 12.5 g of glucose every 15 minutes for 4 hours post-dose. 
During each treatment period for Group 1 (bexagliflozin/metformin DDI) and Group 2 
(bexagliflozin/glimepiride DDI), subjects will be admitted to the clinic on the day before dosing and will 
stay in the clinic until 48 h post-dose. For Group 3 (bexagliflozin/sitagliptin DDI), subjects will stay in 
the clinic until 72 h post-dose. 
For Group 1 and 2, blood samples for PK analysis will be collected in each period prior to dosing (pre-
dose) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose. For Group 3, additional PK 
blood samples will also be collected at 60 and 72 h post-dose. 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-453 
Last Revision Date: 07-Apr-2017 
 
Final 
Page 12 of 34 
CONFIDENTIAL 
 
Urine samples for PD analysis will be collected in 12 h intervals. For Group 1 and 2, urine samples will 
be collected pre-dose (-12 to 0 h) and post-dose at 0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h. For 
Group 3, additional samples at 48 to 60 h and 60 to 72 h post-dose will be collected. 
Clinical laboratory tests and safety monitoring will be conducted during all treatment periods. 
3.2 Randomization 
A total of 54 healthy subjects will be enrolled and assigned to one of three groups of eighteen. Each group 
of eighteen will be randomized to 1 of 6 possible treatment sequences. Subjects who discontinue the study 
early will not be replaced. 
3.3 Hypothesis Testing 
No formal statistical hypothesis testing will be conducted for this study. 
3.4 Interim Analysis 
There will be no interim analysis conducted. 
3.5 Sample Size 
The sample size for this study is not based upon formal statistical consideration. The sample size is 
considered adequate to characterize the PK of bexagliflozin and OHAs, to assess potential drug-drug 
interactions, and to provide safety and tolerability data on bexagliflozin when administered alone and in 
combination with OHAs. 
3.6 Schedule of Assessments and Study Procedures 
 


 
Statistical Analysis Plan 
Protocol No. THR-1442-C-453 
Last Revision Date: 07-Apr-2017 
 
Final 
Page 13 of 34 
CONFIDENTIAL 
 
Table 2. Schedule of Events for Study 1: Bexagliflozin and Metformin Drug-Drug Interaction 
 
Screening 
 
Period 1 
Period 2 
Period 3 
Study activity 
D -28 to -1 
D0 
D1  
pre-
dose 
D1  
post-
dose 
D2 
D3 
D71 
D8  
pre-
dose 
D8  
post-
dose 
D9 
D10 
D141 
D15  
pre-
dose 
D15 
post-
dose 
D16 
D17 
Informed consent form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening for I/E criteria 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Physical examination2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission and discharge 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
Vital signs3 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
ECG4 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
X 
Urinalysis5 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Blood draw for clinical 
lab tests6 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Blood sample for PK7 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urine Collection for PD8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Adverse event and 
concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study completion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: D = day; ECG = electrocardiogram; I/E = inclusion/exclusion; PD = pharmacodynamic; PK = pharmacokinetic. 
1. 
The admission day for Period 2 and 3 will be 4-6 days after discharge from the previous period. 
2. 
A complete physical examination will be performed at screening and day 17 prior to discharge. A partial physical exam will be performed on admission day of Period 1. 
3. 
On days 1, 8 and 15, vital signs will be determined at pre-dose and at 4 h and 48 h (day 3, 10 and 17) post-dose. 
4. 
ECG data will be recorded at screening, on days 1, 8 and 15 at pre-dose and at 4 h post-dose, at the study termination visit and when clinically indicated. 
5. 
Urine samples will be collected for urinalysis at screening, pre-dose and prior to discharge. If urine is dipstick positive for leukocyte esterase or nitrites, sample will be 
sent for microscopic evaluation and culture. Urine drug screen will only be performed at screening, and if it is conducted more than 5 days prior to dosing, screening 
shall be repeated. 
6. 
Blood samples will be drawn for clinical laboratory tests at screening, pre-dose and prior to discharge. Clinical laboratory tests are listed in Table 2 of the protocol. 
7. 
Plasma samples for PK analysis will be collected as described in Section 6.6.2.4 of the protocol. 
8. 
Urine collection for the evaluation of urinary glucose and creatinine are described in Section 6.6.2.3 of the protocol. 
 
 


 
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Table 3. Schedule of Events for Study 2: Bexagliflozin and Glimepiride Drug-Drug Interaction 
 
