Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 25
Healthy volunteers: yes

Brief summary:
The purpose of this study was to investigate the effect of a high-fat meal on the levels of bexagliflozin in the blood in healthy subjects.

Detailed description:
This was a single center, Phase 1, open-label, 2 × 2 crossover study designed to assess the effects of a high-fat meal on the PK of orally administered bexagliflozin tablets in 18 healthy adults. Subjects were randomized 1:1 to receive bexagliflozin tablets with a high-fat meal on day 1 and without a meal on day 8 after an overnight fast or to receive bexagliflozin tablets without a meal on day 1 after an overnight fast and with a high-fat meal on day 8.

Subjects were admitted to the clinic on the day before dosing in each treatment period, and stayed in the clinic until 48 h post-dose.

The subjects dosed in the fed state received an oral bexagliflozin tablet, 20 mg, 30 min after starting to consume a high-fat meal following an overnight fast. The meal was to be ingested in its entirety over an approximate 25-minute period, such that it was completed at least 5 minutes prior to the scheduled time of bexagliflozin dosing for the fed state treatment. Subjects dosed in the fasting state received an oral bexagliflozin tablet, 20 mg, after an overnight fast.

Blood samples for bexagliflozin plasma concentrations were collected at 0 h (pre-dose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose. Urine collection in 12 h batches was performed at pre-dose (-12 to 0 h on day 0 and day 7), and at post-dose (0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h) intervals.

Arms:
arm 1: Group 1 subjects will take one dose of 20 mg of bexagliflozin with food on day 1 after an overnight fast and will take a second dose of bexagliflozin without food on day 8 after an overnight fast. arm 2: Group 2 subjects will take one dose of 20 mg bexagliflozin without food on day 1 after an overnight fast and will take a second dose of bexagliflozin with food on day 8 after an overnight fast.

Interventions: intervention 1: Bexagliflozin
Intervention descriptions: intervention 1: Bexagliflozin tablet, 20 mg

Protocol document:
Prot_000.pdf: 
 
 
Clinical Trial Protocol: THR-1442-C-481 
Study Title: 
A Phase 1, Open-label, Randomized, Two-period, Two-treatment, 
Crossover Study to Evaluate the Effect of A High-Fat Meal on the 
Pharmacokinetics of Bexagliflozin in Healthy Subjects 
Study Number: 
THR-1442-C-481 
Study Phase: 
1 
Product Name: 
Bexagliflozin Tablets 
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 
Sponsor’s 
Protocol 
Representative: 
Xiao-Yan Li, Ph.D. 
Translational Medicine Group  
Massachusetts General Hospital 
185 Cambridge Street, Boston, MA 02114 
Phone: 617-726-7960, Fax: 617-643-8203 
Email: xli@ccib.mgh.harvard.edu 
Medical Monitor: 
Geoffrey Walford, M.D. 
Massachusetts General Hospital 
185 Cambridge Street, Boston, MA 02114 
Phone: 617-643-4986, Fax: 617-643-8203 
E-mail: gwalford@partners.org. 
 
 
Date 
Version 2: 
20 May 2016 
Confidentiality Statement 
The information in this document is confidential information of Theracos Sub, LLC 
(“Theracos”) and must not be disclosed, used, or copied except with prior written approval 
from Theracos or to the extent required by applicable local, state or federal laws, rules and 
regulations. 


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SYNOPSIS 
Sponsor: 
Theracos Sub, LLC. 
Name of Finished Product: 
Bexagliflozin Tablets 
Name of Active Ingredient: 
Bexagliflozin 
Name of Inactive Ingredient: 
Polyethylene oxide, glyceryl behenate, lactose monohydrate, micronized poloxamer 188, 
microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate. 
Study Title: 
A Phase 1, Open-label, Randomized, Two-period, Two-treatment, Crossover Study to 
Evaluate the Effect of A High-Fat Meal on the Pharmacokinetics of Bexagliflozin in Healthy 
Subjects 
Study Number:THR-1442-C-481 
Study Phase: 1 
Primary Objective:  
• 
To evaluate the effect of a high-fat meal on the pharmacokinetics (PK) of bexagliflozin 
extended release tablets in healthy subjects. 
Secondary Objectives: 
• 
To evaluate the safety of bexagliflozin after a single oral dose in a fasted state and in a 
fed state in healthy subjects. 
• 
To evaluate the effect of a high-fat meal on the potential pharmacodynamic activity of 
bexagliflozin by determining urinary glucose excretion in healthy subjects under fasted 
and fed conditions. 
Study Design: 
This is a phase 1, single center, open-label, 2 × 2 crossover study designed to assess the 
effects of a high-fat meal on the PK of orally administered bexagliflozin tablets, 20 mg. 
Following a ≥ 10-h overnight fast, eighteen (18) eligible healthy subjects will be assigned to 
two groups with an equal number (n=9) of subjects per group to receive a single oral dose of 
bexagliflozin tablets, 20 mg, in either a fasted state or 30 min after starting a high-fat meal. A 
washout period of at least 7 days will be used between the two treatment periods, after which, 
subjects will receive bexagliflozin tablets, 20 mg, in a fasted or fed state (high-fat), 
whichever state they had not received previously. The high-fat meal will be ingested in its 
entirety over an approximate 25-minute period, such that it is completed at least 5 minutes 
prior to the scheduled time of bexagliflozin dosing for the group receiving bexagliflozin with 
food. If a portion of the meal is not consumed, the reason and the amount of remaining food 


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will be recorded. No food should be allowed for at least 4 h after drug administration. 
Standard meals will be served to both groups 4 hour after dosing.  
In treatment period 1, subjects will be admitted to the clinic on day 0, the day before dosing, 
and will stay in the clinic until 48-h post-dose. In treatment period 2, subjects will be 
admitted to the clinic on day 7, the day before dosing, and will stay in the clinic until 48-h 
post-dose. Blood samples for bexagliflozin plasma concentrations will be collected in each 
period at pre-dose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose. Urine 
collection in 12 h batches will be performed at pre-dose (-12 to 0 h on day 0 and day 7), and 
at post-dose at 0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h. 
Clinical laboratory tests and safety monitoring will be conducted during both treatment 
periods. 
Study Population: 
Eighteen healthy subjects are planned to be enrolled and dosed. 
Diagnosis and Main Criteria for Inclusion 
1. Healthy subjects who are between the ages of 18 and 65 years, inclusive. 
2. Subjects with body-mass index (BMI) between 18.0 kg/m2 and 32.0 kg/m2, inclusive. 
3. Male subjects who are surgically sterile or male subjects who are not surgically sterile but 
who 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. 
4. Female subjects of childbearing potential who are 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. 
5. Subjects who are non-smokers for at least 3 months prior to screening. 
6. Subjects with adequate venous access at multiple sites in both arms. 
Test Product; Dose; and Mode of Administration:  
Bexagliflozin tablets, 20 mg, oral administration. 
Duration of Treatment: 
Two single dose treatments with at least 7 days apart 
Pharmacokinetic Variables: 
The following PK parameters of bexagliflozin will be determined where feasible after each 
subject is dosed with bexagliflozin in a fasted state and 30 min after starting a high-fat meal. 
Cmax 
 Maximum observed plasma concentration 
Tmax  
 Time of maximum observed plasma concentration 
z        Terminal elimination phase rate constant 
T½        Apparent terminal elimination half-life 


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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 
Safety Assessments: 
• 
Vital signs 
• 
Clinical laboratory tests including blood chemistry and hematology parameters 
• 
Urinalysis 
• 
Adverse events 
• 
Concomitant medication use 
PD Assessment: 
• 
UGE 
• 
Urinary electrolytes, uric acid, and creatinine 
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 a high-fat meal on the PK of bexagliflozin, 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 fed : fasted ratio of 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 
terminal elimination half-life (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 exception of Tmax. Medians and ranges will be 
presented for Tmax. 
Descriptive statistics on the PD parameters will be also performed. The effect of high-fat 
meal on the cumulative UGE between subjects under fasted and fed conditions will be 
compared.   
Date of Original Protocol(V1):  18 May 2016 
Prepared in: Microsoft Word 2010 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................8 
1 
INTRODUCTION ...........................................................................................................11 
1.1 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus ...............................11 
1.2 
Summary of Nonclinical Data with Bexagliflozin.................................................11 
1.3 
Summary of Clinical Data with Bexagliflozin.......................................................11 
2 
STUDY OBJECTIVES ....................................................................................................13 
2.1 
Primary Objective ..................................................................................................13 
2.2 
Secondary Objectives.............................................................................................13 
3 
INVESTIGATIONAL PLAN ..........................................................................................14 
3.1 
Overall Study Design and Plan ..............................................................................14 
3.2 
Rationale for Study Design ....................................................................................15 
3.3 
Study Duration and Dates ......................................................................................15 
4 
STUDY POPULATION SELECTION ...........................................................................16 
4.1 
Study Population ....................................................................................................16 
4.2 
Inclusion Criteria ...................................................................................................16 
4.3 
Exclusion Criteria ..................................................................................................16 
5 
STUDY TREATMENTS .................................................................................................18 
5.1 
Study Drug .............................................................................................................18 
5.2 
Treatments Administered .......................................................................................18 
5.3 
Selection and Timing of Dose for Each Subject ....................................................18 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................19 
5.5 
Blinding..................................................................................................................19 
5.6 
Concomitant Therapy.............................................................................................19 
5.7 
Restrictions ............................................................................................................19 
5.7.1 
Prior Therapy ...............................................................................................19 
5.7.2 
Fluid and Food Intake ..................................................................................19 
5.7.3 
Subject Activity Restrictions .......................................................................20 
5.8 
Treatment Compliance ...........................................................................................20 
5.9 
Packaging and Labeling .........................................................................................20 
5.10 
Storage and Accountability ....................................................................................20 
6 
STUDY PROCEDURES .................................................................................................21 
6.1 
Informed Consent...................................................................................................21 
6.2 
Medical History .....................................................................................................21 
6.3 
Physical Examination.............................................................................................22 


