Clinical trial NCT03296800
Conditions: Type 2 Diabetes Mellitus
Sponsor: Theracos
Start date: 2017-09-27; Completion date: 2017-12-06
Enrollment: 48 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to examine the drug-drug interaction when given the study drug, bexagliflozin, with three commonly prescribed medications, probenecid, verapamil or rifampin. The study is to evaluate how safe the study drug is and how well the study drug is tolerated when taken with probenecid, verapamil or rifampin.

Detailed description:
In this study, a total of 48 healthy subjects were enrolled and assigned to one of three groups of 16 subjects. Each group participated in an open-label, non-randomized, fixed-sequence studies to assess potential interaction of bexagliflozin tablets, 20 mg with probenecid, rifampin or verapamil.

Sequence 1: Bexagliflozin/probenecid Sixteen healthy subjects were dosed with bexagliflozin, qd and/or probenecid tablets, 500 mg, bid, in sequential order as follows: on Day 1 subjects took bexagliflozin; on Days 3 and 4 subjects took probenecid, bid; on Day 5 subjects took one bexagliflozin, and probenecid, bid; and on Day 6 subjects took probenecid tablets, 500 mg, bid.

Sequence 2: Bexagliflozin/rifampin Sixteen healthy subjects were dosed with bexagliflozin, qd and/or 600 mg of rifampin daily in sequential order as follows: on Day 1 subjects took one bexagliflozin tablet; on Days 3 to 5, subjects took rifampin once daily; on Day 6 subjects took one bexagliflozin tablet and rifampin; and on Day 7 subjects took rifampin.

Sequence 3: Bexagliflozin/verapamil Sixteen healthy subjects were dosed with bexagliflozin, and/or verapamil tablets, 120 mg in sequential order as follows: on Day 1 subjects took one bexagliflozin tablet, on Day 4 subjects took one verapamil tablet, 1 hour before taking a bexagliflozin tablet.

Arms: arm 1: Sixteen healthy subjects were dosed with bexagliflozin, qd and/or probenecid tablets, 500 mg, bid, in sequential order as follows: on Day 1 subjects took bexagliflozin; on Days 3 and 4 subjects took probenecid, bid; on Day 5 subjects took one bexagliflozin, and probenecid, bid; and on Day 6 subjects took probenecid tablets, 500 mg, bid. arm 2: Sixteen healthy subjects were dosed with bexagliflozin, qd and/or 600 mg of rifampin daily in sequential order as follows: on Day 1 subjects took one bexagliflozin tablet; on Days 3 to 5, subjects took rifampin once daily; on Day 6 subjects took one bexagliflozin tablet and rifampin; and on Day 7 subjects took rifampin. arm 3: Sixteen healthy subjects were dosed with bexagliflozin, and/or verapamil tablets, 120 mg in sequential order as follows: on Day 1 subjects took one bexagliflozin tablet, on Day 4 subjects took one verapamil tablet, 1 hour before taking a bexagliflozin tablet.
Interventions: intervention 1: Bexagliflozin intervention 2: Probenecid intervention 3: Rifampin intervention 4: Verapamil
Intervention descriptions: intervention 1: Bexagliflozin 20 mg, tablet; qd intervention 2: Probenecid tablets, 500 mg; bid intervention 3: Rifampin, 600 mg (2 x 300 mg capsules); qd intervention 4: Verapamil hydrochloride tablet, 120 mg; qd

Protocol documents:
Prot_000.pdf: 
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Clinical Trial Protocol: THR-1442-C-454 
 
28 August 2017 
 
 
 
 
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Clinical Trial Protocol: THR-1442-C-454 
Study Title: 
A Phase 1, Open-Label, Non-Randomized, Fixed-Sequence Composite 
Study to Evaluate the Effects of Probenecid, Rifampin, and Verapamil 
on the Pharmacokinetics and Pharmacodynamics of Bexagliflozin in 
Healthy Subjects 
Study Number: 
THR-1442-C-454 
Study Phase: 
1 
Product Name: 
Bexagliflozin tablets 
Indication: 
Type 2 Diabetes Mellitus 
Investigators: 
Single center 
Sponsor: 
Theracos Sub, LLC 
Sponsor Study 
Representative: 
Xiao-Yan Li, Ph.D. 
185 Cambridge Street, Boston, MA 02114 
Phone: 617-726-7960, Fax: 617-643-8203 
e-mail: xli@ccib.mgh.harvard.edu 
Medical Monitor: 
Mason W. Freeman, MD 
185 Cambridge Street, Boston, MA 02114 
Phone: 617-724-7704, Fax: 617-643-8203 
e-mail: mfreeman@ccib.mgh.harvard.edu  
 
 
 
 
Date 
Version 1 
28 August 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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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................12 
1 
INTRODUCTION ...........................................................................................................14 
1.1 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus ...............................15 
1.2 
Summary of Nonclinical Data with Bexagliflozin .................................................15 
1.3 
Summary of Clinical Data with Bexagliflozin .......................................................15 
2 
STUDY OBJECTIVES ....................................................................................................17 
2.1 
Primary Objective ..................................................................................................17 
2.2 
Secondary Objective ..............................................................................................17 
3 
INVESTIGATIONAL PLAN ..........................................................................................18 
3.1 
Overall Study Design and Plan ..............................................................................18 
3.2 
Rationale for Study Design and Control Group .....................................................20 
3.2.1 
Rationale for Study Design ..........................................................................20 
3.2.2 
Rationale for Dose Selection .......................................................................21 
3.2.3 
Rationale for PK and PD Sampling Time Points .........................................21 
3.3 
Study Duration and Dates ......................................................................................21 
4 
STUDY POPULATION SELECTION ...........................................................................23 
4.1 
Study Population ....................................................................................................23 
4.2 
Inclusion Criteria ...................................................................................................23 
4.3 
Exclusion Criteria ..................................................................................................23 
5 
STUDY PROCEDURES .................................................................................................26 
5.1 
Description of Investigational Products .................................................................26 
5.1.1 
Bexagliflozin ................................................................................................26 
5.1.2 
Probenecid, Rifampin and Verapamil ..........................................................26 
5.2 
Substances Administered .......................................................................................27 
5.3 
Selection and Timing of Dose for Each Subject ....................................................27 
5.4 
Method of Assigning Subjects to Treatment Groups and Sequences ....................28 
5.5 
Blinding..................................................................................................................28 
5.6 
Concomitant Therapy.............................................................................................28 
5.7 
Restrictions ............................................................................................................28 
5.7.1 
Prior Therapy ...............................................................................................28 
5.7.2 
Fluid and Food Intake ..................................................................................28 
5.7.3 
Subject Activity Restrictions .......................................................................29 
5.8 
Treatment Compliance ...........................................................................................29 
5.9 
Packaging and Labeling .........................................................................................29 


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5.9.1 
Bexagliflozin ................................................................................................29 
5.9.2 
Probenecid, Rifampin and Verapamil ..........................................................29 
5.10 
Storage and Reconciliation ....................................................................................30 
6 
STUDY PROCEDURES .................................................................................................31 
6.1 
Informed Consent...................................................................................................31 
6.2 
Medical History .....................................................................................................31 
6.3 
Physical Examination.............................................................................................32 
6.4 
Vital Signs ..............................................................................................................32 
6.5 
Electrocardiography ...............................................................................................32 
6.6 
Clinical Laboratory Tests .......................................................................................33 
6.6.1 
Laboratory Parameters .................................................................................33 
6.6.2 
Sample Collection, Storage, and Shipping ..................................................34 
6.6.2.1 
Hematology and Blood Chemistry.....................................................34 
6.6.2.2 
Urinalysis ...........................................................................................34 
6.6.2.3 
Urine Collection for PD .....................................................................34 
6.6.2.4 
Plasma Sample Collection for PK......................................................34 
6.7 
Adverse Events Assessments .................................................................................35 
6.7.1 
Collecting and Reporting Adverse Events ...................................................36 
6.7.2 
Immediately Reportable Adverse Events .....................................................37 
6.7.3 
Follow-up of Adverse Events ......................................................................37 
6.7.3.1 
Follow-up of Non-serious Adverse Events ........................................37 
6.7.3.2 
Follow-up of Post-Study Serious Adverse Events .............................37 
6.7.3.3 
Hepatotoxicity ....................................................................................37 
6.7.3.4 
Hypoglycemia ....................................................................................38 
6.8 
Concomitant Medication Assessments ..................................................................39 
6.9 
Removal of Subjects from the Trial or Discontinuation of Investigational 
Product ...................................................................................................................39 
6.10 
Appropriateness of Measurements .........................................................................40 
7 
STUDY ACTIVITIES .....................................................................................................41 
7.1 
Study Activities for Study 1 ...................................................................................41 
7.1.1 
Screening (Day -21 to Day -1) .....................................................................41 
7.1.2 
Day 0 (Clinic Admission) ............................................................................41 
7.1.3 
Day 1 (Dosing Day): Pre-dose .....................................................................42 
7.1.4 
Day 1 (Dosing Day): Dosing .......................................................................42 
7.1.5 
Day 1: Post-dose ..........................................................................................42 
7.1.6 
Day 2 ............................................................................................................43 
7.1.7 
Day 3 (Dosing Day): Pre-dose .....................................................................43 
7.1.8 
Day 3 (Dosing Day): Dosing .......................................................................43 
7.1.9 
Day 3 (Dosing Day): Post-dose ...................................................................43 


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7.1.10 
Day 4 (Dosing Day): Dosing .......................................................................44 
7.1.11 
Day 4: Post-dose ..........................................................................................44 
7.1.12 
Day 5: Pre-dose ............................................................................................44 
7.1.13 
Day 5: Dosing ..............................................................................................44 
7.1.14 
Day 5: Post-dose ..........................................................................................45 
7.1.15 
Day 6: Dosing ..............................................................................................45 
7.1.16 
Day 6: Post-dose ..........................................................................................45 
7.1.17 
Day 7 ............................................................................................................45 
7.2 
Study Activities for Study 2 ...................................................................................46 
7.2.1 
Screening (Day -21 to Day -1) .....................................................................46 
7.2.2 
Day 0 (Clinic Admission) ............................................................................47 
7.2.3 
Day 1 (Dosing Day): Pre-dose .....................................................................47 
7.2.4 
Day 1: Dosing ..............................................................................................47 
7.2.5 
Day 1: Post-Dose .........................................................................................47 
7.2.6 
Day 2 ............................................................................................................48 
7.2.7 
Day 3: Pre-dose ............................................................................................48 
7.2.8 
Day 3: Dosing ..............................................................................................48 
7.2.9 
Day 3: Post-Dose .........................................................................................48 
7.2.10 
Day 4-Day 5: Dosing ...................................................................................49 
7.2.11 
Day 4-Day 5: Post-Dose ..............................................................................49 
7.2.12 
Day 6: Pre-dose ............................................................................................49 
7.2.13 
Day 6: Dosing ..............................................................................................50 
7.2.14 
Day 6: Post-dose Activities ..........................................................................50 
7.2.15 
Day 7 (Dosing):............................................................................................50 
7.2.16 
Day 7: Post-dose ..........................................................................................50 
7.2.17 
Day 8 ............................................................................................................51 
7.3 
Study Activities for Study 3 ...................................................................................51 
7.3.1 
Screening (Day -21 to Day -1) .....................................................................51 
7.3.2 
Day 0 (Clinic Admission) ............................................................................52 
7.3.3 
Day 1 (Dosing Day): Pre-dose .....................................................................52 
7.3.4 
Day 1 (Dosing Day): Dosing .......................................................................53 
7.3.5 
Day 1: Post-dose ..........................................................................................53 
7.3.6 
Day 2 ............................................................................................................53 
7.3.7 
Day 3 ............................................................................................................53 
7.3.8 
Day 4 (Dosing Day): Pre-dose .....................................................................54 
7.3.9 
Day 4 (Dosing Day): Dosing .......................................................................54 
7.3.10 
Day 4 (Dosing Day): Post-dose ...................................................................54 
7.3.11 
Day 5 ............................................................................................................55 


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7.3.12 
Day 6 ............................................................................................................55 
7.4 
Early Termination or Follow-up Procedures .........................................................55 
8 
QUALITY CONTROL AND ASSURANCE .................................................................56 
9 
PLANNED STATISTICAL METHODS ........................................................................57 
9.1 
General Considerations ..........................................................................................57 
9.2 
Determination of Sample Size ...............................................................................57 
9.3 
Analysis Populations ..............................................................................................57 
9.3.1 
Safety Population .........................................................................................57 
9.3.2 
PK Population ..............................................................................................57 
9.3.3 
PD Population ..............................................................................................57 
9.4 
Demographics and Baseline Characteristics ..........................................................57 
9.5 
Pharmacokinetic Analysis ......................................................................................58 
9.5.1 
Calculation of Pharmacokinetic Variables ...................................................58 
9.5.2 
Statistical Analysis of Pharmacokinetic Variables ......................................59 
9.6 
Pharmacodynamic Analysis ...................................................................................59 
9.7 
Safety Analysis ......................................................................................................60 
9.7.1 
Adverse Events ............................................................................................60 
9.7.2 
Hypoglycemia ..............................................................................................60 
9.7.3 
Clinical and Laboratory Events and Analyses .............................................61 
9.7.4 
Concomitant Medications ............................................................................61 
10  ADMINISTRATIVE CONSIDERATIONS ....................................................................62 
10.1 
Investigators and Study Administrative Structure .................................................62 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................62 
10.3 
Ethical Conduct of the Study .................................................................................62 
10.4 
Subject Information and Consent...........................................................................63 
10.5 
Subject Confidentiality ..........................................................................................63 
10.6 
Study Monitoring ...................................................................................................63 
10.7 
Case Report Forms and Study Records .................................................................64 
10.8 
Protocol Violations/Deviations ..............................................................................64 
10.9 
Access to Source Documentation ..........................................................................64 
10.10  Retention of Data ...................................................................................................65 
10.11  Publication and Disclosure Policy .........................................................................65 
11  REFERENCE LIST .........................................................................................................66 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Required Laboratory Tests .........................................................................33 


