Clinical trial NCT03514641
Conditions: Essential Hypertension
Sponsor: Theracos
Start date: 2017-10-18; Completion date: 2018-11-30
Enrollment: 673 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This integrated assessment consists of two studies, 603A and 603B, to be carried out sequentially in a common study population. Participating subjects informed of the trial design and their consent to participate in both studies were to be obtained in a single consent form. Approximately 680 male or female adult subjects were to be enrolled.

Detailed description:
THR-1442-C-603 is an integrated assessment of the potential utility of bexagliflozin tablets, 20 mg for the treatment of essential hypertension. It is composed of two studies, 603A and 603B, measuring effects in a common population.

603A was a multicenter double-blind parallel group placebo-controlled study conducted to determine the placebo-adjusted change from baseline to week 12 in the mean ambulatory systolic blood pressure (SBP) of approximately 680 subjects considered generally representative of the adult hypertensive population in the United States. Secondary endpoints included the placebo-adjusted change from baseline to week 12 of the mean office seated systolic blood pressure, the change to week 12 of the mean ambulatory and mean office seated diastolic blood pressure, the proportion of subjects achieving prespecified goals for absolute systolic and diastolic blood pressure as well as prespecified goals for reduction in systolic and diastolic blood pressure, measured by ambulatory and seated office measurement methodology.

A603B was a multicenter double-blind parallel group placebo-controlled randomized withdrawal study conducted to determine the durability of the antihypertensive effect of bexagliflozin tablets, 20 mg, in a population not pre-selected for existing diabetes. All subjects entered a 12 week run-in period during which they self-administered open label bexagliflozin tablets, 20 mg once daily. At week 12 a baseline ambulatory blood pressure monitoring (ABPM) measurement was made, and the subjects were randomized one to one to receive either bexagliflozin tablets, 20 mg or bexagliflozin tablets, placebo. After a 12 week treatment period a second ABPM measurement was made. The primary endpoint was the intergroup difference in the change from baseline in the mean SBP.

Arms: arm 1: Period 1: Placebo Period 2: Bexagliflozin Period 3: Bexagliflozin arm 2: Period 1: Placebo Period 2: Bexagliflozin Period 3: Placebo arm 3: Period 1: Bexagliflozin Period 2: Bexagliflozin Period 3: Bexagliflozin arm 4: Period 1: Bexagliflozin Period 2: Bexagliflozin Period 3: Placebo
Interventions: intervention 1: Bexagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Bexagliflozin tablet, 20 mg intervention 2: Placebo (inactive) tablet to match the active drug

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol: THR-1442-C-603 
 
Title: 
An Integrated Assessment of the Safety and Effectiveness of 
Bexagliflozin Tablets, 20 mg, for the Management of Essential 
Hypertension 
Protocol Number: 
THR-1442-C-603 
Study Phase: 
2/3 
Product Name: 
Bexagliflozin Tablets 
IND Number: 
134049 
Indication: 
Hypertension 
Investigators: 
Multicenter 
Sponsor: 
Theracos Sub, LLC 
Sponsor 
Representative: 
Tara Thurber, BS 
Translational Medicine Group 
Massachusetts General Hospital 
185 Cambridge Street, Boston, MA 02114 
Phone: 617-643-0699 
Fax: 617-643-8203 
E-mail: tthurber@ccib.mgh.harvard.edu 
 
Medical Monitor: 
Andrew Allegretti, M.D. 
Department of Nephrology 
Massachusetts General Hospital 
165 Cambridge Street, Suite 320, Boston, MA 02114 
Phone:  617-724-8018 
Fax:  617-643-8203 
E-mail:  AALLEGRETTI@PARTNERS.ORG 
 
 
Date 
Protocol V1.0: 
21 May 2017 
Protocol V2.0: 
28 August 2017 
 
Confidentiality Statement 
The information in this document is confidential information of Theracos Sub, LLC 
(“Theracos”) and must not be disclosed, used, or copied except with prior written approval 
from Theracos or to the extent required by applicable local, state or federal laws, rules and 
regulations. 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................16 
1 
INTRODUCTION ...........................................................................................................18 
1.1 
Bexagliflozin for the Treatment of Hypertension ..................................................19 
1.1.1 
Summary of Bexagliflozin Non-clinical Data .............................................19 
1.1.2 
Summary of Bexagliflozin Clinical Data .....................................................19 
2 
OBJECTIVES ..................................................................................................................20 
2.1 
Objectives of Study 603A ......................................................................................20 
2.2 
Objectives of Study 603B ......................................................................................20 
2.3 
Integrative Objectives of Studies 603A and 603B .................................................21 
2.4 
Safety Objectives ...................................................................................................21 
3 
INVESTIGATIONAL PLAN ..........................................................................................22 
3.1 
Overall Design and Plan ........................................................................................22 
3.1.1 
Study 603A ..................................................................................................22 
3.1.2 
Study 603B...................................................................................................23 
3.1.3 
Integrated Management of Hypertension, Including Use of Rescue 
Medications ..................................................................................................23 
3.2 
Rationale for Design and Control Group ...............................................................25 
3.2.1 
Rationale for the Selected Study Design .....................................................25 
3.2.2 
Rationale for the Selected Dose and Once daily Dosing Regimen ..............26 
3.2.3 
Rationale for the Selection of Population ....................................................26 
3.3 
Study Duration and Dates ......................................................................................26 
4 
POPULATION SELECTION ..........................................................................................27 
4.1 
Population ..............................................................................................................27 
4.2 
Inclusion Criteria ...................................................................................................27 
4.3 
Exclusion Criteria ..................................................................................................27 
5 
STUDY TREATMENTS .................................................................................................29 
5.1 
Description of Treatments......................................................................................29 
5.2 
Treatments Administered .......................................................................................29 
5.2.1 
Investigational Product ................................................................................29 
5.2.2 
Background Anti-hypertensive Medications ...............................................29 
5.2.3 
Background Hypoglycemic Agents .............................................................30 
5.3 
Selection and Timing of Dose for Each Subject ....................................................30 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................30 
5.5 
Blinding..................................................................................................................31 


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5.6 
Concomitant Therapy.............................................................................................32 
5.7 
Hypertension Rescue Therapies .............................................................................32 
5.8 
Restrictions ............................................................................................................34 
5.8.1 
Prior Therapy ...............................................................................................34 
5.8.2 
Fluid and Food Intake ..................................................................................34 
5.8.3 
Patient Activity Restrictions ........................................................................34 
5.9 
Treatment Compliance ...........................................................................................35 
5.10 
Packaging and Labeling .........................................................................................35 
5.11 
Storage and Reconciliation ....................................................................................35 
5.12 
Investigational Product Retention at Study Site ....................................................35 
6 
STUDY PROCEDURES .................................................................................................36 
6.1 
Informed Consent...................................................................................................36 
6.2 
Medical History .....................................................................................................36 
6.3 
Medical History .....................................................................................................36 
6.3.1 
General Demographics and Characteristics .................................................36 
6.3.2 
Diabetes History...........................................................................................37 
6.3.3 
Renal and Cardiovascular Disease History ..................................................37 
6.3.4 
Medication History ......................................................................................37 
6.4 
Physical Examination.............................................................................................37 
6.5 
Abbreviated Physical Examination ........................................................................37 
6.6 
Body Weight ..........................................................................................................38 
6.7 
Vital Signs ..............................................................................................................38 
6.8 
12-Lead ECG .........................................................................................................39 
6.9 
Clinical Laboratory Tests .......................................................................................39 
6.9.1 
Laboratory Parameters .................................................................................39 
6.9.2 
Sample Collection, Storage, and Shipping ..................................................40 
6.9.2.1 
Hematology, Blood Chemistry, Serum Lipids, and Glycemic 
Control Assessments ..........................................................................40 
6.9.2.2 
Urinalysis ...........................................................................................41 
6.9.2.3 
Population PK Sampling ....................................................................41 
6.10 
Dispensing Study Drug ..........................................................................................42 
6.10.1 
Run-in Drug .................................................................................................42 
6.10.2 
Double-Blind Study Drug ............................................................................42 
6.11 
Efficacy Assessments.............................................................................................42 
6.11.1 
24-h ABPM ..................................................................................................42 
6.11.2 
SBP and DBP from office visits BP ............................................................43 
6.11.3 
Body weight .................................................................................................43 
6.11.4 
Pulse Pressure ..............................................................................................43 


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6.11.5 
Trough/Peak Ratio .......................................................................................43 
6.12 
Adverse Events Assessments .................................................................................43 
6.12.1 
Definition of Adverse Events.......................................................................43 
6.12.2 
Eliciting and Reporting AEs ........................................................................45 
6.12.3 
Immediately Reportable AEs .......................................................................45 
6.12.4 
Pregnancy .....................................................................................................46 
6.12.5 
Procedure for Breaking the Blind ................................................................47 
6.12.6 
Follow-up of Non-Serious AEs ...................................................................47 
6.12.7 
Follow-up of Post-Study SAEs ....................................................................47 
6.12.8 
Adverse Events of Special Interest (AEOI) .................................................48 
6.12.8.1 
Genital Mycotic Infections (GMIs) ...................................................48 
6.12.8.2 
Urinary Tract Infections (UTIs) .........................................................48 
6.12.8.3 
Hepatotoxicity ....................................................................................48 
6.12.8.4 
Hypoglycemia ....................................................................................49 
6.12.8.5 
Diabetic Ketoacidosis (DKA) ............................................................51 
6.12.8.6 
Acute Kidney Injury ..........................................................................51 
6.12.9 
Major Adverse Cardiovascular Event (MACE) ...........................................53 
6.13 
Concomitant Medication Assessments ..................................................................53 
6.14 
Removal of Patients from the Trial or Study Drug ................................................53 
6.15 
Appropriateness of Measurements .........................................................................54 
7 
STUDY ACTIVITIES .....................................................................................................55 
7.1 
Visit 1 (Day -13 to day -12) ...................................................................................55 
7.2 
Visit 2 (Day -1) ......................................................................................................55 
7.3 
Visit 3 (Day 1)- Study 603A ..................................................................................55 
7.4 
Visit 4 (Cumulative Week 6) .................................................................................56 
7.5 
Visit 5 (Cumulative Week 12) ...............................................................................56 
7.6 
Visit 6 (Cumulative Week 12 + 1 Day) – Study 603B ..........................................56 
7.7 
Visit 7 (Cumulative Week 18) ...............................................................................56 
7.8 
Visit 8 (Cumulative Week 24) ...............................................................................56 
7.9 
Visit 9 (Cumulative Week 24 + 1 Day) .................................................................57 
7.10 
Visit 10 (Cumulative Week 36) .............................................................................57 
7.11 
Visit 11 (Cumulative Week 36 + 1 Day) ...............................................................57 
8 
QUALITY CONTROL AND ASSURANCE .................................................................58 
9 
PLANNED STATISTICAL METHODS ........................................................................59 
9.1 
General Considerations ..........................................................................................59 
9.2 
Determination of Sample Size ...............................................................................59 
9.3 
Analysis Populations ..............................................................................................60 
9.3.1 
Study 603A ..................................................................................................60 
9.3.2 
Study 603B...................................................................................................60 


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9.4 
Demographics and Baseline Characteristics ..........................................................60 
9.5 
Primary Efficacy Endpoints ...................................................................................61 
9.6 
Secondary Efficacy Endpoints ...............................................................................61 
9.7 
Analysis of Safety ..................................................................................................62 
9.7.1 
Adverse Events ............................................................................................62 
9.7.2 
Laboratory Evaluations and Other Safety Assessments ..............................62 
9.7.3 
Physical Examination...................................................................................63 
9.8 
Interim Analysis .....................................................................................................63 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................64 
10.1 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................64 
10.1 
Ethical Conduct of the Study .................................................................................64 
10.2 
Subject Information and Consent...........................................................................65 
10.3 
Subject Confidentiality ..........................................................................................65 
10.4 
Study Monitoring ...................................................................................................65 
10.5 
Case Report Forms and Study Records .................................................................66 
10.6 
Data Monitoring Committee ..................................................................................66 
10.7 
Protocol Violations/Deviations ..............................................................................66 
10.8 
Access to Source Documentation ..........................................................................67 
10.9 
Retention of Data ...................................................................................................67 
10.10 Publication and Disclosure Policy .........................................................................67 
11 REFERENCE LIST .........................................................................................................68 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Guidance for Hypertension Rescue Medication Use ...................................33 
Table 2. 
List of Laboratory Tests ...............................................................................40 
Table 3. 
Classification/Staging System for Acute Kidney Injury ..............................76 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
THR-1442-C-603 Study Design ..................................................................25 
Figure 2. 
BP Measurement Procedure .........................................................................39 
Figure 3. 
Renal Function Monitoring Plan ..................................................................52 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................71 
Appendix 2 
Schedule of Laboratory Tests ............................................................72 
Appendix 3 
Hypertensive Emergency ...................................................................73 


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Appendix 4 
Examples of SGLT2 Inhibitors ..........................................................74 
Appendix 5 
Examples of Medications with Hypotensive Effects .........................75 
Appendix 6 
KDOQI Chronic Kidney Disease Classification and Acute 
Kidney Injury Stage Definition ....................................................................................76 
Appendix 7 
Sponsor Signatures.............................................................................77 
Appendix 8 
Investigator’s Signature .....................................................................78 
 


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SYNOPSIS 
Sponsor: Theracos Sub, LLC 
Name of Finished Product: Bexagliflozin Tablets, 20 mg  
Name of Active Ingredient: Bexagliflozin 
Study Title: An Integrated Assessment of the Safety and Effectiveness of Bexagliflozin 
Tablets, 20 mg, for the Management of Essential Hypertension 
Protocol Number: THR-1442-C-603 
Study Phase: 2/3 
Overall Design: 
This integrated assessment consists of two studies, 603A and 603B, to be carried out 
sequentially in a common study population. Participating subjects will be informed of the 
trial design and their consent to participate in both studies will be obtained in a single consent 
form. 
Primary Objective of Study 603A 
In study 603A, the effectiveness of bexagliflozin tablets, 20 mg, will be assessed in a study 
population randomized 1:1 to receive either active agent or placebo. The primary endpoint 
will be the change from baseline (Day 1) to week 12 of the average ambulatory systolic 
blood pressure (SBP) of the bexagliflozin group compared to the placebo group. 
Secondary Objectives of Study 603A 
Additional effectiveness outcomes will be assessed from ambulatory as well as seated office 
blood pressure measurements. 
Secondary endpoints based on mean ambulatory SBP will include the proportion of subjects 
who achieve a reduction of mean ambulatory SBP of 10 mm Hg or greater and the proportion 
of subjects who achieve a mean ambulatory SBP of 135 mm Hg or less at week 12. 
Secondary endpoints based on seated office SBP will include the placebo-adjusted change 
from baseline to week 12 in seated office SBP and the proportion of subjects who achieve a 
mean seated office SBP of 140 mm Hg or less at week 12. 
Secondary endpoints based on mean ambulatory DBP will include: the placebo-adjusted 
change in mean ambulatory DBP from baseline to week 12; the proportion of subjects who 
achieve a mean ambulatory DBP of 87 mm Hg or less at week 12; and the proportion of 
subjects who achieve a reduction of mean ambulatory DBP of 4 mm Hg or greater at week 
12. 
Secondary endpoints based on seated office DBP will include the placebo-adjusted change 
from baseline to week 12 in seated office DBP and the proportion of subjects who achieve a 
mean seated office DBP of 90 mm Hg or less at week 12. 
An additional objective of study 603A will be an assessment of the maximum and minimum 
treatment effect (peak-trough ratio) by ABPM SBP at week 12. 


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Primary Objective of Study 603B 
In study 603B, the effectiveness of bexagliflozin tablets, 20 mg, will be assessed by 
measurement of the loss of the treatment effect following randomized withdrawal. All study 
entrants will first be dosed with bexagliflozin tablets, 20 mg, for 12 weeks. At week 12 the 
participants will undergo a 1:1 randomization to bexagliflozin tablets, 20 mg, or placebo. The 
primary endpoint will be the change from week 12 to week 24 of the mean ambulatory SBP 
of the bexagliflozin group compared to the placebo group. 
Secondary Objectives of Study 603B 
The secondary objectives of study 603B are based on separate assessments of effects on 
mean ambulatory and seated office systolic and diastolic blood pressures.  
Study 603B will also include a population pharmacokinetic assessment between weeks 6 and 
12, when all participants will be receiving bexagliflozin tablets, 20 mg.  
Integrative Objectives of Study 603A and 603B 
Integration of measures collected in studies 603A and 603B will be used to assess consistent 
effects on mean ambulatory SBP/DBP after 12 weeks of bexagliflozin treatment, as well as 
longer treatment periods, i.e., 24 weeks or 36 weeks of bexagliflozin treatment. 
In addition, the seated office systolic and diastolic blood pressure will be collected at more 
frequent intervals than for ambulatory monitoring, and the changes over time will be 
evaluated to provide a composite profile of treatment effect as a function of time. 
Integrated Safety Objectives: 
The integrated safety objectives will assess the hazard ratio for adverse events associated 
with bexagliflozin exposure compared to placebo in all segments of both studies in which a 
placebo-exposed cohort is present. The assessments will include: 
• 
the frequency and severity of all adverse events 
• 
the frequency and severity of adverse events of special interest 
• 
changes in concomitant medication use 
• 
changes in laboratory test values 
• 
changes in cardiac rhythm determined by 12-lead ECG 
• 
changes in vital signs 
• 
effects on general health detected by physical examination 
Design:  
THR-1442-C-603 is an integrated assessment of the potential utility of bexagliflozin tablets, 
20 mg for the treatment of essential hypertension. It is composed of two studies, 603A and 
603B, measuring effects in a common population. 
Study 603A  
Approximately 680 male or female adult subjects who exhibit an office seated blood pressure 
≥140 mm Hg and <180 mm Hg, and who are taking no more than 4 anti-hypertension 
medications will be enrolled in study 603A. In the desired population, > 10% of the subjects 
will have a baseline ABPM >160 mm Hg and < 30% of the subjects will have type 2 diabetes 


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mellitus. 
Subjects who meet the eligibility criteria at the screening visit (visit 1) will start a 2 week 
run-in period.  At the end of the run-in period, subjects who have not been disqualified by 
laboratory testing results based on samples drawn at the screening visit, who have been 
compliant in taking the run-in medication, and who exhibit a seated SBP ≥ 140 mm Hg and < 
180 mm Hg will be eligible for participation. At the investigative site the subjects will take 
the last dose of run-in drug, will be fitted with an ABPM device and will start a 24-h 
ambulatory blood pressure monitoring (ABPM) to establish the baseline ABPM SBP and 
DBP.  On the following day, qualified subjects who have completed the 24-h ABPM with a 
mean 24-h SBP ≥ 135 mm Hg will be randomly assigned to receive bexagliflozin tablets, 20 
mg or placebo, using an interactive web response system (IWRS).  If < 64 SBP readings are 
recorded, the ABPM must be repeated within 2 days.  Prior to randomization, subjects who 
cannot successfully complete the ABPM within two attempts will be considered screen 
failures. 
Randomization will be stratified according to diabetes status (history of T2DM or not), renal 
function (eGFR ≥ 60 or not), presently medicated for hypertension or not, and ABPM SBP (< 
160 mm Hg or not).   
A bottle of double blind study drug will be dispensed to each randomized subject with an 
instruction to take one tablet daily in the morning with a glass of water before or after 
breakfast.  It will be recommended that subjects take the study drug at about the same time 
every day except on the days of scheduled site visit when the study drug will be administered 
at the investigational site.    
A six week visit to the investigational site will allow seated office measures of systolic and 
diastolic blood pressure to be recorded. 
At week 12 (end of study), the subject will visit the investigational site, consume the final 
tablet, and be fitted for ABPM.  
An interim non-binding futility analysis will be conducted when approximate 50% of the 
randomized subjects have completed study 603A.  The data will be analyzed by an 
independent group that is not part of the study management team. Results from the analysis 
will be reviewed by an independent Data Monitoring Committee (DMC). 
Study 603B 
Upon returning to the investigational site to surrender the ambulatory monitor at the 
conclusion of study 603A, subjects will begin participation in study 603B. They will receive 
a 12-week supply of bexagliflozin tablets, 20 mg. 
At week 6 (cumulative week 18) subjects will return to the investigational site for 
measurement of seated systolic and diastolic blood pressures.  
At week 12 (cumulative week 24) subjects will visit the investigational site to consume the 
bexagliflozin tablet and to be fitted with an ambulatory monitor to record their baseline mean 
blood pressure. 
The following day, subjects will be randomized 1:1 to receive a 12-week supply of 


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bexagliflozin tablets, 20 mg or bexagliflozin tablets, placebo. Assignment to the active or 
placebo arm will be balanced to approximately equalize the representation in each arm of the 
following groups: 
• 
Subjects not requiring rescue medication prior to week 24 and exhibiting a > 20 mm Hg 
reduction in mean SBP between Day 1 and cumulative 24 
• 
Subjects not requiring rescue medication prior to week 24 and exhibiting a > 5 mm Hg 
and ≤ 20 mm Hg reduction in mean SBP between Day 1and cumulative 24 
• 
Subjects not requiring rescue medication prior to week 24 and exhibiting a ≤ 5 mm Hg 
reduction in mean SBP between Day 1 and cumulative 24 
• 
Subjects requiring rescue medication prior to week 24 
 
An assessment of bexagliflozin population pharmacokinetics (PK) will also be conducted, to 
include approximately 200 subjects. Samples will be taken between weeks 6 and 12. The 
population PK study design and analysis plan will be described in a separate designated study 
protocol and the analysis will be reported separately. 
Integrated management of hypertension, including use of rescue medications 
Subjects will be counseled to be compliant with all their medications, to exercise regularly, 
lose weight if overweight or obese, adopt a diet rich in fruits, vegetables and low-fat dairy 
products (the DASH diet, with appropriate modifications for participants with CKD), reduce 
sodium intake and alcohol consumption to recommended levels. Patients who smoke will be 
encouraged to stop. Every effort will be made to secure the continued participation of the 
subjects. 
Rescue medications are recommended following the guidance below if the SBP shows an 
increase of 30 mm Hg from baseline or exceeds 189 mm Hg in office measurements over 3 
consecutive days. 
Guidance for Hypertensive Rescue Medication Use 
Study 603A, cumulative weeks 1-6 
• 
Follow procedures for visits 10 and 11 as early termination visits to obtain 24-h 
ABPM and collect safety data 
• 
Rescue medication should not be administered unless hypertensive emergency 
appears imminent. In those situations, refer the subject to seek urgent care in a clinic 
or hospital. Subject should withdraw from participation in the study and see primary 
care provider to start or intensify anti-hypertensive therapies 
 
Study 603A, cumulative weeks 7-12 
• 
Follow procedures for visits 5 and 6 to obtain 24-h ABPM and collect safety data  
• 
Start visit 6 (start of 603B) without rescue medication.  If a hypertensive emergency 
appears imminent, refer the subject to seek urgent care in a clinic or hospital. 
Prescribe rescue medication at Visit 7 if SBP shows an increase of 30 mm Hg from 
baseline or exceeds 189 mm Hg in office measurements and continue study activities 
 


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Study 603B, cumulative weeks 13-18 
• 
Obtain 24-h ABPM and collect safety data 
• 
Rescue medication should not be administered unless hypertensive emergency 
appears imminent. In those situations, refer the subject to seek urgent care in a clinic 
or hospital. Prescribe rescue medication at Visit 7 if SBP shows an increase of 30 mm 
Hg from baseline or exceeds 189 mm Hg in office measurements and continue study 
activities 
 
Study 603B-Cumulative weeks 19-24 
• 
Obtain 24-h ABPM and collect safety data 
• 
Prescribe rescue medication if SBP shows an increase of 30 mm Hg from baseline or 
exceeds 189 mm Hg in office measurements and continue study activities 
 
Study 603B-Cumulative weeks 25-36 
• 
Obtain 24-h ABPM and collect safety data 
• 
Prescribe rescue medication if SBP shows an increase of 30 mm Hg from baseline or 
exceeds 189 mm Hg in office measurements and continue study activities 
 
Additional study procedures for safety and efficacy endpoint assessment will be performed as 
outlined in the study schedule. 
The effectiveness and safety analyses will be conducted after all subjects have completed or 
withdrawn from study 603B. 
To allow safety data to be collected for up to 36 weeks of exposure, the study will not be 
stopped for overwhelming efficacy.  The DMC will review the unblinded safety data at 
approximately 2 month intervals and may recommend protocol modifications or early 
termination due to safety concerns. 
Study Population:  
A total of 680 patients with essential hypertension will be initially randomized. The subjects 
must be: 
1. Male or female with age ≥ 20 years 
2. Diagnosed with essential hypertension and exhibiting an office seated SBP ≥ 140 and < 
180 mm Hg 
Unmedicated or currently treated by a stable regimen for hypertension. Unmedicated 
subjects are subjects who have never taken pharmacotherapy for hypertension or have not 
taken any anti-hypertensive medication for at least 12 weeks.  To be considered stable, a 
regimen must exhibit no change in dose or frequency for the 4 weeks prior to the 
screening visit 
3. If female and of childbearing potential, willing to use an adequate method of 
contraception and to not become pregnant for the duration of the study. Adequate 
contraceptive measures include, but are not limited to, oral contraceptives, intrauterine 
devices, Depo-Provera, Norplant, hormonal contraceptive implants, bilateral tubal 


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ligation, partner with vasectomy, condom or diaphragm plus contraceptive sponge, foam, 
or jelly, and abstinence 
4. Willing and able to return for all clinic visits and to complete all study-required 
procedures 
5. Able to self-medicate during the run-in period, omitting no more than one day of dosing 
(confirm at visit 2) 
6. Shown to have a seated SBP ≥ 140 and < 180 mm Hg (confirm at visit 2) 
7. Shown to have a mean 24 h SBP ≥ 135 mm Hg (at visit 3) 
Test Product, Dose, and Mode of Administration:  
Bexagliflozin tablets, 20 mg or placebo, to be taken by mouth once daily in the morning 
Duration of Treatment:  up to 36 weeks 
Study 603A 
Primary effectiveness assessment 
• 
Change from baseline (Day 1) to week 12 of the 24-hour mean SBP 
 
Secondary effectiveness assessments include: 
• 
the proportion of subjects who achieve a reduction of mean ambulatory SBP of 10 mm 
Hg or greater; 
• 
the proportion of subjects who achieve a mean ambulatory SBP of 135 mm Hg or less; 
• 
the placebo-adjusted change from baseline to week 12 in seated office SBP; 
• 
the proportion of subjects who achieve a seated office SBP of 140 mm Hg or less at week 
12; 
• 
the placebo-adjusted change in mean ambulatory DBP from baseline to week 12; 
• 
the proportion of subjects who achieve a mean ambulatory DBP of 87 mm Hg or less at 
week 12; 
• 
the proportion of subjects who achieve a reduction of mean ambulatory DBP of 4 mm Hg 
or greater; 
• 
the placebo-adjusted change from baseline to week 12 in seated office DBP; 
• 
the proportion of subjects who achieve a mean seated office DBP of 90 mm Hg or less at 
week 12. 
 
