Conditions: Type2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 20
Healthy volunteers: yes

Brief summary:
The purpose of this study is to examine the drug-drug interaction when given the study drug, bexagliflozin, with one of the most commonly prescribed glucagon-like peptide 1 receptor agonist (GLP-1 RA) exenatide. The study will also evaluate how safe the study drug is and how well the study drug is tolerated when administered with exenatide injection.

Detailed description:
This was a phase 1, single center, open-label, 2 × 2 crossover study designed to assess the effects of exenatide injection on the PK and PD of orally administered bexagliflozin tablets. Healthy subjects were randomly assigned to one of two groups with 10 subjects per group. Each group received both the treatments, alternately, in a crossover fashion with the two treatment periods separated by a 7-day washout period.

In Treatment Period 1, subjects were admitted to the clinic on day 0, the day before dosing, and stayed in the clinic until 48 h post-dose. After an overnight fast of at least 10 h, subjects in Group 1 received a single oral dose of bexagliflozin tablets, 20 mg, alone 30 min before breakfast, and subjects in Group 2 received a subcutaneous (SC) injection of exenatide at 10 µg twice a day (bid) with an initial dose 30 min prior to a single oral dose of bexagliflozin tablets, 20 mg, and 1 hr before breakfast, followed by the second dose of exenatide alone 1 hr prior to the evening meal.

In Treatment Period 2, subjects were admitted to the clinic on day 7, the day before dosing, and stayed in the clinic until 48 hr post-dose. After an overnight fast of at least 10 h, subjects in Group 1 received a SC injection exenatide at 10 µg bid with an initial dose 30 min prior to a single oral dose of bexagliflozin tablets, 20 mg, and 1 hr before breakfast and followed by the second dose of exenatide alone 1 hr prior to the evening meal. Subjects in Group 2 received a single oral dose of bexagliflozin tablets, 20 mg, alone 30 minutes before breakfast.

Blood samples for bexagliflozin plasma concentration were collected during each period at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 hr post-dose. Pre-dose urine samples were collected from -12 to 0 hr for baseline measurement of PD parameters. Post-dose urine samples were collected in four batches: 0 to 12 hr, 12 to 24 hr, 24 to 36 hr, and 36 to 48 hr.

Clinical laboratory tests and safety monitoring were conducted during both treatment periods for each group.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Bexagliflozin intervention 2: Exenatide Injection
Intervention descriptions: intervention 1: Bexagliflozin tablets, 20 mg intervention 2: Byetta® (Exenatide), 10 ug, bid, subcutaneous injection

Protocol document:
Prot_000.pdf: 
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Clinical Trial Protocol: THR-1442-C-458 
 
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Clinical Trial Protocol: THR-1442-C-458 
Study Title: 
A Phase 1, Open-label, Randomized, Two-period, Two-treatment, 
Crossover Study to Evaluate the Effect of Exenatide on the 
Pharmacokinetics and Pharmacodynamics of Bexagliflozin in Healthy 
Subjects 
Study Number: 
THR-1442-C-458 
Study Phase: 
1 
Product Name: 
Bexagliflozin tablets 
IND Number: 
103822103822 
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: 
Roger Albright  
185 Cambridge Street, Boston, MA 02114 
Phone: 617-643-5696 Fax: 617-643-8203 
Email: ralbright@ccib.mgh.harvard.edu 
Medical Monitor: 
Mason W. Freeman, M.D. 
Translational Medicine Group, MGH 
185 Cambridge Street, Boston, MA 02114 
Phone: 617-724-7704 Fax: 617-643-8203 
Email: freeman@molbio.mgh.harvard.edu 
 
 
Date 
Protocol V1.0: 
19 April 2017 
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 Ingredients: Polyethylene oxide, glyceryl behenate, lactose monohydrate, 
poloxamer, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate. 
Name of Reference Therapy: Byetta ®  
Name of Active Ingredient of Reference Therapy: Exenatide  
Name of Inactive Ingredients: metacresol, mannitol, glacial acetic acid, and sodium acetate 
trihydrate in water for injection. 
Study Title: 
A Phase 1, Open-label, Randomized, Two-period, Two-treatment, Crossover Study to 
Evaluate the Effect of Exenatide on the Pharmacokinetics (PK) and Pharmacodynamics (PD) 
of Bexagliflozin in Healthy Subjects. 
Study Number: THR-1442-C-458 
Study Phase: 1 
Primary Objective:  
To evaluate the effect of exenatide injection on the PK and PD of bexagliflozin. 
Secondary Objective: 
To assess the safety and tolerability of bexagliflozin when it is used in combination with 
exenatide.  
Study Design: 
This is a phase 1, single center, open-label, 2 × 2 crossover study designed to assess the 
effects of exenatide injection on the PK and PD of orally administered bexagliflozin tablets. 
Approximately 20 eligible healthy subjects will be randomly assigned to one of the two 
groups (1 or 2) with up to 10 subjects per group. Each group will receive both the 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 in 
Group 1 will receive a single oral dose of bexagliflozin tablets, 20 mg, alone 30 min before 
breakfast, and subjects in Group 2 will receive subcutaneous injection dose of exenatide at 10 
g twice a day (bid) with initial dosing 30 min prior to a single oral dose of bexagliflozin 
tablets, 20 mg, and 1 h before breakfast and followed by the second dosing of exenatide 
alone 1 h prior to evening meals. In Treatment Period 2, subjects in Group 1 will receive 
subcutaneous injection dose of exenatide at 10 g bid with initial dosing 30 min prior to a 
single oral dose of bexagliflozin tablets, 20 mg, and 1 h before breakfast and followed by the 
second dosing of exenatide alone 1 h prior to evening meals and subjects in Group 2 will 
receive a single oral dose of bexagliflozin tablets, 20 mg, alone 30 min before breakfast. 
Clinical laboratory tests and safety monitoring will be conducted during both treatment 


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periods.  
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 at each 
period at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose. 
Urine samples for PD (urinary glucose excretion) analysis will be collected at each period in 
12 h batches at pre-dose (h -12 to 0), and at post-dose at 0 to 12 h, 12 to 24 h, 24 to 36 h, and 
36 to 48 h. 
Study Population:  
Approximately 20 healthy subjects are planned. 
Diagnosis and Main Criteria for Inclusion: 
1. Male and female subjects who are between the ages of 18 and 65 years, inclusive, in 
good health based on medical history, physical examination (PE), electrocardiogram 
(ECG) and routine laboratory tests.  
2. Subjects with body-mass index (BMI) between 18.0 kg/m2 and 32.0 kg/m2, inclusive. 
3. Subjects who are non-smokers for at least 3 months prior to screening. 
4. Subjects with adequate venous access at multiple sites in both arms. 
5. Subjects who are willing and able to be confined to the clinical research facility as 
required by the protocol. 
6. Subjects who have the ability to comprehend and who are willing to provide written 
informed consent in accordance with institutional and regulatory guidelines. 
Test Product; Dose; and Mode of Administration:  
Bexagliflozin tablets, 20 mg, oral administration. 
Reference Therapy; Dose; and Mode of Administration: 
Byetta® (Exenatide), 10 g, bid, subcutaneous injection. 
Duration of Treatment:  
This is a phase 1, two-period, two-treatment, crossover study. Subjects will be screened 
within 21 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 the treatments 
alternately, in a crossover fashion (two-period, two-treatment crossover design), with the two 
treatment periods separated by a 7-day washout period.  
Pharmacokinetics Variables: 
The following PK parameters of bexagliflozin will be determined after each subject is dosed 
with bexagliflozin alone or the combination of exenatide and bexagliflozin. 
Cmax 
     Maximum observed plasma concentration 
tmax  
     Time of maximum observed plasma concentration 
λz            Terminal phase rate constant  
t1/2            Apparent terminal 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 
AUC0-extr  % of AUC0-∞  due to extrapolation from tlast to infinity 
Pharmacodynamics Assessments: 
PD parameters include: 
• Urinary glucose excretion (UGE) 
Safety Assessments: 
• Physical examinations (PE) 
• Vital signs 
• 12-lead ECG 
• Clinical laboratory tests including blood chemistry and hematology parameters 
• Urinalysis  
• Adverse events  
Statistical Methods:  
Statistical analysis will be performed using Statistical Analysis Software SAS (SAS Institute 
Inc., USA). PK parameters of bexagliflozin will be calculated using non-compartmental 
analyses (NCA) of plasma concentration-time data. To assess the effect of co-administration 
of exenatide on the PK of bexagliflozin, 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 ratio of geometric means of PK parameters 
(Cmax, AUC0-t and AUC0-∞) when bexagliflozin is dosed in combination with exenatide 
versus when dosed alone, with 80-125% defined as the lack of interaction boundaries.  
Descriptive statistics for the PK parameters Cmax, tmax, AUC0-∞, AUC0-t, AUC0-extr, 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.  
Descriptive statistics on the PD parameters will also be performed. Descriptive statistics will 
be used to describe any differences in UGE values between treatment groups.  
Date of Original Protocol: 19 April 2017 
Prepared in: Microsoft Word 2010 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................9 
1 
INTRODUCTION ...........................................................................................................11 
1.1 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus ...............................12 
1.1.1 
Summary of Nonclinical Data with Bexagliflozin.......................................12 
1.1.2 
Summary of Clinical Data with Bexagliflozin.............................................12 
1.2 
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and Exenatide ..............12 
2 
STUDY OBJECTIVES ....................................................................................................14 
2.1 
Primary Objective ..................................................................................................14 
2.2 
Secondary Objective ..............................................................................................14 
3 
INVESTIGATIONAL PLAN ..........................................................................................15 
3.1 
Overall Study Design and Plan ..............................................................................15 
3.2 
Rationale for Study Design and Control Group .....................................................15 
3.3 
Study Duration and Dates ......................................................................................16 
4 
STUDY POPULATION SELECTION ...........................................................................17 
4.1 
Study Population ....................................................................................................17 
4.2 
Inclusion Criteria ...................................................................................................17 
4.3 
Exclusion Criteria ..................................................................................................17 
5 
STUDY TREATMENT(S) ..............................................................................................19 
5.1 
Description of Treatment(s) ...................................................................................19 
5.1.1 
Study Drug ...................................................................................................19 
5.1.2 
Exenatide......................................................................................................19 
5.2 
Treatment(s) Administered ....................................................................................19 
5.3 
Selection and Timing of Dose for Each Subject ....................................................21 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................21 
5.5 
Blinding..................................................................................................................21 
5.6 
Concomitant Therapy.............................................................................................21 
5.7 
Restrictions ............................................................................................................22 
5.7.1 
Prior Therapy ...............................................................................................22 
5.7.2 
Fluid and Food Intake ..................................................................................22 
5.7.3 
Subject Activity Restrictions .......................................................................22 
5.8 
Treatment Compliance ...........................................................................................22 
5.9 
Packaging and Labeling .........................................................................................22 
5.9.1 
Bexagliflozin ................................................................................................22 
5.9.2 
Exenatide......................................................................................................22 
5.10 
Storage and Accountability ....................................................................................23 