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LIST OF IN-TEXT FIGURES 
Figure 1 Study design of drug-drug interaction between bexagliflozin and probenecid 
(A), rifampin (B) or verapamil (C) ..............................................................................20 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .....................................................................................68 
Appendix 2 
Sponsor Signatures.....................................................................................74 
Appendix 3 
Investigator’s Signature .............................................................................75 
 
 


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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 Ingredients : 
Polyethylene oxide, glyceryl behenate, lactose monohydrate, micronized poloxamer, 
microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate. 
Name of Reference Therapies: 
Probenecid tablets, rifampin capsules, and verapamil tablets 
Study Title: 
A Phase 1, Open-Label, Non-Randomized, Fixed-Sequence Composite Study to Evaluate the 
Effects of Probenecid, Rifampin, and Verapamil on the Pharmacokinetics and 
Pharmacodynamics of Bexagliflozin in Healthy Subjects 
Study Number:THR-1442-C-454 
Study Phase: 1 
Primary Objective:  
• To evaluate the effects of probenecid, rifampin, and verapamil on the pharmacokinetics 
(PK) and pharmacodynamics (PD) of bexagliflozin in healthy subjects  
Secondary Objective: 
• To assess the safety and tolerability of bexagliflozin co-administered with probenecid, 
rifampin, or verapamil  
 
Study Design: 
In this study, a total of 48 healthy subjects will be enrolled and assigned to one of three 
groups of sixteen. Each group will participate in one of three phase 1, open-label, non-
randomized, fixed-sequence studies: 
Study 1: Bexagliflozin/probenecid (n=16)  
This is an open-label study of bexagliflozin and probenecid taken in a sequential order by 
healthy subjects. Sixteen healthy subjects will take  one bexagliflozin tablet, 20 mg, once 
daily (qd) and/or probenecid tablets, 500 mg, twice daily (bid) in a sequential order as 
follows: on Day 1 subjects will take one bexagliflozin tablet, 20 mg, on Days 3 to 4 subjects 
will take probenecid tablets, 500 mg (bid), on Day 5 subjects will take one bexagliflozin 
tablet, 20 mg  (qd) + probenecid tablets, 500 mg (bid), and on Day 6 subjects will take 
probenecid tablets, 500 mg (bid). 
Blood samples to characterize the PK profile of bexagliflozin and its principal (3’-O-
glucuronide) metabolite EGT0002149 will be collected at pre-dose and at 1, 2, 3, 4, 5, 6, 8, 
10, 12, 16, 24, 36, and 48 h after administration of bexagliflozin on Day 1 and Day 5. 


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Urine samples for PD measurement will be collected at pre-dose (h -12 to 0), and at 0 to 12 
h, 12 to 24 h, 24 to 36 h, and 36 to 48 h after oral administration of bexagliflozin on Day 1 
and Day 5. 
Plasma concentrations of bexagliflozin and EGT0002149 will be determined by validated 
LC-MS/MS assays. 
Study 2: Bexagliflozin/rifampin (n=16)  
This is an open-label study of bexagliflozin and rifampin taken in a sequential order by 
healthy subjects. Sixteen healthy subjects will take bexagliflozin tablets, 20 mg, and/or 600 
mg of rifampin (2 x 300 mg capsules) daily in sequential order as follows: on Day 1 subjects 
will take one bexagliflozin tablet, 20 mg, on Days 3 to 5, subjects will take 600 mg of 
rifampin (2 x 300 mg capsules) once daily, on Day 6 subjects will take one bexagliflozin 
tablet, 20 mg and 600 mg of rifampin, and on Day 7 subjects will take 600 mg of rifampin. 
Blood samples for the characterization of the PK profile of bexagliflozin and its principal 
metabolite EGT0002149 will be collected at pre-dose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 
36, and 48 h after administration of bexagliflozin on Day 1 and Day 6. 
Urine samples for PD (UGE) will be collected at pre-dose (h -12 to 0), and at 0 to 12 h, 12 to 
24 h, 24 to 36 h, and 36 to 48 h after administration of bexagliflozin on Day 1 and Day 6. 
Plasma concentrations of bexagliflozin and EGT0002149 will be determined by validated 
LC-MS/MS assays. 
Study 3: Bexagliflozin/verapamil (n=16)  
This is an open-label study of bexagliflozin and verapamil taken in a sequential order by 
healthy subjects. Sixteen healthy subjects will be administered bexagliflozin tablets, 20 mg 
and/or verapamil tablets, 120 mg, in sequential order as follows: on Day 1 subjects will take 
one bexagliflozin tablet, 20 mg, on Day 4 subjects will take one verapamil tablet, 120 mg one 
hour before taking one bexagliflozin tablet, 20 mg.  
Blood samples for characterization of the PK profile of bexagliflozin will be collected at pre-
dose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h after administration of bexagliflozin 
on Day 1 and Day 3. 
Urine samples for PD (UGE) analysis will be collected at pre-dose (h -12 to 0), and at 0 to 12 
h, 12 to 24 h, 24 to 36 h, and 36 to 48 h after administration of bexagliflozin on Day 1 and 
Day 3. 
Plasma concentrations of bexagliflozin will be determined by validated LC-MS/MS assay. 
Clinical laboratory tests and safety monitoring will be conducted during the study for all 
subjects.  
For study events table, see Appendix 1.  
Study Population: 48 subjects are planned to be enrolled, 16 in each of the 3 studies. 


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Diagnosis and Main Criteria for Inclusion 
1. Healthy subjects who are between the ages of 18 and 55 years, inclusive. 
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 refrain from donating sperm and use 
appropriate birth control such as the use of condoms when engaging in sexual intercourse 
for a period of 30 days after discharge from the clinic. 
4. Subjects who are non-smokers for at least 3 months prior to screening. 
5. Subjects with adequate venous access at multiple sites in both arms. 
Test Product, Dose and Mode of Administration:  Bexagliflozin tablets, 20 mg qd, po. 
Reference Therapy, Dose and Mode of Administration: 
Probenecid tablets, 500 mg bid, po 
Rifampin capsules, 600 mg qd, po 
Verapamil tablets, 120 mg qd, po 
Duration of Treatment:  
A total of 48 healthy subjects will be enrolled in three groups of sixteen. Individuals with 
histories incompatible with enrollment in some groups may be assigned to alternate groups. 
Each group will participate in one of three fixed-sequence studies: 
Study 1: Bexagliflozin/probenecid (n=16)  
Study 2: Bexagliflozin/rifampin(n=16)  
Study 3: Bexagliflozin/verapamil (n=16)  
 
Subjects in Study 1 (probenecid) will check into the clinic on the day before dosing, and void 
their bladders at 12 h prior to anticipated first dose. They will remain domiciled in clinical 
research unit (CRU) until the final plasma sample is collected at 48 h post-dose on the 
morning of study Day 7.  
Subjects in Study 2 (rifampin) will check into the clinic on the day before dosing and void 
their bladders at 12 h prior to the anticipated first dose. They will remain domiciled in CR)  
until the final plasma sample is collected at 48 h post-dose on the morning of study Day 8.  
Subjects in Study 3 (verapamil) will check into the clinic on the day before dosing and void 
their bladders at 12 h prior to the anticipated first dose. They will remain domiciled in CR)  
until the final plasma sample is collected at 48 h post-dose on the morning of study Day 6. 
Screening will be taken place within 21 days before the first intake of study drug. The 
duration of the overall study from screening until study termination is estimated to be a 
maximum of 30 days. For details of the schedule and nature of the investigations, see the 
Schedule of Events in Appendix 1. 
Pharmacokinetic Variables: 
The following PK parameters will be determined after each subject is dosed with 


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bexagliflozin alone or with bexagliflozin and the potential interacting agent  (probenecid, 
rifampin or verapamil). The analytes measured will be bexagliflozin (in all studies) and its 
3’-O-glucuronide (EGT0002149; in study 1 and 2.)  
Cmax 
 Maximum observed plasma concentration 
Tmax  
 Time of maximum observed plasma concentration 
λz       Terminal elimination phase rate constant  
T1/2       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  
AUCextr % of AUC0-∞ due to extrapolation from Tlast to infinity  
M/P AUC Ratio  Metabolite-to-parent ratio for AUC (AUC0-t and AUC0-∞) 
M/P Cmax Ratio  Metabolite-to-parent ratio for Cmax  
Pharmacodynamics Assessments: 
PD parameters include: 
• Urinary glucose excretion (UGE) 
• Urinary creatinine  
Safety Assessments: 
• Physical examinations 
• Vital signs 
• 12-lead electrocardiograms 
• Clinical laboratory tests including blood chemistry and hematology parameters 
• Urinalysis 
• Adverse events 
Statistical Methods:  
An adequate number of subjects will be enrolled to obtain approximately 16 evaluable 
subjects in each study. 
Statistical analysis will be performed using Statistical Analysis Software SAS for Windows® 
(SAS Institute Inc., USA). PK parameters will be calculated using non-compartmental 
analyses of plasma concentration data. To assess the effect of co-administration of the 
interacting agent (probenecid, rifampin and verapamil) on the PK of bexagliflozin, analyses 
of variance (ANOVA) using a linear mixed-effects model will be fitted to the natural 
logarithmic transformation of the PK parameters (Cmax, AUC0-t and AUC0-∞). The linear 
mixed-effects model will include subject as a random effect, and treatment as fixed effects. 


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The 90% confidence intervals will be constructed for the ratio of geometric means of PK 
parameters (Cmax, AUC0-t and AUC0-∞) inferred from bexagliflozin dosing in combination 
with the interacting drug (probenecid, rifampin or verapamil) divided by the values for 
bexagliflozin dosing as a sole agent, with 80-125% defined as the lack of interaction 
boundaries.  
Descriptive statistics for the PK parameters Cmax, Tmax, AUC0-∞ , AUC0-t , AUCextr, M/P Cmax 
and AUC Ratio (AUC0-t and AUC0-∞)  (for Study 1 and Study 2), 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.  
The amount of UGE, urinary creatinine, and creatinine normalized UGE (nUGE) will be 
calculated. The descriptive statistics will be used to describe any differences in these PD 
parameters between treatments. 
  
Date of Protocol V.1.0: 28 August 2017 


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


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PD 
pharmacodynamic 
PE 
physical examination 
po 
by mouth 
Pgp 
p-glycoprotein 
PK 
pharmacokinetic 
SAE 
serious adverse event 
SD 
standard deviation 
SFU 
Sulfonylurea 
SGLT1 
sodium glucose cotransporter 1 
SGLT2 
sodium glucose cotransporter 2 
SOP 
standard operating procedure 
SR 
slow release 
TEAE 
treatment emergent adverse event 
T1/2 
apparent terminal elimination half life 
Tlast 
time of last measurable concentration 
Tmax 
time of maximum observed plasma concentration 
T2DM 
type 2 diabetes mellitus 
UGE 
urine glucose excretion 
ULN 
upper limit of normal 
UGT 
uridine diphosphate glucuronosyltransferases 
UTI 
urinary tract infection 
Vz/F 
apparent volume of distribution 
WBC 
white blood cells 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of child-bearing potential 
 
 
 
 


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1 
INTRODUCTION 
Bexagliflozin is a potent and selective sodium glucose linked transporter 2 (SGLT2) inhibitor 
being developed as a treatment for type 2 diabetes mellitus and hypertension. The transport 
of glucose from the renal tubule lumen into tubular epithelial cells is facilitated by SGLT2, 
which is expressed primarily in the S1 and S2 segments of the proximal tubule (Washburn, 
2009).Bexagliflozin blocks the reabsorption of filtered glucose by inhibiting SGLT2, 
promotes urinary glucose excretion and reduces plasma glucose (Zhang et al., 2011). 
Extended release bexagliflozin tablet formulations have been developed that provide greater 
than 75% release in approximately 8 h in vitro. Clinical pharmacokinetic (PK) studies have 
shown that the peak plasma bexagliflozin concentrations occur between 3 to 5 h and 
thereafter decline in a biphasic manner with mean elimination half-life values ranging from 
7.80 to 9.71 h. Bexagliflozin is cleared predominantly by metabolism to an inactive 
metabolite, bexagliflozin 3’-O-glucuronide by uridine diphosphate glucuronosyltransferase 
isoform 1A9 (UGT1A9). Exposure to the 3’-O-glucuronide occurs at 26%-32% of exposure 
(as AUC) to the parent drug. Although phase 2 metabolism is largely considered to have high 
capacity, the possible consequences of systemic inhibition of UGT1A9, or UGTs in general, 
on bexagliflozin metabolism would be helpful to understand. Both probenecid and valproic 
acid have been suggested to be medically relevant model UGT inhibitors ((FDA), 2012). 
Selective inhibition of UGT1A9 can be achieved with the NSAID niflumic acid (Miners et 
al., 2011) but this agent is not frequently encountered in clinical practice, whereas probenecid 
is more widely prescribed. In this study probenecid will be used to explore possible 
consequences of UGT inhibition.  
In vitro studies have shown that bexagliflozin is not a potent inhibitor for transporters 
including human breast cancer resistance protein (BCRP), organic anion transporting 
polypeptide OATP1B1 and OATP1B3, organic anion transporter 1 (OAT1) and OAT3, bile 
salt export pump (BSEP), or human organic cation transporters OCT1 and OCT2 (IC50≥34.8 
M). Bexagliflozin is a substrate for P-glycoprotein (P-gp) and inhibits P-glycoprotein (P-
gp) efflux ratio with an IC50 of 3.7 M or 1720 ng/mL, about 11 × the Cmax expected for the 
expected marketed dose of 20 mg.  Although bexagliflozin was found to produce changes in 
efflux ratio at relatively low concentrations, much higher concentrations were required to 
produce changes in P-gp-mediated net transport. It is unknown whether an inhibitor of P-gp 
would increase the availability of bexagliflozin in humans. Among the inhibitors of P-gp that 
are available for use as probes, verapamil is attractive for the degree of characterization of its 
action in antecedent studies and for its favorable safety profile.   
Bexagliflozin is neither a significant inducer nor inhibitor of cytochrome P450 (CYP) 
isoenzymes and is a substrate of CYP3A4 in vitro. Phase 1 metabolites EGT0001301, 
EGT0001663, and EGT0001494 have been observed after incubation with CYP3A4 in vitro 
(THR-1442-N-440). Although the contribution of oxidative metabolism to clearance of 
bexagliflozin has been found to be low, the potential for a clinically meaningful decrease in 
plasma concentration following exposure to a potent inducer of xenobiotic metabolism 
cannot be excluded. For the most relevant CYP isoform, CYP3A4, rifampin is known to be a 
strong inducer ((FDA), 2012).  


