Clinical trial NCT03557658
Conditions: Type2 Diabetes Mellitus
Sponsor: Theracos
Start date: 2018-07-26; Completion date: 2018-12-26
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine the drug exposure and drug effects on subjects with moderate hepatic impairment after a single oral dose of bexagliflozin tablets, 20mg. The study will also evaluate how safe the study drug is and how well the study drug is tolerated in subjects with moderate hepatic impairment.

Detailed description:
This was a Phase 1, open-label, parallel-group study designed to assess the effect of moderate hepatic impairment on the PK and PD of orally administered bexagliflozin tablets. A total of 16 subjects comprising eight with moderate hepatic impairment (Child Pugh total score 7 to 9) and eight healthy, matched controls, were enrolled and received a single oral dose of bexagliflozin tablets, 20 mg, after an overnight fast. Food was withheld for at least 2 h after dosing. Water was allowed as desired except within 1 h of drug administration.

Blood samples were collected prior to dosing, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose.

The unbound fraction of bexagliflozin at 24 h post dose and at the maximum plasma concentration for each subject was determined by equilibrium dialysis.

Urine samples for PD analysis were collected for the 12 h interval preceding dosing and for the 0 - 12 h, 12 - 24 h, 24 - 36 h, and 36 - 48 h intervals following dosing.

Arms: arm 1: Subjects with hepatic impairment conforming to the Child-Pugh class B (total score 7-9) arm 2: Subjects with normal hepatic function
Interventions: intervention 1: Bexagliflozin
Intervention descriptions: intervention 1: Single oral dose of bexagliflozin tablet, 20 mg

Protocol documents:
Prot_000.pdf: 
 
 
Clinical Trial Protocol: THR-1442-C-455 
Study Title: 
A Phase 1, Open-label, Parallel-group Study to Evaluate the Effect of 
Moderate Hepatic Impairment on the Pharmacokinetics and 
Pharmacodynamics of Bexagliflozin 
Study Number: 
THR-1442-C-455 
Study Phase: 
1 
Product Name: 
Bexagliflozin tablets 
Sponsor: 
Theracos Sub, LLC 
Sponsor Study 
Representative: 
Xiao-Yan Li, Ph.D. 
185 Cambridge Street, Boston, MA 02114 
Phone: 617-726-7960, Fax: 617-643-8203 
e-mail: xli@ccib.mgh.harvard.edu 
 
Medical Monitor: 
J. Paul Lock, M.D. 
225 Cedar Hill Street, Suite 200, Marlborough, MA 01752 
Phone: 508-735-9491, Fax: 617-643-8203 
e-mail: jplock@theracos.com 
 
 
 
Date 
Protocol V1.1: 
29 May 2018 
Protocol V2.0 
02 August 2018 
Protocol V3.0 
21 August 2018 
 
 
Confidentiality Statement 
The information in this document is confidential and must not be disclosed, used, or copied 
except with prior written approval from Theracos Sub, LLC or to the extent required by 
applicable local, state or federal laws, rules and regulations 
 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................5 
SUMMARY OF CHANGES .....................................................................................................8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................9 
1 
INTRODUCTION ...........................................................................................................11 
1.1 
Summary of Nonclinical Data for Bexagliflozin ...................................................12 
1.2 
Summary of Clinical Data for Bexagliflozin .........................................................13 
2 
STUDY OBJECTIVES ....................................................................................................15 
2.1 
Primary Objective ..................................................................................................15 
2.2 
Secondary Objective ..............................................................................................15 
3 
INVESTIGATIONAL PLAN ..........................................................................................16 
3.1 
Overall Study Design and Plan ..............................................................................16 
3.2 
Rationale for Study Design and Control Group .....................................................16 
3.2.1 
Rationale for Study Design ..........................................................................16 
3.2.2 
Rationale for Dose Selection .......................................................................17 
3.2.3 
Rationale for PK and PD Sampling Time Points .........................................17 
3.3 
Study Duration and Dates ......................................................................................17 
4 
STUDY POPULATION SELECTION ...........................................................................18 
4.1 
Study Population ....................................................................................................18 
4.2 
Inclusion Criteria ...................................................................................................18 
5 
STUDY TREATMENTS .................................................................................................21 
5.1 
Study Drug .............................................................................................................21 
5.2 
Treatments Administered .......................................................................................21 
5.3 
Selection and Timing of Dose for Each Subject ....................................................21 
5.4 
Method of Assigning Subjects to Treatment Groups and Sequences ....................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 
5.10 
Storage and Accountability ....................................................................................23 
6 
STUDY PROCEDURES .................................................................................................24 
6.1 
Informed Consent...................................................................................................24 
6.2 
Medical History .....................................................................................................24 


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6.3 
Physical Examination.............................................................................................25 
6.4 
Vital Signs ..............................................................................................................25 
6.5 
Electrocardiography ...............................................................................................25 
6.6 
Clinical Laboratory Tests .......................................................................................26 
6.6.1 
Laboratory Parameters .................................................................................26 
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 .....................................................................27 
6.6.2.4 
Plasma Sample Collection for PK......................................................28 
6.6.3 
Blood Volume and Frequency for PK and Safety Assessment....................28 
6.7 
Adverse Events Assessments .................................................................................28 
6.7.1 
Collecting and Reporting Adverse Events ...................................................30 
6.7.2 
Immediately Reportable Adverse Events .....................................................30 
6.7.3 
Follow-up of Adverse Events ......................................................................31 
6.7.3.1 
Follow-up of Non-serious Adverse Events ........................................31 
6.7.3.2 
Follow-up of Post-Study Serious Adverse Events .............................31 
6.7.3.3 
Hepatotoxicity ....................................................................................31 
6.7.3.4 
Hypoglycemia ....................................................................................32 
6.8 
Concomitant Medication Assessments ..................................................................32 
6.9 
Removal of Subjects from the Trial .......................................................................33 
6.10 
Appropriateness of Measurements .........................................................................34 
7 
STUDY ACTIVITIES .....................................................................................................35 
7.1 
Study Screening (Day -28 to Day -1) ....................................................................35 
7.2 
Day 0 (D0) (Clinic Admission) ..............................................................................35 
7.3 
Day 1 (D1) (Dosing Day): Predose ........................................................................36 
7.4 
Day 1 (D1) Dosing .................................................................................................36 
7.5 
Day 1 (D1) Postdose ..............................................................................................36 
7.6 
Day 2 (D2) .............................................................................................................37 
7.7 
Day 3 (D3) .............................................................................................................37 
7.8 
Day 15 (D15) ± 1 day Activities ............................................................................37 
7.9 
Early Termination Procedures ...............................................................................38 
8 
QUALITY CONTROL AND ASSURANCE .................................................................39 
9 
PLANNED STATISTICAL METHODS ........................................................................40 
9.1 
General Considerations ..........................................................................................40 
9.2 
Determination of Sample Size ...............................................................................40 
9.3 
Analysis Populations ..............................................................................................40 
9.3.1 
Safety Population .........................................................................................40 
9.3.2 
PK Population ..............................................................................................40 


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9.3.3 
PD Population ..............................................................................................40 
9.4 
Demographics and Baseline Characteristics ..........................................................40 
9.5 
Pharmacokinetic Analysis ......................................................................................40 
9.5.1 
Calculation of Pharmacokinetic Variables ...................................................40 
9.5.2 
Statistical Analysis of Pharmacokinetic Variables ......................................42 
9.6 
Pharmacodynamic Analysis ...................................................................................42 
9.7 
Safety Analysis ......................................................................................................42 
9.7.1 
Adverse Events ............................................................................................43 
9.7.2 
Hypoglycemia ..............................................................................................43 
9.7.3 
Clinical and Laboratory Events and Analyses .............................................43 
9.7.4 
Concomitant Medications ............................................................................44 
10  ADMINISTRATIVE CONSIDERATIONS ....................................................................45 
10.1 
Investigators and Study Administrative Structure .................................................45 
10.2 
Institutional Review Board (IRB) Approval ..........................................................45 
10.3 
Ethical Conduct of the Study .................................................................................45 
10.4 
Subject Information and Consent...........................................................................46 
10.5 
Subject Confidentiality ..........................................................................................46 
10.6 
Study Monitoring ...................................................................................................46 
10.7 
Case Report Forms and Study Records .................................................................47 
10.8 
Protocol Violations/Deviations ..............................................................................47 
10.9 
Access to Source Documentation ..........................................................................47 
10.10  Retention of Data ...................................................................................................48 
10.11  Publication and Disclosure Policy .........................................................................48 
11  REFERENCES ................................................................................................................49 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Required Laboratory Tests .........................................................................26 
Table 2. 
Blood Samples ...........................................................................................28 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .....................................................................................50 
Appendix 2 
The Child-Pugh Classification ...................................................................51 
Appendix 3 
Sponsor Signatures.....................................................................................52 
Appendix 4 
Investigator’s Signature .............................................................................53 
 


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SYNOPSIS 
Sponsor: Theracos Sub, LLC 
Name of Finished Product: Bexagliflozin tablets, 20 mg 
Name of Active Ingredient: Bexagliflozin 
Name of Inactive Ingredient: 
Polyethylene oxide, glyceryl behenate, lactose monohydrate, micronized poloxamer, 
microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate 
Study Title: 
A Phase 1, Open-label, Parallel-group Study to Evaluate the Effect of Moderate Hepatic 
Impairment on the Pharmacokinetics and Pharmacodynamics of Bexagliflozin 
Study Number:THR-1442-C-455 
Study Phase: 1 
Primary Objective:  
• 
To evaluate the effect of moderate hepatic impairment on the pharmacokinetics (PK) 
and pharmacodynamics (PD) of a single oral dose of bexagliflozin tablets, 20 mg   
Secondary Objective: 
• 
To assess the safety and tolerability of bexagliflozin in subjects with moderate hepatic 
impairment 
 
Study Design: 
This is a phase 1, open-label, parallel-group study designed to assess the effects of 
moderate hepatic impairment on the PK and PD of orally administered bexagliflozin 
tablets, 20 mg. Approximately 16 subjects (eight with moderate hepatic impairment 
[Child-Pugh total score 7-9] and eight healthy, matched controls) will receive a single 
oral dose of bexagliflozin tablet, 20 mg.  
Clinical laboratory tests and safety monitoring will be conducted during the treatment 
period and follow-up visit.  
Blood samples for plasma concentrations of bexagliflozin will be collected at predose 
and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h postdose. 
Urine samples for PD analysis will be collected predose and in the following intervals 
after dosing: 0–12, 12–24, 24–36, and 36–48 h. 
Plasma concentrations of bexagliflozin will be determined by validated liquid 
chromatography-mass spectrometry (LC-MS/MS) assays. 
The unbound fraction of bexagliflozin will be determined at 24 h postdose and 
maximum plasma concentration for each subject by equilibrium dialysis. 


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For the schedule of events, see Appendix 1.  
Study Population:  
Approximately 16 subjects (eight with moderate hepatic impairment [Child-Pugh total 
score 7-9] and eight healthy, matched controls) are planned to be enrolled. 
Eligible Subjects: 
Prospective subjects must: 
1. Be male or female adults between the age of 18 to 75 years (inclusive) at screening 
2. Have a body-mass index (BMI) of 18.0 - 40.0 kg m-2 (inclusive) at screening 
3. Have adequate venous access at multiple sites in both arms 
4. Be willing and able to be confined to the clinical research facility as required by the 
protocol 
5. Be able to comprehend the explanation of the informed consent and be willing to 
provide written informed consent in accordance with institutional and regulatory 
guidelines 
6. Be diagnosed with moderate hepatic impairment with a Child-Pugh score 7 to 9 
(classification in Appendix 2) and must be in stable general health apart from hepatic 
impairment and its related conditions (for subjects in the hepatic impairment 
group only)  
7. Be in general good health with matching demographics and baseline characteristics 
to individual subjects in the hepatic impairment group by age (±10 years), weight 
(±10%), sex, and smoking status (for subjects in the healthy control group only) 
8. Have no evidence of an active infection or be receiving any treatment with 
antibiotics at the time of screening (for subjects in the healthy control group only) 
 
 
Duration of Treatment:  
This is a single dose study. Selection and enrollment of study subjects will begin with 
those designated for the hepatic impairment group. A screening visit will be completed 2 
to 28 days prior to study drug administration. Subjects will be admitted to the clinic the 
day before administration of the investigational product and will remain in the clinic for 
at least 48 h following administration. Subjects will return for an end-of-study 
examination within 13 days of the last pharmacokinetic sample collection. Each subject 
from the hepatic impairment group will be matched to a healthy comparator subject. 
For details of the schedule and nature of the investigations, see the Schedule of Events in 
Appendix 1. 
Pharmacokinetics Variables: 
The following PK parameters for bexagliflozin will be determined: 
Cmax 
 Maximum observed plasma concentration 


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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 
AUC0-24 
 Area under the plasma concentration-time curve from the time of dosing to 
24 h postdose 
AUC0-t  Area under the plasma concentration-time curve from the time of dosing to the 
time of last quantifiable plasma concentration 
AUC0-∞ Extrapolated area under the plasma concentration-time curve from the time of 
dosing to infinity  
AUCextr  % of AUC0-∞ due to extrapolation from tlast to infinity 
fu        Unbound fraction, calculated as (free drug concentration)/(total drug concentration) 
Cmax, u  Maximum unbound plasma concentration  
AUCu  Area under the unbound plasma concentration-time curve  
Clu/F Apparent clearance relative to the unbound drug concentration  
Pharmacodynamics Assessments: 
PD parameters will be assessed before dosing and at the end of the treatment period.   
The PD parameters will include: 
• 
Urine glucose concentrations 
• 
Creatine concentrations 
• 
UGE 
• 
Urinary glucose normalized by creatinine. 
Safety Assessments: 
Physical examinations (PE) 
• 
Vital signs (VS) 
• 
12-lead electrocardiograms (ECG) 
• 
Clinical laboratory tests including blood chemistry and hematology parameters 
• 
Urinalyses 
• 
Adverse events (AEs) 
• 
Concomitant medication (CM) use 
 
Statistical Methods:  
Statistical analysis will be performed using Statistical Analysis Software SAS for 
Windows® (SAS Institute Inc., USA). PK parameters for bexagliflozin will be calculated 
using non-compartmental analyses (NCA) of plasma concentration-time data. An 
analyses of variance (ANOVA) with a fixed effect corresponding to the hepatic function 
group will be fitted to the natural logarithmic transformation of the PK parameters (Cmax, 
AUC0-t and AUC0-∞). The 90% confidence intervals will be constructed for the ratio of 
geometric means of PK parameters (total and unbound Cmax, AUC0-t and AUC0-∞). The 