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6 
STUDY PROCEDURES .................................................................................................24 
6.1 
Informed Consent...................................................................................................24 
6.2 
Medical History .....................................................................................................24 
6.3 
Physical Examination.............................................................................................24 
6.4 
Vital Signs ..............................................................................................................25 
6.5 
Electrocardiography ...............................................................................................25 
6.5.1 
12-Lead Electrocardiograms ........................................................................25 
6.6 
Clinical Laboratory Tests .......................................................................................25 
6.6.1 
Laboratory Parameters .................................................................................25 
6.6.2 
Sample Collection, Storage, and Shipping ..................................................27 
6.6.2.1 
Hematology and Blood Chemistry.....................................................27 
6.6.2.2 
Urinalysis ...........................................................................................27 
6.6.2.3 
Urine Collection for PD (UGE) .........................................................27 
6.6.2.4 
Plasma Sample Collection for PK ......................................................27 
6.6.2.5 
Blood and Urine Volume and Frequency for PK, PD, and Safety 
Assessment .........................................................................................27 
6.7 
Pharmacokinetic Assessments ...............................................................................28 
6.8 
Pharmacodynamic Assessment ..............................................................................29 
6.9 
Adverse Events Assessments .................................................................................29 
6.9.1 
Collecting and Reporting Adverse Events ...................................................31 
6.9.2 
Immediately Reportable Adverse Events .....................................................31 
6.9.3 
Pregnancy .....................................................................................................32 
6.9.4 
Follow-up of Adverse Events ......................................................................32 
6.9.4.1 
Follow-up of Non-serious Adverse Events ........................................32 
6.9.4.2 
Follow-up of Post-Study Serious Adverse Events .............................33 
6.9.4.3 
Hepatotoxicity ....................................................................................33 
6.9.4.4 
Hypoglycemia ....................................................................................33 
6.10 
Concomitant Medication Assessments ..................................................................34 
6.11 
Removal of Subjects from the Trial or Study Drug ...............................................35 
6.12 
Appropriateness of Measurements .........................................................................36 
7 
STUDY ACTIVITIES .....................................................................................................37 
7.1 
Screening Visit (Days -21 to -1) ............................................................................37 
7.2 
Clinic Admission (Day 0) ......................................................................................37 
7.3 
Day 1 Activities: Groups 1 and 2 Pre-dose ............................................................38 
7.4 
Day 1 Through 3 Activities: Group 1 Post-dose ....................................................38 
7.5 
Day 1 Through 3 Activities: Group 2 Post-dose ....................................................39 
7.6 
Day 7 Activities: Groups 1 and 2 ...........................................................................40 
7.7 
Day 8 Activities: Groups 1 and 2 Pre-dose ............................................................40 
7.8 
Day 8 through 10 Activities: Group 1 Post-dose ...................................................40 


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7.9 
Day 8 through 10 Activities: Group 2 Post-dose ...................................................41 
7.10 
Early Termination or Follow-up Procedures .........................................................42 
8 
QUALITY CONTROL AND ASSURANCE .................................................................43 
9 
PLANNED STATISTICAL METHODS ........................................................................44 
9.1 
General Considerations ..........................................................................................44 
9.2 
Determination of Sample Size ...............................................................................44 
9.3 
Analysis Populations ..............................................................................................44 
9.4 
Demographics and Baseline Characteristics ..........................................................44 
9.5 
Statistical Analysis of Pharmacokinetic Variables ................................................44 
9.6 
Pharmacodynamic Assessments ............................................................................45 
9.7 
Safety Analysis ......................................................................................................45 
9.7.1 
Adverse Events ............................................................................................45 
9.7.2 
Hypoglycemia ..............................................................................................46 
9.7.3 
Clinical and Laboratory Events and Analyses .............................................46 
9.7.4 
Concomitant Medications ............................................................................46 
9.8 
Interim Analysis .....................................................................................................46 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................47 
10.1 
Investigators and Study Administrative Structure .................................................47 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................47 
10.3 
Ethical Conduct of the Study .................................................................................47 
10.4 
Subject Information and Consent...........................................................................48 
10.5 
Subject Confidentiality ..........................................................................................48 
10.6 
Study Monitoring ...................................................................................................49 
10.7 
Case Report Forms and Study Records .................................................................49 
10.8 
Protocol Violations/Deviations ..............................................................................49 
10.9 
Access to Source Documentation ..........................................................................49 
10.10 Retention of Data ...................................................................................................50 
10.11 Publication and Disclosure Policy .........................................................................50 
11 REFERENCE LIST .........................................................................................................51 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Dosing Schedule ..........................................................................................20 
Table 2. 
Required Laboratory Tests ...........................................................................26 
Table 3. 
Blood and Urine Samples ............................................................................28 
 


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LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................52 
Appendix 2 
 Sponsor Signatures............................................................................53 
Appendix 3 
 Investigator’s Signature ....................................................................54 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ATC 
anatomic therapeutic chemical classification 
AUC 
area under the concentration-time curve 
AUC0-extr 
% of AUC0-∞ due to extrapolation from Tlast to infinity 
AUC0-t  
area under the plasma concentration-time curve from Time 0 to Time t 
AUC0-∞ 
area under the plasma concentration-time curve from Time 0 to infinity 
ANOVA 
analyses of variance 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
BLOQ 
below the limit of quantitation 
CFR 
Code of Federal Regulations 
CL/F 
apparent clearance 
Clast 
observed concentration corresponding to tlast 
Cmax 
maximum observed plasma drug concentration 
CRF 
case report form 
CRO 
contract research organization 
CYP450 
cytochrome P450 
dL 
deciliter 
d 
day 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
GLP-1 RAs 
glucagon-like peptide 1 receptor agonists 
h 
hour (s) 
HBsAg 
hepatitis B surface antigen 
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 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
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 


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LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCA 
non-compartmental analysis 
OADs 
oral antidiabetes drugs 
Pgp 
p-glycoprotein 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PR 
the period of time from the onset of the P wave to the beginning of the QRS complex 
QRS 
the QRS complex is a name for the combination of three of the graphical deflections seen 
on a typical electrocardiogram 
QT 
the 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 
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. 
RR 
respiratory rate 
SAE 
serious adverse event 
SD 
standard deviation 
SC 
subcutaneous 
SGLT1 
sodium glucose cotransporter 1 
SGLT2 
sodium glucose cotransporter 2 
SOP 
standard operating procedure 
RBC 
red blood cell (count) 
T½ 
apparent terminal half-life 
TEAE 
treatment emergent adverse event 
Tlast 
time of last measurable concentration 
Tmax 
time to maximum observed plasma concentration 
T2DM 
type 2 diabetes mellitus  
TG 
triglycerides 
UTI 
urinary tract infection 
WOCBP 
women of childbearing potential 


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1 
INTRODUCTION 
The renal Na+/glucose transport protein SGLT2 actively transports extracellular glucose into 
cells using the driving energy of the transmembrane electrochemical potential for sodium 
ions. Individuals with disruptions in SLC5A2, the gene encoding SGLT2, exhibit prominent 
glucosuria in the absence of significant co-morbidities (Santer, Kinner et al. 2003, Kothare, 
Seger et al. 2012); (van den Heuvel, Assink et al. 2002)). The excretion of glucose in the 
urine of diabetic subjects in amounts comparable or greater than that seen in individuals 
harboring loss of functions mutations in SGLT2 has the potential to improve both fasting and 
postprandial hyperglycemia without increasing insulin secretion, causing weight gain, or 
inducing hypoglycemia.  
Bexagliflozin, a candidate oral antidiabetic agent, is a potent and highly specific inhibitor of 
the SGLT2. Bexagliflozin elicits a prominent and predictable glucosuria as demonstrated in 
laboratory animals and in humans. Type 2 diabetes mellitus (T2DM) is a chronic metabolic 
disease. Patients with T2DM often require multiple drug therapy to control the 
hyperglycemia and other comorbidities.  Glucagon-like peptide 1 receptor agonists (GLP-1 
RAs) offer important benefits as monotherapies or in combination with other oral 
antidiabetes drugs (OADs), with low risk for hypoglycemia and significant weight loss by 
enhancing glucose-dependent insulin secretion, suppressing postprandial glucagon release, 
signaling satiety, and slowing gastric emptying. 
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 were developed to provide greater than 75% release 
in approximately 8 h in vitro.   
Exenatide is one of most commonly prescribed GLP-1 RAs and is administered 
subcutaneously (SC) twice daily (bid) for its relatively short half-life of 2.4 h. Exenatide is 
primarily eliminated by glomerular filtration and subsequent proteolytic degradation, thus, 
interactions involving cytochrome P450 (CYP450) isoenzymes or enzymes responsible for 
phase II metabolism are not expected. As enzymes responsible for phase II metabolism are 
responsible for the elimination of bexagliflozin, drug-drug interaction between bexagliflozin 
and exenatide is not expected ((U.S. Department of Health  and Human Services February, 
2012). However, because exenatide slows gastric emptying, the rate of absorption for 
concurrent orally administered medications may be altered (Hurren and Pinelli 2012) 
(Kothare, Seger et al. 2012). The objective of this study is to evaluate the effects of 
coadministering exenatide on the pharmacokinetics (PK) and pharmacodynamics (PD) of 
bexagliflozin tablets. 


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1.1 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus 
Bexagliflozin is a highly specific inhibitor of sodium glucose cotransporter 2 (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. 
1.1.1 
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. 
1.1.2 
Summary of Clinical Data with Bexagliflozin 
Following administration of bexagliflozin tablets in extended release formulations, tmax was 
reached between 3 to 5 h. A 20 mg bexagliflozin tablet produced exposure with a Cmax of 176 
ng/mL or 134 ng/mL and an AUC0-24 of 1199 ng·h/mL or 1087 ng·h/mL in healthy subjects 
when dosing was after or before 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 treatment study in which doses 
ranged from 5 mg/d to 50 mg/d and up to 96 weeks of treatment were evaluated.  Detailed 
information of bexagliflozin clinical experience and potential risks for study subjects are 
provided in the Investigator’s Brochure. 
1.2 
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and 
Exenatide 
GLP-1 RAs are recommended as an option in patients with T2DM, typically as a second-line 
agent, particularly when weight loss or avoidance of hypoglycemia is a primary 
consideration in the therapeutic strategy. GLP-1 RAs reduce hyperglycemia and promote 
weight loss by enhancing glucose-dependent insulin secretion, suppressing postprandial 
glucagon release, signaling satiety, and slowing gastric emptying. In terms of safety, the most 
common adverse events seen in clinical trials with GLP-1 RAs are of gastrointestinal 
character; mainly nausea, vomiting and diarrhea. However, the incidence diminishes over 
time. Other identified risks include pancreatitis, immunogenicity, acute renal failure and 


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rapid weight loss. Exenatide is one of most widely prescribed GLP-1 RAs. It was approved 
in 2005 and is administered subcutaneously bid at a maximum approved dose in the United 
States of 10 µg. It is recommended to be taken within 60 minutes of the morning meal and 
within 60 minutes of the evening meal (approximately 6 hours or more apart). 
After subcutaneous administration, exenatide is rapidly absorbed, usually reaching peak 
concentrations 2 h post administration. Peak plasma concentrations of exenatide after a 10 µg 
dose reach approximately 200 pg/mL. Exenatide is primarily eliminated by glomerular 
filtration and subsequent proteolytic degradation. After a single subcutaneous dose, it 
exhibits a short half-life of approximately 2.4 h. PK/PD modeling and empirical assessments 
from early clinical studies supported a twice daily dosing regimen. Because of its relatively 
short half-life, significant systemic accumulation is not observed with repeated twice-daily 
dosing.   


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
• To evaluate the effect of exenatide injection on the PK and PD of bexagliflozin tablets. 
2.2 
Secondary Objective  
• To assess the safety and tolerability of bexagliflozin tablets when it is administered in 
combination with exenatide injection. 
 