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6.4 
Vital Signs ..............................................................................................................22 
6.5 
Electrocardiography and Continuous Telemetry Monitoring ................................22 
6.5.1 
12-Lead Electrocardiograms ........................................................................22 
6.6 
Clinical Laboratory Tests .......................................................................................23 
6.6.1 
Laboratory Parameters .................................................................................23 
6.6.2 
Sample Collection, Storage, and Shipping ..................................................24 
6.6.2.1 
Hematology and Blood Chemistry.....................................................24 
6.6.2.2 
Urinalysis ...........................................................................................24 
6.6.2.3 
Urine Collection .................................................................................24 
6.6.2.4 
Plasma Sample Collection for PK ......................................................24 
6.6.2.5 
Blood and Urine Volume and Frequency for PK/PD and Safety 
Assessment .........................................................................................24 
6.7 
Pharmacokinetic Assessments ...............................................................................25 
6.8 
Pharmacodynamic Assessment ..............................................................................26 
6.9 
Adverse Events Assessments .................................................................................26 
6.9.1 
Collecting and Reporting Adverse Events ...................................................28 
6.9.2 
Immediately Reportable Adverse Events .....................................................28 
6.9.3 
Pregnancy .....................................................................................................29 
6.9.4 
Follow-up of Adverse Events ......................................................................29 
6.9.4.1 
Follow-up of Non-serious Adverse Events ........................................29 
6.9.4.2 
Follow-up of Post-Study Serious Adverse Events .............................30 
6.9.4.3 
Hepatotoxicity ....................................................................................30 
6.9.4.4 
Hypoglycemia ....................................................................................30 
6.10 
Concomitant Medication Assessments ..................................................................31 
6.11 
Removal of Subjects from the Trial or Study Drug ...............................................31 
6.12 
Appropriateness of Measurements .........................................................................32 
7 
STUDY ACTIVITIES .....................................................................................................33 
7.1 
Screening (Days -28 to -1) .....................................................................................33 
7.2 
Clinic Admission (Day 0) ......................................................................................33 
7.3 
Day 1 Activities (Pre-dose) ....................................................................................34 
7.4 
Day 1 Through 3 Activities (Post-dose) ................................................................34 
7.5 
Day 7 Activities .....................................................................................................35 
7.6 
Day 8 Activities (Pre-dose) ....................................................................................35 
7.7 
Day 8 through 10 Activities (Post-dose) ................................................................35 
7.8 
Early Termination or Follow-up Procedures .........................................................36 
8 
QUALITY CONTROL AND ASSURANCE .................................................................37 
9 
PLANNED STATISTICAL METHODS ........................................................................38 
9.1 
General Considerations ..........................................................................................38 
9.2 
Determination of Sample Size ...............................................................................38 


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9.3 
Analysis Populations ..............................................................................................38 
9.4 
Demographics and Baseline Characteristics ..........................................................38 
9.5 
Statistical Analysis of Pharmacokinetic Variables ................................................38 
9.6 
Safety Analysis ......................................................................................................39 
9.6.1 
Adverse Events ............................................................................................39 
9.6.2 
Hypoglycemia ..............................................................................................40 
9.6.3 
Clinical and Laboratory Events and Analyses .............................................40 
9.6.4 
Concomitant Medications ............................................................................40 
9.7 
Interim Analysis .....................................................................................................40 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................41 
10.1 
Investigators and Study Administrative Structure .................................................41 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................41 
10.3 
Ethical Conduct of the Study .................................................................................41 
10.4 
Subject Information and Consent...........................................................................42 
10.5 
Subject Confidentiality ..........................................................................................42 
10.6 
Study Monitoring ...................................................................................................42 
10.7 
Case Report Forms and Study Records .................................................................43 
10.8 
Protocol Violations/Deviations ..............................................................................43 
10.9 
Access to Source Documentation ..........................................................................43 
10.10 Retention of Data ...................................................................................................44 
10.11 Publication and Disclosure Policy .........................................................................44 
11 REFERENCE LIST .........................................................................................................45 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Dosing Schedule ..........................................................................................18 
Table 2. 
Required Laboratory Tests ...........................................................................23 
Table 3. 
Blood and Urine Samples ............................................................................24 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................46 
Appendix 2 
Sponsor Signatures.............................................................................47 
Appendix 3 
Investigator’s Signature .....................................................................48 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALB 
albumin 
ALT 
alanine aminotransferase 
ANOVA 
analyses of variance 
AST 
aspartate aminotransferase 
ATC 
anatomic therapeutic chemical classification 
AUC 
area under the time-concentration curve 
AUCextr 
extrapolated area under the plasma concentration-time curve 
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 
CFR 
Code of Federal Regulations 
CK 
creatinine kinase 
Clast 
concentration corresponding to Tlast 
CL/F 
apparent oral clearance 
Cmax 
maximum observed plasma concentration 
CRF 
case report form 
CRO 
contract research organization 
d 
day 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
-GTP 
gamma-glutamyl transferase 
h 
hour(s) 
HBsAg 
hepatitis B surface antigen 
HCO3 
bicarbonate 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein cholesterol 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
IC50 
concentration that produces 50% inhibition of response 


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ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IR 
immediate release 
IRAE 
immediately reportable adverse event 
IRB 
Institutional Review Board 
K2EDTA 
potassium ethylenediaminetetraacetic acid 
λz 
terminal elimination phase rate constant 
LDL-C 
low density lipoprotein cholesterol 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
n 
number 
NCA 
non compartmental analysis 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PE 
physical examination 
Pgp 
p-glycoprotein 
PK 
pharmacokinetic 
QRS 
The QRS complex is a name for the combination of three of the graphical 
deflections seen on a typical electrocardiogram 
QTC 
The corrected QT interval is a measure of the time between the start of the 
Q wave and the end of the T wave in the heart's electrical cycle 
RBC 
red blood cell (count) 
RR 
respiration rate 
SAE 
serious adverse event 
SD 
standard deviation 
SGLT1 
sodium glucose cotransporter 1 
SGLT2 
sodium glucose cotransporter 2 
SOP 
standard operating procedure 
t1/2 
apparent terminal elimination half-life 
TBL 
serum total bilirubin 
TC 
total cholesterol 
TEAE 
treatment emergent adverse events 


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TG 
triglycerides 
Tlast 
time of last measurable (positive) concentration 
Tmax 
time of maximum observed plasma concentration 
UGE 
urinary glucose excretion 
UGT1A9 
UDP glucuronosyltransferase 1 family, polypeptide A9 
ULN 
upper limit of normal (value) 
UTI 
urinary tract infection 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell (count) 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of childbearing potential 
z 
Terminal elimination phase rate constant 
 
 


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1 
INTRODUCTION 
Bexagliflozin, a potent and selective renal Na+/glucose transport protein sodium glucose 
cotransporter 2 (SGLT2) inhibitor is being developed as a treatment for type 2 diabetes 
mellitus. The transport of glucose from the renal tubule into the tubular epithelial cells is 
facilitated by SGLT2 which is expressed primarily in the kidney in the early proximal tubule 
of the nephron (Washburn 2009). By inhibiting SGLT2, bexagliflozin blocks the 
reabsorption of filtered glucose, in turn promoting urinary glucose excretion and thereby 
reducing plasma glucose (Zhang, Welihinda et al. 2011). 
Clinical pharmacokinetic (PK) studies have shown that the peak plasma bexagliflozin 
concentrations occurred between 3 to 5 h and thereafter declined in a biphasic manner with 
mean elimination half-life values ranging from 7.80 to 9.71 h. Bexagliflozin is cleared 
predominantly by metabolism to an inactive metabolite, bexagliflozin 3-O-glucuronide by 
the uridine diphosphate glucuronosyltransferase isoform 1A9 (UGT1A9) pathway. Extended 
release bexagliflozin tablet formulations are developed to provide greater than 75% release in 
approximately 8 h in vitro. The objective of this study is to evaluate the effects of a high-fat 
meal on the PK of extended release bexagliflozin tablets, 20 mg. 
1.1 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus 
Bexagliflozin is a highly specific inhibitor of SGLT2 with an in vitro IC50 of 2 nM or 
0.9 ng/mL and a 2435-fold selectivity for human SGLT2 compared with sodium glucose 
cotransporter 1 (SGLT1). Details of the nonclinical and clinical findings are described in the 
Investigator’s Brochure. 
1.2 
Summary of Nonclinical Data with Bexagliflozin 
Bexagliflozin exhibits high permeability and is a potential Pgp (p-glycoprotein) substrate and 
inhibitor. It is not a significant inducer or inhibitor of cytochrome P450 isozymes and other 
transporters relevant for drug-drug interactions. 
1.3 
 Summary of Clinical Data with Bexagliflozin 
The early clinical studies have been conducted using immediate release (IR) products in 
capsules. Theracos has completed multiple phase 1 studies to evaluate safety, tolerability, 
pharmacokinetics (plasma exposure), pharmacodynamics (glucosuria), and drug metabolism 
in healthy subjects, patients with type 2 diabetes, and diabetic patients with renal impairment.  
Following administration of bexagliflozin IR capsules, time of maximum observed plasma 
concentration (Tmax) was reached within 1 to 3 h. The systemic exposure was dose 
proportional with a maximum observed plasma concentration (Cmax) of 11 ng/mL per mg 
bexagliflozin and an area under the plasma concentration-time curve (AUC0-24) of 
approximately 60 ng·h/mL per mg bexagliflozin in healthy or diabetic subjects. Following 
administration of bexagliflozin tablets in extended release formulations, Tmax was reached 
between 3 to 5 h. The tablets produced dose proportional exposure with a Cmax of 4 or 8 


