Clinical trial NCT03197324
Conditions: Type2 Diabetes Mellitus
Sponsor: Theracos
Start date: 2017-07-24; Completion date: 2017-09-17
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to examine the drug-drug interaction in your body when given the study drug, bexagliflozin, with the heart failure medication digoxin. The study will evaluate whether bexagliflozin effects the amount of digoxin in your blood and how safe the study drug is and how well the study drug is tolerated when taken with digoxin.

Detailed description:
This was a phase 1, single center, open-label, two-period, two-treatment, crossover study to evaluate the effect of bexagliflozin tablets, 20 mg, on the pharmacokinetics (PK) of digoxin, 0.5 mg after co-administration in healthy subjects. Each subject was randomized into one of 2 treatment groups and participated in 2 treatment periods as outlined below. During the duration of the study, each subject received 8 single doses of bexagliflozin and 2 single doses of digoxin. Clinical laboratory tests and safety monitoring were conducted during Periods 1 and 2.

Group 1 - Period 1, Treatment A Subjects were admitted to the clinic on Day 0. Subjects received daily oral doses of a bexagliflozin tablet, 20 mg, starting on Day 1 for 8 days, and a single oral dose of 0.5 mg digoxin (two 0.25 mg tablets) was co-administered with bexagliflozin on Day 3. Blood samples for PK were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours (h) on Day 3, 24 h (Day 4), 48 h (Day 5), 72 h (Day 6), 96 h (Day 7), and 120 h (Day 8) after administration of digoxin. Subjects were discharged on Day 8.

Group 1 - Period 2, Treatment B Subjects were admitted to the clinic on Day 18. On Day 19, subjects received a single oral dose of 0.5 mg digoxin. Blood samples for PK were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h on Day 19, 24 h (Day 20), 48 h (Day 21), 72 h (Day 22), 96 h (Day 23), and 120 h (Day 24) after administration of digoxin. Subjects were discharged on Day 24.

Group 2 - Period 1, Treatment B Subjects were admitted to the clinic on Day 0. On Day 1, subjects received a single oral dose of 0.5 mg digoxin. Blood samples for PK were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h on Day 1, 24 h (Day 2), 48 h (Day 3), 72 h (Day 4), 96 h (Day 5), and 120 h (Day 6) after administration of digoxin. Subjects were discharged on Day 6.

Group 2 - Period 2, Treatment A Subjects were admitted to the clinic on Day 14. Subjects received daily oral doses of a bexagliflozin tablet, 20 mg, for 8 days starting on Day 15, and a single oral dose of 0.5 mg digoxin (two 0.25 mg tablets) was co-administered with bexagliflozin on Day 17. Blood samples for PK were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h on Day 17, 24 h (Day 18), 48 h (Day 19), 72 h (Day 20), 96 h (Day 21), and 120 h (Day 22) after administration of digoxin. Subjects were discharged on Day 22.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Bexagliflozin intervention 2: Digoxin
Intervention descriptions: intervention 1: Bexagliflozin tablets, 20 mg intervention 2: 2 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)

Protocol documents:
Prot_000.pdf: 
 
 
Clinical Trial Protocol: THR-1442-C-443 
Study Title: 
A Phase 1, Open-label, Randomized, Two-period, Two-treatment, 
Crossover Study to Evaluate the Effect of Bexagliflozin on the 
Pharmacokinetics of Digoxin in Healthy Subjects 
Study Number: 
THR-1442-C-443 
Study Phase: 
1 
Product Name: 
Bexagliflozin Tablets, 20 mg 
Indication: 
Type 2 Diabetes Mellitus 
Investigators: 
Single Center 
Sponsor: 
Theracos Sub, LLC 
Sponsor Contact: 
Albert Collinson, Ph.D. 
Theracos Sub, LLC 
225 Cedar Hill Street, Suite 200 
Marlborough, MA 01752 
Sponsor Protocol 
Representative: 
Annie L. Conery, Ph.D. 
185 Cambridge Street, Boston, MA 02114 
Phone: 617-726-5930, Fax: 617-643-8203 
e-mail: aconery@mgh.harvard.edu 
Medical Monitor: 
Mason W. Freeman, M.D. 
185 Cambridge Street, Boston, MA 02114 
Phone: 617-724-7704, Fax:617-643-8203 
Email: mfreeman@ccib.mgh.harvard.edu 
 
 
Date 
Version 2.0: 
13 June 2017 
 
Confidentiality Statement 
The information contained in this protocol is confidential and provided only to the 
investigators, clinical study collaborators, investigational drug managers, study sites and 
institutional review boards participating in the study. The information may, therefore, not be, 
disclosed to any third party except for subjects when receiving their consent, or used for 
purposes other than this study without the written consent of Theracos Sub, LLC 


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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 188, 
microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate (vegetable 
grade). The tablets are film-coated with Opadry II Blue with no markings on the tablets. 
Study Title: 
A Phase 1, Open-label, Randomized, Two-period, Two-treatment, Crossover Study to 
Evaluate the Effect of Bexagliflozin on the Pharmacokinetics of Digoxin in Healthy Subjects  
Study Number: THR-1442-C-443 
Study Phase: 1 
Primary Objective:  
To evaluate the effect of bexagliflozin on the pharmacokinetics (PK) of digoxin 
Secondary Objective: 
To assess the safety and tolerability of digoxin when it is co-administered with bexagliflozin  
Study Design: 
This is a phase 1, single center, open-label, two-period, two-treatment, crossover study to 
evaluate the effect of bexagliflozin tablets, 20 mg, on the pharmacokinetics of digoxin, 0.5 
mg, when co-administered in healthy subjects. Approximately 18 eligible healthy subjects 
will be randomized to one of the two groups (Group 1 and 2) with up to 9 subjects per group. 
Subjects will reside in the clinic for a total of 16 days, divided into two treatment periods, 
Periods 1 and 2. Subjects will be discharged and out of the clinic between the 2 treatment 
periods for 9 days for Group 1 and 7 days for Group 2. During the treatment periods, subjects 
will receive 2 treatments in differing order: Treatment A, bexagliflozin administered once 
daily for 8 days with digoxin co-administered on Day 3 and Treatment B, digoxin 
administered alone on Day 1. Safety monitoring will be conducted throughout the study.  
Group 1:  
Period 1, Treatment A: Subjects randomized to Group 1 will be admitted to the clinic on Day 
0. Starting on Day 1, subjects will receive once daily oral dose of 20 mg bexagliflozin for 8 
days; a single dose of 0.5 mg digoxin will be co-administered with bexagliflozin on Day 3. 
Blood samples for PK will be drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours 
(h) on Day 3, 24 h (Day 4), 48 h (Day 5), 72 h (Day 6), 96 h (Day 7), and 120 h (Day 8) after 
administration of digoxin. Subjects will be discharged on Day 8. 
Period 2, Treatment B: Subjects will be admitted on Day 18 and receive a single oral dose of 
0.5 mg digoxin on Day 19. Blood samples for PK will be drawn at pre-dose and at 0.5, 1, 1.5, 
2, 3, 4, 6, 8, and 12 hours (h) on Day 19, 24 h (Day 20), 48 h (Day 21), 72 h (Day 22), 96 h 
(Day 23), and 120 h (Day 24) after administration of digoxin. Subjects will be discharged 


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from the clinic on Day 24. 
Group 2:  
Period 1, Treatment B: Subjects randomized to Group 2 will be admitted to the clinic on Day 
0. On Day 1, subjects will receive a single oral dose of 0.5 mg digoxin. Blood samples for 
PK will be drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours (h) on Day 1, 24 h 
(Day 2), 48 h (Day 3), 72 h (Day 4), 96 h (Day 5), and 120 h (Day 6) after administration of 
digoxin. Subjects will be discharged on Day 6. 
Period 2, Treatment A: Subjects will be admitted on Day 14. On Day 15, subjects will start to 
receive once daily oral dose of 20 mg bexagliflozin for 8 days; a single dose of 0.5 mg 
digoxin will be co-administered with bexagliflozin on Day 17. Blood samples for PK will be 
drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours (h) on Day 17, 24 h (Day 18), 
48 h (Day 19), 72 h (Day 20), 96 h (Day 21), and 120 h (Day 22) after administration of 
digoxin. Subjects will be discharged from the clinic on Day 22. 
Study Population:  Approximately 18 healthy subjects are planned. 
Diagnosis and Main Criteria for Inclusion: 
1. Subjects who are between the ages of 18 and 55 years, inclusive, in good health based on 
medical history, physical examination, ECG, and routine laboratory tests (blood 
chemistry, electrolytes, hematology, lipids, urinalysis, and drug screen) 
2. Subjects with body-mass index (BMI) between 18.0 kg/m2 and 32.0 kg/m2, inclusive 
3. Subjects who are not surgically sterile must agree to use appropriate birth control when 
engaging in sexual intercourse for a period of 30 days after discharge from the clinic 
4. Subjects who are non-smokers for at least 6 months prior to screening 
Test Product; Dose; and Mode of Administration:  
Bexagliflozin Tablets, 20 mg, oral administration 
Reference Therapy; Dose; and Mode of Administration: 
Digoxin Tablets, 0.5 mg, oral administration 
Duration of Treatment:  
Each study subject will receive a total of 8 doses of bexagliflozin (20 mg) and 2 doses of 
digoxin (0.5 mg) during 2 treatment periods with a study duration of up to 46 days, including 
screening and washout periods. 
Pharmacokinetic Variables: 
The following PK parameters of digoxin, if possible, will be determined after each subject is 
dosed with either digoxin alone, or the combination of digoxin and bexagliflozin. 
Cmax 
Maximum observed plasma concentration 
tmax 
Time of maximum observed plasma concentration 
λz 
Terminal elimination phase rate constant  
t½ 
Apparent terminal elimination half-life 
CL/F 
Apparent oral clearance 
Vz/F 
Apparent volume of distribution 


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AUC0-t 
Area under the plasma concentration-time curve from Time 0 to Time t (time 
of last quantifiable plasma concentration) 
AUC0-∞ 
 
Area under the plasma concentration-time curve from Time 0 to infinity 
Safety Assessments: 
Physical examinations 
Vital signs 
12-lead electrocardiograms 
Clinical laboratory tests including blood chemistry and hematology parameters 
Urinalysis 
Adverse events 
Concomitant medication use 
Statistical Methods:  
Statistical analysis will be performed using Statistical Analysis Software SAS for Windows® 
(SAS, USA). PK parameters of digoxin will be calculated by non-compartmental analyses 
(NCA) of plasma concentration-time data using Phoenix® WinNonlin® 6.4 (Certara, USA). 
To assess the effect of bexagliflozin on the PK of digoxin, an analyses of variance (ANOVA) 
using a linear mixed-effects model will be fitted to the natural logarithmic transformation of 
PK parameters of digoxin (Cmax, AUC 0-t and AUC 0-∞). The linear mixed-effects model will 
include subject as a random effect, and treatment, period, and sequence as fixed effects. The 
90% confidence intervals will be constructed for the (digoxin with bexagliflozin) to (digoxin 
alone) ratio of the least squares (LS) geometric means of PK parameters (Cmax, AUC0-t and 
AUC0-∞), with 80-125% defined as the lack of interaction boundaries.  
Descriptive statistics for the PK parameters Cmax, Tmax, AUC0-∞, AUC0-t , CL/F, Vz/F, λz and 
T1/2 will be tabulated by treatment. Means, standard deviations, medians, ranges (min, max) 
and geometric means and coefficients of variation will be presented for all PK parameters 
with exception of Tmax. Medians and ranges will be presented for Tmax. 
Date of Original Protocol: 09 June 2017 
Date of Most Recent Protocol V.2.0: 13 June 2017 
Prepared in: Microsoft Word 2007 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................9 
1 
INTRODUCTION ...........................................................................................................11 
2 
STUDY OBJECTIVES ....................................................................................................12 
2.1 
Primary Objective ..................................................................................................12 
2.2 
Secondary Objective ..............................................................................................12 
3 
INVESTIGATIONAL PLAN ..........................................................................................13 
3.1 
Overall Study Design and Plan ..............................................................................13 
3.1.1 
Group 1 ........................................................................................................13 
3.1.2 
Group 2 ........................................................................................................13 
3.2 
Rationale for Study Design and Control Group .....................................................14 
3.2.1 
Rationale for Study Design ..........................................................................14 
3.2.2 
Rationale for Dose Selection .......................................................................15 
3.2.3 
Rationale for PK Sampling Time Points ......................................................15 
3.3 
Study Duration and Dates ......................................................................................15 
4 
STUDY POPULATION SELECTION ...........................................................................17 
4.1 
Study Population ....................................................................................................17 
4.2 
Inclusion Criteria ...................................................................................................17 
4.3 
Exclusion Criteria ..................................................................................................18 
5 
STUDY TREATMENT(S) ..............................................................................................20 
5.1 
Description of Treatment(s) ...................................................................................20 
5.1.1 
Investigational Product: Bexagliflozin ........................................................20 
5.1.2 
Cardiovascular Drug: Digoxin .....................................................................20 
5.2 
Treatment(s) Administered ....................................................................................20 
5.3 
Selection and Timing of Dose for Each Subject ....................................................20 
5.3.1 
Bexagliflozin ................................................................................................20 
5.3.2 
Digoxin ........................................................................................................20 
5.3.3 
Bexagliflozin and digoxin ............................................................................20 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................21 
5.5 
Blinding..................................................................................................................21 
5.6 
Concomitant Therapy.............................................................................................21 
5.7 
Restrictions ............................................................................................................21 
5.7.1 
Prior Therapy ...............................................................................................21 
5.7.2 
Fluid and Food Intake ..................................................................................21 
5.7.3 
Subject Activity Restrictions .......................................................................22 


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5.8 
Treatment Compliance ...........................................................................................22 
5.9 
Packaging and Labeling .........................................................................................22 
5.9.1 
Bexagliflozin ................................................................................................22 
5.9.2 
Digoxin ........................................................................................................22 
5.10 
Storage and Accountability ....................................................................................22 
6 
STUDY PROCEDURES .................................................................................................23 
6.1 
Informed Consent...................................................................................................23 
6.2 
Medical History .....................................................................................................23 
6.3 
Physical Examination.............................................................................................24 
6.4 
Vital Signs ..............................................................................................................24 
6.5 
Electrocardiography ...............................................................................................24 
6.6 
Clinical Laboratory Tests .......................................................................................25 
6.6.1 
Laboratory Parameters .................................................................................25 
6.6.2 
Sample Collection, Storage, and Shipping ..................................................26 
6.6.2.1 
Hematology and Blood Chemistry.....................................................26 
6.6.2.2 
Urinalysis ...........................................................................................26 
6.6.2.3 
PK Plasma Sample Collection and Analysis .....................................26 
6.7 
Adverse Events Assessments .................................................................................26 
6.7.1 
Collecting and Reporting Adverse Events ...................................................28 
6.7.2 
Immediately Reportable Adverse Events .....................................................28 
6.7.3 
Pregnancy .....................................................................................................29 
6.7.4 
Follow-up of Adverse Events ......................................................................30 
6.7.4.1 
Follow-up of Non-serious Adverse Events ........................................30 
6.7.4.2 
Follow-up of Post-Study Serious Adverse Events .............................30 
6.7.4.3 
Hepatotoxicity ....................................................................................30 
6.7.4.4 
Hypoglycemia ....................................................................................31 
6.8 
Concomitant Medication Assessments ..................................................................32 
6.9 
Removal of Subjects from the Trial or Discontinuation of Investigational 
Product ...................................................................................................................32 
6.10 
Appropriateness of Measurements .........................................................................33 
7 
STUDY ACTIVITIES .....................................................................................................34 
7.1 
Screening (Days –14 to -1) ....................................................................................34 
7.2 
Group 1 ..................................................................................................................34 
7.2.1 
Period 1 ........................................................................................................34 
7.2.2 
Period 2 ........................................................................................................36 
7.3 
Group 2 ..................................................................................................................37 
7.3.1 
Period 1 ........................................................................................................37 
7.3.2 
Period 2 ........................................................................................................39 
7.4 
Follow-up Procedures or Early Termination .........................................................41 