Study 603B 
Primary effectiveness assessment 
• 
Change from baseline week 12 (cumulative week 24) to week 24 (cumulative week 36) 
of the 24-hour mean SBP 
 
Secondary effectiveness assessments include: 
• 
the placebo-adjusted change from week 12 to week 24 in seated office SBP 
• 
the placebo-adjusted change in mean ambulatory DBP from week 12 to week 24. 
• 
the placebo-adjusted change from week 12 to week 24 in seated office DBP 
Integrated Assessments 


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Assessments for studies 603A and 603B will be combined to further assess the effectiveness 
of bexagliflozin after treatment of 12, 24, and 36 weeks. 
There are four (4) separate treatment sequences after combining studies 603A and 603B, 
namely: 
 
Sequence 
Period 1 
Period 2 
Period 3 
Seq 1 PBB 
(603A) placebo 
(603B) bexagliflozin 
(603B) bexagliflozin 
Seq 2 PBP 
(603A) placebo 
(603B) bexagliflozin 
(603B) placebo 
Seq 3 BBB 
(603A) bexagliflozin 
(603B) bexagliflozin 
(603B) bexagliflozin 
Seq 4 BBP 
(603A) bexagliflozin 
(603B) bexagliflozin 
(603B) placebo 
 
The following assessments will be assessed: 
• Change in mean ambulatory SBP or DBP after 12 weeks treatment of bexagliflozin using 
week 12 assessments for Seq 3 or 4’s Period 1 and Seq 1 or 2’s Period 2; 
• Change in mean ambulatory SBP or DBP after 24 weeks treatment of bexagliflozin using 
cumulative week 24 assessments for Seq 3 or 4’s Period 2 and Seq 1’s Period 3; 
• Change in mean ambulatory SBP or DBP after 36 weeks treatment of bexagliflozin using 
cumulative week 36 assessments for Seq 3’s Period 3; 
• Change in seated office SBP or  DBP after 12 weeks treatment of bexagliflozin using 
week 12 assessments for Seq 3 or 4’s Period 1 and Seq 1 or 2’s Period 2; 
• Change in seated office SBP or DBP after 24 weeks treatment of bexagliflozin using 
cumulative week 24 assessments for Seq 3 or 4’s Period 2 and Seq 1’s Period 3; 
• Change in seated office SBP or DBP after 36 weeks treatment of bexagliflozin using 
cumulative week 36 assessments for Seq 3’s Period 3. 
 
PK Assessments: 
Samples for population PK analysis will be collected and the required plasma concentrations 
determined. The PK parameters will be assessed separately as part of the population PK 
analysis. 
Safety Assessments:  
Safety will be assessed based on an analysis of the adverse events identified by patient 
histories, laboratory data, including hematology, serum chemistry, urinalysis, urinary 
electrolytes and creatinine measurements; by ECGs, measurements of vital signs and 
physical examinations; and by changes in concomitant medication use.   
Statistical Methods:  
The primary endpoint of study 603A is the change from baseline (Day 1) to week 12 in the 
24-hour average SBP of the bexagliflozin group compared to the placebo group using a 
superiority testing at an overall two-sided 0.05 level of significance.   
The primary endpoint of study 603B is the change from week 12 (cumulative week 24) to 
week 24 (cumulative week 36) in the 24-hour average SBP in the bexagliflozin group 
compared to the placebo group using a superiority testing at an overall two-sided 0.05 level 


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of significance. 
The assumptions to estimate the sample size for the primary endpoint of study 603A are: 
1. The magnitude of the decrease from baseline to week 12 of the 24 h mean SBP in the 
bexagliflozin treatment arm will exceed that found in the placebo arm by 5 mm Hg; 
2. The standard deviation of the change from baseline to Week 12 will be 15 mm Hg for 
both the active and placebo groups; 
3. The two-sided significance level is 0.05. 
 
The assumptions to estimate the sample size required for the primary endpoint of study 603B 
are: 
1. Bexagliflozin will remain effective for at least 24 weeks.  The 24-hour average ABPM 
SBP will not change between week 12 and week 24 in those taking bexagliflozin. 
2. Subjects who are randomized to receive placebo will show an increase in the ABPM SBP 
of 4 mm Hg between week 12 and week 24. 
3. The standard deviation of the change will be 15 mm Hg for both the active and placebo 
groups. 
4. The two-sided significance level is 0.05. 
 
A sample size of 254 per arm is required for the measurement to have 85% power to attain 
significance for the primary endpoint of study 603B. It is estimated that 75% of subjects will 
complete the 36 weeks of study treatment following the first randomization. Thus a total 
sample size of 680 subjects is planned for study 603A. It is estimated that approximately 8% 
of subjects will have ceased to participate by the end of study 603A. A sample size of 626 
subjects at the conclusion of study 603A will provide >95% power for the primary endpoint. 
An interim non-binding futility analysis when 300 subjects have completed study 603A will 
be conducted. Using an interpolated spending function of Type II error, i.e., with 0.5 
proportion of Type II error being spent at the interim look, the study may stop for futility 
when the test statistics (Z score) is less than 0.656 (or p-value > 0.512).  The overall power 
for the first primary endpoint remains >95% with this interim look.  The interim analysis will 
be conducted by an independent data monitoring group. 
An analysis of covariance (ANCOVA) method will be used in 603A for analyzing the mean 
change from baseline 24-hour average SBP at week 12, adjusted by diabetes status, renal 
function, medicated/unmedicated status and baseline mean 24 h SBP.  Least squares means 
with 95% confidence intervals (CI) will be generated for the difference between the 
treatment groups at Week 12.  
A similar method of ANCOVA will be used for the primary efficacy endpoint of study 603B.  
Changes from week 12 to week 24 in 24 h mean SBP will be analyzed.  24-hour average SBP 
at week 12 will be used as a covariate.  Least squares means with 95% CIs will be generated 
for the difference between the treatment groups at week 24.  
The primary analysis for 603A will be based on all randomized subjects and evaluations prior 
to the initiation of the rescue hypertensive medication. Last post baseline evaluation will be 


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used for the primary analysis time point at Week 12. 
The primary analysis for 603B will be based on all randomized subjects at week 12, and 
evaluations prior to the initiation of the rescue hypertensive medication (i.e., rescue 
medication between week 12 and week 24). Last post week 12 observation but prior to 
initiation of the rescue medication will be used for the primary analysis time point of week 
24. 
Sensitivity analyses will be conducted for the primary endpoints.  
x Cumulative week 12 and week 36 evaluations after rescue medication will be used in the 
analyses in place of evaluations prior to the rescue medication 
x Analyses will be based on subjects without rescue medication 
x Tipping Point analysis will be conducted as follows:   
o Subjects in the bexagliflozin treatment arm who discontinue participation or initiate 
rescue medication, will be analyzed assuming that their treatment effect has worsened 
by G (where G = 0.5 to 5, in steps of 0.5) compared to the reduction in SBP for subjects 
who are in the study without rescue medication. 
o Subjects in the placebo treatment arm who discontinue study participation or initiate 
rescue medication, will be considered to have experienced a treatment effect the same 
as the change of SBP for subjects who are in the study without rescue medication. 
Date of Protocol V.1.0: 21 May 2017 
Date of Protocol V2.0: 28 August 2017 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABPM 
ambulatory blood pressure monitoring 
ACE 
angiotensin converting enzyme 
AE 
adverse event 
AEOI 
adverse event of interest 
ALT 
alanine aminotransferase (SGPT) 
ANOVA 
analysis of variance 
AP 
alkaline phosphatase 
AST 
aspartate aminotransferase (SGOT) 
bid 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
DASH 
dietary approaches to stop hypertension 
DBP 
diastolic blood pressure 
DKA 
diabetic ketoacidosis 
DMC 
data monitoring committee 
eGFR 
estimated glomerular filtration rate 
ESA 
erythropoiesis-stimulating agent 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GMI 
genital mycotic infections 
Hct 
hematocrit 
HF 
heart failure 
Hgb 
hemoglobin 
HUA 
hospitalization for unstable angina 
ICH 
International Conference for Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug application 
INR 
international normalized ratio 
IRAE 
immediately reportable adverse event 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 


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KDOQI 
Kidney Disease Outcomes Quality Initiative 
LDL-C 
low-density lipoprotein cholesterol 
MACE 
major adverse cardiovascular event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
NYHA 
New York Heart Association 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
RBC 
red blood cell (count) 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SGLT1 
sodium glucose linked transporter 1 
SGLT2 
sodium glucose linked transporter 2 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
T2DM 
type 2 diabetes mellitus 
TEAE 
treatment emergent adverse event 
UADR 
unexpected adverse drug reaction 
UGE 
urinary glucose excretion 
ULN 
upper limit of normal 
UTI 
urinary tract infection 
WBC 
white blood cell (count) 
WOCBP 
woman of childbearing potential 
 


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1 
INTRODUCTION 
Hypertension affects one billion people worldwide, including 30% of U.S adults. The 
incidence of hypertension is expected to continue to rise, especially given current trends in 
the prevalence of obesity and diabetes (Egan et al., 2010). Unfortunately, only half of those 
afflicted achieve goal blood pressure targets (James et al., 2014). Hypertension is a major 
preventable risk factor for cardiovascular disease. There is a direct correlation between 
adverse outcomes and increasing blood pressure over 115/75 mm Hg (Lewington et al., 
2002). Thus, novel anti-hypertensive therapies are needed, especially those that may have 
additional beneficial effects on associated conditions like diabetes mellitus, obesity and 
chronic kidney disease.  
Bexagliflozin is a specific and potent inhibitor of sodium-glucose linked transporter 2 
(SGLT2).  SGLT2 is responsible for the reabsorption of most of the glucose passing through 
the S1 and S2 segments of the renal proximal tubule by a 1:1 cotransport of sodium ions and 
glucose (Hummel et al., 2012; Kanai et al., 1994). Inhibiting SGLT2 action leads to 
glucosuria and natriuresis. The mechanism of the natriuresis is thought to be at least partially 
dependent on osmotic diuresis. Individuals affected by familial renal glucosuria (FRG), a 
syndrome resulting from mutations in the gene encoding SGLT2, SLC5A2 (Calado et al., 
2006; Calado et al., 2004; Calado et al., 2008; Francis et al., 2004; Kleta et al., 2004; Santer 
et al., 2003; van den Heuvel et al., 2002) present with a prominent glucosuria, mild to 
moderate polyuria, and, in severe cases, evidence of volume depletion attributable to 
natriuresis. Affected individuals are euglycemic and exhibit no signs of renal tubular 
dysfunction apart from their glucosuria. In extreme cases of FRG, evidence of sodium 
depletion with mild hypotension and a compensatory activation of the renin-angiotensin-
aldosterone system (RAAS) have been noted (Calado et al., 2006; Calado et al., 2008). 
Several SGLT2 inhibitors have been approved as a single agent or in combination with other 
hypoglycemic agents for the treatment of patients with T2DM (Vivian, 2015; Whalen et al., 
2015). In clinical studies of diabetic adults, SGLT2 inhibitors have been shown to produce an 
antihypertensive effect (Baker et al., 2014; Lovshin and Gilbert, 2015; Mancia et al., 2016; 
Oliva and Bakris, 2014; Reed, 2016; Tikkanen et al., 2015; Weber et al., 2016; Weir et al., 
2014) A meta-analysis of 27 randomized controlled trials with 12,960 subjects showed 
SGLT2 inhibitors reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP) 
by 4.0 and 1.6 mm Hg respectively (Baker et al., 2014). Orthostatic hypotension was rarely 
observed (Baker et al., 2014). Baseline readings were typically low, around 130 mm Hg for 
SBP. 
In a trial assessing the cardiovascular hazards of administration of empagliflozin 
(EMPAREG), diabetic patients with increased cardiovascular risk were treated with 
empagliflozin or placebo in combination with standard of care for approximately 3 years. 
The primary composite outcome of death, MI, and stroke (MACE) occurred in 10.5% of 
patients in the empagliflozin groups and in 12.1% of the patients in the placebo group. 
Empagliflozin has shown decreased rates of eGFR decline in those with mild and moderate 
chronic kidney disease (Zinman et al., 2015). SBP decreased over the course of the treatment 
period in empagliflozin arms compared to placebo (Scheen, 2016). 


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1.1 
Bexagliflozin for the Treatment of Hypertension 
Bexagliflozin is a potent and highly specific inhibitor of the SGLT2 with an in vitro IC50 of 
2 nM or 0.9 ng/mL and a 2435-fold selectivity for human SGLT2 compared with SGLT1. 
Bexagliflozin elicits a prominent and predictable glucosuria in laboratory animals and human 
subjects. 
1.1.1 
Summary of Bexagliflozin Non-clinical Data  
The potential adverse effects of bexagliflozin have been evaluated in studies of non-clinical 
safety pharmacology, acute and chronic general toxicology, genotoxicity, acute and chronic 
reproductive toxicity and two-year carcinogenicity. Repeat dose toxicity studies have found 
exacerbation of chronic progressive nephropathy and gastric irritation, including sporadic 
ulceration, at the lowest observable dose level in male rats, as well as signs of reversible 
cardiac inflammation and abdominal distension at a dose level of 200 mg/kg in monkeys. 
Details of the adverse findings are provided in the Investigator’s Brochure. 
1.1.2 
Summary of Bexagliflozin Clinical Data  
Theracos has completed multiple phase 1 studies to evaluate safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD) and drug metabolism in healthy subjects, 
subjects with T2DM, and diabetic subjects with renal impairment. Bexagliflozin was well 
tolerated by patients with normal and impaired renal function and produced significant 
urinary glucose excretion (UGE) and decreases in blood pressure.  
In a 96-week double blind, placebo controlled study THR-1442-C-418 in 286 patients with 
T2DM, study subjects had a baseline SBP of about 128 mm Hg.  Subjects in the 
bexagliflozin treatment group showed a placebo corrected decrease of 6 mm Hg in SBP.  The 
treatment effect was durable and produced reductions from baseline SBP of 4.6 mm Hg at 
week 96 and4.7 mm Hg at week 97, one week after the last dose.  Among the patients with 
SBP ≥140 mm Hg at baseline (mean SBP of 147±7.8 mm Hg), bexagliflozin treatment 
resulted in a placebo corrected SBP reduction of 7 mm Hg at week 24.  The treatment effect 
correlated with the baseline BP but was independent of the baseline HbA1c.  Details of the 
pharmacology, efficacy, and safety assessments are described in the Investigator’s Brochure 
and summarized in the following sections. 


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2 
OBJECTIVES 
2.1 
Objectives of Study 603A  
Primary Objective of 603A Study 
In study 603A, the effectiveness of bexagliflozin tablets, 20 mg, will be assessed in a study 
population randomized 1:1 to receive either active agent or placebo. The primary endpoint 
will be the change from baseline (Day 1) to week 12 of the average ambulatory systolic 
blood pressure (SBP) of the bexagliflozin group compared to the placebo group. 
Secondary Objectives of Study 603A 
Additional effectiveness outcomes will be assessed from ambulatory as well as seated office 
blood pressure measurements. 
Secondary endpoints based on mean ambulatory SBP will include the proportion of subjects 
who achieve a reduction of mean ambulatory SBP of 10 mm Hg or greater and the proportion 
of subjects who achieve a mean ambulatory SBP of 135 mm Hg or less at week 12. 
Secondary endpoints based on seated office SBP will include the placebo-adjusted change 
from baseline to week 12 in seated office SBP and the proportion of subjects who achieve a 
mean seated office SBP of 140 mm Hg or less at week 12. 
Secondary endpoints based on mean ambulatory DBP will include: the placebo-adjusted 
change in mean ambulatory DBP from baseline to week 12; the proportion of subjects who 
achieve a mean ambulatory DBP of 87 mm Hg or less at week 12; and the proportion of 
subjects who achieve a reduction of mean ambulatory DBP of 4 mm Hg or greater at 
week 12. 
Secondary endpoints based on seated office DBP will include the placebo-adjusted change 
from baseline to week 12 in seated office DBP and the proportion of subjects who achieve a 
mean seated office DBP of 90 mm Hg or less at week 12. 
An additional objective of study 603A will be an assessment of the maximum and minimum 
treatment effect (peak-trough ratio) by ABPM SBP at week 12. 
2.2 
Objectives of Study 603B  
Primary Objective of Study 603B 
In study 603B, the effectiveness of bexagliflozin tablets, 20 mg, will be assessed by 
measurement of the loss of the treatment effect following randomized withdrawal. All study 
entrants will first be dosed with bexagliflozin tablets, 20 mg, for 12 weeks. At week 12 the 
participants will undergo a 1:1 randomization to bexagliflozin tablets, 20 mg, or placebo. The 
primary endpoint will be the change from week 12 to week 24 of the mean ambulatory SBP 
of the bexagliflozin group compared to the placebo group. 


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Secondary Objectives of Study 603B 
The secondary objectives of study 603B are based on separate assessments of effects on 
mean ambulatory and seated office systolic and diastolic blood pressures.  
Study 603B will also include a population pharmacokinetic assessment between weeks 6 and 
12, when all participants will be receiving bexagliflozin tablets, 20 mg.  
2.3 
Integrative Objectives of Studies 603A and 603B  
Integration of measures collected in studies 603A and 603B will be used to assess consistent 
effects on mean ambulatory SBP/DBP after 12 weeks of bexagliflozin treatment, as well as 
longer treatment periods, i.e., 24 weeks or 36 weeks of bexagliflozin treatment. 
In addition, the seated office systolic and diastolic blood pressure will be collected at more 
frequent intervals than for ambulatory monitoring, and the changes over time will be 
evaluated to provide a composite profile of treatment effect as a function of time. 
 
2.4 
Safety Objectives 
The integrated safety objectives will assess the hazard ratio for adverse events associated 
with bexagliflozin exposure compared to placebo in all segments of both studies in which a 
placebo-exposed cohort is present. The assessments will include: 
• 
the frequency and severity of treatment emergent adverse events 
• 
the frequency and severity of treatment emergent adverse events of special interest 
• 
changes in concomitant medication use 
• 
changes in laboratory test values 
• 
changes in cardiac rhythm determined by 12-lead ECG 
• 
changes in vital signs 
• 
effects on general health detected by physical examination 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Design and Plan 
3.1.1 
Study 603A 
Approximately 680 male or female adult subjects who exhibit an office seated blood pressure 
≥ 140 mm Hg and < 180 mm Hg, and who are taking no more than 4 anti-hypertension 
medications will be enrolled in study 603A. In the desired population, > 10% of the subjects 
will have a baseline ABPM > 160 mm Hg and < 30% of the subjects will have type 2 
diabetes mellitus. 
Subjects who meet the eligibility criteria at the screening visit (visit 1) will start a 2 week 
run-in period.  At the end of the run-in period, subjects who have not been disqualified by 
laboratory testing results based on samples drawn at the screening visit, who have been 
compliant in taking the run-in medication, and who exhibit a seated SBP ≥ 140 mm Hg and 
< 180 mm Hg will be eligible for participation. At the investigative site the subjects will take 
the last dose of run-in drug, will be fitted with an ABPM device and will start a 24-h 
ambulatory blood pressure monitoring (ABPM) to establish the baseline ABPM SBP and 
DBP.  On the following day, qualified subjects who have completed the 24-h ABPM with a 
mean 24-h SBP ≥ 135 mm Hg will be randomly assigned to receive bexagliflozin tablets, 
20 mg or placebo, using an interactive web response system (IWRS).  If < 64 SBP readings 
are recorded, the ABPM must be repeated within 2 days.  Prior to randomization, subjects 
who cannot successfully complete the ABPM within two attempts will be considered screen 
failures. 
Randomization will be stratified according to diabetes status (history of T2DM or not), renal 
function (eGFR ≥ 60 or not), presently medicated for hypertension or not, and ABPM SBP 
(< 160 mm Hg or not).   
A bottle of double blind study drug will be dispensed to each randomized subject with an 
instruction to take one tablet daily in the morning with a glass of water before or after 
breakfast.  It will be recommended that subjects take the study drug at about the same time 
every day except on the days of scheduled site visit when the study drug will be administered 
at the investigational site. 
A six week visit to the investigational site will allow seated office measures of systolic and 
diastolic BP to be recorded. 
At week 12 (end of study), the subject will visit the investigational site, consume the final 
tablet, and be fitted for ABMP.  
An interim non-binding futility analysis is planned when approximately 50% of the 
randomized subjects (i.e., 300) have completed study 603A.  The data will be analyzed by an 
independent group who is not part of the study management team. Results from the analysis 
will be reviewed by an independent Data Monitoring Committee (DMC). 


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3.1.2 
Study 603B 
Upon returning to the investigational site to surrender the ambulatory monitor at the 
conclusion of study 603A, subjects will begin participation in study 603B. They will receive 
a 12-week supply of bexagliflozin tablets, 20 mg. 
At week 6 subjects will return to the investigational site for measurement of seated systolic 
and diastolic blood pressures.  
At week 12, subjects will visit the investigational site to consume the final tablet and to be 
fitted with an ambulatory monitor to record their baseline mean blood pressure. 
The following day, subjects will be randomized 1:1 to receive a 12-week supply of 
bexagliflozin tablets, 20 mg or bexagliflozin tablets, placebo. Assignment to the active or 
placebo arm will be balanced to approximately equalize the representation in each arm of the 
following groups: 
• 
Subjects not requiring rescue medication prior to week 24 and exhibiting a > 20 mm Hg 
reduction in mean SBP between Day 1 and cumulative 24 
• 
Subjects not requiring rescue medication prior to week 24 and exhibiting a > 5 mm Hg 
and ≤ 20 mm Hg reduction in mean SBP between Day 1 and cumulative 24 
• 
Subjects not requiring rescue medication prior to week 24 and exhibiting a ≤ 5 mm Hg 
reduction in mean SBP between Day 1 and cumulative 24 
• 
Subjects requiring rescue medication prior to week 24 
 
An assessment of bexagliflozin population pharmacokinetics (PK) will also be conducted to 
include approximately 200 subjects. Samples will be taken between weeks 6 and 12. The 
population PK study design and analysis plan will be described in a designated study 
protocol and the analysis will be reported separately. 
3.1.3 
Integrated Management of Hypertension, Including Use of Rescue 
Medications 
Subjects will be counseled to be compliant with all their medications, to exercise regularly, 
lose weight if overweight or obese, adopt a diet rich in fruits, vegetables and low-fat dairy 
products (the DASH diet, with appropriate modifications for participants with CKD), reduce 
sodium intake and alcohol consumption to recommended levels. Patients who smoke will be 
encouraged to stop (CDC guidance).  
Rescue medications are recommended following the guidance below if the SBP shows an 
increase of 30 mm Hg from baseline or exceeds 189 mm Hg in office measurements over 3 
consecutive days. 


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Guidance for Hypertensive Rescue Medication Use 
Study 603A, cumulative weeks 1-6 
• 
Follow procedures for visits 10 and 11 as early termination visits to obtain 24-h 
ABPM and collect safety data 
• 
Rescue medication should not be administered unless hypertensive emergency 
appears imminent. In those situations, refer the subject to seek urgent care in a clinic 
or hospital. Subject should withdraw from participation in the study and see primary 
care provider to start or intensify anti-hypertensive therapies 
 
Study 603A, cumulative weeks 7-12 
• 
Follow procedures for visits 5 and 6 to obtain 24-h ABPM and collect safety data  
• 
Start visit 6 (start of 603B) without rescue medication.  If a hypertensive emergency 
appears imminent, refer the subject to seek urgent care in a clinic or hospital. 
Prescribe rescue medication at Visit 7 if SBP shows an increase of 30 mm Hg from 
baseline or exceeds 189 mm Hg in office measurements and continue study activities 
 
Study 603B, cumulative weeks 13-18 
• 
Obtain 24-h ABPM at an unscheduled visit 
• 
Rescue medication should not be administered unless hypertensive emergency 
appears imminent. In those situations, refer the subject to seek urgent care in a clinic 
or hospital. Prescribe rescue medication at Visit 7 if SBP shows an increase of 30 mm 
Hg from baseline or exceeds 189 mm Hg in office measurements and continue study 
activities 
 
Study 603B, cumulative weeks 19-24 
• 
Obtain 24-h ABPM and collect safety data 
• 
Prescribe rescue medication if SBP shows an increase of 30 mm Hg from baseline or 
exceeds 189 mm Hg in office measurements and continue study activities 
 
Study 603B, cumulative weeks 25-36 
• 
Obtain 24-h ABPM and collect safety data 
• 
Prescribe rescue medication if SBP shows an increase of 30 mm Hg from baseline or 
exceeds 189 mm Hg in office measurements and continue study activities 
 
Additional study procedures for safety and efficacy endpoint assessment will be performed as 
outlined in the study schedule. 
The effectiveness and safety analyses will be conducted after all subjects have completed or 
withdrawn from study 603B. 
To allow safety data to be collected for up to 36 weeks of exposure the study will not be 
stopped for overwhelming efficacy.  The DMC will review the unblinded safety data at 
approximately 2 month intervals and may recommend protocol modification or early 
stopping due to safety concerns. 


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The integrated program is illustrated in Figure 1. 
 
Figure 1. 
THR-1442-C-603 Study Design 
 
3.2 
Rationale for Design and Control Group 
3.2.1 
Rationale for the Selected Study Design 
Bexagliflozin exhibits diuretic and hypotensive effects in hypertensive diabetics. The diuretic 
effect is immediate and improvement in blood pressure is observed over the first 6 to 12 
weeks of treatment. The antihypertensive effect persists for 96 weeks. The magnitude of the 
effect correlates with the baseline blood pressure but appears to be independent of the 
baseline hemoglobin A1c, a measure of glycemic control. The two studies of protocol THR-
1442-C-603 are designed to explore whether bexagliflozin will reduce blood pressure in 
adults with essential hypertension regardless of diabetes status.  In addition, the use of a 
single treatment population allows extended safety and effectiveness data to be collected.  
Study 603A is planned to evaluate the bexagliflozin treatment effect on SBP after the full 
effect of bexagliflozin has been achieved. Subjects will be randomized 1:1 to receive 
bexagliflozin tablets, 20 mg, or bexagliflozin tablets, placebo, for 12 weeks. The primary 
endpoint is the placebo-corrected change from baseline in ABPM SBP. 
Study 603B, a randomized withdrawal study, is intended to measure the persistence of the 
antihypertensive effect of bexagliflozin. Subjects will receive bexagliflozin tablets, 20 mg for 
12 weeks followed by 1:1 randomization to bexagliflozin tablets, 20 mg or bexagliflozin 
tablets, placebo. The primary endpoint is the placebo-corrected change from week 12 to 
week 24 in the ABPM SBP.   
Under the close monitoring detailed in this protocol, placebo is the appropriate control 
treatment in the subject populations studied during the two 12-week evaluation periods. In 
order to establish baseline blood pressure and to allow compliance with the dosing regimen 
to be monitored, participating subjects will have participated in a 2 week run-in period prior 
to randomization. 