Screening 
Period 1 
Period 2 
Period 3 
Study activity 
D -28 to -1 
D0 
D1  
pre-
dose 
D1  
post-
dose 
D2 
D3 
D71 
D8  
pre-
dose 
D8  
post-
dose 
D9 
D10 
D141 
D15  
pre-
dose 
D15 
post-
dose 
D16 
D17 
Informed consent form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening for I/E criteria 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Physical examination2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission and discharge 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
Vital signs3 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
ECG4 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
X 
Urinalysis5 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Blood draw for clinical 
lab tests6 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Blood sample for PK7 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urine Collection for PD8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Adverse event and 
concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study completion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: D = day; ECG = electrocardiogram; I/E = inclusion/exclusion; PD = pharmacodynamic; PK = pharmacokinetic. 
1. 
The admission day for Period 2 and 3 will be 4-6 days after discharge from the previous period. 
2. 
A complete physical examination will be performed at screening and day 17 prior to discharge. A partial physical exam will be performed on admission day of Period 1. 
3. 
On days 1, 8 and 15, vital signs will be determined at pre-dose and at 4 h and 48 h (day 3, 10 and 17) post-dose. 
4. 
ECG data will be recorded at screening, on days 1, 8 and 15 at pre-dose and at 4 h post-dose, at the study termination visit and when clinically indicated. 
5. 
Urine samples will be collected for urinalysis at screening, pre-dose and prior to discharge. If urine is dipstick positive for leukocyte esterase or nitrites, sample will be 
sent for microscopic evaluation and culture. Urine drug screen will only be performed at screening, and if it is conducted more than 5 days prior to dosing, screening shall 
be repeated. 
6. 
Blood samples will be drawn for clinical laboratory tests at screening, pre-dose and prior to discharge. Clinical laboratory tests are listed in Table 2 of the protocol. 
7. 
Plasma samples for PK analysis will be collected as described in Section 6.6.2.4 of the protocol. 
8. 
Urine collection for the evaluation of urinary glucose and creatinine are described in Section 6.6.2.3 of the protocol. 


 
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Table 4. Schedule of Events for Study 3: Bexagliflozin and Sitagliptin Drug-Drug Interaction 
 
Screening 
Period 1 
Period 2 
Period 3 
Study activity 
D -28 to 
-1 
D0 
D1 
pre-
dose 
D1 
post-
dose 
D2 
D3 
D4 
D71 
D8 
pre-
dose 
D8 
post-
dose 
D9 
D10 
D11 
D14
1 
D15 
pre-
dose 
D15 
post-
dose 
D16 
D
17 
D
18 
Informed consent form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening for I/E 
criteria 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Physical examination2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission and 
discharge 
 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
Vital signs3 
X 
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
ECG4 
X 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
X 
Urinalysis5 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
Blood draw for clinical 
lab tests6 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
Blood sample for PK7 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Urine Collection for 
PD8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Adverse event and 
concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study completion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: D = day; ECG = electrocardiogram; I/E = inclusion/exclusion; PD = pharmacodynamic; PK = pharmacokinetic. 


 
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1. 
The admission day for Period 2 and 3 will be 3-5 days after discharge from the previous period. 
2. 
A complete physical examination will be performed at screening and day 18 prior to discharge. A partial physical exam will be performed on admission day of Period 1. 
3. 
On days 1, 8 and 15, vital signs will be determined at pre-dose and at 4 h and 72 h (day 4, 11 and 18) post-dose. 
4. 
ECG data will be recorded at screening, on days 1, 8 and 15 at pre-dose and at 4 h post-dose, at the study termination visit and when clinically indicated. 
5. 
Urine samples will be collected for urinalysis at screening, pre-dose and prior to discharge. If urine is dipstick positive for leukocyte esterase or nitrites, sample will be sent 
for microscopic evaluation and culture. Urine drug screen will only be performed at screening, and if it is conducted more than 5 days prior to dosing, screening shall be 
repeated. 
6. 
Blood samples will be drawn for clinical laboratory tests at screening, pre-dose and prior to discharge. Clinical laboratory tests are listed in Table 2 of the protocol. 
7. 
Plasma samples for PK analysis will be collected as described in Section 6.6.2.4 of the protocol. 
8. 
Urine collection for the evaluation of urinary glucose and creatinine are described in Section 6.6.2.3 of the protocol. 


 
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4. DATA AND ANALYTICAL QUALITY ASSURANCE 
The overall quality assurance (QA) procedures for the study data, statistical programming and analyses are 
described in Everest’s Standard Operating Procedures (SOPs). Detailed data management (DM) procedures 
are documented in the Data Management Plan, Data Validation Check Specifications, and Data Review 
Plan. Detailed statistical and programming quality control (QC) and QA procedures are documented in the 
Statistical Analysis and Programming QC/QA Plan. 
The study endpoints and analytic approaches are both prospectively defined and documented in the protocol 
and in this SAP. The SAP will be finalized, and protocol violations will be identified and decisions for 
inclusion and exclusion of subjects from the PK Population will be made prior to the database lock and data 
analysis. 
5. ANALYSIS POPULATIONS 
Three subject populations will be evaluated during this study and are defined as follows: 
5.1 Safety Population 
The Safety Population will include all randomized subjects who receive at least one dose of the 
investigational product. Subjects will be analyzed according to the treatment received. 
5.2 Pharmacokinetic Population 
The PK Population will include all randomized subjects who receive at least one dose of the investigational 
product and who have sufficient plasma bexagliflozin and OHA measurements to derive PK parameters 
following dosing. The PK Population will be used to summarize the PK parameters. 
5.3 Pharmacodynamic Population 
The PD Population will include all randomized subjects who receive at least one dose of investigational 
product and will have had at least 2 batches of 12 h urine collection from which to calculate urine glucose 
excretion (UGE) measurement following dosing. The PD Population will be used to summarize the PD 
parameters. 
6. SPECIFICATION OF ENDPOINTS AND VARIABLES 
6.1 Demographic and Baseline Characteristics 
Demographic variables consist of the following: 
• 
Age in years (continuous) derived as the integer value of  
(informed consent date – date of birth + 1)/365.25 
• 
Sex 
• 
Race 
• 
Ethnicity 
Baseline characteristics consist of the following: 
• 
Body mass index (BMI) 
• 
Weight (kg) 