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8 
QUALITY CONTROL AND ASSURANCE .................................................................42 
9 
PLANNED STATISTICAL METHODS ........................................................................43 
9.1 
General Considerations ..........................................................................................43 
9.2 
Determination of Sample Size ...............................................................................43 
9.3 
Analysis Populations ..............................................................................................43 
9.3.1 
Safety Population .........................................................................................43 
9.3.2 
PK Population ..............................................................................................43 
9.4 
Demographics and Baseline Characteristics ..........................................................43 
9.5 
Pharmacokinetic Analysis ......................................................................................43 
9.5.1 
Calculation of Pharmacokinetic Parameters ................................................43 
9.5.2 
Statistical Analysis .......................................................................................45 
9.6 
Safety Analysis ......................................................................................................45 
9.6.1 
Adverse Events ............................................................................................45 
9.6.2 
Hypoglycemia ..............................................................................................46 
9.6.3 
Clinical and Laboratory Events and Analyses .............................................46 
9.6.4 
Concomitant Medications ............................................................................46 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................47 
10.1 
Investigators and Study Administrative Structure .................................................47 
10.2 
Institutional Review Board (IRB) ..........................................................................47 
10.3 
Ethical Conduct of the Study .................................................................................47 
10.4 
Subject Information and Consent...........................................................................48 
10.5 
Subject Confidentiality ..........................................................................................48 
10.6 
Study Monitoring ...................................................................................................48 
10.7 
Case Report Forms and Study Records .................................................................49 
10.8 
Protocol Violations/Deviations ..............................................................................49 
10.9 
Access to Source Documentation ..........................................................................49 
10.10 Retention of Data ...................................................................................................50 
10.11 Publication and Disclosure Policy .........................................................................50 
11 REFERENCE LIST .........................................................................................................51 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Required Laboratory Tests ...........................................................................25 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ................................................................................................14 
 


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LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................52 
Appendix 2 
Dosing Schedule ................................................................................56 
Appendix 3 
Sponsor Signatures.............................................................................57 
Appendix 4 
Investigator’s Signature .....................................................................58 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALT 
alanine aminotransferase  
ANOVA 
analysis of variance 
AP 
alkaline phosphatase 
AST 
aspartate aminotransferase   
ATPase 
adenosine triphosphatase  
AUC 
area under the time-concentration curve 
AUC0-∞ 
area under the plasma concentration-time curve from Time 0 to infinity 
AUC0-t 
area under the plasma concentration-time curve from Time 0 to Time t (time of last 
quantifiable plasma concentration) 
BMI 
body mass index 
BP 
blood pressure  
BUN 
blood urea nitrogen 
Cmax 
maximum plasma drug concentration 
CI 
confidence interval 
CL/F 
Apparent oral clearance 
CRF 
case report form 
CRO 
contract research organization  
DPP-4 
dipeptidyl peptidase-4  
ECG 
electrocardiogram   
eGFR 
estimated glomerular filtration rate  
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
GMI 
genital mycotic infection   
HBsAg 
Hepatitis B surface antigen  
HCV 
Hepatitis C virus  
HIV 
human immunodeficiency virus  
ICH 
International Conference for Harmonisation  
IND 
Investigational New Drug  
IRAE 
Immediately Reportable Adverse Event  
IRB 
Institutional Review Board 
K2EDTA 
potassium ethylenediaminetetraacetic acid  
λz 
terminal elimination phase rate constant 
LC-MS/MS 
liquid chromatography – tandem mass spectrometry   
LS 
least squares   
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
milliliter 
OHAs 
oral hypoglycemic agents 
OTC 
over-the-counter   
PE 
physical examination   
PR 
time from onset of P wave to the start of QRS complex 
P-gp 
P-glycoprotein  


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PK 
pharmacokinetics 
q.d 
once daily 
QRS 
duration of the QRS complex 
QTc 
corrected time from start of Q wave to end of T wave 
RR 
time interval between heart beats 
SAE 
serious adverse event 
SD 
standard deviation 
SE 
standard error  
SGLT2 
sodium glucose cotransporter 2  
SFU 
sulfonylureas 
SOP 
Standard operating procedure 
T2DM 
type 2 diabetes mellitus 
TEAE 
treatment emergent adverse events 
UGE 
urinary glucose excretion   
UGT1A9 
uridine diphosphate glucuronosyltransferase isoform 1A9  
ULN 
upper limit of normal  
UTI 
urinary tract infection 
tmax 
time to maximum plasma concentration 
t½ 
apparent terminal elimination half-life 
US 
United States 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell (count) 
WHO-DD 
World Health Organization Drug Dictionary 
 


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1 
INTRODUCTION 
Bexagliflozin is a candidate OHA that is a potent and highly specific inhibitor of SGLT2. 
(Zhang et al., 2011). Bexagliflozin has been shown to cause dose-dependent increases in 
urinary glucose excretion (UGE) in humans, rats, dogs and monkeys and to reduce HbA1c in 
animal models of T2DM and in diabetic subjects. Bexagliflozin is cleared predominantly by 
metabolism to an inactive metabolite, bexagliflozin 3-O-glucuronide by the uridine 
diphosphate glucuronosyltransferase isoform 1A9 (UGT1A9) pathway.  Detailed information 
regarding bexagliflozin metabolism, clinical studies and potential risks for study subjects are 
provided in the Investigator’s Brochure. 
In vitro studies showed bexagliflozin is a substrate for P-glycoprotein (P-gp) and inhibits P-
glycoprotein (P-gp) mediated transport with an IC50 of 3.7 µM. P-gp is one of the drug 
transporters that determine the uptake and efflux of a range of drugs. Drugs that inhibit P-gp 
can interact with other drugs transported by the pump and therefore affect the exposure of 
other co-administered drugs that are P-gp substrates. 
Digoxin is a P-gp substrate (Tanigawara et al., 1992) that may be co-administered with 
bexagliflozin. Since individuals with T2DM have an increased risk of heart failure (Nichols 
et al., 2001) and atrial fibrillation (Nichols et al., 2009), patients with diabetes and 
hypertension often require treatment with cardiac glycosides such as digoxin.  Digoxin has 
been used for over 2 centuries to treat heart failure and atrial fibrillation. Digoxin acts as a 
positive inotropic agent by inhibiting the sodium-potassium adenosine triphosphatase 
(ATPase), causing an increase in myocardial contractility (US FDA, 2002).  Digoxin is 
excreted largely unchanged in urine and bile. 
Due to the narrow therapeutic index of digoxin (Smith et al., 1969), small changes in 
absorption, bioavailability, or clearance of the drug could lead to decreased therapeutic effect 
or toxicity. Therefore, this study aims to evaluate the effects of co-administered bexagliflozin 
on the pharmacokinetics of digoxin. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the effect of bexagliflozin on the 
pharmacokinetics (PK) of digoxin after co-administration. 
2.2 
Secondary Objective 
The secondary objective of this study is to evaluate the safety and tolerability of digoxin 
when co-administered with bexagliflozin. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a phase 1, single center, open-label, two-treatment period, crossover study to evaluate 
the effect of bexagliflozin tablets, 20 mg, on the PK of digoxin, 0.5 mg after co-
administration in healthy subjects. Approximately 18 eligible healthy subjects who consent to 
the study will be enrolled into the study and randomized to one of the two groups with up to 
9 subjects per group. Each subject will participate in 2 periods during which subjects will 
receive 2 treatments (Treatment A: bexagliflozin co-administered with digoxin, Treatment B: 
digoxin alone).  During the duration of the study, each subject will receive 8 single doses of 
bexagliflozin and 2 single doses of digoxin.  
3.1.1 
Group 1 
Approximately 9 subjects will be admitted to the clinic on Day 0 and will receive the 
following study drugs in two treatment periods: 
Period 1, Treatment A 
Subjects will receive a single oral dose of 20 mg bexagliflozin tablet daily starting on Day 1 
for 8 days, and a single oral dose of 0.5 mg digoxin will be co-administered with 
bexagliflozin on Day 3. Blood samples for PK will be drawn at pre-dose and at 0.5, 1, 1.5, 2, 
3, 4, 6, 8, and 12 hours (h) on Day 3, 24 h (Day 4), 48 h (Day 5), 72 h (Day 6), 96 h (Day 7), 
and 120 h (Day 8) after administration of digoxin. Subjects will be discharged on Day 8 after 
all study activities are completed.  
Period 2, Treatment B 
Subjects will be admitted on Day 18. On Day 19, subjects will receive a single oral dose of 
0.5 mg digoxin. Blood samples for PK will be drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 
8, and 12 hours (h) on Day 19, 24 h (Day 20), 48 h (Day 21), 72 h (Day 22), 96 h (Day 23), 
and 120 h (Day 24) after administration of digoxin. Subjects will be discharged on Day 24 
after all study activities are completed.  
Clinical laboratory tests and safety monitoring will be conducted during Periods 1 and 2.  
3.1.2 
Group 2 
Approximately 9 subjects will be admitted to the clinic on Day 0 and will receive the 
following study drugs in two treatment periods: 
Period 1, Treatment B 
Subjects will receive a single oral dose of 0.5 mg digoxin on Day 1. Blood samples for PK 
will be drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours (h) on Day 1, 24 h 


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(Day 2), 48 h (Day 3), 72 h (Day 4), 96 h (Day 5), and 120 h (Day 6) after administration of 
digoxin. 
Period 2, Treatment A 
Subjects will be admitted on Day 14.  Subjects will receive a single oral dose of 20 mg 
bexagliflozin daily for 8 days starting on Day 15, and a single oral dose of 0.5 mg digoxin 
will be co-administered with bexagliflozin on Day 17. Blood samples for PK will be drawn at 
pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours (h) on Day 17, 24 h (Day 18), 48 h (Day 
19), 72 h (Day 20), 96 h (Day 21), and 120 h (Day 22) after administration of digoxin. 
Subjects will be discharged on Day 22 after all study activities are completed.  
Clinical laboratory tests and safety monitoring will be conducted during Periods 1 and 2.  
For overall study design and dosing schedule, see the Study Design in Figure 1 and the 
Dosing Schedule in Appendix 2. 
 
Figure 1 
Study Design 
 
3.2 
Rationale for Study Design and Control Group 
3.2.1 
Rationale for Study Design 
The primary goal of the study is to test the effect of bexagliflozin on the PK of digoxin. The 
two treatment period, crossover design will allow the PK of digoxin to be studied with and 
without the co-administration of bexagliflozin. This design was chosen to properly separate 
treatment effects from period effects. 
Bexagliflozin is cleared predominantly by metabolism to an inactive metabolite, 
bexagliflozin 3-O-glucuronide by uridine diphosphate glucuronosyltransferase isoform 1A9 
(UGT1A9) pathway. In vitro metabolism studies demonstrated that bexagliflozin is not a 


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potent inhibitor or inducer of CYP450 enzymes. In the urine, unchanged parent drug 
accounted for less than 2% of the dose. In vitro studies showed bexagliflozin is a substrate 
for P-glycoprotein (P-gp) and inhibits P-gp mediated transport with an IC50 of 3.7 µM. P-gp 
is one of the drug transporters that determine the uptake and efflux of a range of drugs. Drugs 
that inhibit P-gp can interact with other drugs transported by the pump and therefore affect 
the exposure of other co-administered drugs that are P-gp substrates. 
Digoxin is a P-gp substrate that may be co-administered with bexagliflozin. The co-
administration of digoxin with P-gp modulators could result in marked changes in the renal 
elimination of digoxin. Meanwhile, digoxin has a narrow therapeutic index and small 
changes in absorption, bioavailability, or clearance of the drug could lead to decreased 
therapeutic effect or toxicity. 
This study is designed to evaluate the extent of the effect of bexagliflozin (a potential P-gp 
inhibitor) on the PK of digoxin (a P-gp substrate). The study results are important for the safe 
and effective use of digoxin and bexagliflozin. 
3.2.2 
Rationale for Dose Selection 
Bexagliflozin produces a dose-dependent, saturable increase in urinary glucose excretion 
(UGE) in healthy volunteers and diabetic subjects. Population pharmacodynamic modeling 
has indicated that bexagliflozin doses of 20 mg result in 90% of the maximal UGE and the 
bexagliflozin tablet, 20 mg will be the commercial product. 
The dosage for digoxin, 0.5 mg, was chosen as it is a safe and effective dose that is in 
between an acute treatment dose and maintenance treatment dose for a 70 kg adult.  The dose 
is considered a safe dose at which possible drug-drug interactions and plasma concentrations 
of digoxin can be detected. 
3.2.3 
Rationale for PK Sampling Time Points 
The T½ of bexagliflozin is 7.80 to 9.71 h, while the T½ of digoxin is significantly longer at 
approximately 35 h. Due to the long half-life of digoxin, the study is designed so that PK 
samples are collected up to 7 half-lives of digoxin. A minimum duration of 16 days (~11 
half-lives of digoxin) is required between the two digoxin administrations to ensure the 
wash-out period is sufficiently long. 
For Treatment A, digoxin will be administered on Day 3 after 2 days (~5 half-lives of 
bexagliflozin) of dosing with bexagliflozin. It is predicted that steady state of bexagliflozin 
will have been achieved at that time.   
3.3 
Study Duration and Dates 
Subjects will be screened within 21 days prior to the start of enrollment. Eligible subjects 
who consent to the study will be randomized to one of two treatment groups (Group 1 and 
Group 2). Each treatment group will receive 2 treatments (Treatment A and Treatment B) in 
a different order during each of the treatment periods (Period 1 and Period 2). The duration 


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of Treatment A is 9 days and Treatment B is 7 days. Subjects will remain in the clinic for 16 
days during the entire study.  Subjects will be out of the clinic between the 2 treatment 
periods for 9 days for Group 1 and 7 days for Group 2. Overall, each study subject will 
receive 8 single oral doses of 20 mg bexagliflozin tablets and 2 single oral doses of 0.5 mg 
digoxin in each treatment period. The duration of the overall study from screening until study 
termination is estimated to be a maximum of 46 days.  