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The overall investigational plan for assessing potential drug-drug interactions of 
bexagliflozin has been designed to comply with the relevant Guidance for Industry 
addressing drug interaction studies ((FDA), 2012). The substrate drug, bexagliflozin, will be 
dosed at the maximum expected planned dose, 20 mg ((FDA), 2012) . The shortest dosing 
interval of the potential interacting drug has been chosen in each case ((FDA), 2012).This 
interval varies according to the interacting drug. For verapamil, previous studies have 
indicated that a maximal effect on absorption can be achieved with a single dose of 120 mg 
administered an hour in advance of the dosing of the target compound. Although the 
bexagliflozin formulation chosen for development has a gastroretentive mechanism, Tmax is 
reached after dosing in the fasted state relatively promptly, and a timing adjustment for the 
dosing of verapamil is not thought to be necessary. The relevant site of action of verapamil 
for its effect on bexagliflozin absorption is the intestine, and hence the lumenal concentration 
of verapamil is arguably more important than the plasma level.  
Assessment of the potential for interaction of bexagliflozin metabolism with probenecid and 
rifampin requires a longer dosing period to allow the latter agents, or their actions, to reach 
steady state. Two prior consecutive days of dosing of probenecid are anticipated to be 
required to attain approximately asymptotic plasma profiles. Although rifampin has a 
relatively short elimination half-life, its effects on induction of xenobiotic metabolizing 
enzymes requires chronic dosing to develop, and based on literature modeling, bexagliflozin 
administration is planned for day four of dosing. Because large increases in elimination half-
life are not expected to be encountered in any of these studies, the bexagliflozin sampling 
will cease at 48 h post-dose for both the initial administration and co-administration phases 
of the study.  
1.1 
Bexagliflozin for the Treatment of Type 2 Diabetes Mellitus 
Bexagliflozin is a highly specific inhibitor of SGLT2 with an in vitro IC50 of 2 nM or 
0.9 ng/mL and a 2435-fold selectivity for human SGLT2 over human SGLT1. Details of the 
nonclinical and clinical findings can be found in the Investigator’s Brochure. 
1.2 
Summary of Nonclinical Data with Bexagliflozin 
Bexagliflozin exhibits high permeability and is a potential Pgp (p-glycoprotein) substrate and 
inhibitor. It is not a significant inducer or inhibitor of cytochrome P450 isozymes and other 
transporters relevant for drug-drug interactions. 
1.3 
 Summary of Clinical Data with Bexagliflozin 
Following administration of bexagliflozin tablets in extended release formulations, Tmax was 
reached between 3 to 5 h. The tablets produced dose proportional exposure with a Cmax of 4 
or 8 ng/mL per mg bexagliflozin and an AUC0-24 of 40 or 50 ng·h/mL per mg bexagliflozin in 
healthy subjects when dosing was before or after a meal, respectively. 
The principal metabolites in humans are similar to those found in monkeys and are 
dominated by glucuronides of the parent compound, for which the AUC is >30% relative to 
parent bexagliflozin. Following oral administration of radiolabeled bexagliflozin, >90% of 


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the ingested radioactivity was recovered, 51% as fecal excretion and 41% as urinary 
excretion. In urine, bexagliflozin accounts for 1.5% of the dose; most of the radioactivity is 
excreted as bexagliflozin 3’-O-glucuronide. The largest fraction of the radioactivity in feces 
is bexagliflozin, accounting for about 30% of the administered dose. 
The safety and tolerability of bexagliflozin in healthy or diabetic subjects was initially 
evaluated in a single-dose study of up to 100 mg, followed by a 4-week treatment study in 
which doses ranged from 5 mg/d to 50 mg/d. The most frequently occurring adverse events 
(AEs) were mild to moderate headache, pollakiuria, nausea, and fatigue. No symptomatic 
hypoglycemia was reported and no treatment-related adverse event led to discontinuation of 
treatment. Extended release tablets of 3 mg to 90 mg strengths were well tolerated in a 
Japanese population with few adverse events reported. 
In study THR-1442-C-481, a delayed Tmax of 5 h was observed under fed conditions 
compared to 3.5 h under fasted conditions and an approximately 30% increase in Cmax under 
fed conditions was seen compared to the Cmax in the fasted state, without significant changes 
in AUC. The 90% CI for the ratios of geometric means between fed and fasted conditions in 
both AUC0-t and AUC0-∞ were contained within 80% to 125% demonstrating that 
bexagliflozin bioavailability was not affected by co-administering with food. 
Detailed information on prior clinical experience with bexagliflozin and potential risks for 
study subjects are provided in the Investigator’s Brochure. 
 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
To evaluate the effects of probenecid, rifampin, and verapamil on the pharmacokinetics (PK) 
and pharmacodynamics (PD) of bexagliflozin in healthy subjects  
2.2 
Secondary Objective 
To assess the safety and tolerability of bexagliflozin when it is co-administered with 
probenecid, rifampin, or verapamil  
 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
In this study, a total of 48 healthy subjects will be enrolled and assigned to three groups of 
sixteen subjects per group. Each group will participate in one of three open-label, non-
randomized, fixed-sequence studies (Figure 1): 
Study 1: Bexagliflozin/probenecid (n=16)  
Study 2: Bexagliflozin/rifampin (n=16)  
Study 3: Bexagliflozin/verapamil (n=16) 
 
Study 1: Bexagliflozin/probenecid (n=16)  
Sixteen healthy subjects will take bexagliflozin tablets, 20 mg, qd and/or probenecid tablets, 
500 mg, bid, in sequential order as follows: on Day 1 subjects will take one bexagliflozin 
tablet, 20 mg. on Days 3 and 4 subjects will take probenecid tablets, 500 mg, bid, on Day 5 
subjects will take one bexagliflozin tablet, 20 mg   and probenecid tablets, 500 mg, bid, and 
on Day 6 subjects will take probenecid tablets, 500 mg, bid. 
Blood samples to characterize the PK profile of bexagliflozin and its principal (3’-O-
glucuronide) metabolite EGT0002149 will be collected at pre-dose and at 1, 2, 3, 4, 5, 6, 8, 
10, 12, 16, 24, 36, and 48 h after administration of bexagliflozin on Day 1 and Day 5. 
Urine samples for PD measurement will be collected at pre-dose (h -12 to 0), and at 0 to 12 
h, 12 to 24 h, 24 to 36 h, and 36 to 48 h after oral administration of bexagliflozin on Day 1 
and Day 5. 
Plasma concentrations of bexagliflozin and EGT0002149 will be determined by validated 
LC-MS/MS assays. 
Study 2: Bexagliflozin/rifampin(n=16)  
Sixteen healthy subjects will take bexagliflozin tablets, 20 mg, and/or 600 mg of rifampin (2 
x 300 mg capsules) daily in sequential order as follows: on Day 1 subjects will take one 
bexagliflozin tablet, 20 mg, on Days 3 to 5, subjects will take 600 mg of rifampin (2 x 300 
mg capsules) once daily, on Day 6 subjects will take one bexagliflozin tablet, 20 mg and 600 
mg of rifampin, and on Day 7 subjects will take 600 mg of rifampin. 
Blood samples for the characterization of the PK profile of bexagliflozin and its principal 
metabolite EGT0002149 will be collected at pre-dose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 
36, and 48 h after administration of bexagliflozin on Day 1 and Day 6. 
Urine samples for PD (UGE) will be collected at pre-dose (h -12 to 0), and at 0 to 12 h, 12 to 
24 h, 24 to 36 h, and 36 to 48 h after administration of bexagliflozin on Day 1 and Day 6. 


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Plasma concentrations of bexagliflozin and EGT0002149 will be determined by validated 
LC-MS/MS assays. 
Study 3: Bexagliflozin/verapamil (n=16)  
This is an open-label study of bexagliflozin and verapamil taken in a sequential order by 
healthy subjects. Sixteen healthy subjects will be administered bexagliflozin tablets, 20 mg 
and/or verapamil tablets, 120 mg, in sequential order as follows: on Day 1 subjects will take 
one bexagliflozin tablet, 20 mg, on Day 4 subjects will take one verapamil tablet, 120 mg one 
hour before taking one bexagliflozin tablet, 20 mg.  
Blood samples for characterization of the PK profile of bexagliflozin will be collected at pre-
dose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h after administration of bexagliflozin 
on Day 1 and Day 3. 
Urine samples for PD (UGE) analysis will be collected at pre-dose (h -12 to 0), and at 0 to 12 
h, 12 to 24 h, 24 to 36 h, and 36 to 48 h after administration of bexagliflozin on Day 1 and 
Day 3. 
Plasma concentrations of bexagliflozin will be determined by validated LC-MS/MS assays. 
For study events table, see Appendix 1.  
A. Study 1: Bexagliflozin/probenecid 
 
 
  
 
 
 
 
B. Study 2: Bexagliflozin/rifampin 
 
 
 
 
 
 
Days 1 2 3 4 5
6
7
Bexagliflozin (20 mg), qd
X
X
Probenecid (500 mg), bid
X
X
X
X
Blood sample
*
*
*
*
*
*
Days 1 2 3 4 5 6 7
8
Bexagliglozin (20 mg)
X
X
Rifampin (600 mg)
X
X
X
X
X
Blood sample
*
*
*
*
*
*


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Study 3: bexagliflozin/verapamil 
 
 
 
 
Figure 1 Study design of drug-drug interaction between bexagliflozin and 
probenecid (A), rifampin (B) or verapamil (C) 
 
Clinical laboratory tests and safety monitoring will be conducted during the study as is 
outlined in Appendix 1 Schedule of Events. 
3.2 
Rationale for Study Design and Control Group 
3.2.1 
Rationale for Study Design 
Previous studies have indicated that bexagliflozin is cleared predominantly by metabolism to 
an inactive metabolite, bexagliflozin 3’-O-glucuronide (EGT0002149), by uridine 
diphosphate glucuronosyltransferase isoform 1A9 (UGT1A9). Additionally, phase 1 
metabolites EGT0001301, EGT0001663, and EGT0001494 have been observed after 
incubation with CYP3A4 (study THR-1442-N-440).  In vitro metabolism studies have shown 
that bexagliflozin is neither a potent inhibitor nor inducer of CYP450 enzymes. In vitro 
studies have shown that bexagliflozin is a substrate for P-glycoprotein (P-gp) and inhibits the 
efflux ratio for P-glycoprotein (P-gp) mediated transport with an IC50 of 3.7 M.  
The uricosuric agent probenecid is commonly used to manage gout (Pui et al., 2013). and is a 
relatively subtype-non-selective inhibitor of UGTs that has been recommended as an 
interacting agent for drugs that are metabolized by glucuronidation ((FDA), 2012). 
Probenecid inhibition of UGTs does not show delayed kinetics(Uchaipichat et al., 2004)  and 
following oral dosing an elimination half-life of 4 to 12 hours has been observed for the 
doses contemplated here (Cunningham et al., 1981).  
The effects of verapamil on dabigatran have been studied by Hartter (Hartter et al., 2013), 
who concluded that a single dose of immediate release verapamil 120 mg, 1 hour before 
dosing with dabigatran produced the greatest effects. A similar study design is appropriate to 
the present context because the proposed mechanism of interaction is the same, and posits 
that verapamil may increase availability of bexagliflozin by reducing intestinal basolateral to 
apical transport by P-gp. Verapamil, 120 mg, was also delivered one hour before dosing with 
the SGLT2 inhibitor empagliflozin in a similar drug interaction study (Macha et al., 2013). 
Rifampin is a strong inducer of CYP3A4 and moderate inducer of CYPs 2C19, 2B6, 2C8 and 
2C9. It also potently induces several UGT enzymes (UGT1A1, UGT1A4, UGT1A9, 
Days 1 2 3 4 5
6
Bexagliflozin (20 mg)
X
X
Verapamil (120 mg)
X
Blood sample
*
*
*
*
*
*


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UGT2B4, and UGT2B7) (Chen and Raymond, 2006; Soars et al., 2003). Physiologically 
based pharmacokinetic modeling of rifampin effects have been conducted by Yamashita 
(Yamashita et al., 2013) and by Baneyx (Baneyx et al., 2014), who predicted that three and 
five days of dosing of rifampin, 600 mg, qd, respectively, would suffice for maximal or 
appropriate induction, respectively. A four day dosing period has been chosen for this 
investigation. 
3.2.2 
Rationale for Dose Selection 
Bexagliflozin produces a dose-related, saturable increase in UGE in healthy volunteers and 
diabetic subjects. Population pharmacodynamic modeling has indicated that the UGE is well 
fit by a simple logistic model.  The ED50 values for healthy and diabetic adults are 3.6 mg 
and 1.2 mg, respectively and the maximum dose intended to be submitted for approval is 20 
mg. FDA guidance recommends that the interaction target be dosed at the maximum 
proposed dosage ((FDA), 2012).  
Conversely, FDA guidance also recommends that the shortest dosing interval of the 
interacting agent be used. The dosage of 500 mg probenecid orally twice a day is the 
recommended adult maintenance dose for gout and after four dose the daily 
pharmacokinetics are expected to be close to asymptotic Physiologically based 
pharmacokinetic modeling studies of rifampin induction kinetics have been predicated on 
once daily administration of 600 mg rifampin. As discussed above three and five days have 
been predicted or recommended and the present treatment has adopted four days as the 
duration for induction. Studies on the effect of verapamil on drug absorption have concluded 
that a single 120 mg dose delivered in advance of dosing produces the greatest effect (Hartter 
et al., 2013), and that course has been adopted here.  
3.2.3 
Rationale for PK and PD Sampling Time Points 
The PK samples for combination treatment will be taken hourly up to hour 6, semi-hourly to 
hour 12, and at hours 16, 24, 36 and 48 post-dose. The times of collection are anticipated to 
allow accurate estimates of any change in Tmax and Cmax and provide sufficient data points for 
measurement of the elimination half-life.   
Urine samples for PD  will be collected at pre-dose (h -12 to 0), and at 0 to 12 h, 12 to 24 h, 
24 to 36 h, and 36 to 48 h after administration of bexagliflozin. 
3.3 
Study Duration and Dates 
A total of 48 healthy subjects will be enrolled in three groups of sixteen. Individuals with 
histories incompatible with enrollment in some groups may be assigned to alternate groups. 
Each group will participate in one of three fixed-sequence studies: 
Study 1: Bexagliflozin/probenecid (n=16)  
Study 2: Bexagliflozin/rifampin (n=16)  
Study 3: Bexagliflozin/verapamil (n=16)  


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Subjects in Study 1 (probenecid) will check into the clinic on the day before dosing, and void 
their bladders at 12 h prior to anticipated first dose. They will remain domiciled in CRU until 
the final plasma sample is collected at 48 h post-dose on the morning of study Day 7.  
Subjects in Study 2 (rifampin) will check into the clinic on the day before dosing and void 
their bladders at 12 h prior to the anticipated first dose. They will remain domiciled in CRU 
until the final plasma sample is collected at 48 h post-dose on the morning of study Day 8.  
Subjects in Study 3 (verapamil) will check into the clinic on the day before dosing and void 
their bladders at 12 h prior to the anticipated first dose. They will remain domiciled in CRU 
until the final plasma sample is collected at 48 h post-dose on the morning of study Day 6. 
Screening will be taken place within 21 days before the first intake of study drug. The 
duration of the overall study from screening until study termination is estimated to be a 
maximum of 30 days. For details of the schedule and nature of the investigations, see the 
Schedule of Events in Appendix 1. 
 