 
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• 
Height (cm) 
• 
Vital signs 
o systolic blood pressure (SBP, mmHg) 
o diastolic blood pressure (DBP, mmHg) 
o oral temperature (oC) 
o pulse (beats per minute) 
o respiration rate  
 
• 
Electrocardiogram (ECG) parameters 
o RR interval (msec) 
o PR interval (msec) 
o QRS duration (msec) 
o QT interval (msec) 
o QTcB interval (msec) 
• 
Medical and surgical history 
• 
Clinical laboratory tests 
• 
Prior and concomitant medication  
• 
Physical examination 
6.1.1 Study Day and Visit Window Definitions 
Table 5.  Time Windows for Safety Assessments for Group 1 and Group 2 
 
 
Time Windows for Safety Assessments 
Scheduled Visit Number 
Visit (label) 
Time Interval (day) 
Target Time Point (day) 
1 
Screening 
-28 to -1 
-28 to -1 
2 
Day 0 
0 
0 
3 
Day 1 
1 
1 
4 
Day 2 
2 
2 
5 
Day 3 
3-6 
3 
6 
Day 7 
7 
7 
7 
Day 8 
8 
8 
8 
Day 9 
9 
9 
9 
Day 10 
10-13 
10 
10 
Day 14 
14 
14 
11 
Day 15 
15 
15 
12 
Day 16 
16 
16 
13 
Day 17 
17 
17 


 
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Table 6.  Time Windows for Safety Assessments for Group 3 
 
Data obtained during unscheduled visits will be allocated to the scheduled visit corresponding to the visit 
window they fall in as specified in Section 6.1.1. Safety data obtained during unscheduled time points will 
be allocated to the scheduled time point corresponding to the time window in which they fall. Data will be 
analyzed based on the nominal visits and nominal time points. If the data from the nominal visit or time 
point is missing, data from unscheduled visits for the same nominal visit or time point will be used. If 
multiple unscheduled assessments fall in the same visit window or time point, the non-missing assessment 
closest to target time point will be selected for analysis. 
6.2 Pharmacokinetics/Pharmacodynamics 
Pharmacokinetic/pharmacodynamic analysis will be performed on the PK and PD Populations respectively 
Plasma samples will be analyzed for bexagliflozin, metformin, glimepiride, and sitagliptin concentrations 
using a validated method. 
For all groups, blood samples for PK analysis will be collected in each period at pre-dose and at 0.5, 1, 2, 3, 
4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post dose. For group 3, additional PK blood samples will also be 
collected at 60 and 72 h post-dose. 
Urine samples for PD analysis will be collected in 12 hr intervals. 
For all groups, urine collection in 12 h batches will be performed at pre-dose (-12 to 0 h), and post-dose at  
0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h. For group 3, additional samples at 48 to 60 h and 60 to 72 h 
post-dose will be collected. 
Time Windows for Safety Assessments 
Scheduled Visit Number 
Visit (label) 
Time Interval (day) 
Target Time Point (day) 
1 
Screening 
-28 to -1 
-28 to -1 
2 
Day 0 
0 
0 
3 
Day 1 
1 
1 
4 
Day 2 
2 
2 
5 
Day 3 
3 
3 
6 
Day 4 
4-6 
4 
7 
Day 7 
7 
7 
8 
Day 8 
8 
8 
9 
Day 9 
9 
9 
10 
Day 10 
10- 
10 
11 
Day 11 
11-13 
11 
12 
Day 14 
14 
14 
13 
Day 15 
15 
15 
14 
Day 16 
16 
16 
15 
Day 17 
17 
17 
16 
Day 18 
18 
18 


 
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6.3 Safety 
Safety analysis will be performed on the Safety Population. 
The safety profile of bexagliflozin and OHAs under investigation will be assessed through the recording, 
reporting, and analyzing of adverse events, clinical evaluations, and laboratory tests. 
Safety variables include the following: 
1. Adverse events 
2. Clinical laboratory measurements – serum chemistry, hematology, and urinalysis 
3. Urine drug screen 
4. Vital signs 
5. ECG 
6. Physical examination 
7. Pregnancy test 
8. Concomitant medications/treatments 
6.3.1 Study Day and Visit Window Definitions 
Refer to section 6.1.1 for details. 
6.3.2 Extent of Exposure to Study Medication 
Subjects who gave consent to participate in the study will be randomly assigned to 1 of 3 groups. Subjects 
in each group will be randomly assigned to receive 1 of 6 treatment regimens in a crossover fashion with 3 
treatment periods separated by a washout period of at least 7 days. Refer to Table 1 under Section 3.1. Up to 
2 additional washout days will be allowed. 
The dosage of bexagliflozin will be 20 mg. 
The dosages for the OHAs are equivalent to the highest single tablet dose available for each OHA (1000 mg 
metformin, 2 mg glimepiride, or 100 mg sitagliptin), and are within recommended daily dose ranges. 
6.3.3 Adverse Events (AEs) 
Adverse events will be collected and coded using version 19.1 (or newer) of MedDRA. Analysis of adverse 
events will be carried out on the Safety Population. All adverse events will be included in the individual 
subject data listings. Only treatment emergent adverse events (TEAEs) will be tabulated in summary tables. 
The incidence of TEAEs will be presented by treatment. If the AE(s) onset date-time or date occurs after 
the first dose up until right before the second dose, the AE(s) will be assigned to the first treatment. If the 
AE(s) onset date-time or date occurs after the second dose up until right before the third dose, the AE(s) 
will be assigned to the second treatment. Any AE(s) that occur after the third dose up until study 
termination will be assigned to the third treatment. 
All adverse events will be assessed by the investigator(s) with respect to severity, relationship to study drug 
and seriousness. 
If an AE becomes serious during the course of the study, the initial AE will be reported with an end date 
equal to the start date of the serious adverse event (SAE) and outcome ‘did not resolve’. The SAE start date 
will be the date the AE became serious. 