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apparent clearance relative to the unbound drug concentration (Clu/F) will be calculated 
as Clu/F = Dose/AUCu. 
Descriptive statistics of plasma concentration-time data will be summarized by hepatic 
function group and timepoint. 
The PK parameters Cmax, Tmax, λz, t1/2, CL/F, Vz/F. AUC0-t, AUC0-∞, AUCextr, AUCu(0-t) 
and AUCu(0-∞) will be summarized by hepatic function group. Means, standard 
deviations, medians, ranges (min, max) and geometric means and coefficients of 
variation will be presented for all parameters will the exception of Tmax. Medians and 
ranges will be presented for Tmax. 
The amount of UGE, and urinary glucose normalized by urinary creatinine will be 
calculated. Descriptive statistics will be used to describe any differences in these PD 
parameters between hepatic function groups. 
Date of Version 1.1: 29 May 2018 
Date of Version 2.0: 02 August 2018 
Date of Version 3.0: 21 August 2018 
 
 
SUMMARY OF CHANGES 
Location 
Modification 
Revision in Version 1.1 
4.3 Exclusion 
Criteria, 21, pg. 22 
A history of vitamin preparation… 
To. 
If destined for the healthy control group, a history of vitamin preparation… 
6.2 Medical 
History, pg. 26 
Medication history including prescription, OTC drugs, and vitamin preparation or 
supplement use (including St. John’s Wort and ginseng) within 7 days or 5 half-
lives of the drug, whichever is longer, prior to D0. 
Added. 
(for subjects in the healthy control group only) 
Appendix 1, pg. 51 
Table Footnote 
Correction in footnote 6 of: 
Plasma samples for PK profile of EGT0002149… 
To. Plasma samples for PK profile of bexagliflozin… 
 
 
Revision in Version 2.0 
4.3 Exclusion 
Criteria, page 22 
Exclusion criteria # 2, 7, 8, 9, 15, 17, 19, and 28 are revised to better represent the 
population with hepatic impairment. 
Revision in Version 3.0 
4.3 Exclusion 
criterion #7, page 
22 
Exclusion criterion #7 was changed from QTc > 500 ms to QTc > 480 ms (corrected 
by Bazett’s formula) 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
AUC 
area under the plasma concentration-time curve 
AUCextr 
% of AUC0-∞ due to extrapolation from tlast to infinity 
AUC0-24 
Area under the plasma concentration-time curve from the time of dosing to 24 h 
postdose 
AUC0-∞ 
Extrapolated area under the plasma concentration-time curve from the time of dosing to 
infinity 
AUC0-t 
   (AUClast) 
Area under the plasma concentration-time curve from the time of dosing to the time of 
last quantifiable plasma concentration  
AUCu 
area under the unbound plasma concentration-time curve  
BMI 
body mass index 
BLOQ 
below limit of quantification 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Cmax 
maximum observed plasma concentration 
Cmax,u 
maximum unbound plasma concentration 
Clast 
concentration corresponding to Tlast 
CL/F 
apparent oral clearance 
CLu 
apparent clearance relative to the unbound drug concentration  
CM 
concomitant medication 
CRF 
case report form 
CV 
coefficient of variation 
CYP 
cytochrome P450 
D0 
day zero 
ECG 
electrocardiogram 
EOS 
End of study 
eGFR 
estimated glomerular filtration rate 
FPG 
fasting plasma glucose 
fu 
unbound fraction 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IP 
investigational product 
INR 
International Normalized Ratio 
IRAE 
immediately reportable adverse event 


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IRB 
Institutional Review Board 
IR 
Immediate release 
λz 
terminal elimination phase rate constant 
MedDRA 
MDRD 
Medical Dictionary for Regulatory Activities 
modification of diet in renal disease study equation 
NCA 
non-compartmental analysis 
nUGE 
Normative UGE 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PE 
physical examination 
P-gp 
p-glycoprotein 
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 
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)] 
RR interval 
intra-beat interval 
SAE 
serious adverse event 
SAS 
statistical analysis software 
SD 
standard deviation 
SGLT1 
sodium glucose cotransporter 1 
SGLT2 
sodium glucose cotransporter 2 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment emergent adverse event 
t1/2 
terminal elimination half life 
tlast 
time of last measurable concentration 
Tmax 
time of maximum observed plasma concentration 
T2DM 
type 2 diabetes mellitus 
UGE 
urinary glucose excretion 
ULN 
upper limit of normal 
UGT 
uridine diphosphate glucuronosyltransferases 
UTI 
urinary tract infection 
Vz/F 
apparent volume of distribution 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 
 
 


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1 
INTRODUCTION 
Bexagliflozin is a potent and selective inhibitor of human sodium-glucose linked transporter 
2 (SGLT2). The clinical pharmacology of bexagliflozin is largely consistent with the 
expected consequences of SGLT2 inhibition. The primary pharmacodynamic effect is a 
glucosuria that increases with glomerular filtration rate and plasma glucose concentration. 
Effects secondary to diuresis, possible natriuresis, and caloric wasting, including reductions 
in blood pressure and body weight, have been observed. Consistent with clinical observations 
that individuals genetically deficient for SGLT2 are euglycemic and normotensive to slightly 
hypotensive, inhibition of SGLT2 function does not appear to confer a risk of hypoglycemia 
or of significant hypotension. Mild hemoconcentration associated with volume depletion 
attributed to the diuretic effect has been observed. Slight elevations in blood urea nitrogen 
(BUN) and creatinine, and corresponding inferred decreases in estimated glomerular 
filtration rate (eGFR), have typically accompanied the pharmacodynamic response and are 
considered to be consistent with diuresis and metabolic shifts favoring protein catabolism. 
Moderate reductions in plasma urate and small increases in LDL cholesterol concentration 
that appear to be class effects have yet to be explained. 
Bexagliflozin tablets, 20 mg, are blue caplet-shaped film-coated tablets with a gastroretentive 
mechanism based on mucoadhesion. Peak plasma bexagliflozin concentrations are observed 
3 to 5 h after dosing and thereafter decline in a biphasic manner with mean elimination half-
life values ranging from 7.8 to 9.7 h. Bexagliflozin is extensively metabolized, 
predominantly to a 3’-O-glucuronide, but also to a mixture of additional glucuronides and 
oxidation products. .  
The relative contributions of different organs to metabolism of bexagliflozin are not known. 
Cytochrome P450 oxidases are found in intestine, kidney and liver, with the latter usually 
considered the most important site for xenobiotic oxidation. Glucuronidation is principally 
carried out in the kidney and liver. Because high amounts of [14C]-bexagliflozin have been 
observed in the kidney in rats and renal recirculation of the compounds appears likely, a 
significant renal contribution cannot be excluded.  
 Metabolism represents the primary pathway for the clearance of bexagliflozin accounting for 
> 60% of the administered drug and is primarily via glucuronidation (hepatic and extra-
hepatic) by uridine diphosphate glucuronyl transferase (UGT1A9) to form a major inactive 
metabolite (EGT0002149), which accounted for 32.2% of systemic exposure of the parent 
drug. Less than 2.0% of the administered bexagliflozin dose is recovered in the urine as 
unchanged drug and most of the radioactivity excreted in urine was associated with 
EGT0002149, accounting for 30.1% of the administered dose.  No glucuronides were found 
in feces, but the possibility of action of microbial glucuronidases could not be excluded.  
(THR-1442-C-410).  
ICH guidelines recommend that the consequences of diminished hepatic function for the 
metabolism of new molecular entities be studied if hepatic metabolism and/or excretion 
accounts for > 20% of the absorbed agent(Industry, 2003). Because bexagliflozin is 
extensively metabolized and the sites of metabolism are unknown, the sponsor has chosen to 


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undertake an investigation of the pharmacokinetics of bexagliflozin in subjects with differing 
degrees of liver dysfunction.   
1.1 
Summary of Nonclinical Data for Bexagliflozin 
Bexagliflozin is highly (97%) bound to protein in human plasma. The degree of binding is 
minimally reduced in plasma from subjects with moderate to severe renal impairment. It is a 
high solubility, low permeability class III BCS agent and is not a significant inducer or 
inhibitor of cytochrome P450 isozymes and transporters relevant for drug-drug interactions. 
It is a substrate for P-gp but does not affect the pharmacokinetics of digoxin, a drug with a 
narrow therapeutic window that is strongly affected by P-gp inhibition. 
The potential adverse effects of bexagliflozin have been evaluated in standard safety 
pharmacology, genotoxicity, repeated-dose toxicity and reproductive toxicity studies. Based 
on findings in rats and monkeys, the potential limiting adverse effects in human subjects 
have been predicted to involve the gastrointestinal (GI) tract and to manifest as diarrhea and 
gastric irritation. Animals given high daily doses of bexagliflozin have also experienced 
adverse effects involving the respiratory system, liver, kidney, heart and bone marrow. 
Chronic toxicity studies have produced similar toxicity profiles with additional 
microvacuolation of renal cortical cells in monkeys. This microscopic pathology occurred 
without clinical chemistry correlates, and the effects generally reversed during the recovery 
phase.  
In rats, bexagliflozin did not affect fertility or reproductive performance by either sex at 
doses representing approximately 600 times the expected clinical exposure. Bexagliflozin 
produced maternal toxicity but did not affect embryo/fetal viability, growth or development 
at dose levels up to 200 mg kg-1 day-1 (in rats) or 150 mg kg-1 day-1 (in rabbits). Maternal 
toxicity was observed at ≥ 40 mg kg-1 day-1 from mid- to late gestation, and litter size and 
average pup weight were slightly lower at 200 mg kg-1 day-1. Bexagliflozin did not affect 
neuromuscular development or reproductive system development in F1 rats. Based on these 
results, bexagliflozin administered during pregnancy and the nursing period was considered 
non-toxic for offspring.  
In a juvenile toxicity study, bexagliflozin up to 100 mg kg-1 day-1 was administered to rats 
from postnatal days 21 through 49 and produced > 300 × the expected Cmax and > 600 × the 
expected AUC of the intended dose of 20 mg in adult humans. The 4-week daily dosing was 
well tolerated with the main findings related to effects on kidney and bone, including renal 
pelvic dilatation, a narrower mean femur width in males and a wider mean femur width and 
narrower mean tibia width in females. 
Studies of rodents dosed daily with bexagliflozin for approximately 2 years (mice) or 1.5 – 2 
years (rats) did not produce evidence of an oncogenic effect. There was no statistically 
significant increase in the incidence of any tumor type in any tissue for either sex. Based on 
the expected AUC of the intended human dose of 20 mg in the extended release tablet 
formulation, the exposure provided safety margins ranging from 149 × (males) to 202 × 
(females) for mice and from 52 × (males) to 88 × (females) for rats. The duration of the rat 


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study was briefer than intended due to an unanticipated increase in mortality affecting all 
male rat cohorts (including vehicle) in a dose-dependent manner 
1.2 
 Summary of Clinical Data for Bexagliflozin 
CLINICAL PHARMACOKINETICS AND METABOLISM 
Following administration of bexagliflozin extended release tablets, time to reach maximum 
observed concentration (Tmax) has typically been observed between 2 and 4 h. The tablets 
produce dose-proportional exposure with a Cmax of 6.4 ng mL-1 mg-1 bexagliflozin and an 
AUC0-t of 45 ng h mg-1 mL-1 in healthy subjects. A food effect has been observed, with a 
delayed Tmax of 5 h following dosing in the fed state compared to 3.5 h following dosing in 
the fasted state. Following dosing in the fed state, the Cmax has been found to be 31% greater 
than the Cmax following dosing in the fasted state, without substantial change in AUC. In 
light of the perceived wide safety margins, the increase in Cmax has not been considered to 
represent a meaningful hazard and dosing in either prandial state has been thought likely to 
elicit similar pharmacological effects and to pose comparable risks.  
The principal metabolites in humans are similar to those found in monkeys and dominated by 
glucuronides of the parent compound, for which the AUC has been < 35% relative to parent 
compound in most studies. All metabolites were reduced in abundance relative to the parent 
species following administration of the sustained release formulation.  
All of the glucuronides have negligible pharmacologic activity in vitro, and are present in 
monkeys, in approximately the same proportion as in humans. The total contribution of 
metabolites to the pharmacology of bexagliflozin is estimated to be less than 1% based on in 
vitro activity measurements and the proportion of metabolites in plasma.  
Following oral administration of radiolabeled bexagliflozin, 91.6% of the ingested 
radioactivity was recovered, 51.1% as fecal excretion and 40.5% as urinary excretion. In 
urine, bexagliflozin accounted for 1.5% of the dose; most of the radioactivity was excreted as 
the 3’-O-glucuronide (EGT0002149). The largest fraction of the radioactivity in feces was 
due to bexagliflozin, accounting for about 28.7% of the administered dose. Disposition of 
radiolabel could be accounted for by known metabolites and only 0.27% of the input 
radioactivity could not be identified, approximately equally divided between one species 
each in urine and feces.  
The PK of bexagliflozin and its principal metabolites was determined in subjects with T2DM 
and renal impairment. Absorption of bexagliflozin was not affected by diminished renal 
function. Reduced clearance due to renal impairment resulted in systemic exposure that 
increased as the glomerular filtration rate (GFR) decreases. Increases in AUC of 34% and 
54% were observed in subjects with moderate and severe impairment, respectively, 
compared to the AUC measured in subjects with normal renal function. Exposure to the main 
metabolite, the glucuronide EGT0002149, increased up to 2.2-fold in subjects with severe 
renal impairment. Given the moderate increase in exposure and wide safety margins for 
bexagliflozin, dose adjustment for individuals with mild to moderate renal impairment has 
not been expected to be necessary.  