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3.2.2 
Rationale for the Selected Dose and Once daily Dosing Regimen 
The pharmacodynamics of bexagliflozin can be directly measured by quantitation of urinary 
glucose excretion (UGE). The UGE data from healthy volunteers are fit by a logistic 
equation with maximum effect size of 76.3 g/24 h and an ED50 of 3.63 mg. The proposed 
doses of 20 mg are predicted to produce 85% of the maximum effect. Doses of 20 mg have 
been administered for 96 weeks to an international study cohort with few adverse 
consequences. In a shorter-term study a modest dose dependence of adverse event accrual 
was observed. 
The risk of induced hypoglycemia as a consequence of the inhibition of SGLT2 activity is 
low based on published data reporting the euglycemic status of individuals with genetic 
mutations in SLC5A2 (the gene encoding SGLT2), in subjects that have been treated with 
other SGLT2 inhibitors, and from previous clinical studies in healthy or diabetic subjects 
treated with bexagliflozin. The potential risk of diuretic effects such as hypotension or 
electrolyte imbalance has been monitored. There has been one event each of hyponatremia 
(on day 99), hypokalemia (on day 86), and hypotension (on day 284) among study subjects 
who have received daily doses of 20 mg bexagliflozin in completed studies. The incidence 
rate for all electrolyte events is approximately 0.2%. 
Bexagliflozin is formulated as a prolonged release tablet.  The average plasma concentration 
is above 10 ng/mL at 24 h after dosing which is about 10 times the in vitro IC50 for SGLT2 
inhibition.  These data support a once daily dosing regimen. 
3.2.3 
Rationale for the Selection of Population 
Bexagliflozin is being developed for the management of essential hypertension in the U.S. 
adult population, and the study sites and entry criteria are consistent with this objective. 
Subjects who exhibit uncontrolled hypertension despite administration of five or more 
medications are considered to be likely non-compliant or to have unusual syndromes not 
representative of the hypertension exhibited by the general population. Otherwise, the entry 
criteria conform to medically accepted definitions of hypertension. Ambulatory monitoring 
typically produces mean measurements that are lower than those seen in office visits, because 
many adult hypertensives experience a decrease in blood pressure while sleeping. The entry 
criteria reflect this consideration.  The target population will contain adequate representation 
of poorly controlled hypertensives (greater than 10% of the total randomized population must 
have mean 24 h SBP ≥ 160 mm Hg.). Although diabetes and hypertension are common 
comorbidities, the target population will consist of no more than 30% of subjects with both 
conditions, to avoid possible confounding influences attributable to potential effects specific 
to this population. 
3.3 
Study Duration and Dates 
Subjects who complete both studies will spend 38 weeks including the initial 2 weeks of run-
in. For details of the schedule and nature of the investigations, see the Schedule of Events in 
Appendix 1. 


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4 
POPULATION SELECTION 
4.1 
Population 
The study population for the integrated program will include approximately 680 subjects 
with essential hypertension. Eligible subjects who consent to participate in the program will 
be enrolled in clinical investigational sites in the United States. Study subjects will be 
informed of the purpose of the program, the potential risks of participation in both studies, 
and will be requested to consent to the procedures and blood collection on a single consent 
form. 
Plasma samples will be collected for population PK analysis in study 603B. Study subjects 
will be informed of the purpose of the PK study and requested to consent to the additional 
procedures and blood collection.  
4.2 
Inclusion Criteria 
Approximately 680 patients with essential hypertension will be initially randomized. The 
subjects must be: 
1. Male or female with age ≥ 20 years 
2. Diagnosed with essential hypertension and exhibiting an office seated SBP ≥ 140 and 
< 180 mm Hg 
3. Unmedicated or medicated by no more than 4 agents for hypertension. Unmedicated 
subjects are subjects who have never taken pharmacotherapy for hypertension or have not 
taken any anti-hypertension medication for at least 3 months.   A stable dose means no 
change in dose or frequency for the 4 weeks prior to the screening visit 
4. If female and of childbearing potential, willing to use an adequate method of 
contraception and to not become pregnant for the duration of the study. Adequate 
contraceptive measures include, but are not limited to, oral contraceptives, intrauterine 
devices, Depo-Provera, Norplant, hormonal contraceptive implants, bilateral tubal 
ligation, partner with vasectomy, condom or diaphragm plus contraceptive sponge, foam, 
or jelly, and abstinence 
5. Willing and able to return for all clinic visits and to complete all study-required 
procedures 
6. Able to self-medicate during the run-in period, omitting no more than one day of dosing 
(confirm at visit 2) 
7. Shown to have a seated SBP ≥ 140 and < 180 mm Hg (confirm at visit 2) 
8. Shown to exhibit a mean 24 h SBP ≥ 135 mm Hg (at visit 3) 
 
4.3 
Exclusion Criteria 
Patients who have any of the following attributes will be excluded from the study. 
1. Diagnosis of type 1 diabetes mellitus or maturity–onset/diabetes of the young (MODY) 


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2. Known history of secondary or malignant hypertension 
3. Seated DBP >110 mm Hg at screening 
4. Requiring insulin to control blood glucose 
5. Taking more than 4 anti-hypertension medications 
6. Genitourinary tract infection within 6 weeks of screening or history of ≥ 3 genitourinary 
infections requiring treatment within the last 6 months 
7. Cancer, active or in remission for < 3 years (Non-melanoma skin cancer or basal cell 
carcinoma or carcinoma in situ of the cervix will not be grounds for exclusion) 
8. History of alcohol or illicit drug abuse in the past 2 years 
9. History of MI, stroke or hospitalization for heart failure in the prior 6 months 
10. Previous treatment with bexagliflozin or EGT0001474 
11. History of hypertensive emergency (Appendix 3) 
12. History of SGLT2 inhibitor treatment in the last 3 months (Appendix 4) 
13. Known intolerance or allergy to SGTL2 inhibitors 
14. Any condition, disease, disorder, or clinically relevant laboratory abnormality that, in the 
opinion of the PI, would jeopardize the subject’s appropriate participation in this study or 
obscure the effects of treatment 
15. Pregnancy or nursing 
16. Current participation in another interventional trial or having been exposed to an 
investigational drug within 30 days or 7 half-lives of screening, whichever is longer 
17. Arm circumference too large or small to allow for accurate blood pressure readings 
18. History of kidney transplant 
19. Occupational or other lifestyle factors that could hamper the collection of valid ABPM 
data 
 
The exclusion criteria must be verified at visit 2 after the laboratory report of the samples 
drawn at screening visit (visit 1) is available from the central laboratory.  A subject will be 
excluded if any of the following laboratory observations are made: 
20. Evidence of abnormal liver function tests (total bilirubin or alkaline phosphatase > 1.5 x 
upper limit of normal (ULN) with the exception of isolated Gilbert’s syndrome); or 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x ULN 
21. eGFR, as calculated by the modification of diet in renal disease study equation (MDRD), 
< 45 mL/min/1.73 m2 or requiring dialysis  
22. HbA1c > 9.5% 
23. Positive urine pregnancy test (performed at the site) in female subjects of child bearing 
potential only 
 


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5 
STUDY TREATMENTS 
5.1 
Description of Treatments 
Bexagliflozin tablets, 20 mg and placebo, 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 drug products exhibit 
a greater than 75% release of drug substance by 8 h in simulated gastric fluid in vitro. 
The following investigational drugs will be used for oral administration: 
• 
Bexagliflozin tablets, 20 mg: tablets containing 20 mg of bexagliflozin 
• 
Bexagliflozin tablets, placebo: tablets containing no bexagliflozin 
 
5.2 
Treatments Administered 
The study subject will take one tablet per day of the following investigational products in 
addition to background medications such as drugs to control diabetes, hyperlipidemia, or 
hypertension: 
• 
Run-in period: placebo run-in medication 
• 
Study 603A: bexagliflozin tablets, 20 mg or placebo 
• 
Study 603B week 1 to week 12: bexagliflozin tablets, 20 mg  
• 
Study 603B week 13 to week 24: bexagliflozin tablets, 20 mg or placebo 
 
5.2.1 
Investigational Product 
The study drug in bottles will be dispensed by the investigator or designated staff based on 
kit numbers assigned by the Interactive Web Response System (IWRS) at the specified study 
visits (Appendix 1).  Bexagliflozin tablets, 20 mg or placebo, should be self-administered 
orally once daily before or after breakfast with a cup of liquid.  
5.2.2 
Background Anti-hypertensive Medications 
Adjustment of treatment for hypertension will not be permitted during the run-in period. If a 
change in treatment is required to improve management of hypertension, the subject may re-
enter screening after the clinical condition and treatment regimen have not changed for at 
least 4 weeks. The screening activities should be performed and subject will be assigned a 
new subject number. 
Subjects who take anti-hypertensive medications will continue taking background therapies 
for managing hypertension during the entire study at an unchanged dose, time, and frequency 
as prescribed to subjects prior to screening unless the investigator deems adjustment 
(decrease or increase) necessary for the medical well-being of the subject.  


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Unmedicated subjects who experience persistent hypertension may receive anti-hypertensive 
medications following the guidance in Section 5.7. 
Anti-hypertensive medications can be reduced to mitigate symptomatic hypotension at the 
discretion of the investigator at any time. Guidance for rescue medications for hypertension 
is described in Section 5.7. Changes to the dose, frequency, or time of administration should 
be recorded in the concomitant medication log. 
5.2.3 
Background Hypoglycemic Agents 
Subjects with type 2 diabetes mellitus will continue taking background oral hypoglycemic 
agents for managing glycemic control at an unchanged dose, time, and frequency as 
prescribed to subjects prior to screening unless the investigator deems adjustment (decrease 
or increase) necessary for the medical well-being of the subject. 
5.3 
Selection and Timing of Dose for Each Subject 
Bexagliflozin tablets, active or placebo, should be taken at approximately the same time each 
day, before or after breakfast, with one cup (250 mL) of fluid. 
On the day of scheduled clinic visits for which a fasting blood sample is to be drawn or an 
ABPM is to be initiated, administration of investigational product should be delayed until 
after blood is drawn. The product should be taken in the clinic with one cup (250 mL) of 
fluid. 
5.4 
Method of Assigning Subjects to Treatment Groups 
The study will be conducted in multiple investigative sites and will involve variable numbers 
of subjects at each site. Enrollment will be on a competitive basis, but each site will be 
capped at 68 randomized subjects. Activation of investigational sites will be centrally 
controlled by IWRS. 
Subjects who meet the eligibility criteria required at the screening visit (visit 1) must be 
registered in the IWRS in order to be assigned a subject number and a bottle of run-in drug. 
A new bottle will be assigned to the subject every 12 weeks by the IWRS at visits 3, 6, and 9. 
There are two randomization procedures planned in this program, at visit 3 and visit 9 
(Appendix 1).  
Subjects who complete the run-in period and meet the ABPM SBP ≥ 135 mm Hg criterion at 
visit 3 will be randomized to receive a bottle of bexagliflozin, 20 mg or placebo.  Subjects 
will be assigned to each group in a 1:1 ratio. Randomization will be stratified according to 
diabetes status (history of diabetes or not), baseline ABPM SBP (≥ 160 mm Hg or not), 
unmedicated or not, and renal function (eGFR ≥ 60 or not). The investigator or designated 
staff will log into the IWRS to receive the randomization code and assigned kit number for 
bexagliflozin tablets, active or placebo. 


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At visit 6 after a subject has completed the ABPM successfully, a second bottle of study drug 
will be assigned to the subject by IWRS.  All subjects will receive active treatment for the 
following 12 weeks. Subjects who experience persistent hypertension during the first 12 
weeks of treatment may complete visits 5 and 6 prior to week 12 as described in Section 5.7.   
At visit 9 after a subject has completed the 24 h-ABPM successfully, the subject will be 
randomly assigned to receive either active or placebo in a 1:1 ratio. A new randomization 
number and a new bottle of double blind study drug will be assigned and dispensed to the 
subject. Assignment to the active or placebo arm will be balanced to approximately equalize 
the representation in each arm of the following groups: 
• 
Subjects not requiring rescue medication prior to week 24 and exhibiting a > 20 mm Hg 
reduction in mean SBP between Day 1 and cumulative 24 
• 
Subjects not requiring rescue medication prior to week 24 and exhibiting a > 5 mm Hg 
and ≤ 20 mm Hg reduction in mean SBP between Day 1 and cumulative 24 
• 
Subjects not requiring rescue medication prior to week 24 and exhibiting a ≤ 5 mm Hg 
reduction in mean SBP between Day 1 and cumulative 24 
• 
Subjects requiring rescue medication prior to week 24 
 
If the mean SBP is missing at cumulative week 24, the subject will be withdrawn.  
Subject randomization will be deactivated for all sites when the planned number of subjects 
is met and a minimum of 10% of the subjects have an average 24 h ABPM SBP ≥ 160 and 
< 180 mm Hg at visit 3. However, if a potential subject has started the run-in period at that 
time and wishes to continue to participate, the subject will be allowed to continue and, if 
eligible, to be randomized.  
5.5 
Blinding 
Both studies will have double-blind treatment phases. The sponsor study management team, 
investigators, study coordinators, pharmacists, study subjects and cardiovascular endpoint 
committee (CEC) will be blinded to the study medications.  
To maintain blinding of the individual treatment assignment, the results of urinary glucose 
testing will not be made available to any study personnel or subjects. If knowledge of the test 
results is needed to manage a subject’s condition, the investigator will contact the IWRS to 
obtain the treatment assignment. If unblinding occurs for any reason, the time and reason for 
breaking the blind will be recorded on the case report form (CRF) and the sponsor must be 
notified within 24 h.  
A designated independent personnel who is not involved with the study operation will hold 
the treatment codes. The unblinded treatment information can be provided to the DMC to 
facilitate the evaluation of any clinically important increase in the rate of a serious suspected 
adverse reaction or to the designated safety contact when the treatment information is 
required to determine if an expedited safety report must be submitted to regulatory agencies.  


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The treatment assignment will continue to be withheld from the CEC adjudication committee 
members until all global investigational studies are completed and final analyses to assess 
cardiovascular risks are conducted.  
There is a planned interim futility analysis after approximately 50% of the randomized 
subjects (i.e., 300) have received at least 12 weeks of treatment to evaluate the effectiveness 
of bexagliflozin. All study subjects will continue to receive the investigational products 
during the data cleaning and analysis time. Results of the futility analysis will be reviewed by 
an independent DMC.  
5.6 
Concomitant Therapy 
During the course of the study, investigators will manage glucose and lipid levels according 
to local or regional standard of care guidance documents. Subjects will be allowed to take 
any medications or medicinal supplements prescribed except another SGLT2 inhibitor 
(Appendix 4) to manage medical conditions during the study. Any concurrent medication or 
supplemental treatment of other medical conditions should be continued at a stable dose and 
frequency for the entire study duration unless there is a clinical reason to change the dose or 
frequency.  
Subjects may receive any medications for AEs that are necessary in the investigators’ 
judgment. Medications prescribed after the informed consent is signed are to be recorded on 
the CRF. The medication name, dose, frequency, route of administration, date(s) of 
administration, and reason for administration must be recorded. This documentation should 
continue through the treatment periods.  
Medications that are prescribed for non-blood pressure modifying purpose but are known to 
cause blood pressure change should be used judiciously.  For example, using a beta-blocker 
to manage unstable angina may lower blood pressure. Other examples of medications that are 
frequently prescribed in this population are provided in Appendix 5. 
5.7 
Hypertension Rescue Therapies 
A rescue medication is defined as a dose increase of an existing blood pressure medication or 
initiation of a new blood pressure medication for the purpose of lowering blood pressure. 
Medications prescribed for other treatment indications are not considered rescue medications. 
Investigators can use any approved agent to treat blood pressure above the rescue threshold. 
Titrating up existing medications to the maximally tolerated/recommended doses prior to 
adding additional agents is recommended.  
Subjects will be counseled to be compliant with all their medications, to exercise regularly, 
lose weight if overweight or obese, adopt a diet rich in fruits, vegetables and low-fat dairy 
products (the DASH diet, with appropriate modifications for participants with CKD), reduce 
sodium intake and alcohol consumption to recommended levels. Patients who smoke will be 
encouraged to stop (CDC guidance). Every effort will be made to secure the continued 
participation of the subjects. 


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Rescue medications are recommended following the guidance below if the SBP shows an 
increase of 30 mm Hg from baseline or exceeds 189 mm Hg in office measurements over 3 
consecutive days. The confirmatory measurements should be performed in the clinic if 
possible.  If the subjects cannot complete the recommended office visits to confirm blood 
pressure elevation, an appropriate cuff may be provided by the clinic so the subject can report 
the blood pressure from home measurements. 
Any subject with elevated blood pressure with symptoms suggestive of a hypertensive 
emergency should be immediately evaluated by the investigator, and/or referred for 
emergency evaluation, at the investigator’s discretion. The following guidance should be 
followed when a subject meets the rescue criteria: 
Table 1. 
Guidance for Hypertension Rescue Medication Use 
Study/ 
Cumulative 
weeks  
Procedure 
603A 
weeks 1 to 6 
• Follow procedures for visits 10 and 11 as early termination visits to obtain 24-h 
ABPM and collect safety data 
• Rescue medication should not be administered unless hypertensive emergency 
appears imminent. In those situations, refer the subject to seek urgent care in a 
clinic or hospital. Subject should withdraw from participation in the study and see 
primary care provider to start or intensify anti-hypertensive therapies 
603A 
weeks 7 to 12 
• Follow procedures for visits 5 and 6 to obtain 24-h ABPM and collect safety data  
• Start visit 6 (start of 603B) without rescue medication.  If a hypertensive 
emergency appears imminent, refer the subject to seek urgent care in a clinic or 
hospital. Prescribe rescue medication at Visit 7 if SBP shows an increase of 30 
mm Hg from baseline or exceeds 189 mm Hg in office measurements and 
continue study activities 
603B 
weeks 13 to 
18 
• Obtain 24-h ABPM and collect safety data 
• Rescue medication should not be administered unless hypertensive emergency 
appears imminent. In those situations, refer the subject to seek urgent care in a 
clinic or hospital. Prescribe rescue medication at Visit 7 if SBP shows an 
increase of 30 mm Hg from baseline or exceeds 189 mm Hg in office 
measurements and continue study activities 
603B 
weeks 19 to 
24 
• 
Obtain 24-h ABPM and collect safety data 
• 
Prescribe rescue medication if SBP shows an increase of 30 mm Hg from 
baseline or exceeds 189 mm Hg in office measurements and continue study 
activities 
603B 
weeks 25 to 
36 
• 
Obtain 24-h ABPM and collect safety data 
• 
Prescribe rescue medication if SBP shows an increase of 30 mm Hg from 
baseline or exceeds 189 mm Hg in office measurements and continue study 
activities 
 


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Choice of rescue therapy should take into consideration current antihypertensive treatment, 
as well as co-morbidities, such as cardiovascular or renal disease, and severity of BP 
elevation. Site investigators should use their best clinical judgement when determining rescue 
medications. 
The following strategies are recommended, but not required: 
• 
Amlodipine should be considered first line among calcium channel blockers. 
• 
For patients with diabetes or chronic kidney disease with proteinuria, consider addition of 
an ACE inhibitor or ARB, but not both in combination. 
• 
For patients with cardiovascular disease, consider use of a beta blocker. 
• 
For patients with volume overload, consider use of diuretics, though caution should be 
used if the patient is on an additional diuretic such as a thiazide. 
 
Step down therapy: For SBP < 110 with symptoms attributable to hypotension, investigators 
should decrease the dose or remove the most recently added agent, at the investigator’s 
discretion. Investigational product should be continued unless the investigator feels it is 
necessary to stop for the safety of the patient.  
5.8 
Restrictions 
5.8.1 
Prior Therapy 
All subjects will continue regimens for medical conditions during the study as indicated 
above. No subject shall have been treated with an investigational drug within 30 days of 
screening or within a period equal to less than 7 half-lives of the investigational drug, 
whichever is longer. No subject shall have been treated with insulin or an SGLT2 inhibitor 
within 3 months of screening. 
5.8.2 
Fluid and Food Intake  
During the study, subjects will be counseled to remain adequately hydrated at all times. In 
addition, subjects should be counseled by site staff to eat a diet low in saturated fat, high in 
fiber, low in simple carbohydrates, and contain appropriate caloric intake to maintain weight.  
Subjects will fast for approximately 8 h prior to the scheduled blood sample draws. During 
fasting, only water will be permitted. 
5.8.3 
Patient Activity Restrictions 
Lifestyle modification should be counseled at the screening visit. Specific recommendations 
will include: a) weight loss in those who are overweight or obese; b) adoption of a diet rich in 
fruits, vegetables and low-fat dairy products (the DASH diet) with appropriate modifications 
for participants with CKD; c) reduction in sodium intake to recommended levels; d) 
reduction of alcohol consumption to recommended levels; and e) participation in regular 
aerobic exercise. Patients who smoke will be encouraged to stop (CDC guidance). 


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5.9 
Treatment Compliance 
Subjects will be provided with dosing instructions when the study drugs are dispensed. 
Subjects will also be instructed to bring their study drug with them at every visit. During the 
run-in period, subjects will be excluded from randomization if more than 1 day of placebo 
run-in medication doses has been omitted. If, in the judgement of the investigator, it was 
appropriate for the subject to omit these doses, this requirement may be waived. 
At each visit after the start of the run-in period, the study staff will review medication use 
with the subject and record the drug consumption in the CRF. Reasons for non-adherence 
will also be recorded in the protocol deviation log if applicable. 
5.10 Packaging and Labeling 
Investigational products will be provided to the pharmacist or designated site personnel in 
high-density polyethylene (HDPE) bottles of 90 tablets sealed with a child-resistant cap. A 
bottle of 15 bexagliflozin tablets, placebo will be provided for the 2-week run-in portion of 
the study. All investigational product supplies will be prepared and labeled according to the 
requirements of local laws and regulations. The pharmacist or designated site personnel will 
dispense the investigational products for each subject according to the randomization 
assignment.  
5.11 Storage and Reconciliation 
Bexagliflozin tablets should be stored below 30oC (86°F). The sponsor will notify the sites of 
the process for returning unused drug. 
5.12 Investigational Product Retention at Study Site 
The investigational products shall be stored in a secure area with limited access. The drug 
storage facility must comply with the medication storage instructions. The investigational 
products should be stored in a room temperature < 30oC until ready for dispensing to study 
subjects. The trial staff must record the amount of investigational products dispensed to each 
subject on the dosing record. To ensure adequate recordkeeping, subjects must bring all 
investigational products to each visit. The remaining tablets will be accounted for in the CRF 
and drug consumption forms. The procedures for obtaining drug resupply will be provided by 
the sponsor. All unused drug must be returned to a sponsor-designated depot after drug 
accountability is verified by the sponsor or its designee.  


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6 
STUDY PROCEDURES 
The following sections describe procedures that are conducted in the protocol.  The clinical 
investigator must personally conduct or supervise the procedures that are required in the 
protocol.  The clinical investigator must personally conduct the informed consent process 
while other study tasks may be delegated to qualified staff after training is completed.  
Procedures that require clinical /medical knowledge must be performed by the investigator or 
qualified sub-investigators. 
6.1 
Informed Consent 
Before each subject is enrolled in the clinical study, written informed consent shall be 
obtained according to the regulatory and legal requirements of the participating country. As 
part of this procedure, the investigator must explain orally and in writing the nature, duration, 
purpose of the study, and the action of the drug, in such a manner that the study subject is 
aware of the potential risks, inconveniences, or AEs that may occur. The investigator should 
educate potential subjects about the scientific importance of their data and the vital role that 
their participation has for the outcome of the entire study. The subject must be informed that 
he/she is free to withdraw from the study at any time. He or she will receive all information 
that is required by federal regulations.  
The informed consent document must be signed and dated; one copy will be given to the 
patient, 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 must also be documented. 
6.2 
Medical History 
At the initial screening visit, the investigator should review the inclusion and exclusion 
criteria based on the information collected at the screening visit. He or she should evaluate 
any change to status affecting conformance to inclusion and exclusion criteria at subsequent 
visits prior to randomization. At randomization, the investigator should confirm the run-in 
drug compliance. 
6.3 
Medical History 
The following information will be collected at the screening visit: 
6.3.1 
General Demographics and Characteristics  
• 
Date of birth, age, sex, and race, and whether a female subject is of childbearing potential 
or not 
• 
Significant medical and surgical history, including dates of diagnoses, procedures and 
whether the condition is ongoing, if applicable 
 


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6.3.2 
Diabetes History  
• 
Date of diabetes diagnosis  
• 
History of all medications used to treat diabetes (to be recorded in the concomitant 
medication form), including start date, duration of use, and stop date, if applicable 
• 
History of complications due to diabetes, including diabetic ketoacidosis, glaucoma, 
retinopathy, neuropathy, gastroparesis, nephropathy, foot ulcerations, or non-traumatic 
amputations, including date of diagnosis 
• 
Frequency of hypoglycemic events (per week) that are symptomatic or require assistance 
 
6.3.3 
Renal and Cardiovascular Disease History  
• 
Chronic kidney disease stage, based on KDOQI CKD classification and duration 
(Appendix 5) 
• 
Whether currently receiving an erythropoiesis-stimulating agent (ESA) for anemia and 
time of starting ESA 
• 
History of bone disease 
• 
History of disorders of calcium and phosphorus metabolism or hyperparathyroidism 
• 
History of neuropathy 
• 
History of cardiovascular diseases including hypertension, dyslipidemia, angina, 
congestive heart failure (including NYHA classification), known atherosclerotic 
cardiovascular disease, prior MI, transient ischemic attack or stroke, and prior cardiac or 
peripheral re-vascularization procedures. The history should include the date of diagnosis 
and the current status of diagnosis (resolved or ongoing). 
 
6.3.4 
Medication History  
• 
Use of prescribed or non-prescribed medications, including name of medication, 
indications for usage, start and stop dates, dose, and frequency 
• 
Use of supplements, including over the counter drugs, vitamins, herbal preparations, and 
dietary supplements within the past 30 days prior to screening. Each medication history 
should include the agent used, indication for usage, start and stop dates, dose, and 
frequency 
• 
History of medication allergies and intolerance 
 
6.4 
Physical Examination 
A complete physical examination shall be performed by the investigator at the time points 
indicated in the Schedule of Events (Appendix 1). The examination shall include a general 
assessment of all body systems including the skin, head, eyes, ears, nose, throat, neck, heart, 
lungs, abdomen, lymph nodes, and extremities. 
6.5 
Abbreviated Physical Examination 
An abbreviated physical examination will include measurement of height at screening V1 
only and a general assessment of the skin, heart, lungs and abdomen. The investigator will 


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perform abbreviated physical examinations at the time points indicated in the Schedule of 
Events (Appendix 1), unless clinically indicated. 
6.6 
Body Weight 
Body weight will be determined in the visits indicated in the Schedule of Events (Appendix 
1). The weight must be determined using a scale that is calibrated. Every effort should be 
made to use the same scale throughout the study duration. 
6.7 
Vital Signs 
Vital signs will be measured at the time points indicated in the Schedule of Events 
(Appendix 1) and will include sitting, supine, and standing BP measurements, and heart rate. 
Only the BP measured in the seated position will be used to determine eligibility. The vital 
signs shall be obtained before the scheduled blood draw. 
Devices designed to measure BP from the finger or wrist may not be used. BP shall be 
measured using an appropriately sized cuff (cuff bladder encircling at least 80% of the arm) 
that is applied on the upper arm at heart level. The left arm and same cuff size should be used 
for each measurement at all visits. If the left arm cannot be used at the screening visit or 
during the study for BP measurements, the reason should be documented, and the right arm 
should be used for BP measurements for all subsequent visits. 
At each visit, BP measurements shall be obtained using a calibrated sphygmomanometer 
while the subject is in sitting, supine, and standing positions. Prior to measuring seated BP, 
the subject should be seated quietly in a chair, not an examination table, for at least 5 minutes 
with feet on the floor and arm supported at heart level.  
A single heart rate measurement shall be taken just prior to the BP evaluation in the sitting, 
supine, and standing positions. Blood pressure must be taken twice with at least 2 minutes 
apart with the cuff fully deflated between each reading. If any of the two SBP measurements 
differ by more than 8 mm Hg or if any of the two DBP measurements differ by more than 5 
mm Hg, a second set of 2 BP measurements should be obtained. The second set of readings 
should be entered into the CRF. Original and repeat readings must all be recorded in the 
source documents with an explanation. The average of the 2 serial blood pressure 
measurements will be used for the efficacy analyses.  
BP will be assessed first in the seated position. After seated BP measurement has been 
completed, supine and standing BP will be measured to evaluate orthostatic vital signs. 
Supine and standing blood pressure measures will not be used to determine eligibility for the 
study. The subject will lie flat for 5 min and have heart rate and supine blood pressure 
measured using the same equipment and arm as described for seated BP. Once the supine BP 
measurement is complete, the subject will stand. Standing BP and heart rate will be measured 
after 2 min of standing. For standing BP measurements, the arm should be supported and 
extended such that the cuff is at heart level. The procedure for vital sign measurement is 
shown in Figure 2. 