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ng/mL per mg bexagliflozin and an AUC0-24 of 40 or 50 ng·h/mL per mg bexagliflozin in 
healthy subjects when dosing was before or after a meal, respectively. 
The principal metabolites in humans are similar to those found in monkeys and are 
dominated by glucuronides of the parent compound, for which the AUC is >30% relative to 
parent bexagliflozin. Modest accumulation consistent with an extended half-life has been 
seen following multiple daily dosing. Following oral administration of radiolabeled 
bexagliflozin, >90% of the ingested radioactivity was recovered, 51% as fecal excretion and 
41% as urinary excretion. In urine, bexagliflozin accounts for 1.5% of the dose; most of the 
radioactivity is excreted as bexagliflozin 3’-O-glucuronide. The largest fraction of the 
radioactivity in feces is due to bexagliflozin, accounting for about 30% of the administered 
dose. 
The safety and tolerability of bexagliflozin in healthy or diabetic subjects was initially 
evaluated in a single-dose study of up to 100 mg, followed by a 4-week treatment study in 
which doses ranged from 5 mg/d to 50 mg/d. The most frequently occurring adverse events 
(AEs) were mild to moderate headache, pollakiuria, nausea, and fatigue. No symptomatic 
hypoglycemia was reported and no treatment-related adverse event led to discontinuation of 
treatment. Extended release tablets of 3 mg to 90 mg strengths were well tolerated in a 
Japanese population with few adverse events reported. 
Detailed information of bexagliflozin clinical experience and potential risks for study 
subjects are provided in the Investigator’s Brochure. 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
To evaluate the effect of a high-fat meal on the pharmacokinetics of bexagliflozin extended 
release tablets in healthy subjects. 
2.2 
Secondary Objectives  
To evaluate the safety of bexagliflozin after a single oral dose in fasted or fed state in healthy 
subjects. 
To evaluate the effect of a high-fat meal on the potential pharmacodynamic activity of 
bexagliflozin by determining urinary glucose excretion in healthy subjects under fasted and 
fed conditions. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This single center, phase 1, open-label, 2 × 2 crossover study is designed to assess the effects 
of a high-fat meal on the PK of orally administered bexagliflozin tablets. Eighteen eligible 
healthy subjects will be randomized into two groups such that an equal number (n=9) of 
subjects will receive a single oral dose of a bexagliflozin tablets, 20 mg, with or without a 
meal on treatment day 1. Subjects randomized to receive bexagliflozin tablets with a high-fat 
meal on day 1 will receive a second dose of bexagliflozin tablets without a meal on treatment 
day 8 after an overnight fast. Subjects randomized to receive bexagliflozin tablets without a 
meal on treatment day 1 after an overnight fast will receive a second dose of bexagliflozin 
tablets with a high-fat meal on treatment day 8. 
Bexagliflozin will be taken orally with 240 mL of water in the morning (approximately 8 
a.m. to 10 a.m.). The time of dosing for a given subject will be the same (as far as 
practicalities permit) in both treatment periods. 
The high-fat meal will follow the FDA guidance (Food Drug Administration 2002) on high-
fat (50% of total caloric content of the meal) and high-caloric (800 to 1000 cal) content. An 
example of the high-fat meal would be two eggs fried in butter, two strips of bacon, two 
slices of toast with butter, four ounces of hash brown potatoes and eight ounces of whole 
milk. Substitutions in this meal can be made as long as the meal provides a similar amount of 
calories from protein, carbohydrate, and fat and has comparable meal volume and viscosity. 
Subjects dosed in the fed state will receive an oral bexagliflozin tablets, 20 mg, 30 min after 
starting to consume a high-fat meal after an overnight fast. No additional food should be 
allowed for at least 4 h post-dose. Water will be allowed as desired except for one hour 
before and after drug administration. The meal will be ingested in its entirety over an 
approximate 25-minute period, such that it is completed at least 5 minutes prior to the 
scheduled time of bexagliflozin dosing for the fed state treatment. If a portion of the meal is 
not consumed, the reason and the amount of remaining food will be recorded. Subjects 
should receive standard meals scheduled at the same time in each period of the study. 
Subjects dosed in the fasting state will receive an oral bexagliflozin tablets, 20 mg, after an 
overnight fast. No food should be allowed for at least 4 h post-dose. Water will be allowed as 
desired except for one hour before and after drug administration. Subjects should receive 
standard meals scheduled at the same time in each period of the study. 
Subjects will be admitted to the clinic on day 0 and day 7, the day before dosing in each 
treatment period, and will stay in the clinic until 48-h post-dose. Standard meals will be 
served at the clinic during the stay. Blood samples (2 mL) for bexagliflozin plasma 
concentrations will be collected at 0 h (pre-dose), and at, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 
and 48 h post-dose (days 1-3 in treatment period 1 and days 8-10 in treatment period 2 
respectively). Urine collection in 12 h batches will be performed at pre-dose (-12 to 0 h on 
day 0 and day 7), and at post-dose at 0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h. 


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Clinical laboratory tests and safety monitoring will be conducted during both treatment 
periods. 
For the Schedule of Events table, see Appendix 1. For the overall Dosing Schedule, see Table 
1. 
3.2 
Rationale for Study Design 
The PK profile of bexagliflozin formulated as an extended release product at 10 and 30 mg 
has been evaluated in an early clinical trial (THR-1442-C-445). The effects of dose 
administration in the fasted and fed states were assessed in healthy Japanese subjects for 
absorption, distribution, metabolism and excretion of bexagliflozin. Twelve subjects were 
randomized evenly to two dose groups (10 and 30 mg). Each group received first dose of 
bexagliflozin tablets under fed state on day 1, then after 7-day washout, subjects received 
second dose under fasted state. The administration of bexagliflozin at 10 and 30 mg with a 
standard meal resulted in increased average Cmax (range 39% to 59% for bexagliflozin and 
19% to 28% for bexagliflozin 3-O-glucuronide) and decreased half-life (range 23-40% for 
bexagliflozin and 10% to 21% for bexagliflozin 3-O-glucuronide). However, no meaningful 
change in the Tmax of either analyte was observed. No effect of food on the overall systemic 
exposure [area under the plasma concentration-time curve (AUC)] of bexagliflozin and 
bexagliflozin 3-O-glucuronide was observed.  
In general, meals that are high in total calories and fat content are more likely to affect the 
gastrointestinal physiology and thereby result in a maximal effect on the bioavailability of a 
drug substance. Therefore, a high-fat meal will be used in this study to evaluate the potential 
maximum effect of food on the PK of bexagliflozin tablets, 20 mg, which is the intended 
commercial product. The planned sample size in this crossover study will be powered to 
provide sufficient data for a statistical testing of food effect on the PK of bexagliflozin. The 
results will provide a guide for the timing of dosing relative to meals for this bexagliflozin 
product. 
3.3 
Study Duration and Dates 
This is a phase 1, two-period, two-treatment, crossover study. Subjects will be screened 
within 28 days of the initiation of study drug dosing. Eligible subjects who consent to the 
study will be randomly assigned to 1 of 2 groups, each group will receive both treatments 
alternately, in a crossover fashion (two-period, two-treatment crossover design), with the two 
treatment periods separated by a 7-day washout period.  
In treatment period 1, subjects will be admitted to the clinic on day 0, the day before dosing, 
and will stay in the clinic until 48 h post-dose. In treatment period 2, subjects will be 
admitted to the clinic on day 7, the day before dosing, and will stay in the clinic until 48 h 
post-dose. The scheduled visits and procedures for each visit are provided in Appendix 1. 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Eighteen eligible healthy 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. Subjects who are between 18-65 years of age inclusive with body-mass index (BMI) 
between 18.0 kg/m2 and 32.0 kg/m2, inclusive. 
2. Male subjects who are surgically sterile or male subjects who are not surgically sterile 
must 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. 
3. Female subjects of childbearing potential who are willing to use an adequate method of 
contraception and to not become pregnant for the duration of the study. 
4. 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. 
5. Subjects who are non-smokers for at least 3 months prior to screening. 
6. Subjects with adequate venous access at multiple sites in both arms. 
7. Subjects who are willing and able to be confined to the clinical research facility as 
required by the protocol. 
8. Subjects who have the ability to comprehend and willingness 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, including impairment of the 
central nervous system, circulatory system, respiratory system, blood/hematopoietic 
function system, gastrointestinal system, liver/kidney function, thyroid function, pituitary 
function and/or adrenal function. 
2. Female subjects who are nursing or pregnant. 
3. Subjects with a clinically significant history of allergy to drugs or latex. 
4. Subjects with a history of alcohol or drug dependence in the last 12 months. 
5. Subjects who had 400 mL of whole blood collected within four months or 200 mL of 
whole blood collected within one month of the screening test. 
6. Subjects who had blood component collection within 14 days prior to the screening test. 
7. Subjects who have used prescription or over-the-counter (OTC) drugs within 14 days 
prior to the first dose. 