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Bexagliflozin exposure has been moderately affected by co-administration of the commonly 
co-prescribed oral hypoglycemic agents metformin, glimepiride and sitagliptin. An increase 
in glimepiride exposure upon co-administration with bexagliflozin has been observed 
although the increase has not been deemed clinically significant. Administration of 
bexagliflozin 30 minutes after injection of exenatide, a glucagon-like peptide-1 (GLP-1) 
agonist, results in delayed absorption and an approximately 50% increase in systemic 
exposure to bexagliflozin. A decrease in exposure has been observed following co-
administration with rifampin, an inducer of xenobiotic metabolism. Although bexagliflozin is 
a P-gp substrate, the pharmacokinetics of the P-gp substrate digoxin have been unaffected by 
co-administration of the extended release formulation to healthy subjects. Adjustment of the 
bexagliflozin dose to compensate for drug-drug interactions is not expected to be necessary 
in general. 
PHARMACODYNAMICS AND EFFICACY OF BEXAGLIFLOZIN IN HUMANS 
Dose-titration studies have shown that the primary pharmacodynamic effect, urinary glucose 
excretion (UGE), can be described in both healthy and diabetic subjects by a simple logistic 
equation. The median effective dose (ED50) is estimated to be 3.6 mg in healthy subjects and 
1.2 mg in diabetic subjects. From this, a 20 mg dose is expected to produce 85% or 94% of 
the theoretical maximum UGE in healthy or diabetic subjects, respectively. After a single 
dose of bexagliflozin, diabetic subjects have exhibited significant glucosuria and experienced 
meaningful reductions in fasting plasma glucose (FPG). Healthy and diabetic subjects have 
also experienced a moderate diuretic effect. The dose-related glucosurias observed in 
Japanese and American populations have been similar in magnitude.  
Although bexagliflozin is a potent glucosuric agent, hypoglycemia and hypotension have not 
been observed in the setting of monotherapy. All reports of hypoglycemia and hypotension 
have occurred in the context of additional anti-diabetic or anti-hypertensive agents. Insulin 
and insulin secretagogues of the sulfonylurea class have been frequently implicated in 
bexagliflozin-associated hypoglycemia.  
SAFETY INFORMATION FROM HUMAN EXPOSURE 
 Bexagliflozin has been well tolerated whether administered as immediate release capsules or 
extended release tablets. The proportion of subjects who have experienced any treatment-
emergent adverse event (AE) has been comparable between active and placebo arms. The 
most frequently occurring AEs (> 5%) have been urinary tract infections and hypoglycemia. 
For both types of event, the rate has been higher in the combined placebo group than in the 
combined bexagliflozin groups (of all strengths). Similarly, taking all completed studies into 
consideration, a higher percentage of subjects in the placebo or comparator groups have 
experienced serious adverse events (SAEs) than subjects in the bexagliflozin treatment 
groups, taking all dosage levels combined. Neither death nor serious adverse event has been 
observed in any of the phase 1 clinical pharmacology studies. Deaths have occurred in 
multiple phase 2 and 3 studies, particularly in a large, ongoing cardiovascular safety study. 
 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
To evaluate the effect of moderate hepatic impairment on the pharmacokinetics (PK) and 
pharmacodynamics (PD) of a single oral dose of bexagliflozin tablets, 20 mg   
2.2 
Secondary Objective 
To assess the safety and tolerability of bexagliflozin in subjects with moderate hepatic 
impairment. 
 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
Approximately 16 subjects (eight with moderate hepatic impairment [Child-Pugh total score 
7-9] and eight healthy, matched controls) will be enrolled.  
The Child-Pugh grading system will be used to assess the severity and prognosis of hepatic 
disease. Male or female subjects with hepatic impairment conforming to the Child-Pugh 
classification of B (Child-Pugh total score 7-9) based on the Child-Pugh scoring method 
described in Appendix 2 will be enrolled. For each enrolled subject with liver dysfunction a 
matching control subject (healthy subject) with similar age (±10 years), weight (±10%), sex, 
and smoking status will be enrolled.  
Each subject will take a single bexagliflozin tablet, 20 mg, with 240 mL of water in the 
morning (approximately 8 a.m. to 10 a.m.) after an overnight fast. Food will be withheld for 
at least 2 h postdose. Water will be allowed as desired except for one hour before and after 
drug administration.  
Blood samples for determining the plasma concentrations of bexagliflozin will be collected at 
predose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h postdose. 
Urine samples for PD analysis will be collected predose and in the following intervals after 
dosing: 0–12, 12–24, 24–36, and 36–48 h. 
Plasma concentrations of bexagliflozin will be determined by validated liquid 
chromatography-mass spectrometry (LC-MS/MS) methods. 
The unbound fraction of bexagliflozin will be determined at 24 h postdose (or earlier if the 
24 h postdose sample has a concentration below the limit of quantitation) and at the 
maximum plasma concentration for each subject by equilibrium dialysis.   
Clinical laboratory tests and safety monitoring will be conducted during the treatment period 
and at the follow-up visit. The study event table is provided in Appendix 1. 
3.2 
Rationale for Study Design and Control Group 
3.2.1 
Rationale for Study Design 
Pharmacokinetic studies are used to identify special subgroups of patients for whom an 
alternative dosing regimen may be indicated for efficacy and/or safety reasons. Liver 
dysfunction of all types, from transient injury to acute liver failure, are common in adult 
populations. Through a variety of oxidative and conjugative metabolic pathways, the liver is 
involved in the clearance of many drugs. In addition, the liver directly excretes xenobiotic 
compounds and their metabolites into bile. Because the liver produces the majority of protein 
in plasma, hepatic failure can also affect plasma protein binding, which can influence the 
distribution or elimination of protein-bound drugs.  


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In this study, the PK, PD and safety profile produced by a single oral dose of bexagliflozin 
tablets, 20 mg, will be compared between patients with moderate hepatic impairment and 
demographically matched subjects with normal hepatic function. 
3.2.2 
Rationale for Dose Selection 
Bexagliflozin produces a dose-dependent and saturable UGE in healthy volunteers and 
diabetic subjects. A population PD model has predicted that bexagliflozin tablets, 20 mg, 
produced 85% and 94% of the maximal UGE in healthy and diabetic subjects, respectively. 
Bexagliflozin has consistently demonstrated wide safety margins in clinical and nonclinical 
studies. . 
A single-dose study is considered sufficient since previous studies show bexagliflozin exhibit 
linear and time-independent pharmacokinetics (THR100-CLR-002). 
3.2.3 
Rationale for PK and PD Sampling Time Points 
Plasma and urine samples will be collected for 48 hours after dosing. The excretion of total 
radioactivity in urine occurred principally in the first 48 h following oral dose of [14C] 
- bexagliflozin in humans (THR-1442-C-410).  
3.3 
Study Duration and Dates 
This is a single dose study. Selection and enrollment of study subjects will begin with those 
designated for the hepatic impairment group. A screening visit will be completed 2 to 28 
days prior to study drug administration. Subjects will be admitted to the clinic the day before 
administration of the investigational product and will remain in the clinic for at least 48 h 
following administration. Subjects will return for an end-of-study examination within 13 
days of the last pharmacokinetic sample collection. Each subject from the hepatic impairment 
group will be matched to a healthy comparator subject. 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 
The study population comprise eight subjects with hepatic impairment conforming to the 
Child-Pugh class B (Child-Pugh total score 7-9) and eight control subjects (healthy subjects 
with normal hepatic function). Each healthy control subject will be matched with an 
individual subject in the hepatic impairment group by age (±10 years), weight (±10%), sex, 
and smoking status.  
Eligible subjects who consent to participate in the study will be enrolled in clinical 
investigational sites in the United States. Study subjects will be informed of the purpose and 
potential risks of participation in the study. 
4.2 
Inclusion Criteria 
Prospective subjects must: 
1. Be male or female adults between the age of 18 to 75 years (inclusive) at screening 
2. Have a body-mass index (BMI) of 18.0 - 40.0 kg m-2 (inclusive) at screening 
3. Have adequate venous access at multiple sites in both arms 
4. Be willing and able to be confined to the clinical research facility as required by the 
protocol 
5. Be able to comprehend the explanation of the informed consent and be willing to provide 
written informed consent in accordance with institutional and regulatory guidelines 
6. Be diagnosed with moderate hepatic impairment with a Child-Pugh score 7 to 9 
(classification in Appendix 2) and must be in stable general health apart from hepatic 
impairment and its related conditions (for subjects in the hepatic impairment group 
only)  
7. Be in general good health with matching demographics and baseline characteristics to 
individual subjects in the hepatic impairment group by age (±10 years), weight (±10%), 
sex, and smoking status (for subjects in the healthy control group only) 
8. Have no evidence of an active infection or be receiving any treatment with antibiotics at 
the time of screening (for subjects in the healthy control group only) 
 
4.3 
Exclusion Criteria 
Subjects who have any of the following attributes will be excluded from the study: 
1. A clinically significant history of allergy to drugs or latex (at the investigator’s 
discretion) 
2. A positive alcohol or drug result based on urine sample or breathalyzer testing at 
screening or at clinic admission (D0).  A subject may be eligible upon medical monitor 


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review and approval if the positive urine drug test is from stable dose of prescription 
medication 
3. A record of donation of 400 mL of whole blood within two months, 200 mL of whole 
blood within one month, or blood components or plasma within 14 days prior to D0. 
4. A history of exposure to an investigational drug within 30 days or 5 half-lives of the 
investigational drug prior to D0, whichever is longer 
5. A history of exposure to any SGLT2 inhibitor within 3 months prior to D0 or 
participation in previous bexagliflozin clinical trials 
6. A history of exposure to probenecid, rifampin or any potential strong UGT1A9 inducers 
or inhibitors within 2 months of D0 
7. A clinically significantly abnormal screening ECG that includes but is not limited to: 
heart rate <40 or >110 bpm, QRS > 160 ms, QTc > 480 ms (corrected by Bazett’s 
formula), or any clinically significant arrhythmia including Mobitz type II 2nd Degree 
Heartblock, and bifascicular block. 
8. If destined for the hepatic impairment group, a seated systolic blood pressure <80 or > 
160, confirmed by repeat or diastolic blood pressure of < 40 or >100  
9. If destined for the healthy control group, a seated systolic blood pressure <90 or > 140, 
confirmed by repeat or diastolic blood pressure of < 40 or > 90 
10. A history of HIV infection or a positive titer for human immunodeficiency virus (HIV) 
antibody 
11. A history of vaccination (with the exception of the flu vaccine) within 30 days prior to 
D0 
12. An estimated glomerular filtration rate (eGFR) < 60 mL min-1 per 1.73 m2 as calculated 
by the modification of diet in renal disease study equation (MDRD), at screening 
13. Severe or moderate renal dysfunction or a history of kidney, other organ, bone marrow or 
stem cell transplant 
14. If male, refusing to refrain from donating sperm or use of appropriate birth control when 
engaging in sexual intercourse for the duration of the study and a period of 14 days after 
discharge from the clinic. Appropriate birth control methods include condoms with 
spermicide, female partner’s use of diaphragm with spermicide, female partner’s use of 
stable oral, implanted, or injected contraceptive hormones or an intrauterine device. Male 
subjects who are surgically sterile are eligible 
15. If female and of childbearing potential, refusing to use an adequate method of 
contraception to avoid prevent pregnancy for the duration of the study and a period of 14 
days after discharge from the clinic. Adequate methods of contraception for female 
subjects of childbearing potential include bilateral tubal ligation, intrauterine device, 
diaphragm with spermicide and male partner’s use of male condom with spermicide. 
Female subjects who are surgically sterile (i.e. have undergone full hysterectomy, or 
bilateral oophorectomy) or postmenopausal (absence of menses greater than 12 months 
and age > 45 years) are eligible. All females must have negative pregnancy test at screen 
and at admission 
16. Unwilling to forgo consumption of grapefruit and grapefruit products from 7 days prior 
to D0 through discharge from the clinic 


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17. Pre-existing thrombocytopenia (platelet blood count < 30,000 platelets) at screening or 
other clinically significant findings in CBC  
18. A history of current febrile illness, hepatocellular carcinoma, acute liver disease, severe 
hepatic encephalopathy, or biliary liver cirrhosis 
19. A history of significant acute medical illness (new conditions, exacerbation of preexisting 
conditions or major surgery within 4 weeks of study drug administration), active 
alcoholic hepatitis, current or recent (within 2months before D0) history of significant 
gastrointestinal disease 
20. Clinical evidence of severe ascites, as judged by the investigator 
21. A history of surgical portosystemic shunt 
22. If destined for the healthy control group, a history of vitamin preparation or supplement 
use (including St. John’s Wort and ginseng) within 7 days prior to D0, or caffeine and 
xanthine containing foods/beverages within 48 h prior to D0  
23. If destined for the hepatic impairment group, a history of any new prescription 
medication within 30 days prior to D0  
24. If destined for the hepatic impairment group, a history of fluctuating or rapidly 
deteriorating hepatic function or the production of widely varying or worsening clinical 
and/or laboratory signs of hepatic impairment within the screening period  
25. If destined for the healthy control group, a history of prescription or over-the-counter 
(OTC) drug use within 7 days or 5 half-lives of the drug, whichever is longer, prior to D0  
26. If destined for the healthy control group, a history of liver disease or liver injury as 
indicated by an alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
> 2.5 × the upper limit of normal (ULN) at screening, or serum bilirubin > 1.5 × ULN  
27. If destined for the healthy control group, evidence of HBV or HCV infection. 
28. Any other serious medical condition that, in the opinion of the investigator, would pose a 
significant risk to the subject or interfere with the interpretation of safety, PK, or PD data. 
 
 
 


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5 
STUDY TREATMENTS 
5.1 
Study Drug 
Bexagliflozin tablets, 20 mg, are prolonged release, 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 tablets 
exhibit a > 75% release of drug substance by 8 hours in simulated gastric fluid in vitro. 
5.2 
Treatments Administered 
Subjects who consent to participate and meet all inclusion/exclusion criteria will receive a 
single oral dose of bexagliflozin tablets, 20 mg.  
5.3 
Selection and Timing of Dose for Each Subject 
Subjects in the hepatic impairment group will be dosed first. Control subjects will be enrolled 
after at least one subject in the hepatic impairment group is enrolled. Each control subject 
will be matched with individual subject in hepatic impairment group. Each subject will 
receive a single oral dose of bexagliflozin tablets, 20 mg, with 240 mL of water on Day 1 
(D1) after an overnight fast of at least 10 h. 
5.4 
Method of Assigning Subjects to Treatment Groups and 
Sequences 
This is an open-label, parallel-group study. An adequate number of male or female subjects 
with moderate hepatic impairment [Child-Pugh total score 7-9] will be enrolled to obtain 
eight evaluable subjects. Another adequate number of healthy subjects with normal hepatic 
function will be enrolled to obtain at least 8 evaluable subjects who are matched with the 
subjects in the moderate hepatic impairment group individually for age (±10 years), weight 
(±10%), sex, and smoking status.  
Subjects who withdraw early for safety reasons will not be replaced.  
5.5 
Blinding 
This is an open-labeled study. 
5.6 
Concomitant Therapy 
Participants in the healthy control group will be prohibited from taking any prescription or 
OTC drugs, supplements, or vitamins 7 days prior to D0, as well as for the duration of the 
study. Subjects in the hepatic impairment group must not have changed the dose or frequency 
of administration of any prescription medications for 30 days prior to D0.   
Medications may be prescribed for management of an adverse event (AE). Subjects may 
receive any medications for AEs that are necessary to treat the event or minimize the 


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likelihood of having serious adverse events (SAEs) in the investigators’ judgment. 
Concomitant medications administered during the study are to be recorded on the case report 
form (CRF). The medication name, dose, frequency, route of administration, date(s) of 
administration and reason for administration shall be recorded. This documentation shall 
continue until the end of the study. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
No study subject shall have been dosed with any SGLT2 inhibitor within 3 months prior to 
D0, nor with an investigational drug within 30 days or 5 half-lives. No subject shall have 
previously participated in a bexagliflozin clinical trial. No subject in the control group shall 
have taken any OTC drugs, vitamins, or supplements 7 days prior to D0 or shall have 
consumed caffeine or similar methylxanthine-containing foods/beverages (tea, hot chocolate, 
energy drinks) within 48 h prior to D0. Subjects in the hepatic impairment group must not 
have changed the dose or frequency of administration of any prescription medications for 30 
days prior to D0.  
5.7.2 
Fluid and Food Intake  
Bexagliflozin will be administered to subjects after an overnight fast of at least 10 h with 
approximately 240 mL water. Subjects should fast at least 8 h prior to any safety laboratory 
collection. Water will be allowed as desired except for one hour before and after drug 
administration. 
5.7.3 
Subject Activity Restrictions 
Alcohol consumption is restricted for 72 hours prior to D0 and throughout the study. 
5.8 
Treatment Compliance 
To ensure compliance, all medication dosing will be supervised by the Investigator or 
qualified staff in the clinic. The exact times of dosing will be recorded in the CRFs, including 
a record of drug administration checks followed by hand and mouth inspection. 
5.9 
Packaging and Labeling 
Bexagliflozin tablets, 20 mg, are packaged in high-density polyethylene bottles sealed with a 
child resistant closure. The product is packaged in 90 count bottles. 
Investigational product bottles will be labeled with the protocol number, drug name and 
strength, lot number, sponsor’s name, storage condition, and the investigational drug caution 
statement. 