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Figure 2. 
BP Measurement Procedure 
The date, time, and all readings are to be entered into the source document and CRF for all 
subjects. 
6.8 
12-Lead ECG 
A 12-lead electrocardiogram (ECG) shall be conducted at the time points indicated in the 
Schedule of Events in Appendix 1 and whenever clinically indicated. This procedure should 
be performed in the supine position after 10 min without exertion. ECG parameters measured 
will be the RR interval, PR interval, QRS duration, and QT interval. Each ECG should also 
be assessed by the investigator for signs of ischemia, clinically significant hypertrophy, and 
clinically significant T-wave abnormalities or arrhythmia.  
It is the investigator’s responsibility to review the results of the ECG as they become 
available. For each abnormal ECG result, the investigator shall ascertain if the observation 
represents a clinically significant change from the screening ECG for that individual 
subject.  This determination does not necessarily need to be made the first time an abnormal 
result is observed. The investigator may repeat the ECG to verify the original result. If the 
ECG result is determined to be a clinically significant and abnormal change from baseline for 
that subject, it is considered to reflect an AE. 
6.9 
Clinical Laboratory Tests 
6.9.1 
Laboratory Parameters 
Clinical laboratory test parameters are listed in Table 1.  


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Table 2. 
List of Laboratory Tests 
Hematology: 
• 
Hematocrit (Hct) 
• 
Hemoglobin (Hgb) 
• 
Mean corpuscular hemoglobin (MCH) 
• 
Mean corpuscular hemoglobin 
concentration (MCHC) 
• 
Mean corpuscular volume (MCV) 
• 
Platelet count 
• 
Red blood cell (RBC) count  
• 
White blood cell (WBC) count with 
differential  
 
Urinalysis:  
• 
Appearance 
• 
Bilirubin 
• 
Color 
• 
Glucose 
• 
Ketones 
• 
Microscopic examination of sediment  
• 
Nitrite  
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
 
Pregnancy test: 
Urine human chorionic gonadotropin (hCG) 
(only for females who are not diagnosed as 
postmenopausal) 
Serum Chemistry: 
• 
Albumin (ALB) 
• 
Alkaline phosphatase (ALK-P) 
• 
Alanine aminotransferase (ALT) 
• 
Aspartate aminotransferase (AST) 
• 
creatinine kinase (CK) 
• 
Blood urea nitrogen (BUN) 
• 
Calcium (Ca) 
• 
Bicarbonate (HCO3) 
• 
Chloride (Cl) 
• 
Creatinine 
• 
Glucose 
• 
Magnesium (Mg) 
• 
Phosphorus 
• 
Potassium (K) 
• 
Sodium (Na) 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Total cholesterol 
• 
HDL-cholesterol 
• 
LDL-cholesterol 
• 
Total protein 
• 
Triglycerides 
• 
Uric acid 
 
Glycemic control 
• 
HbA1c 
Population PK Sampling 
• 
Bexagliflozin plasma level 
 
6.9.2 
Sample Collection, Storage, and Shipping 
6.9.2.1 
Hematology, Blood Chemistry, Serum Lipids, and Glycemic Control 
Assessments 
Blood samples for hematology, chemistry, serum lipids and glycemic control assessments 
shall be collected. Subjects shall be in a seated or supine position during blood collection. 
Samples shall be collected at the time points indicated in the schedule of events in Appendix 
1 and Appendix 2. 
The study staff shall contact each subject prior to a scheduled clinic visit to confirm the time 
of the visit and to remind the subject of proper fasting practice. A subject must be queried to 
assess compliance with approximately 8 h fast prior to blood draw to ensure the lipid values 
can be accurately determined. If a subject has not fasted, the subject should return as soon as 
can be arranged to provide a specimen after proper fasting.  


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LDL-C will be calculated by the Friedewald equation. If triglycerides are > 400 mg/dL, the 
calculated LDL-C value is invalid by this equation and will be set as missing. Direct LDL-C 
will be determined in subjects whose triglycerides are > 350 mg/dL at the screening visit. All 
subsequent LDL-C of these subjects will be determined by the same direct LDL-C 
measurements only. 
An investigator can perform additional laboratory testing to diagnose or to follow up an 
adverse event progression or resolution. Clinical samples should be analyzed in a local 
laboratory if a fast turnaround is necessary to determine the treatment plan.  
6.9.2.2 
Urinalysis  
Urine samples shall be collected routinely at designated clinic visits from a clean catch 
sample. Urinalysis shall be performed at the time points indicated in the schedule of events 
(Appendix 1 and Appendix 2). Investigator or staff should document if pre-menopausal 
female subjects are menstruating and note it in the source documents since hematuria is 
likely to be identified on dipstick urinalysis. 
Urine samples will be transported to the central laboratory for urinalysis. Microscopy will be 
conducted if the subject has a positive result on the leukocyte esterase or nitrite dipstick tests 
to clarify the significance of the finding. Results of glucose measurement in the urinalysis 
must be suppressed from the laboratory reports so the sponsor, investigators, study 
coordinators, pharmacists, study subjects, and the CEC members will remain blinded to the 
dosing assignment. 
In addition, strips to assess leukocyte esterase and nitrite but not glucose will be provided for 
immediate assessment at the clinical sites. If more than trace positive results are shown in the 
leukocyte esterase and /or nitrite testing, a urine culture should be performed in a designated 
laboratory regardless of patient reported signs or symptoms. Results of the urinalysis and 
possible urine culture will be documented in the CRFs. 
6.9.2.3 
Population PK Sampling 
Blood samples for the population PK analysis will be drawn when the subjects return to the 
clinic during week 18 (V7) and/or week 24 (V8) from 200 subjects who consent to 
participating in the PK study in selected trial centers. One blood sample will be drawn at each 
of the 3 timepoints from each subject for a total of 3 post-dose samples per subject. 
Approximately 100 subjects will be sampled at 0.25 to1 h, 7 to 10 h, and 20 to 24 h post dose 
(routine 1). Another 100 subjects will be sampled at 1.5 to 3 h, 3.5 to 6.5 h and 7 to 10 h 
post-dose (routine 2). The sampling time should take into consideration the study subject 
availability and can be on any of the days during the week of the specified clinical visits. The 
precise dosing time and sample draw time must be recorded in the CRF. 
Two mL (2 mL) of whole venous blood will be collected from a peripheral vein. Samples 
will be placed in tubes containing K2EDTA, stored on ice, and centrifuged under 
refrigeration for at least ten minutes at 3,000 rpm. After centrifugation, plasma will be 
removed and stored frozen in 3 aliquots of 200 PL at or below -20oC. Processed frozen 


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plasma samples will be transferred on dry ice to the analytical laboratory and will be stored at 
or below -20oC until analysis.  
Plasma concentrations of bexagliflozin will be determined by a validated LC-MS/MS 
method. Approximately 600 measurements of bexagliflozin plasma concentrations will be 
collected from an estimated 200 subjects who will have received active drug in this study. 
6.10 Dispensing Study Drug 
6.10.1 
Run-in Drug 
The investigator or designated personnel will dispense one bottle of 15-count bexagliflozin 
tablets at visit 1. Prior to registering a subject in the IWRS at visit 1 to receive the designated 
kit numbers of run-in drug, the signed ICF and eligibility criteria required at screening visit 
must be confirmed.   
Subjects shall be instructed to take the first dose of run-in drug at the clinic with 1 cup 
(~250 mL) of water.  Subjects shall be instructed to withhold the study drug administration 
on the day of visit 2 until they are in the clinic. 
6.10.2 
Double-Blind Study Drug 
The double blind study drug shall be dispensed to the subject after the 24 h-ABPM values are 
retrieved and ≥ 51 day time and ≥ 13 night time BP readings are recorded successfully.  The 
24 h-ABPM may be repeated if necessary.  
The IWRS will assign a double blind study drug kit number for each subject at visits 3, 6, 
and 9. The subject will be provided with a bottle of the double blind study drug and 
instructed to self-administer the first dose of investigational product at the clinic and to take 
one tablet at approximately the same time each day, before or after breakfast, with one cup 
(250 mL) of liquid. The day of first double blind study drug dosing is considered Day 1 of 
the study day. Each bottle of the investigational products will provide daily dosing for 90 
days. 
On the days of clinic visit, subject should not take the study drug until the visit procedures 
are completed. 
6.11 Efficacy Assessments 
6.11.1 
24-h ABPM 
ABPM will be performed for 24 hours, with measurements every 15 minutes during the day 
(16 h) and every 30 minutes during the night (8 h).  Subjects will be fitted with the ABPM 
device, administer one tablet of study drug, and wear the cuff for 24 consecutive hours at the 
specified visit (Appendix 1).  Subjects should take the study drugs while taking all their 
normal medications and performing normal daily activities. Subjects will be instructed to 
refrain from strenuous exercise or shower during this period. The ABPM device will be 


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placed on the arm by study staff and begin recording values immediately following the 
dosing.   
If the ABPM is not completed or if < 64 BP readings (51 day time and 13 night time BP 
readings) are recorded, the procedure must be repeated.  A new bottle of double blind study 
drug can be dispensed to a subject only after the 24 h ABPM is completed successfully. 
Prior to randomization, subject who cannot complete the 24h ABPM within two attempts will 
be considered a screen fail. After randomization, if a subject cannot complete a 24h ABPM 
within two attempts, the data will be considered missing. 
6.11.2 
SBP and DBP from office visits BP 
Vital signs will be measured as indicated in the Schedule of Events (Appendix 1) and will 
include pulse, sitting, supine, and standing BP.  Vitals should be measured prior to blood 
draws following the procedures described in Section 6.7. 
6.11.3 
Body weight 
The body weight must be determined using a scale that is calibrated.  The same scale should 
be used throughout the study duration.  
6.11.4 
Pulse Pressure 
The pulse pressure will be calculated as the difference between mean systolic and diastolic 
BP of the ABPM. 
6.11.5 
Trough/Peak Ratio 
Trough/Peak ratio will be calculated based on the four valid measurements centered on 
approximate Tmax (4 h post-dose) and the four valid measurements immediately preceding the 
removal of the monitor and prior to administering a tablet. 
6.12 Adverse Events Assessments 
6.12.1 
Definition of Adverse Events  
Adverse event (AE): Any untoward medical occurrence in a subject administered a 
pharmaceutical product that does not necessarily have a causal relationship with the 
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 a medicinal 
product, whether or not it is considered related to the medicinal product use. 
Serious adverse event (SAE): A serious AE (SAE) or reaction is any untoward medical 
occurrence that at any dose:  


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• 
results in death  
• 
is life-threatening (NOTE: The term "life-threatening" in this context refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe) 
• 
requires inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity  
• 
is a congenital anomaly/birth defect  
• 
is a medically important event or reaction. Medical and scientific judgment should be 
exercised in deciding whether a situation should be considered serious. Important medical 
events which jeopardize the subject or require intervention to prevent one of the 
outcomes listed above should usually be considered serious. 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  
 
Adverse Reaction: An adverse reaction means any AE caused by a drug. Adverse reactions 
are a subset of all suspected AEs in which there is a reason to conclude that the drug caused 
the event. 
Expectedness: 
• 
Defines any adverse events that are expected, based on the Investigator Brochure and 
previous clinical trials. 
• 
Describe the means for determining and reporting unexpected adverse events. 
Unexpected Adverse Drug Reaction (UADR): An adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g. Investigator’s 
Brochure for an unapproved investigational medicinal product). 
Serious and Unexpected Suspected Adverse Reaction (SUSAR): A serious UADR. The 
sponsor must report any suspected SUSAR in an IND safety report (21 CFR 312.32(c)(1)(i)). 
Before submitting an IND safety report, the sponsor needs to ensure that the event meets all 
three of the definitions:  
• 
Suspected adverse reaction  
• 
Serious  
• 
Unexpected  
 
Severity: AEs will be graded on a 3-point scale and reported as indicated in the CRF. The 
intensity of an AE is defined as follows: 
1 = Mild: event is medically significant but produces no disruption to daily activity 
2 = Moderate: event is medically significant and reduces or affects normal daily activity 
3 = Severe: event is medically significant and results in inability to work or perform 
normal daily activity 


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Investigational Product Causality: An assignment made by the investigator based on the 
circumstances of the event and its analysis. Cases with causal relationship classified as 
possible, probable, or definite are defined as related. Cases with causal relationship 
categorized as not likely or unrelated are defined as not related. Relationship of an AE to 
dosing will be assessed as follows: 
• 
Definite: The event responds to withdrawal of the investigational product (dechallenge), 
and recurs with rechallenge by administration of the investigational product  
• 
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 dechallenge response is 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 not a temporal or causal relationship to investigational product 
administration 
 
6.12.2 
Eliciting and Reporting AEs  
After a subject consents to participation in the study, the investigator will periodically assess 
subjects for the occurrence of AEs. To avoid bias in collecting information about AEs, the 
investigator should ask subjects the following question: "How have you felt since you were 
last checked?" All AEs (serious and non-serious) reported by the subject must be recorded in 
the source documents and CRFs.  
It is the investigator's responsibility to review the results of all laboratory tests as they 
become available. For each abnormal laboratory test result, the investigator needs to ascertain 
if this is a clinically significant change from baseline for that individual subject. This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed. The investigator may repeat the laboratory test or request additional tests 
to verify the results of the original laboratory tests. If the laboratory value is determined to be 
a clinically significant and abnormal change from baseline for that subject, this is considered 
a laboratory AE. 
In addition, the sponsor’s Medical Monitor or its designated personnel must be notified 
immediately by telephone, email, or fax of any immediately reportable AEs (IRAE) 
according to the procedure outlined below. Special attention should be paid to recording 
hospitalization and concomitant medications. 
6.12.3 
Immediately Reportable AEs  
The investigator must report any SAE to the sponsor or its representative immediately after 
the investigator becomes aware of the event. An SAE form should be completed and sent to 
the sponsor or its representative within 24 hours of knowledge of the event. 


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Non-serious events that require discontinuation of investigational product (including 
laboratory abnormalities) should be reported to the sponsor within 3 working days. The CRF 
AE form should be completed as directed by to the sponsor. 
Subjects experiencing an SAE should be followed clinically until their health has returned to 
baseline status or no further improvement in condition can be expected with further care. It is 
expected that the investigator will provide or arrange appropriate supportive care for the 
subject. 
6.12.4 
Pregnancy  
Women of childbearing potential (WOCBP) are defined as any female who has experienced 
menarche and who is not permanently sterile or postmenopausal. Postmenopausal is defined 
as 12 consecutive months with no menses without an alternative medical cause. WOCBP 
who are sexually active must use an effective method of birth control during the course of the 
study, in a manner such that risk of failure is minimized. 
Before enrolling WOCBP in this clinical trial, investigators must review guidelines about 
study participation for WOCBP. The topics should generally include: 
• 
General information 
• 
Informed consent form 
• 
Pregnancy prevention information 
• 
Drug interactions with hormonal contraceptives 
• 
Contraceptives in current use 
• 
Guidelines for the follow-up of a reported pregnancy 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy. The 
subject must sign an informed consent form confirming that the above-mentioned risk factors 
and that the consequences were discussed with her. 
During the study, all WOCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (e.g. missed or late menstrual cycle). 
If a subject or investigator suspects that the subject may be pregnant prior to investigational 
product administration, the investigational product administration must be withheld until the 
results of serum pregnancy tests are available. If the pregnancy is confirmed, the subject must 
not receive the investigational product and must not be enrolled or remain in the study. If 
pregnancy is suspected while the subject is receiving study treatment, the investigational 
product must be withheld immediately until the result of the pregnancy test is known. If 
pregnancy is confirmed, the investigational product will be permanently discontinued and the 
subject will be withdrawn from the trial. Exceptions to study discontinuation may be 
considered for life-threatening conditions only after consultations with a sponsor Medical 
Monitor or designated personnel. The investigator must notify the Medical Monitor within 3 
working days of any female subject who becomes pregnant. This reporting requirement will 
continue until 4 weeks after the last investigational product exposure.  


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The investigator must record the event on the Pregnancy Surveillance Form and forward it to 
sponsor’s Medical Monitor. 
Protocol required procedures for study discontinuation and follow-up must be performed on 
the subject unless contraindicated by pregnancy (e.g. x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator must report to the sponsor, on the appropriate Pregnancy Surveillance Form, 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants will be followed for a minimum of six months. 
6.12.5 
Procedure for Breaking the Blind  
As indicated in Section 5.5 above, the sponsor, medical monitor, study coordinators, 
pharmacists, study subjects, and the CEC members will be blinded to the treatment 
assignment during the study. The investigator should also remain blinded to the subject 
treatment during the entire study unless knowledge of the subject’s treatment is required for 
clinical care and safety. The Emergency Code Break module in the IWRS is used for such 
situations. The investigator must confirm the intention to unblind the subject’s treatment to 
obtain the dose information in IWRS. Upon completion of the unblinding, the system will 
send an alert to designated study team members that an unblinding event has occurred. 
Documentation of breaking the blind should be recorded in the subject’s medical record with 
the date and time the blind was broken, and the names of the personnel requesting and 
authorizing unblinding. The treatment assignment will continue to be withheld from the CEC 
members. 
6.12.6 
Follow-up of Non-Serious AEs  
Non-serious AEs that are identified on the last scheduled contact must be recorded in the AE 
CRF with the current status noted. All non-serious events that are ongoing at the time will be 
recorded as ongoing in the CRF. 
6.12.7 
Follow-up of Post-Study SAEs  
SAEs that are identified on the last scheduled contact must be recorded on the AE CRF page 
and reported to the sponsor according to the reporting procedures outlined in Section 6.12.3. 
These may include unresolved previously reported SAEs, or new SAEs. The investigator 
should follow these SAEs until the events are resolved, or the subject is lost to follow-up. 
Resolution means the subject has returned to the baseline state of health, or the investigator 
does not expect any further improvement or worsening of the subject’s condition. The 
investigator should continue to report any significant follow-up information to the sponsor 
until the event has been resolved.  
Any new SAEs reported by the subject to the investigator that occur after the last scheduled 
contact, and are determined by the investigator to be reasonably associated with the use of 
the investigational product, should be reported to the sponsor or designated personnel. This 
may include SAEs that are captured on follow-up telephone contact or at any other time point 
after the defined study period (i.e. up to last scheduled contact). The investigator should 


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follow SAEs identified after the last scheduled contact until the events are resolved, or the 
subject is lost to follow-up. The investigator should continue to report any significant follow-
up information to the sponsor until the event has been resolved. This study requires that 
subjects be actively monitored for SAEs for at least 4 weeks after the last treatment. 
6.12.8 
Adverse Events of Special Interest (AEOI) 
AEOI include the following categories: genital mycotic infections, urinary tract infections 
including urosepsis and pyelonephritis, diuretic effects including hypovolemia, hypotension 
episodes, hepatotoxicity, hypoglycemia, falls and fractures, malignancies, hypersensitivity 
reactions, acid-base disorders including DKA, renal failure events, and major adverse 
cardiovascular events.  AEOI should be monitored carefully and documented in the CRFs.  
6.12.8.1 
Genital Mycotic Infections (GMIs)  
The investigator shall query the subjects for signs or symptoms that may represent a GMI at 
all clinic visits. GMIs will be diagnosed based on symptoms and, if appropriate, physical 
exam and laboratory findings. Investigators must exclude the possibility of sexually 
transmitted infections before diagnosing GMI. Diagnosis of GMIs must be documented in 
the CRF. 
6.12.8.2 
Urinary Tract Infections (UTIs)  
Events potentially representing UTIs, including cystitis, urethritis, pyelonephritis, or 
urosepsis, should be carefully evaluated. Documentation of signs, symptoms, culture results 
for infectious agent, and treatment should be undertaken when appropriate.  
The investigator should query the subject at specified clinical visit for symptoms that may be 
related to a UTI and, if appropriate, document these events as symptomatic UTI in the CRF 
unless an alternative diagnosis is present. In addition, a clean catch urine sample will be 
obtained at the time points indicated in the schedule of events and a urinalysis will be 
performed on that sample at these visits. A positive urinalysis will be defined as one with 
detectable leukocyte esterase and/or nitrites. If the subject reports symptoms consistent with 
a UTI or the urinalysis at the clinical site is positive, a urine culture will be performed at the 
central laboratory. A positive urine culture will be defined as one with 105 CFU of any 
species. The investigator may also perform a urine culture using local resources if necessary 
for clinical care.  
6.12.8.3 
Hepatotoxicity  
If plasma AST and/or ALT concentrations > 3 x ULN are detected, the investigator will 
record in the source documents: 
• 
the date corresponding to the date of the laboratory abnormality 
• 
the type, frequency, and dose of any concurrent medications or supplements taken by the 
subject within the 14 days of the detected abnormality 
• 
any symptoms or change in physical exam that have occurred since the prior assessment 


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The investigator should perform additional laboratory and imaging tests to attempt to 
establish the cause of the AST and ALT elevations, including ruling out any potential 
contribution from bone or muscle etiologies. 
Any clinically significant increase in hepatic enzymes and specifically any ALT or AST > 3 
x ULN requires immediate repeat test within 48 to 72 hours to confirm the hepatic enzyme 
elevation. Testing should be repeated based on the clinical situation at least every 96 hours (4 
days) until ALT and AST return to < 2.5 x ULN or until the liver function test results are 
stable and significant changes are not expected anymore. Study medication should be 
stopped and the event should be reported as a laboratory AE within the CRF if the enzyme 
elevation is confirmed or worsening.  
Should it be determined that the etiology is an unrelated acute or chronic medical condition 
(e.g.; NASH, Hepatitis A) and the return of LFT abnormalities to normal is unlikely during 
the course of the illness, further testing and follow up is at the investigator’s discretion. 
Hepatotoxicity will be diagnosed and entered as an AE should any of the following occur: 
• 
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%) 
 
In the event of hepatotoxicity, investigational product should be permanently discontinued. 
The investigator is encouraged to consult with the Medical Monitor regarding diagnostic 
evaluation for the hepatic enzyme elevations. Consultation with a hepatologist may also be 
appropriate in some circumstances. 
6.12.8.4 
Hypoglycemia  
Events of hypoglycemia or potentially representing hypoglycemia should be carefully 
evaluated. In the event of signs or symptoms, a diabetic subject is expected to check the 
blood glucose if it is reasonably safe to do so, and, if appropriate, consume carbohydrates to 
treat hypoglycemia.  
Subjects who have type 2 diabetes mellitus will be expected to record the following 
information for each hypoglycemic event in the glycemic control diary: 
• 
Signs and symptoms attributed to hypoglycemia and the time and date on which they 
occurred  
• 
SMBG reading at the time of the signs and symptoms attributed to hypoglycemia 
• 
Time elapsed from the most recent meal to the onset of signs and symptoms 
• 
Duration, intensity, and type of any exercise within the 24 h prior to the signs and 
symptoms 
• 
Type of treatment used (e.g., juice, crackers) for the signs and symptoms and whether 
assistance was required from another person to administer the treatment 


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• 
SMBG reading 15 minutes after treatment with carbohydrate and the time at which this 
was measured 
• 
Whether or not the signs and symptoms attributed to hypoglycemia resolved after blood 
glucose returned to normal 
 
Subjects are encouraged to call the study clinic should signs and symptoms potentially 
related to hypoglycemia occur. 
At each study visit, the investigator should query the subject with regard to the occurrence of 
signs and symptoms potentially related to hypoglycemia.  
In the event of a blood glucose value < 70 mg/dL or signs and symptoms potentially related 
to hypoglycemia, the investigator should complete the supplemental CRF w.  
Hypoglycemia events will be recorded in the hypoglycemia log under 5 categories: 
1. Severe hypoglycemia: an event requiring assistance by another person to actively 
administer carbohydrate, 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 should be recorded as SAEs in the CRF 
2. 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) 
3. Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of 
hypoglycemia but with a measured blood glucose concentration < 70 mg/dL 
(3.9 mmol/L) 
4. Probable symptomatic hypoglycemia: an event during which symptoms of hypoglycemia 
are not accompanied by a blood glucose determination but that is presumably caused by a 
blood glucose concentration < 70 mg/dL (3.9 mmol/L) 
5. Relative hypoglycemia: An event during which the person with diabetes reports any of 
the typical symptoms of hypoglycemia, and interprets those as indicative of 
hypoglycemia, but with a measured plasma glucose concentration ≥ 70 mg/dL 
(3.9 mmol/L). 
 
While each event meeting the criteria above will be entered into the hypoglycemia log, only 
severe hypoglycemia, documented symptomatic hypoglycemia, and asymptomatic 
hypoglycemia, will be entered as AEs.  
The investigator should be alerted to the likelihood of improper glucose measurement 
technique if a study subject reports an SMBG value < 55 mg/dL that is not associated with 
any signs or symptoms of hypoglycemia and is not treated by some form of glucose 
administration.  


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In the event of probable symptomatic hypoglycemia, the investigator should encourage the 
subject to obtain glucose values, when possible, in the context of signs and symptoms of 
hypoglycemia, even if the glucose value is measured after treatment for the symptoms is 
administered. 
If hypoglycemia occurs, the total daily dose of the hypoglycemic medication should be 
reduced 50% or more at the discretion of the investigator. 
6.12.8.5 
Diabetic Ketoacidosis (DKA)  
DKA is a serious, acute complication of diabetes and can be life-threatening. Subjects with 
diabetes will be educated on the signs and symptoms of DKA and will be required to call the 
study clinic and seek treatment should such signs and symptoms occur.  
During the clinical trial period, potential DKA in diabetic subjects will be monitored by the 
routine measurement of urinary ketones and assessment for signs or symptoms of acidosis at 
every clinic visit. Clinical presentations, such as difficulty breathing, abdominal pain, nausea, 
vomiting, lethargy, a fruity smell in the breath, or laboratory values that suggest clinically-
significant acidosis should be documented. Treatment of DKA should be provided when 
appropriate.  
If ongoing symptoms or signs suggest a possible DKA, the investigator should perform 
relevant laboratory testing while directing appropriate medical care for the subject. If DKA is 
suspected, regardless of the blood glucose level, the following assessments should be done 
immediately: physical exam and serum glucose, bicarbonate, electrolytes, and serum ketones. 
Laboratory values should be measured STAT at a local laboratory. If ketoacidosis is likely, 
investigational product administration should be discontinued and immediate appropriate 
medical therapy, including insulin, should be initiated. A glucose infusion may be provided if 
necessary to avoid hypoglycemia during insulin therapy. Insulin treatment should continue 
until resolution of the ketoacidosis and stabilization of the subject’s clinical condition. 
Investigational product administration may be resumed following stabilization of the 
subject’s condition.  The investigator should collect the data necessary for the completion of 
the DKA CRF.  
If symptoms suggestive of DKA may have occurred but are not ongoing, investigator should 
review available data in order to complete the DKA CRF. The investigator may also perform 
laboratory assessment using local resources if necessary for clinical care.  
6.12.8.6 
Acute Kidney Injury 
Evaluation and management of subjects with and at risk for acute kidney injury (AKI) should 
be performed during the study period based on the Kidney Disease: Improving Global 
Outcomes (KDIGO) Clinical Practice Guideline in 2012 (KDIGO Clinical Practice Guideline 
for AKI, 2012).  The classification/staging System for AKI is described in Appendix 5. 
If serum creatinine increases suggesting a possible stage 1 AKI, the investigator should 
confirm the increase in serum creatinine within one week of learning the result and enter an 


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AE into the CRF if the serum creatinine does not spontaneously returns to < 0.3 mg/dL from 
baseline. The investigator should encourage the subjects to maintain hydration and pursue 
any additional clinically relevant investigations to elucidate the cause or potential 
consequences of the decline in renal function. Study drug administration may be suspended if 
clinically indicated until the creatinine value returns to < 0.3 mg/dL from baseline. Serum 
creatinine should be monitored based on the investigator’s judgment until creatinine returns 
to baseline level, within 0.3 mg/dL difference.  
If serum creatinine increases or other signs suggesting a possible stage 2 or 3 AKI, the 
subject should be monitored daily and nephrology consultation or hospitalization within 24 h 
should be considered.  Study drug administration should be stopped until the creatinine value 
returns to < 0.3 mg/dL from baseline. If potentially life-threatening conditions (i.e., uremia, 
pulmonary edema, arrhythmia, disseminated intravascular coagulation, hyperkalemia, 
metabolic acidosis) are present occurring in the setting of a possible stage 2 or 3 AKI event, 
the administration of study drug must be stopped and the medical monitor should be 
informed. The medical monitor will advise on whether the study drug can be restarted after 
the resolution of the potentially life-threatening condition. Local laboratory testing will be 
acceptable when immediate lab results are necessary for clinical assessment. 
If interrupted, study drug may be reinitiated when serum creatinine returns to within 
0.3 mg/dL of the randomization value or if renal function remains 0.5 mg/dL above the 
randomization value but an alternative cause of the worsened renal function has been 
identified. Dosing of study drug will be permanently discontinued if the subject is to start 
dialysis or other renal replacement therapies. 
The renal function monitoring plan is summarized in Figure 3. 
 