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Approximately 18 healthy subjects who consent to participate in this study will be enrolled.  
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study. 
1. Subjects who are between the ages of 18 to 55 years, inclusive at time of consent, in good 
health based on medical history, physical examination (PE), electrocardiogram (ECG), 
and routine laboratory tests, including blood chemistry, hematology, urinalysis, and drug 
screen. 
2. Subjects with body-mass index (BMI) between 18.0 kg/m2 and 32.0 kg/m2 at screening, 
inclusive. 
3. Subjects who are non-smokers for at least 6 months prior to screening. 
4. Subjects with adequate venous access at multiple sites in both arms. 
5. Subjects who are willing to refrain from smoking, alcohol, grapefruit, grapefruit juice or 
related products, caffeine consumption (including chocolate), and strenuous exercise 
within 72 h prior to first dose and through the end of the study. 
6. Male subjects who are surgically sterile or agree to refrain from donating sperm and use 
appropriate birth control when engaging in sexual intercourse for a period of 30 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 with an intrauterine device. 
7. Female subjects of childbearing potential who are willing to use an adequate method of 
contraception and to not become pregnant for the duration of the study. 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 partial or full hysterectomy, or bilateral oophorectomy) or postmenopausal 
(absence of menses greater than 12 months and age > 50 years) are eligible if they test 
negative on the urine pregnancy test. 
8. Subjects who are willing and able to be confined to the clinical research facility and 
comply with study activities and restrictions as required by the protocol.  
9. Subjects who have the ability to comprehend and who are willing to provide written 
informed consent in accordance with institutional and regulatory guidelines 
 


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4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Subjects who are determined by the investigator or sub-investigator to be unsuitable for 
participating in the study based on medical conditions or factors that would influence 
adherence to study activities. 
2. Subjects with a clinically significant history of allergy to drugs or latex. 
3. Subjects with a history of alcohol or drug dependence in the 12 months prior to the first 
dose. 
4. Subjects who have donated 400 mL of whole blood within 56 days, 200 mL of whole 
blood within one month, or donated blood components within 14 days prior to first dose. 
5. Subjects who have used prescription or over-the-counter (OTC) drugs within 14 days 
prior to the first dose.  
6. Subjects who have used vitamin preparations within 7 days or supplements (including St. 
John’s Wort and ginseng) within 14 days prior to the first dose. 
7. Subjects who have been treated with an investigational drug within 30 days or 7 half-
lives of the investigational drug, whichever is longer, prior to the first dose. 
8. Subjects who have previously received EGT0001474 or bexagliflozin, or any other 
SGLT2 inhibitors within three months prior to the first dose, or have participated in 
previous bexagliflozin clinical trials, regardless of whether they received bexagliflozin or 
placebo in those trials.  
9. Subject who had previously taken digoxin or drugs of the same class within 3 months 
prior to the first dose. 
10. Subjects whose screening ECG demonstrates at least one of the following: heart rate > 
100 bpm, QRS > 120 msec, QTc > 430 msec (corrected by Bazett’s formula), PR > 220 
msec (a subject with PR > 220 msec will generally be excluded but exceptions may be 
allowed at the discretion of the investigator), or any rhythm other than sinus rhythm, 
sinus bradycardia, or sinus arrhythmia. 
11. Subjects whose sitting blood pressure is above 140/90 mmHg at screening.  If the sitting 
blood pressure at screening is above 140/90 mmHg, one repeat measurement is allowed 
and the subject may be randomized if the repeat screening blood pressure is 140/90 +/-5 
mmHg at the discretion of the Investigator. 
12. Subjects with a heart rate <60 beats per minute. 
13. Subjects with evidence of abnormal liver function tests (total bilirubin or alkaline 
phosphatase > 1.5 x upper limit of normal (ULN) with the exception of isolated Gilbert’s 
syndrome); or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 
x ULN. 
14. Subjects who have had a cholecystectomy. 
15. Subjects with estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 or a 
history of kidney transplant. 


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16. Subjects who have a positive result of hepatitis B surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody, urinary drug or urinary cotinine test. 
17. Subjects with known human immunodeficiency virus (HIV) infection. 
18. Subjects with a history of recurrent yeast or urinary tract infections or any such infection 
in the 6 months prior to the first dose. 
19. Subjects who have had a febrile illness within 5 days prior to first dose.  
20. Subjects vaccinated (within the exception of the flu vaccine) within 30 days prior to first 
dose. 
 


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5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
Investigational Product: Bexagliflozin 
Bexagliflozin tablets, 20 mg, are blue caplet-shaped, film-coated tablets that are intended for 
use in investigational studies in humans. The tablets contain excipients designed to promote 
extended release through a gastroretentive mechanism. The active tablets exhibit a greater 
than 75% release of drug substance by 8 hours in simulated gastric fluid in vitro.  
5.1.2 
Cardiovascular Drug: Digoxin 
Digoxin is a cardiac glycoside that mediates its effects on Na/K ATPase to increase cardiac 
output. Majority of digoxin is excreted in urine and bile unchanged, and metabolism of 
digoxin appears to be minimal (Iisalo, 1977). After oral administration, the absorption of 
digoxin is mediated by P-glycoprotein (P-gp). 0.25 mg digoxin tablets are white, round 
tablets with an imprint code JSP-545. 0.25 mg digoxin tablets are the highest available tablet 
dose, and two 0.25 mg tablets will be taken q.d. for this study. 
5.2 
Treatment(s) Administered 
Each study subject will be administered 8 single oral doses of bexagliflozin tablet, 20 mg and 
2 single oral doses of 0.5 mg digoxin in 2 treatment periods. See Appendix 2 for the Dosing 
Schedule.  
5.3 
Selection and Timing of Dose for Each Subject 
5.3.1 
Bexagliflozin  
After an overnight fast of at least 10 hours, subjects will take a 20 mg bexagliflozin tablet 
orally in the morning with approximately 240 mL of water at least 1 hour prior to drinking 
and 4 hours prior to eating.  
5.3.2 
Digoxin  
After an overnight fast of at least 10 hours, subjects will take 0.5 mg digoxin orally in the 
morning with approximately 240 mL of water at least 1 hour prior to drinking and 4 hours 
prior to eating.  
5.3.3 
Bexagliflozin and digoxin 
After an overnight fast of at least 10 hours, 0.5 mg digoxin and 20 mg bexagliflozin tablet 
will be co-administered orally with approximately 240 mL of water at least 1 hour prior to 
drinking and 4 hours prior to eating. 


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5.4 
Method of Assigning Subjects to Treatment Groups 
A total of 18 healthy subjects who consent to participate in the study will be enrolled in the 
study.  Subjects will be randomized to one of the two study groups (Group 1 and Group 2). 
Subjects who discontinue the study early due to safety issues will not be replaced.  
• Group 1: Treatment A first, followed by Treatment B 
• Group 2: Treatment B first, followed by Treatment A 
 
5.5 
Blinding 
This is an open-label study. 
5.6 
Concomitant Therapy 
The participants are not allowed to take any prescription or non-prescription drugs or dietary 
supplements with the exception of acetaminophen and topical medications at any time during 
14 days prior to (first) drug administration and for the duration of each study period. 
Vitamins are prohibited for 7 days prior to first drug administration and for the duration of 
the study.  No other concomitant medications are permitted with the exception of those 
required for treatment of an adverse event. Subjects may receive any medications for adverse 
events that are necessary to control or minimize the likelihood of more serious adverse events 
in the investigators’ judgment. 
Concomitant medications administered at the time of randomization and during the study are 
to be recorded on the case report form (CRF). The medication name, dose, frequency, route 
of administration, date(s) of administration and reason for administration must be recorded. 
This documentation should continue until the end of the last study period. Medications that a 
subject receives after entering the study and prior to randomization must be recorded in the 
CRF. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
No study subject shall have been dosed with any SGLT2 inhibitor within 3 months prior to 
the first dose of study medication, nor with an investigational drug within 30 days or 7 half-
lives prior to first dose, or used any prescription medication or herbal supplements within 14 
days or vitamins 7 days prior to the first dose of study medication. 
5.7.2 
Fluid and Food Intake  
An overnight fast of at least 10 hours prior to dosing is required. Study drug(s) will be taken 
in the morning with approximately 240 mL of water prior to any drinking or eating. Water is 
permitted during the fasting period up to 1 hour before and after the administration of each 
study drug administration. Adequate hydration is encouraged during the study period. Food 
can be consumed 4 h after dosing.  


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5.7.3 
Subject Activity Restrictions 
Light physical activity is permitted. Subjects should not perform strenuous activity which 
could result in elevations of muscle creatine kinase levels within 72 h prior to first dose and 
through the end of the study. Smoking during the study is prohibited. Alcohol consumption is 
restricted for 24 hours prior to each clinic admission check-in. Subjects must refrain from 
smoking, or consuming alcohol, grapefruit, grapefruit juice or related products, or caffeine 
(including chocolate), during the duration of 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 medication dosing will be recorded in the 
CRFs, including a record of checks followed by hand mouth inspection. 
5.9 
Packaging and Labeling 
5.9.1 
Bexagliflozin 
Bexagliflozin tablets, 20 mg, are packaged in high density polyethylene bottles sealed with a 
child resistant closure. The product is packaged with 90 tablets per bottle. Investigational 
product bottles will be labeled with protocol number, drug name and strength, lot number, 
sponsor’s name, storage condition, and the investigational drug caution statement. 
5.9.2 
Digoxin 
Digoxin tablets are packaged with 100 tablets per bottle. Digoxin bottles are labeled with 
drug name, strength, lot number, expiration date, storage and dispensation information and 
drug caution statement. 
5.10 Storage and Accountability 
All drug supplies should be stored in a secure area with access limited to authorized 
personnel. Bexagliflozin tablets should be stored below 30°C. Digoxin should be stored at 
15° to 25°C in a dry place and protected from light, and dispensed according to label 
instructions. The sponsor will perform an ongoing inventory of study products. The 
responsible pharmacist must keep a careful inventory of drug shipments received and the 
number of tablets dispensed per study subject. A full reconciliation of drug inventory will be 
performed at the end of the study and the results of this inventory must be recorded in the 
Clinical Trial Material Inventory Logs and Accountability Logs. At study close out after the 
post-study inventory reconciliation is completed, empty and partially used bottles of 
bexagliflozin tablets will be returned to the originating IP depot for destruction.  Digoxin 
bottles may be discarded according to the study sites’ regulations for the disposal of 
investigational drug products. 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Before each subject is enrolled in the clinical study, written informed consent will be 
obtained from the subjects according to the regulatory and legal requirements. As part of this 
procedure, the investigator or designee must explain orally and in writing the nature, duration, 
and purpose of the study, and the action of the drug in such a manner that the study subject is 
aware of the potential risks, inconveniences, or AEs that may occur. The investigator should 
educate potential subjects about the scientific importance of their data and the vital role that 
their participation has for the outcome of the entire study. The subject must be informed that 
he/she is free to withdraw from the study at any time. He/she will receive all information that 
is required by federal regulations and International Council 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, surgical history (i.e. cholecystectomy, kidney transplant, etc.) and 
timeframe of the history relative to study screening, if applicable. 
• Clinically significant history of allergy including drugs and latex. 
• History of smoking in the last 6 months prior to first dose, and alcohol or drug 
dependence, or abuse in the last 12 months prior to first dose. 
• Any blood donation within 56 days or blood component donation in the last 14 days prior 
to first dose. 
• Use of any medications including OTC drugs or dietary supplements in the last 14 days 
prior to first dose. Use of any vitamins in the last 7 days prior to first dose. 
• History of vaccination (except the flu vaccine) within 30 days prior to first dose. 
• History of diagnosis with HIV, hepatitis B or hepatitis C. 
• Use of any investigational drug in the previous 30 days or 7 half-lives prior to first dose, 
whichever time frame is longer. 
• Prior exposure to bexagliflozin (or EGT0001474), or any other SGLT2 inhibitors in the 
last 3 months prior to first dose. 
• Prior exposure to digoxin in the last 3 months prior to first dose. 
• History of recurrent yeast or urinary tract infections or any such infections in the last 6 
months prior to first dose. 


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6.3 
Physical Examination 
The investigator or designated qualified individual will perform the PEs. A complete PE will 
be performed at screening and on the last day of Period 2 prior to discharge. Partial PEs will 
be performed on scheduled days as described in Appendix 1. 
A complete PE will include measurement of body weight and height (height will be 
measured only at screening), general assessment of all body systems including the skin, head, 
eyes, ears, nose, throat, neck, lungs, heart, abdomen, lymph nodes, and extremities. A partial 
PE will include body weight and an update of the general assessment of the skin, heart, lungs 
and abdomen. 
6.4 
Vital Signs 
Vitals signs, including pulse, systolic and diastolic blood pressure (BP), respiration rate, and 
oral temperature, will be measured on scheduled visits as described in Appendix 1.  
Vital signs should be measured prior to blood draws. 
Pulse, systolic and diastolic BP should be measured in a seated position after a subject has 
been sitting for 5 minutes. 
Respiration rate should be measured after at least 5 minutes of rest.  
BP measures will be obtained using a calibrated sphygmomanometer or calibrated automated 
vitals machine. 
6.5 
Electrocardiography 
A 12-lead electrocardiography (ECG) will be conducted as listed in Appendix 1 and 
whenever clinically indicated. 
This procedure should be performed in the supine position after at least 5 minutes of rest. 
ECG parameters measured will be the RR interval, PR interval, QRS duration, and QT. Each 
ECG should also be assessed by the investigator for signs of ischemia, clinically significant 
hypertrophy, and clinically significant T-wave abnormalities. 
It is the investigator or designee’s responsibility to review the results of the ECG as they 
become available. For each abnormal ECG result, the investigator needs to ascertain if this is 
a clinically significant change from the screening ECG for that individual subject. This 
determination, however, does not necessarily need to be made the first time an abnormal 
result is observed. The investigator may repeat the ECG to verify the results of the original 
result. If the ECG result is determined to be a clinically significant and an abnormal change 
from baseline for that subject, this is considered an AE. 