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5.10 Storage and Accountability 
Bexagliflozin tablets will be stored below 30°C (86°F) in a secure area with access limited to 
authorized personnel. The pharmacist shall maintain an inventory of bexagliflozin product 
and the number of tablets dispensed per study subject. A reconciliation of drug inventory will 
be performed at the end of the study and the results of this inventory shall be recorded in the 
Drug Consumption Form (or equivalent). Empty, partially used and unused bottles must be 
returned to the depot for destruction at study close out, after the Drug Consumption Form (or 
equivalent) is completed. 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Before each subject is enrolled in the clinical study, written informed consent will be 
obtained from the subject according to the regulatory and legal requirements. As part of this 
procedure, the investigator or designee must explain orally and in writing the nature, duration, 
and purpose of the study, and the action of the drug in such a manner that the study subject is 
aware of the potential risks, inconveniences, or AEs that may occur. The investigator should 
educate potential subjects about the scientific importance of their data and the vital role that 
their participation has for the outcome of the entire study. The subject must be informed that 
he/she is free to withdraw from the study at any time. He/she will receive all information that 
is required by federal regulations and International Council for Harmonisation (ICH) 
guidelines. 
The informed consent document must be signed and dated. One copy will be given to the 
subjects, and the investigator will retain a copy as part of the clinical study records. The 
investigator will not undertake any investigation specifically required for the clinical study 
until written consent has been obtained. The terms of the consent and when it was obtained 
must also be documented. 
6.2 
Medical History 
The following information will be collected at the screening visit: 
• 
Demographic information including age, sex, and race. 
• 
Significant medical and surgical history with documentation of the dates relative to the 
time of study screening, if applicable. 
• 
History of clinically significant allergies including to drugs and latex. 
• 
History of smoking. 
• 
History of blood donation within two months or blood components or plasma donation in 
the 14 days prior to D0. 
• 
History of vaccination within 30 days prior to D0. 
• 
History of diagnosis of HIV. 
• 
History of severe or moderate renal dysfunction or a history of kidney, other organ, bone 
marrow or stem cell transplant.  
• 
History of Hepatitis B, or Hepatitis C virus infection. 
• 
History of exposure to any investigational drug in the previous 30 days or 5 half-lives 
prior to D0, whichever is longer. 
• 
History of exposure to any SGLT2 inhibitors in the last 3 months prior to D0. 
• 
History of participation in any bexagliflozin clinical trial. 
• 
Medication history including prescription, OTC drugs, and vitamin preparation or 
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the drug, whichever is longer, prior to D0 (for subjects in the healthy control group 
only).  
• 
A history of any change in dose or frequency of dosing of prescription medication within 
30 days prior to D0 (for subjects in hepatic impairment group only) 
 
6.3 
Physical Examination 
The investigator or designated qualified individual will perform the PEs. A complete PE will 
be performed at screening, and on clinic admission (D0).  A partial PE will be performed on 
day 1, and at follow up visit as described in Appendix 1. 
A complete PE will include body weight, height and general assessment of all body systems 
including the skin, head, eyes, ears, nose, throat, neck, lungs, heart, abdomen, lymph nodes, 
and extremities. A partial PE will include a general assessment of the skin, heart, lungs and 
abdomen. 
6.4 
Vital Signs 
Vitals signs (VS), including pulse, systolic and diastolic blood pressure (BP), respiration rate, 
and oral cavity temperature, will be measured on scheduled visits as described in Appendix 
1.  
Vital signs, including pulse, systolic and diastolic BP, shall be measured prior to blood draws 
and after a subject has been sitting for 5 minutes. 
Respiration rate should be measured after at least 5 minutes of rest.  
BP measurements will be obtained using a calibrated manual or oscillometric 
sphygmomanometer. 
6.5 
Electrocardiography 
A 12-lead electrocardiography (ECG) will be conducted as listed in Appendix 1 and 
whenever clinically indicated. 
The data should be collected from the subject in the supine position after at least 5 minutes of 
rest. ECG parameters measured will be the RR interval, PR interval, QRS duration, and QT. 
Each ECG shall 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 shall ascertain if the 
abnormality represents a clinically significant change from the screening ECG for that 
individual subject. This determination, however, need not be made the first time an abnormal 
result is observed. The investigator may repeat the ECG to verify the results of the original 


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result. If the ECG result is determined to be a clinically significant and abnormal change 
from baseline for that subject, the finding shall be 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 tests will be performed at the scheduled visits 
(Appendix 1). Blood samples shall be drawn after overnight fasting (at least 8 h). The details 
of the required laboratory tests are listed in Table 1.  
 Table 1. 
Required Laboratory Tests 
Test Name 
 
mL 
(sample) 
Hematology 
8.5 (blood) 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
International normalized ration (INR) 
Mean corpuscular volume 
Platelet count 
Red blood cell count  
White blood cell count with differential  
 
 
Serum Chemistry, Electrolytes and Lipids 
 
4.0 (blood) 
Albumin 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Blood urea nitrogen (BUN) 
Glucose 
Bicarbonate 
Creatinine 
Creatinine kinase 
Chloride 
Total protein 
Low-density lipoprotein cholesterol, calculated 
Triglycerides 
Calcium 
Magnesium 
Alkaline Phosphatase (ALP) 
Phosphorus 
Potassium  
Sodium  
Total bilirubin 
Direct bilirubin 
Uric acid 
Total cholesterol 
High-density lipoprotein 
cholesterol 
 
Urinalysis 
 
20 (urine) 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Microscopic examination will be performed if protein, 
leukocyte esterase, nitrite, or blood is positive 
Nitrite  
pH 
Occult blood 
Protein 
Specific gravity 
Urobilinogen 
Leukocyte esterase 
 


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 Table 1. 
Required Laboratory Tests 
Test Name 
 
mL 
(sample) 
Urine Drug Screen 
 
10 (urine) 
Amphetamines 
Barbiturates 
Cocaine Metabolites 
MDMA 
TCA 
PCP 
Opiates 
Benzodiazepines 
Cannabinoids (THC) 
Methamphetamine 
Methadone 
OXY 
Alcohol  
 
Urine pregnancy test (Female only) 
 
5.0 (urine) 
Infectious Disease Testing (measured at screening 
only)  
 
4.0 (blood) 
Hepatitis B surface antigen (HBsAg) 
Human Immunodeficiency Virus antibody (HIV) 
Hepatitis C virus (HCV) 
 
 
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 sample collection 
is described in Appendix 1. 
6.6.2.2 
Urinalysis 
Clean-catch, midstream urine samples will be collected per the schedule outlined in Section 7 
and in Appendix 1. Dipstick urinalysis will be conducted at the local laboratory. If protein, 
leukocyte esterase, nitrite or blood is positive in the dipstick analysis, a microscopic 
examination will be performed. If microscopic examination is suggestive, then a culture may 
be performed at the discretion of the investigator. In addition, unscheduled urinalysis will be 
performed from a clean-catch urine sample from subjects with symptoms of UTI or 
pyelonephritis. 
6.6.2.3 
Urine Collection for PD  
Predose urine samples must be collected from -12 to 0 h for baseline measurement. Subjects 
will empty their bladders prior to dosing. Postdose urine will be collected without 
preservative in four (4) batches at 0-12, 12 to 24, 24 to 36, and 36 to 48 h after oral 
administration of bexagliflozin. Urine must be refrigerated at 2-8 °C during collection. After 
collection, the total volume of each batch and collection time will be recorded. A 20 mL 
aliquots of the urine at each batch will be prepared from well-mixed urine collections. One 
aliquot of the urine samples will be analyzed for urinary glucose and creatinine at the local 
lab (for PD analysis).  


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6.6.2.4 
Plasma Sample Collection for PK  
Whole venous blood samples of 6 mL will be collected from a peripheral vein at predose and 
at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h after oral administration of bexagliflozin. 
Blood samples will be collected in tubes containing potassium ethylenediaminetetraacetic 
acid (K2EDTA) and stored on ice until centrifuged under refrigeration for at least 10 min at 
3,000 rpm. After centrifugation, plasma will be removed, divided into 3 aliquots of 
approximately 1.0 mL, frozen and stored at or below -20 °C.  Plasma should be processed 
and frozen within 2 h of blood collection. Processed frozen plasma samples will be 
transferred on dry ice to the analytical laboratory and will be stored at or below -20 °C until 
LC-MS/MS analysis and protein binding determination. 
6.6.3 
Blood Volume and Frequency for PK and Safety Assessment 
The approximately total volume and number of sampling times for blood collections are 
outlined in Table 2. 
Table 2. 
Blood Samples 
Test 
Volume per sample (mL) 
No. of Samples 
Total* 
Storage 
Blood 
 
 
 
Hematology 
8.5 
5 
42.5 
4 °C 
Chemistry and infectious 
disease testing 
4 
6 
24 
4 °C 
Virology testing 
7 
1 
7 
4 °C 
PK 
6 
15 
90 
-20 °C 
*Total blood volume required in each subject: approximately 178.5 mL, including additional 15 mL blood for heparin locks 
for PK draws. 
 
6.7 
Adverse Events Assessments 
Adverse Event (AE): Any untoward medical occurrence in clinical investigation subject 
administered a pharmaceutical product. An AE does not necessarily have to have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of 
an investigational product, whether or not it is considered related to the investigational 
product. 
Serious Adverse Event (SAE): A serious adverse event (experience) or reaction is any 
untoward medical occurrence that at any dose: 
• 
results in death, 


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• 
is life-threatening (NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the patient was at risk of death at the time of the event and does not 
refer to an event which hypothetically might have caused death if it were more severe.), 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
results in persistent or significant disability/incapacity, 
• 
is a congenital anomaly/birth defect, 
• 
is an important medical event. 
 
An important medical event is an event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
Non-serious adverse events are all events that do not meet the criteria for a "serious" adverse 
event. 
Immediately Reportable Adverse Event (IRAE): Any serious adverse event or any 
adverse event that necessitates discontinuation of investigational product. 
Clinical Laboratory Changes: It is the investigator’s responsibility to review the results of 
all laboratory tests as they become available. For each abnormal laboratory test result, the 
investigator needs to ascertain if this is a clinically significant change from baseline for that 
individual subject. This determination, however, does not necessarily need to be made the 
first time an abnormal value is observed. The investigator may repeat the laboratory test or 
request additional tests to verify the results of the original laboratory tests. If this laboratory 
value is determined to be a clinically significant 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-1 and 
documented as described in Section 6.7.3.4. 
Any clinical significant increase in hepatic enzymes and specifically ALT or AST > or = 3x 
ULN (for healthy control subjects), or AST or ALT >or = to 3x the subject’s baseline values, 
whichever is greater will be considered a clinical laboratory adverse event. 
An increase in creatinine from baseline by 0.5 mg dL-1 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 


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3 = Severe: inability to work or perform normal daily activity 
Investigational Product Causality: The site and database should ask for the causality 
relative to the study compound. Relationship of an adverse event to dosing will be assessed 
as follows: 
Definite: There is a reasonable causal relationship between the investigational product and 
the AE when the event responds to withdrawal of the investigational product (dechallenge), 
and recurs with administration of the investigational product (rechallenge). 
Probable: There is a reasonable causal relationship between the investigational product and 
the AE. The event responds to dechallenge. Rechallenge is not required. 
Possible: There is a reasonable causal relationship between the investigational product and 
the AE. Dechallenge is lacking or unclear. 
Not Likely: There is a temporal relationship to investigational product administration, but 
there is not a reasonable causal relationship between the investigational product and the 
event. 
Unrelated: There is no temporal or causal relationship to investigational product 
administration. 
6.7.1 
Collecting and Reporting Adverse Events 
Adverse event data collection will begin on the first clinical admission day. The investigator 
will periodically assess subjects for the occurrence of adverse events. To avoid bias in 
collecting information about adverse events, the investigator should ask subjects the 
following question: "How have you felt since you were last checked?" All adverse events 
(serious and non-serious) reported by the subject must be recorded on the source documents 
and CRFs provided by the sponsor. 
In addition, the study Medical Monitor or the designated Sponsor personnel must be notified 
immediately by telephone or email of any immediately reportable adverse events according 
to the procedure outlined below. Special attention should be paid to recording hospitalization 
and concomitant medications. 
6.7.2 
Immediately Reportable Adverse Events 
The investigator must report any SAE, by telephone, email, or fax, to Theracos or its 
representative immediately after the investigator becomes aware of the event. An IRAE form 
should be completed and sent by email, 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, fax or overnight courier to the sponsor. 


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Subjects experiencing an SAE should be followed clinically until their health has returned to 
baseline status or until all parameters have returned to normal, or have otherwise been 
explained. It is expected that the investigator will provide or arrange appropriate supportive 
care for the subject. 
6.7.3 
Follow-up of Adverse Events 
6.7.3.1 
Follow-up of Non-serious Adverse Events 
Non-serious adverse events that are identified on the last scheduled contact must be recorded 
on the AE CRF with the current status noted. All non-serious events that are ongoing at the 
time will be recorded as ongoing on the CRF. 
6.7.3.2 
Follow-up of Post-Study Serious Adverse Events 
SAEs that are identified on the last scheduled contact must be recorded on the AE CRF page 
and reported to Theracos according to the reporting procedures outlined in Section 6.7.1. 
These may include unresolved previously reported SAEs, or new SAEs. The investigator 
should follow these subjects until the events are resolved, or the subject is lost to follow-up. 
Resolution means the subject has returned to the baseline state of health, or the investigator 
does not expect any further improvement or worsening of the subject’s condition. The 
investigator should continue to report any significant follow-up information to Theracos until 
the event has been resolved. 
Any new SAEs reported by the subject to the investigator that occur after the last scheduled 
contact, and are determined by the investigator to be reasonably associated with the use of 
the investigational product, should be reported to the Medical Monitor or the sponsor’s 
designated personnel. These may include SAEs that are captured on follow-up telephone 
contact or at any other time point after the defined study period (i.e., up to last scheduled 
contact). The investigator should follow subjects with SAEs identified after the last 
scheduled contact until the events are resolved, or the subject is lost to follow-up. The 
investigator should continue to report any significant follow-up information to the Sponsor 
until the event has been resolved. This study requires that subjects be actively monitored for 
SAEs for at least 14 days after discharge from the study.  
6.7.3.3 
Hepatotoxicity 
Any clinical significant increase in hepatic enzymes and specifically ALT or AST > or = 3x 
ULN (for healthy control subjects), or AST or ALT >or = to 3x the subject’s baseline values, 
whichever is greater,  requires immediate repeat test within 48 to 72 h to confirm the hepatic 
enzyme elevation. The event should be reported as an adverse event within the CRF if the 
enzyme elevation is confirmed or worsening. Potential contributors to hepatic enzyme 
elevation should be evaluated by the investigator. The investigator is encouraged to consult 
with the Medical Monitor regarding ongoing diagnostic workup. 