 
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6.3.3.1 Treatment-Emergent AE (TEAE) 
An adverse event is considered treatment-emergent if the date of onset is on or after the date of first dose of 
study medication, or worsens during the treatment period (intensity/severity grades worsen). 
6.3.3.2 Serious Adverse Events (SAE) 
AEs will be categorized as serious or non-serious using the definition specified in Section 6.7 of the study 
protocol. 
6.3.3.3 Immediately Reportable AE (IRAE) 
An IRAE is any serious adverse event or any adverse event that necessitates discontinuation of the study 
drug. 
6.3.3.4 Adverse Events Counting Rules 
1. A subject with more than one different AE in a particular system organ class (SOC) will be counted 
only once in the total of subjects experiencing adverse events in that particular SOC. 
2. A subject having experienced the same event (AE preferred term) more than once during the study 
will be counted only once in the number of subjects with that event. 
3. A subject having experienced the same event (AE preferred term) more than once during the study 
with a different severity or seriousness, it will be counted only once with the worst grade and 
seriousness respectively. 
4. A subject having experienced the same event (AE preferred term) more than once during the study 
with a different causal relationship to the study drug, it will be counted only once by considering 
the most-related documented degree of relationship. 
6.3.3.5 AE Severity 
Adverse events will be graded on a 3-point scale and reported as indicated on the case report form (CRF). 
The intensity of an adverse experience will be graded as “Mild”, “Moderate”, and “Severe” using the 
criteria specified in Section 6.7 of the study protocol. 
6.3.3.6 Relationship to the Investigational Medicinal Product 
The relationship of an AE to dosing will be assessed as “Definite”, “Probable”, “Possible”, “Not Likely”, or 
Unrelated using the criteria specified in Section 6.7 of the study protocol. 
6.3.3.7 AE with Irregular Start/End Dates 
Partial dates may be imputed when appropriate. Imputed dates will be used to determine Study Day. 
If a partial date is reported for the start of an AE, a complete date will be imputed by the following 
algorithm: 
1. Only the year is reported: If the subject started receiving study medication in the previous year, then 
January 1 will be used as the starting date of the event. If the subject started receiving study 
medication in the year reported, then the date of the first dose of study medication will be used as 
the start of the event. 


 
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2. The month and year is reported: If the subject started receiving study medication prior to the month 
and year reported, then the first day of the month will be used as the starting date of the event. If the 
subject started receiving study medication during the month and year reported, then the date of the 
first dose of study medication will be used as the start of the event. 
If a partial date is reported for the end of an adverse event and the adverse event is not continuing, a 
complete date will be imputed by the following algorithm: 
1. Only the year is reported: If the subject started receiving study drug in the previous year, then the 
date of final study contact with the subject will be used as the end of the adverse event. If the 
subject started receiving study medication in the year reported, then the earlier of December 31 or 
the date of final study contact with the subject will be used as the end of the adverse event. 
2. The month and year reported: The earlier of the last date of the month or the date of final contact 
with the subject will be used as the end of the AE. 
The above rules are subject to logical sense, for example, imputed start date should be on or prior to 
imputed end date. 
All AEs will be included in the tabulations regardless the completeness of the onset dates. 
6.3.4 Laboratory Data 
Clinical laboratory tests on hematology, serum chemistry, electrolytes, and lipids and urinalysis will be 
performed according to the schedule in Section 3.6. Investigators will assess whether there are any 
clinically significant abnormalities and record the abnormality on medical history or AE forms. 
Conversion to the International System of Units 
All laboratory data will be stored in the database with the units in which they are originally reported.  
Laboratory data in summary tables and subject data listings will be presented in the International System of 
Units (SI units; Système International d’Unités).  Laboratory data not reported in SI units will be converted 
to SI units before further processing or data analysis. 
Abnormal Values 
Based upon laboratory normal ranges, laboratory test results will be categorized according to the normal 
range as low, normal and high. Subjects with laboratory data outside the normal range will be listed with 
abnormal values flagged. 