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


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6.6.2 
Sample Collection, Storage, and Shipping 
6.6.2.1 
Hematology and Blood Chemistry 
Blood samples for hematology and chemistry will be collected. Timing of the collection is 
described in Appendix 1. 
6.6.2.2 
Urinalysis 
Clean-catch, midstream urine samples will be collected per schedule outlined in Section 7 
and in Appendix 1. Dipstick urinalysis will be conducted. Microscopy will be obtained if the 
subject has a positive result on any of the dipstick tests that require microscopic follow-up to 
clarify their significance. If urine is dipstick positive for white blood cell (count) (WBC) or 
blood (except female subjects who are menstruating), urine sample will be sent for 
microscopic evaluation and culture. In addition, urinalysis will be performed from a clean-
catch urine sample at any time in subjects with symptoms of UTI or pyelonephritis.  
6.6.2.3 
PK Plasma Sample Collection and Analysis 
Whole venous blood samples of 3 mL will be collected from a peripheral vein in each period 
at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h post-dose of digoxin 
for Groups 1 and 2.  Blood samples will be collected in tubes containing potassium 
ethylenediaminetetraacetic acid (K2EDTA) and stored on ice until centrifuged under 
refrigeration for at least 5 min at 3,000 rpm. After centrifugation, plasma will be removed, 
divided into 2 aliquots of approximately 0.5 mL, frozen and stored at or below -20°C.  
Plasma should be processed and frozen within 2 h of blood collection. Processed frozen 
plasma samples will be transferred on dry ice to the analytical laboratory and will be stored at 
or below -20oC until analysis. 
Plasma concentrations of digoxin will be determined at Covance by validated liquid 
chromatography - mass spectrometry (LC-MS/MS) method, with lower limit of quantitation 
(LLOQ) of 0.05 ng/mL for digoxin. 
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: 


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• results in death, 
• is life-threatening (NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the patient was at risk of death at the time of the event 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 and 
documented as described in Section 6.7.4.4. 
Any increase in liver function tests (aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), or bilirubin) greater than 3 times the upper limit of normal (ULN) 
for the laboratory utilized will be considered a clinical laboratory adverse event. 
An increase in creatinine from baseline by 0.5 mg/dL or more will be reported as a laboratory 
adverse event. 
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on the 
CRF. The intensity of an adverse experience is defined as follows: 
1 = Mild: discomfort noticed, but no disruption to daily activity 


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2 = Moderate: discomfort sufficient to reduce or affect normal daily activity 
3 = Severe: inability to work or perform normal daily activity 
Investigational Product Causality: The site and database should ask for the causality 
relative to the study compound. Relationship of an adverse event to dosing will be assessed 
as follows: 
Definite: There is a reasonable causal relationship between the investigational product and 
the AE when the event responds to withdrawal of the investigational product (dechallenge), 
and recurs with administration of the investigational product (rechallenge). 
Probable: There is a reasonable causal relationship between the investigational product and 
the AE. The event responds to dechallenge. Rechallenge is not required. 
Possible: There is a reasonable causal relationship between the investigational product and 
the AE. Dechallenge is lacking or unclear. 
Not Likely: There is a temporal relationship to investigational product administration, but 
there is not a reasonable causal relationship between the investigational product and the 
event. 
Unrelated: There is no temporal or causal relationship to investigational product 
administration. 
6.7.1 
Collecting and Reporting Adverse Events 
Adverse event collection will begin on the first clinical admission day. The investigator will 
periodically assess subjects for the occurrence of adverse events. To avoid bias in collecting 
information about adverse events, the investigator should ask subjects the following question: 
"How have you felt since you were last checked?" All adverse events (serious and non-
serious) reported by the subject must be recorded on the source documents and CRFs 
provided by the sponsor. 
In addition, Theracos’ Medical Monitor or its designated personnel must be notified 
immediately by telephone or fax of any immediately reportable adverse events according to 
the procedure outlined below. Special attention should be paid to recording hospitalization 
and concomitant medications. 
6.7.2 
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 or fax or overnight courier to the sponsor within 24 h 
of knowledge of the event. 


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Non-serious events that require discontinuation of investigational product (including 
laboratory abnormalities) should be reported to Theracos within 3 working days. The IRAE 
form should be completed and sent by email or fax or overnight courier to the sponsor. 
Subjects experiencing an SAE should be followed clinically until their health has returned to 
baseline status or until all parameters have returned to normal, or have otherwise been 
explained. It is expected that the investigator will provide or arrange appropriate supportive 
care for the subject. 
6.7.3 
Pregnancy 
Women of childbearing potential (WOCBP) who are sexually active must use an effective 
method of birth control during the course of the study, in a manner such that risk of failure is 
minimized. 
Before enrolling WOCBP in this clinical trial, investigators must review guidelines about 
study participation for WOCBP. The topics should generally include: 
1. General information. 
2. Informed consent form. 
3. Pregnancy prevention information. 
4. Contraceptives in current use. 
5. Guidelines for the follow-up of a reported pregnancy. 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy. The 
subject must sign an informed consent form stating the above-mentioned risk factors and that 
the consequences were discussed with her. 
During the study, all WOCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (e.g., missed or late menstrual cycle). 
If a subject or investigator suspects that the subject may be pregnant prior to investigational 
product administration, the investigational product administration must be withheld until the 
results of serum pregnancy tests are available. If the pregnancy is confirmed, the subject must 
not receive the investigational product and must not remain in or be enrolled in the study. 
The investigator must notify the Medical Monitor within 3 working days of the receipt of 
information that any female subject who has become pregnant.  
The investigator must record the event on the Pregnancy Surveillance Form and forward it to 
the sponsor’s clinical or designated personnel.  


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6.7.4 
Follow-up of Adverse Events  
6.7.4.1 
Follow-up of Non-serious Adverse Events 
Non-serious adverse events that are identified on the last scheduled contact must be recorded 
on the AE CRF with the current status noted. All non-serious events that are ongoing at the 
time will be recorded as ongoing on the CRF. 
6.7.4.2 
Follow-up of Post-Study Serious Adverse Events 
SAEs that are identified on the last scheduled contact must be recorded on the AE CRF page 
and reported to Theracos according to the reporting procedures outlined in Section 6.7.1. 
These may include unresolved previously reported SAEs, or new SAEs. The investigator 
should follow these subjects until the events are resolved, or the subject is lost to follow-up. 
Resolution means the subject has returned to the baseline state of health, or the investigator 
does not expect any further improvement or worsening of the subject’s condition. The 
investigator should continue to report any significant follow-up information to Theracos until 
the event has been resolved. 
Any new SAEs reported by the subject to the investigator that occur after the last scheduled 
contact, and are determined by the investigator to be reasonably associated with the use of 
the investigational product, should be reported to the Medical Monitor or the sponsor’s 
designated personnel. These may include SAEs that are captured on follow-up telephone 
contact or at any other time point after the defined study period (i.e., up to last scheduled 
contact). The investigator should follow subjects with SAEs identified after the last 
scheduled contact until the events are resolved, or the subject is lost to follow-up. The 
investigator should continue to report any significant follow-up information to the Sponsor 
until the event has been resolved. This study requires that subjects be actively monitored for 
SAEs for at least 14 days after discharge from the study.  
6.7.4.3 
Hepatotoxicity 
Any clinically significant increase in hepatic enzymes and specifically ALT or AST ≥ 3x 
ULN requires immediate repeat test within 48 to 72 h to confirm the hepatic enzyme 
elevation. Study medication should be stopped and the event should be reported as an 
adverse event within the CRF if the enzyme elevation is confirmed or worsening. Potential 
contributors to hepatic enzyme elevation should be evaluated by the investigator. The 
investigator is encouraged to consult with the Medical Monitor regarding ongoing diagnostic 
workup. 
Investigational product should be permanently discontinued if any of the following criteria is 
met: 
• ALT or AST > 8 x ULN, 
• ALT or AST > 3 x ULN and (total bilirubin > 2 x ULN or INR > 1.5), 


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• ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
 
6.7.4.4 
Hypoglycemia 
Hypoglycemia will be recorded under 5 categories: 
• Critical hypoglycemia: An event requiring assistance of another person to actively 
administer carbohydrate, glucagons, or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose 
measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration. All such 
events should be recorded as serious adverse events in the CRF. 
• Documented symptomatic hypoglycemia: An event during which typical symptoms of 
hypoglycemia are accompanied by a measured plasma glucose concentration ≤ 70 mg/dL 
(3.9 mmol/L). 
• Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration ≤ 70 mg/dL 
(3.9 mmol/L). 
• Probable symptomatic hypoglycemia: An event during which symptoms of hypoglycemia 
are not accompanied by a plasma glucose determination but that was presumably caused 
by a plasma glucose concentration ≤ 70 mg/dL (3.9 mmol/L). 
• Relative hypoglycemia: An event during which the person reports any of the typical 
symptoms of hypoglycemia, and interprets those as indicative of hypoglycemia, but with 
a measured plasma glucose concentration > 70 mg/dL (3.9 mmol/L). 
 
If a subject experiences symptomatic hypoglycemia, confirmed by point-of-care glucose 
monitoring at the time of symptoms with a blood sugar level < 70 mg/dL (3.9 mmol/L), the 
subject should be treated with 15 to 20 grams of oral glucose or simple carbohydrate (glucose 
tablets, raisins, orange juice, glucose-containing soda, or soft sugar candies). 
If a subject with symptomatic hypoglycemia is unable to self-administer glucose tablets, 
candies, or glucose-containing solutions, then the appropriate study staff should administer 
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. 


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6.8 
Concomitant Medication Assessments 
A concomitant medication is any medication the subject enters the trial taking and is 
expected to continue taking for some portion of the trial, as well as any medication the 
subject takes during the course of the trial. All prescription and over-the-counter medications, 
including vitamins and herbal supplements, that subjects receive during the trial must be 
documented on the CRF. This documentation should continue until the subjects are 
discharged. 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A table of concomitant medications based on the anatomic 
therapeutic chemical classification and preferred name will be produced. A listing of 
concomitant medications will include all medications taken by any subjects during the course 
of the study. 
Concomitant medications administered during the study are to be recorded on the CRF. The 
medication name, dose, frequency, route of administration, date(s) of administration and 
reason for administration must be recorded. This documentation should continue until 
discharge from the study. 
6.9 
Removal of Subjects from the Trial or Discontinuation of 
Investigational Product 
The investigator must emphasize to potential subjects the importance of continued 
participation for the full duration of the trial during the informed consent process. 
Participation in the study is voluntary. A participant has the right to withdraw from the study 
at any moment for any reason. The investigator will be informed immediately. 
The investigator has the right to terminate participation of a subject in case it is difficult to 
obtain blood samples, in case of violation of the protocol or in case of severe or serious 
adverse events. 
In case a subject withdraws from the study, the study monitor will be informed immediately. 
If there is a medical reason for withdrawal, the volunteer should remain under the 
supervision of the medical investigator until satisfactory health returns. 
Subjects who discontinue the active dosing phase of the study due to adverse event(s) or 
other safety concerns will not be replaced. 
When the decision is made to discontinue a subject’s participation in the study, no further 
investigational product medication should be administered. Every attempt should be made to 
complete all required study evaluations and procedures. Reasons for all withdrawals should 
be recorded on the CRF. 
The investigator may withdraw a subject from the THR-1442-C-443 trial for any of the 
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• A protocol violation occurs, or 
• A serious or intolerable adverse event occurs, or 
• A clinically significant change in a laboratory parameter occurs, or 
• The sponsor or investigator terminates the study, or 
• The subject requests to be discontinued from the study. 
 
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.  


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7 
STUDY ACTIVITIES 
7.1 
Screening (Days –14 to -1) 
During the screening period, the following information will be gathered and the indicated 
procedures will be performed: 
• Explain the content of informed consent to the subject and collect signed informed 
consent 
• Obtain medical history and demographic information 
• Perform a complete physical examination, including height and weight measurements as 
described in Section 6.3. 
• Collect vital signs including pulse, temperature, respiratory rate, and blood pressure taken 
in the sitting position after at least 5 min of rest as described in Section 6.4 
• Conduct 12-lead ECG in the supine position after at least 5 min of rest as described in 
Section 6.5 
• Collect clean-catch urine for urinalysis 
• Conduct urine screen for use of drugs including amphetamines, barbiturates, cocaine 
metabolites, opiates, benzodiazepines, and cannabinoids 
• Conduct urine pregnancy test for all female subjects 
• Draw blood for hematology, serum chemistry, electrolytes and lipids and serology as 
detailed in Section 6.6  
• Evaluate inclusion/exclusion criteria based on the information collected at the screening 
examination 
 
 
7.2 
Group 1 
7.2.1 
Period 1 
DAY 0 
• Admit eligible subjects to Phase I unit 
• Draw blood for hematology, serum chemistry, electrolytes and lipids as detailed in 
Section 6.6   
• Perform abbreviated physical examination as described in Section 6.3. 
• Conduct urine pregnancy test for all female subjects 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 


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DAY 1 
• Collect vital signs including pulse, temperature, respiratory rate, and blood pressure taken 
in the sitting position after at least 5 min of rest, pre-dose and 4 h post-dose 
• Conduct 12-lead ECG in the supine position after at least 5 min of rest, pre-dose and 4 h 
post-dose 
• Conduct urinalysis on clean-catch urine pre-dose 
• Re-confirm eligibility criteria prior to randomization based on results for clinical lab tests 
from Day 0 and vital signs, ECG and urinalysis results from Day 1 pre-dose 
• Randomization of subjects 
• Administer bexagliflozin to subjects as described in Section 5.3 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 2 
• Administer bexagliflozin to subjects as described in Section 5.3 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 3 
• Draw blood for hematology, serum chemistry, electrolytes and lipids pre-dose 
• Conduct urinalysis on clean-catch urine pre-dose 
• Perform abbreviated physical examination pre-dose 
• Collect vital signs collected including pulse, temperature, respiratory rate, and blood 
pressure taken in the sitting position after at least 5 min of rest, pre-dose and 4 h post-
dose 
• Conduct 12-lead ECG in the supine position after at least 5 min of rest, pre-dose, 4 and 8 
h post-dose 
• Administer both bexagliflozin and digoxin to subjects as described in Section 5.3 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 4 
• Administer bexagliflozin to subjects as described in Section 5.3 
• Conduct 12-lead ECG in the supine position after at least 5 min of rest, 24 h post-dose 
digoxin 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 


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DAY 5 TO DAY 7 
• Administer bexagliflozin to subjects as described in Section 5.3 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 8 
• Draw blood for hematology, serum chemistry, electrolytes and lipids as detailed in 
Section 6.6  
• Administer bexagliflozin to subjects as described in Section 5.3 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Collect vital signs including pulse, temperature, respiratory rate, and blood pressure in 
the sitting position after at least 5 min of rest as described in Section 6.4 
• Conduct urinalysis on clean-catch urine 
• Assess adverse events and record concomitant medications as described in Section 6.7 
• Discharge subjects after all study activities are completed 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the study termination day except for PK sample collection must be completed. The reason for 
termination must be entered onto the case report form. 
 