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6.7.3.4 
Hypoglycemia 
Hypoglycemia will be recorded under 5 categories: 
• 
Critical hypoglycemia: An event requiring assistance of another person to actively 
administer carbohydrate, glucagons, or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose 
measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration. All such 
events should be recorded as serious adverse events in the CRF. 
• 
Documented symptomatic hypoglycemia: An event during which typical symptoms of 
hypoglycemia are accompanied by a measured plasma glucose concentration 
≤ 70 mg dL -1 (3.9 mmol L-1). 
• 
Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration ≤ 70 mg dL-1 
(3.9 mmol L- 1). 
• 
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-1 (3.9 mmol L- 1). 
• 
Relative hypoglycemia: An event during which the person reports any of the typical 
symptoms of hypoglycemia, and interprets those as indicative of hypoglycemia, but with 
a measured plasma glucose concentration > 70 mg dL-1 (3.9 mmol L- 1). 
 
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-1 (3.9 mmol L- 1), 
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 
50% IV Dextrose as soon as possible. If IV Dextrose is unable to be administered, an 
injection of 1.0 mg of glucagon should be administered intramuscularly or subcutaneously, 
and the injection may need to be repeated after 15 minutes depending on the response.  
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-1. 
6.8 
Concomitant Medication Assessments 
A concomitant medication is any medication the subject enters the trial taking and is 
expected to continue taking for some portion of the trial, as well as any medication the 
subject takes during the course of the trial. All prescription and over-the-counter medications, 


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including vitamins and herbal supplements, that subjects receive during the trial must be 
documented on the CRF. This documentation should continue until the subjects are 
discharged. 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A table of concomitant medications based on the anatomic 
therapeutic chemical (ATC) classification and preferred name will be produced. A listing of 
concomitant medications will include all medications taken by any subjects during the course 
of the study. 
Concomitant medications administered during the study are to be recorded on the CRF. The 
medication name, dose, frequency, route of administration, date(s) of administration and 
reason for administration must be recorded. This documentation should continue until 
discharge from the study. 
6.9 
Removal of Subjects from the Trial 
The investigator must emphasize to potential subjects the importance of continued 
participation for the full duration of the trial during the informed consent process. 
Participation in the study is voluntary. A participant has the right to withdraw from the study 
at any moment for any reason. The investigator will be informed immediately. 
The investigator has the right to terminate participation of a subject in case it is difficult to 
obtain blood samples, in case of violation of the protocol or in case of severe or serious 
adverse events. 
In case a subject withdraws from the study, the study monitor will be informed immediately. 
If there is a medical reason for withdrawal, the volunteer should remain under the 
supervision of the medical investigator until satisfactory health returns. 
Subjects who withdraw from the study due to adverse event(s) or other safety concerns will 
not be replaced. 
After a decision is made to withdraw a subject, 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 for any of the following reasons: 
• 
A protocol violation occurs, or 
• 
A serious or intolerable adverse event occurs, or 
• 
A clinically significant change in a laboratory parameter occurs, or 
• 
The sponsor or investigator terminates the study, or 
• 
The subject requests to withdraw from the study. 
 


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


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7 
STUDY ACTIVITIES 
7.1 
Study Screening (Day -28 to Day -1) 
During the screening period, the following information will be gathered and the indicated 
procedures will be performed: 
• 
The content of informed consent will be explained to the subject and the signed informed 
consent collected. 
• 
Medical history and demographic information will be obtained. 
• 
A complete physical examination will be conducted, including height and weight 
measurements as described in Section 6.3. 
• 
Vital signs will be measured, including pulse, body temperature, respiratory rate, and 
blood pressure taken in the sitting position after at least 5 min of rest as described in 
Section 6.4. 
• 
A 12-lead ECG will be taken in the supine position after at least 5 min of rest as 
described in Section 6.5. 
• 
A clean-catch, mid-stream urine specimen will be collected for urinalysis as described in 
Section 6.6.2.2. A microscopic examination will be performed if protein, leukocyte 
esterase, nitrite or blood tests are positive. If the results of microscopic analysis are 
suggestive a culture may be performed at the investigator’s discretion. 
• 
A urine drug screen will be conducted for drugs of abuse.  A urine (or breath) alcohol test 
will also be conducted. 
• 
All female subjects will receive urine pregnancy test. 
• 
Blood will be drawn for hematology, serum chemistry, and serology as detailed in 
Section 6.6.2.1. 
• 
Subject conformance to inclusion/exclusion criteria will be evaluated based on the 
information collected at the screening examination. 
 
7.2 
Day 0 (D0) (Clinic Admission) 
The following information will be gathered and the indicated procedures will be performed: 
• 
A complete PE will be performed as described in Section 6.3. 
• 
Inclusion and exclusion criteria will be evaluated.  
• 
A urine drug screen will be conducted for drugs of abuse. A urine (or breath) alcohol test 
will also be conducted. 
• 
All female subjects will receive a urine pregnancy test. 
• 
A urine sample will be collected for predose urinalysis as described in Section 6.6.2.2. If 
the urine specimen is positive for protein, leukocyte esterase, blood or nitrites, a sample 
is to be sent for microscopic evaluation. If the results of microscopic analysis are 
suggestive, a culture may be performed at the investigator’s discretion.  


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• 
Predose blood will be drawn for hematology and serum chemistry as detailed in Section 
6.6.2.1. 
• 
If the subject is still eligible based on the study inclusion and exclusion criteria, the 
subject will be admitted to the study. 
• 
Predose urine will be collected until 0 h (-12 h to 0 h batch) for PD analysis as described 
in Section 6.6.2.3. 
• 
Concomitant medications and adverse event information will be collected as appropriate. 
 
7.3 
Day 1 (D1) (Dosing Day): Predose 
• 
A partial PE will be performed as described in Section 6.3. 
• 
Vital signs will be recorded predose. 
• 
A 12-lead ECG will be taken in the supine position after at least 5 min of rest predose, as 
described in Section 6.5. 
• 
 A predose urine will be collected until 0 h (-12 h to 0 h batch) for PD analysis as 
described in Section 6.6.2.3. 
• 
A urine sample will be collected for predose urinalysis as described in Section 6.6.2.2. If 
the urine specimen is positive for protein, leukocyte esterase, blood or nitrites, a sample 
is to be sent for microscopic evaluation. If the results of microscopic analysis are 
suggestive then a culture may be performed at the investigator’s discretion.  
• 
Predose blood will be drawn for hematology, and serum chemistry as detailed in Section 
6.6.2.1. 
• 
Predose plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4. 
• 
Predose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.4 
Day 1 (D1) Dosing 
• 
Subjects will receive a single dose of bexagliflozin tablets, 20 mg, with approximately 
240 mL water after an overnight fast of at least 10 h as detailed in Section 5.3. 
 
7.5 
Day 1 (D1) Postdose  
• 
Vital signs will be recorded at 4 h post-oral dose. 
• 
A 12-lead ECG will be taken in the supine position after at least 5 min of rest at 4 h 
postdose. 
• 
Urine samples for PD analysis will be collected at 0-12 h and 12-24 h after oral 
administration of bexagliflozin, as described in Section 6.6.2.3. 
• 
Blood samples for PK samples will be collected at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 h after 
oral administration of bexagliflozin.  


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• 
Postdose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.6 
Day 2 (D2) 
• 
Vital signs will be recorded at 24 h post-oral dose. 
• 
Urine samples for PD analysis will be collected at 12-24 h, 24-36 h and 36-48 h after oral 
administration of bexagliflozin, as described in Section 6.6.2.3. 
• 
Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 24 and 36 
h postdose.   
• 
Postdose concomitant medications and adverse event information will be collected as 
appropriate.  
 
7.7 
Day 3 (D3) 
• 
A 12-lead ECG will be taken at 48 h postdose in the supine position after at least 5 min of 
rest as described in Section 6.5. 
• 
Vital signs will be recorded at 48 h postdose. 
• 
Urine samples for PD analysis will be collected at 36-48 h after oral administration of 
bexagliflozin, as described in Section 6.6.2.3. 
• 
Urine will be collected for urinalysis as described in Section 6.6.2.2. 
• 
Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
• 
Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 48 h 
postdose  
• 
Postdose concomitant medications and adverse event information will be collected as 
appropriate. 
• 
The subject will be discharged after completion of all activities 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
Day 15 (D15) ± 1 day except for PK and PD sample collection must be completed. The 
reason for termination must be entered into the case report form. 
 
7.8 
Day 15 (D15) ± 1 day Activities 
On day 15 (±1 day), the following information will be gathered and the indicated procedures 
will be performed after dosing: 
• 
PA partial physical examination will be performed as described in Section 6.3. 
• 
Vital signs will be recorded as indicated in Section 6.4. 
• 
A 12-lead ECG will be recorded in the supine position after at least 5 min of rest. 
• 
Urine will be collected as described in Section 6.6.2.2 for urinalysis. 


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• 
All female subjects will receive a urine pregnancy test. 
• 
Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
• 
Concomitant medications and adverse event information will be collected as appropriate. 
 
7.9 
Early Termination Procedures 
Subjects who withdraw consent and have received investigational product should have a 
follow-up examination, including a partial physical examination, and undergo collection of 
vital signs, ECG data, urine pregnancy test outcomes (female only), and samples for clinical 
laboratory tests (hematology, serum chemistry, and urinalysis). 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 ensure 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 clinical research organization 
(CRO) and the sponsor. Review procedures will be implemented at the CRO for all 
documents that are generated in relation to the study. 
 
 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The statistical evaluation of PK and PD parameters will be conducted by the designated 
CRO. A detailed Statistical Analysis Plan will be generated prior to any PK/PD statistical 
analysis of the data. Statistical analysis will be performed using Statistical Analysis Software 
SAS for Windows® (SAS, USA). Non-compartmental analysis (NCA) will be performed 
using Phoenix®WinNonlin® 6.4 or later (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 detect clinically relevant PK or PD differences between 
healthy and hepatic impairment subjects.   
9.3 
Analysis Populations 
9.3.1 
Safety Population 
The Safety Population will include all subjects who are dispensed study drug. Subjects will 
be analyzed according to the respective hepatic function group. 
9.3.2 
PK Population 
The PK Population will include all subjects without major protocol violations who are 
dispensed study drug and who provide an observation for ≥ 1 primary pharmacokinetic 
endpoint. The PK Population will be used to summarize the PK parameters. 
9.3.3 
PD Population 
The PD Population will include all subjects without major protocol violations who are 
dispensed study drug and who produce at least the first 12 h postdose urine. The PD 
Population will be used to summarize the PD parameters. 
9.4 
Demographics and Baseline Characteristics 
Baseline characteristics will be summarized for all subjects in the Safety and PK Populations. 
Descriptive statistics will be calculated. 
9.5 
Pharmacokinetic Analysis 
9.5.1 
Calculation of Pharmacokinetic Variables 
A non-compartmental analysis will be used to calculate the PK parameters of bexagliflozin 
using Phoenix® WinNonlin® 6.4 or later (Certara, USA). From the plasma concentration-time 
data, the following PK parameters will be estimated for each subject where feasible. 


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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 
AUC0-24 
 Area under the plasma concentration-time curve from the time of dosing to 24 
h postdose 
AUC0-t  Area under the plasma concentration-time curve from the time of dosing to the 
time of last quantifiable plasma concentration 
AUC0-∞ Extrapolated area under the plasma concentration-time curve from the time of 
dosing to infinity  
AUCextr  % of AUC0-∞ due to extrapolation from tlast to infinity 
fu        Unbound fraction, calculated as (free drug concentration)/(total drug concentration) 
Cmax, u  Maximum unbound plasma concentration  
AUCu  Area under the unbound plasma concentration-time curve  
Clu/F Apparent clearance relative to the unbound drug concentration  
 
 
Cmax and Tmax will be obtained directly from experimental observations. If two or more 
concentrations are equal and maximum, the first will be taken as the Tmax. 
The apparent terminal elimination half-life, t1/2, where determinable, will be calculated as the 
natural log of 2 divided by the terminal phase rate constant, λz. The number of data points 
included in the regression will be determined by visual inspection, but a minimum of three 
data points in the terminal phase, excluding Cmax, is required to estimate λz. In order for the 
selection to take place, the adjusted r2 value reported by Phoenix®WinNonlin® must be ≥ 0.7.  
AUC0-t, AUC0-24 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 predose, in which 
case they will be set to zero. All values that are below the limit of quantitation (BLOQ) prior 
to Tmax will be set to zero. BLOQ values that occur after Tmax will be considered missing. 
When ≥ 2 consecutive plasma concentrations that are BLOQ are encountered after Tmax, 
these and all subsequent values will be excluded from the analysis.  
AUC0-∞ will be calculated according to the following equation: 
AUC0-∞= AUClast + (Clast / λz), where Clast is the last temporal quantifiable plasma 
concentration corresponding to Tlast. 


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The proportion of AUC0-∞ due to extrapolation (AUCextr) will be calculated and expressed as 
a percentage. AUC0-∞ values will be considered unreliable estimates if the AUCextr is greater 
than 20%. 
CL/F will be calculated as Dose/AUC0-∞. 
Vz/F will be calculated as Dose/(λz × AUC0-∞). 
t½ will be calculated as 0.693/λz. 
 
9.5.2 
Statistical Analysis of Pharmacokinetic Variables 
Statistical analysis will be performed using Statistical Analysis Software SAS for Windows® 
(SAS Institute Inc., USA). PK parameters for bexagliflozin will be calculated using non-
compartmental analyses (NCA) of plasma concentration-time data. An analyses of variance 
(ANOVA) with a fixed effect corresponding to the hepatic function group will be fitted to the 
natural logarithmic transformation of the PK parameters (Cmax, AUC0-t and AUC0-∞). The 
90% confidence intervals will be constructed for the ratio of geometric means of PK 
parameters (total and unbound Cmax, AUC0-t and AUC0-∞). The apparent clearance relative to 
the unbound drug concentration (Clu/F) will be calculated as Clu/F = Dose/AUCu. 
 