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8. Subjects who have used vitamin preparations or supplements (including St. John’s Wort 
and ginseng) within 14 days prior to the first dose. 
9. Subjects who have undergone strenuous activity within 72 hours prior to Day 1 in each 
period. 
10. Subjects who are unable (e.g., food intolerance) or unwilling to consume a high-fat 
breakfast within 25 minutes. 
11. 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 study drug 
in this trial. 
12. Subjects who had previously received EGT0001474 or bexagliflozin, or any other 
SGLT2 inhibitors within 3 months from the screening. 
13. Subjects whose screening electrocardiogram (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 
rhythm that is not sinus rhythm, sinus bradycardia, or sinus arrhythmia. 
14. Subjects whose sitting blood pressure is above 140/90 mmHg at screening. 
15. Subjects who have a positive result of HBsAg antigen, HCV antibody, urinary drug or 
urinary cotinine test. 
16. Subjects with known human immunodeficiency virus (HIV) disease. 
17. Subjects with abnormal vital signs, laboratory values, symptoms or signs that are deemed 
clinically significant by the investigator. 
18. Subjects who have had a febrile illness within 5 days prior to the first dose of study 
medication. 
19. Subjects vaccinated within 30 days prior to the first dose of medication. 
20. Detectable urine glucose at screening (trace or greater). 
21. Subjects with eGFR < 90 mL/min/1.73 m2 or a history of kidney transplant. 
22. Subjects with digestion problems, including gastroesophageal reflux disease, irritable 
bowel syndrome, gastroparesis, and any other disorder deemed by the investigator to be 
clinically significant. 
 


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5 
STUDY TREATMENTS 
5.1 
Study Drug 
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. 
5.2 
Treatments Administered 
Subjects who consent to be in the study will be randomly assigned to 1 of 2 treatment groups. 
Each group will be dosed with bexagliflozin under a fasted state in one period and under a 
fed state (high fat, high calorie) in the other period. A single oral dose of bexagliflozin 
tablets, 20 mg, will be provided to subjects in each treatment period. 
The detailed dosing schedule is shown in Table 1. 
Table 1. 
Dosing Schedule 
Subject 
Group 
 
Treatment Period 
Treatment Period 1  
(Day 1) 
Treatment Period 2  
(Day 8) 
Dosing Time (h) 
-0.5 
0 
4 
-0.5 
0 
4 
Group 1 
Bexagliflozin single 
oral dose 
 
X 
 
 
X 
 
*Meal 
X 
 
X 
 
 
X 
Group 2 
Bexagliflozin single 
oral dose 
 
X 
 
 
X 
 
*Meal 
 
 
X 
X 
 
X 
*High-fat meal will be provided at time -0.5 h, while standard meal will be provided at other times. 
 
5.3 
Selection and Timing of Dose for Each Subject 
Dosing order with bexagliflozin alone or in combination with food will be based on 
randomized assignment. Results from previous clinical trials indicate that doses of 1.7 mg to 
100 mg of bexagliflozin are well tolerated and the planned dose of bexagliflozin tablets, 20 
mg, produced significant glucosuria and is not expected to produce serious drug-related 
adverse events. 
• 
Bexagliflozin alone: After an overnight fast of at least 10 h, a bexagliflozin tablets, 20 
mg, will be administered 4 h prior to the first meal of the day with 240 mL of water. 
• 
Co-administration of bexagliflozin with food: After an overnight fast of at least 10 h, a 
bexagliflozin tablets, 20 mg, will be administered 30 min after starting to consume a 
high-fat meal with 240 mL water. 


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If for some reason, a portion of the water is not consumed, the reason and the amount of 
remaining water will be recorded.  
5.4 
Method of Assigning Subjects to Treatment Groups 
A sufficient number of subjects will be screened to ensure that up to 18 subjects will be 
randomized. Eligible subjects will be randomly assigned to group 1 or group 2 in a 1:1 ratio. 
Subjects who discontinue the study after randomization for non-safety related reasons may be 
replaced to ensure that the number of evaluable subjects in each group should not be less than 
8. 
5.5 
Blinding 
This is an open-label study. There is no blinding process in this protocol. 
5.6 
Concomitant Therapy 
The participants are not allowed to take any prescription or non-prescription drugs, vitamins, 
or dietary supplements at any time during 14 days prior to (first) drug administration and for 
the duration of each study period.  No other concomitant medications are permitted with the 
exception of those required for treatment of an adverse event. Subjects may receive any 
medications for adverse events 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 1 week from the end of the last study product 
dosing.  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 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. For the fasting state treatment 
group, oral intake of food (standard meals) will be restricted for 4 h following administration 
of bexagliflozin.  


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The fed state treatment will consist of a bexagliflozin tablet, 20 mg, taken 30 min after 
subjects start to consume a high-fat (approximately 50% of total caloric content of the meal), 
high-calorie (approximately 800–1000 cal) meal after an overnight fast.  
Each dose will be administered with 240 mL tap water. Food intake will be forbidden during 
the first 4 h post dosing. Water can be allowed as desired except for one hour before and after 
drug administration 
Subjects are expected to consume 100% of the high-fat meal and 240 mL of water provided. 
If a portion of the meal and water is not consumed, the reason and the amount of remaining 
meal and water will be recorded.  
Subjects should receive standard meals scheduled at the same time in each period of the 
study. 
5.7.3 
Subject Activity Restrictions 
Light physical activity is permitted. Subjects should not perform strenuous activity during the 
clinical stay and during the washout period as this could result in elevations of muscle 
creatinine kinase (CK) 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 medication dosing will be recorded in the 
CRFs, including a record of checks followed by hand mouth inspection. 
5.9 
Packaging and Labeling 
Investigational product will be provided to the pharmacist or designated site personnel in 
bottles of 90 tablets enclosed with a child-resistant cap. The pharmacist or designated site 
personnel will dispense the investigational products for each subject according to 
randomization assignment. 
5.10 Storage and Accountability 
Bexagliflozin tablets should be stored at controlled room temperature, 15 to 30°C (59 to 
86°F) in a secure area with access limited to authorized personnel. The drug storage facility 
must comply with the medication storage instructions. The trial staff must record the amount 
of investigational product dispensed to each subject in the dosing record. 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. All unused drug must be returned to a 
sponsor-designated depot after drug accounting is verified by the sponsor or its designee. 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
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 Conference 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 and whether childbearing potential 
if female. 
• 
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, alcohol or drug dependence, or abuse in the last 12 months. 
• 
Any blood donation or blood component donation within 4 months. 
• 
Use of any medications including over the counter drugs, vitamins, or dietary 
supplements within 14 days. 
• 
History of vaccination 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 is 
longer. 
• 
Prior exposure to bexagliflozin (or EGT0001474), or any other SGLT2 inhibitors within 
3 months from the screening. 
 
 


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6.3 
Physical Examination 
The investigator or designated qualified individual will perform the physical examinations 
(PEs). A complete physical examination will be performed at screening and at the 
termination visit. Partial physical examinations will be performed at scheduled visits. 
A complete physical examination will include measurement of body weight and height 
(height will be measured only at screening), general assessment of all body systems including 
the skin, head, eyes, ears, nose, throat, neck, lungs, heart, abdomen, lymph nodes, and 
extremities. A partial physical examination 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) in a seated position 
will be obtained after a subject has been sitting for 5 min, respiration rate (RR), and oral 
temperature, will be measured at the scheduled visits described in Appendix 1. BP measures 
will be obtained using a calibrated sphygmomanometer. 
Vital signs should be measured prior to blood draws. 
Respiration rate should be measured after at least 5 min of rest. Devices designed to measure 
BP from the finger or wrist may not be used. 
6.5 
Electrocardiography and Continuous Telemetry Monitoring 
6.5.1 
12-Lead Electrocardiograms 
A 12-lead electrocardiogram (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 10 min 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 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 supine position during blood collection. Clinical blood 
chemistry and hematology 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 
 
Blood or urine  
Vol. (mL) 
Hematology 
3 (blood) 
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration 
(MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count  
White blood cell (WBC) count with 
differential  
 
Serum Chemistry and Electrolytes 
 
10 (serum) 
Albumin (ALB) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Blood urea nitrogen (BUN) 
Glucose 
Bicarbonate (HCO3) 
Creatinine Chloride (Cl) 
Total protein 
Calcium (Ca) 
Magnesium 
Phosphorus 
Potassium (K) 
Sodium (Na) 
Total bilirubin 
Direct bilirubin 
Uric acid 
 
Serum Lipids 
 
6 (serum) 
Total cholesterol (TC) 
High-density lipoprotein cholesterol (HDL-C) 
Triglycerides (TG) 
Low-density lipoprotein cholesterol (LDL-
C), calculated 
 
 
Urinalysis 
 
10 (urine) 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Microscopic examination of sediment  
Nitrite  
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
Leukocyte esterase 
 
Urine Collection (in 12-h batches) 
Glucose 
Creatinine 
Sodium 
 
Potassium 
Calcium 
Uric acid 
All (urine) 
Urine drug screen 
 
10 (urine) 
Amphetamines 
Barbiturates 
Cocaine Metabolites 
Cotinine 
Opiates 
Benzodiazepines 
Cannabinoids 
 
Urine pregnancy test  
 
2 (urine) 
Infectious Disease Testing 
 
6 (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 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 clean catch urine 
sample at any time in subjects with symptoms of urinary tract infection (UTI) or 
pyelonephritis. 
6.6.2.3 
Urine Collection 
Pre-dose urine samples must be collected from -12 to 0 h for baseline measurement, 
immediately after which subjects will empty their bladders.  Post dose urine will be collected 
without preservative in four (4) batches: 0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h 
collections.  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 (PD), 
uric acid, creatinine, and electrolytes. 
6.6.2.4 
Plasma Sample Collection for PK  
Whole venous blood samples of 2 mL will be collected from a peripheral vein in each period 
at pre-dose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose. Samples will be 
placed 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 and stored frozen in 3 aliquots of 200 L at or below 
-20°C. Processed frozen plasma samples will be transferred on dry ice to the analytical 
laboratory and will be stored at or below -20oC until analysis. 
6.6.2.5 
Blood and Urine Volume and Frequency for PK/PD and Safety Assessment 
The total volume and number of sampling times for blood and urine collections are outlined 
in Table 3. 
Table 3. 
Blood and Urine Samples 
Test 
Volume/sample (mL) 
No. of Samples 
Total 
Storage 
Blood 
 
 
 
Hematology 
3 
6 
18 
 
Chemistry  
16 
6 
96 
 
Infectious Disease Testing 
6 
1 
6 
 
PK 
2 
28 
56 
≤ -20oC 


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Table 3. 
Blood and Urine Samples 
Test 
Volume/sample (mL) 
No. of Samples 
Total 
Storage 
Urine Collection   
 
 
 
Urinalysis 
10 
6 
60 
+4oC 
PD 
20 
10 
200 
+4oC 
Urine Drug Screen 
10 
1 
10 
 
Urine Pregnancy Test  
2 
1 
2 
+4oC 
Total blood volume required in each subject: 176 mL; total urine volume required in each subject: 272 mL. 
 