7.2.2 
Period 2 
DAY 18 
• Admit Group 1 subjects to the Phase 1 clinic 
• Perform abbreviated physical examination as described in  Section 6.3 
• Conduct urine pregnancy test for all female subjects 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 19 
• Draw blood for hematology, serum chemistry, electrolytes and lipids pre-dose 
• Conduct urinalysis on clean-catch urine pre-dose 
• Perform abbreviated physical examination pre-dose 
• Collect vital signs collected including pulse, temperature, respiratory rate, and blood 
pressure taken in the sitting position after at least 5 min of rest, pre-dose and 4 h post-
dose 
• Conduct 12-lead ECG in the supine position after at least 5 min of rest, pre-dose, 4 and 8 
h post-dose 


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• Administer digoxin to subjects as described in Section 5.3 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 20 
• Conduct 12-lead ECG in the supine position after at least 5 min of rest, 24 h post-dose 
digoxin 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 21 TO DAY 23 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 24 
• Draw blood for hematology, serum chemistry, electrolytes and lipids as detailed in 
Section 6.6  
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Collect vital signs including pulse, temperature, respiratory rate, and blood pressure in 
the sitting position after at least 5 min of rest as described in Section 6.4 
• Conduct urinalysis on clean-catch urine 
• Conduct 12-lead ECG in the supine position after at least 5 min of rest as described in 
Section 6.5 
• Perform a full physical examination as described in  Section 6.3 
• Assess adverse events and record concomitant medications as described in Section 6.7 
• Discharge subjects after all study activities are completed 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the study termination day except for PK sample collection must be completed. The reason for 
termination must be entered onto the case report form. 
 
7.3 
Group 2 
7.3.1 
Period 1  
DAY 0 
• Admit eligible subjects to the Phase 1 clinic 


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• Draw blood for hematology, serum chemistry, electrolytes and lipids as detailed in 
Section 6.6 
• Perform abbreviated physical examination as described in  Section 6.3 
• Conduct urine pregnancy test for all female subjects 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 1 
• Conduct urinalysis on clean-catch urine pre-dose 
• Perform abbreviated physical examination pre-dose 
• Collect vital signs collected including pulse, temperature, respiratory rate, and blood 
pressure taken in the sitting position after at least 5 min of rest, pre-dose and 4 h post-
dose 
• Conduct 12-lead ECG in the supine position after at least 5 min of rest, pre-dose, 4 and 8 
h post-dose 
• Re-confirm eligibility criteria prior to randomization based on results for clinical lab tests 
from Day 0 and vital signs, ECG and urinalysis results from Day 1 pre-dose 
• Randomization of subjects 
• Administer digoxin to subjects as described in Section 5.3 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 2 
• Conduct 12-lead ECG in the supine position after at least 5 min of rest, 24 h post-dose 
digoxin 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 3 TO DAY 5 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 6 
• Draw blood for hematology, serum chemistry, electrolytes and lipids as detailed in 
Section 6.6  
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Collect vital signs including pulse, temperature, respiratory rate, and blood pressure in 
the sitting position after at least 5 min of rest as described in Section 6.4 


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• Conduct urinalysis on clean-catch urine 
• Assess adverse events and record concomitant medications as described in Section 6.7 
• Discharge subjects after all study activities are completed 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the study termination day except for PK sample collection must be completed. The reason for 
termination must be entered onto the case report form. 
 
7.3.2 
Period 2 
DAY 14 
• Admit Group 2 subjects to Phase I unit 
• Perform abbreviated physical examination as described in  Section 6.3 
• Conduct urine pregnancy test for all female subjects 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 15 
• Draw blood for hematology, serum chemistry, electrolytes and lipids as detailed in 
Section 6.6 
• Collect vital signs including pulse, temperature, respiratory rate, and blood pressure taken 
in the sitting position after at least 5 min of rest, pre-dose and 4 h post-dose 
• Conduct 12-lead ECG in the supine position after at least 5 min of rest, pre-dose and 4 h 
post-dose 
• Conduct urinalysis on clean-catch urine pre-dose 
• Administer bexagliflozin to subjects as described in Section 5.3 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 16 
• Administer bexagliflozin to subjects as described in Section 5.3 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 17 
• Draw blood for hematology, serum chemistry, electrolytes and lipids pre-dose 
• Conduct urinalysis on clean-catch urine pre-dose 
• Perform abbreviated physical examination pre-dose 
• Collect vital signs collected including pulse, temperature, respiratory rate, and blood 
pressure taken in the sitting position after at least 5 min of rest, pre-dose and 4 h post-
dose 


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• Conduct 12-lead ECG in the supine position after at least 5 min of rest, pre-dose, 4 and 8 
h post-dose 
• Administer both bexagliflozin and digoxin to subjects as described in Section 5.3 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 18 
• Administer bexagliflozin to subjects as described in Section 5.3 
• Conduct 12-lead ECG in the supine position after at least 5 min of rest, 24 h post-dose 
digoxin 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 19 TO DAY 21 
• Administer bexagliflozin to subjects as described in Section 5.3 
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Assess adverse events and record concomitant medications as described in Section 6.7 
 
DAY 22 
• Draw blood for hematology, serum chemistry, electrolytes and lipids as detailed in 
Section 6.6 
• Administer bexagliflozin to subjects as described in Section 5.3  
• Collect plasma samples for PK analysis as detailed in Section 6.6 
• Collect vital signs including pulse, temperature, respiratory rate, and blood pressure in 
the sitting position after at least 5 min of rest as described in Section 6.4 
• Conduct urinalysis on clean-catch urine 
• Conduct 12-lead ECG in the supine position after at least 5 min of rest as described in 
Section 6.5 
• Perform a full physical examination as described in  Section 6.3 
• Assess adverse events and record concomitant medications as described in Section 6.7 
• Discharge subjects after all study activities are completed 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the study termination day except for PK sample collection must be completed. The reason for 
termination must be entered onto the case report form. 
 


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7.4 
Follow-up Procedures or Early Termination 
Subjects who have completed study activities or have withdrawn consent and have received 
investigational product should have a follow-up examination if clinically indicated, including 
a complete physical examination, vital signs, ECG, and clinical laboratory tests (hematology, 
and serum chemistry). The sponsor must be notified in the event that a subject withdraws or 
has been withdrawn from the study. 
 


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


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The statistical evaluation of PK parameters will be conducted by the designated CRO. A 
detailed Statistical and Analytical Plan will be generated prior to any PK statistical analysis 
of the data. Statistical analysis will be performed using Statistical Analysis Software SAS for 
Windows® (SAS, USA). Non-compartmental analysis will be performed using 
Phoenix®WinNonlin® 6.4 (Certara, USA). 
9.2 
Determination of Sample Size 
The sample size for this study is not based upon formal statistical consideration. The sample 
size is considered adequate to characterize the PK of digoxin, to assess potential drug-drug 
interactions and to provide safety and tolerability data on the compound when administered 
either alone or with bexagliflozin. 
9.3 
Analysis Populations 
9.3.1 
Safety Population 
The Safety Population will include all randomized subjects who received at least one dose of 
study drug. Subjects will be analyzed according to the treatment received. 
9.3.2 
PK Population 
The PK Population will include all randomized subjects who receive at least one dose of 
study drug and who have sufficient plasma digoxin measurements to derive PK parameters 
following dosing. The PK Population will be used to summarize the PK 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 performed. 
9.5 
Pharmacokinetic Analysis 
9.5.1 
Calculation of Pharmacokinetic Parameters 
A non-compartmental analysis will be used to calculate the PK parameters of digoxin when 
administered alone or with bexagliflozin using the software Phoenix® WinNonlin® 6.4 
(Certara, USA). From the plasma digoxin concentration-time data, the following PK 
parameters will be estimated for each subject where feasible. 
Cmax:  
Maximum observed plasma concentration 
Tmax:  
Time of maximum observed plasma concentration 
λz:  
 
Terminal elimination phase rate constant 


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


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9.5.2 
Statistical Analysis 
To assess the effect of bexagliflozin on the PK of digoxin, an analyses of variance (ANOVA) 
using a linear mixed-effects model will be fitted to the natural logarithmic transformation of 
PK parameters of digoxin (Cmax, AUC0-t and AUC0-∞). The linear mixed-effects model will 
include subject as a random effect, and treatment, period, and sequence as fixed effects. The 
90% confidence intervals will be constructed for digoxin administered with bexagliflozin to 
digoxin alone ratio of the least squares (LS) geometric means of PK parameters (Cmax, AUC0-
t and AUC0-∞), with 80-125% defined as the lack of interaction boundaries. 
Descriptive statistics for the PK parameters Cmax, Tmax, AUC0-∞ , AUC0-t , CL/F, Vz/F, λz, and 
T1/2 will be tabulated by treatment. Means, standard deviations, medians, ranges (min, max) 
and geometric means and coefficients of variation will be presented for all PK parameters 
with the exception of Tmax. Medians and ranges will be presented for Tmax.  
A listing of derived PK parameters of bexagliflozin by Subject ID, Period and Sex/Gender 
will be provided.  
9.6 
Safety Analysis 
Safety data will include AEs, PE results, vital signs, ECG results, and clinical lab results, 
including serum chemistry, hematology, and urinalysis. Observed data will be described as 
counts and percentages for discrete variables and estimation of means, standard deviations 
(SDs), medians, inter-quartile range, minimum and maximum for continuous metrics. All 
subjects in the Safety Population will be included in the safety analyses. All safety data will 
be presented in by-subject listings and included in the clinical trial report. 
9.6.1 
Adverse Events  
Adverse events will be mapped to preferred term and body system using the Medical 
Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects 
reporting adverse events will be determined by relationship to treatment and by severity of 
the event. Drug-related adverse events will be considered those to be possibly related to 
bexagliflozin administration. 
Adverse event listings will be provided for the following subsets: 
• all treatment emergent AEs (TEAEs). 
• all TEAEs at least possibly related to bexagliflozin. 
• serious TEAEs (if any). 
• TEAEs leading to study discontinuation (if any). 
 
AEs are dosing emergent if they occur on or after bexagliflozin administration. TEAEs will 
be considered at least possibly related to bexagliflozin based on the investigator’s 
assessment. Only TEAEs will be tabulated in summary tables. If the AE(s) onset date-time or 
date occurs after the first dose up until right before the next dose, the AE(s) will be assigned 


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to the first treatment. Any AE(s) that occur after the second dose up until the follow-up visit 
will be assigned to the second treatment. 
Tabulations will display TEAEs by severity and relationship to bexagliflozin. 
9.6.2 
Hypoglycemia 
Hypoglycemia as defined in Section 6.7.4.4 will be presented in listings and summarized. 
9.6.3 
Clinical and Laboratory Events and Analyses 
Clinical and laboratory metrics are measured at baseline (pre-dose measurement of each 
period) and during the treatment periods (Appendix 1). These variables include vital signs 
(blood pressure, respiration, temperature), clinical laboratory results (see Section 6.6 for a 
complete list), and ECGs. 
Serum chemistry, hematology, and urinalysis (quantitative parameters) data will be 
summarized for each treatment period. Summaries for change from baseline will be 
presented for these laboratory tests.  
ECG results will be summarized as changes from baseline in intervals. Abnormalities as well 
as changes from previous assessment will be listed. 
9.6.4 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A by-subject listing of concomitant medications will include all 
medications taken during the study. 


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


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


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11 REFERENCE LIST 
Iisalo, E. (1977). Clinical pharmacokinetics of digoxin. Clinical pharmacokinetics 2, 1-16. 
Nichols, G.A., Hillier, T.A., Erbey, J.R., and Brown, J.B. (2001). Congestive heart failure in 
type 2 diabetes: prevalence, incidence, and risk factors. Diabetes care 24, 1614-1619. 
Nichols, G.A., Reinier, K., and Chugh, S.S. (2009). Independent contribution of diabetes to 
increased prevalence and incidence of atrial fibrillation. Diabetes care 32, 1851-1856. 
Smith, T.W., Butler, V.P., Jr., and Haber, E. (1969). Determination of therapeutic and toxic 
serum digoxin concentrations by radioimmunoassay. The New England journal of medicine 
281, 1212-1216. 
Tanigawara, Y., Okamura, N., Hirai, M., Yasuhara, M., Ueda, K., Kioka, N., Komano, T., 
and Hori, R. (1992). Transport of digoxin by human P-glycoprotein expressed in a porcine 
kidney epithelial cell line (LLC-PK1). The Journal of pharmacology and experimental 
therapeutics 263, 840-845. 
US FDA (2002). Digoxin tablets label. 
Zhang, W., Welihinda, A., Mechanic, J., Ding, H., Zhu, L., Lu, Y., Deng, Z., Sheng, Z., Lv, 
B., Chen, Y., et al. (2011). EGT1442, a potent and selective SGLT2 inhibitor, attenuates 
blood glucose and HbA(1c) levels in db/db mice and prolongs the survival of stroke-prone 
rats. Pharmacol Res 63, 284-293. 
 


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Appendix 1 
Schedule of Events 
GROUP 1 SCHEDULE OF EVENTS 
Evaluation 
Screening 
Period 1:  Treatment A 
Period 2:  Treatment B 
Days to randomization (days) 
-21 to -1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
18 
19 
20 
21 
22 
23 
24 
Medical history and ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review for I/E criteria1 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam2 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
X 
Admission or discharge3  
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer bexagliflozin4 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Administer digoxin4 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Vital signs5 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
ECG6 
X 
 
X 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
X 
Urinalysis7 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
Urine drug screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (for females only) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Blood draw for clinical lab tests8 
X 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
Blood samples for PK9 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Adverse event and concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study termination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 
Eligibility criteria will be re-confirmed on Day 1 prior to randomization, based on results for clinical lab tests from Day 0 and vital signs, ECG and 
urinalysis results from Day 1 pre-dose. 
2 
Weight and height will be recorded as part of the physical examination. Height will be recorded once at screening only. A complete physical exam (PE) will 
be performed at screening visit and the day of study termination, Day 24. A partial PE will be performed on Days 0, 3, 18 and 19. On Days 3 and 19, the PE 
will be performed prior to dosing. 
3 
Group 1 subjects will be admitted to the clinic on Day 0, discharged on Day 8 for Period 1.  For Period 2, subjects will be admitted on Day 18 and 
discharged on Day 24.  
4 
See Appendix 2 for dosing schedule. 


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5 
Vital signs include pulse, body temperature, respiratory rate, and blood pressure after at least 5 minutes of rest. On Days 1, 3, and 19, vital signs will be 
measured pre-dose and 4 h post-dose. 
6 
12-lead ECG will be conducted after 5 min of rest.  On Day 1, ECG will be recorded pre-dose and 4 h post-dose of bexagliflozin. On Days 3, 4, 19 and 20, 
ECG will be recorded at pre-dose and post-dose of digoxin at hours 4, 8 and 24. ECG will be recorded at additional time points when clinically indicated. 
7 
Clean-catch urine will be collected for urinalysis on indicated days or if symptoms or signs suggestive of urinary tract infection are present. If urine is 
dipstick positive for WBC or blood (except female subjects who are menstruating), sample is to be sent for microscopic evaluation and culture. Urinalysis 
on Days 1, 3, and 19 will be done pre-dose. 
8 
Blood for clinical chemistry and hematology will be drawn after a minimum of 10 h fasting prior to breakfast. Infectious disease testing will be conducted at 
screening only. Clinical lab test blood draw will be done pre-dose. 
9 
PK plasma samples will be collected at the following time points: pre-dose of digoxin (0 h) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h post 
dose of digoxin. 
 