Descriptive statistics of plasma concentration-time data will be summarized by hepatic 
function group and timepoint. 
The PK parameters Cmax, Tmax, λz, t1/2, CL/F, Vz/F. AUC0-t, AUC0-∞, AUCextr, AUCu(0-t) and 
AUCu(0-∞) will be summarized by hepatic function group. Means, standard deviations, 
medians, ranges (min, max) and geometric means and coefficients of variation will be 
presented for all parameters will the exception of Tmax. Medians and ranges will be presented 
for Tmax. 
9.6 
Pharmacodynamic Analysis 
The PD parameters, glucose concentrations, creatinine concentrations, UGE and UGE 
normalized by urinary creatinine, including UGEt1-t2 over specified time interval, and total 
24-hour, 48-hour UGE, will be determined. UGEt1-t2 (mg) will be derived from urine volume 
(Vt1-t2, mL) × glucose concentration (mg dL-1) / 100. UGE and nUGE will be listed and 
summarized by hepatic function group using descriptive statistics. 
Reported predose values for PD data that are below the defined limit will be set to zero. Any 
missing values or values below the reported defined limit that appear after predose for PD 
data will be set to missing. 
9.7 
Safety Analysis 
Safety data will include AEs, PE results, VS results, ECG results, and clinical lab results, 
including those of serum chemistry, hematology, and urinalysis. Observed data will be 


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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 study report 
(CSR). 
9.7.1 
Adverse Events 
Adverse events will be mapped to preferred term (PT) and system organ class (SOC) using 
the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of 
subjects reporting adverse events will be determined by relationship to treatment and by 
severity of the event. Causality for AEs will be ascribed by the investigator according to the 
investigational product causality guidelines of section 6.7. 
Adverse event listings will be provided for the following subsets: 
• 
all treatment emergent AEs (TEAEs). 
• 
all TEAEs at least possibly related to bexagliflozin 
• 
serious TEAEs (if any). 
• 
TEAEs leading to withdrawal (if any). 
 
AEs are dosing emergent if they occur on or after bexagliflozin administration. Causality for 
TEAEs will be ascribed by the investigator according to the investigational product causality 
guidelines of section 6.7. Only TEAEs will be tabulated in summary tables.  
Tabulations will display TEAEs by severity and relationship to bexagliflozin. 
9.7.2 
Hypoglycemia 
Hypoglycemia as defined in Section 6.7.4.4 will be presented in listings and summarized. 
9.7.3 
Clinical and Laboratory Events and Analyses 
Clinical and laboratory metrics are measured at baseline (predose measurement of each 
period) and during the treatment period (Appendix 1). These variables include vital signs 
(blood pressure, respiration, temperature), clinical laboratory results (see Section 6.6 for a 
complete list), and ECGs. 
Serum chemistry, hematology, and urinalysis (quantitative parameters) data will be 
summarized for each treatment period. Summaries for change from baseline will be 
presented for these laboratory tests.  
ECG results will be summarized as changes from baseline in intervals. Abnormalities as well 
as changes from previous assessment will be listed. 


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9.7.4 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A by-subject listing of concomitant medications will include all 
medications taken during the study. 
 
 


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


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The investigator will permit authorized representatives of the sponsor and the respective 
national or local health authorities, other authorized regulatory authorities, and IRB to inspect 
facilities and records relevant to this study. 
10.7 Case Report Forms and Study Records 
For each subject consented, a CRF, in paper or electronic format, will be supplied and 
maintained by the contract research organization (CRO) staff and signed by the investigator 
or authorized designee to indicate that he/she has reviewed and agrees with the entered data. 
This also applies to those subjects who fail to complete the trial. The reason a subject is 
withdrawn must be recorded in the case report form. 
Entries made in the CRF must be verifiable against source documents. Source documents are 
defined as all medical records, medical notes, laboratory results, ECG traces and any 
additional document other than the CRF that has original subject information contained 
within it. 
All CRFs and source documents should be completed following GCPs and the CRO’s 
standard operating procedures. 
10.8 Protocol Violations/Deviations 
It is important to conduct the study according to the protocol. Protocol deviations will not be 
prospectively granted by the sponsor. If deviations occur, such as a visit or sampling window 
being missed, the investigator must decide whether to proceed, for example, whether or not 
to complete the visit or sample collection outside of the protocol-defined window. The 
sponsor’s medical monitor must be notified immediately when protocol deviations are 
discovered so that a decision about whether to keep the subject in the study can be made. 
Only when an emergency occurs that requires a departure from the protocol for an individual 
subject will there be such a departure without the sponsor’s pre-approval. The nature and 
reasons for the protocol deviation will be recorded in the subject’s CRF, and the principal 
investigator must notify the Sponsor. 
Protocol violations must be reported in the final study report. 
10.9 Access to Source Documentation 
Authorized sponsor representatives will conduct site visits to inspect study data, subjects’ 
medical records, and CRFs in accordance with ICH guidelines, GCPs, and the respective 
local and national government regulations and guidelines. 
The investigator will permit authorized representatives of the sponsor and the respective 
national or local health authorities, other authorized regulatory authorities, and IRB to inspect 
facilities and records relevant to this study. 


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


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11 REFERENCES 
US Food and Drug Administration. (2003). Guidance for Industry Pharmacokinetics in 
Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact 
on Dosing and Labeling. 
 
 
 


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Appendix 1 
Schedule of Events 
 
Screening 
In-Clinic 
Follow-up 
Study activity 
D -28 to -1 
D0 
D1 predose 
D1 postdose 
D2 
D3 
D15±1d 
Medical history and ICF 
X 
 
 
 
 
 
 
Screening for I/E criteria 
X 
X 
 
 
 
 
 
Physical exam1 
X 
X 
X 
 
 
 
X 
Demographics 
X 
 
 
 
 
 
 
Admission and discharge 
 
X 
 
 
 
X 
X 
Vital signs2 
X 
 
X 
X 
X 
X 
X 
ECG3 
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 
 
Urine collection7 
 
X 
X 
X 
X 
X 
 
Urine pregnancy test (Female only) 
X 
X 
 
 
 
 
X 
Adverse event and concomitant medication 
 
X 
X 
X 
X 
X 
X 
Study completion8 
 
 
 
 
 
 
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 on clinical admission (D0). A partial PE will be performed on day 1 and at follow up visit 
2. 
Vital signs include pulse, body temperature, respiratory rate, systolic and diastolic blood pressure. Vital signs will be determined at predose and at 4 h, 24 h (day 2) and 48 h 
(day 3) postdose and at the follow up visit. 
3. 
12-lead ECG will be conducted after 5 min resting. ECG data will be recorded at screening, on day 1 at predose and at 4 h postdose and day 3, and at follow up visit on day 
15 and when clinically indicated. 
4. 
Clean sample to be collected at each visit. If urine dipstick is positive for protein, leukocyte esterase, blood or nitrites, a microscopic examination will be performed. If the 
microscopic exam is suggestive, a culture may be performed at the investigators discretion. Urine drug screen will be performed at screening visit and clinic admission (D0). 
Alcohol (via urine or breath) will be tested at clinic admission (D0) only. 
5. 
Blood sample at the designated visits for clinical chemistry and hematology parameters are listed in Table 1. Infectious disease testing will be conducted at screening only. 
6. 
Plasma samples for PK profile of bexagliflozin will be collected at predose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h postdose. 
7. 
Urine for PD will be collected at predose (h -12 to 0), and at postdose at 0–12, 12–24, 24–36, and 36–48 h. 
8. 
If early withdrawal occurs, activities scheduled for follow up visit should be conducted. Reasons for all withdrawals should be recorded on the CRF. 


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Appendix 2 
The Child-Pugh Classification 
 
1 Grade 0: normal consciousness, personality, neurological examination, electroencephalogram  
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second 
waves  
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves  
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves  
Grade 4: unarousable coma, no personality/behavior, decerebrate, slow 2-3 cycles per second delta activity  
 
2 
Ascites is graded according to the following criteria:  
Absent: No ascites detectable by manual investigation.  
Slight: Ascites palpation doubtful  
Moderate: Ascites detectable by palpation  
Severe: Necessity of paracentesis, does not respond to medication treatment. 
 
 
 
 
 
 
 
Finding 
Points Scored for Each Observed Finding 
1 
2 
3 
Encephalopathy1 
None 
1 or 2 (or suppressed with 
medication) 
3 or 4 (or refractory) 
Ascites2 
Absent 
Slight or Subject on 1 
medication to control 
ascites 
Moderate or Severe or 
Subject on 2 medications 
to control ascites 
Bilirubin ( mg dL-1 ) 
<2 
2 to 3 
>3 
Albumin ( g dL-1 ) 
>3.5 
2.8 to 3.5 
<2.8 
INR 
<1.7 
1.7 to 2.3 
>2.3 
Total Score 
Group 
Severity 
5-6 
A 
Mild 
7-9 
B 
Moderate 
10-15 
C 
Severe 







SAP_001.pdf: 
 
Statistical Analysis Plan 
Protocol Number: THR-1442-C-455 
Last Revision Date: 31-May-2019 
 
Final 
Page 1 of 32 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Trial Sponsor: 
Protocol Number: 
Theracos Sub, LLC. 
THR-1442-C-455 
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, Parallel-group Study to Evaluate the Effect of Moderate 
Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Bexagliflozin 
 
 
 
 
Last Revision Date: 
31-May-2019 
 
 
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-455 
Last Revision Date: 31-May-2019 
 
Final 
Page 2 of 32 
CONFIDENTIAL 
 
 
FIRST SIGN-OFF APPROVAL 
 
 
Author: 
Erin Lepic 
Principal Pharmacokinetic Scientist 
Everest Clinical Research 
 
 
 
 
 
 
Signature 
Date 
 
 
 
 
Peer Review 
Biostatistician: 
Michael Edwardes 
Principal Biostatistician Statistical Operations 
Everest Clinical Research 
 
 
 
 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 
Approved by: 
Yuan-Di Halvorsen 
Clinical Trial Manager 
Translational Medicine Group 
Massachusetts General Hospital 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 
 
 
 




 
Statistical Analysis Plan 
Protocol No: THR-1442-C-455 
Last Revision Date: 31-May-2019 
 
Final 
Page 3 of 32 
CONFIDENTIAL 
 
CHANGE LOG FOR CHANGES MADE AFTER THE INITIAL APPROVAL 
 
 
Revision 
Date** 
 
Section(s) 
Modified 
 
Brief Description of Revision(s) or 
Reason(s) for Revision 
Modifications Reviewed and 
Approved by* 
Sponsor, Everest 
18-Jan-2019 
Section 6.1.1; 
Section 8.3 
Scheduled visit numbers updated in Table 4. 
Addition of hepatic impairment history. 
YH, ME 
01-Mar-2019 
Section 6.1.1 
Addition of procedure for results out-of -
window. 
YH, ME 
01-Mar-2019 
Sections 7.2 
and 13 
ISCV removed from analysis (not appropriate) 
YH, ME 
24 May, 2019 
Section 5.3 
Fix of PD population definition 
ME 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*   ME = Michael Edwardes; YH = Yuan-Di Halvorsen 
** Update the Last Revision Dates on the cover page and the document header. 
 
 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-455 
Last Revision Date: 31-May-2019 
 
Final 
Page 4 of 32 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
 
 
INTRODUCTION .......................................................................................................................................... 11 
 
STUDY OBJECTIVES................................................................................................................................... 12 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................. 12 
2.2 
SECONDARY OBJECTIVES .......................................................................................................................... 12 
 
STUDY DESIGN ............................................................................................................................................ 12 
3.1 
STUDY DESIGN .......................................................................................................................................... 12 
3.2 
RANDOMIZATION ...................................................................................................................................... 12 
3.3 
HYPOTHESIS TESTING ............................................................................................................................... 12 
3.4 
INTERIM ANALYSIS ................................................................................................................................... 12 
3.5 
SAMPLE SIZE ............................................................................................................................................. 12 
3.6 
SCHEDULE OF ASSESSMENTS AND STUDY PROCEDURES ........................................................................... 13 
 
DATA AND ANALYTICAL QUALITY ASSURANCE ............................................................................. 15 
 
ANALYSIS POPULATIONS ........................................................................................................................ 15 
5.1 
SAFETY POPULATION ................................................................................................................................ 15 
5.2 
PHARMACOKINETIC POPULATION.............................................................................................................. 15 
5.3 
PHARMACODYNAMIC POPULATION ........................................................................................................... 15 
 
SPECIFICATION OF ENDPOINTS AND VARIABLES .......................................................................... 15 
6.1 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 15 
6.1.1 
Study Day and Visit Window Definitions ................................................................................ 16 
6.2 
PHARMACOKINETICS/PHARMACODYNAMICS ............................................................................................ 17 
6.3 
SAFETY ..................................................................................................................................................... 17 
6.3.1 
Study Day and Visit Window Definitions ................................................................................ 17 
6.3.2 
Extent of Exposure to Study Medication .................................................................................. 17 
6.3.3 
Adverse Events (AEs) ............................................................................................................... 17 
6.3.4 
Laboratory Data ........................................................................................................................ 19 
6.3.5 
Vital Signs ................................................................................................................................ 21 
6.3.6 
Electrocardiogram..................................................................................................................... 21 
6.3.7 
Physical Examination ............................................................................................................... 21 
6.3.8 
Pregnancy Test ......................................................................................................................... 22 
6.3.9 
Concomitant Medications/Treatments ...................................................................................... 22 
 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES .............................................................. 23 
7.1 
GENERAL CONSIDERATIONS ...................................................................................................................... 23 
7.2 
PHARMACOKINETIC ANALYSES ................................................................................................................. 23 
7.3 
PHARMACODYNAMIC ANALYSES .............................................................................................................. 25 
 
STATISTICAL ANALYSIS .......................................................................................................................... 26 
8.1 
GENERAL DATA HANDLING RULES AND DEFINITIONS .............................................................................. 26 
8.2 
SUBJECT DISPOSITION ............................................................................................................................... 26 
8.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 26 
8.4 
SAFETY ANALYSES ................................................................................................................................... 27 
8.4.1 
Adverse Events ......................................................................................................................... 27 
8.4.2 
Laboratory Data ........................................................................................................................ 27 
8.4.3 
Vital Signs (VS) .................................................................................................................... 2728 
8.4.4 
Electrocardiogram (ECG) ......................................................................................................... 28 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-455 
Last Revision Date: 31-May-2019 
 
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Page 5 of 32 
CONFIDENTIAL 
 
8.4.5 
Physical examinations (PE) ...................................................................................................... 28 
8.4.6 
Pregnancy Test ......................................................................................................................... 28 
8.4.7 
Protocol Deviations .................................................................................................................. 28 
 