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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 exenatide injection on the PK and PD of orally administered bexagliflozin tablets. 
Approximately 20 eligible healthy subjects will be randomly assigned to one of the two 
groups (1 or 2) with up to 10 subjects per group. Each group will receive both the 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 in 
Group 1 will receive a single oral dose of bexagliflozin tablets, 20 mg, alone 30 min before 
breakfast, and subjects in Group 2 will receive subcutaneous injection dose of exenatide at 10 
g bid with initial dosing 30 min prior to a single oral dose of bexagliflozin tablets, 20 mg, 
and 1 h before breakfast and followed by the second dosing of exenatide alone 1 h prior to 
evening meals. In Treatment Period 2, subjects in Group 1 will receive subcutaneous 
injection dose of exenatide at 10 g bid with initial dosing 30 min prior to a single oral dose 
of bexagliflozin tablets, 20 mg, and 1 h before breakfast and followed by the second dosing 
of exenatide alone 1 h prior to evening meals and subjects in Group 2 will receive a single 
oral dose of bexagliflozin tablets, 20 mg, alone 30 min before breakfast.  
Clinical laboratory tests and safety monitoring will be conducted during both treatment 
periods.  
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 at each 
period at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose of 
bexagliflozin. 
Urine samples for PD analysis will be collected at each period in 12 h batch at pre-dose (h -
12 to 0), and at post-dose of bexagliflozin at 0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h.  
Sampling time was determined based on previous pilot PK and PD studies. 
For the schedule of study events table, see Appendix 1. For overall dosing schedule, see 
Table 1.  
3.2 
Rationale for Study Design and Control Group 
The primary goal of the study is to assess the safety, tolerability, PK and PD of orally 
administered bexagliflozin tablets when it is concurrently administered with exenatide 
injection in healthy subjects.   
This study is designed to be a two-period, two-treatment, crossover study with a 7-day 
washout period (>10 plasma apparent terminal elimination half-lives for both bexagliflozin 
and exenatide). The crossover study will allow direct comparison of two treatments in the 


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same subjects. Such an approach eliminates the influence of difference in subject 
characteristics seen in parallel group design. The primary route for excretion of exenatide is 
glomerular filtration and subsequent degradation of peptide bonds. Thus, drug interaction 
involving CYP450 and phase II enzymes are not expected between bexagliflozin and 
exenatide. However, because of slowing of gastric emptying, exenatide is expected to alter 
the absorption of orally administered concomitant medications especially when exenatide is 
administered prior to co-administered drug, typically resulting in a minor reduction of 
maximum plasma concentration (Cmax) and a prolonged time of maximum concentration 
(tmax). Drug exposures are not expected to be significantly altered. In order to observe the 
maximal potential effect of exenatide on the absorption rate of bexagliflozin, bexagliflozin 
will be administered orally 30 min after subcutaneous exenatide injection, at 10 g bid (the 
highest dose approved for use in the United States), meanwhile, the highest dose used (10 g 
bid exenatide injection in the United States) or intended to be used (20 mg bexagliflozin 
tablets) clinically will be selected.   
Previous studies showed that the PK parameters after multiple dosing were consistent with 
those after single doses for both bexagliflozin and exenatide. Thus a single oral dose of 
bexagliflozin tablets will be administered to healthy subjects in this study to evaluate the 
potential drug-drug interaction between bexagliflozin and exenatide. In this protocol, the 
effect of bexagliflozin on PK/PD of exenatide injection will not be measured since the PK of 
exenatide injection is unlikely to be affected by CYP450 and phase II enzymes involved 
pharmacokinetic interactions.    
3.3 
Study Duration and Dates 
This is a phase 1, two-period, two-treatment, crossover study. Subjects will be screened 
within 21 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 the 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 postdose.  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 
postdose. For details of the schedule and nature of the investigations, see the Schedule of 
Events in Appendix 1.  


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Twenty (20) 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. Male and female subjects who are between the ages of 18 and 65 years, inclusive, in 
good health based on medical history, physical examination (PE), electrocardiogram 
(ECG) and routine laboratory tests.  
2. Subjects with body-mass index (BMI) between 18.0 kg/m2 and 32.0 kg/m2, inclusive. 
3. Subjects who are non-smokers for at least 3 months prior to screening. 
4. Subjects with adequate venous access at multiple sites in both arms. 
5. Subjects who are willing and able to be confined to the clinical research facility as 
required by the protocol. 
6. Subjects who have the ability to comprehend and who are willing to provide written 
informed consent in accordance with institutional and regulatory guidelines. 
 
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Subjects who are determined by the investigator or sub-investigator to be unsuitable for 
participating in the study based on medical conditions or factors that would influence 
adherence to study activities. 
2. Subjects with a clinically significant history of allergy to drugs or latex. 
3. Subjects with a history of hypoglycemia. 
4. Subjects with a history of alcohol or drug dependence in the last 12 months. 
5. Subjects who have donated 400 mL of whole blood within 56 days, 200 mL of whole 
blood within one month, or donated blood components within 14 days of screening. 
6. Subjects who have used prescription or over-the-counter (OTC) drugs within 14 days 
prior to the first dose. 
7. Subjects who have used vitamin preparations or supplements (including St. John's Wort 
and ginseng) within 14 days prior to the first dose . 
8. Subjects who are not willing to refrain from smoking, alcohol, grapefruit, grapefruit 
juice or related products, caffeine consumption (including chocolate), and strenuous 
exercise within 72 h prior to day 1 and through the end of the PK study. 
9. Male subjects who do not agree to refrain from donating sperm and use appropriate birth 
control methods including condoms with spermicide, female partner’s use of diaphragm 
with spermicide, or stable oral, implanted, or injected contraceptive hormones, or with 
an intrauterine device, or female partner is surgically sterile (i.e. have undergone partial 


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or full hysterectomy, or bilateral oophorectomy) or postmenopausal (absence of menses 
greater than 12 months and age > 45 years), for a period of 30 days after discharge from 
the clinic.  
10. Female subjects of childbearing potential who are not willing to use an adequate 
methods of contraception including bilateral tubal ligation, intrauterine device, 
diaphragm with spermicide and male partner’s use of male condom with spermicide, and 
to not become pregnant for the duration of the study. Female subjects who are surgically 
sterile (partial or full hysterectomy, or bilateral oophorectomy) or postmenopausal 
(absence of menses greater than 12 months and age > 45 years) are eligible if they test 
negative on the pregnancy test. 
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 have previously received exenatide ,or any other GLP-1 RAs within three 
months from the screening or subjects who have had any GLP-1 RA and suffered an 
adverse reaction due to the medication. 
13. Subjects who had previously received EGT0001474 or EGT0001442, or any other 
SGLT2 inhibitors within 3 months from the screening. 
14. Subjects whose screening electrocardiogram (ECG) demonstrates any one of the 
following: heart rate > 100 bpm, QRS > 120 msec, QTc > 470 msec (corrected by 
Fridericia's formula), PR > 220 msec (a subject with PR > 220 msec will generally be 
excluded but exceptions may be allowed at the discretion of the investigator), or any 
clinically significant arrhythmia. 
15. Subjects whose sitting blood pressure is above 140/90 mmHg at screening. If the sitting 
blood pressure at screening is above 140/90 mmHg, one repeat measurement is allowed 
and the subject may be randomized if the blood pressure is 140/90 +/-5 mmHg at the 
discretion of the Investigator. 
16. Subjects who have a positive result of hepatitis B surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody, urinary drug or urinary cotinine test. 
17. Subjects with human immunodeficiency virus (HIV) infection. 
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 (with the exception of the flu vaccine) prior to the 
first dose of investigational drug. 
20. Subjects with a history of acute or chronic pancreatitis or gall stones. 
21. Positive urine glucose at screening. 
22. Subjects with estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 or a 
history of kidney transplant. 
23. 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 TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
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. 
5.1.2 
Exenatide 
Subcutaneous exenatide injection at 10 g/dose bid in a 2.4 mL prefilled pen that is procured 
from a licensed manufacturer. 
5.2 
Treatment(s) Administered 
Approximately 20 eligible healthy subjects will be randomly assigned to one of the two 
groups (1 or 2) with up to 10 subjects per group. Each group will receive both the 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 in 
Group 1 will receive a single oral dose of bexagliflozin tablets, 20 mg, alone 30 min before 
breakfast, and subjects in Group 2 will receive subcutaneous injection dose of exenatide at 10 
g bid with initial dosing 30 min prior to a single oral dose of bexagliflozin tablets, 20 mg, 
and 1 h before breakfast and followed by the second dosing of exenatide alone 1 h prior to 
evening meals. In Treatment Period 2, subjects in Group 1 will receive subcutaneous 
injection dose of exenatide at 10 g bid with initial dosing 30 min prior to a single oral dose 
of bexagliflozin tablets, 20 mg, and 1 h before breakfast and followed by the second dosing 
of exenatide alone 1 h prior to evening meals and subjects in Group 2 will receive a single 
oral dose of bexagliflozin tablets, 20 mg, alone 30 min before breakfast. 
The detailed dosing schedule is shown in Table 1. 


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Table 1. 
Dosing Schedule  
Subject 
Group 
Treatment Period  
Treatment Period 1(Day 1) 
Treatment Period 2 (Day 8) 
Dosing Time (h) 
0 
0.5 
1 
4-6 
9 
10 
0 
0.5 
1 
4-6 
9 
10 
Group 1 
Bexagliflozin tablets, 20 mg 
Single oral dose 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Exenatide at 10 µg bid 
SC 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Meal 
 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
Group 2 
Bexagliflozin tablets, 20 mg 
Single oral dose 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Exenatide at 10 µg bid 
SC 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Meal 
 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 


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5.3 
Selection and Timing of Dose for Each Subject 
Dosing order with bexagliflozin alone or in combination with exenatide will be based on 
randomized assignment. Results from pre-clinical data and previous clinical trials indicate 
that the doses of 1.7 mg to 100 mg bexagliflozin are well tolerated and the planned dose of 
20 mg bexagliflozin tablets produced significant glucosuria and is not expected to produce 
serious drug-related adverse events. Subcutaneous exenatide at 10 g bid is the 
recommended clinical dose in patients with T2DM.  
• Bexagliflozin alone: After an overnight fast of at least 10 h, 20 mg bexagliflozin tablets 
will be administered 30 min before the first meal of the day with 240 mL of water. 
• Co-administration of bexagliflozin tablets and exenatide: After an overnight fast of at 
least 10 h, subcutaneous exenatide at 10 g bid will be administered 30 min prior to a 
single oral dose of bexagliflozin and 1 h before breakfast and followed by the second 
dosing of exenatide alone 1 h prior to evening meals. 
 
5.4 
Method of Assigning Subjects to Treatment Groups 
Twenty 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-labeled 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. Intermittent use of up to 2 grams per day of acetaminophen 
may be administered if approved by the Investigator or designee. 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, dates of administration and reason for administration must be recorded.    
Medications that a subject receives after entering the study and prior to randomization must 
be recorded in the CRF. 


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5.7 
Restrictions 
5.7.1 
Prior Therapy 
No study subject shall have been treated with any SGLT2 inhibitors within 3 months prior to 
the screening, or 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. Bexagliflozin tablets will be 
taken in the morning with 240 mL of water prior to any drinking or eating. 
Water can be allowed as desired except for one hour before and after drug administration. 
Water can be allowed during breakfast on D1 and D8.  
5.7.3 
Subject Activity Restrictions 
Light physical activity is permitted. Subjects should not perform strenuous activity as this 
could result in elevations of muscle creatine kinase levels. Smoking during the study is 
prohibited.  
5.8 
Treatment Compliance 
To ensure compliance, all medication dosing will be supervised by the Investigator or 
qualified staff in the clinic. The exact times of medication dosing will be recorded in the 
CRFs, including a record of checks followed by hand mouth inspection. 
5.9 
Packaging and Labeling 
5.9.1 
Bexagliflozin 
Bexagliflozin tablets, 20 mg, are packaged in high density polyethylene bottles sealed with a 
child resistant closure. The product is packaged with 90 tablets per bottle. 
Investigational product bottles will be labeled with protocol number, drug name and strength, 
lot number, sponsor’s name, storage condition, and the investigational drug caution 
statement. 
5.9.2 
Exenatide 
Exenatide in its Byetta form will be supplied as a sterile solution for subcutaneous injection 
containing 250 g/mL exenatide. The subcutaneous injection (do not inject into a vein or 
muscle) of Byetta will be given under the skin of upper arm. The package will be provided as 
10 g per dose, 60 doses, 2.4 mL prefilled pen. The pens are not to be shared with other 
subjects. A new needle will be provided for each injection of exenatide. 