 
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Table 6 Clinical Laboratory Tests 
Hematology 
Hematocrit (Hct) 
Mean corpuscular volume (MCV) 
Hemoglobin (Hgb) 
Platelet count 
Mean corpuscular hemoglobin (MCH) 
Red blood cell (RBC) count 
Mean corpuscular hemoglobin concentration (MCHC) 
White blood cell (WBC) count with differential 
Serum Chemistry, Electrolytes, and Lipids 
Albumin (ALB) 
Calcium (Ca) 
Alanine aminotransferase (ALT) 
Magnesium 
Aspartate aminotransferase (AST) 
Phosphorus 
Blood urea nitrogen (BUN) 
Potassium (K) 
Glucose 
Sodium (Na) 
Total carbon dioxide 
Total bilirubin 
Creatinine  
Direct bilirubin 
Chloride (Cl) 
Uric acid 
Total protein 
Low-density lipoprotein cholesterol (LDL-C), calculated 
Total cholesterol (TC) 
 
High-density lipoprotein cholesterol (HDL-C) 
 
Triglycerides (TG) 
 
Urinalysis 
Appearance 
Nitrite 
Bilirubin 
pH 
Color 
Protein 
Glucose 
Specific gravity 
Ketones 
Urobilinogen 
Microscopic examination of sediment 
Leukocyte esterase 
Urine Collection 
Glucose 
Creatinine 
Urine Drug Screen 
Amphetamines 
Opiates 
Barbiturates 
Benzodiazepines 
Cocaine Metabolites 
Cannabinoids 
Cotinine 
 
Urine Pregnancy Test 


 
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Infectious Disease Testing 
Hepatitis B Surface Antigen (HbsAg) 
Hepatitis C virus (HCV) 
6.3.5 Vital Signs 
Vital signs include pulse (beats/min), SBP and DBP (mmHg), oral temperature (oC) and respiration rate 
(breaths/min). 
Vital sign changes from baseline will be summarized by treatment and treatment group. 
Baseline values are those measured at last evaluation prior to administration of study drug in each treatment 
period. 
Change from baseline to time point t, denoted Changet, will be calculated as: 
Changet = Valuet – ValueBaseline. 
6.3.6 Electrocardiogram 
ECG parameters, including the RR interval (intra-beat interval), PR interval (the period that extends from 
the beginning of the P wave [the onset of atrial depolarization] until the beginning of the QRS complex [the 
onset of ventricular depolarization]), QRS duration, and QT interval (the corrected QT interval is the 
measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical 
cycle), will be measured according to the study assessment schedule as specified in Section 3.6. Each ECG 
will be assessed by the Investigator for signs of ischemia, clinically significant hypertrophy, and clinically 
significant T-wave (repolarization of the ventricles) abnormalities. Baseline ECGs will be defined as the 
last evaluation performed prior to the administration of study drug in each treatment period. 
ECG changes from baseline will be summarized by treatment and treatment group. 
Change from baseline to time point t, denoted Changet, will be calculated as: 
Changet = Valuet – ValueBaseline. 
6.3.7 Physical Examination 
A complete PE will include measurement of body weight and height (height will be measured only at 
screening), general assessment of all body systems including the skin, head, eyes, ears, nose, throat, neck, 
lungs, heart, abdomen, lymph nodes, and extremities. 
Physical examination results will be presented in individual subject data listings. 
6.3.8 Pregnancy Test 
Only pregnancies considered by the investigator as related to study treatment (e.g., resulting from an 
interaction between study drug and a contraceptive medication) are considered AEs unto themselves. 
However, all pregnancies with an estimated conception date during the AE reporting period, must be 
recorded in the AE section of the eCRF. This applies to both pregnancies in female subjects and in female 
partners of male subjects. 
6.3.9 Concomitant Medications/Treatments 
Concomitant medications administered at the time of randomization and during the study will be recorded 
on the CRF. The medication name, indication, dose, unit, frequency, route of administration, date(s) of 


 
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administration and reason for administration will be recorded. This documentation should continue until 
discharge from the study. 
A concomitant medication is any medication the subject enters the trial taking and is expected to continue 
taking for some portion of the trial, as well as any medication the subject takes during the course of the trial. 
All prescription and over-the-counter (OTC) medications (non-prescription drugs), including vitamins and 
herbal supplements, that subjects receive during the trial must be documented on the CRF. This 
documentation will continue until the subjects are discharged. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary (WHO-DD). 
All prior and concomitant medication will be presented in individual subject data listings. 
For medications with incomplete dates, imputation will be used to convert to a complete date. Imputed 
dates will be used to determine Study Day. 
Partial medication start dates will be imputed as follows:  
1. Only the year is reported: If the subject started to receive study drug in the year reported, then the 
date of the first dose of study drug will be used as the starting date of the medication. Otherwise, 
January 1 will be used as the start of the medication. 
2. The month and year is reported: If the subject started to receive study drug during the month and 
year reported, then the date of first dose of study drug will be used as the starting date of the 
medication. Otherwise, the first day of the month will be used as the start of the medication. 
Partial medication end dates will be imputed for non-ongoing medications as follows: 
1. Only the year is reported: If the subject stopped to receive study drug in the year reported, then the 
date of the last dose of study drug will be used as the end date of the medication. Otherwise, 
December 31 will be used as the end of the medication. 
2. The month and year is reported: If the subject stopped to receive study drug during the month and 
year reported, then the date of last dose of study drug will be used as the end date of the medication. 
Otherwise, the last day of the month will be used as the end of the medication. 
The above rules are subject to logical sense, for example, imputed start date should be on or prior to 
imputed end date. 
Verbatim terms will be coded and assigned a preferred (PT) term and an ATC (anatomic therapeutic class) 
term. 
7. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES 
7.1 General Considerations 
The PK Population will be used for PK analyses. The PD Population will be used for PD analyses. 
Statistical and PK analyses will be performed by Everest Clinical Research. Statistical analysis will be 
performed using Statistical Analysis Software SAS for Windows® (SAS Institute Inc., USA). Non-
compartmental analysis (NCA) will be performed using Phoenix® WinNonlin® 6.4 (Certara, USA). 