ANALYSES PERFORMED BEFORE DATABASE CLOSURE .............................................................. 28 
 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL ......................................................... 28 
 
STATISTICAL SOFTWARE ........................................................................................................................ 28 
 
REFERENCES ............................................................................................................................................... 28 
 
APPENDIX 1   DATA HANDLING RULES ............................................................................................... 29 
 
APPENDIX 2   SAS CODE FOR STATISTICAL ANALYSES ................................................................. 30 
 
APPENDIX 3   THE CHILD-PUGH CLASSIFICATION ......................................................................... 31 
 
APPENDIX 4   MOCKUP TABLES, LISTINGS, AND FIGURES (TLFS) ............................................. 32 
 
 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-455 
Last Revision Date: 31-May-2019 
 
Final 
Page 6 of 32 
CONFIDENTIAL 
 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALB 
albumin 
ALP 
alkaline phosphatase 
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 from tlast to 
infinity 
AUC0-24 
area under the plasma concentration-time curve from the time of dosing 
(Time 0) to 24 hrs post-dose 
AUC0-∞ 
area under the plasma concentration-time curve from the time of dosing  
(Time 0) to infinity 
AUCu (0-∞) area under the unbound plasma concentration-time curve from time 0 to infinity 
AUC0-t 
area under the plasma concentration-time curve from the time of dosing  
(Time 0) to Time t 
AUCu (0-t) area under the unbound plasma concentration-time curve from time 0 to time t 
BLOQ 
below the limit of quantitation 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Ca 
calcium 
CI 
confidence interval 
Cl 
chloride 
Clast 
concentration corresponding to Tlast 
CL/F 
apparent oral clearance 
CLu/F 
apparent clearance relative to unbound drug concentration 
cm 
centimeter 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-455 
Last Revision Date: 31-May-2019 
 
Final 
Page 7 of 32 
CONFIDENTIAL 
 
GLOSSARY OF ABBREVIATIONS 
Cmax 
maximum observed plasma concentration 
Cmaxu 
maximum unbound plasma concentration 
cps 
cycles per second 
CRF 
case report form 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
dL 
deciliter 
DM 
data management 
ECG 
electrocardiogram 
fu 
Unbound fraction, calculated as (free drug concentration)/(total drug 
concentration) 
hr 
hour(s) 
HbsAg 
hepatitis B surface antigen 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein cholesterol 
Hgb 
hemoglobin 
HIV 
human immmunodeficiency virus 
ICF 
informed consent form 
INR 
international normalized ration 
IRAE 
immediately reportable adverse event 
K 
potassium 
kg 
kilogram 
KR 
Kenward-Roger 
L 
liter 
λz 
terminal elimination phase rate constant 


 
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GLOSSARY OF ABBREVIATIONS 
LC-MS/MS 
liquid chromatography/mass spectrometry 
LDL-C 
low density lipoprotein cholesterol 
LLN 
lower limit of normal 
LS 
least square 
max 
maximum 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDMA 
methylenedioxymethamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minute 
mL 
milliliter 
msec 
millisecond 
Na 
sodium 
NCA 
non compartmental analysis 
NTR 
not treatment related, includes unrelated 
nUGE 
creatinine normalized UGE 
OTC 
over the counter 
PCP 
phencyclidine 
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). 


 
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GLOSSARY OF ABBREVIATIONS 
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 
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 
TCA 
tricyclic antidepressant 
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 


 
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GLOSSARY OF ABBREVIATIONS 
T-wave 
repolarization of the ventricles 
UGE 
urinary glucose excretion 
ULN 
upper limit of normal (value) 
VS 
vital sign 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell (count) 
WHO-DD 
World Health Organization Drug Dictionary 


 
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 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 3.0 dated 21-Aug-2018. 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 latest version of the protocol mentioned above and the 
final version of the annotated CRFs dated 11-SEP-2018. 
This document 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 21.0 or newer). 
Concomitant medications will be coded using the World Health Organization Drug Dictionary (WHO-
DD). 
This is a phase 1, open-label, parallel-group study designed to evaluate the effect of moderate hepatic 
impairment on the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered 
bexagliflozin tablets, 20 mg.  
Approximately 16 subjects (eight with moderate hepatic impairment [Child-Pugh total score 7-9] and 
eight healthy, matched controls) will receive a single oral dose of bexagliflozin tablet, 20 mg. 
The Child-Pugh grading system will be used to assess the severity and prognosis of hepatic disease. The 
study population will be comprised of male and female subjects with hepatic impairment conforming to 
the Child-Pugh classification of B (Child-Pugh total score 7-9) based on the Child-Pugh scoring method 
described in Appendix 3. 
For each enrolled subject with liver dysfunction a matched control subject (healthy subject) of similar age 
(±10 years), weight (±10%), sex, and smoking status will be enrolled. 
Blood samples to characterize the 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 hrs post-dose. 
Urine samples for PD analysis will be collected at pre-dose (-12 to 0 hr), and in the following intervals 
post-dose 0–12, 12–24, 24–36, and 36–48 hrs. 
Plasma concentrations of bexagliflozin will be determined by a validated liquid chromatography-mass 
spectrometry (LC-MS/MS) assay. 
The unbound fraction of bexagliflozin will be determined at the maximal plasma concentration and at 24 
h (or earlier if the 24 h post-dose sample has a concentration below the limit of quantitation) postdose for 
each subject by an equilibrium dialysis method. 
(See Protocol Sections 3.1 to 3.3 for additional details). 


 
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 STUDY OBJECTIVES 
2.1 Primary Objective 
To evaluate the effect of moderate hepatic impairment on the PK and PD of a single oral dose of 
bexagliflozin tablets, 20 mg.   
2.2 Secondary Objectives 
To assess the safety and tolerability of bexagliflozin in subjects with moderate hepatic impairment. 
 STUDY DESIGN 
3.1 Study Design 
This is a phase 1, open-label, parallel-group study. Subjects will be screened within 28 days of the 
initiation of study drug dosing. Eligible subjects who consent to participate in the study will receive a 
single oral dose of bexagliflozin tablets, 20 mg, and then will be kept under close medical surveillance at 
the trial center for at least 48 hrs following drug administration. Subjects will return for an end-of-study 
examination within 13 days of the last PK sample collection. 
 
Blood samples for characterization of the 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 hrs after oral administration of bexagliflozin. 
 
Urine samples for PD analysis will be collected prior to dosing (-12 to 0 h) and in the following intervals 
after dosing: 0–12, 12–24, 24–36, and 36–48 hrs. 
 
Plasma concentrations of bexagliflozin will be determined by a validated liquid chromatography-mass 
spectrometry (LC-MS/MS) assay. 
The unbound fraction of bexagliflozin will be determined at 24 h postdose and maximal plasma 
concentration for each subject by equilibrium dialysis. 
3.2 Randomization 
Approximately 16 subjects (eight with moderate hepatic impairment [Child-Pugh total score 7-9] and 
eight healthy, matched controls) will be enrolled. This study is non-randomized. 
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 detect clinically relevant PK differences between healthy and hepatic impairment 
subjects.   


 
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3.6 Schedule of Assessments and Study Procedures 
 


 
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Table 1. Schedule of Events 
 
 
Screening 
In-Clinic 
Follow-up 
Study activity 
D -28 to -1 
D0 
D1 pre-dose 
D1 post-dose 
D2 
D3 
D15 ± 1 
day 
Medical history and ICF 
X 
 
 
 
 
 
 
Screening for I/E criteria 
X 
X 
 
 
 
 
 
Physical exam1 
X 
X 
X 
 
 
 
X 
Demographics 
X 
 
 
 
 
 
 
Admission and discharge 
 
X 
 
 
 
X 
X 
Vital signs2 
X 
 
X 
X 
X 
X 
X 
ECG3 
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 
 
Urine collection7 
 
X 
X 
X 
X 
X 
 
Urine pregnancy test 
(Female only) 
X 
X 
 
 
 
 
X 
Adverse event and 
concomitant medication 
 
X 
X 
X 
X 
X 
X 
Study termination8 
 
 
 
 
 
 
X 
Abbreviations: D = day; ECG = electrocardiogram; ICF = informed consent form; 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 on clinical admission (D0). A partial PE 
will be performed on day 1 and at the follow-up visit. 
2. 
Vital signs include: pulse, body temperature, respiratory rate, systolic and diastolic blood pressure. Vital signs will 
be determined at predose and at 4 h, 24 h (day 2), 48 h (day 3) postdose and at the follow up visit. 
3. 
12-lead ECG will be conducted after 5 mins of resting. ECG data will be recorded at screening, on day 1 at predose 
and at 4 h postdose and day 3, and at the follow up visit and when clinically indicated. 
4. 
A clean sample will be collected at each visit. If urine dipstick is positive for protein, leukocyte esterase, blood or 
nitrites, a microscopic examination will be performed. If the microscopic exam is suggestive, a culture may be 
performed at the investigators discretion. Urine drug screen will be performed at the screening visit and clinic 
admission (D0). Alcohol (via urine or breath) will be tested at clinic admission (D0) only. 
5. 
Blood sample at the designated visits for clinical chemistry and hematology parameters are listed in Table 1. 
Infectious disease testing will be conducted at screening only. 
6. 
Plasma samples for the 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 PD will be collected at  pre-dose (h -12 to 0), and during the following intervals post-dose 0-12, 12–24,  
24–36, and 36–48 h. 
8. 
If early withdrawal occurs, activities scheduled for the follow up visit should be conducted. Reasons for all 
withdrawals should be recorded on the CRF. 
 
 
 
 


 
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 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 (DMP), 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. 
 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 subjects who have been dispensed study drug and who have received 
study drug. Subjects will be analyzed according to the respective hepatic function group. 
5.2 Pharmacokinetic Population 
The PK Population will include all subjects who have been dispensed study drug and who have received 
study drug and provided an observation for ≥1 primary PK endpoints, and without major protocol 
violations. The PK Population will be used to summarize the PK parameters. 
5.3 Pharmacodynamic Population 
The PD Population will include all subjects without major protocol violations who have been dispensed 
study drug and who have received study drug and who have had pre-dose urine collection and at least a 
postdose 0-12 hr urine sample collected. The PD Population will be used to summarize the PD parameters. 
 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) (kg m-2) 
 
Weight (kg) 


 
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 
Smoking status (non-smoker, current smoker, former smoker) 
 
Height (cm) 
 
Vital signs (VS) 
o systolic blood pressure (SBP, mmHg) 
o diastolic blood pressure (DBP, mmHg) 
o oral cavity temperature (oC) 
o pulse (beats per minute) 
o respiration rate (breaths/min) 
 
 
Electrocardiogram (ECG) parameters 
o RR interval (msec) 
o PR interval (msec) 
o QRS duration/interval (msec) 
o QT interval (msec) 
o QTcB interval (msec) (corrected by Bazett’s formula) 
 
Medical history and baseline conditions 
 
Clinical laboratory test values 
 
Prior and concomitant medication  
 
Physical examination (PE) 
6.1.1 Study Day and Visit Window Definitions 
Table 4.  Time Windows for Safety Assessments 
 
Data obtained during unscheduled visits will be allocated to the scheduled visit corresponding to the visit 
window they fall in as specified in Table 4. 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, the latest assessment will be selected for analysis. 
 
Time Windows for Safety Assessments 
Scheduled Visit Number 
Visit (label) 
Time Interval (day) 
Nominal Target Time Point 
(day) 
1 
Screening 
-28 to -1 
-28 to -1 
2 
Day 0 
0 
0 
3 
Day 1 
Day 1 pre-dose 
Day 1 pre-dose 
3 
Day 1 
Day 1 post-dose 
Day 1, 4 hrs post-dose 
4 
Day 2 
2 
2 
5 
Day 3 
3 
3 
6 
Day 15 
15 ± 1 day 
15  


 
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If there are multiple unscheduled visits within the interval of 15 ± 1 day the latest unscheduled visit within 
this window will be used. If there are multiple unscheduled visits outside of the time interval of 15 ±1 day, 
and there is no visit in the interval 15 ±1 day, the visit closest to the interval of 15 ± 1 will be used. 
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 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 prior to dosing (-12 to 0 h) and in the following intervals 
after dosing: 0–12, 12–24, 24–36, and 36–48 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 AEs, 
clinical evaluations (PE results, VS results, ECG results), and clinical laboratory testing. 
Safety variables include the following: 
1. AEs 
2. Clinical laboratory measurements – serum chemistry, hematology, and urinalysis 
3. Urine drug screen 
4. VS 
5. ECG 
6. PE 
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 
This is a single dose study. Subjects will receive a single dose of 20 mg of bexagliflozin. 
6.3.3 Adverse Events (AEs) 
Adverse events will be collected and coded using version 21.0 (or newer) of MedDRA. Analysis of AEs 
will be carried out on the Safety Population. All AEs 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 hepatic function group.  
If the AE(s) onset date-time or date occurs after the dose of bexagliflozin up until the end of the study, the 
AE(s) will be assigned to bexagliflozin.  
All adverse events will be assessed by the investigator(s) with respect to severity, relationship to study drug 
and seriousness. 


 
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6.3.3.1 Treatment-Emergent AE (TEAE) 
An adverse event is considered treatment-emergent if it occurs after treatment with the study drug, and if 
the date of onset is on or after the date of the dose of study medication, or worsens during the treatment 
period (intensity/severity grades worsen). 
6.3.3.2 Serious Adverse Events (SAE) 
AEs will be categorized as serious or non-serious using the definition specified in Section 6.7 of the study 
protocol. 
6.3.3.3 Immediately Reportable AE (IRAE) 
An IRAE is any serious adverse event that is reported within 24 hrs of the site being aware of the event.  
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 [PT]) more than once during the 
study will be counted only once in the number of subjects with that event. 
3. For a subject who experienced the same event (AE preferred term) more than once during the study 
with a different severity or seriousness, the AE will be counted only once with the worst grade and 
seriousness respectively. 
4. For a subject who experienced the same event (AE preferred term) more than once during the study 
with a different causal relationship to the study drug, the AE 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 Grade 1 “Mild”, Grade 2 “Moderate”, and Grade 3 
“Severe” using the criteria specified in Section 6.7 of the study protocol. 
6.3.3.6 Relationship to the Investigational Medicinal Product 
The relationship of an AE to dosing will be assessed as “Definite”, “Probable”, “Possible”, “Not Likely”, or 
Unrelated using the criteria specified in Section 6.7 of the study protocol. 
6.3.3.7 AE with Irregular Start/End Dates or Times 
Partial dates or times may be imputed when appropriate. Imputed dates will be used to determine Study 
Day. 
If a partial date and/or time is reported for the start of an AE, a complete date and time 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 
January 1 will be used as the starting date of the event. If the subject started receiving study drug in 
the year reported, then the date of the first dose of study drug will be used as the start date of the 
event. 