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GROUP 2 SCHEDULE OF EVENTS 
Evaluation 
Screening 
Period 1:  Treatment B 
Period 2:  Treatment A 
Days to randomization (days) 
-21 to -1 
0 
1 
2 
3 
4 
5 
6 
14 
15 
16 
17 
18 
19 
20 
21 
22 
Medical history and ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review for I/E criteria1 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam2 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Admission or discharge3  
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer bexagliflozin4 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Administer digoxin4 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Vital signs5 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
ECG6 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
X 
Urinalysis7 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
Urine drug screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (for females only) 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Blood draw for clinical lab tests8 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
Blood samples for PK9 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Adverse event and concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study termination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 
Eligibility criteria will be re-confirmed on Day 1 prior to randomization, based on results for clinical lab tests from Day 0 and vital signs, ECG and 
urinalysis results from Day 1 pre-dose. 
2 
Weight and height will be recorded as part of the physical examination. Height will be recorded once at screening only. A complete physical exam (PE) 
will be performed at screening visit and the day of study termination, Day 22. A partial PE will be performed on Days 0, 1, 14, and 17. On Days 1 and 17, 
the PE will be performed prior to dosing.  
3 
Group 2 subjects will be admitted to the clinic on Day 0, discharged on Day 6 for Period 1.  For Period 2, subjects will be admitted on Day 14 and 
discharged on Day 22.  
4 
See Appendix 2 for dosing schedule. 
5 
Vital signs include pulse, body temperature, respiratory rate, and blood pressure after at least 5 minutes of rest. On Days 1, 15, and 17, vital signs will be 
measured pre-dose and 4 h post-dose. 


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6 
12-lead ECG will be conducted after 5 min of rest.  On Day 15, ECG will be recorded pre-dose and 4 hr post-dose of bexagliflozin. On Days 1, 2, 17 and 
18, ECG will be recorded at pre-dose and post-dose of digoxin at hours 4, 8 and 24. ECG will be recorded at additional time points when clinically 
indicated. 
7 
Clean-catch urine will be collected for urinalysis on the indicated days, or if symptoms or signs suggestive of urinary tract infection are present. If urine is 
dipstick positive for WBC or blood (except female subjects who are menstruating), sample is to be sent for microscopic evaluation and culture. Urinalysis 
on Days 1, 15 and 17 will be done pre-dose. 
8 
Blood for clinical chemistry and hematology will be drawn after a minimum of 10 h fasting prior to breakfast. Infectious disease testing will be conducted 
at screening only. Clinical lab test blood draw will be done pre-dose. 
9 
PK plasma samples will be collected at the following time points: pre-dose of digoxin (0 h) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h post 
dose of digoxin. 
 
 


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Appendix 2 
Dosing Schedule 
 
 
 
                        PERIOD 1 
 
 
             PERIOD 2 
 
 
 
 
 
 
Treatment A 
 
 
            Treatment B 
 
Day(s) 
1 
2 
3 
4 
5 
6 
7 
8 
 
 
19 
20 
21 
22 
23 
24 
 
GROUP 1 
Bexagliflozin tablet, 20 mg 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Digoxin, 0.5 mg 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
         Treatment B 
 
 
 
            Treatment A 
 
Day(s) 
 
1 
2 
3 
4 
5 
6 
 
15 
16 
17 
18 
19 
20 
21 
22 
 
GROUP 2 
Bexagliflozin tablet, 20 mg 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Digoxin, 0.5 mg 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 





SAP_001.pdf: 
 
Statistical Analysis Plan 
Protocol Number: THR-1442-C-443 
Last Revision Date: 18-Oct-2017
 
Final 
Page 1 of 31 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Trial Sponsor: 
Protocol Number: 
Theracos Sub, LLC. 
THR-1442-C-443 
IND Number: 
103822
Investigational Drug: 
Indication: 
Bexagliflozin Tablets 
Type 2 Diabetes Mellitus 
Dosage Form/Strength: 
Tablets/20 mg - Bexagliflozin 
 
 
Protocol Title:  A Phase 1, Open-label, Randomized, Two-period, Two-treatment, Crossover 
Study to Evaluate the Effect of Bexagliflozin on the Pharmacokinetics of Digoxin in Healthy 
Subjects 
 
 
 
 
 
Last Revision Date:
18-Oct-2017 
 
 
The information contained in this statistical analysis plan is confidential and provided only to 
Theracos Sub, LLC. Therefore, the information may not be disclosed to, used, or copied by any 
third party without the written consent of Theracos Sub, LLC or to the extent required by 
applicable laws, rules and regulations. 
 




 
Statistical Analysis Plan 
Protocol No: THR-1442-C-443 
Last Revision Date: 18-Oct-2017
 
Final 
Page 3 of 31 
CONFIDENTIAL 
 
CHANGE LOG FOR CHANGES MADE AFTER THE INITIAL APPROVAL 
 
 
Revision 
Date** 
 
Section(s) 
Modified 
 
Brief Description of Revision(s) or 
Reason(s) for Revision 
Modifications Reviewed and 
Approved by* 
Sponsor, Everest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*   Provide person’s initial and last name. 
** Update the Last Revision Dates on the cover page and the document header. 
 
 


 
Statistical Analysis Plan 
Protocol No: THR-1442-C-443 
Last Revision Date: 18-Oct-2017
 
Final 
Page 4 of 31 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION .......................................................................................................................................... 10 
2. 
STUDY OBJECTIVES .................................................................................................................................. 11 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................. 11 
2.2 
SECONDARY OBJECTIVES .......................................................................................................................... 11 
3. 
STUDY DESIGN ............................................................................................................................................ 11 
3.1 
STUDY DESIGN .......................................................................................................................................... 11 
3.2 
RANDOMIZATION ...................................................................................................................................... 12 
3.3 
HYPOTHESIS TESTING ............................................................................................................................... 12 
3.4 
INTERIM ANALYSIS ................................................................................................................................... 12 
3.5 
SAMPLE SIZE ............................................................................................................................................. 12 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE ............................................................................. 14 
5. 
ANALYSIS POPULATIONS ........................................................................................................................ 14 
5.1 
SAFETY POPULATION ................................................................................................................................ 14 
5.2 
PHARMACOKINETIC POPULATION ............................................................................................................. 14 
6. 
SPECIFICATION OF ENDPOINTS AND VARIABLES .......................................................................... 15 
6.1 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 15 
6.1.1 
Study Day and Visit Window Definitions ................................................................................ 15 
6.2 
PHARMACOKINETICS ................................................................................................................................. 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)............................................................................................................... 18 
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 ......................................................................................................................... 21 
6.3.9 
Concomitant Medications/Treatments ...................................................................................... 22 
7. 
PHARMACOKINETIC ANALYSES ........................................................................................................... 22 
7.1 
GENERAL CONSIDERATIONS ...................................................................................................................... 22 
7.2 
PHARMACOKINETIC ANALYSES ................................................................................................................. 23 
8. 
STATISTICAL ANALYSIS .......................................................................................................................... 24 
8.1 
GENERAL DATA HANDLING RULES AND DEFINITIONS .............................................................................. 24 
8.2 
SUBJECT DISPOSITION ............................................................................................................................... 25 
8.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 25 
8.4 
SAFETY ANALYSES ................................................................................................................................... 25 
8.4.1 
Adverse Events ......................................................................................................................... 25 
8.4.2 
Laboratory Data ........................................................................................................................ 26 
8.4.3 
Vital Signs ................................................................................................................................ 26 
8.4.4 
Electrocardiogram (ECG) ......................................................................................................... 26 
8.4.5 
Physical examinations .............................................................................................................. 26 
8.4.6 
Pregnancy Test ......................................................................................................................... 26 


 
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9. 
ANALYSES PERFORMED BEFORE DATABASE CLOSURE .............................................................. 27 
10. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL ......................................................... 27 
11. 
STATISTICAL SOFTWARE ........................................................................................................................ 27 
12. 
REFERENCES ............................................................................................................................................... 27 
13. 
APPENDIX 1   DATA HANDLING RULES ............................................................................................... 28 
14. 
APPENDIX 2   SAS CODE FOR STATISTICAL ANALYSES ................................................................. 29 
15. 
APPENDIX 3   REFERENCE RANGES AND CLINICALLY RELEVANT CHANGES FROM 
BASELINE FOR MARKED LABORATORY ABNORMALITIES ......................................................... 30 
16. 
APPENDIX 4   MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS) .............................................. 31 
 
 


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


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


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


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


 
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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary and analysis 
of data collected within the scope of Theracos Sub, LLC protocol version 2.0 dated 13-Jun-2017. As with 
any SAP, the proposed methods and approaches to the data analysis should be deemed as flexible. The 
analysis of the data should allow changes in the plan to the extent that deviations from the original plan 
would provide a more reliable and valid analysis of the data. As such, the statistical analysis to a certain 
degree is iterative since much of the planning is based on assumptions that require verification. The 
purpose of this plan is to provide general guidelines from which the analysis will proceed. Nevertheless, 
deviations from these guidelines must be substantiated by a sound statistical rationale. 
This SAP should be read in conjunction with the study protocol and the Case Report Forms (CRFs). This 
version of the SAP has been developed using the final version of the protocol mentioned above and the 
final version of the annotated CRFs dated 26-JUL-2017 (signed 27-JUL-2017). 
The SAP details the analysis of the data collected in the study and the presentation of the results of the 
analyses. The table, listing, and figure (TLF) shells are displayed in a companion document which 
provides information on the layout of the data displays. 
All statistical analyses will be performed using SAS® version 9.4. Adverse events will be coded using the 
latest version of the Medical Dictionary for Regulatory Activities (MedDRA version 20.1 or newer). 
This is a phase 1, single center, open-label, two-period, two-treatment, crossover study to evaluate the 
effect of bexagliflozin tablets, 20 mg, on the pharmacokinetics (PK) of digoxin, 0.5 mg, when co-
administered in healthy subjects. Approximately 18 eligible healthy subjects will be randomized to one of 
the two groups (Group 1 and 2) with up to 9 subjects per group. Subjects will reside in the clinic for a 
total of 16 days, divided into two treatment periods, Periods 1 and 2. Subjects will be discharged and out 
of the clinic between the 2 treatment periods for 9 days for Group 1 and 7 days for Group 2. During the 
treatment periods, subjects will receive 2 treatments in differing order: Treatment A, bexagliflozin 
administered once daily for 8 days with digoxin co-administered on Day 3 and Treatment B, digoxin 
administered alone on Day 1. Safety monitoring will be conducted throughout the study. 
 
Group 1: 
Period 1, Treatment A: Subjects randomized to Group 1 will be admitted to the clinic on Day 0. Starting 
on Day 1, subjects will receive once daily oral dose of 20 mg bexagliflozin for 8 days; a single dose of 0.5 
mg digoxin will be co-administered with bexagliflozin on Day 3. Blood samples for PK will be drawn at 
pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours (h) on Day 3, 24 h (Day 4), 48 h (Day 5), 72 h (Day 
6), 96 h (Day 7), and 120 h (Day 8) after administration of digoxin. Subjects will be discharged on Day 8.  
 
Period 2, Treatment B: Subjects will be admitted on Day 18 and receive a single oral dose of 0.5 mg 
digoxin on Day 19. Blood samples for PK will be drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 
hours (h) on Day 19, 24 h (Day 20), 48 h (Day 21), 72 h (Day 22), 96 h (Day 23), and 120 h (Day 24) 
after administration of digoxin. Subjects will be discharged from the clinic on Day 24.  
Group 2:  
Period 1, Treatment B: Subjects randomized to Group 2 will be admitted to the clinic on Day 0. On Day 
1, subjects will receive a single oral dose of 0.5 mg digoxin. Blood samples for PK will be drawn at pre-
dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours (h) on Day 1, 24 h (Day 2), 48 h (Day 3), 72 h (Day 4), 
96 h (Day 5), and 120 h (Day 6) after administration of digoxin. Subjects will be discharged on Day 6.  


 
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Period 2, Treatment A: Subjects will be admitted on Day 14. On Day 15, subjects will start to receive 
once daily oral dose of 20 mg bexagliflozin for 8 days; a single dose of 0.5 mg digoxin will be co-
administered with bexagliflozin on Day 17. Blood samples for PK will be drawn at pre-dose and at 0.5, 1, 
1.5, 2, 3, 4, 6, 8, and 12 hours (h) on Day 17, 24 h (Day 18), 48 h (Day 19), 72 h (Day 20), 96 h (Day 21), 
and 120 h (Day 22) after administration of digoxin. Subjects will be discharged from the clinic on Day 22.  
(See Protocol Sections 3.1 to 3.3 for additional details). 
2. STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of this study is to evaluate the effect of bexagliflozin on the PK of digoxin after co-
administration. 
2.2 Secondary Objectives 
The secondary objective of this study is to evaluate the safety and tolerability of digoxin when co-
administered with bexagliflozin. 
3. STUDY DESIGN 
3.1 Study Design 
This is a phase 1, single center, open-label, two-treatment period, crossover study to evaluate the effect of 
bexagliflozin tablets, 20 mg, on the PK of digoxin, 0.5 mg after co-administration in healthy subjects. 
Approximately 18 eligible healthy subjects who consent to the study will be enrolled into the study and 
randomized to one of the two groups with up to 9 subjects per group. Each subject will participate in 2 
periods during which subjects will receive 2 treatments (Treatment A: bexagliflozin co-administered with 
digoxin, Treatment B: digoxin alone). During the duration of the study, each subject will receive 8 single 
doses of bexagliflozin and 2 single doses of digoxin. 
Group 1 
Approximately 9 subjects will be admitted to the clinic on Day 0 and will receive the following study 
drugs in two treatment periods: 
 
Period 1, Treatment A 
Subjects will receive a single oral dose of 20 mg bexagliflozin tablet daily starting on Day 1 for 8 days, 
and a single oral dose of 0.5 mg digoxin will be co-administered with bexagliflozin on Day 3. Blood 
samples for PK will be drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours (h) on Day 3, 24 h 
(Day 4), 48 h (Day 5), 72 h (Day 6), 96 h (Day 7), and 120 h (Day 8) after administration of digoxin. 
Subjects will be discharged on Day 8 after all study activities are completed. 
Period 2, Treatment B 
Subjects will be admitted on Day 18. On Day 19, subjects will receive a single oral dose of 0.5 mg 
digoxin. Blood samples for PK will be drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours (h) 
on Day 19, 24 h (Day 20), 48 h (Day 21), 72 h (Day 22), 96 h (Day 23), and 120 h (Day 24) after 
administration of digoxin. Subjects will be discharged on Day 24 after all study activities are completed.  
 