 
Figure 3. 
Renal Function Monitoring Plan 
 


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6.12.9 
Major Adverse Cardiovascular Event (MACE)  
Evaluation of MACE will be undertaken across the development program for bexagliflozin. 
All MACE reports should also be captured as SAEs and every effort will be made to ensure 
that events recorded as MACE are coded in a similar manner within the safety database. The 
SAE listing will also be reviewed periodically by the CEC members to identify potential 
MACE that may not have been reported by the site investigators. All subjects will be 
followed by investigators for MACE for the duration of the study even if study medication 
has been permanently withdrawn. 
The independent CEC will receive and adjudicate the following events.  
x 
All deaths 
x 
Suspected non-fatal MI 
x 
Suspected hospitalization for unstable angina (HUA) 
x 
Suspected TIA and stroke  
x 
Suspected hospitalization for heart failure (HF) 
x 
Reported coronary revascularization procedure 
6.13 Concomitant Medication Assessments 
A concomitant medication is any medication that the subject has been taking prior to 
enrollment and that the subject is expected to continue to take for some portion of the trial, as 
well as any medication other than the investigational product that the subject takes during the 
course of the trial. Changes in dose and/or frequency from therapies taken prior to 
randomization and their rationale must be recorded in the CRF. 
The medications or treatment for controlling hypertension must be recorded as concomitant 
medications in the CRF. Any medication given to treat hypertension and continued for more 
than 2 weeks is considered a rescue therapy and should be recorded in the rescue medication 
form and concomitant medication log.  
All prescription and over-the-counter medications, including vitamins and herbal 
supplements, that subjects receive during the trial must be documented on the CRF. This 
documentation should continue until the subjects complete the study.  
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). A table of concomitant medications based on the anatomic 
therapeutic chemical classification (ATC) and preferred name will be produced. A listing of 
concomitant medications will include all medications taken by any subjects during the course 
of the study. 
6.14 Removal of Patients from the Trial or Study Drug 
The investigator must emphasize to potential subjects the importance of continued 
participation for the full duration of the trial during the informed consent process. Potential 
subjects should be informed that the trial procedures will allow additional medications to 


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control hypertension or other adverse conditions. It is also important to emphasize that 
missing data and missed visits could affect the entire trial. If subjects are dissatisfied with the 
conduct of the trial but have not withdrawn, the investigators should make an effort to 
address their concerns and retain them in the trial if possible. In doing so, investigators must 
be careful that the efforts do not cross over into coercion.  
Participation in a clinical trial is voluntary.  A subject can withdraw from the study at any 
time.  The sponsor may terminate the study for medical or administrative reasons. An 
investigator may decline to participate in the conduct of the study if either the investigator or 
the IRB/EC determines that, based on good medical judgment, immediate cessation is 
appropriate for subject safety. If a decision is made to withdraw a subject from the study, no 
further investigational product should be administered.  Reasons for all withdrawals should 
be recorded on the CRF.  Examples of reasons for withdrawal include:   
1. A protocol violation has occurred, 
2. A serious or intolerable AE has occurred, 
3. A clinically significant change in a laboratory parameter has occurred,  
4. The sponsor terminates the study, or 
5. The patient requests to be withdrawn from the study. 
 
Subjects who do not complete the study but who have received investigational product 
should complete the exit visit procedures including a physical examination, vital signs, ECG 
and clinical laboratory tests according to Section 7. 
Subjects who withdraw from the study will not be replaced. 
6.15 Appropriateness of Measurements 
The study procedures and measurements in this protocol are widely used and generally 
recognized as reliable, accurate, and relevant for subjects with essential hypertension. 


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7 
STUDY ACTIVITIES 
The activities at each clinic visit listed below are presented in Appendix 1. The required 
laboratory tests scheduled at each visit are listed in Appendix 2. Detailed procedures are 
described in Section 6.  
A visit window of ± 3 days is allowed for post-randomization visits. Visit 3 is the day of 
randomization and the basis for the visit window.  A repeat ABPM shall be performed within 
2 days if the 24h-ABPM is incomplete.  Only the second set of ABPM data will be entered in 
the case report form on visits 2-3, 5-6, 8-9, and 10-11. The other specified procedures in the 
same assessment period do not need to be repeated.  If the ABPM fails twice at visit 3 prior 
to randomization, the subject is considered a screen failed subject.  If the ABPM fails twice 
after randomization, the ABPM BP on that assessment period is considered missing. 
Procedures listed for visit 10 will be completed if a subject is withdrawn from the study. 
7.1 
Visit 1 (Day -13 to day -12) 
• 
Explain the content of the informed consent materials to the subject and collect signed 
informed consent 
• 
Collect needed information and evaluate conformance to inclusion and exclusion criteria 
• 
Obtain Medical History and Demographic Information 
• 
Perform an abbreviated physical examination 
• 
Measure vital signs, including BPs and heart rate 
• 
Perform a 12-lead ECG measurement 
• 
Draw blood and collect a urine sample for clinical laboratory tests. The specific 
laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Dispense kits for the run-in period 
 
7.2 
Visit 2 (Day -1) 
• 
Collect needed information and evaluate conformance to inclusion and exclusion criteria 
• 
Perform a complete physical examination 
• 
Measure vital signs, including BPs and heart rate 
• 
Perform a 12-lead ECG measurement 
• 
Draw blood and collect a urine sample for clinical laboratory tests. The specific 
laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Begin 24 hour ABPM  
• 
Assess AEs 
• 
Record concomitant medications 
 
7.3 
Visit 3 (Day 1)- Study 603A 
• 
Collect needed information and evaluate conformance to inclusion and exclusion criteria 
• 
Measure vital signs, including BPs and heart rate 


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• 
End 24-h ABPM and download readings. The 24-h ABPM should be repeated within 2 
days if <64 BP readings (51 day time and 13 night time BP readings) are recorded 
successfully. 
• 
Complete subject randomization using IWRS 
• 
Dispense investigational product based on randomization 
 
7.4 
Visit 4 (Cumulative Week 6) 
• 
Measure vital signs, including BPs and heart rate 
• 
Assess AEs 
• 
Record concomitant medications 
 
7.5 
Visit 5 (Cumulative Week 12) 
• 
Perform an abbreviated physical examination 
• 
Measure vital signs, including BPs and heart rate 
• 
Perform a 12-lead ECG measurement 
• 
Draw blood and collect a urine sample for clinical laboratory tests. The specific 
laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Begin 24 hour ABPM  
• 
Assess AEs 
• 
Record concomitant medications 
 
7.6 
Visit 6 (Cumulative Week 12 + 1 Day) – Study 603B 
• 
Measure vital signs, including BPs and heart rate 
• 
End 24-h ABPM and download readings. The 24-h ABPM should be repeated within 2 
days if <64 BP readings (51 day time and 13 night time BP readings) are recorded 
successfully. 
• 
Dispense investigational product based on randomization 
 
7.7 
Visit 7 (Cumulative Week 18) 
• 
Measure vital signs, including BPs and heart rate 
• 
Collect blood specimens for sparse PK sampling from selected subjects in participating 
centers. Alternatively, blood sample can be on any of the days during the week of the 
clinical visit 
• 
Assess AEs 
• 
Record concomitant medications 
 
7.8 
Visit 8 (Cumulative Week 24) 
• 
Perform an abbreviated physical examination 
• 
Measure vital signs, including BPs and heart rate 
• 
Perform a 12-lead ECG measurement 


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• 
Draw blood and collect a urine sample for clinical laboratory tests. The specific 
laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Collect blood specimens for sparse PK sampling from selected subjects in participating 
centers. Alternatively, blood sample can be on any of the days during the week of the 
clinical visit 
• 
Begin 24 hour ABPM  
• 
Assess AEs 
• 
Record concomitant medications 
 
7.9 
Visit 9 (Cumulative Week 24 + 1 Day) 
• 
Measure vital signs, including BPs and heart rate 
• 
End 24-h ABPM and download readings. The 24-h ABPM should be repeated within 2 
days if <64 BP readings (51 day time and 13 night time BP readings) are recorded 
successfully. 
• 
Complete subject randomization using IWRS 
• 
Dispense investigational product based on randomization 
 
7.10 Visit 10 (Cumulative Week 36) 
• 
Perform an abbreviated physical examination 
• 
Measure vital signs, including BPs and heart rate 
• 
Perform a 12-lead ECG measurement 
• 
Draw blood and collect a urine sample for clinical laboratory tests. The specific 
laboratory tests scheduled for this visit are listed in Appendix 2 
• 
Begin 24 hour ABPM  
• 
Assess AEs 
• 
Record concomitant medications 
 
7.11 Visit 11 (Cumulative Week 36 + 1 Day) 
• 
Measure vital signs, including BPs and heart rate 
• 
End 24-h ABPM and download readings. The 24-h ABPM should be repeated within 2 
days if <64 BP readings (51 day time and 13 night time BP readings) are recorded 
successfully 
• 
Assess AEs 
• 
Record concomitant medications 
 
 


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8 
QUALITY CONTROL AND ASSURANCE 
The clinical research facility will be monitored by the study monitor to ensure correct 
performance of the study procedures and to ensure that the study is conducted according to 
the protocol and relevant regulatory requirements. CRF entries will be verified with the 
source documentation. 
Quality control principles will be applied throughout the performance of this study by 
following the Standard Operating Procedures (SOPs) of the contract research organization 
(CRO) and the sponsor. Review procedures will be implemented at the CRO for all 
documents that are generated in relation to the study. 
The laboratory testing will be performed by a CLIA certified central laboratory to ensure the 
laboratory values are determined consistently. 
 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The following sections provide a summary of the planned analysis of the trial data but a 
complete statistical analysis plan will be developed with further details before any unblinding 
occurs.   
 
In general, descriptive summary statistics for continuous variables will include the number of 
subjects [N], mean, median, standard deviation [SD], quartiles, and minimum and maximum.  
Descriptive statistics in categorical variables will include number and percentage of subjects 
in each category.  Summary statistics will be presented by treatment groups.  Statistical 
analysis will be carried out using SAS version 9.2 or later. 
 
Unless otherwise specified, all tests will be two-sided at a 0.05 level of significance.  All 
confidence intervals (CIs) will be two-sided 95% confidence intervals.   
9.2 
Determination of Sample Size 
The primary endpoint of study 603A is the change from baseline (Day 1) to week 12 in the 
24-hour average SBP of the bexagliflozin group compared to the placebo group using a 
superiority testing at an overall two-sided 0.05 level of significance.   
The primary endpoint of study 603B is the change from week 12 (cumulative week 24) to 
week 24 (cumulative week 36) in the 24-hour average SBP in the bexagliflozin group 
compared to the placebo group using a superiority testing at an overall two-sided 0.05 level 
of significance. 
The assumptions to estimate the sample size for the primary endpoint of study 603A are: 
1. The magnitude of the decrease from baseline (Day 1) to week 12 of the 24 h mean SBP in 
the bexagliflozin treatment arm will exceed that found in the placebo arm by 5 mm Hg; 
2. The standard deviation of the change from baseline to week 12 will be 15 mm Hg for 
both the active and placebo groups; 
3. The two-sided significance level is 0.05. 
 
The assumptions to estimate the sample size required for the primary endpoint of study 603B 
are: 
1. Bexagliflozin will remain effective for at least 24 weeks.  The 24-hour average ABPM 
SBP will not change between week 12 and week 24 (cumulative week 24 and week 36). 
2. Subjects who are randomized to receive placebo will show an increase in the ABPM SBP 
of 4 mm Hg between week 12 and week 24 (cumulative week 24 and week 36). 
3. The standard deviation of the change is 15 mm Hg for both the active and placebo 
groups. 
4. The two-sided significance level is 0.05. 


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A sample size of 254 per arm is required for the measurement to have 85% power to attain 
significance for the second primary endpoint. It is estimated that 75% of subjects will have 
completed the 36 weeks of study treatment since the first randomization. Thus a total sample 
size of 680 subjects is planned for the first randomization. It is estimated that approximately 
8% will drop out for the first 12 weeks. With a sample size of 626 subjects at the end of 
study 603A, it will provide >95% power for the first primary endpoint. 
An interim non-binding futility analysis when approximately half (i.e., 300) patients 
completed the first 12 weeks of the treatment will be conducted. Using interpolated spending 
function of Type II error, i.e., with 0.5 proportion of Type II error being spent at the interim 
look, the study may stop for futility when the test statistics (Z score) is less than 0.656 (or p-
value>0.512).  The overall power for the first primary endpoint maintains >95% with this 
interim look. 
9.3 
Analysis Populations  
The following populations will be used for analyses: 
9.3.1 
Study 603A 
• 
Intention-to-Treat (ITT) Analysis Set: Include all subjects who are randomized to the 
study. All subjects will be analyzed according to the treatment to which they were 
randomized to receive. 
• 
Safety Analysis Set: Include all subjects who are randomized to the study and are treated. 
This data set will be used for both study 603A alone summaries and combined study 
603A and 603B summaries. 
  
9.3.2 
Study 603B 
• 
Intention-to-Treat (ITT) Analysis Set: Include all subjects who are randomized at week 
12 (cumulative week 24).  All subjects will be analyzed according to the treatment to 
which they were randomized to receive. 
• 
Safety Analysis Set: Include all subjects who are treated. 
• 
Safety Analysis Set for withdrawal period: Include all subjects who are randomized at 
week 12 and are treated with at least one dose. 
 
9.4 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be descriptively summarized for all ITT 
subjects by treatment group for study 603A and study 603B.  Key variables include, but are 
not limited to: age, gender, race, ethnicity, baseline vital signs, ECG measures, and renal 
function.  In general, baseline measurement is defined as the last measurement prior to the 
randomization for each study. 


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9.5 
Primary Efficacy Endpoints 
The primary endpoint of study 603A is the change from baseline (Day 1) to week 12 of the 
24 h mean SBP in the bexagliflozin group compared to the change in the placebo group, 
testing for superiority at a two-sided 0.05 level of significance.  
The primary endpoint of study 603B is the change from week 12 to week 24 (cumulative 
week 24 to week 36) of the 24 h mean SBP in the bexagliflozin group compared to the 
change in the placebo group, testing for superiority at a two-sided 0.05 level of significance.  
For the primary efficacy assessment in study 603A, an analysis of covariance (ANCOVA) 
will be applied to analyze the mean change from baseline to week 12 of the 24-hour average 
ABPM SBP, adjusted for diabetes status, renal function, medicated or unmedicated status, 
and baseline ABPM SBP value. Least squares means with 95% confidence intervals (CIs) 
will be generated for the difference between the treatment groups at week 12. If a subject 
receives rescue medication or is withdrawn from the study early, the last post baseline 
observed value will be used for the primary analysis time point of week 12. 
For the primary efficacy assessment in study 603B, a similar ANCOVA method will be 
applied, adjusted by the ABPM SBP evaluations at week 12 (cumulative week 24). Changes 
from week 12 to week 24 ABPM SBP will be analyzed. Least squares means with 95% CIs 
will be generated for the difference between the treatment groups at week 24. 
Additional sensitivity analyses will be conducted as follows for missing data due to early 
withdrawal of the study or receiving rescue medications.  
• 
Cumulative week 12 and week 36 evaluations after rescue medication will be used in the 
analyses in place of evaluations prior to the rescue medication 
• 
Analyses will be based on subjects without rescue medication 
• 
Tipping Point analysis will be conducted as follows:   
o Subjects in the bexagliflozin treatment arm who discontinue study participation or 
initiate rescue medication, will be analyzed assuming that their treatment effect has 
worsened by G (where G = 0.5 to 5, with steps of 0.5) compared to the reduction of 
SBP for subjects who are in the study without rescue medication. 
o Subjects in the placebo treatment arm who discontinue study participation or initiate 
rescue medication, will be considered to have experienced a treatment effect the same 
as the reduction of SBP for subjects who are in the study without rescue medication. 
 
9.6 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be accessed without multiplicity adjustment. Analyses will 
be primarily based on ITT analysis sets. 
Absolute values and changes from baseline (Day 1 for study 603A or Week 12 value for 
study 603B) in vital signs measurements, pulse pressure, body weight, peak-trough ratio of 
ABPM SBP, and HbA1c will be summarized descriptively. Mean treatment effects will be 
estimated based on ANCOVA using similar method as described for the primary endpoint.  


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The responder assessments, such as the proportion of subjects who achieve specific goals, 
will be summarized by frequency table; logistic regression will be used to analyze the 
treatment effect with 95% CIs for the fraction responding within each treatment group and 
between treatment groups. Analyses will be based on all observed assessments prior to rescue 
medication or study end.  In addition, a sensitivity analysis by assuming non-responder for 
subjects who had no post baseline assessments prior to early withdrawal of the study or 
initiation of the rescue medication, will also be performed. 
In addition, changes in mean ambulatory SBP/DBP or office seated SBP/DBP after 12, 24, or 
36 weeks of bexagliflozin treatment will also be summarized using combined 603A and 
603B evaluations.  
Detailed analyses will be defined in the statistical analysis plan. 
9.7 
Analysis of Safety 
Safety data include AEs, physical exam results, vital signs, ECG results, and clinical lab 
results including serum chemistry, hematology parameters and urinalysis. Observed data will 
be summarized by treatment group within each study (603A, 603B) or pooled studies using 
the safety analysis sets as defined in sections 9.3.1 and 9.3.2. 
9.7.1 
Adverse Events 
AEs will be mapped to preferred term and body system using the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. AEs that begin at or after the first 
administration of double-blind study medication (i.e., first dose of study 603A) or existing 
AEs that worsen in severity after the first dose of double-blind study medication are 
considered treatment emergent AEs (TEAE). Treatment emergent periods will be divided 
into three periods: study 603A, study 603B prior to randomization, and study 603B after 
randomization. The number and percentage of subjects reporting TEAEs will be summarized 
for each treatment group by MedDRA system organ class and preferred term, for each period 
as well as all periods combined. Further summaries by severity and by relationship to study 
treatment will also be provided. Drug-related AE will be considered those to be at least 
possibly related to the study treatments based on the investigators assessment.  
Similarly, the number and percentage of subjects reporting serious AEs, and the number and 
percentage of subjects reporting AEs leading to treatment discontinuation will also be 
summarized for each treatment group by MedDRA system organ class and preferred term. 
In addition, adverse events of special interest include, but not limited to UTI, GMI, 
hypoglycemia, hepatotoxicity, MACE, and DKA events, will be separately summarized. 
9.7.2 
Laboratory Evaluations and Other Safety Assessments 
Clinical laboratory tests (see Section 6 for a complete list), vital signs, and 12-lead ECG 
assessments will be descriptively summarized for actual values and changes from baseline 
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Laboratory data will be classified as low, normal or high relative to the parameter’s reference 
range. Laboratory abnormalities for each treatment will also be summarized by study with 
shift tables for selected parameters.  
In addition, summaries based on assessments from both studies (603A and 603B) will also be 
presented.  The changes from the last assessment prior to first dose of bexagliflozin to after 
bexagliflozin treatment of 12 weeks, 24 weeks, and 36 weeks will be provided. 
9.7.3 
Physical Examination 
Physical examination findings will be presented in a by subject listing. 
9.8 
Interim Analysis 
An interim non-binding futility analysis when approximately half patients completed the first 
12 weeks of study 603A will be conducted. Using interpolated spending function of Type II 
error, i.e., with 0.5 proportion of Type II error being spent at the interim look, the study may 
stop for futility when the test statistics (Z score) is less than 0.656 (or p-value>0.512).  The 
overall power for the first primary endpoint maintains > 95% with this interim look.  The 
interim analysis will be conducted by an independent data monitoring group.  


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10 ADMINISTRATIVE CONSIDERATIONS 
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. 
10.1 Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
The study protocol, informed consent document, relevant supporting information, and all 
types of subject recruitment or advertisement information must be submitted to the 
independent review board (IRB) or independent ethics committee (IEC) for review and must 
be approved by the sponsor and the IRB/IEC before the study is initiated. Any amendments 
or addenda to the protocol must also be approved by the IRB/IEC prior to implementing 
changes in the study. The investigator is responsible for keeping the IRB/IEC informed of the 
progress of the study and of any changes made to the protocol as deemed appropriate, but in 
any case at least once a year. The investigator must also keep the IRB/IEC informed of any 
SAEs occurring to subjects under their supervision. 
10.1 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 
ICH GCP guidelines (E6) 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 other authorized 
regulatory authorities representatives may occur at any time. The investigator must agree to 
the inspection of study-related records by the regulatory authority/sponsor representatives, 
and must allow direct access to source documents to the regulatory authority/sponsor 
representatives. 
The investigator is responsible for complying with the protocol and all appropriate 
regulations and guidelines governing global clinical research. Additionally, he/she is 
responsible for ensuring that all participating staff members are adequately trained and 
competent to perform his/her assigned tasks. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator may implement a 
deviation from or a change of the protocol to eliminate any immediate hazards to the trial 
subjects without prior IRB/IEC or sponsor approval/favorable opinion. As soon as possible, 
the implemented deviation or change, the reasons for it, and if appropriate, the proposed 
protocol amendment should be submitted to the IRB/IEC and sponsor. 
Any deviations from the protocol must be fully explained and documented by the 
investigator. The circumstances, action taken, and impact of the deviation on the trial must be 


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communicated by the principal investigator to the designated medical monitor. Any 
subsequent actions will be assessed by the designated medical monitor and documented. 
10.2 Subject Information and Consent 
Prior to the beginning of the study, the investigator must have received from the IEC or IRB 
the written approval or favorable opinion of the informed-consent form and any other written 
information to be provided to subjects. The written approval of the IRB/IEC together with 
the approved subject information/informed consent forms must be filed. The informed 
consent form must contain all elements required by authorized regulatory authorities and the 
ICH GCP guidelines (E6), in addition to any other elements required by local regulations or 
institutional policy. 
Written informed consent must be obtained before any study-specific procedure takes place. 
Participation in the study and date of informed consent given by the subject should be 
documented appropriately in the subject’s files. A copy of the signed informed consent form 
must be provided to the subject. If applicable, it will be provided in a certified translation in 
the language understood by the subject, if not English. Signed consent forms must remain in 
each subject’s study file and must be available for verification by study monitors at any time. 
10.3 Subject Confidentiality 
The information obtained during the conduct of this clinical study is confidential, and 
disclosure to third parties other than those noted below is prohibited. Information obtained 
during the conduct of this study will be used by the sponsor in connection with the 
development of the investigational product. The study investigator is obliged to provide the 
sponsor with complete test results and all data developed in this study. Subject-specific 
information may be provided to other appropriate medical personnel only with the subject’s 
permission. To ensure compliance with current ICH guidelines, data generated by this study 
must be available for inspection upon request by representatives of national and local health 
authorities, the sponsor, and the IRB/IEC for each study site. Study information from this 
protocol will be posted on clinicaltrials.gov and any local regulatory registry websites, as 
required by regulation. 
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. 
10.4 Study Monitoring 
An authorized sponsor representative will conduct site visits to inspect study data, subjects’ 
medical records, and CRFs in accordance with ICH guidelines, GCP, and the respective 
national and local government regulations and guidelines. 
The investigator will permit authorized representatives of the sponsor and the respective 
national or local health authorities, other authorized regulatory authorities, and IRB/IEC to 
inspect facilities and records relevant to this study. 


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10.5 Case Report Forms and Study Records 
For each subject consented, a CRF, in paper or electronic format, will be supplied and 
maintained by the CRO staff and signed by the investigator or authorized designee to indicate 
that he/she has reviewed and agrees with the entered data. This also applies to those subjects 
who fail to complete the trial. The reason a subject is withdrawn must be recorded in the 
CRF. 
Entries made in the CRF must be verifiable against source documents. Source documents are 
defined as all medical records, medical notes, laboratory results, ECG traces, and any 
additional document other than the CRF that has original subject information contained 
within it. 
All CRFs and source documents should be completed following GCP and the sponsor or its 
designee’s SOPs. 
10.6 Data Monitoring Committee 
An independent DMC will monitor overall safety information during the bexagliflozin 
development program. The safety review activity and potential risk benefit assessments 
utilized by the DMC will be defined in its charter. 
10.7 Protocol Violations/Deviations 
Protocol violations include deviations from the inclusion and exclusion criteria, concomitant 
medication restrictions, and any other protocol requirement that results in a significant added 
risk to the patient or has an impact on the quality of the data collected or the outcome of the 
study. A deviation occurs when there is non-adherence to study procedures or schedules, as 
specified by the protocol, which does not involve inclusion/exclusion criteria or the primary 
endpoint and which does not place the patient at any added risk or affect the data quality or 
study outcome. Examples of deviations may include common out-of-window visits, a missed 
procedure, etc. Protocol violations will reported in the final clinical study report, whereas 
protocol deviations may be mentioned but are not required to be reported. 
It is important to conduct the study according to the protocol. Protocol deviation waivers will 
not be prospectively granted by the sponsor. If minor protocol deviations occur, the 
investigator must decide the most appropriate way to proceed with study activities and 
should consult the study representative for assistance. If major protocol deviations occur, the 
sponsor’s Medical Monitor must be notified immediately 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 can there be a departure without the sponsor’s pre-approval. The nature and reasons 
for the protocol deviation/violations will be recorded in the subject’s CRF, and the principal 
investigator must notify the sponsor. 
Protocol deviations/violations must be reported in the final study report. 