 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Forty-eight eligible healthy male and female subjects who consent to participate in this study 
will be enrolled.  
4.2 
Inclusion Criteria 
To be enrolled in this study a subject must: 
1. be between 18 and 55 years of age at screening, inclusive, and in good health based on 
medical history, physical examination (PE), electrocardiogram (ECG) and routine 
laboratory tests. 
2. have a body-mass index (BMI) between 18.0 kg/m2 and 32.0 kg/m2 at screening, 
inclusive. 
3. have abstained from tobacco consumption for at least 3 months prior to screening. 
4. have adequate venous access at multiple sites in both arms. 
5. be willing and able to be confined to the clinical research facility as required by the 
protocol. 
6. be able to comprehend the explanation of the informed consent and be willing to provide 
written informed consent in accordance with institutional and regulatory guidelines. 
 
4.3 
Exclusion Criteria 
Subjects who exhibit any of the following characteristics will be excluded from the study. 
1. A clinically significant history of allergy to drugs or latex (at the investigator’s 
discretion.) 
2. A history of alcohol or drug dependence in the last 12 months. 
3. A history of donation of 400 mL of whole blood within two months, 200 mL of whole 
blood within one month, or blood components within 14 days prior to the first dose. 
4. A history of prescription or over-the-counter (OTC) drug use within 14 days prior to the 
first dose. 
5. A history of vitamin preparation or supplement use (including St. John’s Wort and 
ginseng) within 14 days prior to the first dose. 
6. A history of strenuous physical activity within 72 hours prior to dosing. 
7. A history of exposure to an investigational drug within 30 days or 7 half-lives of the 
investigational drug, whichever is longer, prior to the first dose of investigational drug in 
this trial. 
8. A history of prior exposure to EGT0001474 or bexagliflozin at any time, or of exposure 
to any other SGLT2 inhibitors within 3 months from screening or of participation in 
previous bexagliflozin clinical trials. 


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9. A history of consumption of probenecid, rifampin or verapamil within 3 months of 
screening. 
10. A screening ECG that demonstrates any one of the following: heart rate > 100 bpm, QRS 
> 120 msec, QTc > 470 msec (corrected by Bazett’s formula), PR > 220 msec (a subject 
with PR > 220 msec will generally be excluded but exceptions may be allowed at the 
discretion of the investigator), or any clinically significant arrhythmia. 
11. A sitting blood pressure that is above 140/90 mmHg at screening.  If the sitting blood 
pressure at screening is above 140/90 mmHg, one repeat measurement can be taken. 
Subjects will be excluded if the repeated sitting blood pressure is above 140/90 mmHg 
but exceptions may be allowed at the discretion of the investigator.    
12. A positive result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) 
antibody, or for urinary drug or cotinine tests. 
13. A history of human immunodeficiency virus (HIV) infection. 
14. A history of febrile illness within 5 days prior to the first dose of investigational drug. 
15. A history of vaccination (with the exception of the flu vaccine) within 30 days prior to 
the first dose of investigational drug. 
16. An estimated glomerular filtration rate (eGFR) < 80 mL/min/1.73 m2 or a history of 
kidney transplant. 
17. If male who are not surgically sterile, unwilling to refrain from donating sperm and 
unwilling to 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 of 
an intrauterine device. 
18. If female of childbearing potential, unwilling to use an adequate method of contraception 
and/or  to avoid pregnancy for the duration of the study. Hormonal contraceptive methods 
are inadequate for subjects enrolled in the rifampin study. Appropriate methods of 
contraception for female subjects of childbearing potential in the rifampin study 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 > 45 years) are eligible if they test 
negative on a urine pregnancy test. 
19. Evidence of anemia if selected for probenecid study. 
20. Evidence of abnormal liver function tests (total bilirubin > 1.5 x upper limit of normal 
(ULN)); or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x 
ULN. 
21. If selected for the rifampin study, unwilling to refrain from the use of soft contact lenses 
during the study. 
22. Unwilling to forgo consumption of alcohol 72 hours pre admission and throughout the 
study. 
23. Unwilling to forgo consumption of grapefruit and grapefruit products from 7 days prior 
to dosing through discharge from the clinic. 


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24. A history of recurrent yeast or urinary tract infections or any such infections in the 6 
months prior to first dose. 
25. A history of gout, glucose-6-phosphate dehydrogenase deficiency or nephrolithiasis if a 
candidate for the probenecid study. 
 
 
 


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5 
STUDY PROCEDURES 
5.1 
Description of Investigational Products 
5.1.1 
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 
Probenecid, Rifampin and Verapamil 
Probenecid tablets, 500 mg, rifampin capsules, 300 mg and verapamil hydrochloride tablets, 
120 mg, will be procured by Covance pharmacy. 
Probenecid is a competitive inhibitor of organic acid transport in the kidney and other organs, 
primarily used as a uricosuric agent for the treatment of chronic gout. It has also been used to 
enhance plasma levels of β-lactam antibiotics. Absorption of probenecid is essentially 
complete following oral administration. The drug is extensively metabolized by glucuronide 
conjugation and by oxidation of the alkyl side chains. The half-life of probenecid in plasma is 
dose-dependent and falls in the range of 4 to 12 hours for the 500 mg dose planned here 
(Cunningham et al., 1981). 
Rifampin is an inhibitor of bacterial RNA polymerase typically used to treat mycobacterial 
infections. Common side effects include nausea, vomiting, diarrhea, and loss of appetite. 
Rifampin is a red substance and may cause the appearance of a red or orange color in urine, 
sweat, and tears. Soft (hydrogel) contact lenses may become discolored as a result. Liver 
enzyme elevation or allergic reactions have been observed. 
Oral delivery of rifampin results in peak plasma concentrations in about two to four hours. 
Only about 7% of the administered drug is excreted unchanged in urine, though urinary 
elimination accounts for only about 30% of the drug excretion. About 60% to 65% is 
excreted through feces. The half-life of rifampin ranges from 1.5 to 5.0 hours, though hepatic 
impairment significantly increases it. Food consumption inhibits its absorption from the GI 
tract, and the drug is more quickly eliminated. When rifampin is taken with a meal, its peak 
blood concentration falls by 36%. 
Verapamil is an inhibitor of cardiac L-type calcium channels used predominantly for the 
management of hypertension and arrhythmias. Common side effects include headache, 
hypotension, nausea, and constipation. Other side effects include allergic reactions and 
arthralgia.  
More than 90% of verapamil is absorbed following oral administration, but due to high first-
pass metabolism, the absolute bioavailability is 10–35%. Tmax is 1 to 2 hours post-dose. It 
undergoes extensive hepatic metabolism.  


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Verapamil hydrochloride tablets, 120 mg (Mylan) will be provided for this study. 
5.2 
Substances Administered 
Subjects who consent to participation will be assigned to 1 of 3 groups. Each subject in Study 
1 will receive a single bexagliflozin tablet, 20 mg, alone, 4-days dosing of probenecid 
capsules, 500 mg (bid), including the combination of both (bexagliflozin tablet and 
probenecid) on Day 5.  
Every subject in Study 2 will receive a single bexagliflozin tablet, 20 mg, alone, 5-days 
dosing of 600 mg of rifampin (2 x 300mg capsules) qd including the combination of both 
(bexagliflozin tablet and rifampin capsules) on Day 6. 
Every subject in Study 3 will receive a single bexagliflozin tablet, 20 mg, alone, and a 
combination of a single bexagliflozin tablet, 20 mg and one verapamil tablet, 120 mg on Day 
4. 
5.3 
Selection and Timing of Dose for Each Subject 
Dosing order with bexagliflozin alone, or bexagliflozin in combination with probenecid, 
rifampin or verapamil will be based on a fixed-sequence schedule.  
For subjects in Study 1, on Day 1 each subject will receive a single dose of bexagliflozin 
tablets, 20 mg (~30 minutes after breakfast, standard low-fat meal) with approximately 240 
mL water. PK samples will be collected from Days 1 to 3 at pre-specified time points. On 
Days 3 to 4 subjects will take probenecid tablets, 500 mg, bid, about 30 min after standard 
meal with approximately 240 mL water. On Day 5, subjects will take bexagliflozin tablets, 
20 mg and probenecid tablets, 500 mg, ~30 min after breakfast with approximately 240 mL 
water. And 10-12 h later, subjects will receive probenecid tablets, 500 mg, ~30 min after 
night meal with approximately 240 mL water. On Day 6 subjects will take probenecid 
tablets, 500 mg, bid, with approximately 240 mL water. Subjects will be discharged after the 
48-h PK sample collection on day 7.    
For subjects in Study 2, on Day 1, subjects will receive a single dose of bexagliflozin tablets, 
20 mg, after an overnight fast of at least 10 h with approximately 240 mL water. PK samples 
will be collected from Days 1 to 3 at pre-specified time points. On Days 3 to 5, subjects will 
take daily dose of two 300-mg rifampin capsules alone after overnight fast with 
approximately 240 mL water. On Day 6 subjects will take bexagliflozin tablets, 20 mg and 
two 300-mg rifampin capsules after overnight fast with approximately 240 mL water. On 
Day 7, subjects will take a single dose of two 300-mg rifampin capsules alone after overnight 
fast with approximately 240 mL water. Subjects will be discharged after the 48-h PK sample 
collection on Day 8.  
For subjects in study 3, on Day 1 each subject will receive a single dose of bexagliflozin 
tablets, 20 mg (~30 minutes after breakfast, standard low-fat meal) with approximately 240 
mL water. PK samples will be collected from Days 1 to 3 at pre-specified time points. On 
Day 4, subjects will take one verapamil tablet, 120 mg one hour before taking one 


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bexagliflozin tablet, 20 mg, about 30 min after breakfast with approximately 240 mL water. 
Subjects will be discharged after the 48-h PK sample collection on Day 6. 
5.4 
Method of Assigning Subjects to Treatment Groups and 
Sequences 
A total of 48 healthy subjects will be enrolled and assigned to one of three groups of sixteen. 
Each group of sixteen will receive a fixed-sequence treatment. Subjects who discontinue 
participation due to safety reasons will not be replaced.  
5.5 
Blinding 
This is an open-label study. 
5.6 
Concomitant Therapy 
Participants will be prohibited from taking any prescription or non-prescription drugs, 
vitamins or dietary supplements at any time during the 14 days prior to first drug 
administration and for the duration of the study. Medications may be prescribed for 
management of an AE. Subjects may receive any medications for AEs that are necessary to 
treat the event or minimize the likelihood of more serious adverse events in the investigators’ 
judgment. 
Concomitant medications administered during the study are to be recorded on the case report 
form (CRF). The medication name, dose, frequency, route of administration, date(s) of 
administration and reason for administration shall be recorded. This documentation shall 
continue until the end of the study.  
5.7 
Restrictions 
5.7.1 
Prior Therapy 
No study subject shall have been dosed with any SGLT2 inhibitor within 3 months prior to 
screening, nor with an investigational drug within 30 days or 7 half-lives, nor consumed any 
medication, vitamin or herbal supplement within 14 days prior to the first dose of study 
medication. 
5.7.2 
Fluid and Food Intake  
For subjects in Study 1, bexagliflozin and probenecid will be administered ~30 minutes after 
standard meal with approximately 240 mL water. Water can be allowed as desired except for 
one hour before and after drug administration. 
For subjects in Study 2, bexagliflozin and rifampin will be administered to subjects after an 
overnight fast of at least 10 h with approximately 240 mL water. Water can be allowed as 
desired except for one hour before and after drug administration. 