 


 
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Group 2 
Approximately 9 subjects will be admitted to the clinic on Day 0 and will receive the following study 
drugs in two treatment periods:  
 
Period 1, Treatment B  
Subjects will receive a single oral dose of 0.5 mg digoxin on Day 1. Blood samples for PK will be drawn 
at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours (h) on Day 1, 24 h (Day 2), 48 h (Day 3), 72 h 
(Day 4), 96 h (Day 5), and 120 h (Day 6) after administration of digoxin.  
Period 2, Treatment A  
Subjects will be admitted on Day 14. Subjects will receive a single oral dose of 20 mg bexagliflozin daily 
for 8 days starting on Day 15, and a single oral dose of 0.5 mg digoxin will be co-administered with 
bexagliflozin on Day 17. Blood samples for PK will be drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 
and 12 hours (h) on Day 17, 24 h (Day 18), 48 h (Day 19), 72 h (Day 20), 96 h (Day 21), and 120 h (Day 
22) after administration of digoxin. Subjects will be discharged on Day 22 after all study activities are 
completed. 
Clinical laboratory tests and safety monitoring will be conducted during both treatment periods for both 
groups. 
3.2 Randomization 
A total of 18 healthy subjects will be enrolled and randomly assigned to group 1 or group 2 in a 1:1 ratio. 
Subjects who discontinue the study after randomization will not be replaced. 
3.3 Hypothesis Testing 
No formal statistical hypothesis testing will be conducted for this study. 
3.4 Interim Analysis 
There will be no interim analysis conducted. 
3.5 Sample Size 
The sample size for this study is not based upon formal statistical consideration. The sample size is 
considered adequate to characterize the PK of digoxin, to assess potential drug-drug interactions and to 
provide safety and tolerability data on the compound when administered either alone or with 
bexagliflozin. 
 


 
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Table 1. Schedule of Events – Group 1 
 
Evaluation 
Screening 
Period 1:  Treatment A 
Period 2:  Treatm
Days to randomization (days) 
-21 to -1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
18 
19 
20 
21 
2
Medical history and ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review for I/E criteria1 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam2 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Admission or discharge3  
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Administer bexagliflozin4 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Administer digoxin4 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Vital signs5 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
ECG6 
X 
 
X 
 
X 
X 
 
 
 
 
 
X 
X 
 
Urinalysis7 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
Urine drug screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (for females only) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Blood draw for clinical lab tests8 
X 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
 
Blood samples for PK9 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X
dverse event and concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Study termination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
criteria must be re-confirmed on Day 1 prior to randomization, based on results for clinical lab tests from Day 0 and vital signs, ECG and urinalysis resu
d 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 per
visit and the day of study termination, Day 24. A partial PE will be performed on Days 0, 3, 18 and 19.  On Days 3 and 19, the PE will be performed prio
ubjects will be admitted to the clinic on Day 0, discharged on Day 8 for Period 1.  For Period 2, subjects will be admitted on Day 18 and discharged on D
ndix 2 for dosing schedule. 
s include pulse, body temperature, respiratory rate, and blood pressure after at least 5 minutes of rest. On Days 1, 3, and 19, vital signs will be measured p
se. Vital signs will also be measured on Day 8 and Day 24. 
CG will be conducted after 5 min of rest.  On Day 1, ECG will be recorded pre-dose and 4 hr post-dose of bexagliflozin. On Days 3, and 19, ECG will be
nd post-dose of digoxin at hours 4 and 8.. On Days 4 and 20 ECG will be recorded at 24 hrs post dose of digoxin on Day 3 and Day 19 respectively.ECG
on Day 24. ECG will be recorded at additional time points when clinically indicated. 
ch urine will be collected for urinalysis on indicated days or if symptoms or signs suggestive of urinary tract infection are present. If urine is dipstick posi
sample is to be sent for microscopic evaluation and culture. Urinalysis on Days 1, 3, and 19 will be done pre-dose. 
clinical chemistry and hematology will be drawn after a minimum of 10 h fasting prior to breakfast. Infectious disease testing will be conducted at screen
b test blood draw will be done pre-dose. 
a samples will be collected at the following time points: pre-dose of digoxin (0 h) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h post dose of d
 
 
 
Table 2. Schedule of Events – Group 2 
Evaluation 
Screening 
Period 1:  Treatment B 
Period 2:  Treatment A 
Days to randomization (days) 
-21 to -1 
0 
1 
2 
3 
4 
5 
6 
14 
15 
16 
17 
18 
19 
20 
21 
22 
Medical history and ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review for I/E criteria1 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam2 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Admission or discharge3  
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer bexagliflozin4 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Administer digoxin4 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Vital signs5 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 


 
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ECG6 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
X 
Urinalysis7 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
Urine drug screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (for females only) 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Blood draw for clinical lab tests8 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
Blood samples for PK9 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Adverse event and concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study termination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 
Eligibility criteria will be re-confirmed on Day 1 prior to randomization, based on results for clinical lab tests from Day 0 and vital signs, ECG and urinalysis results from Day 1 
pre-dose. 
2 
Weight and height will be recorded as part of the physical examination. Height will be recorded once at screening only. A complete physical exam (PE) will be performed at 
screening visit and the day of study termination, Day 22. A partial PE will be performed on Days 0, 1, 14, and 17. On Days 1 and 17, the PE will be performed prior to dosing. 
3 
Group 2 subjects will be admitted to the clinic on Day 0, discharged on Day 6 for Period 1.  For Period 2, subjects will be admitted on Day 14 and discharged on Day 22. 
4 
See Appendix 2 for dosing schedule. 
5 
Vital signs include pulse, body temperature, respiratory rate, and blood pressure after at least 5 minutes of rest. On Days 1, 15, and 17, vital signs will be measured pre-dose and 4 
hr post-dose. Vital signs will also be measured on Day 6 and Day 22. 
6 
12-lead ECG will be conducted after 5 min of rest.  On Day 15, ECG will be recorded pre-dose and 4 hr post-dose of bexagliflozin. On Days 1 and17, ECG will be recorded at 
pre-dose and post-dose of digoxin at hours 4, 8.. On Days 2 and 18 ECG will be recorded at 24 hrs post dose of digoxin on Day 1 and Day 17 respectively. ECG will also be 
recorded on Day 22. ECG will be recorded at additional time points when clinically indicated. 
7 
Clean-catch urine will be collected for urinalysis on the indicated days, or if symptoms or signs suggestive of urinary tract infection are present. If urine is dipstick positive for 
WBC or blood, sample is to be sent for microscopic evaluation and culture. Urinalysis on Days 1, 15 and 17 will be done pre-dose. 
8 
Blood for clinical chemistry and hematology will be drawn after a minimum of 10 h fasting prior to breakfast. Infectious disease testing will be conducted at screening only. 
Clinical lab test blood draw will be done pre-dose. 
9 
PK plasma samples will be collected at the following time points: pre-dose of digoxin (0 h) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h post dose of digoxin. 
 
4. DATA AND ANALYTICAL QUALITY ASSURANCE 
The overall quality assurance (QA) procedures for the study data, statistical programming and analyses are 
described in Everest’s Standard Operating Procedures (SOPs). Detailed data management (DM) procedures 
are documented in the Data Management Plan, Data Validation Check Specifications, and Data Review 
Plan. Detailed statistical and programming quality control (QC) and QA procedures are documented in the 
Statistical Analysis and Programming QC/QA Plan. 
The study endpoints and analytic approaches are both prospectively defined and documented in the protocol 
and in this SAP. The SAP will be finalized, and protocol violations will be identified and decisions for 
inclusion and exclusion of subjects from the PK Population will be made prior to the database lock and data 
analysis. 
5. ANALYSIS POPULATIONS 
Two subject populations will be evaluated during this study and are defined as follows: 
5.1 Safety Population 
The Safety Population will include all randomized subjects who receive at least one dose of either study 
drug. Subjects will be analyzed according to the treatment received. 
5.2 Pharmacokinetic Population 
The PK Population will include all randomized subjects who receive at least one dose of study drug and 
who have sufficient plasma digoxin measurements to derive at least one PK parameter following dosing. 


 
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The PK Population will be used to summarize the PK parameters. Subjects will be analyzed according to 
the treatment received. 
6. SPECIFICATION OF ENDPOINTS AND VARIABLES 
6.1 Demographic and Baseline Characteristics 
Demographic variables consist of the following: 
 
Age in years (continuous) derived as the integer value of  
(informed consent date – date of birth + 1)/365.25 
 
Sex 
 
Race 
 
Ethnicity 
Baseline characteristics consist of the following: 
 
Body mass index (BMI) 
 
Weight (kg) 
 
Height (cm) 
 
Vital signs 
o systolic blood pressure (SBP, mmHg) 
o diastolic blood pressure (DBP, mmHg) 
o oral temperature (oC) 
o pulse (beats per minute) 
o respiration rate  
 
 
Electrocardiogram (ECG) parameters 
o RR interval (msec) 
o PR interval (msec) 
o QRS duration (msec) 
o QT interval (msec) 
o QTcB interval (msec) 
 
Medical history and baseline conditions 
 
Clinical laboratory tests 
 
Prior and concomitant medication  
 
Physical examination 
6.1.1 Study Day and Visit Window Definitions 
Table 3.  Time Windows for Safety Assessments  
Time Windows for Safety Assessments 
Scheduled Visit Number 
Visit (label) 
Time Interval (day) 
Target Time Point (day) 
1 
Screening 
-21 to -1 
-21 to -1 


 
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2 
Day 0 
0 
0 
3 
Day 1 
1 
1 
4 
Day 2 
2 
2 
5 
Day 3 
3 
3 
6 
Day 4 
4 
4 
7 
Day 5 
5 
5 
8 
Day 6 
6 
6 
9 
Day 7 
7 
7 
10 
Day 8 
8 
8 
11 
Day 14 
14 
14 
12 
Day 15 
15 
15 
13 
Day 16 
16 
16 
14 
Day 17 
17 
17 
15 
Day 18 
18 
18 
16 
Day 19 
19 
19 
17 
Day 20 
20 
20 
18 
Day 21 
21 
21 
19 
Day 22 
22 
22 
20 
Day 23 
23 
23 
21 
Day 24 
24 
24 


 
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Data obtained during unscheduled visits will be allocated to the scheduled visit corresponding to the visit 
window they fall in as specified in Section 6.1.1. Safety data obtained during unscheduled time points will 
be allocated to the scheduled time point corresponding to the time window in which they fall. Data will be 
analyzed based on the nominal visits and nominal time points. If the data from the nominal visit or time 
point is missing, data from unscheduled visits for the same nominal visit or time point will be used. If 
multiple unscheduled assessments fall in the same visit window or time point, the non-missing assessment 
closest to target time point will be selected for analysis. 
For ECG safety data the below data handling rules will apply: 
For ECG tests that occur after pre-dose but prior to 4 hrs post-dose, these results will be associated with the 
4 hr post-dose assessment. For ECG tests that occur after 4 hrs post dose, but within a 2 hour window of the 
4 hour postdose timepoint this data will be associated with the 4 hr post-dose timepoint. 
For ECG tests that occur after the 4 hr post-dose timepoint but prior to 8 hrs post-dose, these results will be 
associated with the 8 hr post-dose assessment if they occur within 2 hrs prior to the 8 hr post-dose 
timepoint. 
6.2 Pharmacokinetics 
Pharmacokinetic analysis will be performed on the PK Population respectively 
Plasma samples will be analyzed for digoxin concentrations using a validated method. 
PK plasma samples will be collected at the following time points: pre-dose of digoxin (0 h) and 0.5, 1, 1.5, 
2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h post dose of digoxin. 
6.3 Safety 
Safety analysis will be performed on the Safety Population. 
The safety profile of digoxin will be assessed through the recording, reporting, and analyzing of adverse 
events, clinical evaluations, and laboratory tests. 
Safety variables include the following: 
1. Adverse events 
2. Clinical laboratory measurements – serum chemistry, hematology, and urinalysis 
3. Urine drug screen 
4. Vital signs 
5. ECG 
6. Physical examination 
7. Pregnancy test 
8. Concomitant medications/treatments 
6.3.1 Study Day and Visit Window Definitions 
Refer to section 6.1.1 for details. 
6.3.2 Extent of Exposure to Study Medication 
Subjects who gave consent to participate in the study will be randomly assigned to 1 of the 2 treatment 
groups (Group 1 and Group 2). Each treatment group will receive 2 treatments (Treatment A and Treatment 
B) in a different order during each of the treatment periods (Period 1 and Period 2). The duration of 


 
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Treatment A is 9 days and Treatment B is 7 days. Subjects will remain in the clinic for 16 days during the 
entire study. Subjects will be out of the clinic between the 2 treatment periods for 9 days for Group 1 and 7 
days for Group 2. Overall, each study subject will receive 8 single oral doses of 20 mg bexagliflozin tablets 
and 2 single oral doses of 0.5 mg digoxin in each treatment period. The duration of the overall study from 
screening until study termination is to be a maximum of 46 days. 
6.3.3 Adverse Events (AEs) 
Adverse events will be collected and coded using version 20.1 Sept 2017 (or newer) of MedDRA. Analysis 
of adverse events will be carried out on the Safety Population. All adverse events will be included in the 
individual subject data listings. Only treatment emergent adverse events (TEAEs) will be tabulated in 
summary tables. The incidence of TEAEs will be presented by treatment. If the AE(s) onset date-time or 
date occurs after the first dose up until right before the first dose in the second treatment period, the AE(s) 
will be assigned to the first treatment period. If the AE(s) onset date-time or date occurs after the first dose 
in the second treatment period, the AE(s) will be assigned to the second treatment period. A similar 
approach will be used with respect to all subsequent treatments. 
All adverse events will be assessed by the investigator(s) with respect to severity, relationship to study drug 
and seriousness. 
6.3.3.1 Treatment-Emergent AE (TEAE) 
An adverse event is considered treatment-emergent if it occurs after digoxin and/or bexagliflozin 
administration and if the date –time or date of onset is on or after the date of first dose of study medication, 
or worsens during the treatment period (intensity/severity grades worsen). 
6.3.3.2 Serious Adverse Events (SAE) 
AEs will be categorized as serious or non-serious using the definition specified in Section 6.9 of the study 
protocol. 
6.3.3.3 Immediately Reportable AE (IRAE) 
An IRAE is any serious adverse event or any adverse event that necessitates discontinuation of the study 
drug. 
6.3.3.4 Adverse Events Counting Rules 
1. A subject with more than one different AE in a particular system organ class (SOC) will be counted 
only once in the total of subjects experiencing adverse events in that particular SOC. 
2. A subject having experienced the same event (AE preferred term) more than once during the study 
will be counted only once in the number of subjects with that event. 
3. A subject having experienced the same event (AE preferred term) more than once during the study 
with a different severity or seriousness, it will be counted only once with the worst grade and 
seriousness respectively. 
4. A subject having experienced the same event (AE preferred term) more than once during the study 
with a different causal relationship to the study drug, it will be counted only once by considering 
the most-related documented degree of relationship. 