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10.8 Access to Source Documentation 
Authorized sponsor representatives will conduct site visits to inspect study data, subjects’ 
medical records, and CRFs in accordance with ICH guidelines, GCPs, and the respective 
local and national government regulations and guidelines. 
The investigator will permit authorized representatives of the sponsor and the respective 
national or local health authorities, other authorized regulatory authorities, and IRB/IEC to 
inspect facilities and records relevant to this study. 
Each 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. 
10.9 Retention of Data 
The study file and all source data should be retained until notification is given by the sponsor 
for destruction. 
If the investigator withdraws from the trial and relinquishes his/her responsibility for the 
maintenance and retention of records, he/she must notify the sponsor in writing so that 
arrangements can be made to properly store the trial materials. 
10.10 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 
Baker, W.L., Smyth, L.R., Riche, D.M., Bourret, E.M., Chamberlin, K.W., and White, W.B. 
(2014). Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic 
review and meta-analysis. Journal of the American Society of Hypertension : JASH 8, 262-
275 e269. 
Calado, J., Loeffler, J., Sakallioglu, O., Gok, F., Lhotta, K., Barata, J., and Rueff, J. (2006). 
Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting. Kidney 
international 69, 852-855. 
Calado, J., Soto, K., Clemente, C., Correia, P., and Rueff, J. (2004). Novel compound 
heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria. 
Human genetics 114, 314-316. 
Calado, J., Sznajer, Y., Metzger, D., Rita, A., Hogan, M.C., Kattamis, A., Scharf, M., Tasic, 
V., Greil, J., Brinkert, F., et al. (2008). Twenty-one additional cases of familial renal 
glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and 
further evidence of volume depletion. Nephrol Dial Transplant. 
Egan, B.M., Zhao, Y., and Axon, R.N. (2010). US trends in prevalence, awareness, 
treatment, and control of hypertension, 1988-2008. JAMA : the journal of the American 
Medical Association 303, 2043-2050. 
Francis, J., Zhang, J., Farhi, A., Carey, H., and Geller, D.S. (2004). A novel SGLT2 mutation 
in a patient with autosomal recessive renal glucosuria. Nephrol Dial Transplant 19, 2893-
2895. 
Hummel, C.S., Lu, C., Liu, J., Ghezzi, C., Hirayama, B.A., Loo, D.D., Kepe, V., Barrio, J.R., 
and Wright, E.M. (2012). Structural selectivity of human SGLT inhibitors. American journal 
of physiology Cell physiology 302, C373-382. 
James, P.A., Oparil, S., Carter, B.L., Cushman, W.C., Dennison-Himmelfarb, C., Handler, J., 
Lackland, D.T., LeFevre, M.L., MacKenzie, T.D., Ogedegbe, O., et al. (2014). 2014 
evidence-based guideline for the management of high blood pressure in adults: report from 
the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA : the 
journal of the American Medical Association 311, 507-520. 
Kanai, Y., Lee, W.S., You, G., Brown, D., and Hediger, M.A. (1994). The human kidney low 
affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive 
mechanism for D-glucose. The Journal of clinical investigation 93, 397-404. 
Kleta, R., Stuart, C., Gill, F.A., and Gahl, W.A. (2004). Renal glucosuria due to SGLT2 
mutations. Molecular genetics and metabolism 82, 56-58. 


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Lewington, S., Clarke, R., Qizilbash, N., Peto, R., Collins, R., and Prospective Studies, C. 
(2002). Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis 
of individual data for one million adults in 61 prospective studies. Lancet 360, 1903-1913. 
Lovshin, J.A., and Gilbert, R.E. (2015). Are SGLT2 inhibitors reasonable antihypertensive 
drugs and renoprotective? Current hypertension reports 17, 551. 
Mancia, G., Cannon, C.P., Tikkanen, I., Zeller, C., Ley, L., Woerle, H.J., Broedl, U.C., and 
Johansen, O.E. (2016). Impact of Empagliflozin on Blood Pressure in Patients With Type 2 
Diabetes Mellitus and Hypertension by Background Antihypertensive Medication. 
Hypertension 68, 1355-1364. 
Oliva, R.V., and Bakris, G.L. (2014). Blood pressure effects of sodium-glucose co-transport 
2 (SGLT2) inhibitors. Journal of the American Society of Hypertension : JASH 8, 330-339. 
Reed, J.W. (2016). Impact of sodium-glucose cotransporter 2 inhibitors on blood pressure. 
Vascular health and risk management 12, 393-405. 
Santer, R., Kinner, M., Lassen, C.L., Schneppenheim, R., Eggert, P., Bald, M., Brodehl, J., 
Daschner, M., Ehrich, J.H., Kemper, M., et al. (2003). Molecular analysis of the SGLT2 gene 
in patients with renal glucosuria. J Am Soc Nephrol 14, 2873-2882. 
Scheen, A.J. (2016). Effects of reducing blood pressure on cardiovascular outcomes and 
mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG 
OUTCOME. Diabetes research and clinical practice 121, 204-214. 
Tikkanen, I., Narko, K., Zeller, C., Green, A., Salsali, A., Broedl, U.C., Woerle, H.J., and 
Investigators, E.-R.B. (2015). Empagliflozin reduces blood pressure in patients with type 2 
diabetes and hypertension. Diabetes Care 38, 420-428. 
van den Heuvel, L.P., Assink, K., Willemsen, M., and Monnens, L. (2002). Autosomal 
recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter 
(SGLT2). Human genetics 111, 544-547. 
Vivian, E. (2015). Sodium-Glucose Cotransporter 2 Inhibitors in the Treatment of Type 2 
Diabetes Mellitus. The Diabetes educator. 
Weber, M.A., Mansfield, T.A., Alessi, F., Iqbal, N., Parikh, S., and Ptaszynska, A. (2016). 
Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-
angiotensin system blockade. Blood pressure 25, 93-103. 
Weir, M.R., Januszewicz, A., Gilbert, R.E., Vijapurkar, U., Kline, I., Fung, A., and 
Meininger, G. (2014). Effect of canagliflozin on blood pressure and adverse events related to 
osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J 
Clin Hypertens (Greenwich) 16, 875-882. 


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Whalen, K., Miller, S., and Onge, E.S. (2015). The Role of Sodium-Glucose Co-Transporter 
2 Inhibitors in the Treatment of Type 2 Diabetes. Clinical therapeutics 37, 1150-1166. 
Zinman, B., Wanner, C., Lachin, J.M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., 
Devins, T., Johansen, O.E., Woerle, H.J., et al. (2015). Empagliflozin, Cardiovascular 
Outcomes, and Mortality in Type 2 Diabetes. The New England journal of medicine 373, 
2117-2128. 
 


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Appendix 1 
Schedule of Events 
 
Screening/ 
Run-in 
Study 603A 
Study 603B 
Procedures 
 
weeks 1 to 12 
weeks 1 to 12 
weeks 13 to 24 
Cumulative study week 
 
1 -12 
13-24 
25-36 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Time to randomization 
-13 or 
-12 d 
-1d 
0w 
+1d 
6w 
12w 12w 
+1d 
18w 
24w 
24w 
+1d 
36
w 
36w 
+1d 
Informed Consent 
X 
 
Medical History 
X 
 
Inclusion/Exclusion 
Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
Run-in drug dispensation 
X 
 
Randomization 
 
X 
 
X 
Begin 24-h ABPM 
 
X 
 
X 
X 
X 
 
End 24-h ABPM 
 
X 
 
X 
X 
X 
Double blind drug 
dispensation 
 
 
X 
 
 
X 
 
 
X 
 
 
Clinical Laboratory Tests 
X 
X 
 
X 
X 
X 
 
Population PK Sampling 
 
 
 
 
 
 
X 
X 
 
 
 
12-Lead ECG 
X 
X 
 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviated PE & weight 
X 
 
X 
X 
X 
Complete PE & weight 
 
X 
 
 
 
Adverse Events 
Assessments 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Concomitant Medication 
Assessments 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 


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Appendix 2 
Schedule of Laboratory Tests 
 
Screening/ 
Run-in 
Study 603A 
Study 603B 
Procedures 
 
weeks 1 to 12 
weeks 1 to 12 
weeks 13 to 24 
Cumulative study 
week 
 
1 -12 
13-24 
25-36 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Time (week) to 
randomization 
-12 to 
-13 d 
-1d 
0w 
+1d 
6w 
12w 
12w 
+1d 
18w 
24w 
24w 
+1d 
36w 
36w 
+1d 
Randomization 
X 
X 
Whole blood 
sample 
X 
X 
 
 
X 
 
 
X 
 
X 
 
Hematology 
X 
X 
X 
X 
X 
HbA1c 
X 
X 
X 
X 
Serum sample 
X 
Chemistry 
X 
X 
X 
X 
X 
Lipids 
X 
X 
X 
X 
X 
Urine sample 
Urinalysis 
X 
X 
X 
X 
X 
Pregnancy test 
(WOCBP) 
X 
X 
 
 
X 
 
 
X 
 
X 
 
Population PK 
Sampling 
 
 
 
 
 
 
X 
X 
 
 
 
 


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Appendix 3 
Hypertensive Emergency 
A hypertensive emergency is defined as a blood pressure above either 180 mm Hg SBP or 
120 mm Hg DBP (or an acute rise deemed significant by the clinician’s judgement) with 
symptoms reflecting the possibility of end organ damage. These can include: generalized 
neurologic symptoms (agitation, delirium, stupor, seizures, visual disturbances), focal 
neurologic symptoms consistent with ischemic or hemorrhagic stroke, funduscopic findings 
consistent with hypertensive retinopathy (flame hemorrhages, exudates, papilledema), 
nausea/vomiting, chest pain consistent with myocardial infarction/aortic dissection, acute 
back pain consistent with aortic dissection, dyspnea consistent with pulmonary edema.  


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Appendix 4 
Examples of SGLT2 Inhibitors 
The following medications are prohibited during the study. Other medications containing 
SGLT2 inhibitors that may become approved for the treatment of T2DM during the THR-
1442-C-603 study will also be prohibited in this study. 
Generic Name 
Trade Name 
canagliflozin 
Invokana™ 
canagliflozin plus metformin 
Invokamet™ 
dapagliflozin 
Farxiga™ or Forxiga™ 
empagliflozin 
Jardiance® 
empagliflozin plus linagliptin 
Glyxambi® 
 


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Appendix 5 
Examples of Medications with Hypotensive Effects 
Class of 
Medications 
Indication 
Example 
Diuretics 
heart failure associated edema 
furosemide, hydrochlorothiazide 
Alpha blocker 
prostrate enlargement 
prazosin, terazosin 
Beta blocker 
angina, tachycardia 
atenolol, propranolol 
Dopamine agonist 
Parkinson’s disease 
pramipexole, levodopa 
Tricyclic 
antidepressants 
Depression 
doxepin, imipramine 
Phosphodiesterase 
inhibitor 
Erectile dysfunction 
sildenafil, tadalafil 
 


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Appendix 6 
KDOQI Chronic Kidney Disease Classification and 
Acute Kidney Injury Stage Definition 
Chronic kidney disease (CKD) is defined as either kidney damage or GFR < 60 
mL/min/1.73 m3 for ≥3 months.  Kidney damage is defined as pathologic abnormalities or 
markers of damage, including abnormalities in blood or urine tests or imaging studies (NFK 
KDOQ guidelines). 
Stages of CKD are outlined in Table 2. 
KDOQI CKD Stages 
Stage 
Description 
GFR (mL/min/1.73 m2) 
1 
Kidney damage with normal or ↑↓GFR 
≥ 90 
2 
Kidney damage with mild ↓GFR 
60-89 
3 
Moderate ↓GFR 
30-59 
4 
Severe ↓GFR 
15-29 
5 
Kidney failure 
< 15 (or dialysis) 
 
Acute kidney injury stages based on the Definition by the Acute Kidney Injury Network 
(AKIN) are outlined in Table 3 (KDIGO Clinical Practice Guideline for AKI, 2012). 
Table 3. 
Classification/Staging System for Acute Kidney Injury 
Stage 
Serum creatinine criteria 
Urine output criteria 
1 
1.5 to 1.9 times baseline or ≥ 0.3 mg/dL (≥ 26.5 Pmol/L) increase from 
baseline 
<0.5 mL/kg/h for 6 to 12 h 
2 
2.0 to 2.9 times baseline 
< 0.5 mL/kg/h for ≥ 12 h 
3 
3.0 times baseline, or 
Increase in serum creatinine to ≥4.0 mg/dL (≥ 353.6 Pmol/L), or 
Initiation of renal replacement therapy, or 
In patients < 18 years, decrease in eGFR to < 35 mL/min per 1.73 m2 
< 0.3 mL/kg/h for ≥ 24 h or 
anuria for ≥ 12 h 
 
 




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Appendix 8 
Investigator’s Signature 
Study Title: 
An Integrated Assessment of the Safety and Effectiveness of 
Bexagliflozin Tablets, 20 mg, for the Management of Essential 
Hypertension 
Study Number: 
THR-1442-C-603 
Final Date: 
28 August 2017 
 
I have read the protocol described above. I agree to comply with the International Conference 
on Harmonisation (ICH) Tripartite guideline on Good Clinical Practice (GCP) and all 
applicable regulations and to conduct the study as described in the protocol.  
I agree to ensure that Financial Disclosure Statements will be completed by myself and my 
subinvestigators at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status.  
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation without 
the prior written consent of Theracos Sub, LLC.  
 
 
 
 
Signed: 
 
 
Date:  
 
Clinical Investigator 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Theracos Sub, LLC 
Version 2.0 
THR-1442-C-603 
 
1010242 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 1 of 59 
Sponsor Name: 
Theracos Sub, LLC 
Protocol Number and Title: 
 
THR-1442-C-603 An Integrated Assessment of 
the Safety and Effectiveness of Bexagliflozin 
Tablets, 20 mg, for the Management of 
Essential Hypertension 
Protocol Version and Date: 
Version 2.0, 28 August 2017 
 
 
INC Research Project Code: 
1010242 
Author(s): 
Fang Zhu, Senior Biostatistician 
SAP Version: 
Version 2.0 
SAP Version Date:  
07 December 2018 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Theracos Sub, LLC. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Theracos Sub, LLC.  However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation, INC Research should be notified 
promptly. 


Statistical Analysis Plan 
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Version 2.0 
THR-1442-C-603 
 
1010242 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
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Page 2 of 59 
Revision History 
 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document 
Owner 
Revision Summary 
Version 0.1 
06-Sep-2017 
Fang Zhu 
Initial Release Version 
Version 0.2 
13-Sep-2017 
Fang Zhu 
Update per comments 
Version 0.3 
14-Sep-2017 
Fang Zhu 
Update per comments 
Version 0.4 
06-Dec-2017 
Fang Zhu 
Update per comments on TLF shells 
Version 1.0 
21-Dec-2017 
Fang Zhu 
Update per comments on TLF shells 
Version 1.1 
27-Feb-2018 
Fang Zhu 
Update per FDA request:  
1. Further clarification was made for use 
of last available ABPM in the primary 
analysis of ABPM;  
2. Additional non-parametric sensitivity 
analysis (Wilcoxon rank test) was added 
per FDA suggestion.   
Version 2.0 
07-Dec-2018 
Fang Zhu 
1. Wilcoxon rank test was updated per 
FDA suggestion.   
2. Additional exploratory analyses on 
ABPM for subgroup of patients taking 
appropriate doses of three or more 
types of antihypertensive therapies at 
baseline of study 603A. 
3. Additional exploratory analyses on 
ABPM during treatment withdrawal 
period (ie, from Week 12 to Week 24 
in study 603B) by response status of 
patients prior to withdrawal.  
4. Other clinical relevant exploratory 
analyses were added, such as heart 
rate change, HbA1c change for 
diabetes subjects, etc. 6. Minor 
cosmetic, typographic error 
corrections.  
 
 


09 December 2018
Yuan-Di 
Halvorsen
Digitally signed by Yuan-Di Halvorsen 
DN: cn=Yuan-Di Halvorsen, o=MGH, 
ou=CCIB/TMG, 
email=yhalvorsen@ccib.mgh.harvard.edu, 
c=US 
Date: 2018.12.09 09:28:49 -05'00'


Statistical Analysis Plan 
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TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................ 8 
2. 
PURPOSE ..................................................................................................... 11 
2.1. 
Responsibilities ................................................................................................................. 11 
2.2. 
Timings of Analyses .......................................................................................................... 11 
3. 
STUDY OBJECTIVES ................................................................................... 12 
3.1. 
Study 603A ......................................................................................................................... 12 
3.1.1. 
Primary Objective ........................................................................................................ 12 
3.1.2. 
Secondary Objectives ................................................................................................. 12 
3.2. 
Study 603B ......................................................................................................................... 13 
3.2.1. 
Primary Objective ........................................................................................................ 13 
3.2.2. 
Secondary Objectives of Study 603B ......................................................................... 13 
3.3. 
Integrative Objectives of Study 603A and 603B ............................................................. 13 
3.4. 
Safety Objectives ............................................................................................................... 13 
3.5. 
Brief Description ................................................................................................................ 14 
3.5.1. 
Study 603A .................................................................................................................. 14 
3.5.2. 
Study 603B .................................................................................................................. 15 
3.6. 
Subject Selection ............................................................................................................... 15 
3.6.1. 
Inclusion Criteria ......................................................................................................... 15 
3.6.2. 
Exclusion Criteria ........................................................................................................ 15 
3.7. 
Determination of Sample Size .......................................................................................... 15 
3.8. 
Treatment Assignment & Blinding ................................................................................... 17 
3.8.1. 
Treatment Assignment ................................................................................................ 17 
3.8.2. 
Blinding ........................................................................................................................ 18 
3.9. 
Administration of Study Medication ................................................................................ 18 
3.10. 
Study Procedures and Flowchart ..................................................................................... 19 
4. 
ENDPOINTS .................................................................................................. 21 


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4.1. 
Study 603A ......................................................................................................................... 21 
4.1.1. 
Primary Efficacy Endpoint ........................................................................................... 21 
4.1.2. 
Secondary Efficacy Endpoints .................................................................................... 21 
4.1.3. 
Exploratory Efficacy Endpoints ................................................................................... 21 
4.2. 
Study 603B ......................................................................................................................... 22 
4.2.1. 
Primary Efficacy Endpoint ........................................................................................... 22 
4.2.2. 
Secondary Efficacy Endpoints .................................................................................... 22 
4.2.3. 
Exploratory Efficacy Endpoints ................................................................................... 22 
4.3. 
Integrated Analyses ........................................................................................................... 22 
4.4. 
Safety Endpoints ................................................................................................................ 23 
5. 
ANALYSIS SETS .......................................................................................... 25 
5.1.1. 
Study 603A .................................................................................................................. 25 
5.1.2. 
Study 603B .................................................................................................................. 25 
5.1.3. 
Integrated Analyses .................................................................................................... 25 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 26 
6.1. 
General Methods ................................................................................................................ 26 
6.2. 
Key Definitions ................................................................................................................... 26 
6.2.1. 
Baseline Values .......................................................................................................... 26 
6.2.2. 
First Dose Date ........................................................................................................... 27 
6.2.3. 
Last Dose Date ........................................................................................................... 27 
6.2.4. 
Study Day .................................................................................................................... 27 
6.2.5. 
Duration ....................................................................................................................... 27 
6.2.6. 
The 24-hr Mean ABPM ............................................................................................... 27 
6.3. 
Missing Data ....................................................................................................................... 28 
6.4. 
Analysis Visit Windows ..................................................................................................... 28 
6.5. 
Pooling of Centers ............................................................................................................. 28 
6.6. 
Terminology Used in SAP ................................................................................................. 28 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ....................................................................................................... 29 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 29 
7.2. 
Subject Eligibility and Protocol Deviations .................................................................... 29 


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7.3. 
Demographic and Other Baseline Characteristics ......................................................... 29 
7.4. 
Medical History .................................................................................................................. 30 
7.5. 
Medication .......................................................................................................................... 30 
7.5.1. 
Prior Medication .......................................................................................................... 31 
7.5.2. 
Concomitant Medication .............................................................................................. 31 
8. 
EFFICACY ..................................................................................................... 33 
8.1. 
Study 603A ......................................................................................................................... 33 
8.1.1. 
Primary Efficacy Endpoint and Analysis ..................................................................... 33 
8.1.2. 
Secondary Efficacy Endpoints and Analyses .............................................................. 35 
8.1.3. 
Exploratory Endpoints and Analyses .......................................................................... 37 
8.2. 
Study 603B ......................................................................................................................... 39 
8.2.1. 
Primary Efficacy Endpoint and Analysis ..................................................................... 39 
8.2.2. 
Secondary Efficacy Endpoint(s) and Analyses ........................................................... 40 
8.2.3. 
Exploratory Endpoints and Analyses .......................................................................... 41 
8.3. 
Integrated Analyses ........................................................................................................... 41 
8.3.1. 
Change in mean ambulatory SBP or DBP after 12, 24, and 36 weeks of treatment of 
bexagliflozin .................................................................................................................................. 42 
8.3.2. 
Change in seated office SBP or DBP after 12, 24, and 36 weeks treatment of 
bexagliflozin .................................................................................................................................. 42 
8.3.3. 
Cumulative mean change from baseline in seated office SBP and DBP as a function 
of time (including all scheduled office visits) for subjects exposed to bexagliflozin ..................... 42 
9. 
SAFETY ......................................................................................................... 42 
9.1. 
Extent of Exposure ............................................................................................................ 43 
9.2. 
Treatment Compliance ...................................................................................................... 43 
9.3. 
Adverse Events .................................................................................................................. 44 
9.3.1. 
Derived Data ............................................................................................................... 44 
9.3.2. 
Data Summarization .................................................................................................... 44 
9.3.3. 
AEs of Special Interest ................................................................................................ 46 
9.4. 
Laboratory Evaluations ..................................................................................................... 47 
9.5. 
Vital Signs ........................................................................................................................... 49 
9.6. 
Electrocardiogram ............................................................................................................. 50 
9.7. 
Physical Examination ........................................................................................................ 50 


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10. 
INTERIM ANALYSIS ................................................................................. 51 
11. 
DATA AND SAFETY MONITORING BOARD ........................................... 51 
12. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ......................... 51 
13. 
PROGRAMMING CONSIDERATIONS ...................................................... 53 
13.1. 
General Considerations .................................................................................................... 54 
13.2. 
Table, Listing, and Figure Format .................................................................................... 54 
13.2.1. 
General ........................................................................................................................ 54 
13.2.2. 
Headers ....................................................................................................................... 54 
13.2.3. 
Display Titles ............................................................................................................... 55 
13.2.4. 
Column Headers ......................................................................................................... 55 
13.2.5. 
Body of the Data Display ............................................................................................. 55 
13.2.6. 
Footnotes .................................................................................................................... 58 
14. 
QUALITY CONTROL ................................................................................. 58 
15. 
MOCK-UPS ................................................................................................ 59 
 
 


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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
ABPM 
Ambulatory blood pressure monitoring 
AE 
Adverse Event 
ALB 
Albumin 
ALK-P 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CEC 
Cardiovascular Endpoint Committee 
CI 
Confidence Interval 
Cl 
Chloride 
CRF 
Case Report Form 
dL  
Deciliter 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ET 
Early Termination 
eGFR 
Estimating Glomerular Filtration Rate 
GMI 
Genital Mycotic Infection 
HbA1c 
Hemoglobin A1c 
Hct 
Hematocrit 
HDL-C 
High Density Lipoprotein Cholesterol 
Hgb 
Hemoglobin 


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Abbreviation 
Description 
ICH 
International Conference on Harmonization 
ITT 
Intention-to-Treat 
IWRS 
Interactive Web Response System 
LDL-C  
Low Density Lipoprotein Cholesterol  
MACE  
Major Adverse Cardiovascular Event  
MCH  
Mean Cell Hemoglobin  
MCHC  
Mean Cell Hematocrit  
MCV  
Mean Cell Volume  
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram  
MI 
Myocardial Infarction  
Min 
Minimum 
mL 
Milliliter 
NA 
Not Applicable 
Na 
Sodium 
PP 
Per Protocol  
PR 
Time from the beginning of the P wave to the beginning of the 
QRS complex in electrocardiogram 
PT 
Preferred Term 
QRS 
Graphical deflections corresponding to ventricular 
depolarization in a typical electrocardiogram 
QTc 
Time between the start of the Q wave and the end of the T 
wave in the ECG, corrected for heart rate 
RBC 
Red Blood Cell  
RR 
Time between the start of one R wave and the start of the 
next R wave in the ECG 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 


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Abbreviation 
Description 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
T2DM 
Type 2 Diabetes Mellitus 
TC 
Total Cholesterol 
TEAE 
Treatment Emergent Adverse Event 
TG 
Triglycerides 
TLF 
Table, Listing And Figure 
UTI 
Urinary Tract Infection 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures that will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives.  Population pharmacokinetic assessments obtained for the study 
will be integrated with other studies, and will not be independently analyzed.  A 
separate analysis plan details the integrated analysis methods.  
2.1. 
RESPONSIBILITIES 
Theracos has designed the study protocol and is responsible for the conduct of the 
study.  INC Research is responsible for the development and validation of a clinical 
database using the MediData RAVE platform.   
INC Research will perform the statistical analyses and is responsible for the production 
and quality control of all tables, figures and listings. 
Adverse events that have met the seriousness criteria defined in the protocol are 
reported on the serious adverse event (SAE) forms using the MediData RAVE platform.  
An SAE case consists of the information reported in the SAE forms, subject 
characteristics documented in the case report forms, and additional source data such as 
hospital discharge summaries.  Each SAE case is recorded in a validated ARGUS database 
which is managed by Covance. Any discrepancies in critical data fields of each SAE will 
be reconciled between the AUGUS and THR-1442-C-603 clinical database prior to 
database lock.  The SAE coding, analyses and summaries are based on the final study 
data recorded in the clinical database.  Detailed serious adverse event follow-up data 
will be reported from the ARGUS database and are not included in this report. 
Theracos will perform review of all tables, figures and listings before the finalization. 
2.2. 
TIMINGS OF ANALYSES 
An interim non-binding futility analysis is planned when 50% of the randomized subjects 
(i.e., 300) have completed 12 weeks of double blind treatment in study 603A. 
The final analysis of safety and efficacy is planned after all subjects complete the 
planned 36 weeks of blinded study treatment or terminate early from the studies.  
 
 


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3. 
STUDY OBJECTIVES 
3.1. 
STUDY 603A 
In study 603A, the effectiveness of bexagliflozin tablets, 20 mg, will be assessed in a 
study population randomized 1:1 to receive either active agent or placebo. 
3.1.1. 
Primary Objective 
The primary endpoint will be the change from baseline (Day 1) to week 12 of the 
average ambulatory systolic blood pressure (SBP) of the bexagliflozin group compared to 
the placebo group. 
3.1.2. 
Secondary Objectives 
Secondary objectives based on mean ambulatory SBP: 
x 
The proportion of subjects who achieve a reduction of mean ambulatory SBP of 
10 mm Hg or greater; 
x 
The proportion of subjects who achieve a mean ambulatory SBP of 135 mm Hg or 
less at week 12; 
x 
The maximum and minimum treatment effect (trough-to-peak ratio) by 
Ambulatory blood pressure monitoring (ABPM) SBP at week 12. 
Secondary objectives based on seated office SBP: 
x 
The placebo-adjusted change from baseline to week 12 in seated office SBP;  
x 
The proportion of subjects who achieve a mean seated office SBP of 140 mm Hg 
or less at week 12. 
Secondary objectives based on mean ambulatory diastolic blood pressure (DBP): 
x 
The placebo-adjusted change in mean ambulatory DBP from baseline to week 12; 
x 
The proportion of subjects who achieve a mean ambulatory DBP of 87 mm Hg or 
less at week 12;  
x 
The proportion of subjects who achieve a reduction of mean ambulatory DBP of 4 
mm Hg or greater at week 12. 
Secondary endpoints based on seated office DBP 
x 
The placebo-adjusted change from baseline to week 12 in seated office DBP; 
x 
The proportion of subjects who achieve a mean seated office DBP of 90 mm Hg 
or less at week 12. 