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For subjects in Study 3, bexagliflozin and verapamil will be administered ~30 minutes after 
standard meal with approximately 240 mL water. Water can be allowed as desired except for 
one hour before and after drug administration. 
5.7.3 
Subject Activity Restrictions 
Subjects should not perform strenuous or repetitive activities that could result in elevations of 
muscle creatine kinase levels. Smoking during the study is prohibited. Alcohol consumption 
should be avoided for 72 hours prior to each clinic admission check-in. 
5.8 
Treatment Compliance 
To ensure compliance, all medication dosing will be supervised by the Investigator or 
qualified staff in the clinic. The exact times of dosing will be recorded in the CRFs, including 
a record of hand and mouth inspections. 
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 in 90 count bottles. 
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 
Probenecid, Rifampin and Verapamil 
Probenecid tablets USP 500 mg (Watson) are bisected, capsule-shaped, yellow, film-coated 
tablets imprinted DAN DAN and 5347 supplied in bottles of 100. Probenecid Tablets USP 
500 mg contain the following inactive ingredients: colloidal silicon dioxide, D&C Yellow 
No. 10, FD&C Blue No. 1, FD&C Yellow No. 6, hypromellose, magnesium stearate, 
microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium lauryl sulfate, 
sodium starch glycolate and titanium dioxide. 
Rifampin capsules 300 mg (Lannett) are maroon/red capsules imprinted with LANNETT on 
the cap and 1315 on the body. The capsules are supplied in bottles of 30. The inactive 
ingredients include pregelatinized starch, colloidal silicon dioxide, talc, magnesium stearate, 
D&C Red # 28, FD&C Blue # 1, FD&C Red # 40, gelatin, and titanium dioxide. 
Verapamil hydrochloride tablets, 120 mg (Mylan), are white, film-coated, round tablets 
debossed with MYLAN above the score and 772 below the score on one side of the tablet 
and blank on the other side. The tablets are supplied in bottles of 100. The inactive 
ingredients include calcium sulfate, colloidal silicon dioxide, croscarmellose sodium, 
hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, 


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polyethylene glycol, pregelatinized starch (corn), sodium lauryl sulfate, talc and titanium 
dioxide. 
5.10 Storage and Reconciliation 
Bexagliflozin will be stored below 30 °C (86 °F) in a secure area with access limited to 
authorized personnel. Verapamil tablets, probenecid tablets and rifampin capsules will be 
stored at controlled room temperature 20-25 °C (between 68 and 77 °F), protected from 
moisture and heat. The pharmacist shall maintain an inventory of bexagliflozin product and 
the number of tablets dispensed per study subject. A reconciliation of drug inventory will be 
performed at the end of the study and the results of this inventory shall be recorded in the 
Drug Consumption Form. Empty and partially used bottles may be discarded after use 
according to the study site’s regulations for the disposal of investigational drug substances at 
study close out, after the Drug Accountability Form is completed. 
 
 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Before each subject is enrolled, written informed consent will be obtained according to the 
applicable regulatory and legal requirements. As part of this procedure, the investigator or 
designee shall 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 shall 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 shall be informed that he/she is free to withdraw 
from the study at any time.  
The informed consent document shall be signed and dated. One copy will be given to the 
subject, 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 the time it was 
obtained shall also be documented. 
6.2 
Medical History 
The following information will be collected at the screening visit: 
• Demographic information including age, sex, and race. 
• Significant medical and surgical history and with documentation of the dates relative to 
the time of study screening, if applicable. 
• History of clinically significant allergies including to drugs and latex. 
• History of smoking in the 6 months prior to first dose, of alcohol or drug dependence, or 
abuse of substances in the 12 months prior to first dose. 
• History of blood donation within 2 months or blood component donation in the 14 days 
prior to first dose. 
• Medication history including OTC drugs, dietary supplements and vitamins to span the 
14 days prior to first dose.  
• History of vaccination within 30 days prior to first dose. 
• History of diagnosis of HIV, hepatitis B or hepatitis C infection. 
• History of exposure to any investigational drug in the previous 30 days or 7 half-lives 
prior to first dose, whichever is longer. 
• History of exposure to bexagliflozin (or EGT0001474), or any other SGLT2 inhibitors in 
the last 3 months prior to first dose. 
• History of exposure to probenecid, rifampin or verapamil in the 3 months prior to first 
dose. 
• History of recurrent yeast or urinary tract infections or any such infections in the 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 clinic 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 cavity temperature, will be measured on scheduled visits as described in Appendix 1.  
Vital signs shall be measured prior to blood draws and after a subject has been sitting for 5 
minutes. 
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 measurements will be obtained using a calibrated manual or oscillometric 
sphygmomanometer. 
6.5 
Electrocardiography 
A 12-lead electrocardiography (ECG) will be conducted as listed in Appendix 1 and 
whenever clinically indicated. 
This procedure shall 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 
shall also be assessed by the investigator for signs of ischemia, clinically significant 
hypertrophy, and clinically significant T-wave abnormalities. 
It is the investigator or designee’s responsibility to review the results of the ECG as they 
become available. For each abnormal ECG result, the investigator shall ascertain if the 
abnormality represents a clinically significant change from the screening ECG for that 
individual subject. This determination, however, need not be made the first time an abnormal 
result is observed. The investigator may repeat the ECG to verify the results of the original 
result. If the ECG result is determined to be a clinically significant and abnormal change 
from baseline for that subject, the finding shall be considered an AE. 


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6.6 
Clinical Laboratory Tests 
6.6.1 
Laboratory Parameters 
Subjects will be in a seated, semi-recumbent or supine position during blood collection. 
Clinical blood chemistry and hematology tests will be performed at the scheduled visits 
(Appendix 1). Blood samples shall be drawn after overnight fasting (at least 8 h). The details 
of the required laboratory tests are listed in Table 1.  
Table 1. 
Required Laboratory Tests 
Test Name 
 
mL (sample) 
Hematology 
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 (blood) 
Albumin 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Blood urea nitrogen (BUN) 
Glucose 
Bicarbonate 
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 Collection 
 
 
Glucose 
Creatinine 
 
All (urine) 
Urine Drug Screen 
 
10 (urine) 
Amphetamines 
Barbiturates 
Cocaine Metabolites 
Opiates 
Benzodiazepines 
Cannabinoids 
 


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Table 1. 
Required Laboratory Tests 
Test Name 
 
mL (sample) 
Cotinine 
Urine Pregnancy Test (Female only) 
 
5 (urine) 
Infectious Disease Testing 
 
3.5 (blood) 
Hepatitis B surface antigen (HBsAg) 
Hepatitis C virus (HCV)  
 
 
6.6.2 
Sample Collection, Storage, and Shipping 
6.6.2.1 
Hematology and Blood Chemistry 
Blood samples for hematology and chemistry will be collected. Timing of the collection is 
described in Appendix 1. 
6.6.2.2 
Urinalysis 
Clean-catch, midstream urine samples will be collected according to the schedule outlined in 
Section 7 and in Appendix 1. Dipstick urinalysis will be conducted. Microscopic examination 
will be performed if a subject has a positive result on any of the dipstick tests that require 
microscopic follow-up to clarify their significance. If the urine is dipstick positive for 
leukocyte esterase or nitrites, a 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 
Urine Collection for PD  
Pre-dose urine samples shall be collected from -12 to 0 h for baseline measurement. Subjects 
shall empty their bladders 12 h prior to dosing with bexagliflozin and accumulate their urine 
output into separate containers at 12 h intervals beginning at the time of dosing and ending 
48 h after dosing. Urine must be refrigerated at 2-8 °C during collection. A 20 mL aliquot of 
urine will be prepared for analysis from well mixed urine collections. The samples will be 
analyzed for urinary glucose and creatinine.  
6.6.2.4 
Plasma Sample Collection for PK  
Whole venous blood samples of 3 mL will be collected from a peripheral vein at pre-dose 
and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h after administration of bexagliflozin . 
Blood samples will be collected in tubes containing K2EDTA and stored on ice until 
processing by centrifugation under refrigeration for at least 10 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 shall be processed and frozen within 2 h of 
blood collection. Frozen plasma samples will be transferred on dry ice to the analytical 
laboratory and will be stored at or below -20 °C until analysis. 


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6.7 
Adverse Events Assessments 
Adverse Event (AE): Any untoward medical occurrence in a 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), symptom, or disease temporally associated with the use of an 
investigational product, whether or not it is considered related to exposure to the 
investigational product. 
Serious Adverse Event (SAE): A serious adverse event (experience) or reaction is any 
untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening (NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the patient was at risk of death at the time of the event and does not 
refer to an event which hypothetically might have caused death if it were more severe.), 
• requires inpatient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, 
• is an important medical event. 
 
An important medical event is an event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
Non-serious adverse events are all events that do not meet the criteria for a "serious" adverse 
event. 
Immediately Reportable Adverse Event (IRAE): Any serious adverse event or any 
adverse event that necessitates discontinuation of investigational product. 
Adverse Clinical Laboratory Change: An abnormal laboratory test result can be an adverse 
event if it is a clinically significant and deleterious change from baseline (at predose on Day 
1) 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 deleterious change from baseline 
for that subject, this is considered an AE. 


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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 testing laboratory will be considered a clinical laboratory adverse event. 
An increase in creatinine from baseline by 0.5 mg/dL or more will be reported as a laboratory 
adverse event. 
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on the 
CRF. The intensity of an adverse experience is defined as follows: 
1 = Mild: discomfort noticed, but no disruption to daily activity 
2 = Moderate: discomfort sufficient to reduce or affect normal daily activity 
3 = Severe: inability to work or perform normal daily activity 
Investigational Product Causality: A determination of potential dependence on study 
compound administration shall be performed. 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 recording will begin from the time of signing the informed consent form. 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 shall be recorded on the source documents 
and CRFs provided by the sponsor. 


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In addition, Theracos’ Medical Monitor or its designated personnel shall be notified 
immediately by telephone or fax of any immediately reportable adverse events according to 
the procedure outlined below. Special attention shall be paid to recording hospitalizations 
and concomitant medications. 
6.7.2 
Immediately Reportable Adverse Events 
The investigator shall 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 
shall be completed and sent by email or fax or overnight courier to the sponsor within 24 h of 
knowledge of the event. 
Non-serious events that require discontinuation of investigational product (including 
laboratory abnormalities) shall be reported to Theracos within 3 working days. The IRAE 
form shall be completed and sent by email or fax or overnight courier to the sponsor. 
Subjects experiencing an SAE shall be followed clinically until their health has returned to 
baseline status or until all parameters have returned to normal, or have otherwise been 
explained. It is expected that the investigator will provide or arrange appropriate supportive 
care for the subject. 
6.7.3 
Follow-up of Adverse Events 
6.7.3.1 
Follow-up of Non-serious Adverse Events 
Non-serious adverse events that are identified on the last scheduled contact shall be recorded 
on the AE CRF with the current status noted. All non-serious events that are ongoing at the 
time shall be recorded as ongoing on the CRF. 
6.7.3.2 
Follow-up of Post-Study Serious Adverse Events 
Any new SAEs reported by the subject to the investigator that occur after discharge, and are 
determined by the investigator to be reasonably associated with the use of the investigational 
product, shall 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 discharge. The investigator shall follow subjects with SAEs identified after 
discharge until the events are resolved, or the subject is lost to follow-up. The investigator 
shall continue to report any significant follow-up information to the Sponsor until the event 
has been resolved.  
6.7.3.3 
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 shall be stopped and the event shall be reported as an adverse 
event within the CRF if the enzyme elevation is confirmed or worsening. Potential 
contributors to hepatic enzyme elevation shall be evaluated by the investigator. The 


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investigator is encouraged to consult with the Medical Monitor regarding ongoing diagnostic 
workup. 
Investigational product shall 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), 
• 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%). 
 
6.7.3.4 
Hypoglycemia 
Hypoglycemia will be recorded under 5 categories: 
• Critical hypoglycemia: An event requiring assistance of another person to actively 
administer carbohydrates, glucagon, 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 shall 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 shall administer 


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50% IV Dextrose as soon as possible. If IV Dextrose is unable to be administered, an 
injection of 1.0 mg of glucagon shall be administered intramuscularly or subcutaneously, and 
the injection may need to be repeated after 15 minutes depending on the response.  
Blood glucose monitoring shall be done by appropriate study staff using a point-of-care 
glucose monitor beginning at the time of hypoglycemia detection and continue every fifteen 
minutes, or more frequently if required, until that time that the subject’s level of alertness has 
returned to appropriate levels and point-of-care glucose levels are above 70 mg/dL. 
6.8 
Concomitant Medication Assessments 
A concomitant medication is any medication the subject takes during the course of the trial. 
All prescription and non-prescription medications, vitamins and herbal supplements that 
subjects receive during the trial shall be documented on the CRF. This documentation shall 
continue until the subjects are discharged. 
Concomitant medications shall 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 shall be produced. A listing of 
concomitant medications shall include all medications taken by any subjects during the 
course of the study. 
Concomitant medications administered during the study shall be recorded on the CRF. The 
medication name, dose, frequency, route of administration, date(s) of administration and 
reason for administration shall be recorded. This documentation shall continue until 
discharge from the study. 
6.9 
Removal of Subjects from the Trial or Discontinuation of 
Investigational Product 
The investigator shall 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 shall 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 shall be informed immediately. 
If there is a medical reason for withdrawal, the volunteer shall remain under the supervision 
of the medical investigator until satisfactory health returns or the condition has evolved to the 
point that further meaningful change is unlikely. 
Subjects who discontinue the active dosing phase of the study due to adverse event(s) or 
other safety concerns shall not be replaced. 


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If the decision is made to discontinue a subject’s participation in the study, no further 
investigational product medication shall be administered. Every attempt shall be made to 
complete all required study evaluations and procedures. Reasons for all withdrawals shall be 
recorded on the CRF. 
The investigator may withdraw a subject from the THR-1442-C-454 trial for any of the 
following reasons: 
• A protocol violation occurs, or 
• A serious or intolerable adverse event occurs, or 
• A clinically significant change in a laboratory parameter occurs, or 
• The sponsor or investigator terminates the study, or 
• The subject requests to be discontinued from the study. 
 
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, 
and clinical laboratory tests if clinically indicated and feasible according to Section 7. 
 
6.10 Appropriateness of Measurements 
PK and safety parameters in this protocol are standard assessments and are widely used and 
generally recognized as reliable, accurate, and relevant measurements.  
Determination of urinary glucose is a non-invasive and quantitative method that allows 
immediate assessment of the PD effects of an SGLT2 inhibitor. 
 