6.7 
Pharmacokinetic Assessments 
A non-compartmental analysis (NCA) will be used to calculate the PK parameters of 
bexagliflozin 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 
z      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 above 
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 


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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 according to the following equation: 
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%. 
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 by Treatment and 
Timepoint will be provided. A listing of plasma concentrations by SubjectID, Treatment 
Period and Timepoint will also be provided. 
6.8 
Pharmacodynamic Assessment 
Urinary glucose excretion will be determined as the pharmacodynamic (PD) parameter at 
baseline (day 0 and day 7), and up to 48 h postdose (days 1-3 and 8-10). The effect of high-
fat meal will be evaluated by comparing the mean cumulative urinary glucose excretion 
(UGE) between subjects under fasted and fed conditions. Potential effects on urinary 
creatinine, uric acid, sodium, potassium, and calcium will also be analyzed. 
6.9 
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 a 
medicinal product, whether or not considered related to the medicinal product. 
Serious adverse event (SAE): A serious adverse event (experience) or reaction is any 
untoward medical occurrence that at any dose: 


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• 
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; it does not refer to an event 
which hypothetically might have caused death if it were more severe.) 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
results in persistent or significant disability/incapacity, or 
• 
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 study drug. 
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 FPG (fasting plasma glucose) value < 70 mg/dL and 
documented as described in Section 6.9.4.4. 
Any increase in liver function tests (AST, aspartate 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. 
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 not iced, but no disruption to daily activity; 
2 = Moderate: discomfort sufficient to reduce or affect normal daily activity; 


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3 = Severe: inability to work or perform normal daily activity. 
 
Study Drug 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 study drug and the AE when 
the event responds to withdrawal of the study drug (dechallenge), and recurs with rechallenge 
by administration of the study drug. 
Probable: There is a reasonable causal relationship between the study drug and the AE. The 
event responds to dechallenge. Rechallenge is not required. 
Possible: There is a reasonable causal relationship between the study drug and the AE. 
Dechallenge is lacking or unclear. 
Not Likely: There is a temporal relationship to study drug administration, but there is not a 
reasonable causal relationship between the study drug and the event. 
Unrelated: There is not a temporal or causal relationship to study-drug administration. 
6.9.1 
Collecting and Reporting Adverse Events 
The investigator will periodically assess subjects for the occurrence of adverse events. To 
avoid bias in collecting information about adverse events, the investigator should ask 
subjects the following question: "How have you felt since you were last checked?" All 
adverse events (serious and non-serious) reported by the subject must be recorded on the 
source documents and CRFs provided by the sponsor. 
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. 
6.9.2 
Immediately Reportable Adverse Events 
The investigator must report any serious adverse event (SAE), by telephone, email, or fax, to 
Theracos or its representative immediately after the investigator becomes aware of the event.  
An immediately reportable adverse event (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 study drug (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 


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explained. It is expected that the investigator will provide or arrange appropriate supportive 
care for the subject. 
6.9.3 
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. 
The investigator must notify the Medical Monitor within 3 working days of the receipt of 
information that any female subject who has become pregnant. This reporting requirement 
will continue until 4 weeks after the last investigational product exposure. 
The investigator must record the event on the Pregnancy Surveillance form and forward it to 
the sponsor’s clinical or designated personnel. 
6.9.4 
Follow-up of Adverse Events 
6.9.4.1 
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. 


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6.9.4.2 
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 6.9.1. 
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 study drug, 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. 
6.9.4.3 
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. 
Study drug should be permanently discontinued if any of the following criteria is met: 
• 
ALT or AST > 8xULN; 
• 
ALT or AST > 3xULN and (TBL > 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%). 
6.9.4.4 
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 


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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). 
 
6.10 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. 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A table of concomitant medications based on the anatomic 
therapeutic chemical classification (ATC) and preferred name will be produced. A listing of 
concomitant medications will include all medications taken by any subjects during the course 
of the study. 
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. 
6.11 Removal of Subjects from the Trial or Study Drug 
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. 


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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 
study drug 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 THR-1442-C-481 trial for any of the 
following reasons: 
• 
A protocol violation occurs, 
• 
A serious or intolerable adverse event occurs, 
• 
A clinically significant change in a laboratory parameter occurs, 
• 
The sponsor or investigator terminates the study, or 
• 
The subject requests to be discontinued from the study. 
 
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. 
6.12 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 pharmacodynamic effects of an SGLT2 inhibitor.  The excreted 
glucose is dose dependent, saturable, and correlates with lowering of fasting plasma glucose 
and of hemoglobin A1c based on data from bexagliflozin studies and other SGLT2 inhibitors. 


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7 
STUDY ACTIVITIES 
7.1 
Screening (Days -28 to -1) 
During the screening period, the following information will be gathered and the indicated 
procedures will be performed: 
• 
Explain the content of informed consent to the subject and collect signed informed 
consent. 
• 
Medical history and demographic information obtained. 
• 
Perform a physical examination, including height and weight measurements as described 
in Section 6.3. 
• 
Vital signs collected 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 taken in the supine position after at least 10 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 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. 
• 
Women will receive urine pregnancy test. 
• 
Blood will be drawn for hematology, serum chemistry, and serology as detailed in 
Section 6.6.2.1. 
• 
The inclusion/exclusion criteria will be evaluated based on the information collected at 
the screening examination. 
 
7.2 
Clinic Admission (Day 0) 
• 
On day 0 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. 
• 
A partial physical examination must be performed as described in Section 6.3. 
• 
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 at -12 h to 0 h (on day 0) for baseline analysis of 
electrolytes, uric acid and creatinine and for UGE (PD) analysis as described in 
Section 6.6.2.3. 
 


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7.3 
Day 1 Activities (Pre-dose) 
The following information will be gathered and the indicated procedures will be performed 
Pre-dose: 
• 
Record vital signs pre-dose. 
• 
Perform 12-lead ECG taken in the supine position after at least 10 min of rest pre-dose. 
• 
Complete pre-dose urine collection at 0 h (-12 h to 0 h) for baseline UGE analysis and 
analysis of electrolytes, uric acid and creatinine analysis as described in Section 6.6.2.3. 
• 
Urine sample will be prepared 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 collected as 
appropriate. 
 
7.4 
Day 1 Through 3 Activities (Post-dose) 
• 
For group 1 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
will be administered 30 min after the start of the high-fat meal as detailed in Section 5.2. 
• 
For group 2 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
will be administered 4 h prior to the first meal of the day as detailed in Section 5.2. 
• 
Record vital signs at 4 h (day 1) and 48 h (day 3) post-dose. 
• 
Perform 12-lead ECG taken in the supine position after at least 10 min of rest at 4 h (day 
1) post-dose. 
• 
Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 1, 2, 3, 4, 
5, 6, 8, 10, 12, 16, 24, 36 (day 2) and 48 h (day 3). 
• 
Urine collection in 12 h batches at 0 to 12 h and 12 to 24 h, 24 to 36 h and 36 to 48 h for 
analysis of electrolytes, uric acid and creatinine and for UGE (PD) analysis as described 
in Section 6.6.2.3. 
• 
Post-dose concomitant medications and adverse event information is collected as 
appropriate. 
• 
On day 3 urine will be collected as described in Section 6.6.2.2 for urinalysis. 
• 
On day 3 blood will be drawn for hematology and serum chemistry as detailed in Section 
6.6.2.1. 
• 
After completion of all day 3 activities the subject will be discharged and scheduled for 
day 8 (period 2) of the study. 
 
Subjects who are terminated from the study for any reason after dosing has started must have 
the information and procedures shown for day 8 collected and completed and the reason for 
termination entered onto the case report form. 


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7.5 
Day 7 Activities 
On day 7 the following information will be gathered and the indicated procedures will be 
performed: 
• 
If the subject is still eligible based on the study inclusion and exclusion criteria, the 
subject will be admitted for the cross-over phase of the study. 
• 
Concomitant medications and adverse event information will be collected as appropriate. 
 
Pre-dose urine collection in 12 h batches at -12 h to 0 h (day 1) for baseline analysis of 
electrolytes, uric acid and creatinine and for UGE (PD) analysis as described in Section 
6.6.2.3. Subjects who are terminated from the study at this time must have the reason for 
termination entered onto the case report form. 
 