 
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2. The month and year is reported: If the subject started receiving study drug 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 drug during the month and year reported, then the date of the first 
dose of study drug will be used as the start date of the event. 
3. Time is not reported: If the event date, or imputed date (from rule 1 or 2), is on the same date as 
study drug start, then time of start of the drug will be used as the start time. For other dates or 
imputed dates, 12 AM (00:00) will be imputed as the start time. 
If a partial date is reported for the end of an AE and the AE 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 drug 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 date of the AE. 
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. 
3. Time is not reported: Impute 23:59. 
The above rules are subject to logical sense, for example, imputed start date should be on or prior to 
imputed end date, and end time must equal or exceed start time, if on the same date and end time should 
equal or exceed start time on the same 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, 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 
International normalized ration (INR) 
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) 
Bicarbonate 
Total bilirubin 
Creatinine  
Direct bilirubin 
Creatinine kinase 
Alkaline Phosphatase (ALP) 
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 (performed if 
protein, leukocyte esterase, nitrite, or blood is positive) 
Leukocyte esterase 
Occult blood 
 
Urine Collection 
Glucose 
Creatinine 
Urine Drug Screen 


 
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Amphetamines 
Opiates 
Barbiturates 
Benzodiazepines 
Cocaine Metabolites 
Cannabinoids 
MDMA 
Methamphetamine 
TCA 
Methadone 
PCP 
OXY 
Alcohol 
 
Pregnancy Test - Urine 
Infectious Disease Testing (measured at screening only) 
Hepatitis B Surface Antigen (HbsAg) 
Hepatitis C virus (HCV) 
Human Immunodeficiency Virus antibody (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 hepatic function group. 
Baseline values are those measured at last evaluation prior to administration of study drug. 
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 interval, 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), and 
QTcB interval 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. 
ECG changes from baseline will be summarized by hepatic function group. 
Change from baseline to time point t, denoted Changet, will be calculated as: 
Changet = Valuet – ValueBaseline. 
6.3.7 Physical Examination 
A complete PE will include measurement of body weight and height (height will be measured only at 
screening), general assessment of all body systems including the skin, head, eyes, ears, nose, throat, neck, 
lungs, heart, abdomen, lymph nodes, and extremities. 
Physical examination results will be presented in individual subject data listings. 


 
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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 during the study will be recorded on the CRF. The medication 
name, indication, dose, unit, frequency, route of administration, start/stop date(s) and time(s) of 
administration and reason for administration will be recorded. If the concomitant medication is ongoing this 
will be documented on the CRF. 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 or times, imputation will be used to convert to a complete date and 
time. Imputed dates will be used to determine Study Day. 
Partial medication start dates and times 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 date 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 date of the medication. 
3. Time is not reported: If the medication start date, or imputed date (from rule 1 or 2), is on the same 
date as study drug start, then time of start of the study drug will be used as the start time. For other 
dates or imputed dates, 12 AM (00:00) will be imputed as the start time. 
 
Partial medication end dates and times 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. 
3. Time is not reported: Impute 23:59. 
The above rules are subject to logical sense, for example, imputed start date should be on or prior to 
imputed end date. 


 
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Verbatim terms will be coded and assigned a preferred (PT) term and an ATC (anatomic therapeutic class) 
term. 
 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, PK, and PD 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) or later. 
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 
AUC0-24 
Area under the plasma concentration-time curve from the time of dosing to 24 h post-dose 
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 
AUCextr 
The proportion of AUC0-∞ due to extrapolation from Tlast to infinity, expressed as a % 
Cmaxu 
Maximum unbound plasma concentration 
AUCu (0-t) 
Area under the unbound plasma concentration-time curve from time 0 to time t 
AUCu (0-∞) 
Area under the unbound plasma concentration-time curve from time 0 to infinity 
Clu/F 
Apparent clearance relative to the unbound drug concentration 
 
Cmax and Tmax will be obtained directly from experimental observations. If multiple maxima occur at equal 
concentrations, the first temporal value will be taken as the Cmax and Tmax. 
The apparent terminal elimination half-life, T1/2, where determinable, will be calculated as the natural log 
of 2 divided by the terminal phase rate constant, λz. The number of data points included in the regression 
will be determined by visual inspection, but a minimum of three data points in the terminal phase, excluding 
Cmax, is required to estimate λz. In order for the selection to take place the adjusted r2 value reported in 
Phoenix®WinNonlin® must be ≥ 0.7. 


 
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AUC0-24, 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 that are BLOQ are encountered after Tmax, these and all subsequent values will be 
excluded from the analysis. 
AUC0-∞ will be calculated as outlined below: 
AUC0-∞= AUClast + (Clast / λz), where Clast is the last temporal quantifiable plasma concentration 
corresponding to Tlast. 
The proportion of AUC0-∞ due to extrapolation (AUCextr) will be calculated and expressed as a percentage. 
AUC0-∞ values will be considered unreliable estimates if the AUCextr is greater than 20% and will be 
excluded from summary tables but will be listed. 
CL/F will be calculated as Dose/AUC0-∞. 
Vz/F will be calculated as Dose/(λz × AUC0-∞). 
T½ will be calculated as 0.693/λz. 
The fraction unbound (fu) will be calculated as free drug concentration/total drug concentration. 
The apparent clearance relative to the unbound drug concentration (Clu/F) will be calculated as 
Clu/F=Dose/AUCu.  
Listings of plasma concentrations by Subject Number, hepatic function group, and timepoint will also be 
provided. 
To assess the effect of moderate hepatic impairment on the PK of bexagliflozin, an analyses of variance 
(ANOVA) with a fixed effect corresponding to the hepatic function group (normal or moderate hepatic 
impairment) will be fitted to the natural logarithmic transformation of PK parameters (Cmax, AUC0-t and 
AUC0-∞). The 90% confidence intervals will be constructed for the ratio of least squares (LS) geometric 
means of PK parameters (total and unbound Cmax, AUC0-t and AUC0-∞) for the moderate hepatic function 
group vs the normal group, with 80-125% defined as the boundaries for subjects in the PK Population.  
The ratios of geometric least squares means and corresponding 90% confidence interval (CI) for the 
treatment comparison will be determined by exponentiating the mean differences between treatments on the 
logarithm scale.  
The appropriateness of the mixed model will be assessed through residual analyses. Any modifications 
required due to poor fit will be reported and executed. 
Refer to Appendix 2 for the SAS code. 
Descriptive statistics of total and unbound plasma concentration time data will be summarized by hepatic 
function group and timepoint. 
A listing of bexagliflozin concentration-time data by Subject Number, hepatic function group and timepoint 
will be provided. 
The PK parameters Cmax, tmax, λz, t1/2, CL/F, Vz/F, AUC0-t, AUC0-24, AUC0-∞, AUCextr, AUCu (0-t), AUCu (0-∞), 
Cmaxu, and Clu/F will be summarized by hepatic function group for bexagliflozin.  


 
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Descriptive statistics of total and unbound PK parameters will be summarized by hepatic function group for 
the PK Population. 
Means, standard deviation (SD), medians, ranges (min, max) and geometric means and coefficients of 
variation will be presented for all parameters will the exception of Tmax. Medians and ranges will be 
presented for Tmax. 
A listing of derived PK parameters of bexagliflozin for total and unbound bexagliflozin by Subject Number 
and hepatic function group will be provided. 
Descriptive statistics for urinary glucose concentrations, urinary glucose excretion (UGE), urinary 
creatinine concentrations, and urinary glucose/creatinine by hepatic function group and collection interval 
will be summarized for the PD Population. Because concentration values that were below the limit of 
quantitation (BLOQ) prior to Tmax will be set to zero, which cannot be included in calculation of a 
geometric mean, then geometric means and percent CV calculated for data including BLOQ values will be 
based only on the subjects with non-BLOQ data 
A listing of urinary PD parameters will be provided by Subject Number, hepatic function group and 
collection interval. 
Plasma protein bound and unbound bexagliflozin will be determined by an equilibrium dialysis method. 
The bexagliflozin unbound fraction will be calculated for each subject by dividing the bexagliflozin 
concentration in the dialysate by the bexagliflozin concentration in plasma. The unbound fraction from the 
plasma sample at the maximum plasma concentration will be used to calculate the unbound plasma 
concentration at each time point prior to 24 hrs for each individual subject.   The unbound fraction from the 
plasma sample at 24 hrs postdose will be used to calculate the unbound plasma concentration at each time 
point at or after 24 hrs postdose for each subject. If the unbound fraction at 24 hrs is not available, the 
unbound fraction at the maximum plasma concentration will be used to calculate the unbound plasma 
concentration at all time points. 
7.3 Pharmacodynamic Analyses 
Urinary glucose excretion (UGE) and creatinine normalized UGE (nUGE) will be determined as PD 
parameters at baseline and up to 48 hours post-dose.  
UGEt1-t2 (g) will be derived from urine volume and glucose concentration as follows: 
[urine volume (Vt1-t2, mL) x glucose concentration (mg/dL)/100]/1000. 
UGE normalized by urinary creatinine will be calculated as per below: 
[urine volume (Vt1-t2, mL) x creatinine concentration (mg/dL)/100]/1000. 
The total 24-hour and 48-hour quantity of glucose excreted in urine will be calculated by adding the 
amounts collected during each post-dose interval. 
Descriptive statistics will be used to describe any differences in these PD parameters between treatment 
groups (normal hepatic function and moderate hepatic impairment).  
For PD data, reported pre-dose values that are below the defined limit will be set to zero. Any missing 
values or values below the reported defined limit that appear after pre-dose for PD data (glucose, UGE, 
creatinine) will be set to missing. Because zero values cannot be included in calculation of a geometric 
mean, then geometric means and percent CV calculated for data including values below the defined limit 
will be based only on the subjects without such zero value data 
PD data will also be reported in listings. 


 
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 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 treated 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 hepatic function 
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 treated, completed, and those who withdraw study participation early. The number and percentage 
of subjects who are included in the PK, Safety and PD Populations will also be tabulated. 
Subject disposition by site and hepatic function group will also be summarized for the Safety Population. 
These tabulations will include the number of subjects dosed, completed, and those who withdraw study 
participation early along with the corresponding primary reasons for early withdrawal. 
Subjects in the Safety Population who prematurely discontinued from the study will be summarized by 
primary reason for early withdrawal. 
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 site and by hepatic function group for both 
the Safety and PK Populations and listed for the Safety Population. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be presented for 
continuous variables. Frequency distributions (counts and percentages) will be presented for categorical 
variables. 
Medical history and baseline conditions will be summarized by hepatic function group and for all subjects 
and listed for the Safety Population. 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 electronic CRF. The World Health Organization Drug 
Dictionary (WHO-DD), version March 2018 or newer, will be used to classify prior and concomitant 
medications by therapeutic class and drug name and hepatic impairment history. 


 
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Abnormalities in the subjects’ medical and surgical histories will be coded using version 21.0 
(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 hepatic function 
group. 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 hepatic function group. 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 treatment related [TR]). Summary 
tables will be organized by SOC, then PT. 
The following summaries will be presented for TEAEs for each hepatic function group and for all subjects 
for selective summaries for the Safety Population. 
 
Overall Summary of TEAEs by hepatic function group 
 
Incidence of TEAEs by hepatic function group, system organ class, and preferred term 
 
Incidence of Treatment Emergent Serious Adverse Events by hepatic function group, system 
organ class, and preferred term 
Subjects who prematurely withdraw due to TEAEs and subjects with serious TEAEs will be listed for the 
Safety Population. 
8.4.2 Laboratory Data 
Summary tables for laboratory parameters (including hematology, chemistry, and urinalysis) will be 
summarized for subjects in the Safety Population. Summaries for change from baseline for hematology, 
chemistry, and urinalysis parameters will include descriptive statistics (the number of non-missing values, 
mean, standard deviation, median, minimum and maximum) for values and change from baseline values for 
all continuous variables, and frequency counts and percentages for categorical variables, by treatment. 
Subjects with laboratory data outside the normal range will be listed with abnormal values flagged. 
8.4.3 Vital Signs (VS) 
Summary tables for VS 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 
hepatic function group. 


 
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A listing of VS results will be provided for all subjects in the Safety Population. 
8.4.4 Electrocardiogram (ECG)  
ECG parameters (RR interval, PR interval, QRS interval, QT interval, and QTcB interval) will be 
summarized by changes from baseline values by hepatic function 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 (PE) 
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. 
8.4.7 Protocol Deviations 
All protocol deviations will be listed. 
 ANALYSES PERFORMED BEFORE DATABASE CLOSURE 
No interim analyses are planned for this study. 
 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. 
 STATISTICAL SOFTWARE 
The statistical software to be used for generation of the tables, listings, and figures is SAS® version 9.4. 
 REFERENCES 
Not Applicable. 


 
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 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 
PD 
Data below the 
defined limit; 
Missing data 
For PD data, reported pre-dose values that are below the defined limit will be set 
to zero. Any missing values or values below the reported defined limit that appear 
after pre-dose for PD data (glucose, UGE, creatinine) will be set to missing. 
PK 
Missing data 
For PK data, 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 that are BLOQ are encountered after Tmax, 
these and all subsequent values will be excluded from the analysis. 


 
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 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 SUBJ as a random 
effect and HEPATIC FUNCTION GROUP as a fixed effect. “Y” 
denotes the response measure (log (AUC), log (CMAX)). “KR” 
denotes Kenward-Roger method. “CL” denotes confidence limits. 
 
 
PROC MIXED METHOD=REML; 
   CLASS SUBJ TRTP; 
   MODEL Y = TRTP/ DDFM=KR; 
   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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 APPENDIX 3   THE CHILD-PUGH CLASSIFICATION 
Finding 
Points Scored for Each Observed Finding 
1 
2 
3 
Encephalopathy 1 
None 
1 or 2 (or suppressed with medication) 
3 or 4 (or refractory) 
Ascites 2 
Absent 
Slight or Subject on 1 medication to control 
ascites 
Moderate or Severe or Subject on 2 
medications to control ascites 
Bilirubin (mg/dL) 
<2 
2 to 3 
>3 
Albumin (g/dL) 
>3.5 
2.8 to 3.5 
<2.8 
INR 
<1.7 
1.7 to 2.3 
>2.3 
 
 
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second (cps) 
waves 
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
Grade 4: unarousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity 
 
2 Ascites is graded according to the following criteria: 
Absent: No ascites detectable by manual investigation. 
Slight: Ascites palpation doubtful 
Moderate: Ascites detectable by palpation 
Severe: Necessity of paracentesis, does not respond to medication treatment. 
 
Total Score 
Group 
Severity 
5-6 
A 
Mild 
7-9 
B 
Moderate 
10-15 
C 
Severe 
 
 


 
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 APPENDIX 4   MOCKUP TABLES, LISTINGS, AND FIGURES (TLFS) 
Mockup tables, listings, and figures are presented in a separate document.