 


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7 
STUDY ACTIVITIES 
7.1 
Study Activities for Study 1 
7.1.1 
Screening (Day -21 to Day -1) 
During the screening period, the following information will be gathered and the indicated 
procedures will be performed: 
• Content of informed consent will be explained to the subject and the signed informed 
consent collected. 
• Medical history and demographic information will be obtained as described in Section 
6.2. 
• Physical examination will be conducted, including height and weight measurements as 
described in Section 6.3. 
• Vital signs will be measured, including pulse, temperature, respiratory rate, and blood 
pressure taken in the sitting position after at least 5 min of rest as described in Section 
6.4. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest as described 
in Section 6.5. 
• Clean-catch, mid-stream urine will be collected for urinalysis as described in Section 
6.6.2.2. If urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent 
for microscopic evaluation and culture.  
• Urine screen will be conducted for drug abuse and cotinine. If the drug screen is 
conducted more than 5 days pre-dose, the drug screen shall be repeated prior to dosing. 
Drug abuse testing includes amphetamines, barbiturates, cocaine metabolites, opiates, 
benzodiazepines, cotinine, and cannabinoids. 
• All female subjects will receive urine pregnancy test. 
• Blood will be drawn for hematology, serum chemistry, and serology as detailed in 
Section 6.6.2.1. 
• Inclusion/exclusion criteria will be evaluated based on the information collected at the 
screening examination. 
 
7.1.2 
Day 0 (Clinic Admission) 
The following information will be gathered and the indicated procedures will be performed: 
• Partial PE will be performed as described in Section 6.3. 
• If screening was conducted more than 5 days prior to dosing, the inclusion and exclusion 
criteria shall be confirmed and a urine drug screen performed. 
• All female subjects will receive urine pregnancy test. 


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• Subjects will void their bladders at 12 h prior to dosing and begin the collection of the  -
12 h to 0 h batch for baseline analysis of UGE and creatinine (PD) as described in 
Section 6.6.2.3. 
• Concomitant medications and adverse event information will be collected as appropriate. 
• If the subject is still eligible based on the study inclusion and exclusion criteria, the 
subject will be admitted into the study. 
 
7.1.3 
Day 1 (Dosing Day): Pre-dose  
The following information will be gathered and the indicated procedures will be performed 
pre-dose: 
• Vital signs will be recorded pre-dose. 
• Pre-dose urine will be collected until 0 h (-12 h to 0 h batch) for baseline UGE and 
creatinine (PD) analysis as described in Section 6.6.2.3. 
• Urine sample will be collected for pre-dose urinalysis as described in Section 6.6.2.2. If 
urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for 
microscopic evaluation and culture. If screening is conducted more than 5 days prior to 
dosing, drug screening shall be repeated. 
• Pre-dose blood will be drawn for hematology, and serum chemistry as detailed in Section 
6.6.2.1. 
• Pre-dose plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4. 
• Pre-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.1.4 
Day 1 (Dosing Day): Dosing 
• Bexagliflozin tablets, 20 mg, will be administered ~30 minutes after breakfast (standard 
low-fat meal), as detailed in Section 5.3.  
 
7.1.5 
Day 1: Post-dose  
• Vital signs will be recorded at 4 h post-oral dose 
• Urine samples for PD (UGE and creatinine) analysis will be at specified time interval 
after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Blood samples for PK samples will be collected at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 h after 
oral administration of bexagliflozin.  
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 


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For subjects who are terminated from the study for any reason after dosing, all activities for 
the clinic day except for PK and PD sample collection shall be completed. The reason for 
termination shall be entered onto the case report form. 
7.1.6 
Day 2  
• Urine samples for PD (UGE and creatinine) analysis will be collected at specified time 
interval after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 24 and 36 
h post-dose.   
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.1.7 
Day 3 (Dosing Day): Pre-dose  
• Partial PE will be performed as described in Section 6.3. 
• Vital signs will be recorded at 48 h post-dose (from day 1). 
• Urine samples for PD (UGE and creatinine) analysis will be collected at specified time 
interval after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Plasma samples will be drawn for PK analysis  
• Concomitant medications and adverse event information will be collected as appropriate. 
• Urine will be collected for urinalysis as described in Section 6.6.2.2. If urine is dipstick 
positive for leukocyte esterase or nitrites, sample is to be sent for microscopic evaluation 
and culture.  
• Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
 
7.1.8 
Day 3 (Dosing Day): Dosing 
• Probenecid tablets, 500 mg, will be administered twice a day about 30 min after standard 
meal with approximately 240 mL water as detailed in Section 5.3. 
 
7.1.9 
Day 3 (Dosing Day): Post-dose  
• Vital signs will be recorded at 4 h post-oral dose 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the last clinic day except for PK and PD sample collection shall be completed. The reason for 
termination shall be entered onto the case report form. 


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7.1.10 
Day 4 (Dosing Day): Dosing  
• Probenecid tablets, 500 mg, will be administered twice a day about 30 min after standard 
meal with approximately 240 mL water as detailed in Section 5.3. 
 
7.1.11 
Day 4: Post-dose  
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
• Pre-dose urine will be collected (-12 h to 0 h batch) for PD (UGE and creatinine) analysis 
as described in Section 6.6.2.3. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the last clinic day except for PK and PD sample collection shall be completed. The reason for 
termination shall be entered onto the case report form. 
7.1.12 
Day 5: Pre-dose  
• Partial PE will be performed as described in Section 6.3. 
• Vital signs will be recorded at pre-dose. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest as described 
in Section 6.5. 
• Pre-dose urine will be collected until 0 h (-12 h to 0 h batch) for PD (UGE and creatinine) 
analysis as described in Section 6.6.2.3. 
• Urine sample will be collected for pre-dose urinalysis as described in Section 6.6.2.2. If 
urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for 
microscopic evaluation and culture.  
• Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
• Pre-dose plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4. 
• Pre-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.1.13 
Day 5: Dosing 
• Subjects will take bexagliflozin tablets, 20 mg and probenecid tablets, 500 mg, ~30 min 
after breakfast with approximately 240 mL water. And 10-12 h later, subjects will receive 
500 mg probenecid ~30 min after night meal with approximately 240 mL water, as 
detailed in Section 5.3. 
 


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7.1.14 
Day 5: Post-dose  
• Vital signs will be recorded at 4 h post-oral dose 
• 12-lead ECG will be taken at 4 h post-dose in the supine position after at least 5 min of 
rest. 
• Urine samples for PD (UGE and creatinine) will be collected at specified time interval 
after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Blood samples for PK analysis will be collected as detailed in Section 6.6.2.4 at 1, 2, 3, 4, 
5, 6, 8, 10, 12, 16 h after oral administration of bexagliflozin 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the last clinic day except for PK and PD sample collection shall be completed. The reason for 
termination shall be entered onto the case report form. 
7.1.15 
Day 6: Dosing 
• Subjects will take probenecid tablets, 500 mg, ~30 min after breakfast with 
approximately 240 mL water. And 10-12 h later, subjects will receive 500 mg probenecid 
~30 min after night meal with approximately 240 mL water, as detailed in Section 5.3. 
 
7.1.16 
Day 6: Post-dose  
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 24 and 36 
h post-dose of bexagliflozin. 
• Urine samples for PD (UGE and creatinine) analysis will be collected at specified time 
interval after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the last clinic day except for PK and PD sample collection shall be completed. The reason for 
termination shall be entered onto the case report form. 
7.1.17 
Day 7  
The following information will be gathered and the indicated procedures will be performed 
pre-dose: 
• Complete PE will be performed as described in Section 6.3 
• Vital signs will be recorded 48 h post-dose of bexagliflozin (from day 5) 


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• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 48 h post-
dose (from Day 5) 
• Urine samples for PD (UGE and creatinine) analysis will be collected at specified time 
interval after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Urine will be collected for urinalysis as described in Section 6.6.2.2. 
• Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
• Subject will be discharged after completion of all activities. 
 
7.2 
Study Activities for Study 2 
7.2.1 
Screening (Day -21 to Day -1) 
During the screening period, the following information will be gathered and the indicated 
procedures will be performed: 
• Content of informed consent will be explained to the subject and the signed informed 
consent collected. 
• Medical history and demographic information will be obtained. 
• Physical examination will be conducted, including height and weight measurements as 
described in Section 6.3. 
• Vital signs will be measured, including pulse, temperature, respiratory rate, and blood 
pressure taken in the sitting position after at least 5 min of rest as described in Section 
6.4. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest as described 
in Section 6.5. 
• Clean-catch, mid-stream urine will be collected for urinalysis as described in Section 
6.6.2.2. If urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent 
for microscopic evaluation and culture.  
• Urine screen will be conducted for drug abuse and cotinine. If the drug screen is 
conducted more than 5 days pre-dose, the drug screen shall be repeated prior to dosing. 
Drug abuse testing includes amphetamines, barbiturates, cocaine metabolites, opiates, 
benzodiazepines, cotinine, and cannabinoids. 
• All female subjects will receive urine pregnancy test. 
• Blood will be drawn for hematology, serum chemistry, and serology as detailed in 
Section 6.6.2.1. 
• Inclusion/exclusion criteria will be evaluated based on the information collected at the 
screening examination. 
 


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7.2.2 
Day 0 (Clinic Admission) 
The following information will be gathered and the indicated procedures will be performed: 
• Partial PE will be performed as described in Section 6.3. 
• If screening was conducted more than 5 days prior to dosing, the inclusion and exclusion 
criteria shall be confirmed and a urine drug screen performed. 
• All female subjects will receive urine pregnancy test. 
• Pre-dose urine collection in 12 h batches will begin with the -12 h to 0 h batch for 
baseline analysis of UGE and creatinine (PD) as described in Section 6.6.2.3. 
• Concomitant medications and adverse event information will be collected as appropriate. 
• If the subject is still eligible based on the study inclusion and exclusion criteria, the 
subject will be admitted into the study. 
 
7.2.3 
Day 1 (Dosing Day): Pre-dose 
• Vital signs will be recorded pre-dose. 
• Pre-dose urine will be collected until 0 h (-12 h to 0 h batch) for baseline UGE and 
creatinine (PD) analysis as described in Section 6.6.2.3. 
• Urine sample will be collected for pre-dose urinalysis as described in Section 6.6.2.2. If 
urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for 
microscopic evaluation and culture. If screening is conducted more than 5 days prior to 
dosing, drug screening shall be repeated. 
• Pre-dose blood will be drawn for hematology, and serum chemistry as detailed in Section 
6.6.2.1. 
• Pre-dose plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4. 
• Pre-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.2.4 
Day 1: Dosing 
• Subjects will receive a single dose of bexagliflozin tablets, 20 mg, after an overnight fast 
of at least 10 h with approximately 240 mL water as detailed in Section 5.3 
 
7.2.5 
Day 1: Post-Dose  
• Vital signs will be recorded at 4 h post-oral dose 
• Urine samples for PD (UGE and creatinine) analysis will be at specified time interval 
after oral administration of bexagliflozin, as described in Section 6.6.2.3. 


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• Blood samples for PK samples will be collected at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 h after 
oral administration of bexagliflozin.  
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the clinic day except for PK and PD sample collection shall be completed. The reason for 
termination shall be entered onto the case report form. 
7.2.6 
Day 2  
• Urine samples for PD (UGE and creatinine) analysis will be collected at 24-36 h and 36-
48 h after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 24 and 36 
h post-dose.   
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate.  
 
7.2.7 
Day 3: Pre-dose 
• Partial PE will be performed as described in Section 6.3. 
• Vital signs will be recorded at 48 h post-dose (from day 1). 
• Urine samples for PD (UGE and creatinine) analysis will be collected at specified time 
interval after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Plasma samples will be drawn for PK analysis  
• Concomitant medications and adverse event information will be collected as appropriate. 
• Urine will be collected for urinalysis as described in Section 6.6.2.2. If urine is dipstick 
positive for leukocyte esterase or nitrites, sample is to be sent for microscopic evaluation 
and culture.  
• Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
 
7.2.8 
Day 3: Dosing 
• After an overnight fast of at least 10 h, rifampin capsules, 600 mg ((2 x 300 mg capsules), 
will be administered with approximately 240 mL water  prior to first meal of the day as 
detailed in Section 5.3 
 
7.2.9 
Day 3: Post-Dose  
• Vital signs will be recorded at 4 h post-oral dose 


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• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the last clinic day except for PK and PD sample collection shall be completed. The reason for 
termination shall be entered onto the case report form. 
7.2.10 
Day 4-Day 5: Dosing 
• After an overnight fast of at least 10 h, rifampin tablets, 600 mg, will be administered 
with approximately 240 mL water prior to first meal of the day as detailed in Section 5.3 
 
7.2.11 
Day 4-Day 5: Post-Dose  
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
• Pre-dose urine will be collected on Day 5 (-12 h to 0 h batch) for PD (UGE and 
creatinine) analysis as described in Section 6.6.2.3. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the study termination day except for PK and PD sample collection shall be completed. The 
reason for termination shall be entered onto the case report form. 
7.2.12 
Day 6: Pre-dose 
• Partial PE will be performed as described in Section 6.3. 
• Vital signs will be recorded at pre-dose. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest as described 
in Section 6.5. 
• Pre-dose urine will be collected until 0 h (-12 h to 0 h batch) for PD (UGE and creatinine) 
analysis as described in Section 6.6.2.3. 
• Urine sample will be collected for pre-dose urinalysis as described in Section 6.6.2.2. If 
urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for 
microscopic evaluation and culture.  
• Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
• Pre-dose plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4. 
• Pre-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 


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7.2.13 
Day 6: Dosing 
• After an overnight fast of at least 10 h, rifampin capsules, 600 mg (2 x 300 mg capsules), 
and bexagliflozin tablets, 20 mg, will be administered with approximately 240 mL water 
prior to first meal of the day as detailed in Section 5.3 
 
7.2.14 
Day 6: Post-dose Activities 
• Vital signs will be recorded at 4 h post-oral dose 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest at 4 h post-
dose. 
• Urine samples for PD (UGE and creatinine) analysis will be at specified time interval 
after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Blood samples for PK samples will be collected at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 h after 
oral administration of bexagliflozin.  
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the clinic day except for PK and PD sample collection shall be completed. The reason for 
termination shall be entered onto the case report form. 
7.2.15 
Day 7 (Dosing):  
• After an overnight fast of at least 10 h, rifampin capsules, 600 mg (2 x 300 mg capsules), 
will be administered with approximately 240 mL water prior to first meal of the day as 
detailed in Section 5.3 
 
7.2.16 
Day 7: Post-dose  
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 24 and 36 
h post-dose of bexagliflozin on Day 6. 
• Urine samples for PD (UGE and creatinine) analysis will be collected at 24-36 h and 36-
48 h after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the last clinic day except for PK and PD sample collection shall be completed. The reason for 
termination shall be entered onto the case report form. 