7.6 
Day 8 Activities (Pre-dose) 
On day 8 the following information will be gathered and the indicated procedures will be 
performed Pre-dose: 
• 
Record vital signs pre-dose. 
• 
Perform 12-lead ECG taken in the supine position after at least 10 min of rest pre-dose. 
• 
Complete pre-dose urine collection at 0 h (-12 h to 0 h) for baseline UGE analysis and 
analysis of electrolytes, uric acid and creatinine analysis as described in Section 6.6.2.3 
• 
Urine will be collected pre-dose as described in Section 6.6.2.2 for urinalysis. 
• 
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. 
• 
Concomitant medications and adverse event information is collected as appropriate. 
 
 
7.7 
Day 8 through 10 Activities (Post-dose) 
• 
For group 1 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
will be administered 4 h prior to the first meal of the day as detailed in Section 5.2. 
• 
For group 2 subjects, after an overnight fast of at least 10 h, bexagliflozin tablets, 20 mg, 
will be administered 30 min after the start of the high-fat meal as detailed in Section 5.2. 
• 
Record vital signs at 4 h (day 8) and 48 h (day 10) post-dose. 
• 
Perform 12-lead ECG taken in the supine position after at least 10 min of rest at 4h (day 
8) and 48 h (day 10) post-dose. 
• 
Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4  at 1, 2, 3, 4, 
5, 6, 8, 10, 12, 16, 24 (day 9), 36 (day 9) and 48 h (day 10). 
• 
Urine collection in 12 h batches at 0 to 12 h and 12 to 24 h, 24 to 36 h and 36 to 48 h for 
analysis of electrolytes, uric acid and creatinine and for UGE (PD) analysis as described 
in Section 6.6.2.3.Concomitant medications and adverse event information is collected as 
appropriate. 


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• 
On day 10 perform a physical examination as described in Section 6.3. 
• 
On day 10, urine will be collected as described in Section 6.6.2.2 for urinalysis. 
• 
On day 10, blood will be drawn for hematology and serum chemistry as detailed in 
Section 6.6.2.1. 
• 
After completion of all day 10 activities the subject will be discharged.  A follow up visit 
may be scheduled on day 15 if clinically indicated. If a subject who withdraws consent 
prior to completion of all study activities, a follow up visit may be scheduled if clinically 
indicated. 
 
7.8 
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, 
serum chemistry, and glycemic control). The sponsor must be notified in the event that a 
subject withdraws or has been withdrawn from the study. 
 


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8 
QUALITY CONTROL AND ASSURANCE 
The clinical research facility will be monitored by the study monitor to ensure correct 
performance of the study procedures and 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 initiation of the study. 
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, to assess potential food-
drug interactions, and to provide safety and tolerability data on bexagliflozin when 
administered with food (Food and Drug Administration 2002). 
9.3 
Analysis Populations 
Statistical analysis populations will include: 
Safety: The Safety Population will include all randomized subjects who receive at least one 
dose of the drug. Subjects will be analyzed according to the treatment received. 
PK: The PK Population will include all randomized subjects who receive study drug and 
who have sufficient plasma bexagliflozin measurements to derive at least one PK parameter 
following dosing. The PK Population will be used to summarize the PK parameters. 
9.4 
Demographics and Baseline Characteristics 
Baseline characteristics including demographics, physical examination, ECG parameters, and 
safety laboratory values will be summarized for all subjects in the Safety and the PK 
Populations. Descriptive statistics will be performed. 
9.5 
Statistical Analysis of Pharmacokinetic Variables 
To assess the effect of a high-fat meal on the PK of bexagliflozin, 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 fed: 
fasted 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. 
 


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Descriptive statistics for the PK parameters Cmax, Tmax, AUC0-∞ , AUC0-t , CL/F, Vz/F, λz, and 
terminal elimination half-life (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 SubjectID and Treatment Period will 
be provided.  
Descriptive statistics on the PD parameters will be also performed. The effect of high-fat 
meal on the cumulative UGE between subjects under fasted and fed conditions will be 
compared.   
9.6 
Safety Analysis 
Safety data will include adverse events (AEs), physical exam 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. 
9.6.1 
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. 


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9.6.2 
Hypoglycemia 
Hypoglycemia as defined in Section 6.9.4.4 will be presented in listings and summarized. 
9.6.3 
Clinical and Laboratory Events and Analyses 
Clinical and laboratory metrics are measured at baseline 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. 
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. In addition, all serum biochemistry, hematology, and 
urinalysis data outside the reference ranges will be summarized by parameter. 
Laboratory data will be summarized using Low-Normal-High shift tables. ECG results will 
be summarized as changes from baseline in intervals. Abnormalities as well as changes from 
previous assessment will be listed. 
9.6.4 
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.  
9.7 
Interim Analysis 
There will be no interim analysis conducted. 


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Clinical Trial Protocol: THR-1442-C-481 
 
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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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Clinical Trial Protocol: THR-1442-C-481 
 
20 May 2016 
 
 
 
 
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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 Ethics 
Committee or IRB the written approval or favorable opinion of the informed-consent form 
and any other written information to be provided to subjects.  The written approval of the 
IRB/IEC together with the approved subject information/ informed consent forms must be 
filed. The informed consent form must contain all elements required by the FDA under 21 
CFR 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 study drug. 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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Clinical Trial Protocol: THR-1442-C-481 
 
20 May 2016 
 
 
 
 
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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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Bexagliflozin, 20 mg 
Clinical Trial Protocol: THR-1442-C-481 
 
20 May 2016 
 
 
 
 
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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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Bexagliflozin, 20 mg 
Clinical Trial Protocol: THR-1442-C-481 
 
20 May 2016 
 
 
 
 
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11 REFERENCE LIST 
Food Drug Administration, H. H. S. (2002). "Guidance for Industry Food-Effect 
Bioavailability and Fed Bioequivalence Studies." 
 
Washburn, W. N. (2009). "Evolution of sodium glucose co-transporter 2 inhibitors as anti-
diabetic agents." Expert Opin Ther Pat 19(11): 1485-1499. 
 
Zhang, W., A. Welihinda, J. Mechanic, H. Ding, L. Zhu, Y. Lu, Z. Deng, Z. Sheng, B. Lv, Y. 
Chen, J. Y. Roberge, B. Seed and Y. X. Wang (2011). "EGT1442, a potent and selective 
SGLT2 inhibitor, attenuates blood glucose and HbA(1c) levels in db/db mice and prolongs 
the survival of stroke-prone rats." Pharmacol Res 63(4): 284-293. 
 
 


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Clinical Trial Protocol: THR-1442-C-481 
 
20 May 2016 
 
 
 
 
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Appendix 1 
Schedule of Events 
 
Screening 
Period 1 
Period 2 
Study activity 
D -28 to -
1 
D0 
D1  
pre-
dose 
D1  
post-
dose 
D2 
D3 
D7 
D8  
pre-
dose 
D8  
post-
dose 
D9 
D10 
Medical history and ICF 
X 
 
 
 
 
 
 
 
 
 
 
Screening for I/E criteria1 
X 
X 
 
 
 
 
X 
 
 
 
 
Physical exam2 
X 
X 
 
 
 
 
 
 
 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Admission and discharge 
 
X 
 
 
 
X 
X 
 
 
 
X 
Vital signs3 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
ECG4 
X 
 
X 
X 
 
 
 
X 
X 
 
X 
Urinalysis5 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Blood draw for clinical lab 
tests6 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Blood sample for PK7 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urine Collection8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
 
Adverse event and 
concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study termination 
 
 
 
 
 
 
 
 
 
 
X 
1. 
Subject compliance with inclusion and exclusion criteria will be verified at check-in of each period (on 
day 0 and day 7).  
2. 
Weight and height will be recorded as part of the physical examination. Height will be recorded once 
at screening only. A complete physical exam (PE) will be performed at screening and day 10 prior to 
discharge. 
3. 
Vital signs include: pulse, body temperature, respiration rate, systolic and diastolic blood pressure. On 
days 1 and 8, vital signs will be determined at pre-dose and at 4 h and 48 h (day 3 or 10) post-dose. 
4. 
12-lead ECG will be conducted after 10 min of rest. ECG data will be recorded at screening, on days 1 
and 8 at pre-dose and at 4 h post-dose and when clinically indicated. 
5. 
Clean sample to be collected at each visit. If urine is dipstick positive for leukocyte esterase or nitrites, 
sample is to be sent for microscopic evaluation and culture. Urine drug screen will be performed on 
screening visit only. If screening is conducted more than 5 days prior to dosing, drug screening shall be 
repeated. 
6. 
Blood samples at the designated visits for clinical chemistry and hematology parameters are listed in 
Table 2. 
7. 
Plasma samples for the PK profile of bexagliflozin will be collected at pre-dose and at 1, 2, 3, 4, 5, 6, 
8, 10, 12, 16, 24, 36, and 48 h post-dose. 
8. 
Urine collection for urinary glucose (PD), electrolytes, uric acid & creatinine are described in Section 
6.6.2.3. 
 