 
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7.2 Pharmacokinetic Analyses 
From the plasma concentration-time data, the following PK parameters will be estimated for each subject 
where feasible. 
Table 7.  Pharmacokinetic Parameters 
Pharmacokinetic Parameters 
Cmax 
Maximum observed plasma concentration 
Tmax 
Time of maximum observed plasma concentration 
λz 
Terminal elimination phase rate constant 
T½ 
Apparent terminal elimination half life 
CL/F 
Apparent oral clearance 
Vz/F 
Apparent volume of distribution 
AUC0-t 
Area under the plasma concentration-time curve from time 0 to time t (time of last quantifiable plasma 
concentration) 
AUC0-∞ 
Area under the plasma concentration-time curve from time 0 to infinity 
 
Cmax and Tmax will be obtained directly from experimental observations. If multiple maxima occur at equal 
concentrations, the first temporal value will be taken. 
The apparent terminal elimination half-life, T1/2, where determinable, will be calculated as the natural log 
of 2 divided by the terminal phase rate constant, λz. The number of data points included in the regression 
will be determined by visual inspection, but a minimum of three data points in the terminal phase, excluding 
Cmax, is required to estimate λz. In order for the selection to take place the adjusted r2 value reported in 
Phoenix®WinNonlin® must be ≥ 0.7. 
AUC0-t and AUC0-∞ will be calculated using the linear trapezoidal linear interpolation method, using actual 
elapsed time values. If the actual collection time is unknown the nominal collection time may be used for 
the purposes of PK parameter estimation. For the purpose of calculating AUC, all missing values will be 
treated as missing in the PK analysis and excluded from analysis except when they occur at pre-dose where 
they will be set to zero. All values that were below the limit of quantitation (BLOQ) prior to Tmax will be set 
to zero. BLOQ values that occur after Tmax will be set to missing. When ≥ 2 consecutive plasma 
concentrations below the limit of quantitation (BLOQ) are encountered after Tmax, these and all subsequent 
values will be excluded from the analysis. 
AUC0-∞ will be calculated as outlined below: 
AUC0-∞= AUClast + (Clast / λz), where Clast is the last temporal quantifiable plasma concentration 
corresponding to Tlast. 
The proportion of AUC0-∞ due to extrapolation (AUCextr) will be calculated and expressed as a percentage. 
AUC0-∞ values will be considered unreliable estimates if the AUCextr is greater than 20% and will be 
excluded from summary tables but will be listed. 
CL/F will be calculated as Dose/AUC0-∞. 
Vz/F will be calculated as Dose/(λz × AUC0-∞). 
T½ will be calculated as 0.693/λz. 


 
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Descriptive statistics for the plasma concentrations of measured analytes by Treatment and Timepoint will 
be provided for each group. Listings of plasma concentrations by Subject Number, Treatment Group, 
Treatment, Treatment Period, and Timepoint will also be provided. 
To assess the effect of the OHAs metformin, glimepiride, and sitagliptin on the PK of bexagliflozin and 
vice versa, an analyses of variance (ANOVA) using a linear mixed-effects model will be fitted to the 
natural logarithmic transformation of PK parameters of bexagliflozin (Cmax, AUC0-t and AUC0-∞). The linear 
mixed-effects model will include subject as a random effect, and treatment, period, and sequence as fixed 
effects. The 90% confidence intervals (CIs) will be constructed for the (bexagliflozin and OHA in 
combination) to (bexagliflozin alone) or (OHA alone) ratio of the least squares (LS) geometric means of PK 
parameters (Cmax, AUC0-t and AUC0-∞), with 80-125% defined as the lack of interaction boundaries. 
The ratios of geometric least squares means and corresponding 90% CI for the treatment comparison will be 
determined by exponentiating the mean differences between treatments on the logarithm scale. The intra-
subject geometric CV%, 100%*
1
)
exp(
−
residual
, where residual = the residual variance component and 
where exp is the natural exponential function, will be reported. 
The appropriateness of the mixed model will be assessed through residual analyses. Any modifications 
required due to poor fit will be reported and executed. 
Descriptive statistics for the PK parameters Cmax, Tmax, AUC0-∞ , AUC0-t , CL/F, Vz/F, λz, and T1/2 will be 
tabulated by treatment for each group. Means, standard deviations (SD), medians, ranges (minimum; 
maximum), and geometric means and coefficients of variation (CV) will be presented for all PK parameters 
with the exception of Tmax. Medians and ranges will be presented for Tmax. 
A listing of derived PK parameters by Subject Number, Treatment Group, and Treatment Period will be 
provided. 
Refer to Appendix 2 for the SAS code. 
7.3 Pharmacodynamic Analyses 
Urinary glucose excretion will be determined as a PD parameter at baseline and up to 48 hours (Group 1 
and Group 2) and up to 72 hours (Group 3). The DDI effect between bexagliflozin and OHAs will be 
evaluated by comparing the mean cumulative UGE between subjects taking bexagliflozin or OHA alone 
and bexagliflozin and OHA in combination. 
Descriptive statistics of glucose concentrations and UGE will be summarized by Treatment Group, 
Treatment, and Timepoint. 
The quantity of glucose excreted in urine will be determined by multiplying the urine glucose concentration 
for each time interval by the volume of urine collected for the corresponding collection interval. The total 
24-hour, 48-hour, and 72-hour quantity of glucose excreted in urine will be calculated by adding the 
amounts collected during each interval. 
PD data will also be reported in listings. 
The effect of an OHA on the cumulative UGE between subjects administered bexagliflozin alone or in 
combination with an OHA will be compared. The PD parameters, UGE and UGE normalized by urinary 
creatinine, including UGEt1-t2, in 12 hour and 24 hour increments, and total 24-hour, 48-hour, and 72-hour 
UGE, will be determined. UGEt1-t2 (mg) will be derived from urine volume (Vt1-t2, mL) x glucose 
concentration (mg/dL)/100. 