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5.10 Storage and Accountability 
Bexagliflozin tablets should be stored below 30°C in a secure area with access limited to 
authorized personnel. The sponsor will perform an ongoing inventory of study products. The 
responsible pharmacist must keep a careful inventory of drug shipments received and the 
number of tablets dispensed per study subject. A full reconciliation of drug inventory will be 
performed at the end of the study and the results of this inventory must be recorded in the 
Drug Accountability Form. Partially used bottles may be discarded after use according to the 
study sites’ regulations for the disposal of investigational drug substances at study close out, 
after the drug accountability form is completed. 
Prior to first use, exenatide (Byetta) must be stored refrigerated at 36ºF to 46ºF (2ºC to 8ºC). 
After first use, exenatide can be kept at a temperature not to exceed 77ºF (25ºC). Do not 
freeze. Use exenatide (Byetta) only if it is clear, colorless and contains no particles. Do not 
use exenatide if it has been frozen. Exenatide should be protected from light. The pen should 
be discarded 30 days after first use, even if some drug remains in the pen. 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All subjects will be informed of the nature and purpose of the study and their written 
informed consent will be obtained during the pre-study screening procedures conducted 
within three weeks prior to the first dosing day. A copy of the Informed Consent Forms, 
including subject information, will be provided to each subject. 
6.2 
Medical History 
The following information will be collected at the screening period: 
• Demographic information including age, sex, and race 
• Significant medical, surgical history and timeframe of the history relative to study 
screening, if applicable 
• History or knowledge of allergy including drugs and latex 
• History of smoking, alcohol or drug dependence or abuse 
• Any blood donation or blood component donation within 14 days 
• Use of any medications including over the counter drugs, vitamins, or dietary 
supplements within a month 
• History of vaccination within 30 days prior to the first dose of study medication 
• History of diagnosis with HIV, hepatitis B or hepatitis C 
• History of acute or chronic pancreatitis or gall stones 
• Use of any investigational drug in the previous 30 days or seven half-lives, whichever is 
longer 
• Prior exposure to EGT0001442 (or EGT0001474) or exenatide 
 
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. 
 


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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 or calibrated automated vitals 
machine. 
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  
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. 
6.6 
Clinical Laboratory Tests 
6.6.1 
Laboratory Parameters 
Subjects will be in a seated, semi-recumbent 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. The details of the 
required laboratory tests are listed in Table 2. 


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Table 2. 
Required Laboratory Tests 
Test Name 
 
Blood or 
urine  
Vol. (mL) 
Shipment  
Hematology 
3 (blood) 
Ambient 
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count  
White blood cell (WBC) count with 
differential  
 
 
Serum Chemistry and Electrolytes 
 
5 (serum)  
Ambient 
Albumin (ALB) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Blood urea nitrogen (BUN) 
Glucose 
Bicarbonate (Total CO2) 
Creatinine 
Chloride (Cl) 
Total protein 
Calcium (Ca) 
Magnesium 
Phosphorus 
Potassium (K) 
Sodium (Na) 
Total bilirubin 
Direct bilirubin 
Uric acid 
 
 
Serum Lipids  
 
 
Ambient 
Total cholesterol (TC) 
High-density lipoprotein cholesterol 
(HDL-C) 
Triglycerides (TG) 
Low-density lipoprotein cholesterol 
(LDL-C), calculated 
 
 
 
Urinalysis 
 
10 (urine) 
Ambient 
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 
 
 
 
Urine Drug Screen 
 
10 (urine) 
Ambient 
Amphetamines 
Barbiturates 
Cocaine Metabolites 
Cotinine 
Opiates 
Benzodiazepines 
Cannabinoids 
 
 
Pregnancy Test (female only) 
 
 
 
Infectious Disease Testing 
 
5 (serum)  
 
HBsAg 
HIV 
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 Schedule of Events (see 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 leukocytes esterase or nitrites 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 for PD (UGE)  
Pre-dose urine samples must be collected from -12 to 0 h for baseline measurement of UGE. 
Post-dose urine will be collected without preservative in four 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 to 8oC during 
collection.  After collection, the total volume of each batch and collection time will be 
recorded. Aliquots will be prepared from well mixed collections for the PD of bexagliflozin. 
6.6.2.4 
Plasma Sample Collection for PK  
Whole venous blood samples of 3 mL will be collected from a peripheral vein at each period 
at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose of 
bexagliflozin. 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 aliquot 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 outline in 
Table 3. 


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Table 3. 
Blood and Urine Samples 
Test 
Volume/sample (mL) 
No. of Samples 
Total 
Storage 
Blood 
 
 
 
Hematology 
3 
5 
15 
 
Chemistry  
5 
5 
25 
 
Infectious Disease Testing 
5 
1 
5 
 
PK 
3 
30 
90 
≤ -20oC 
Urine Collection (12 h batches) 
 
 
 
PD 
All 
10 
All 
+4oC 
Total blood volume required in each subject: 135 mL 
 
6.7 
Pharmacokinetic Assessments  
A non-compartmental pharmacokinetic analysis (WinNonlin 6.4, Pharsight Corp., Certara, 
USA) will be used to calculate the PK parameters for each subject to determine the PK 
parameters of bexagliflozin. 
Cmax 
 
Maximum plasma concentration 
tmax  
 
Time of maximum plasma concentration 
λz  
 
Terminal phase rate constant  
t1/2  
 
Apparent terminal 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 
AUC0-extr   % of AUC0-∞ due to extrapolation from tlast to infinity 
Cmax and tmax will be obtained directly from experimental observations. If multiple maxima 
occurred at equal concentrations, the first temporal value will be taken. 
The apparent terminal 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 rule, using actual elapsed 
time values. If the actual time of sample collection is not available the nominal time may be 
used for the purposes of 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 


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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. 
The proportion of AUC0-∞ due to extrapolation (AUC0-extr) will be calculated, expressed as a 
percentage and reported. AUC0-∞ values will be considered unreliable estimates if the AUC0-
extr is greater than 20%. 
CL/F will be calculated as Dose/AUC0-∞ 
Vz/F will be calculated as Dose/(λz × AUC0-∞) 
Descriptive statistics for the plasma concentrations of bexagliflozin by Treatment and 
Timepoint will be provided. A listing of plasma concentrations by Subject, Treatment 
Period and Timepoint will also be provided. 
6.8 
Pharmacodynamic Assessment 
Urinary glucose excretion (UGE) will be determined as the PD parameter. Urinary creatinine 
will be determined to calculate the creatinine normalized UGE. 
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. 
Serious adverse event (SAE): A serious adverse event (experience) or reaction is any 
untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening (NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the patient was at risk of death at the time of the event and does not 
refer to an event which hypothetically might have caused death if it were more severe.), 
• requires inpatient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, 
• is an important medical event. 
 
An important medical event is an event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to 


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prevent one of the other outcomes listed in the definition above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
Non-serious adverse events are all events that do not meet the criteria for a "serious" adverse 
event. 
Immediately Reportable Adverse Event (IRAE): Any serious adverse event or any 
adverse event that necessitates discontinuation of investigational product. 
Clinical Laboratory Changes: It is the investigator’s responsibility to review the results of 
all laboratory tests as they become available. For each abnormal laboratory test result, the 
investigator needs to ascertain if this is a clinically significant change from baseline for that 
individual subject. This determination, however, does not necessarily need to be made the 
first time an abnormal value is observed. The investigator may repeat the laboratory test or 
request additional tests to verify the results of the original laboratory tests. If this laboratory 
value is determined to be an abnormal change from baseline for that subject, this is 
considered an AE. 
Hypoglycemia will be defined as any fasting plasma glucose (FPG) value < 70 mg/dL and 
documented as described in Section 6.9.4.4. 
Any increase in liver function tests (AST, 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 noticed, but no disruption to daily activity 
2 = Moderate: discomfort sufficient to reduce or affect normal daily activity 
3 = Severe: inability to work or perform normal daily activity 
Investigational Product Causality: The site and database should ask for the causality 
relative to the study compound. Relationship of an adverse event to dosing will be assessed 
as follows: 
Definite: There is a reasonable causal relationship between the investigational product and 
the AE when the event responds to withdrawal of the investigational product (dechallenge), 
and recurs with administration of the investigational product (rechallenge). 


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Probable: There is a reasonable causal relationship between the investigational product and 
the AE. The event responds to dechallenge. Rechallenge is not required. 
Possible: There is a reasonable causal relationship between the investigational product and 
the AE. Dechallenge is lacking or unclear. 
Not Likely: There is a temporal relationship to investigational product administration, but 
there is not a reasonable causal relationship between the investigational product and the 
event. 
Unrelated: There is no temporal or causal relationship to investigational product 
administration. 
6.9.1 
Collecting and Reporting Adverse Events 
The investigator or designee will periodically assess subjects for the occurrence of adverse 
events. To avoid bias in collecting information about adverse events, the investigator or 
designee 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 or designee must report any serious adverse event (SAE), by telephone, 
email, or fax, to Theracos or its representative immediately after the investigator or study 
staff 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 investigational product (including 
laboratory abnormalities) should be reported to Theracos within 3 working days. The IRAE 
form should be completed and sent by email or fax or overnight courier to the sponsor. 
Subjects experiencing an SAE should be followed clinically until their health has returned to 
baseline status or until all parameters have returned to normal, or have otherwise been 
explained. It is expected that the investigator will provide or arrange appropriate supportive 
care for the subject. 


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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 or designated 
study staff immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
cycle). 
If a subject, investigator or designee 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 or designee must notify the Medical Monitor within 3 working days of the 
receipt of information that any female subject who has become pregnant.  
The investigator or designee 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 or 
designee 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 or designee should continue to report any significant follow-up 
information to Theracos until the event has been resolved. 
Any new SAEs reported by the subject to the investigator that occur after the last scheduled 
contact, and are determined by the investigator to be reasonably associated with the use of 
the investigational product, should be reported to the Medical Monitor or the sponsor’s 
designated personnel. These may include SAEs that are captured on follow-up telephone 
contact or at any other time point after the defined study period (i.e., up to last scheduled 
contact). The investigator or designee 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 or designee should continue to report any significant follow-up information to 
the Sponsor until the event has been resolved. 
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. 
Investigational product should be permanently discontinued if any of the following criteria is 
met: 
• ALT or AST > 8xULN, 
• ALT or AST > 3xULN and (total bilirubin > 2xULN or INR > 1.5), 
• ALT or AST > 3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
 
6.9.4.4 
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 


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measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration. All such 
events should be recorded as serious adverse events in the CRF. 
• Documented symptomatic hypoglycemia: An event during which typical symptoms of 
hypoglycemia are accompanied by a measured plasma glucose concentration ≤ 70 mg/dL 
(3.9 mmol/L). 
• Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration ≤ 70 mg/dL (3.9 
mmol/L). 
• Probable symptomatic hypoglycemia: An event during which symptoms of hypoglycemia 
are not accompanied by a plasma glucose determination but that was presumably caused 
by a plasma glucose concentration ≤70 mg/dL (3.9 mmol/L). 
• Relative hypoglycemia: An event during which the subjects report 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). 
 
If a subject experiences symptomatic hypoglycemia, confirmed by point-of-care glucose 
monitoring at the time of symptoms with a blood sugar level < 70 mg/dL (3.9 mmol/L), the 
subject should be treated with 15 to 20 grams of oral glucose or simple carbohydrate (glucose 
tablets, raisins, orange juice, glucose-containing soda, or soft sugar candies).  
If a subject with symptomatic hypoglycemia is unable to self-administer glucose tablets, 
candies, or glucose-containing solutions, then the appropriate study staff should administer 
either intramuscularly or subcutaneously a single injection of 1.0 mg of glucagon. A single 
dose of glucagon should restore consciousness within approximately fifteen minutes. Failure 
to correct hypoglycemia within this timeframe or observation by appropriate study staff of 
profound low sugar with accompanying coma or seizure will be treated by intravenous 
infusion of 5% dextrose.  
Blood glucose monitoring will be done by appropriate study staff using a point-of-care 
glucose monitor beginning at the time of hypoglycemia detection and continue every fifteen 
minutes, or more frequently if required, until that time that the subject’s level of alertness has 
returned to appropriate levels and point-of-care glucose levels are above 70 mg/dL.  
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 other than 
the investigational product that the subject takes during the course of the trial. All 
prescription and over-the-counter medications, including vitamins and herbal supplements, 
that subjects receive during the trial must be documented on the CRF. This documentation 
should continue until the subjects are discharged.  