 
 
 





SAP_001.pdf: 
 
Statistical Analysis Plan 
Protocol Number. THR-1442-C-481 
Last Revision Date: 13-Sep-2016 
 
Final 
Page 1 of 30 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Trial Sponsor: 
Protocol Number: 
Theracos Sub, LLC. 
THR-1442-C-481 
IND Number: 
103822 
Investigational Drug: 
Indication: 
Bexagliflozin Tablets 
Type 2 Diabetes Mellitus 
Drug Number: 
 
Dosage Form/Strength: 
Tablets/20 mg 
 
 
Protocol Title:  A Phase 1, Open-label, Randomized, Two-period, Two-treatment, Crossover Study to 
Evaluate the Effect of A High-Fat Meal on the Pharmacokinetics of Bexagliflozin in Healthy Subjects  
 
 
 
 
First Sign-off Date: 
dd-Mmm-yyyy 
Last Revision Date: 
13-Sep-2016 
Final Sign-off Date: 
dd-Mmm-yyyy 
 
 
 
 




 
Statistical Analysis Plan 
Protocol No. THR-1442-C-481 
Last Revision Date: 13-Sep-2016 
 
Final 
Page 3 of 30 
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-481 
Last Revision Date: 13-Sep-2016 
 
Final 
Page 4 of 30 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION .......................................................................................................................................... 10 
2. 
STUDY OBJECTIVES................................................................................................................................... 10 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................. 10 
2.2 
SECONDARY OBJECTIVES .......................................................................................................................... 10 
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 ............................................................................. 14 
5. 
ANALYSIS POPULATIONS ........................................................................................................................ 14 
5.1 
SAFETY POPULATION ................................................................................................................................ 14 
5.2 
PHARMACOKINETIC POPULATION.............................................................................................................. 14 
5.3 
PHARMACODYNAMIC POPULATION ........................................................................................................... 14 
6. 
SPECIFICATION OF ENDPOINTS AND VARIABLES .......................................................................... 14 
6.1 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 14 
6.1.1 
Study Day and Visit Window Definitions ................................................................................ 15 
6.2 
PHARMACOKINETICS/PHARMACODYNAMICS ............................................................................................ 15 
6.3 
SAFETY ..................................................................................................................................................... 16 
6.3.1 
Study Day and Visit Window Definitions ................................................................................ 16 
6.3.2 
Extent of Exposure to Study Medication .................................................................................. 16 
6.3.3 
Adverse Events (AEs) ............................................................................................................... 16 
6.3.4 
Laboratory Data ........................................................................................................................ 18 
6.3.5 
Vital Signs ................................................................................................................................ 19 
6.3.6 
Electrocardiogram..................................................................................................................... 20 
6.3.7 
Physical Examination ............................................................................................................... 20 
6.3.8 
Pregnancy Test ......................................................................................................................... 20 
6.3.9 
Concomitant Medications/Treatments ...................................................................................... 20 
7. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES .............................................................. 21 
7.1 
GENERAL CONSIDERATIONS ...................................................................................................................... 21 
7.2 
PHARMACOKINETIC ANALYSES ................................................................................................................. 21 
7.3 
PHARMACODYNAMIC ANALYSES .............................................................................................................. 23 
8. 
STATISTICAL ANALYSIS .......................................................................................................................... 23 
8.1 
GENERAL DATA HANDLING RULES AND DEFINITIONS .............................................................................. 23 
8.2 
SUBJECT DISPOSITION ............................................................................................................................... 24 
8.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 24 
8.4 
SAFETY ANALYSES ................................................................................................................................... 24 
8.4.1 
Adverse Events ......................................................................................................................... 25 
8.4.2 
Laboratory Data ........................................................................................................................ 25 
8.4.3 
Vital Signs ................................................................................................................................ 25 
8.4.4 
Electrocardiogram (ECG) ......................................................................................................... 25 


 
Statistical Analysis Plan 
Protocol No. THR-1442-C-481 
Last Revision Date: 13-Sep-2016 
 
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CONFIDENTIAL 
 
8.4.5 
Physical examinations .............................................................................................................. 25 
8.4.6 
Pregnancy Test ......................................................................................................................... 26 
9. 
ANALYSES PERFORMED BEFORE DATABASE CLOSURE .............................................................. 26 
10. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL ......................................................... 26 
11. 
STATISTICAL SOFTWARE ........................................................................................................................ 26 
12. 
REFERENCES ............................................................................................................................................... 26 
13. 
APPENDIX 1   DATA HANDLING RULES ............................................................................................... 27 
14. 
APPENDIX 2   SAS CODE FOR STATISTICAL ANALYSES ................................................................. 28 
15. 
APPENDIX 3   REFERENCE RANGES AND CLINICALLY RELEVANT CHANGES FROM 
BASELINE FOR MARKED LABORATORY ABNORMALITIES ......................................................... 29 
16. 
APPENDIX 4   MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS) .............................................. 30 
 
 


 
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Protocol No. THR-1442-C-481 
Last Revision Date: 13-Sep-2016 
 
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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 
creatinine 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 
dL 
deciliter 
DM 
data management 
ECG 
electrocardiogram 
 


 
Statistical Analysis Plan 
Protocol No. THR-1442-C-481 
Last Revision Date: 13-Sep-2016 
 
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CONFIDENTIAL 
 
Abbreviation 
Term 
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-481 
Last Revision Date: 13-Sep-2016 
 
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CONFIDENTIAL 
 
Abbreviation 
Term 
mL 
milliliter 
msec 
millisecond 
Na 
sodium 
NCA 
non compartmental analysis 
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. 
RBC 
red blood cell (count) 
REML 
restricted maximum likelihood 
RR interval 
intra-beat interval  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
T½ 
apparent terminal elimination half-life 


 
Statistical Analysis Plan 
Protocol No. THR-1442-C-481 
Last Revision Date: 13-Sep-2016 
 
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CONFIDENTIAL 
 
Abbreviation 
Term 
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 
T-wave 
Repolarization of the ventricles 
UGE 
urinary 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-481 
Last Revision Date: 13-Sep-2016 
 
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Page 10 of 30 
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 THR-1442-C-481 version 2 dated 20-
May 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 30-Jun-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 9.3. Adverse events will be coded using the 
latest version of the Medical Dictionary for Regulatory Activities (MedDRA version 19.0 or newer). 
This is a single center, phase 1, open-label, 2 × 2 crossover study designed to assess the effects of a high-
fat meal on the pharmacokinetics (PK) of orally administered bexagliflozin tablets. Approximately 18 
eligible healthy subjects are planned to be randomized into two treatment groups such that an equal 
number (n = 9) of subjects will receive a single oral dose of 20 mg of bexagliflozin with or without a meal 
on treatment day 1. Subjects randomized to receive bexagliflozin with a high-fat meal on day 1 will 
receive a second dose of bexagliflozin without a meal on treatment day 8 after an overnight fast. Subjects 
randomized to receive bexagliflozin without a meal on treatment day 1 after an overnight fast will receive 
a second dose of bexagliflozin with a high-fat meal on treatment day 8. 
(See Protocol Sections 3.1 to 3.3 for details). 
2. STUDY OBJECTIVES 
2.1 Primary Objective 
To evaluate the effect of a high-fat meal on the PK of bexagliflozin extended release tablets in healthy 
subjects. 
2.2 Secondary Objectives 
To evaluate the safety of bexagliflozin after a single oral dose in a fasted state and in a fed state in healthy 
subjects. 
To evaluate the effect of a high-fat meal on the potential pharmacodynamic (PD) activity of bexagliflozin 
by determining urinary glucose excretion (UGE) in healthy subjects under fasted and fed conditions. 


 
Statistical Analysis Plan 
Protocol No. THR-1442-C-481 
Last Revision Date: 13-Sep-2016 
 
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CONFIDENTIAL 
 
3. STUDY DESIGN 
3.1 Study Design 
This single center, phase 1, open-label, 2 × 2 crossover study is designed to assess the effects of a high-fat 
meal on the PK of orally administered bexagliflozin tablets. Eighteen (18) eligible healthy subjects will be 
randomized into two treatment groups such that an equal number (n = 9) of subjects will receive a single 
oral dose of 20 mg of bexagliflozin with or without a meal on treatment day 1. Subjects randomized to 
receive bexagliflozin tablets with a high-fat meal on day 1 will receive a second dose of bexagliflozin 
tablets without a meal on treatment day 8 after an overnight fast. Subjects randomized to receive 
bexagliflozin tablets without a meal on treatment day 1 after an overnight fast will receive a second dose 
of bexagliflozin tablets with a high-fat meal on treatment day 8. 
Bexagliflozin will be taken orally with 240 mL of water in the morning (approximately 8 a.m. to 10 a.m.). 
The time of dosing for a given subject will be the same (as far as practicalities permit) in both treatment 
periods. 
The high-fat meal will follow the FDA guidance (Food and Drug Administration 2002) on high-fat (50% 
of total caloric content of the meal) and high-caloric (800 to 1000 calories) content. An example of the 
high-fat meal would be two eggs fried in butter, two strips of bacon, two slices of toast with butter, four 
ounces of hash brown potatoes and eight ounces of whole milk. Substitutions in this meal can be made as 
long as the meal provides a similar amount of calories from protein, carbohydrate, and fat and has 
comparable meal volume and viscosity. 
Subjects dosed in the fed state will receive a 20 mg oral bexagliflozin tablet 30 min after starting to 
consume a high-fat meal after an overnight fast. No additional food should be allowed for at least 4 h 
post-dose. Water will be allowed as desired except for one hour before and after drug administration. The 
meal will be ingested in its entirety over an approximate 25-minute period, such that it is completed at 
least 5 minutes prior to the scheduled time of bexagliflozin dosing for the fed state treatment. If for some 
reason, a portion of the meal is not consumed, the reason and the amount of remaining food will be 
recorded. Subjects should receive standard meals at approximately the same time in each period of the 
study. 
Subjects dosed in the fasting state will receive a 20 mg oral bexagliflozin tablet after an overnight fast. No 
food should be allowed for at least 4 h post-dose. Water will be allowed as desired except for one hour 
before and after drug administration. Subjects should receive standard meals at approximately the same 
time in each period of the study. 
Subjects will be admitted to the clinic on day 0 and day 7, the day before dosing in each treatment period, 
and will stay in the clinic until 48-h post-dose. Standard meals will be served at the clinic during the stay. 
Blood samples (2 mL) for bexagliflozin plasma concentrations will be collected at 0 h (pre-dose), and at 
1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose (days 1-3 in treatment period 1 and days 8-10 in 
treatment period 2 respectively). 
Urine collection in 12 h batches will be performed at pre-dose (-12 to 0 h on day 1 and day 8), and at 
post-dose at 0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h. 
Clinical laboratory tests and safety monitoring will be conducted during both treatment periods. 