 
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6.3.3.5 AE Severity 
Adverse events will be graded on a 3-point scale and reported as indicated on the case report form (CRF). 
The intensity of an adverse experience will be graded as “Mild”, “Moderate”, and “Severe” using the 
criteria specified in Section 6.9 of the study protocol. 
6.3.3.6 Relationship to the Investigational Medicinal Product 
The relationship of an AE to dosing will be assessed as “Definite”, “Probable”, “Possible”, “Not Likely”, or 
Unrelated using the criteria specified in Section 6.9 of the study protocol. 
6.3.3.7 AE with Irregular Start/End Dates 
Partial dates may be imputed when appropriate. Imputed dates will be used to determine Study Day. 
If a partial date is reported for the start of an AE, a complete date will be imputed by the following 
algorithm: 
1. Only the year is reported: If the subject started receiving study medication in the previous year, then 
January 1 will be used as the starting date of the event. If the subject started receiving study 
medication in the year reported, then the date of the first dose of study medication will be used as 
the start of the event. 
2. The month and year is reported: If the subject started receiving study medication prior to the month 
and year reported, then the first day of the month will be used as the starting date of the event. If the 
subject started receiving study medication during the month and year reported, then the date of the 
first dose of study medication will be used as the start of the event. 
If a partial date is reported for the end of an adverse event and the adverse event is not continuing, a 
complete date will be imputed by the following algorithm: 
1. Only the year is reported: If the subject started receiving study drug in the previous year, then the 
date of final study contact with the subject will be used as the end of the adverse event. If the 
subject started receiving study medication in the year reported, then the earlier of December 31 or 
the date of final study contact with the subject will be used as the end of the adverse event. 
2. The month and year is reported: The earlier of the last date of the month or the date of final contact 
with the subject will be used as the end of the AE. 
The above rules are subject to logical sense, for example, imputed start date should be on or prior to 
imputed end date. 
All AEs will be included in the listings regardless the completeness of the onset dates. 
6.3.4 Laboratory Data 
Clinical laboratory tests on hematology, serum chemistry, electrolytes, and lipids and urinalysis will be 
performed according to the schedule presented earlier in this SAP. 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 


 
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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. 
Table 4.  Clinical Laboratory Tests 
Hematology 
Hematocrit (Hct) 
Mean corpuscular volume (MCV) 
Hemoglobin (Hgb) 
Platelet count 
Mean corpuscular hemoglobin (MCH) 
Red blood cell (RBC) count 
Mean corpuscular hemoglobin concentration (MCHC) 
White blood cell (WBC) count with differential 
Serum Chemistry, Electrolytes, and Lipids 
Albumin (ALB) 
Calcium (Ca) 
Alanine aminotransferase (ALT) 
Magnesium 
Aspartate aminotransferase (AST) 
Phosphorus 
Blood urea nitrogen (BUN) 
Potassium (K) 
Glucose 
Sodium (Na) 
Total carbon dioxide 
Total bilirubin 
Creatinine  
Direct bilirubin 
Chloride (Cl) 
Uric acid 
Total protein 
Low-density lipoprotein cholesterol (LDL-C), calculated 
Total cholesterol (TC) 
 
High-density lipoprotein cholesterol (HDL-C) 
 
Triglycerides (TG) 
 
Urinalysis 
Appearance 
Nitrite 
Bilirubin 
pH 
Color 
Protein 
Glucose 
Specific gravity 
Ketones 
Urobilinogen 
Microscopic examination of sediment 
Leukocyte esterase 
Urine Drug Screen 


 
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Amphetamines 
Opiates 
Barbiturates 
Benzodiazepines 
Cocaine Metabolites 
Cannabinoids 
Cotinine 
 
Urine Pregnancy Test 
Infectious Disease Testing 
Hepatitis B Surface Antigen (HbsAg) 
Hepatitis C virus (HCV) 
6.3.5 Vital Signs 
Vital signs include pulse (beats/min), SBP and DBP (mmHg), oral temperature (oC) and respiration rate 
(breaths/min). 
Vital sign changes from baseline will be summarized by treatment. 
Baseline values are those measured at last evaluation prior to administration of study drug in each treatment 
period. 
Change from baseline to time point t, denoted Changet, will be calculated as: 
Changet = Valuet – ValueBaseline. 
6.3.6 Electrocardiogram 
ECG parameters, including the RR interval (intra-beat interval), PR interval (the period that extends from 
the beginning of the P wave [the onset of atrial depolarization] until the beginning of the QRS complex [the 
onset of ventricular depolarization]), QRS duration, and QT interval (the corrected QT interval is the 
measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical 
cycle), will be measured according to the study assessment schedule. Each ECG will be assessed by the 
Investigator for signs of ischemia, clinically significant hypertrophy, and clinically significant T-wave 
(repolarization of the ventricles) abnormalities. Baseline ECGs will be defined as the last evaluation 
performed prior to the administration of study drug in each treatment period. 
ECG changes from baseline will be summarized by treatment. 
Change from baseline to time point t, denoted Changet, will be calculated as: 
Changet = Valuet – ValueBaseline. 
6.3.7 Physical Examination 
A complete PE will include measurement of body weight and height (height will be measured only at 
screening), general assessment of all body systems including the skin, head, eyes, ears, nose, throat, neck, 
lungs, heart, abdomen, lymph nodes, and extremities. 
Physical examination results will be presented in individual subject data listings. 
6.3.8 Pregnancy Test 
Only pregnancies considered by the investigator as related to study treatment (e.g., resulting from an 
interaction between study drug and a contraceptive medication) are considered AEs unto themselves.  


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


 
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Statistical and PK analyses will be performed by Everest Clinical Research. Statistical analysis will be 
performed using Statistical Analysis Software SAS for Windows® (SAS Institute Inc., USA). Non-
compartmental analysis (NCA) will be performed using Phoenix® WinNonlin® 6.4 (Certara, USA). 
7.2 Pharmacokinetic Analyses 
From the plasma concentration-time data, the following PK parameters will be estimated for each subject 
where feasible. 
Table 5.  Pharmacokinetic Parameters 
Pharmacokinetic Parameters 
Cmax 
Maximum observed plasma concentration 
Tmax 
Time of maximum observed plasma concentration 
z 
Terminal elimination phase rate constant 
T½ 
Apparent terminal elimination half life 
CL/F 
Apparent oral clearance 
Vz/F 
Apparent volume of distribution 
AUC0-t 
Area under the plasma concentration-time curve from time 0 to time t (time of last quantifiable plasma 
concentration) 
AUC0-∞ 
Area under the plasma concentration-time curve from time 0 to infinity 
 
Cmax and Tmax will be obtained directly from experimental observations. If multiple maxima occur at equal 
concentrations, the first temporal value will be taken. 
The apparent terminal elimination half-life, T1/2, where determinable, will be calculated as the natural log 
of 2 divided by the terminal phase rate constant, λz. The number of data points included in the regression 
will be determined by visual inspection, but a minimum of three data points in the terminal phase, excluding 
Cmax, is required to estimate λz. In order for the selection to take place the adjusted r2 value reported in 
Phoenix®WinNonlin® must be ≥ 0.7. 
AUC0-t and AUC0-∞ will be calculated using the linear trapezoidal linear interpolation method, using actual 
elapsed time values. If the actual collection time is unknown the nominal collection time may be used for 
the purposes of PK parameter estimation. For the purpose of calculating AUC, all missing values will be 
treated as missing in the PK analysis and excluded from analysis except when they occur at pre-dose where 
they will be set to zero. All values that were below the limit of quantitation (BLOQ) prior to Tmax will be set 
to zero. BLOQ values that occur after Tmax will be set to missing. When ≥ 2 consecutive plasma 
concentrations below the limit of quantitation (BLOQ) are encountered after Tmax, these and all subsequent 
values will be excluded from the analysis. 
AUC0-∞ will be calculated as outlined below: 
AUC0-∞= AUClast + (Clast / λz), where Clast is the last temporal quantifiable plasma concentration 
corresponding to Tlast. 
The proportion of AUC0-∞ due to extrapolation (AUCextr) will be calculated and expressed as a percentage. 
AUC0-∞ values will be considered unreliable estimates if the AUCextr is greater than 20% and will be 
excluded from summary tables but will be listed. 


 
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CL/F will be calculated as Dose/AUC0-∞. 
Vz/F will be calculated as Dose/(λz × AUC0-∞). 
T½ will be calculated as 0.693/λz. 
Descriptive statistics for the plasma concentrations of digoxin by Treatment, Timepoint and Sex/Gender 
will be provided. A listing of plasma concentrations by Subject Number, Treatment Period, Timepoint and 
Sex/Gender will also be provided. 
To assess the effect of bexagliflozin on the PK of digoxin, an analyses of variance (ANOVA) using a linear 
mixed-effects model will be fitted to the natural logarithmic transformation of PK parameters of digoxin 
(Cmax, AUC0-t and AUC0-∞). The linear mixed-effects model will include subject as a random effect, and 
treatment, period, and sequence as fixed effects. The 90% confidence intervals will be constructed for 
digoxin administered with bexagliflozin to digoxin alone ratio of the least squares (LS) geometric means of 
PK parameters (Cmax, AUC0-t and AUC0-∞), with 80-125% defined as the lack of interaction boundaries.  
 
Descriptive statistics for the PK parameters Cmax, Tmax, AUC0-∞ ,AUC0-t , AUCextr, CL/F,Vz/F, λz, and T1/2 
will be tabulated by treatment. Means, standard deviations, medians, ranges (min, max) and geometric 
means and coefficients of variation will be presented for all PK parameters with the exception of Tmax. 
Medians and ranges will be presented for Tmax. 
 
A listing of derived PK parameters of digoxin by Subject Number, Treatment Period and Sex/Gender will 
be provided. 
The ratios of geometric least squares means and corresponding 90% CI for the treatment comparison will be 
determined by exponentiating the mean differences between treatments on the logarithm scale. The intra-
subject geometric CV%, 100%*
1
)
exp(

residual
, where residual = the residual variance component and 
where exp is the natural exponential function, will be reported. 
The appropriateness of the mixed model will be assessed through residual analyses. Any modifications 
required due to poor fit will be reported and executed. 
Refer to Appendix 2 for the SAS code. 
8. STATISTICAL ANALYSIS 
8.1 General Data Handling Rules and Definitions 
All data collected on CRFs will be provided in listings, except data collected only for confirmation of study 
entry criteria and for study administrative purposes. If any randomized subject is found to be without valid 
documented informed consent, that subject’s data will be excluded from the report, except as necessary to 
document the error. 
All statistical analyses will be conducted using SAS version 9.4 or newer. 
Except where specified, all continuous variables will be summarized with descriptive statistics (the number 
of non-missing values, mean, standard deviation, median, minimum and maximum) and all categorical 
variables will be summarized with frequency counts and percentages, by treatment and treatment group. 
Unless otherwise specified, the mean and median will be displayed to 1 more decimal place than the 
original data, and standard deviation will be displayed to two more decimal places than the original data. 
All frequencies will be rounded to 1 decimal place. 


 
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Missing data will be maintained as missing unless specified otherwise.  For variables where missing data is 
imputed, the analysis dataset will contain one variable with the imputed value and the original variable with 
missing maintained as missing. 
8.2 Subject Disposition 
An overall disposition table for all subjects will be presented. This tabulation will include the number of 
subjects randomized, treated, completed, and those who discontinued early from the study. The number and 
percentage of randomized subjects who are included in the PK and Safety Populations will also be 
tabulated. 
Subject disposition by treatment, and treatment sequence, will also be summarized. These tabulations will 
include the number of subjects dosed, completed, and those who discontinued early from the study along 
with the corresponding primary reasons for early termination. 
Subjects in the Safety Population who prematurely discontinued from the study will be summarized by 
primary reason for early termination. 
Subject disposition will be listed for all subjects in the Safety Population. 
8.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment, and by treatment sequence, for 
both the Safety and PK Populations and listed. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be presented for 
continuous variables. Frequency distributions (counts and percentages) will be presented for categorical 
variables. 
Medical history and baseline conditions will be summarized by treatment sequence and listed. Physical 
examination, as well as prior and concomitant medications, will also be listed. Prior and concomitant 
medications will be listed with the drug names and ATC classification codes based on the data collected in 
the eCRF. The World Health Organization (WHO) Drug Dictionary, version Sept 2017 or newer, will be 
used to classify prior and concomitant medications by therapeutic class and drug name. 
Abnormalities in the subjects’ medical and surgical histories will be coded using version 20.1 
(or newer) of MedDRA Medical Dictionary for Regulatory Activities, and summarized and listed. 
8.4 Safety Analyses 
Safety analyses will be performed using the Safety Population, unless otherwise specified. 
Safety measurements will include AEs, clinical laboratory tests (i.e. serum chemistry, hematology and 
urinalysis), ECGs, physical exams and vital signs. All safety data will be summarized by treatment. 
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. 


 
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The incidence of all TEAEs will be summarized by treatment. In the summary tables, subjects may be 
counted under multiple SOCs and PTs, but for each SOC and PT, subjects are only counted once. If a 
subject has the same AE on multiple occasions, the highest severity (severe > moderate > mild) or drug 
relationship (definite > probable > possible > not likely related > unrelated) recorded for the event will be 
presented. If severity is missing, subjects will be included as missing (for severity). If drug relationship is 
missing, subjects will be included in related tables (e.g., considered related). Summary tables will be 
organized by SOC, then PT. 
The following summaries will be presented for TEAEs: 
 
Overall Summary of TEAEs by Treatment 
 
Incidence of TEAEs by Treatment, System Organ Class, and Preferred Term 
 
Incidence of Treatment Emergent Serious Adverse Events by Treatment, System Organ Class, 
and Preferred Term 
Subjects who prematurely discontinued due to TEAEs and subjects with serious TEAEs will be listed. 
8.4.2 Laboratory Data 
Summary tables for laboratory parameters (including hematology and chemistry) will be summarized for 
each treatment. Summaries for change from baseline for hematology, and chemistry 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. 
Urinalysis results will be listed. 
8.4.3 Vital Signs 
Summary tables for vital signs data will include descriptive statistics (the number of non-missing values, 
mean, standard deviation, median, minimum and maximum) for values and change from baseline values by 
treatment. 
A listing of vital signs results will be provided for all subjects in the Safety Population. 
8.4.4 Electrocardiogram (ECG)  
ECG parameters (RR interval, PR interval, QRS duration, QT interval, and QTcB interval) will be 
summarized by changes from baseline values by treatment and treatment group using descriptive statistics. 
For each parameter, only subjects who had both baseline and a post-baseline assessment will be included in 
the summary. 
A listing of ECG results will be provided for all subjects in the Safety Population. 
8.4.5 Physical examinations 
Physical examination results will be presented in individual subject data listings.  
8.4.6 Pregnancy Test  
Pregnancy test results prior to treatment will be listed. 


 
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9. ANALYSES PERFORMED BEFORE DATABASE CLOSURE 
No interim analyses are planned for this study. 
10.  CHANGES FROM METHODS PLANNED IN THE PROTOCOL 
Any changes to methods planned in this SAP will be documented in a revision to this statistical plan prior to 
database lock, or identified in the clinical study report. 
11. STATISTICAL SOFTWARE 
The statistical software to be used for generation of the tables, listings, and figures is SAS® version 9.4. 
12. REFERENCES 
Not Applicable. 


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


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


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


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