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Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A table of concomitant medications based on the anatomic 
therapeutic chemical classification (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 or designee must emphasize to potential subjects the importance of 
continued participation for the full duration of the trial during the informed consent process. 
Participation in the study is voluntary. A participant has the right to withdraw from the study 
at any moment for any reason. The investigator will be informed immediately. 
The investigator has the right to terminate participation of a subject in case it is difficult to 
obtain blood samples, in case of violation of the protocol or in case of severe or serious 
adverse events. 
In case a subject withdraws from the study, the study monitor will be informed immediately. 
If there is a medical reason for withdrawal, the volunteer should remain under the 
supervision of the medical investigator until satisfactory health returns. 
Subjects who discontinue the active dosing phase of the study due to adverse event(s) or 
other safety concerns will not be replaced. 
When the decision is made to discontinue a subject’s participation in the study, no further 
investigational product medication should be administered. Every attempt should be made to 
complete all required study evaluations and procedures. Reasons for all withdrawals should 
be recorded on the CRF. 
The investigator may withdraw a subject from the THR-1442-C-458 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. 


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6.12 Appropriateness of Measurements 
PK parameters and safety assessments used in this study are standard assessments and are 
widely used and generally recognized as reliable, accurate, and relevant measurements.  
Determination of urinary glucose is a non-invasive and quantitative method that allows 
immediate assessment of the PD effects of an SGLT2 inhibitor. 


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7 
STUDY ACTIVITIES 
7.1 
Screening Visit (Days -21 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 complete 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 will be conducted for drug abuse and cotinine. If the drug screen is 
conducted more than 5 days pre-dose, the drug screen must be repeated prior to dosing. 
• Drug abuse testing includes amphetamines, barbiturates, cocaine metabolites, opiates, 
benzodiazepines, Cotinine and cannabinoids. 
• All female subjects will receive 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. 
• All female subjects will receive pregnancy test. 
• 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. 
• Perform 12-lead ECG taken in the supine position after at least 10 min of rest. 
• Urinalysis will be collected 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 drug screen will be performed if drug screening is conducted more than 5 
days prior to dosing. 


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• Blood will be drawn for hematology, and serum chemistry 
• 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. 
• Pre-dose urine collection in 12 h batches at -12 h to 0 h (on day 1) before bexagliflozin 
dosing for baseline analysis of creatinine and glucose for UGE (PD) analysis as described 
in Section 6.6.2.2 and Section 6.6.2.3. 
• Concomitant medications and adverse event information will be collected as appropriate 
 
7.3 
Day 1 Activities: Groups 1 and 2 Pre-dose 
Pre-dose blood glucose levels will be determined using a point-of-care blood glucose 
monitor. If the blood glucose levels are below 70 mg/dL, the study drug will not be 
administered. For subjects with pre-dose blood glucose levels < 70 mg/dL, oral glucose 
solution will be administered and once the subject's blood glucose is > 70 mg/dL, the study 
drug will be administered. 
On day 1 the following information will be gathered and the indicated procedures will be 
performed PREDOSE (prior to whichever drug is taken first): 
• 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) before bexagliflozin dosing for 
baseline UGE analysis and analysis of creatinine as described in Section 6.6.2.3. 
• 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: Group 1 Post-dose 
On days 1 through 3 the following information will be gathered for group 1 subjects and the 
indicated procedures will be performed after dosing: 
• Dosing with bexagliflozin tablets will occur 30 min before the start of the meal as 
detailed in Section 5.2. 
• Record vital signs at 4 h (day 1) and 48 h (day 3) postdose of bexagliflozin. 
• Perform 12-lead ECG taken in the supine position after at least 10 min of rest at 4 h (day 
1) postdose of bexagliflozin. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 0.5, 1, 2, 
3, 4, 5, 6, 8, 10, 12, 16, 24, 36 (day 2) and 48 h (day 3) postdose of bexagliflozin. 
• 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 
postdose of bexagliflozin for UGE analysis and analysis of creatinine as described in 
Section 6.6.2.3. 


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• Postdose concomitant medications and adverse event information is collected as 
appropriate. 
• On day 3 perform a partial physical examination as described in Section 6.3. 
• 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 to 
return to the clinical research unit on Day 7. 
 
Subjects who are terminated from the study for any reason after dosing has started must have 
the information and procedures shown for day 10 collected and completed and the reason for 
termination entered onto the case report form. 
 
7.5 
Day 1 Through 3 Activities: Group 2 Post-dose 
On days 1 through 3 the following information will be gathered for group 2 subjects and the 
indicated procedures will be performed after dosing: 
• Dosing with first dose of subcutaneous exenatide 30 min prior to bexagliflozin tablets 
dosing will occur 1 h before the start of the breakfast as detailed in Section 5.2. 
• Dosing with second dose of subcutaneous exenatide 12 h after the first dose will occur 1 
h before the start of the evening meal as detailed in Section 5.2. 
• Record vital signs at 4 h (day 1) and 48 h (day 3) postdose of bexagliflozin. 
• Perform 12-lead ECG taken in the supine position after at least 10 min of rest at 4 h (day 
1) postdose of bexagliflozin. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 0.5, 1, 2, 
3, 4, 5, 6, 8, 10, 12, 16, 24, 36 (day 2) and 48 h (day 3) postdose of bexagliflozin. 
• 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 
postdose of bexagliflozin for UGE analysis and analysis of creatinine as described in 
Section 6.6.2.3. 
• Postdose concomitant medications and adverse event information is collected as 
appropriate. 
• On day 3 perform a partial physical examination as described in Section 6.3. 
• 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 to 
return to the clinical research unit on Day 7. 
 
Subjects who are terminated from the study for any reason after dosing has started must have 
the information and procedures shown for day 10 collected and completed and the reason for 
termination entered onto the case report form.  
 


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7.6 
Day 7 Activities: Groups 1 and 2 
Pre-dose blood glucose levels will be determined using a point-of-care blood glucose 
monitor. If the blood glucose levels are below 70 mg/dL, the study drug will not be 
administered. For subjects with pre-dose blood glucose levels < 70 mg/dL, oral glucose 
solution will be administered and once the subject's blood glucose is > 70 mg/dL, the study 
drug will be administered. 
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. 
• Record vital signs. 
• Perform 12-lead ECG taken in the supine position after at least 10 min of rest. 
• Urine drug screen and clean catch urinalysis will be collected 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. 
• All female subjects will receive pregnancy test. 
• Blood will be drawn for hematology, and serum chemistry 
• Perform a partial physical examination as described in Section 6.3. 
• Pre-dose urine collection in 12 h batches at -12 h to 0 h (on day 1) before bexagliflozin 
dosing for baseline analysis of creatinine and glucose for UGE (PD) analysis as described 
in Section 6.6.2.2 and Section 6.6.2.3. 
• Concomitant medications and adverse event information will be collected as appropriate.   
 
7.7 
Day 8 Activities: Groups 1 and 2 Pre-dose 
On day 8 the following information will be gathered and the indicated procedures will be 
performed PREDOSE: 
• 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) before bexagliflozin dosing for 
baseline UGE analysis and analysis of creatinine as described in Section 6.6.2.3. 
• 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. 
 
7.8 
Day 8 through 10 Activities: Group 1 Post-dose 
On days 8 through 10 the following information will be gathered for group 1 and the 
indicated procedures will be performed after dosing: 


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• Dosing with first dose of subcutaneous exenatide 30 min prior to bexagliflozin tablets 
dosing will occur 1 h before the start of the breakfast as detailed in Section 5.2. 
• Dosing with second dose of subcutaneous exenatide 12 h after the first dose will occur 1 
h before the start of the evening meal as detailed in Section 5.2. 
• Record vital signs at 4 h (day 8) and 48 h (day 10) postdose of bexagliflozin. 
• 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) postdose of bexagliflozin. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 0.5, 1, 2, 
3, 4, 5, 6, 8, 10, 12, 16, 24 (day 9), 36 (day 9) and 48 h (day 10) postdose of 
bexagliflozin. 
• Urine collection in 12 h batches at 0 to 12 h and 12 to 24 h (day 8), 24 to 36 h and 36 to 
48 h (day 10) for analysis of creatinine and glucose 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 10 perform a complete 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 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. 
 
Subjects who are terminated from the study for any reason after dosing has started must have 
the information and procedures shown for day 10 collected and completed and the reason for 
termination entered onto the case report form. 
 
7.9 
Day 8 through 10 Activities: Group 2 Post-dose 
On days 8 through 10 the following information will be gathered for group 2 and the 
indicated procedures will be performed after dosing: 
• Dosing with bexagliflozin tablets will occur 30 min before the start of the meal as 
detailed in Section 5.2. 
• Record vital signs at 4 h (day 8) and 48 h (day 10) postdose of bexagliflozin. 
• 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) postdose of bexagliflozin. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 0.5, 1, 2, 
3, 4, 5, 6, 8, 10, 12, 16, 24 (day 9), 36 (day 9) and 48 h (day 10) postdose of 
bexagliflozin. 


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• Urine collection in 12 h batches at 0 to 12 h and 12 to 24 h (day 8), 24 to 36 h and 36 to 
48 h (day 10) postdose of bexagliflozin for analysis of creatinine and glucose 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 10 perform a complete 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 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. 
 
Subjects who are terminated from the study for any reason after dosing has started must have 
the information and procedures shown for day 10 collected and completed and the reason for 
termination entered onto the case report form. 
 
7.10 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, urinalysis and clinical laboratory tests 
(hematology, and serum chemistry). The sponsor must be notified in the event that a subject 
withdraws or has been withdrawn from the study. 
 
 


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


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The statistical evaluation of pharmacokinetic and pharmacodynamic 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 (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 drug-
drug interactions and to provide safety and tolerability data on bexagliflozin when 
administered with exenatide. 
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. 
PD: The PD population will include all randomized subjects who receive study drug and will 
have had at least 2 batches of 12 h urine collection from which to calculate UGE 
measurement following dosing. The PD population will be used to summarize the PD 
parameters. 
9.4 
Demographics and Baseline Characteristics 
Baseline characteristics will be descriptively summarized for all subjects in the safety and the 
PK or PD populations. No statistical tests will be performed. 
9.5 
Statistical Analysis of Pharmacokinetic Variables 
To assess the effect of co-administration of exenatide on the PK of bexagliflozin, 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 ratio of the least squares (LS) geometric means of PK parameters (Cmax, AUC0-t and 


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AUC0-∞) when bexagliflozin is dosed in combination with exenatide versus when dosed 
alone, with 80-125% defined as the lack of interaction boundaries.  
Descriptive statistics for the PK parameters Cmax, tmax, AUC0-∞, AUC0-t, AUC0-extr, 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 Subject and Treatment Period will be 
provided.  
9.6 
Pharmacodynamic Assessments 
UGE and urinary creatinine will be assessed before first dosing and at the end of each 
treatment period.   
UGE, including UGEt1-t2 and the total 0-24, 24-48 and 0-48 h UGE, will be determined. 
UGEt1-t2 (mg) will be derived from urine volume (Vt1-t2 , mL) × glucose concentration 
(mg/dL) ÷ 100. Parameters normalized for urinary creatinine excretion will also be 
determined. UGE0-12h , UGE12-24h , UGE24-36h, UGE36-48h and the total 48 h UGE will be listed 
and presented in by subject listing and in summary tables for each group. 
UGE in 12 h intervals up to 48 h post-dose, including the baseline, will be graphically 
presented against the corresponding treatment, bexagliflozin alone, and combination with 
exenatide. 
The descriptive statistics will be used to describe any differences in UGE values between 
treatment groups.  
9.7 
Safety Analysis 
Safety data 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. 
9.7.1 
Adverse Events 
Adverse events will be mapped to preferred term and body system using the Medical 
Dictionary for Regulatory Activities (MedDRA).  In treatment period 1, 10 subjects in group 
1 will receive a single oral dose of 20 mg bexagliflozin and in treatment period 2 another 10 
subjects will receive the same dosing. As a result, a total of 20 subjects will receive a single 
oral dose of bexagliflozin alone. Likewise, a total of 20 subjects will receive a co-
administration of bexagliflozin and exenatide. The number and percentage of subjects 


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reporting adverse events will be determined by relationship to dosing and by severity of the 
event.  Drug-related adverse events will be considered those to be at least possibly related to 
bexagliflozin and/or exenatide administration. 
Adverse event listings will be provided for the following subsets: 
• all treatment emergent AEs (TEAEs) 
• all TEAEs at least possibly related to bexagliflozin or exenatide 
• serious TEAEs (if any) 
• TEAEs leading to study discontinuation (if any). 
 