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7.2.17 
Day 8 
The following information will be gathered and the indicated procedures will be performed 
post-dose: 
• Complete PE will be performed as described in Section 6.3 
• Vital signs will be recorded 48 h post-dose of bexagliflozin (from Day 6) 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 48 h post-
dose (from Day 6) 
• Urine samples for PD (UGE and creatinine) analysis will be collected at 36-48 h post 
dose (from Day 6) as described in Section 6.6.2.3. 
• Urine will be collected for urinalysis as described in Section 6.6.2.2. 
• Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
• Subject will be discharged after completion of all activities 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the study termination day except for PK and PD sample collection shall be completed. The 
reason for termination shall be entered onto the case report form. 
7.3 
Study Activities for Study 3 
7.3.1 
Screening (Day -21 to Day -1) 
During the screening period, the following information will be gathered and the indicated 
procedures will be performed: 
• Content of informed consent will be explained to the subject and the signed informed 
consent collected. 
• Medical history and demographic information will be obtained as described in Section 
6.2. 
• Physical examination will be conducted, including height and weight measurements as 
described in Section 6.3. 
• Vital signs will be measured, including pulse, temperature, respiratory rate, and blood 
pressure taken in the sitting position after at least 5 min of rest as described in Section 
6.4. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest as described 
in Section 6.5. 


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• Clean-catch, mid-stream urine will be collected for urinalysis as described in Section 
6.6.2.2. If urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent 
for microscopic evaluation and culture.  
• Urine screen will be conducted for drug abuse and cotinine. If the drug screen is 
conducted more than 5 days pre-dose, the drug screen shall be repeated prior to dosing. 
Drug abuse testing includes amphetamines, barbiturates, cocaine metabolites, opiates, 
benzodiazepines, cotinine, and cannabinoids. 
• All female subjects will receive urine pregnancy test. 
• Blood will be drawn for hematology, serum chemistry, and serology as detailed in 
Section 6.6.2.1. 
• Inclusion/exclusion criteria will be evaluated based on the information collected at the 
screening examination. 
 
7.3.2 
Day 0 (Clinic Admission) 
The following information will be gathered and the indicated procedures will be performed: 
• Partial PE will be performed as described in Section 6.3. 
• If screening was conducted more than 5 days prior to dosing, the inclusion and exclusion 
criteria shall be confirmed and a urine drug screen performed. 
• All female subjects will receive urine pregnancy test. 
• Subjects will void their bladders at 12 h prior to dosing and begin the collection of the  -
12 h to 0 h batch for baseline analysis of UGE and creatinine (PD) as described in 
Section 6.6.2.3. 
• Concomitant medications and adverse event information will be collected as appropriate. 
• If the subject is still eligible based on the study inclusion and exclusion criteria, the 
subject will be admitted into the study. 
 
7.3.3 
Day 1 (Dosing Day): Pre-dose  
The following information will be gathered and the indicated procedures will be performed 
pre-dose: 
• Vital signs will be recorded pre-dose. 
• Pre-dose urine will be collected until 0 h (-12 h to 0 h batch) for baseline UGE and 
creatinine (PD) analysis as described in Section 6.6.2.3. 
• Urine sample will be collected for pre-dose urinalysis as described in Section 6.6.2.2. If 
urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for 
microscopic evaluation and culture. If screening is conducted more than 5 days prior to 
dosing, drug screening shall be repeated. 


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• Pre-dose blood will be drawn for hematology, and serum chemistry as detailed in Section 
6.6.2.1. 
• Pre-dose plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4. 
• Pre-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.3.4 
Day 1 (Dosing Day): Dosing 
• Bexagliflozin tablets, 20 mg, will be administered ~30 minutes after breakfast (standard 
low-fat meal), as detailed in Section 5.3.  
 
7.3.5 
Day 1: Post-dose  
• Vital signs will be recorded at 4 h post-oral dose 
• Urine samples for PD (UGE and creatinine) analysis will be at specified time interval 
after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Blood samples for PK samples will be collected at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 h after 
oral administration of bexagliflozin.  
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the clinic day except for PK and PD sample collection shall be completed. The reason for 
termination shall be entered onto the case report form. 
7.3.6 
Day 2  
• Urine samples for PD (UGE and creatinine) analysis will be collected at specified time 
interval after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 24 and 36 
h post-dose.   
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.3.7 
Day 3  
• Vital signs will be recorded at 48 h post-dose (from day 1). 
• Urine samples for PD (UGE and creatinine) analysis will be collected at specified time 
interval after oral administration of bexagliflozin, pre-dose urine will also be collected 
until 0 h (-12 h to 0 h batch), as described in Section 6.6.2.3. 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 48 h post-
dose  


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• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.3.8 
Day 4 (Dosing Day): Pre-dose  
• Partial PE will be performed as described in Section 6.3. 
• Vital signs will be recorded at pre-dose. 
• 12-lead ECG will be taken in the supine position after at least 5 min of rest as described 
in Section 6.5. 
• Pre-dose urine will be collected until 0 h (-12 h to 0 h batch) for PD (UGE and creatinine) 
analysis as described in Section 6.6.2.3. 
• Urine sample will be collected for pre-dose urinalysis as described in Section 6.6.2.2. If 
urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for 
microscopic evaluation and culture.  
• Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
• Pre-dose plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4. 
• Pre-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
7.3.9 
Day 4 (Dosing Day): Dosing 
• About 30 min after breakfast, subjects will take one verapamil tablet, 120 mg, and one 
hour later one bexagliflozin tablet, 20 mg will be taken with approximately 240 mL water 
as detailed in Section 5.3. 
 
7.3.10 
Day 4 (Dosing Day): Post-dose  
• Vital signs will be recorded at 4 h post-oral dose 
• 12-lead ECG will be taken at 4 h post-dose in the supine position after at least 5 min of 
rest. 
• Urine samples for PD (UGE and creatinine) will be collected at specified time interval 
after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Blood samples for PK analysis will be collected as detailed in Section 6.6.2.4 at 1, 2, 3, 4, 
5, 6, 8, 10, 12, 16 h after oral administration of bexagliflozin 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the last clinic day except for PK and PD sample collection shall be completed. The reason for 
termination shall be entered onto the case report form. 


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7.3.11 
Day 5  
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 24 and 36 
h post-dose of bexagliflozin on Day 4. 
• Urine samples for PD (UGE and creatinine) analysis will be collected at 24-36 h and 36-
48 h after oral administration of bexagliflozin, as described in Section 6.6.2.3. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the last clinic day except for PK and PD sample collection shall be completed. The reason for 
termination shall be entered onto the case report form. 
7.3.12 
Day 6 
The following information will be gathered and the indicated procedures will be performed 
post-dose: 
• Complete PE will be performed as described in Section 6.3 
• Vital signs will be recorded 48 h post-dose of bexagliflozin (from Day 4) 
• Plasma samples will be drawn for PK analysis as detailed in Section 6.6.2.4 at 48 h post-
dose (from Day 4) 
• Urine samples for PD (UGE and creatinine) analysis will be collected at 36-48 h post 
dose (from Day 4) as described in Section 6.6.2.3. 
• Urine will be collected for urinalysis as described in Section 6.6.2.2. 
• Blood will be drawn for hematology and serum chemistry as detailed in Section 6.6.2.1. 
• Post-dose concomitant medications and adverse event information will be collected as 
appropriate. 
• Subject will be discharged after completion of all activities 
 
For subjects who are terminated from the study for any reason after dosing, all activities for 
the study termination day except for PK and PD sample collection shall be completed. The 
reason for termination shall be entered onto the case report form. 
7.4 
Early Termination or Follow-up Procedures 
Subjects who have withdrawn consent and have received investigational product should have 
a follow-up examination if feasible and clinically indicated, including a complete physical 
examination, vital signs, and clinical laboratory tests (hematology, and serum chemistry). 
The sponsor shall 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 shall 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 shall be verified with the 
source documentation. 
Quality control principles shall 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 shall 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 bexagliflozin to assess the potential 
effect of probenecid, rifampin or verapamil on bexagliflozin.  
9.3 
Analysis Populations 
9.3.1 
Safety Population 
The Safety Population will include all 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 subjects who receive at least one dose of study drug and 
who have sufficient plasma bexagliflozin and metabolite (where applicable) measurements to 
derive PK parameters following dosing. The PK Population will be used to summarize the 
PK parameters. Subjects will be analyzed according to the treatment received. 
9.3.3 
PD Population 
The PD Population will include all randomized subjects who receive at least one dose of 
investigational product and have pre-dose urine collection and postdose 0-12 and 12-24 hour 
post dose urine samples from which to calculate UGE measurement following dosing for at 
least one study day. The PD Population will be used to summarize the PD parameters. 
Subjects will be analyzed according to the treatment received. 
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. 


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9.5 
Pharmacokinetic Analysis 
9.5.1 
Calculation of Pharmacokinetic Variables 
A non-compartmental analysis will be used to calculate the PK parameters of bexagliflozin in 
all three studies and its 3’-O-glucuronide (EGT0002149; in study 1 and 2) after each subject 
is dosed with bexagliflozin using the software Phoenix® WinNonlin® 6.4 (Certara, USA). 
From the plasma concentration 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  
T1/2       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  
AUCextr % of AUC0-∞ due to extrapolation from Tlast to infinity 
M/P AUC Ratio  Metabolite-to-parent ratio for AUC (AUC0-t and AUC0-∞) 
M/P Cmax Ratio  Metabolite-to-parent ratio for Cmax 
 
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: 


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AUC0-∞= AUClast + (Clast / λz), where Clast is the last temporal quantifiable plasma 
concentration corresponding to Tlast. 
The proportion of AUC0-∞ due to extrapolation (AUCextr) will be calculated and expressed as 
a percentage. AUC0-∞ values will be considered unreliable estimates if the AUCextr is greater 
than 20%. 
CL/F will be calculated as Dose/AUC0-∞. 
Vz/F will be calculated as Dose/(λz × AUC0-∞). 
T½ will be calculated as 0.693/λz. 
Descriptive statistics for the plasma concentrations of bexagliflozin and/or EGT0002149 by 
Treatment, and Timepoint will be provided. A listing of plasma concentrations by Subject 
Number, Treatment Period, Timepoint and Sex/Gender will also be provided. 
9.5.2 
Statistical Analysis of Pharmacokinetic Variables 
To assess the effect of probenecid, rifampin and verapamil on the PK of bexagliflozin in all 
three studies and EGT0002149 (Study 1 and Study 2 only), an analyses of variance 
(ANOVA) using a linear mixed-effects model will be fitted to the natural logarithmic 
transformation of PK parameters of bexagliflozin (Cmax, AUC0-t and AUC0-∞). The linear 
mixed-effects model will include subject as a random effect, and treatment as fixed effects. 
The 90% confidence intervals will be constructed for the ratio of geometric means of PK 
parameters (Cmax, AUC0-t and AUC0-∞) when bexagliflozin is dosed in combination with 
interacting drug (probenecid, rifampin or verapamil) versus when dosed alone, with 80-125% 
defined as the lack of interaction boundaries.  
Descriptive statistics for the PK parameters Cmax, Tmax, AUC0-∞ , AUC0-t , AUCextr, M/P Cmax  
and AUC Ratio (AUC0-t and AUC0-∞)  (for Study 1 and Study 2), 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 and/or EGT0002149 by Subject ID, 
Period and Sex will be provided.  
9.6 
Pharmacodynamic Analysis 
The amount of urinary glucose excretion (UGE), urinary creatinine, and creatinine 
normalized UGE (nUGE) will be determined as a PD parameter at baseline and up to 48 h 
post-dose. Descriptive statistics will be used to describe any differences in these PD 
parameters between treatments. The drug-drug interaction effect between bexagliflozin and 
interaction drugs (probenecid, rifampin and verapamil) will be evaluated by comparing the 
mean cumulative UGE and creatinine normalized UGE (nUGE) between subjects taking 
bexagliflozin alone and bexagliflozin and interaction drug in combination. 


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The PD parameter, UGE and UGE normalized by urinary creatinine, including UGEt1-t2 over 
specified time interval, and total 24-hour, 48-hour UGE, will be determined. UGEt1-t2 (mg) 
will be derived from urine volume (Vt1-t2, mL) × glucose concentration (mg/dL) / 100. UGE 
and nUGE will be listed and summarized by treatment arm using descriptive statistics. 
9.7 
Safety Analysis 
Safety data will include AEs, PE results, vital signs, ECG results, and clinical lab results, 
including serum chemistry, hematology, and urinalysis. Observed data will be described as 
counts and percentages for discrete variables and estimation of means, standard deviations 
(SDs), medians, inter-quartile range, minimum and maximum for continuous metrics. All 
subjects in the Safety Population will be included in the safety analyses. All safety data will 
be presented in by-subject listings and included in the clinical trial report. 
9.7.1 
Adverse Events 
Adverse events will be mapped to preferred term and body system using the Medical 
Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects 
reporting adverse events will be determined by relationship to treatment and by severity of 
the event. Drug-related adverse events will be considered those to be possibly related to 
bexagliflozin or interacting drug administration. 
Adverse event listings will be provided for the following subsets: 
• all treatment emergent AEs (TEAEs). 
• all TEAEs at least possibly related to bexagliflozin or interacting drug. 
• serious TEAEs (if any). 
• TEAEs leading to study discontinuation (if any). 
 