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3.2. 
STUDY 603B 
In study 603B, the effectiveness of bexagliflozin tablets, 20 mg, will be assessed by 
measurement of the loss of the treatment effect following randomized withdrawal. All 
study entrants will first be dosed with bexagliflozin tablets, 20 mg, for 12 weeks. At 
week 12 the participants will undergo a 1:1 randomization to bexagliflozin tablets, 20 
mg, or placebo. 
3.2.1. 
Primary Objective 
The primary endpoint will be the change from week 12 to week 24 of the mean 
ambulatory SBP of the bexagliflozin group compared to the placebo group. 
3.2.2. 
Secondary Objectives of Study 603B 
The secondary objectives of study 603B are based on assessments of effects on mean 
ambulatory and seated office systolic and diastolic blood pressures from week 12 to 
week 24. These will include: 
x 
The placebo-adjusted change from week 12 to week 24 in seated office SBP;  
x 
The placebo-adjusted change from week 12 to week 24 in ambulatory DBP;  
x 
The placebo-adjusted change from week 12 to week 24 in seated office DBP; 
Study 603B will also include a population pharmacokinetic assessment between weeks 6 
and 12, when all participants will be receiving bexagliflozin tablets, 20 mg.  
Population pharmacokinetic assessments obtained for the study will be integrated with 
other studies, and will not be independently analyzed. A separate analysis plan details 
the integrated analysis methods 
3.3. 
INTEGRATIVE OBJECTIVES OF STUDY 603A AND 603B 
x 
To assess consistent effects on mean ambulatory SBP/DBP after 12 weeks of 
bexagliflozin treatment, as well as longer treatment periods, i.e., 24 weeks or 
36 weeks of bexagliflozin treatment. 
x 
The seated office systolic and diastolic blood pressure will be collected at more 
frequent intervals than for ambulatory monitoring, and the changes over time 
will be evaluated to provide a composite profile of treatment effect as a 
function of time. 
3.4. 
SAFETY OBJECTIVES 
The integrated safety objectives will assess the hazard ratio for adverse events 
associated with bexagliflozin exposure compared to placebo in all segments of both 


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studies in which a placebo-exposed cohort is present.  The safety objectives of the 
study are: 
• To determine the frequency and severity of treatment emergent adverse events 
• To determine the frequency and severity of treatment emergent adverse events of 
special interest 
• To record and evaluate concomitant medication use 
• To evaluate any potentially adverse changes in laboratory test values 
• To assess changes in cardiac rhythm through 12-lead ECG 
• To evaluate vital signs 
• To assess general health detected by physical examination 
3.5. 
BRIEF DESCRIPTION 
THR-1442-C-603 is an integrated assessment of the potential utility of bexagliflozin 
tablets, 20 mg, for the treatment of essential hypertension. It is composed of two 
studies, 603A and 603B, measuring effects in a common population. 
3.5.1. 
Study 603A 
Study 603A is a double blind, placebo controlled multi-center study. Approximately 680 
male and female adult subjects with an office sitting blood pressure ≥ 140 mm Hg and 
< 180 mm Hg, and who are taking no more than 4 anti-hypertensive medications will be 
enrolled in study 603A. The overall population should be selected to contain > 10% of 
subjects with a baseline ABPM >160 mm Hg and < 30% of subjects with type 2 diabetes 
mellitus. 
Subjects who meet the eligibility criteria at the screening visit (visit 1) will start a 2 
week run-in period.  At the end of the run-in period, subjects who have not been 
disqualified will be eligible for participation.  At the investigative site the subjects will 
take the last dose of run-in drug, will be fitted with an ABPM device and will start a 24-
h ABPM to establish the baseline ABPM SBP and DBP.  On the following day, qualified 
subjects who have completed the 24-h ABPM with a mean 24-h SBP ≥ 135 mm Hg will be 
randomly assigned to receive bexagliflozin tablets, 20 mg or placebo, using an 
interactive web response system (IWRS).  If < 64 BP readings are recorded, the ABPM 
must be repeated within 2 days.  Prior to randomization, subjects who cannot 
successfully complete the ABPM within two attempts will be considered screen failures. 
A six week visit to the investigational site will allow seated office measures of systolic 
and diastolic BP to be recorded. At week 12 (end of study), the subject will visit the 
investigational site, consume the final tablet, and be fitted for ABPM.  
An interim non-binding futility analysis is planned when 50% of the randomized subjects 
(i.e., 300) have completed study 603A. 


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3.5.2. 
Study 603B 
Upon returning to the investigational site to return the ambulatory monitor at the 
conclusion of study 603A, subjects will begin participation in study 603B. They will 
receive a 12-week supply of bexagliflozin tablets, 20 mg. 
At week 6 subjects will return to the investigational site for measurement of seated 
systolic and diastolic blood pressures.  At week 12, subjects will visit the investigational 
site to consume the final tablet and to be fitted with an ambulatory monitor to record 
their baseline mean ambulatory blood pressure. 
The following day, subjects will be randomized 1:1 to receive a 12-week supply of 
bexagliflozin tablets, 20 mg or bexagliflozin tablets, placebo.  
An assessment of bexagliflozin population pharmacokinetics will also be conducted to 
include approximately 200 subjects. Samples will be taken between weeks 6 and 12. 
The population PK study design and analysis plan will be described in a designated study 
protocol and the analysis will be reported separately. 
3.6. 
SUBJECT SELECTION 
The study population for the integrated program will include approximately 680 
subjects with essential hypertension. Eligible subjects who consent to participate in the 
study will be enrolled in clinical investigational sites in the United States.  Study 
subjects will be informed of the purpose of the program, the potential risks of 
participation in both studies, and will be requested to consent to the procedures and 
blood collection on a single consent form. 
Plasma samples will be collected for population PK analysis in study 603B. Study 
subjects will be informed of the purpose of the PK study and requested to consent to 
the additional procedures and blood collection. 
3.6.1. 
Inclusion Criteria 
Refer to protocol section 4.2 for inclusion criteria. 
3.6.2. 
Exclusion Criteria 
Refer to protocol section 4.3 for exclusion criteria. 
3.7. 
DETERMINATION OF SAMPLE SIZE 
The primary efficacy endpoint of study 603A is the change from baseline (Day 1) to 
week 12 in the 24-hour average SBP of the bexagliflozin group compared to the placebo 
group using superiority testing at an overall two-sided 0.05 level of significance. 


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The primary efficacy endpoint of study 603B is the change from week 12 to week 24 in 
the 24-hour average SBP in the bexagliflozin group compared to the placebo group using 
superiority testing at an overall two-sided 0.05 level of significance. 
Although the patient population was anticipated to be nearly identical between the two 
studies, they were to be carried out as independent investigations with respect to their 
individual primary and secondary endpoints.  The assumptions used to estimate the 
sample size for the primary endpoint of study 603A were: 
1. The magnitude of the decrease from baseline (Day 1) to week 12 of the 24 h mean 
SBP in the bexagliflozin treatment arm will exceed that found in the placebo arm by 
5 mm Hg; 
2. The standard deviation of the change from baseline to week 12 will be 15 mm Hg for 
both the active and placebo groups; 
3. The two-sided significance level is 0.05. 
The assumptions to estimate the sample size required for the primary endpoint of study 
603B were: 
1. Bexagliflozin will remain effective for at least 24 weeks. The 24-hour average ABPM 
SBP will not change between Week 12 and Week 24. 
2. Subjects who are randomized to receive placebo will show an increase in ABPM SBP of 
4 mm Hg between Week 12 and Week 24. 
3. The standard deviation of the change is 15 mm Hg for both the active and placebo 
groups. 
4. The two-sided significance level is 0.05. 
A sample size of 254 per arm is required for the measurement to have 85% power to 
attain significance for the second primary endpoint. It is estimated that 75% of subjects 
will have completed the 36 weeks of study treatment since the first randomization. 
Thus a total sample size of 680 subjects is planned for the first randomization. It is 
estimated that approximately 8% will drop out for the first 12 weeks. A sample size of 
626 subjects at the end of the first 12 weeks will provide >95% power for the first 
primary endpoint. 
An interim non-binding futility analysis when half (i.e., 300) of subjects have completed 
the first 12 weeks of the treatment period will be conducted. Using an interpolated 
spending function of Type II error, i.e., with 0.5 proportion of Type II error being spent 
at the interim look, the study may stop for futility when the test statistic (Z score) is 
less than 0.656 (or p-value > 0.512). The overall power for the first primary endpoint 
remains >95% with this interim look.  The futility boundary of this study is non-binding, 
meaning that the Type I error is properly controlled even if the study is continued after 
the futility boundary is crossed at the interim analysis. 


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3.8. 
TREATMENT ASSIGNMENT & BLINDING 
3.8.1. 
Treatment Assignment 
The study will be conducted in multiple investigative sites and will involve variable 
numbers of subjects at each site. Enrollment will be on a competitive basis, but each 
site will be capped at 68 randomized subjects. Activation of investigational sites will be 
centrally controlled by IWRS. 
Subjects who meet the eligibility criteria required at the screening visit (visit 1) must be 
registered in the IWRS in order to be assigned a subject number and a bottle of run-in 
drug. During the study treatment periods, a new bottle will be assigned to the subject 
every 12 weeks by the IWRS at visits 3, 6, and 9.  There are two randomization 
procedures planned in this study, at visit 3 and visit 9. 
Subjects who complete the run-in period and meet the ABPM SBP ≥ 135 mm Hg criterion 
at visit 3 will be randomized to receive a bottle of bexagliflozin, 20 mg or placebo. 
Subjects will be assigned to each group in a 1:1 ratio. Randomization will be stratified 
according to diabetes status (history of type 2 diabetes or not), baseline ABPM SBP 
(≥ 160 mm Hg or not), unmedicated or not, and renal function (eGFR ≥ 60 or not). The 
investigator or designated staff will log into the IWRS to receive the randomization code 
and assigned kit number for bexagliflozin tablets, 20 mg or placebo. 
At visit 6 after a subject has completed the ABPM successfully, a second bottle of study 
drug will be assigned to the subject by IWRS. All subjects will receive active treatment 
for the following 12 weeks.  Subjects who experience persistent hypertension during the 
first 12 weeks of treatment may complete visits 5 and 6 prior to week 12. 
At visit 9 after a subject has completed the 24 h ABPM successfully, the subject will be 
randomly assigned to receive either bexagliflozin or placebo. A new randomization 
number and a new bottle of double blind study drug will be assigned and dispensed to 
the subject.  Assignment to the active or control arm will be balanced to approximately 
equalize the representation in each arm of the following groups: 
x 
Subjects not requiring rescue medication prior to week 24 and exhibiting a > 
20 mm Hg reduction in mean SBP between cumulative weeks 1 and 24; 
x 
Subjects not requiring rescue medication prior to week 24 and exhibiting a > 
5 mm Hg and ≤ 20 mm Hg reduction in mean SBP between cumulative weeks 1 and 
24; 
x 
Subjects not requiring rescue medication prior to week 24 and exhibiting a ≤ 
5 mm Hg reduction in mean SBP between cumulative weeks 1 and 24; 
x 
Subjects requiring rescue medication prior to week 24. 
If the mean SBP is missing at cumulative week 24, the subject will be withdrawn. 


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Subject randomization will be deactivated for all sites when the planned number of 
subjects is met and a minimum of 10% of the subjects have an average 24 h ABPM SBP 
≥160 and <180 mm Hg at visit 3. However, if a potential subject has started the run-in 
period at that time and wishes to continue to participate, the subject will be allowed to 
continue and, if eligible, to be randomized. 
3.8.2. 
Blinding 
Both studies will have double-blind treatment phases.  The sponsor study management 
team, investigators, study coordinators, pharmacists, study subjects and cardiovascular 
endpoint committee (CEC) will be blinded to the study medications.  Protocol section 
5.5 provides the general rule to maintain blinding of the individual treatment 
assignment. 
There are periodical data safety monitoring reports and meetings planned for 
THR-1442-603.  A designated unblinded statistician who is not involved with the study 
operation will hold the treatment codes and prepare reports to facilitate these 
activities.  A separate data and safety monitoring board statistical analysis plan contains 
details for the types of analyses required and procedures to preserve blinding to 
treatment assignment. 
A planned interim futility analysis was conducted by the unblinded statistician and an 
independent Data Monitoring Committee (DMC) after 50% of the randomized subjects 
received at least 12 weeks of treatment to evaluate the effectiveness of bexagliflozin.  
All study subjects were to continue to receive the investigational products during the 
data cleaning and analysis time.  The unblinded statistician was responsible for 
preparation of the interim analysis report.  The same procedures specified in the safety 
monitoring board statistical analysis plan were followed to preserve blinding and handle 
accidental unblinding.  
3.9. 
ADMINISTRATION OF STUDY MEDICATION 
The study subject will take one tablet per day of the following investigational products 
in addition to background medications such as treatments for diabetes, hyperlipidemia, 
or hypertension: 
• Run-in period: placebo run-in medication 
• Study 603A: bexagliflozin tablets, 20 mg or placebo 
• Study 603B week 1 to week 12: bexagliflozin tablets, 20 mg only 
• Study 603B week 13 to week 24: bexagliflozin tablets, 20 mg or placebo 
The integrated dosing schedule is illustrated in Figure 1. 


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Figure 1 
THR-1442-C-603 Study Design 
 
3.10. 
STUDY PROCEDURES AND FLOWCHART 
The activities that must be performed at each clinic visit listed below are presented in 
Table 1. 
A visit window of ± 3 days is allowed for all post-randomization visits. Visit 3 is the day 
of randomization and the basis for the visit window. A repeat ABPM shall be performed 
within 2 days if the 24h-ABPM is incomplete. Only the second set of ABPM data will be 
entered in the case report form on visits 2-3, 5-6, 8-9, and 10-11. The other specified 
procedures in the same assessment period do not need to be repeated. If the ABPM fails 
twice at visit 3 prior to randomization, the subject is considered a screen failed 
subject. If the ABPM cannot be completed successfully twice after randomization, the 
ABPM BP for that assessment period is considered missing. 
Procedures listed for visit 10 and 11 will be completed if a subject is withdrawn from 
the study. 
 


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Table 1 
Schedule of Events 
 
Screening/ 
Run-in  
Study 603A  
Study 603B 
Procedures 
 
Weeks 1 to 12 
Weeks 1 to 12 
Week 13 to 24 
Cumulative study 
week 
 
1 -12 
13-24 
25-36 
Visit Number  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
Time to first 
randomization 
-13 or 
-12 d 
-1d 
0w 
+1d 
6w 
12w 
12w 
+1d 
18w 
24w 
24w 
+1d 
36w 
36w 
+1d 
Informed Consent  
x  
 
 
 
 
 
 
 
 
 
 
Medical History  
x  
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria  
x  
x  
x  
 
 
 
 
 
 
 
 
Run-in drug 
dispensation  
x  
 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
x  
 
 
 
 
 
x  
 
 
Begin 24-h ABPM  
 
x  
 
 
x  
 
 
x  
 
x  
 
End 24-h ABPM  
 
 
x  
 
 
x  
 
 
x  
 
x  
Double blind drug 
dispensation  
 
 
x  
 
 
x  
 
 
x  
 
 
Whole blood sample  
x  
x  
 
 
x  
 
 
x  
 
x  
 
Hematology  
x  
x  
 
 
x  
 
 
x  
 
x  
 
HbA1c  
x  
x  
 
 
x  
 
 
x  
 
 
 
Serum sample  
 
 
 
 
 
 
 
 
 
x  
 
Chemistry  
x  
x  
 
 
x  
 
 
x  
 
x  
 
Lipids  
x  
x  
 
 
x  
 
 
x  
 
x  
 
Urine sample  
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
x  
x  
 
 
x  
 
 
x  
 
x  
 
Pregnancy test 
(WCBP)  
x  
x  
 
 
x  
 
 
x  
 
x  
 
Population PK 
Sampling  
 
 
 
 
 
 
x  
x  
 
 
 
12-Lead ECG  
x  
x  
 
 
x  
 
 
x  
 
x  
 
Vital Signs  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Abbreviated PE & 
weight  
x  
 
 
 
x  
 
 
x  
 
x  
 
Complete PE & 
weight  
 
x  
 
 
 
 
 
 
 
 
 
Adverse Events 
Assessments  
 
x  
 
x  
x  
 
x  
x  
 
x  
x  
Concomitant 
Medication 
Assessments  
 
x  
 
x  
x  
 
x  
x  
 
x  
x  
 


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4. 
ENDPOINTS 
4.1. 
STUDY 603A 
4.1.1. 
Primary Efficacy Endpoint 
x 
Change from baseline (Day 1) to week 12 of the 24-hour mean SBP.  
4.1.2. 
Secondary Efficacy Endpoints 
x 
The proportion of subjects who achieve a reduction of mean ambulatory SBP of 
10 mm Hg or greater; 
x 
The proportion of subjects who achieve a mean ambulatory SBP of 135 mm Hg or 
less; 
x 
The trough-to-peak ratio of ambulatory SBP at week 12; 
x 
The placebo-adjusted change from baseline to week 12 in seated office SBP; 
x 
The proportion of subjects who achieve a mean seated office SBP of 140 mm Hg or 
less at week 12; 
x 
The placebo-adjusted change in mean ambulatory DBP from baseline to week 12; 
x 
The proportion of subjects who achieve a mean ambulatory DBP of 87 mm Hg or less 
at week 12; 
x 
The proportion of subjects who achieve a reduction of mean ambulatory DBP of 4 
mm Hg or greater; 
x 
The placebo-adjusted change from baseline to week 12 in seated office DBP; 
x 
The proportion of subjects who achieve a mean seated office DBP of 90 mm Hg or 
less at week 12; 
4.1.3. 
Exploratory Efficacy Endpoints 
To further assess treatment effect in key subset populations as well as clinically 
relevant measurements associated with blood pressures, following exploratory efficacy 
endpoints will be analyzed.  
x 
The placebo-adjusted change from baseline in the 24-hour mean ambulatory SBP at 
week 12 for subjects who had three or more types of antihypertensive therapies at 
baseline; 
x 
The placebo-adjusted change from baseline in 24-hour mean pulse pressure at week 
12; 


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x 
The placebo-adjusted change from baseline to week 12 in 24-hour mean ambulatory 
SBP (among dippers, and among non-dippers); 
x 
The placebo-adjusted change from baseline to week 12 in 24-hour mean ambulatory 
heart rate (HR); 
x 
The placebo-adjusted change from baseline to week 12 in body weight; 
x 
The placebo-adjusted change from baseline to week 12 in HbA1c; 
x 
The proportion of subjects requiring any rescue medication at week 12. 
4.2. 
STUDY 603B 
4.2.1. 
Primary Efficacy Endpoint 
x 
Change from baseline week 12 (cumulative week 24) to week 24 (cumulative week 
36) of the 24-hour mean SBP. 
4.2.2. 
Secondary Efficacy Endpoints 
x 
The placebo-adjusted change from week 12 to week 24 in seated office SBP; 
x 
The placebo-adjusted change in mean ambulatory DBP from week 12 to week 24; 
x 
The placebo-adjusted change from week 12 to week 24 in seated office DBP. 
4.2.3. 
Exploratory Efficacy Endpoints 
To further assess treatment withdrawal effect, following exploratory endpoints will be 
analyzed. 
x 
The placebo-adjusted change from baseline week 12 to week 24 in 24-hour mean 
ambulatory SBP by baseline week 12 response status (rescued, >20 mm Hg, >5 and 
≤20 mm Hg, ≤5 mm Hg, and >5 mm Hg);  
x 
The proportion of subjects requiring any rescue medication at week 24. 
4.3. 
INTEGRATED ANALYSES 
Assessments for studies 603A and 603B will be combined to further assess the 
effectiveness of bexagliflozin after treatment of 12, 24, and 36 weeks. 
There are four (4) separate treatment sequences after combining studies 603A and 603B 
(Table 2). 


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Table 2 
Treatment Sequences for combined studies 603A and 603B 
Sequence 
Period 1 
Period 2 
Period 3 
Seq 1 PBB 
(603A) placebo 
(603B) bexagliflozin 
(603B) bexagliflozin 
Seq 2 PBP 
(603A) placebo 
(603B) bexagliflozin 
(603B) placebo 
Seq 3 BBB 
(603A) bexagliflozin 
(603B) bexagliflozin 
(603B) bexagliflozin 
Seq 4 BBP 
(603A) bexagliflozin 
(603B) bexagliflozin 
(603B) placebo 
 
The following secondary endpoints will be assessed: 
x 
Change in mean ambulatory SBP or DBP after 12 weeks treatment with bexagliflozin 
using week 12 assessments for Seq 3 or 4 (end of Period 1) and cumulative week 24 
assessments for Seq 1 or 2 (end of Period 2); 
x 
Change in mean ambulatory SBP or DBP after 24 weeks treatment with bexagliflozin 
using cumulative week 24 assessments for Seq 3 or 4 (end of Period 2) and 
cumulative week 36 assessment of Seq 1 (end of Period 3); 
x 
Change in mean ambulatory SBP or DBP after 36 weeks treatment with bexagliflozin 
using cumulative week 36 assessments for Seq 3 (end of Period 3); 
x 
Change in seated office SBP or DBP after 12 weeks treatment with bexagliflozin 
using week 12 assessments for Seq 3 or 4 (end of Period 1) and cumulative week 24 
assessments of Seq 1 or 2 (end of Period 2); 
x 
Change in seated office SBP or DBP after 24 weeks treatment with bexagliflozin 
using cumulative week 24 assessments for Seq 3 or 4 (end of Period 2) and 
cumulative week 36 assessments for Seq 1 (end of Period 3); 
x 
Change in seated office SBP or DBP after 36 weeks treatment with bexagliflozin 
using cumulative week 36 assessments for Seq 3 (end of Period 3). 
x 
Cumulative mean change from baseline in seated office SBP as a function of time 
(including all scheduled office visits) for subjects exposed to bexagliflozin  
x 
Cumulative mean change from baseline in seated office DBP as a function of time 
(including all scheduled office visits) for subjects exposed to bexagliflozin  
4.4. 
SAFETY ENDPOINTS  
x 
Treatment emergent adverse events  
x 
Treatment emergent adverse events of special interest  
x 
Concomitant medication use 


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x 
Laboratory test  
x 
Cardiac rhythm determined by 12-lead ECG 
x 
Vital signs 
x 
Physical examination 
 
 


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5. 
ANALYSIS SETS 
5.1.1. 
Study 603A 
The following analysis sets will be analyzed: 
x 
Intention-to-Treat (ITT) Analysis Set: will include all subjects who are randomized to 
the study.  All subjects will be analyzed according to the treatment to which they 
were randomized to receive. 
x 
Safety Analysis Set:  will include all subjects who are randomized to the study and 
have taken at least one dose of double blind investigational product.  This analysis 
set will be used for study 603A safety analyses. All subjects will be analyzed 
according to the treatment they receive. 
 
5.1.2. 
Study 603B 
x 
ITT Analysis Set: will include all subjects who are randomized at week 12.  All 
subjects will be analyzed according to the treatment to which they were 
randomized to receive. 
x 
Safety Analysis Set: will include all subjects who have taken at least one dose of 
investigational product. 
x 
Safety Analysis Set for withdrawal period: will include all subjects who are 
randomized at week 12 and have taken at least one dose of double blind 
investigational product. All subjects will be analyzed according to the treatment 
they receive. 
 
5.1.3. 
Integrated Analyses 
x 
Integrated ITT Analysis Set: will include all subjects who are randomized to 
bexagliflozin in 603A, or entered study 603B run-in period.  The set will include all 
subjects to whom a study kit is dispensed in 603B run-in period, and subjects who 
are randomized to bexagliflozin in 603A. 
x 
Integrated Safety Analysis Set: will include all subjects who are treated with at least 
one dose of bexagliflozin in either study.  This will include subjects in the 603B 
safety analysis set and subjects who received at least one dose of bexagliflozin 
during 603A. 


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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
Statistical methodology and analyses are in accordance with the principles outlined by 
the ICH E9 guidelines.  All statistical analyses will be conducted using SAS statistical 
software version 9.3 or higher.  
Tables, listings and figures (TLFs) will be produced in accordance with the principles 
outlined by the ICH E3 guidelines.  For most summary statistics, data will be analyzed 
by the following treatment groups:  Bexagliflozin 20 mg; Placebo.  For 603B, unless 
otherwise specified, data will be analyzed by treatment in the 603B withdrawal period. 
Treatment in 603B withdrawal period will be further split by treatment sequence (as 
shown in Table 2).  For integrated analyses, unless otherwise specified, summaries will 
be by total of all patients in the analysis set.  
Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], Q1, median, Q3, minimum and maximum) for continuous variables, and 
frequency and percentage of subjects for categorical and ordinal variables, unless 
otherwise specified.  
Unless otherwise specified, all statistical tests will be two-tailed using a 0.05 level of 
significance. All confidence intervals (CIs) will be two-sided 95% CIs. 
Only scheduled visits will be included in by visit summaries.  All visit assessment data 
will be included in shift tables and will appear in the subject listings.   
No data imputation will be applied for missing values in safety analysis.  Efficacy data 
imputation method will be described in Section 8.  
6.2. 
KEY DEFINITIONS 
6.2.1. 
Baseline Values 
Unless otherwise specified, baseline is defined as: 
x 
For study 603A endpoints, baseline is defined as the last non-missing measurement 
prior to the first dose of double-blind study medication in 603A.   
x 
For study 603B endpoints, baseline is defined as the last non-missing measurement 
prior to the first dose of double-blind study medication in 603B.  
x 
For integrated endpoints by weeks from first exposure to bexagliflozin, baseline is 
defined as the last non-missing measurement prior to the first exposure of 
bexagliflozin.  Considering the 4 sequences in Table 2, baseline for Seq 3 or 4 is the 


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last non-missing measurement prior to first dose of bexagliflozin in 603A.  Baseline 
for Seq 1 or 2 is defined as the last non-missing measurement prior to the first dose 
of bexagliflozin in 603B run-in period. This applies to all integrated efficacy 
endpoints or the safety summaries by weeks of bexagliflozin treatment. 
6.2.2. 
First Dose Date 
In general, the first dose date for 603A will be the date that the first dose of study drug 
is administered after the first randomization.  The first dose date for 603B will be the 
date that the first dose of study drug is administered after the second randomization. 
The first dose date for integrated analysis will be the date that the first dose of 
bexagliflozin is administered. 
6.2.3. 
Last Dose Date  
The date of the last dose will be recorded in CRF at Day -1, cumulative weeks 12, 24, 
and 36.  The last dose date for 603A will be the date recorded at week 12 and 603B will 
be the one recorded at 603B week 24.  The date of the last dose in integrated analyses 
will be the latest last dose dates for any bexagliflozin kit dispensed. 
6.2.4. 
Study Day 
Study Day is the number of days starting from the first administration of double-blind 
study drug in each study, which is counted as Study Day 1.  If the assessment date is 
after the date of the first double-blind medication, the study day is calculated as date 
of assessment - date of the first dose administration + 1.  If the assessment date is prior 
to the date of the first double-blind medication, the study day is calculated as date of 
assessment - date of the first dose administration. 
6.2.5. 
Duration 
Duration of treatment for each period will be determined as Duration = date of the last 
dose in the specific period minus date of the first dose date in the specific period 
plus 1.   
6.2.6. 
The 24-hr Mean ABPM  
The 24-hour mean ABPM is computed following the steps below: 
x 
The mean for each clock hour on each day are computed as the average of all 
readings within the hour on that day, e.g. Day 1 hour 9 is the average of all values 
on Day 1 09:00 – 09:59. The measures on different days from same clock hour are 
considered as separate values. 
x 
The 24-hour mean will be computed as the average all available hourly mean.  
 