AEs are treatment emergent if they occur on or after bexagliflozin and/or exenatide 
administration. TEAEs will be considered at least possibly related to bexagliflozin or 
exenatide 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 and/or 
exenatide. 
9.7.2 
Hypoglycemia  
Hypoglycemia as defined in Section 6.9.4.4 will be presented in listings and summarized. 
9.7.3 
Clinical and Laboratory Events and Analyses 
Clinical and laboratory metrics are measured at baseline and during the treatment.  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. 
9.7.4 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD).  A by-subject listing of concomitant medications will include all 
medications taken during the study.   
9.8 
Interim Analysis 
There will be no interim analysis conducted. 


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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 Guidelines and the guiding principles detailed in the Declaration of 
Helsinki. The study will also be carried out in keeping with applicable local laws and 
regulations. An inspection by the sponsor representatives and/or their designee and/or healthy 
authority or other authorized regulatory authorities representatives may occur at any time. 
The investigator must agree to the inspection of study-related records by the regulatory 
authority/sponsor representatives, and must allow direct access to source documents to the 
regulatory authority/sponsor representatives. 
The investigator is responsible for complying with the protocol and all appropriate 
regulations and guidelines governing global clinical research. Additionally, he/she is 
responsible for ensuring that all participating staff members are adequately trained and 
competent to perform his/her assigned tasks. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator may implement a 
deviation from or a change of the protocol to eliminate any immediate hazards to the trial 
subjects without prior IRB/IEC or sponsor approval/favorable opinion. As soon as possible, 
the implemented deviation or change, the reasons for it, and if appropriate, the proposed 
protocol amendment should be submitted to the head of the investigational site, IRB (via the 
head of the investigational site) /sponsor. 


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Any deviations from the protocol must be fully explained and documented by the 
investigator. The circumstances, action taken, and impact of the deviation on the trial must be 
communicated by the principal investigator to the designated medical monitor.  Any 
subsequent actions will be assessed by the designated medical monitor and documented. 
10.4 Subject Information and Consent 
The Investigator will draft the informed consent form based on the protocol and CRO’s draft 
informed consent form. The sponsor will review the investigator’s draft informed consent 
form prior to submission to the IRB/IEC and the final IRB/IEC approved document must be 
provided to the sponsor for regulatory purposes. 
Prior to the beginning of the study, the investigator must have received from the 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 Food and Drug 
Administration (FDA) under 21 Code of Federal Regulations (CFR) Part 50 and the 
International Conference for Harmonisation (ICH) Good Clinical Practices (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. 


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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. 
The investigator will permit authorized representatives of the sponsor and the respective 
national or local health authorities, other authorized regulatory authorities, and IRB 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. 


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


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11 REFERENCE LIST 
Hurren, K. M. and N. R. Pinelli (2012). "Drug-drug interactions with glucagon-like peptide-1 
receptor agonists." Ann Pharmacother 46(5): 710-717. 
Kothare, P. A., M. E. Seger, J. Northrup, K. Mace, M. I. Mitchell and H. Linnebjerg (2012). 
"Effect of exenatide on the pharmacokinetics of a combination oral contraceptive in healthy 
women: an open-label, randomised, crossover trial." BMC Clin Pharmacol 12: 8. 
Santer, R., M. Kinner, C. L. Lassen, R. Schneppenheim, P. Eggert, M. Bald, J. Brodehl, M. 
Daschner, J. H. Ehrich, M. Kemper, S. Li Volti, T. Neuhaus, F. Skovby, P. G. Swift, J. 
Schaub and D. Klaerke (2003). "Molecular analysis of the SGLT2 gene in patients with renal 
glucosuria." J Am Soc Nephrol 14(11): 2873-2882. 
U.S. Department of Health  and Human Services, F. a. D. A., Center for Drug Evaluation and 
Research (CDER), Center for Biologics Evaluation and Research (CBER) (February, 2012). 
"Guidance for Industry Drug Interaction Studies Study Design, Data Analysis, Implications:   
Population Pharmacokinetics." 
van den Heuvel, L. P., K. Assink, M. Willemsen and L. Monnens (2002). "Autosomal 
recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter 
(SGLT2)." Hum Genet 111(6): 544-547. 
 


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Appendix 1 
Schedule of Events 
 
Screening 
Period 1 
Period 2 
Study activity 
D -21 
to -1 
D 0 
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 
criteria 
X 
X 
 
 
 
 
X 
 
 
 
 
Physical exam1 
X 
X 
 
 
 
X 
X 
 
 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Admission and 
discharge 
 
X 
 
 
 
X 
X 
 
 
 
X 
Vital signs2 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
ECG3 
X 
X 
X 
X 
 
 
X 
X 
X 
 
X 
Urinalysis4 
X 
X 
 
 
 
X 
X 
 
 
 
X 
Blood draw for 
clinical lab tests5 
X 
X 
 
 
 
X 
X 
 
 
 
X 
Blood sample for 
PK6 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urine collection7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test  
X 
X 
 
 
 
 
X 
 
 
 
 
Adverse event 
and concomitant 
medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study 
termination 
 
 
 
 
 
 
 
 
 
 
X 
1 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 day10 prior to discharge. A partial PE will be performed 
on days 0, 3 and 7. 
2 Vital signs include: pulse, body temperature, respiratory rate, systolic and diastolic blood pressure. Vital signs will be 
recorded at screening, on days 0, 1 (predose, 4 h postdose), 3 (48 h postdose), 7, 8 (predose, 4 h postdose), and 10 (48 h 
postdose), and when clinically indicated. 
3 12-lead ECG will be conducted after 10 min resting. ECG data will be recorded at screening, on days 0, 1 (predose, 4 h 
postdose), 7, 8 (predose, 4 h postdose), and 10 (48 h postdose), and when clinically indicated. 
4 Urine samples will be collected at screening, on days 0, 7 and prior to discharge in each period. 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 and on day 7. If drug screening is conducted more than 5 days prior to dosing, 
screening shall be repeated.  
5  Blood sample at the designated visits (screening, on days 0, 3, 7 and 10 for clinical chemistry and hematology parameters 
are listed in Table 2.  Blood will be drawn after 10 h of fasting prior to breakfast (i.e. only water is allowed, no caloric 
intake) 
6  Plasma samples for PK profile of bexagliflozin will be collected at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 
36, and 48 h post-dose. 
7 Urine  for urinary glucose (PD) and creatinine will be collected at  pre-dose (h -12 to 0), 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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Appendix 3  
Investigator’s Signature 
Study Title: 
A Phase 1, Open-label, Randomized, Two-period, Two-treatment, 
Crossover Study to Evaluate the Effect of Exenatide on the 
Pharmacokinetics and Pharmacodynamics of Bexagliflozin Tablets in 
Healthy Subjects. 
Study Number: 
THR-1442-C-458 
Final Date: 
19 April 2017 
I have read the protocol described above. I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  
 
 
Signed: 
 
 
Date:  
 
Kelly Whitehurst, MD  
Covance CRU 
617 Oakley Street 
Evansville, IN 47710 
(812) 474-5000 

SAP_001.pdf: 
 
Statistical Analysis Plan 
Protocol Number: THR-1442-C-458 
Last Revision Date: 26-Jul-2017
 
Final 
Page 1 of 30 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Trial Sponsor: 
Protocol Number: 
Theracos Sub, LLC. 
THR-1442-C-458 
IND Number: 
103822
Investigational Drug: 
Indication: 
Bexagliflozin Tablets 
Type 2 Diabetes Mellitus 
Dosage Form/Strength: 
Tablets/20 mg - Bexagliflozin 
 
 
Protocol Title:  A Phase 1, Open-label, Randomized, Two-Period, Two-treatment, Crossover Study 
to Evaluate the Effect of Exenatide on the Pharmacokinetics and Pharmacodynamics of Bexagliflozin in 
Healthy Subjects 
 
 
 
 
Last Revision Date:
26-Jul-2017 
 
 
The information contained in this statistical analysis plan is confidential and provided only to 
Theracos Sub, LLC. Therefore, the information may not be disclosed to, used, or copied by any 
third party without the written consent of Theracos Sub, LLC or to the extent required by 
applicable laws, rules and regulations. 
 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-458 
Last Revision Date: 26-Jul-2017
 
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FIRST SIGN-OFF APPROVAL 
 
 
Study 
Biostatistician: 
Erin Lepic 
Senior Pharmacokinetic Scientist/Project Lead 
Everest Clinical Research 
 
 
 
 
 
 
Signature 
Date 
 
 
 
 
Peer Review 
Biostatistician: 
Wei Wu 
Associate Director Statistical Operations 
Everest Clinical Research 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
Peer Review 
Biostatistician: 
Michael Edwardes 
Principal Biostatistician 
Everest Clinical Research 
 
 
 
 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 
Approved by: 
Roger Albright 
Clinical Trial Manager 
Translational Medicine Group 
Massachusetts General Hospital 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 
 
 
 
 
 
Xiaoyan Li 
Clinical Trial Manager 
Translational Medicine Group 
Massachusetts General Hospital 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 




 
Statistical Analysis Plan 
Protocol No: THR-1442-C-458 
Last Revision Date: 26-Jul-2017
 
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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-458 
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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 ...................................................................................................................................... 11 
3.3 
HYPOTHESIS TESTING ............................................................................................................................... 11 
3.4 
INTERIM ANALYSIS ................................................................................................................................... 11 
3.5 
SAMPLE SIZE ............................................................................................................................................. 11 
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 ............................................................................................ 16 
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)............................................................................................................... 17 
6.3.4 
Laboratory Data ........................................................................................................................ 18 
6.3.5 
Vital Signs ................................................................................................................................ 20 
6.3.6 
Electrocardiogram .................................................................................................................... 20 
6.3.7 
Physical Examination ............................................................................................................... 20 
6.3.8 
Pregnancy Test ......................................................................................................................... 21 
6.3.9 
Concomitant Medications/Treatments ...................................................................................... 21 
7. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES .............................................................. 22 
7.1 
GENERAL CONSIDERATIONS ...................................................................................................................... 22 
7.2 
PHARMACOKINETIC ANALYSES ................................................................................................................. 22 
7.3 
PHARMACODYNAMIC ANALYSES .............................................................................................................. 23 
8. 
STATISTICAL ANALYSIS .......................................................................................................................... 24 
8.1 
GENERAL DATA HANDLING RULES AND DEFINITIONS .............................................................................. 24 
8.2 
SUBJECT DISPOSITION ............................................................................................................................... 24 
8.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 24 
8.4 
SAFETY ANALYSES ................................................................................................................................... 25 
8.4.1 
Adverse Events ......................................................................................................................... 25 
8.4.2 
Laboratory Data ........................................................................................................................ 25 
8.4.3 
Vital Signs ................................................................................................................................ 26 
8.4.4 
Electrocardiogram (ECG) ......................................................................................................... 26 


 
Statistical Analysis Plan 
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8.4.5 
Physical examinations .............................................................................................................. 26 
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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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
ALB 
albumin 
ALT 
alanine aminotransferase 
ANOVA 
analyses of variance 
AST 
aspartate aminotransferase 
ATC 
anatomic therapeutic class 
AUC 
area under the plasma concentration-time curve 
AUCextr 
extrapolated area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve from Time 0 to infinity 
AUC0-t 
area under the plasma concentration-time curve from Time 0 to Time t 
BLOQ 
below the limit of quantitation 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Ca 
calcium 
Cl 
chloride 
Clast 
concentration corresponding to Tlast 
CL/F 
apparent oral clearance 
cm 
centimeter 
Cmax 
maximum observed plasma concentration 
CRF 
case report form 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
dL 
deciliter 
DM 
data management 
 