 
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8. STATISTICAL ANALYSIS 
8.1 General Data Handling Rules and Definitions 
All data collected on CRFs will be provided in listings, except data collected only for confirmation of study 
entry criteria and for study administrative purposes. If any randomized subject is found to be without valid 
documented informed consent, that subject’s data will be excluded from the report, except as necessary to 
document the error. 
All statistical analyses will be conducted using SAS version 9.4 or newer. 
Except where specified, all continuous variables will be summarized with descriptive statistics (the number 
of non-missing values, mean, standard deviation, median, minimum and maximum) and all categorical 
variables will be summarized with frequency counts and percentages, by treatment and treatment group. 
Unless otherwise specified, the mean and median will be displayed to 1 more decimal place than the 
original data, and standard deviation will be displayed to two more decimal places than the original data. 
All frequencies will be rounded to 1 decimal place. 
Missing data will be maintained as missing unless specified otherwise.  For variables where missing data is 
imputed, the analysis dataset will contain one variable with the imputed value and the original variable with 
missing maintained as missing. 
8.2 Subject Disposition 
An overall disposition table for all subjects will be presented. This tabulation will include the number of 
subjects randomized, treated, completed, and those who discontinued early from the study. The number and 
percentage of randomized subjects who are included in the PK, Safety and PD Populations will also be 
tabulated. 
Subject disposition by treatment and treatment group, and treatment sequence and treatment group, will also 
be summarized. These tabulations will include the number of subjects dosed, completed, and those who 
discontinued early from the study along with the corresponding primary reasons for early termination. 
Subjects in the Safety Population who prematurely discontinued from the study will be summarized by 
primary reason for early termination. 
All subjects in the Safety Population will be listed. 
8.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment and treatment group, and by 
treatment sequence and treatment group, for both the Safety and PK Populations and listed. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be presented for 
continuous variables. Frequency distributions (counts and percentages) will be presented for categorical 
variables. 
Medical and surgical history will be summarized and listed. Physical examination, as well as prior and 
concomitant medications, will also be listed. Prior and concomitant medications will be listed with the drug 
names and ATC classification codes based on the data collected in the eCRF. The World Health 
Organization (WHO) Drug Dictionary, version March 2016 or newer, will be used to classify prior and 
concomitant medications by therapeutic class and drug name. 