AEs are dosing emergent if they occur on or after bexagliflozin or interacting drug 
administration. TEAEs will be considered at least possibly related to bexagliflozin or 
interacting drug based on the investigator’s assessment. Only TEAEs will be tabulated in 
summary tables. If the AE(s) onset date-time or date occurs after the first dose up until right 
before the next dose, the AE(s) will be assigned to the first treatment. Any AE(s) that occur 
after the first dose of interacting drug up until the follow-up visit will be assigned to the 
second treatment (combination treatment). 
Tabulations will display TEAEs by severity and relationship to bexagliflozin or interacting 
drug. 
Tabulations will display TEAEs by severity and relationship to bexagliflozin or interacting 
drug. 
9.7.2 
Hypoglycemia 
Hypoglycemia as defined in Section 6.7.3.4 will be presented in listings and summarized. 


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9.7.3 
Clinical and Laboratory Events and Analyses 
Clinical and laboratory metrics are measured at baseline (pre-dose on Day 1) 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. 
9.7.4 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A by-subject listing of concomitant medications will include all 
medications taken during the study. 
 
 


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
Information regarding key personnel involved in the conduct of the study, including names 
and contact details of participating investigators, monitors, clinical laboratories, and technical 
departments and/or institutions, as well as information on members of additional study 
committees, will be found in the study files of the investigational site. 
10.2 Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
The study protocol, informed consent document, relevant supporting information, and all 
types of subject recruitment or advertisement information shall be submitted to the IRB for 
review and shall be approved by the sponsor and the IRB before the study is initiated. Any 
amendments or addenda to the protocol shall 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 shall 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 shall agree to the inspection of study-related records by the 
regulatory authority/sponsor representatives, and shall 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 shall 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 shall be fully explained and documented by the 
investigator. The circumstances, action taken, and impact of the deviation on the trial shall 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 shall be provided to the sponsor for regulatory purposes. 
Prior to the beginning of the study, the investigator shall 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 shall be filed. The informed 
consent form shall 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 shall be obtained before any study-specific procedure takes place. 
Participation in the study and date of informed consent given by the subject shall be 
documented appropriately in the subject’s files. A copy of the signed informed consent form 
shall 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 shall remain in 
each subject’s study file and shall 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 
shall 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 
shall be recorded in the case report form. 
Entries made in the CRF shall 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 shall 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 shall 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 shall 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 shall notify the Sponsor. 
Protocol violations shall 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 shall 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 shall 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 
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Data Analysis, Implications for Dosing, and Labeling Recommendations. 1-79. 
Baneyx, G., Parrott, N., Meille, C., Iliadis, A., and Lave, T. (2014). Physiologically based 
pharmacokinetic modeling of CYP3A4 induction by rifampicin in human: influence of time 
between substrate and inducer administration. European journal of pharmaceutical sciences : 
official journal of the European Federation for Pharmaceutical Sciences 56, 1-15. 
Chen, J., and Raymond, K. (2006). Roles of rifampicin in drug-drug interactions: underlying 
molecular mechanisms involving the nuclear pregnane X receptor. Ann Clin Microbiol 
Antimicrob 5, 3. 
Cunningham, R.F., Israili, Z.H., and Dayton, P.G. (1981). Clinical pharmacokinetics of 
probenecid. Clinical pharmacokinetics 6, 135-151. 
Hartter, S., Sennewald, R., Nehmiz, G., and Reilly, P. (2013). Oral bioavailability of 
dabigatran etexilate (Pradaxa((R)) ) after co-medication with verapamil in healthy subjects. 
British journal of clinical pharmacology 75, 1053-1062. 
Macha, S., Sennewald, R., Rose, P., Schoene, K., Pinnetti, S., Woerle, H.J., and Broedl, U.C. 
(2013). Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium 
glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers. 
Clinical therapeutics 35, 226-235. 
Miners, J.O., Bowalgaha, K., Elliot, D.J., Baranczewski, P., and Knights, K.M. (2011). 
Characterization of niflumic acid as a selective inhibitor of human liver microsomal UDP-
glucuronosyltransferase 1A9: application to the reaction phenotyping of acetaminophen 
glucuronidation. Drug metabolism and disposition: the biological fate of chemicals 39, 644-
652. 
Pui, K., Gow, P.J., and Dalbeth, N. (2013). Efficacy and tolerability of probenecid as urate-
lowering therapy in gout; clinical experience in high-prevalence population. The Journal of 
rheumatology 40, 872-876. 
Soars, M.G., Ring, B.J., and Wrighton, S.A. (2003). The effect of incubation conditions on 
the enzyme kinetics of udp-glucuronosyltransferases. Drug metabolism and disposition: the 
biological fate of chemicals 31, 762-767. 
Uchaipichat, V., Mackenzie, P.I., Guo, X.H., Gardner-Stephen, D., Galetin, A., Houston, 
J.B., and Miners, J.O. (2004). Human udp-glucuronosyltransferases: isoform selectivity and 
kinetics of 4-methylumbelliferone and 1-naphthol glucuronidation, effects of organic 
solvents, and inhibition by diclofenac and probenecid. Drug metabolism and disposition: the 
biological fate of chemicals 32, 413-423. 


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Washburn, W.N. (2009). Evolution of sodium glucose co-transporter 2 inhibitors as anti-
diabetic agents. Expert opinion on therapeutic patents 19, 1485-1499. 
Yamashita, F., Sasa, Y., Yoshida, S., Hisaka, A., Asai, Y., Kitano, H., Hashida, M., and 
Suzuki, H. (2013). Modeling of rifampicin-induced CYP3A4 activation dynamics for the 
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Zhang, W., Welihinda, A., Mechanic, J., Ding, H., Zhu, L., Lu, Y., Deng, Z., Sheng, Z., Lv, 
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Appendix 1 
Schedule of Events 
A. SCHEDULE OF EVENTS FOR STUDY 1 (BEXAGLIFLOZIN AND PROBENECID): 
 
1. 
If screening is conducted more than 5 days prior to dosing, subject eligibility criteria must be confirmed on Day 0. 
2. 
Weight and height will be recorded as part of the physical examination. Height will be recorded once at screening only. A complete physical exam (PE) will 
be performed at screening and last day of clinic prior to discharge. A partial PE will be performed on Day 0, Day 3, Day 5, and Day 6. 
3. 
Vital signs include: pulse, body temperature, respiratory rate, systolic and diastolic blood pressure. On Day 1, and Day 5, vital signs will be determined at 
pre- and at 4 h post-oral dose, and 48 h post dose (Day 3), and on the last day of clinic (Day 7) prior to discharge and when clinically indicated. 
 
Screening 
Treatment 
Period 
Study activity 
D -21 to -1 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Medical history and ICF 
X 
 
 
 
 
 
 
 
 
Screening for I/E criteria1 
X 
X 
 
 
 
 
 
 
 
Physical exam2 
X 
X 
 
 
X 
 
X 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
Admission and discharge 
 
X 
 
 
 
 
 
 
X 
Dispense investigational study drug bexagliflozin 
 
 
X 
 
 
 
X 
 
 
Dispense interaction drug probenecid 
 
 
 
 
X 
X 
X 
X 
 
Vital signs3 
X 
 
X 
 
X 
 
X 
 
X 
ECG4 
X 
 
 
 
 
 
X 
 
 
Urinalysis5 
X 
 
X 
 
X 
 
X 
 
X 
Blood draw for clinical lab tests6 
X 
 
X 
 
X 
 
X 
 
X 
Blood sample for PK7 
 
 
X 
X 
X 
 
X 
X 
X 
Urine collection8 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
X 
X 
 
 
 
 
 
 
 
Adverse event and concomitant medication 
 
 
  X 
X 
X 
X 
X 
X 
X 
X 
Study termination9 
 
 
 
 
 
 
X 


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4. 
12-lead ECG will be conducted after 5 min resting. ECG data will be recorded at screening, on Day 5, at pre- and at 4 h post-oral dose and when clinically 
indicated. 
5. 
Clean sample to be collected at each visit. If urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for microscopic evaluation and 
culture. Urine drug screen will be performed on screening visit only. If screening is conducted more than 5 days prior to dosing, drug screening shall be 
repeated. 
6. 
Blood 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.  
7. 
Plasma samples for PK will be collected at pre-dose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h after oral administration of bexagliflozin on Day 1 
and Day 5. 
8. 
Urine samples for PD (UGE) analysis are described in Section 6.6.2.3. 
9. 
If early termination occurs, activities scheduled for the last day of clinic prior to discharge should be conducted. Reasons for all withdrawals shall be 
recorded on the CRF. 
 
 


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B. SCHEDULE OF EVENTS FOR STUDY 2 (BEXAGLIFLOZIN AND RIFAMPIN): 
1. 
If screening is conducted more than 5 days prior to dosing, subject eligibility criteria must be confirmed on Day 0. 
2. 
Weight and height will be recorded as part of the physical examination. Height will be recorded once at screening only. A complete physical exam (PE) will 
be performed at screening and last day of clinic (Day 8) prior to discharge. A partial PE will be performed on Day 0, Day 3 and Day 6. 
3. 
Vital signs include: pulse, body temperature, respiratory rate, systolic and diastolic blood pressure. On Day 1, and Day 6, vital signs will be determined at 
pre- and at 4 h post-oral dose, and 48 h post dose (Day 3), and on the last day of clinic (Day 8) prior to discharge and when clinically indicated. 
4. 
12-lead ECG will be conducted after 5 min resting. ECG data will be recorded at screening, on Day 6 at pre- and at 4 h post-oral dose, and when clinically 
indicated. 
 
Screening 
Treatment 
Period 
Study activity 
D -21 to -1 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
Medical history and ICF 
X 
 
 
 
 
 
 
 
 
 
Screening for I/E criteria1 
X 
X 
 
 
 
 
 
 
 
 
Physical exam2 
X 
X 
 
 
X 
 
 
X 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Admission and discharge 
 
X 
 
 
 
 
 
 
 
X 
Dispense investigational study drug bexagliflozin 
 
 
X 
 
 
 
 
X 
 
 
Dispense interaction drug rifampin 
 
 
 
 
X 
X 
X 
X 
X 
 
Vital signs3 
X 
 
X 
 
X 
 
 
X 
 
X 
ECG4 
X 
 
 
 
 
 
 
X 
 
 
Urinalysis5 
X 
 
X 
 
X 
 
 
X 
 
X 
Blood draw for clinical lab tests6 
X 
 
X 
 
X 
 
 
X 
 
X 
Blood sample for PK7 
 
 
X 
X 
X 
 
 
X 
X 
X 
Urine collection8 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urine pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
Adverse event and concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study termination9 
 
 
 
 
 
 
 
 
 
X 


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5. 
Clean sample to be collected at each visit. If urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for microscopic evaluation and 
culture. Urine drug screen will be performed on screening visit only. If screening is conducted more than 5 days prior to dosing, drug screening shall be 
repeated. 
6. 
Blood 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.  
7. 
Plasma samples for PK will be collected at pre-dose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h after oral administration of bexagliflozin on Day 1 
and Day 6. 
8. 
Urine samples for PD (UGE) analysis are described in Section 6.6.2.3. 
9. 
If early termination occurs, activities scheduled for the last day of clinic prior to discharge should be conducted. Reasons for all withdrawals shall be 
recorded on the CRF. 
 
 


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C. SCHEDULE OF EVENTS FOR STUDY 3 (BEXAGLIFLOZIN AND VERAPAMIL): 
1. 
If screening is conducted more than 5 days prior to dosing, subject eligibility criteria must be confirmed on Day 0. 
2. 
Weight and height will be recorded as part of the physical examination. Height will be recorded once at screening only. A complete physical exam (PE) will 
be performed at screening and last day of clinic prior to discharge. A partial PE will be performed on Day 0, and Day 4. 
3. 
Vital signs include: pulse, body temperature, respiratory rate, systolic and diastolic blood pressure. On Day 1, and Day 4, vital signs will be determined at 
pre- and at 4 h post-oral dose, and 48 h post dose (Day 3), and on the last day of clinic (Day 6) prior to discharge and when clinically indicated. 
4. 
12-lead ECG will be conducted after 5 min resting. ECG data will be recorded at screening, on Day 4, at pre- and at 4 h post-oral dose and when clinically 
indicated. 
 
Screening 
Treatment 
Period 
Study activity 
D -21 to -1 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
Medical history and ICF 
X 
 
 
 
 
 
 
 
 
Screening for I/E criteria1 
X 
X 
 
 
 
 
 
 
 
Physical exam2 
X 
X 
 
 
 
X 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
Admission and discharge 
 
X 
 
 
 
 
 
X 
Dispense investigational study drug bexagliflozin 
 
 
X 
 
 
X 
 
 
 
Dispense interaction drug verapamil 
 
 
 
 
 
X 
 
 
 
Vital signs3 
X 
 
X 
 
X 
X 
 
X 
ECG4 
X 
 
 
 
 
X 
 
 
 
Urinalysis5 
X 
 
X 
 
 
X 
 
X 
Blood draw for clinical lab tests6 
X 
 
X 
 
 
X 
 
X 
Blood sample for PK7 
 
 
X 
X 
X 
X 
X 
X 
Urine collection8 
 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
X 
X 
 
 
 
 
 
 
 
Adverse event and concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
Study termination9 
 
 
 
 
 
X 


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5. 
Clean sample to be collected at each visit. If urine is dipstick positive for leukocyte esterase or nitrites, sample is to be sent for microscopic evaluation and 
culture. Urine drug screen will be performed on screening visit only. If screening is conducted more than 5 days prior to dosing, drug screening shall be 
repeated. 
6. 
Blood 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.  
7. 
Plasma samples for PK will be collected at pre-dose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h after oral administration of bexagliflozin on Day 1 
and Day 4. 
8. 
Urine samples for PD (UGE) analysis are described in Section 6.6.2.3. 
9. 
If early termination occurs, activities scheduled for the last day of clinic prior to discharge should be conducted. Reasons for all withdrawals shall be 
recorded on the CRF. 
 
 
 
 





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