 
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Abbreviation 
Term 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
FPG 
fasting plasma glucose 
h 
hour(s) 
HBsAg 
hepatitis B surface antigen 
HCO3 
Bicarbonate 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein cholesterol 
Hgb 
hemoglobin 
ICF 
informed consent form 
IRAE 
immediately reportable adverse event 
K 
potassium 
kg 
kilogram 
KR 
Kenward-Roger 
L 
liter 
λz 
terminal elimination phase rate constant 
LDL-C 
low density lipoprotein cholesterol 
LLN 
lower limit of normal 
LS 
least square 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minute 


 
Statistical Analysis Plan 
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Abbreviation 
Term 
mL 
milliliter 
msec 
millisecond 
Na 
sodium 
NCA 
non compartmental analysis 
NTR 
not treatment related, includes unrelated 
OHA 
oral hypoglycemic agent 
OTC 
over the counter 
PCS 
potentially clinically significant 
PD 
pharmacodynamic 
PE 
physical examination 
PK 
pharmacokinetic 
PR 
The period that extends from the beginning of the P wave (the onset of atrial 
depolarization) until the beginning of the QRS complex (the onset of ventricular 
depolarization). 
PT 
preferred term 
QA 
quality assurance 
QC 
quality control 
QRS 
The combination of three of the graphical deflections seen on a typical 
electrocardiogram. 
QT 
Time from electrocardiogram Q wave to the end of the T wave corresponding to 
the electrical system 
QTcB 
QT corrected using Bazetts formula [QT/(RR1/2)] 
RBC 
red blood cell (count) 
REML 
restricted maximum likelihood 
RR interval 
intra-beat interval  
SAE 
serious adverse event 
SAP 
statistical analysis plan 


 
Statistical Analysis Plan 
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Last Revision Date: 26-Jul-2017
 
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Abbreviation 
Term 
SAS 
statistical analysis software 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
T½ 
apparent terminal elimination half-life 
TC 
total cholesterol 
TEAE 
treatment emergent adverse event 
TG 
triglycerides 
Tlast 
time of last measurable (positive) concentration 
TLF 
table, listing, figure 
Tmax 
time of maximum observed plasma concentration 
TR 
Treatment related - includes definitely, probably, possibly, and not likely related 
T-wave 
repolarization of the ventricles 
UGE 
urine glucose excretion 
ULN 
upper limit of normal (value) 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell (count) 
WHO-DD 
World Health Organization Drug Dictionary 


 
Statistical Analysis Plan 
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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 version 1.0 dated 19-Apr-2017. 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 12-JUN-2017. 
The SAP details the analysis of the data collected in the study and the presentation of the results of the 
analyses. The table, listing, and figure (TLF) shells are displayed in a companion document which 
provides information on the layout of the data displays. 
All statistical analyses will be performed using SAS® version 9.4. Adverse events will be coded using the 
latest version of the Medical Dictionary for Regulatory Activities (MedDRA version 20.0 or newer). 
This is a phase 1, single-center, open-label, randomized, two-period, two-treatment crossover study to 
assess the effects of exenatide injection on the pharmacokinetics (PK) and pharmacodynamics (PD) of 
bexagliflozin in healthy subjects. A total of 20 eligible healthy subjects will be enrolled and assigned to 
one of the two groups, with up to 10 subjects per group. Each group will receive both the treatments 
alternatively, 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 in Group 1 will receive a single oral dose of bexagliflozin tablets, 20 mg, 
alone 30 min before breakfast, and subjects in Group 2 will receive a subcutaneous injection dose of 
exenatide at 10 µg twice a day (bid) with initial dosing 30 min prior to a single oral dose of bexagliflozin 
tablets, 20 mg, and 1 h before breakfast and followed by a second dosing of exenatide alone 1 h prior to 
evening meals. In Treatment Period 2, subjects in Group 1 will receive a subcutaneous  injection dose of 
exenatide at 10 µg bid with initial dosing 30 min prior to a single oral dose of bexagliflozin tablets, 20 
mg, and 1 hr before breakfast and followed by the second dosing of exenatide alone 1 h prior to evening 
meals and subjects in Group 2 will receive a single oral dose of bexagliflozin tablets, 20 mg, alone 30 min 
before breakfast. 
 (See Protocol Sections 3.1 to 3.3 for additional details). 
2. STUDY OBJECTIVES 
2.1 Primary Objective 
To evaluate the effect of exenatide injection on the PK and PD of bexagliflozin tablets. 
2.2 Secondary Objectives 
To assess the safety and tolerability of bexagliflozin tablets when administered in combination with 
exenatide injection. 


 
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3. STUDY DESIGN 
3.1 Study Design 
This single center, phase 1, open-label, 2 x 2 crossover study is designed to assess the effects of exenatide 
injection on the PK and PD of orally administered bexagliflozin tablets. Approximately 20 eligible 
healthy subjects will be randomly assigned to one of the two groups (1 or 2) with up to 10 subjects per 
group. Each group will receive both the 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 in Group 1 will receive a single oral dose of bexagliflozin tablets, 20 mg, 
alone 30 min before breakfast, and subjects in Group 2 will receive subcutaneous injection dose of 
exenatide at 10 µg bid with initial dosing 30 min prior to a single oral dose of bexagliflozin tablets, 20 
mg, and 1 h before breakfast and followed by the second dosing of exenatide alone 1 h prior to evening 
meals. In Treatment Period 2, subjects in Group 1 will receive subcutaneous injection dose of exenatide at 
10 µg bid with initial dosing 30 min prior to a single oral dose of bexagliflozin tablets, 20 mg, and 1 h 
before breakfast and followed by a second dosing of exenatide alone 1 h prior to evening meals and 
subjects in Group 2 will receive a single oral dose of bexagliflozin tablets, 20 mg, alone 30 min before 
breakfast. 
Clinical laboratory tests and safety monitoring will be conducted during both treatment periods. 
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 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 
24, 36, and 48 h post-dose of bexagliflozin. 
Urine samples for PD analysis will be collected in each period in 12 h batches at pre-dose (-12 to 0), and 
at post-dose of bexagliflozin at 0 to 12 h, 12 to 24 hr, 24 to 36 h, and 36 to 48 h. 
3.2 Randomization 
A total of 20 healthy subjects will be enrolled and 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 is not 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 
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 drug-drug interactions, 
and to provide safety and tolerability data on bexagliflozin when administered with exenatide. 


 
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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 -21 to -1 
D
 
0 
D1 
pre-
dose 
D1 
post-
dose 
D
2 
D3 
D7 
D8 
pre-
dose 
D8 
post-
dose 
D
9 
D10 
Medical history and ICF 
X 
 
 
 
 
 
 
 
 
 
 
Screening for I/E criteria 
X 
X
 
 
 
 
X 
 
 
 
 
Physical exam1 
X 
X
 
 
 
X 
X 
 
 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X
 
 
 
 
 
 
 
 
 
Admission and discharge 
 
X
 
 
 
X 
X 
 
 
 
X 
Vital signs2 
X 
X
X 
X 
 
X 
X 
X 
X 
 
X 
ECG3 
X 
X
X 
X 
 
 
X 
X 
X 
 
X 
Urinalysis4 
X 
X
 
 
 
X 
X 
 
 
 
X 
Blood draw for clinical lab 
tests5 
X 
X
 
 
 
X 
X 
 
 
 
X 
Blood sample for PK6 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urine collection7 
 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test  
X 
X
 
 
 
 
X 
 
 
 
 
Adverse event and 
concomitant medication 
 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study termination 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: D = day; ECG = electrocardiogram; I/E = inclusion/exclusion; PD = pharmacodynamic; PK = pharmacokinetic. 
1. 
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 day10 prior to discharge. A partial PE will 
be performed on days 0, 3 and 7. 
2. 
Vital signs include: pulse, body temperature, respiratory rate, systolic and diastolic blood pressure. Vital signs will be 
recorded at screening, on days 0, 1 (predose, 4 h postdose), 3 (48 h postdose), 7, 8 (predose, 4 h postdose), and 10 (48 
h postdose), and when clinically indicated. 
3. 
12-lead ECG will be conducted after 10 min resting. ECG data will be recorded at screening, on days 0, 1 (predose, 4 
h postdose), 7, 8 (predose, 4 h postdose), and 10 (48 h postdose), and when clinically indicated. 
4. 
Urine samples will be collected at screening, on days 0, 7 and prior to discharge in each period. 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 and on day 7. If drug screening is conducted more than 5 days prior to 
dosing, screening shall be repeated.  
5. 
Blood sample at the designated visits (screening, on days 0, 3, 7 and 10 for clinical chemistry and hematology 
parameters are listed in Table 2.  Blood will be drawn after 10 h of fasting prior to breakfast (i.e. only water is 
allowed, no caloric intake).   
6. 
Plasma samples for PK profile of bexagliflozin will be collected at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 
24, 36, and 48 h post-dose. 
7. 
Urine  for urinary glucose (PD) and creatinine will be collected at  pre-dose (h -12 to 0), 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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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 and PD Populations 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. Subjects will be analyzed according to the 
treatment received. 
5.3 Pharmacodynamic Population 
The PD Population will include all randomized subjects who receive study drug and have had 0-12 hr and 
12 to 24 hr urine collection from which to calculate 24-hour UGE  following dosing. The PD Population 
will be used to summarize the PD parameters. Subjects will be analyzed according to the treatment 
received. 
6. SPECIFICATION OF ENDPOINTS AND VARIABLES 
6.1 Demographic and Baseline Characteristics 
Demographic variables consist of the following: 
 
Age in years (continuous) derived as the integer value of  
(informed consent date – date of birth + 1)/365.25 
 
Sex 
 
Race 
 
Ethnicity 
Baseline characteristics consist of the following: 
 
Body mass index (BMI) 


 
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 
Weight (kg) 
 
Height (cm) 
 
Vital signs 
o systolic blood pressure (SBP, mmHg) 
o diastolic blood pressure (DBP, mmHg) 
o oral temperature (oC) 
o pulse (beats per minute) 
o respiration rate  
 
 
Electrocardiogram (ECG) parameters 
o RR interval (msec) 
o PR interval (msec) 
o QRS duration (msec) 
o QT interval (msec) 
o QTcF interval (msec) 
 
Medical history and baseline conditions 
 
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 
 
 
Time Windows for Safety Assessments 
Scheduled Visit Number 
Visit (label) 
Time Interval (day) 
Target Time Point (day) 
1 
Screening 
-21 to -1 
-21 to -1 
2 
Day 0 
0 
0 
3 
Day 1 
1 
1 
4 
Day 2 
2 
2 
5 
Day 3 
3-5 
3 
6 
Day 7 
7 
7 
7 
Day 8 
8 
8 
8 
Day 9 
9 
9 
9 
Day 10 
10-12 
10 