 
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Abnormalities in the subjects’ medical and surgical histories will be coded using version 19.1  
(or newer) of MedDRA Medical Dictionary for Regulatory Activities, and summarized and listed. 
8.4 Safety Analyses 
Safety analyses will be performed using the Safety Population, unless otherwise specified. 
Safety measurements will include AEs, clinical laboratory tests (i.e. serum chemistry, hematology and 
urinalysis), ECGs, physical exams and vital signs. All safety data will be summarized by treatment group 
and treatment. Baseline values for clinical laboratory tests, vital signs and ECGs will be defined as the last 
evaluation performed prior to administration of study drug. 
8.4.1 Adverse Events 
All AEs will be coded to system organ class (SOC), and preferred term (PT), using the latest Medical 
Dictionary for Regulatory Activities coding dictionary (version to be specified in the clinical study report). 
All reported AEs will be listed, but only TEAEs will be summarized. 
The incidence of all TEAEs will be summarized by treatment group and treatment. In the summary tables, 
subjects may be counted under multiple SOCs and PTs, but for each SOC and PT, subjects are only counted 
once. If a subject has the same AE on multiple occasions, the highest severity (severe > moderate > mild) or 
drug relationship (definite > probable > possible > not likely related > unrelated) recorded for the event will 
be presented. If severity is missing, subjects will be included as missing (for severity). If drug relationship 
is missing, subjects will be included in related tables (e.g., considered related). Summary tables will be 
organized by SOC, then PT. 
The following summaries will be presented for TEAEs: 
• 
Overall Summary of TEAEs by Treatment Group and Treatment 
• 
Incidence of TEAEs by Treatment Group, Treatment, System Organ Class, and Preferred Term 
• 
Incidence of Treatment Emergent Serious Adverse Events by Treatment Group, Treatment, 
System Organ Class, and Preferred Term 
Subjects who prematurely discontinued due to TEAEs and subjects with serious TEAEs will be listed. 
8.4.2 Laboratory Data 
Summary tables for laboratory parameters (including hematology, chemistry, and urinalysis) will be 
summarized for each treatment group and treatment. Summaries for change from baseline for hematology, 
chemistry, and urinalysis parameters will include descriptive statistics (the number of non-missing values, 
mean, standard deviation, median, minimum and maximum) for values and change from baseline values for 
all continuous variables, and frequency counts and percentages for categorical variables, by treatment. 
Subjects with laboratory data outside the normal range will be listed with abnormal values flagged. 
8.4.3 Vital Signs 
Summary tables for vital signs data will include descriptive statistics (the number of non-missing values, 
mean, standard deviation, median, minimum and maximum) for values and change from baseline values by 
treatment and treatment group. 
A listing of vital signs results will be provided for all subjects in the Safety Population. 


 
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8.4.4 Electrocardiogram (ECG)  
ECG parameters (RR interval, PR interval, QRS duration, QT interval, and QTcB interval) will be 
summarized by changes from baseline values by treatment and treatment group using descriptive statistics. 
For each parameter, only subjects who had both baseline and a post-baseline assessment will be included in 
the summary. 
A listing of ECG results will be provided for all subjects in the Safety Population. 
8.4.5 Physical examinations 
Physical examination results will be presented in individual subject data listings.  
8.4.6 Pregnancy Test  
Pregnancy test results prior to treatment will be listed. 
9. ANALYSES PERFORMED BEFORE DATABASE CLOSURE 
No interim analyses are planned for this study. 
10.  CHANGES FROM METHODS PLANNED IN THE PROTOCOL 
Any changes to methods planned in this SAP will be documented in a revision to this statistical plan prior to 
database lock, or identified in the clinical study report. 
11. STATISTICAL SOFTWARE 
The statistical software to be used for generation of the tables, listings, and figures is SAS® version 9.4. 
12. REFERENCES 
Not Applicable. 


 
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13. APPENDIX 1   DATA HANDLING RULES 
Category 
Description 
Data Handling Rules 
Demographics 
Age at informed 
consent 
Age = integer ([date of informed consent signed – date of birth + 1]/365.25) 
 
If in date of birth, only day is missing, it is imputed by 15th of the month of birth; 
both day and month are missing, it is imputed by July 1st of the year of birth. 
Baseline 
 
Baseline was defined as the last assessment made before the dose of the 
investigational product. 
Vital 
Signs/ECG/Lab 
Change from 
baseline 
Changet = Valuet - ValueBaseline 


 
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14. APPENDIX 2   SAS CODE FOR STATISTICAL ANALYSES 
This section will be completed after examining the existing data and prior to the final signoff of 
this SAP. 
Test 
Table/Figure 
SAS Codes for Modeling 
 
ANOVA using a linear 
mixed-effects model. 
PK endpoints 
requiring ANOVA. 
Analysis using PROC MIXED in SAS with SEQ, SUBJ, PERIOD, 
and TRTP identifying SEQUENCE, SUBJECT, PERIOD and 
TREATMENT variables. “Y” denotes the response measure (log 
(AUC), log (CMAX)). “KR” denotes Kenward-Roger method. 
“CL” denotes confidence limits. 
 
 
PROC MIXED METHOD=REML; 
   CLASS SUBJ SEQ PERIOD TRTP; 
   MODEL Y = SEQ PERIOD TRTP/ DDFM=KR; 
   RANDOM SUBJ(SEQ); 
   LSMEANS TRTP/ PDIFF CL ALPHA = 0.10; 
  ESTIMATE ‘T/R’ TREAT -1 1/CL ALPHA = 0.1; 
RUN; 
 
Anti-log transformation to obtain the geometric means.  “GEO” 
denotes geometric and “LS” denotes least square. 
 
DATA LSMEANS; 
   SET LSMEAN 
   GEOLSMEAN = EXP(ESTIMATE);  
RUN; 
 
Anti-log transformation to obtain the ratio of geometric means 
(point estimate) and 90% confidence interval (CI) – lower and 
upper bounds. 
 
DATA DIFFS; 
   SET ESTIMATE; 
   RATIO = EXP(ESTIMATE)*100; 
   LOWER = EXP(LOWER)*100; 
   UPPER = EXP(UPPER) * 100; 
RUN; 
 
 
 


 
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15. APPENDIX 3   REFERENCE RANGES AND CLINICALLY RELEVANT CHANGES 
FROM BASELINE FOR MARKED LABORATORY ABNORMALITIES 
<To be inserted> 


 
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16. APPENDIX 4   MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGs) 
Mockup tables, listings, and graphs are presented in a separate document.