 
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3.2 Randomization 
A sufficient number of subjects will be screened to ensure that up to 18 subjects will be randomized. 
Eligible subjects will be randomly assigned to treatment group 1 or treatment group 2 in a 1:1 ratio. 
Subjects who discontinue the study after randomization for non-safety related reasons may be replaced to 
ensure that the number of evaluable subjects in each treatment group should not be less than 8. 
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 
For this Phase 1 food effect study, a sample size of 18 subjects is considered sufficient. 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, to assess potential food-drug interactions, and to provide safety and 
tolerability data on bexagliflozin when administered with food. 
3.6 Schedule of Assessments and Study Procedures 
 


 
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Table 1. Schedule of Events 
 
Screening 
Period 1 
Period 2 
Study activity 
D -28 to -1 
D0 
D1  
pre-dose 
D1  
post-dose 
D2 
D3 
D7 
D8  
pre-dose 
D8  
post-dose 
D9 
D10 
Medical history and ICF 
X 
 
 
 
 
 
 
 
 
 
 
Screening for I/E criteria1 
X 
X 
 
 
 
 
X 
 
 
 
 
Physical exam2 
X 
X 
 
 
 
 
 
 
 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Admission and discharge 
 
X 
 
 
 
X 
X 
 
 
 
X 
Vital signs3 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
ECG4 
X 
 
X 
X 
 
 
 
X 
X 
 
X 
Urinalysis5 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Blood draw for clinical lab tests6 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Blood sample for PK7 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urine Collection8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
Adverse event and concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study termination 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: D = day; ECG = electrocardiogram; ICF = informed consent form; I/E = inclusion/exclusion; PK = pharmacokinetic. 
1. 
Subject compliance with inclusion and exclusion criteria will be verified at check-in of each period (on day 0 and day 7). 
2. 
Weight and height will be recorded as part of the physical examination (PE). Height will be recorded once at screening only. A complete PE will be performed at 
screening and day 10 prior to discharge. 
3. 
Vital signs include: pulse, body temperature, respiration rate, systolic and diastolic blood pressure (BP). On days 1 and 8, vital signs will be determined at pre-dose 
and at 4 h and 48 h (day 3 or 10) post-dose. 
4. 
12-lead electrocardiogram (ECG) will be conducted after 10 min of rest. ECG data will be recorded at screening, on days 1 and 8 at pre-dose and at 4 h post-dose, 
and when clinically indicated. 
5. 
Clean sample to be collected at each visit. If urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for microscopic evaluation and culture. 
Urine drug screen will be performed on screening visit only. If screening is conducted more than 5 days prior to dosing, drug screening shall be repeated. 
6. 
Blood samples at the designated visits for clinical chemistry and hematology parameters are listed in Table 2. 
7. 
Plasma samples for the PK profile of bexagliflozin will be collected at pre-dose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose. 
8. 
Urine collection for urinary glucose (PD), electrolytes, uric acid & creatinine. Pre-dose urine samples will be collected from -12 to 0 h for baseline measurement.   
Post-dose urine will be collected in four batches: 0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h collections. 


 
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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 drug. 
Subjects will be analyzed according to the treatment received. 
5.2 Pharmacokinetic Population 
The PK Population will include all randomized subjects who receive study drug and who have sufficient 
plasma bexagliflozin measurements to derive at least one PK parameter 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 have PD parameter data available in both 
treatment periods. 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: 
 
Weight (kg) 
 
Height (cm) 
 
Vital signs 


 
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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) 
 
Medical and surgical history 
 
Clinical laboratory tests 
 
Prior and concomitant medication  
 
Physical examination 
6.1.1 Study Day and Visit Window Definitions 
Table 2.  Time Windows for Safety Assessments 
 
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 Pharmacokinetic and 
Pharmacodynamic Populations respectively 
Plasma samples will be analyzed for bexagliflozin concentrations using a validated method. 
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 1 
1 
1 
3 
Day 2 
2 
2 
4 
Day 3 
3-6 
3 
5 
Day 7 
7 
7 
6 
Day 8 
8 
8 
7 
Day 9 
9 
9 
8 
Day 10 
10 
10 


 
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Blood samples for bexagliflozin plasma concentrations will be collected in each period at pre-dose and at 1, 
2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post dose. 
Urine samples will be collected in 12 hr intervals to evaluate the mean UGE. 
Urine collection in 12 h batches will be performed at pre-dose (-12 to 0 h on Day 1 and Day 8), and at post-
dose at 0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h in each treatment period. 
6.3 Safety 
Safety analysis will be performed on the Safety Population. 
The safety profile of bexagliflozin under fasting and fed (high-fat, high-calorie) conditions 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. Vital signs 
4. ECG 
5. Physical examination 
6. Pregnancy test 
7. 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 2 treatment groups. 
Each group will be dosed with bexagliflozin under a fasted state in one period and under a fed state (high 
fat, high calorie) in the other period. A single oral dose of 20 mg of bexagliflozin will be provided to 
subjects in each treatment period. 
6.3.3 Adverse Events (AEs) 
Adverse events will be collected and coded using version 19.0 (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 next dose, the AE(s) will be assigned to the first treatment. Any 
AE(s) that occur after the second dose up until study termination will be assigned to the second 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 6.9 of the study 
protocol. 
6.3.3.3 Immediately Reportable AE (IRAE) 
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 CRF. The intensity of an 
adverse experience will be graded as “Mild”, “Moderate”, and “Severe” using the criteria specified in 
Section 6.9 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 6.9 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. 
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 


 
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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 and electrolytes, serum lipids, 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 4 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 and Electrolytes 
Albumin (ALB) 
Calcium (Ca) 
Alanine aminotransferase (ALT) 
Magnesium 
Aspartate aminotransferase (AST) 
Phosphorus 
Blood urea nitrogen (BUN) 
Potassium (K) 
Glucose 
Sodium (Na) 
Bicarbonate (HCO3) 
Total bilirubin 
Creatinine Chloride (Cl) 
Direct bilirubin 
Total protein 
Uric acid 
Serum lipids 
Total cholesterol (TC) 
Low-density lipoprotein cholesterol (LDL-C), calculated 
High-density lipoprotein cholesterol (HDL-C) 
 
Triglycerides (TG) 
 
Urinalysis 
Appearance 
Nitrite 
Bilirubin 
Occult blood 
Colour 
pH 
Glucose 
Protein 
Ketones 
Specific gravity 
Microscopic examination of sediment 
Urobilinogen 
 
Leukocyte esterase 
Urine Collection 
 
Glucose 
Potassium 
Creatinine 
Calcium 
Sodium 
Uric acid 
6.3.5 Vital Signs 
Vital signs include pulse (beats/min), SBP and DBP (mmHg), oral temperature (oC) and respiration rate 
(breaths/min). 


 
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Vital sign changes from baseline will be summarized by treatment. 
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. 
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 case report form (CRF). The medication name, indication, dose, unit, frequency, route of 
administration, date(s) of 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. 


 
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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. 
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 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). 
7.2 Pharmacokinetic Analyses 
From the plasma bexagliflozin concentration-time data, the following PK parameters will be estimated for 
each subject where feasible. 


 
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Table 3.  Pharmacokinetic Parameters 
Pharmacokinetic Parameters 
Cmax 
Maximum observed plasma concentration 
Tmax 
Time of maximum observed plasma concentration 
z 
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%. 
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 by Treatment and Timepoint will be 
provided. A listing of plasma concentrations by Subject Number, Treatment Period and Timepoint will also 
be provided. 


 
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To assess the lack of interaction effect of a high-fat meal on the PK of bexagliflozin, 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 fed: fasted 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. 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 of bexagliflozin by Subject Number and Treatment Period will be 
provided. 
Refer to Appendix 2 for the SAS code. 
7.3 Pharmacodynamic Analyses 
Descriptive statistics of glucose concentrations and UGE will be summarized by 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 and 48-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 a high-fat meal will be evaluated by comparing the mean cumulative UGE between subjects 
under fasted and fed (high-fat, high-calorie conditions). Potential effects on urinary creatinine, uric acid, 
sodium, potassium, and calcium will also be analyzed. 
8. STATISTICAL ANALYSIS 
8.1 General Data Handling Rules and Definitions 
All data collected on case report forms will be provided in listings, except data collected only for 
confirmation of study entry criteria and for study administrative purposes. If any randomized patient 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 9.3 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 


 
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variables will be summarized with frequency counts and percentages, by treatment. 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, not treated, completed, and those who discontinued early from the study along 
with the corresponding primary reasons for early termination. 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 sequence will also be summarized. 
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 sequence 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, physical examination, as well as prior and concomitant medications will 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. 
Abnormalities in the subjects’ medical and surgical histories will be coded using version 19.0  
(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. 
Baseline values for clinical laboratory tests, vital signs and ECGs will be defined as the last evaluation 
performed prior to administration of study drug. 


 
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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. 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 
 
Incidence of TEAEs by Treatment, System Organ Class and Preferred Term 
 
Incidence of Treatment Emergent Serious Adverse Events by 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. 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. 
A listing of vital signs results will be provided for all subjects in the Safety Population. 
8.4.4 Electrocardiogram (ECG)  
ECG parameters (RR interval, PR interval, QRS duration and QT interval) will be summarized by changes 
from baseline values by treatment 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.  


 
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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 statistical analysis plan 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 9.3. 
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.