 
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Data obtained during unscheduled visits will be allocated to the scheduled visit corresponding to the visit 
window they fall in as specified in Section 6.1.1. Safety data obtained during unscheduled time points will 
be allocated to the scheduled time point corresponding to the time window in which they fall. Data will be 
analyzed based on the nominal visits and nominal time points. If the data from the nominal visit or time 
point is missing, data from unscheduled visits for the same nominal visit or time point will be used. If 
multiple unscheduled assessments fall in the same visit window or time point, the non-missing assessment 
closest to target time point will be selected for analysis. 
6.2 Pharmacokinetics/Pharmacodynamics 
Pharmacokinetic/pharmacodynamic analysis will be performed on the PK and PD Populations respectively 
Plasma samples will be analyzed for bexagliflozin concentrations using a validated method. 
Blood samples for PK analysis will be collected in each period at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 
12, 16, 24, 36, and 48 h post dose.  
Urine samples for PD analysis will be collected in 12 hr intervals. 
Urine collection in 12 h batches will be performed at pre-dose (-12 to 0 h), and post-dose at  
0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h.  
6.3 Safety 
Safety analysis will be performed on the Safety Population. 
The safety profile of bexagliflozin will be assessed through the recording, reporting, and analyzing of 
adverse events, clinical evaluations, and laboratory tests. 
Safety variables include the following: 
1. Adverse events 
2. Clinical laboratory measurements – serum chemistry, hematology, and urinalysis 
3. Urine drug screen 
4. Vital signs 
5. ECG 
6. Physical examination 
7. Pregnancy test 
8. Concomitant medications/treatments 
6.3.1 Study Day and Visit Window Definitions 
Refer to section 6.1.1 for details. 
6.3.2 Extent of Exposure to Study Medication 
Subjects who gave consent to participate in the study will be randomly assigned to 1 of the 2 groups. 
Subjects in each group will be randomly assigned to receive 1 of 2 treatment regimens in a crossover 
fashion with 2 treatment periods separated by a washout period of at least 7 days. Refer to Table 1 under 
Section 3.6. 
In order to observe the maximal potential effect of exenatide on the absorption rate of bexagliflozin, 
bexagliflozin will be administered orally 30 min after subcutaneous exenatide injection, at 10 µg bid (the 
highest dose approved for use in the United States), meanwhile, the highest dose used (10 µg bid exenatide 


 
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injection in the United States) or intended to be used (20 mg bexagliflozin tablets) clinically will be 
selected. 
6.3.3 Adverse Events (AEs) 
Adverse events will be collected and coded using version 20.0 (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 second dose, the AE(s) will be assigned to the first treatment. If the 
AE(s) onset date-time or date occurs after the second dose, the AE(s) 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. 
6.3.3.1 Treatment-Emergent AE (TEAE) 
An adverse event is considered treatment-emergent if it occurs after bexagliflozin and/or exenatide 
administration and 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) 
An IRAE is any serious adverse event or any adverse event that necessitates discontinuation of the study 
drug. 
6.3.3.4 Adverse Events Counting Rules 
1. A subject with more than one different AE in a particular system organ class (SOC) will be counted 
only once in the total of subjects experiencing adverse events in that particular SOC. 
2. A subject having experienced the same event (AE preferred term) more than once during the study 
will be counted only once in the number of subjects with that event. 
3. A subject having experienced the same event (AE preferred term) more than once during the study 
with a different severity or seriousness, it will be counted only once with the worst grade and 
seriousness respectively. 
4. A subject having experienced the same event (AE preferred term) more than once during the study 
with a different causal relationship to the study drug, it will be counted only once by considering 
the most-related documented degree of relationship. 
6.3.3.5 AE Severity 
Adverse events will be graded on a 3-point scale and reported as indicated on the case report form (CRF). 
The intensity of an adverse experience will be graded as “Mild”, “Moderate”, and “Severe” using the 
criteria specified in Section 6.9 of the study protocol. 


 
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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 
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 is 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 listings regardless the completeness of the onset dates. 
6.3.4 Laboratory Data 
Clinical laboratory tests on hematology, serum chemistry, electrolytes, and lipids and urinalysis will be 
performed according to the schedule in Section 3.6. Investigators will assess whether there are any 
clinically significant abnormalities and record the abnormality on medical history or AE forms. 
Conversion to the International System of Units 
All laboratory data will be stored in the database with the units in which they are originally reported.  
Laboratory data in summary tables and subject data listings will be presented in the International System of 
Units (SI units; Système International d’Unités).  Laboratory data not reported in SI units will be converted 
to SI units before further processing or data analysis. 
Abnormal Values 
Based upon laboratory normal ranges, laboratory test results will be categorized according to the normal 
range as low, normal and high. Subjects with laboratory data outside the normal range will be listed with 
abnormal values flagged. 


 
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Table 3 Clinical Laboratory Tests 
Hematology 
Hematocrit (Hct) 
Mean corpuscular volume (MCV) 
Hemoglobin (Hgb) 
Platelet count 
Mean corpuscular hemoglobin (MCH) 
Red blood cell (RBC) count 
Mean corpuscular hemoglobin concentration (MCHC) 
White blood cell (WBC) count with differential 
Serum Chemistry, Electrolytes, and Lipids 
Albumin (ALB) 
Calcium (Ca) 
Alanine aminotransferase (ALT) 
Magnesium 
Aspartate aminotransferase (AST) 
Phosphorus 
Blood urea nitrogen (BUN) 
Potassium (K) 
Glucose 
Sodium (Na) 
Total carbon dioxide 
Total bilirubin 
Creatinine  
Direct bilirubin 
Chloride (Cl) 
Uric acid 
Total protein 
Low-density lipoprotein cholesterol (LDL-C), calculated 
Total cholesterol (TC) 
 
High-density lipoprotein cholesterol (HDL-C) 
 
Triglycerides (TG) 
 
Urinalysis 
Appearance 
Nitrite 
Bilirubin 
pH 
Color 
Protein 
Glucose 
Specific gravity 
Ketones 
Urobilinogen 
Microscopic examination of sediment 
Leukocyte esterase 
Occult blood 
 
Urine Collection 
Glucose 
Creatinine 
Urine Drug Screen 


 
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Amphetamines 
Opiates 
Barbiturates 
Benzodiazepines 
Cocaine Metabolites 
Cannabinoids 
Cotinine 
 
Pregnancy Test 
Infectious Disease Testing 
Hepatitis B Surface Antigen (HbsAg) 
Hepatitis C virus (HCV) 
HIV 
 
6.3.5 Vital Signs 
Vital signs include pulse (beats/min), SBP and DBP (mmHg), oral temperature (oC) and respiration rate 
(breaths/min). 
Vital sign changes from baseline will be summarized by treatment. 
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. 


 
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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.  
6.3.9 Concomitant Medications/Treatments 
Concomitant medications administered at the time of randomization and during the study will be recorded 
on the CRF. The medication name, indication, dose, unit, frequency, route of administration, date(s) of 
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 other than the investigational product that the 
subject takes during the course of the trial. All prescription and over-the-counter (OTC) medications (non-
prescription drugs), including vitamins and herbal supplements, that subjects receive during the trial must 
be documented on the CRF. This documentation will continue until the subjects are discharged. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary (WHO-DD). 
All prior and concomitant medication will be presented in individual subject data listings. 
For medications with incomplete dates, imputation will be used to convert to a complete date. Imputed 
dates will be used to determine Study Day. 
Partial medication start dates will be imputed as follows:  
1. Only the year is reported: If the subject started to receive study drug in the year reported, then the 
date of the first dose of study drug will be used as the starting date of the medication. Otherwise, 
January 1 will be used as the start of the medication. 
2. The month and year is reported: If the subject started to receive study drug during the month and 
year reported, then the date of first dose of study drug will be used as the starting date of the 
medication. Otherwise, the first day of the month will be used as the start of the medication. 
Partial medication end dates will be imputed for non-ongoing medications as follows: 
1. Only the year is reported: If the subject stopped to receive study drug in the year reported, then the 
date of the last dose of study drug will be used as the end date of the medication. Otherwise, 
December 31 will be used as the end of the medication. 
2. The month and year is reported: If the subject stopped to receive study drug during the month and 
year reported, then the date of last dose of study drug will be used as the end date of the medication. 
Otherwise, the last day of the month will be used as the end of the medication. 
The above rules are subject to logical sense, for example, imputed start date should be on or prior to 
imputed end date. 
Verbatim terms will be coded and assigned a preferred (PT) term and an ATC (anatomic therapeutic class) 
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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 concentration-time data, the following PK parameters will be estimated for each subject 
where feasible. 
Table 7.  Pharmacokinetic Parameters 
Pharmacokinetic Parameters 
Cmax 
Maximum observed plasma concentration 
Tmax 
Time of maximum observed plasma concentration 
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: 


 
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AUC0-∞= AUClast + (Clast / λz), where Clast is the last temporal quantifiable plasma concentration 
corresponding to Tlast. 
The proportion of AUC0-∞ due to extrapolation (AUCextr) will be calculated and expressed as a percentage. 
AUC0-∞ values will be considered unreliable estimates if the AUCextr is greater than 20% and will be 
excluded from summary tables but will be listed. 
CL/F will be calculated as Dose/AUC0-∞. 
Vz/F will be calculated as Dose/(λz × AUC0-∞). 
T½ will be calculated as 0.693/λz. 
Descriptive statistics for the plasma concentrations of bexagliflozin by Treatment and Timepoint will be 
provided. Listings of plasma concentrations by Subject Number, Treatment Sequence/Treatment, Period, 
and Timepoint will also be provided. 
To assess the effect of co-administration of exenatide 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 ratio of the least squares (LS) geometric means of PK parameters (Cmax, AUC0-t 
and AUC0-∞), when bexagliflozin is dosed in combination with exenatide versus when dosed alone, 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 by Subject Number, Treatment Period, and Treatment will be provided. 
Refer to Appendix 2 for the SAS code. 
7.3 Pharmacodynamic Analyses 
Urinary glucose excretion will be determined as a PD parameter at baseline and up to 48 hours.  
Descriptive statistics of glucose concentrations, creatinine concentrations, UGE, and urinary 
glucose/urinary creatinine 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. 


 
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The PD parameters, UGE and UGE normalized by urinary creatinine, including UGEt1-t2, in 12 hour and 24 
hour increments, and total 24-hour and 48-hour UGE, will be determined. UGEt1-t2 (g) will be derived from 
urine volume (Vt1-t2, mL) x glucose concentration (mg/dL)/100/1000. 
UGE normalized by urinary creatinine will be derived by dividing the UGE for each interval by the 
corresponding urinary creatinine concentration. 
8. STATISTICAL ANALYSIS 
8.1 General Data Handling Rules and Definitions 
All data collected on CRFs will be provided in listings, except data collected only for confirmation of study 
entry criteria and for study administrative purposes. If any randomized subject is found to be without valid 
documented informed consent, that subject’s data will be excluded from the report, except as necessary to 
document the error. 
All statistical analyses will be conducted using SAS version 9.4 or newer. 
Except where specified, all continuous variables will be summarized with descriptive statistics (the number 
of non-missing values, mean, standard deviation, median, minimum and maximum) and all categorical 
variables will be summarized with frequency counts and percentages, by treatment and treatment group. 
Unless otherwise specified, the mean and median will be displayed to 1 more decimal place than the 
original data, and standard deviation will be displayed to two more decimal places than the original data. 
All frequencies will be rounded to 1 decimal place. 
Missing data will be maintained as missing unless specified otherwise.  For variables where missing data is 
imputed, the analysis dataset will contain one variable with the imputed value and the original variable with 
missing maintained as missing. 
8.2 Subject Disposition 
An overall disposition table for all subjects will be presented. This tabulation will include the number of 
subjects randomized, treated, completed, and those who discontinued early from the study. The number and 
percentage of randomized subjects who are included in the PK, Safety and PD Populations will also be 
tabulated. 
Subject disposition by treatment, and treatment sequence, will also be summarized. These tabulations will 
include the number of subjects dosed, completed, and those who discontinued early from the study along 
with the corresponding primary reasons for early termination. 
Subjects in the Safety Population who prematurely discontinued from the study will be summarized by 
primary reason for early termination. 
Subject disposition will be listed for all subjects in the Safety Population. 
8.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment, and by treatment sequence, for 
both the Safety and PK Populations and listed. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be presented for 
continuous variables. Frequency distributions (counts and percentages) will be presented for categorical 
variables. 


 
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Medical history and baseline conditions will be summarized by treatment sequence and listed. Physical 
examination, as well as prior and concomitant medications, will also be listed. Prior and concomitant 
medications will be listed with the drug names and ATC classification codes based on the data collected in 
the eCRF. The World Health Organization (WHO) Drug Dictionary, version March 2016 or newer, will be 
used to classify prior and concomitant medications by therapeutic class and drug name. 
Abnormalities in the subjects’ medical and surgical histories will be coded using version 20.0 
(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. 
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. 


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


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


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


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


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