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6.3. 
MISSING DATA 
The handling of missing or incomplete data is described for each endpoint and data type 
(as needed) in Section 7 to 9.   
6.4. 
ANALYSIS VISIT WINDOWS 
No analysis visit windows will be used.  For by visit safety analysis, the early 
termination (ET) visit will be included in the derivation of the end of the study visit.  
For efficacy analysis, unscheduled or ET visit will be used if the scheduled visit is 
missing, described in Section 8.  Nominal visits will be used for scheduled visit.  In case 
if there are multiple assessments for a visit, the later one will be used. 
6.5. 
POOLING OF CENTERS 
Analysis will not be pooled by center.   
6.6. 
TERMINOLOGY USED IN SAP 
In general, terms below will be used: 
x 
“Weeks” refer to study week, unless cumulative week is specified;  
x 
Analysis for 603B refers to after randomization in 603B.  The bexagliflozin dosing 
period before randomization is referred to as the “603B run-in period”. 
 
 


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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition data will be presented in list form. Separate disposition tables will 
present the number and percentage of subjects who complete each of the salient study 
milestones. The disposition table for study 603A will be presented by treatment in 603A 
and overall. Those milestones will be: signing of the informed consent, screen pass prior 
to 603A run-in, screen pass after 603A run-in, randomization to 603A, completion of 
603A, entered into 603B run-in.  Table for 603B will be presented first by treatment 
sequence, then by treatment in 603B, and lastly, overall.  Milestones will be: 
completion of the 603B run-in, randomization to 603B, and completion of 603B. In 
addition, the number and percentage of subjects who require rescue medication will be 
listed for each overall treatment period, either 603A (Period 1), 603B run-in (Period 2), 
or 603B (Period 3). 
The reasons for early withdrawal will be summarized.   
Assignment to the analysis sets (safety, ITT) at study 603A, study 603B will be 
summarized.  
7.2. 
SUBJECT ELIGIBILITY AND PROTOCOL DEVIATIONS 
All subjects, including screen failure subjects before and after run-in, who do not meet 
the Inclusion/exclusion criteria, will be listed.  A table will display the number of 
subjects who fail at screening or 603A run-in (non-randomized subjects) with a summary 
of the reasons for screen fail prior to randomization. 
The number and percent of subjects who had any major deviation will be tabulated 
along with disposition tables for the ITT Analysis Set.   
7.3. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographics and baseline characteristics will be descriptively summarized for all ITT 
analysis sets by treatment group for studies 603A, 603B, and integrated ITT analysis set.  
Key variables will include: age, gender, race, ethnicity, baseline vital signs (includes 
office pulse, SBP, DBP in sitting, supine, and standing positions, 24-hour mean 
ambulatory SBP and 24-hour mean ambulatory DBP), ECG measures (to include RR 
interval, PR interval, QRS duration, and QT interval), renal function (to include eGFR), 
body weight, BMI, initial randomization stratification factors (to include diabetic status 
[history of type 2 diabetes or not], baseline ABPM SBP [≥ 160 mm Hg or not], and renal 
function [eGFR ≥ 60 mL/min/1.73 m2 or not]), and background antihypertensive 
medications (4 most common medication types determined by ATC class 4 and all other 


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antihypertensive medications). Separate demographic and baseline characteristics 
tables will be prepared for each study.  Summary descriptive statistics by treatment will 
include counts and percentages for discrete variables and estimation of means, 
standard deviations, medians, inter-quartile range (Q1, Q3), minimum, and maximum 
for continuous variables. Subject age will be calculated in the clinical database as the 
age at date of informed consent in 603A. Summaries for integrated analyses will be 
presented by bexagliflozin 20 mg in 603A, placebo in 603A and entered 603B, and all 
subjects in integrated ITT analysis set.  Subjects randomized to the placebo arm in 603A 
and did not enter 603B will also be summarized in a separate group.  
7.4. 
MEDICAL HISTORY 
Significant medical, allergies, intolerance, and surgical history, including dates of 
diagnoses and procedures and whether the condition is ongoing, if applicable, will be 
collected. Each condition will be recorded as a verbatim term, date of onset, date 
resolved, and a checkbox that indicates ongoing conditions.  Significant surgical and 
medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 19.0 or above. 
Medical and surgical history will be summarized for the safety analysis set by system 
organ class (SOC), and MedDRA preferred term (PT) for each study. Subject data will be 
listed. Medical history for 603B will be summarized by treatment received during 
withdrawal period. 
Subject diabetic, renal, and cardiovascular disease histories will be summarized for all 
categorical variables by frequency and percentage for both studies in the safety analysis 
set. Cardiovascular disease histories for 603B will be summarized by treatment received 
during the withdrawal period, then further split by treatment sequence.  Diabetic and 
renal disease histories for 603B will be summarized by treatment received during 603 
withdrawal period. 
7.5. 
MEDICATION 
All medication will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) version March 2016 or above.  Preferred drug name, Anatomical/ 
Therapeutic/ Chemical (ATC) class will be reported for inclusion in the database.   
Medication summaries based on ATC level 2, and the preferred drug names will be 
produced for the safety analysis set. The summaries will present for each study, by the 
frequency and percentage of subjects who used any medication in an ATC class, or any 
medication based on a single preferred drug name. Subjects will be counted only once 
for each medication class and each preferred drug name.  


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7.5.1. 
Prior Medication 
Any medication with a stop date prior to the first dose date for study 603A will be 
considered a prior medication.   
No summary for prior medication will be presented.  Prior and concomitant medications 
will be presented together in a single listing.  The listing will be ordered by subject 
number, and medication start/end dates. Prior medication for study 603A will be 
flagged separately.   
7.5.2. 
Concomitant Medication 
A concomitant medication is any medication that the subject has been taking prior to 
the first dose of double blind study medication and that the subject is expected to 
continue to take for some portion of the study treatment period, as well as any 
medication other than the investigational product that the subject takes during the 
course of the study treatment period. Concomitant medication for 603B will be 
summarized by treatment received during the withdrawal period.  
A rescue medication is defined as a dose increase of an existing blood pressure 
medication or initiation of a new blood pressure medication for the purpose of lowering 
blood pressure.  Medications prescribed for other indications are not considered rescue 
medication. Replacing a blood pressure lowering medication with another medication of 
the same class within the recommended dose will not be considered a rescue 
medication. Rescue medication will be summarized for 603A, 603B run-in period, 603B, 
and integrated.  For period-specific summaries of 603A and 603B, rescue medication 
will be summarized for the period during which the medication started or the dose 
increased.  For integrated summaries, any rescue medication started or dose increased 
during bexagliflozin treatment will be included.   
Concomitant medications will be presented in summary tables for  
1) 603A, based on the 603A safety analysis set;  
2) 603B, based on the safety analysis set for withdrawal period; 
3) Integrated, based on the integrated safety analysis set. 
Medication is considered to be concomitant to 603A, the 603B run-in period, or 603B, if 
it satisfies the conditions below: 
x 
The start date is before the last dose of the study medication for that period;  
x 
The end date is after the first dose of the study medication for that period or 
the medication is ongoing. 
For integrated summaries, medication is considered to be concomitant to bexagliflozin 
if it satisfies the condition below: 


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x 
The start date is before the last dose of bexagliflozin; 
x 
The end date is after the first dose of bexagliflozin or the medication is ongoing. 
In the case of completely missing stop date, medication will be assumed to be 
concomitant to all treatment periods.   
 
 
 


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8. 
EFFICACY 
Changes from baseline for efficacy data will be calculated as the post-treatment value 
minus the corresponding defined baseline (see Section 6.2.1).  Descriptive summaries 
will be presented for observed and change values by treatment and visit. Assessment of 
proportion data will be presented by frequency and proportion by treatment and visit.   
8.1. 
STUDY 603A 
For all analyses at Week 12, LOCF will be used for subjects who lack Week 12 
assessments or who require intensification of anti-hypertensive therapy.  Only 
post-baseline values before rescue medication will be carried forward.  
8.1.1. 
Primary Efficacy Endpoint and Analysis 
The primary efficacy endpoint is the change from baseline to week 12 of the 24-hour 
mean ambulatory SBP in the bexagliflozin group compared to the change in the placebo 
group, testing for superiority at a two-sided 0.05 level of significance. A valid ABPM 
reading will require: 
x 
≥ 64 BP total readings; and  
x 
≥ 51 BP daytime readings or ≥ 13 BP nighttime readings.  
Only valid ABPM will be used for analysis. 
8.1.1.1. Primary Efficacy Analysis 
Let μBexagliflozon, 12 and μPBO, 12 represent the mean changes from baseline in 24-hour 
ambulatory SBP at Week 12 for bexagliflozin and placebo arm, respectively. The 
following hypotheses will be tested: 
H0: μBexagliflozon, 12 = μPBO, 12 versus H1: μBexagliflozon, 12 ≠ μPBO, 12 
To test this hypothesis, an analysis of covariance (ANCOVA) will be applied to analyze 
the mean change in 24-hour average ABPM SBP.  The ANCOVA model will include terms 
for diabetes status (history of type 2 diabetes mellitus [T2DM] or not), renal function 
(eGFR at screening as continuous variable), pre-treatment status (presently medicated 
for hypertension or not), randomized treatment, and the baseline 24-hour mean SBP as 
fixed effect covariates.  Change from baseline will be the dependent variable.  Analysis 
will be conducted on ITT analysis set. The last ABPM SBP post baseline will be used for 
the analysis.   


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Descriptive statistics (n, mean, Q1, median, Q3, SD, minimum, and maximum) will be 
reported by treatment group, along with the least squares means, differences between 
LS means, a 2-sided 95% confidence interval (CI) for each difference, p-value from the 
model effects.  
8.1.1.2. Sensitivity Analysis 
Sensitivity analyses will be conducted to examine the robustness of the inference: 
x 
If subject receives rescue medication and has an ABPM value after rescue 
medication, this value will be analyzed as an outcome. In study 603A, a subject 
who requires rescue medication will attempt to complete an ABPM before 
initiating rescue medication. A subject will be terminated if rescue medication 
starts within the first 6 weeks, or will start study 603B (after the first 6 weeks).  
No post-rescue medication value is expected and as a result, analysis of post-
rescue data will not be conducted. This sensitivity analysis will only be 
conducted if >5 subjects have post rescue medication values. 
x 
Subjects without scheduled Week 12 assessment (i.e., post baseline ABPM for 
subjects who did not complete 12 weeks treatment) will be excluded from the 
analysis.   
x 
A tipping point analysis will be conducted for subjects without Week 12 
assessments.  The following steps will be taken: 
o If subject has withdrawn from the study or has initiated rescue 
medication, the value will be considered as missing.   
o A regression model will be used to impute the missing change value using 
SAS PROC MI procedure.  Covariate will include baseline 24-hr mean SBP, 
diabetes status (history of T2DM or not), renal function (eGFR at 
screening), pre-treatment status (presently medicated for hypertension 
or not) and randomized treatment. One hundred datasets will be 
imputed.  
o If subjects with missing values are in the placebo treatment arm, the 
imputed value will be used in the analysis.  
o If the subject is in the bexagliflozin treatment arm, a series of δ mm Hg 
will be added to the imputed values. The δ value will range from 0.5 to 
5, with step size of 0.5.  
o The same ANCOVA analysis from Section 8.1.1.1 will be conducted for 
each imputed dataset and δ.  The results will be combined using PROC 
MIANALYZE in SAS. 
x 
Wilcoxon rank sum test will be conducted including all post baseline ABPM SBP 
values. For a subject who has no post baseline assessment, the worst outcome 
within the treatment group (i.e., change from baseline = the maximum increase 
from baseline in the same treatment group) will be considered.  


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8.1.1.3. Subgroup Analysis 
The primary efficacy endpoint will be descriptively summarized by the following 
subgroups: 
x 
Age (< 65 years or ≥ 65 years); 
x 
Gender (male or female); 
x 
Race (White or Caucasian; Black or African-American; Asian; Other).  If the 
number of Asian subjects is less than 5 in any treatment group, they will be 
included with Other; subjects identifying with more than one racial group will 
also be treated as Other; 
x 
Diabetes status (history of T2DM or not); 
x 
Renal function (eGFR at screening ≥ 60 or not); 
x 
Pre-treatment status (presently medicated for hypertension or not); 
x 
Types of anti-hypertension medication used; 
x 
Baseline 24-hour mean SBP status (SBP≤160 mm Hg or SBP>160 mm Hg); 
Same summary and ANCOVA model will be presented as in section 8.1.1.1 for each level 
of the subgroup. 
In addition, univariate and multivariate exploratory analyses will be conducted to assess 
potential baseline and diagnosis effect in controlling of hypertension. For univariate 
analysis, ANOVA with each subgroup factor, treatment, and interaction between 
subgroup factor and treatment will be performed. Statistically significant subgroup 
factors, judging by the type 3 test of the factor (P-value < 0.1), will be further explored 
in multivariate analyses.  ANOVA with these subgroup factors and treatment will be 
implemented.   
8.1.2. 
Secondary Efficacy Endpoints and Analyses 
The secondary efficacy endpoints include mean ambulatory and seated office SBP, mean 
ambulatory and seated office DBP. Secondary efficacy endpoints will be accessed 
without multiplicity adjustment. Analyses will be primarily based on ITT analysis set.   
8.1.2.1. The proportion of subjects who achieve a reduction of mean 
ambulatory SBP of 10 mm Hg or greater 
Subjects who achieve a reduction of mean ambulatory SBP of ≥ 10 mm Hg will be 
summarized using frequency and percentage by treatment arm.  Logistic regression will 
be used to analyze the treatment effect.  The model will include diabetes status 
(history of T2DM or not), renal function (eGFR at screening as continuous variable), pre-
treatment status (presently medicated for hypertension or not), baseline mean 


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ambulatory SBP value and randomized treatment. The LS Mean responding proportion 
and 95% CI will be estimated within each treatment group from a logistic regression 
model. A p-value for comparison by treatment group will also be provided.  Two 
different outcomes will be explored: 
x 
Responder will be defined using the last-post baseline value.  If a subject received 
rescue medication, the value prior to the initiation of rescue medication will be 
used (primary analysis);  
x 
Subjects with no post baseline assessments prior to early withdrawal from the study 
or initiation of the rescue medication will be considered as non-responders 
(sensitivity analysis). 
8.1.2.2. The proportion of subjects who achieve ambulatory SBP of 
135 mm Hg or less 
The summary and analyses will be provided as in section 8.1.2.1. 
8.1.2.3. The placebo-adjusted change from baseline to week 12 in seated 
office SBP  
A summary and ANCOVA model will be presented as in section 8.1.1.1.  The model will 
use baseline seated office SBP in place of baseline mean ambulatory SBP. 
8.1.2.4. The proportion of subjects who achieve a mean seated office SBP 
of 140 mm Hg or less at week 12 
A summary and analysis will be presented as in section 8.1.2.1.  The model will use 
baseline seated office SBP in place of baseline mean ambulatory SBP. 
8.1.2.5. The placebo-adjusted change from baseline to week 12 in mean 
ambulatory DBP  
A summary and ANCOVA model will be presented as in section 8.1.1.1.  The model will 
use baseline mean ambulatory DBP in place of baseline mean ambulatory SBP. 
8.1.2.6. The proportion of subjects who achieve a mean ambulatory DBP of 
87 mm Hg or less at week 12 
A summary and analysis will be presented as in section 8.1.2.1. The model will use 
baseline mean ambulatory DBP in place of baseline mean ambulatory SBP. 


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8.1.2.7. The proportion of subjects who achieve a mean ambulatory DBP of 
4 mm Hg or greater 
A summary and analysis will be presented as in section 8.1.2.1. The model will use 
baseline mean ambulatory DBP in place of baseline mean ambulatory SBP. 
8.1.2.8. The placebo-adjusted change from baseline to week 12 in seated 
office DBP  
A summary and ANCOVA model will be presented as in section 8.1.1.1.  The model will 
use baseline seated office DBP in place of baseline mean ambulatory SBP. 
8.1.2.9. The proportion of subjects who achieve a mean seated office DBP 
of 90 mm Hg or less at week 12 
A summary and logistic model will be presented as in section 8.1.2.1.  The model will 
use baseline seated office DBP in place of baseline mean ambulatory SBP. 
8.1.2.10. The trough-to-peak ratio of ABPM SBP at week 12 
Trough/Peak ratio will be calculated based on the four valid measurements centered on 
approximate Tmax (4 h post-dose, i.e. 2 measurements on or before 4 h and 2 
measurements after 4 h) and the four valid measurements immediately preceding the 
removal of the monitor and prior to administering a tablet.  The ratio will be 
summarized by treatment arm at week 12. The first 24-hour hourly change from 
baseline since dose administration will be summarized by treatment group and time 
(i.e., 0h post-dose, 2h post-dose, …, and 23h post-dose). Hour 0 will be the hour when 
dosing is occurred. All measures at 0h post-dose are measures within the same clock 
hour, but after dosing. 
8.1.3. 
Exploratory Endpoints and Analyses 
The exploratory efficacy endpoints include change from baseline in 24-hours mean 
ambulatory SBP, DBP, heart rate, pulse pressure, body weight, HbA1c, and subjects 
requiring rescue medication. Analyses will be primarily based on ITT analysis set.   
8.1.3.1. The placebo-adjusted change from baseline to week 12 in 24-hour 
mean ABPM SBP among subjects taking appropriate doses of three 
or more types of antihypertensive therapies at baseline  
A summary and ANCOVA model will be presented as in section 8.1.1.1 using only 
subjects taking ≥ 3 types of antihypertensive therapies at baseline.  


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8.1.3.2. The placebo-adjusted 24-hour mean pulse pressure at week 12 
The pulse pressure will be calculated as the difference between ambulatory SBP and 
ambulatory DBP. The 24-hour mean pulse pressure will be calculated as the mean of all 
hourly ambulatory pulse per day per clock hour. A summary and ANCOVA model will be 
presented as in section 8.1.1.1.  The model will include baseline pulse pressure in place 
of baseline mean ambulatory SBP. 
8.1.3.3. The placebo-adjusted change from baseline to week 12 in 24-hour 
ambulatory SBP among dippers and non-dippers 
Dippers and non-dippers are defined as: 
Dippers: nocturnal mean SBP ≤ 90% of diurnal mean SBP; 
Non-dippers: nocturnal mean SBP >90% of diurnal mean SBP. 
The nocturnal time interval is between 12:00 AM – 8:00 AM and diurnal time interval is 
between 11:00 AM – 7:00 PM. The nocturnal time mean is computed as the mean of 8 (or 
fewer, if failures occur) hourly mean SBP values in the nocturnal range and the diurnal 
time mean SBP is computed as the mean of 8 (or fewer) hourly mean SBP in the diurnal 
range of times. 
Summaries and ANCOVA models will be presented as in section 8.1.1.1 for dippers and 
non-dippers, respectively.  
8.1.3.4. The placebo-adjusted change from baseline in 24-hour ambulatory 
HR at week 12 
A summary and ANCOVA model will be presented as in section 8.1.1.1. In addition, 
baseline 24-hour ambulatory HR will also be included as covariate. 
8.1.3.5. The placebo-adjusted change from baseline in body weight at week 
12 
A summary and ANCOVA model will be presented as in section 8.1.1.1.  The model will 
include baseline weight in place of baseline mean ambulatory SBP. Baseline 24-hour 
ambulatory SBP will also be included as covariate. 
8.1.3.6. The placebo-adjusted change from baseline in HbA1c at week 12 
A summary and ANCOVA model will be presented as in section 8.1.1.1.  The model will 
include baseline HbA1c in place of baseline mean ambulatory SBP. Baseline 24-hour 
ambulatory SBP will also be included as covariate. 


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8.1.3.7. The proportion of subjects requiring any rescue medication at 
week 12 
The summary and analyses will be provided as in section 8.1.2.1 primary analysis. 
8.2. 
STUDY 603B 
For all efficacy analyses in study 603B the baseline will be defined as the last non-
missing measurement prior to the first dose of double-blind study medication in 603B. 
Change is defined as the observed value minus baseline value.  Similar to study 603A, 
the values from early termination visits, or values before the initiation of rescue 
medication in 603B will be used. 
8.2.1. 
Primary Efficacy Endpoint and Analysis 
The primary efficacy endpoint is the change from baseline (at week 12) to week 24 of 
the 24-hour mean ambulatory SBP in the bexagliflozin group compared to the change in 
the placebo group, testing for superiority at a two-sided 0.05 level of significance. 
8.2.1.1. Primary Efficacy Analysis 
Let μBexagliflozon, 24 and μPBO, 24 represent the mean changes from baseline in 24-hour 
ambulatory SBP at Week 24 for bexagliflozin and placebo, respectively. The following 
hypotheses will be tested: 
H0: μBexagliflozon, 24 = μPBO, 24 versus H1: μBexagliflozon, 24 ≠ μPBO, 24 
To test this hypothesis, an ANCOVA will be applied to analyze the mean change in 
24-hour average ABPM SBP.  The ANCOVA model will be used to adjust for the treatment 
group stratification by rescue medication/response as assessed by ABPM SBP at baseline 
(Week 12) (i.e., require rescue medication, not require rescue medication: SBP 
change≤5 mmHg, >5 to ≤20 mmHg, >20 mmHg), baseline ABPM SBP value, and 
randomized treatment for study 603B as fixed effects.  
Similar descriptive analysis as in Section 8.1.1.1 will be provided. 
In addition, the interaction of the response stratification class (response ≤ 5 mm Hg, 5 < 
response ≤ 20 mm Hg, and response > 20 mm Hg, requiring rescue medication prior to 
week 24) and randomized treatment for study 603B will be added to the model.  P-value 
for the type 3 test will be presented to check the significance of the interaction terms 
at 0.10 significant level.  LS means, standard errors, and 95% CI for each combination of 
stratification class and treatment will be estimated from the model. 


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8.2.1.2. Sensitivity Analysis 
x 
If subject has received rescue medication and has an ABPM value after rescue 
medication, this value will be analyzed as an outcome. Per protocol, if subject 
requires rescue medication, ABPM will be taken before starting rescue 
medication. In such case, ABPM is not normally measured again after rescue 
medication. This sensitivity analysis will only be conducted if >5 subjects have 
post rescue medication values.  
x 
Subjects without scheduled Week 24 assessments will be excluded from the 
analysis.   
x 
A tipping point analysis will be conducted if there are subjects missing Week 24 
assessment.  Steps below will be followed: 
o If subject used rescue medication or discontinued during withdrawal 
period, value will be considered as missing.   
o A regression model will be used to impute the missing change value using 
SAS PROC MI procedure.  Covariate will include baseline 24-hr mean SBP, 
the treatment group stratification by response as assessed by ABPM SBP 
at baseline (Week 12), and randomized treatment for study 603B. One 
hundred datasets will be imputed.  
o If subjects with missing value are in the placebo treatment arm, the 
imputed values will be used.  
o If the subject is in the bexagliflozin treatment arm, a series of δ will be 
added to the imputed values. The δ value will range from 0.5 to 5, with 
step size equals 0.5.  
o Same ANCOVA analysis from Section 8.2.1.1 will be conducted for each 
imputed dataset and δ.  Results will be combined using PROC MIANALYZE 
in SAS. 
x 
Wilcoxon rank sum test will be conducted including all Week 24 ABPM SBP 
values. If subject requires rescue medication, ABPM before starting rescue 
medication will be used; for a subject who has no post baseline assessment, the 
worst outcome within the treatment group (i.e., change from baseline = the 
maximum increase from baseline in the same treatment group) will be 
considered.  
8.2.2. 
Secondary Efficacy Endpoint(s) and Analyses 
The secondary efficacy endpoints include mean seated office SBP, and mean ambulatory 
and seated office DBP. No adjustment for multiple comparisons will be applied.   
8.2.2.1. The placebo-adjusted change from week 12 to week 24 in seated 
office SBP  
A summary and analyses will be provided as in section 8.2.1.1.  The model will include 
baseline seated office SBP in place of baseline mean ambulatory SBP.   


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8.2.2.2. The placebo-adjusted change from week 12 to week 24 in mean 
ambulatory DBP from week 12 to week 24  
A summary and analyses will be provided as in section 8.2.1.1.  The model will include 
baseline mean ambulatory DBP in place of baseline mean ambulatory SBP. 
8.2.2.3. The placebo-adjusted change from week 12 to week 24 in seated 
office DBP  
A summary and analyses will be provided as in section 8.2.1.1.  The model will include 
baseline seated office DBP in place of baseline mean ambulatory SBP.  
8.2.3. 
Exploratory Endpoints and Analyses 
8.2.3.1. The proportion of subjects requiring any rescue medication at 
week 24 
Subjects who require any rescue medication will be summarized using frequency and 
percentage by treatment arm.  Logistic regression will be used to analyze the treatment 
effect.  The model will include the rescue medication/response as assessed by ABPM 
SBP at baseline (Week 12) (i.e., require rescue medication, not require rescue 
medication: SBP change ≤ 5 mmHg, > 5 - ≤ 20 mmHg, > 20 mmHg), baseline ABPM SBP 
value, and randomized treatment for study 603B as fixed effects. LS Mean responding 
proportion and 95% CI will be estimated within each treatment group from the logistic 
regression model. P-value for comparison of treatment group will also be provided.  
8.2.3.2. The placebo-adjusted change from week 12 to week 24 in 24-hour ABPM 
SBP by response status 
The effect of withdrawal will be studied for each subgroup of subjects separated by 
their response status at baseline week 12 (i.e., require rescue medication, not require 
rescue medication: SBP change ≤ 5 mmHg, > 5 - ≤ 20 mmHg, > 20 mmHg, and >5 mmHg).  
A summary and analyses will be provided as in section 8.2.1.1 for subjects in each 
group. Baseline ABPM SBP value will be used as covariate and the randomized treatment 
will be included as the fix effects in the model. 
8.3. 
INTEGRATED ANALYSES 
Assessments for studies 603A and 603B will be combined to further assess the 
effectiveness of bexagliflozin after treatment for 12, 24, and 36 weeks.  The sequence 
numbers in this section refer to the numbers in Table 2.  All analyses will be based on 
the integrated ITT analysis set.  


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8.3.1. 
Change in mean ambulatory SBP or DBP after 12, 24, and 36 weeks 
of treatment of bexagliflozin 
Summary statistics will be provided for actual value at baseline, and actual value and 
change from baseline after 12, 24, and 36 weeks treatment with bexagliflozin.  The 95% 
CI based on normal distribution will also be presented for the change value. For subjects 
who require rescue medication, the ABPM taken prior to rescue medication (as was used 
for the primary analyses for studies 603A and 603B) for the time point will be used.   
The proportion of subjects who achieve defined goals will be summarized after 12, 24, 
and 36 weeks treatment with bexagliflozin using frequency, percentage and 95% 
binomial confidence interval.  These goals will include: 
x 
A reduction of mean ambulatory SBP of 10 mm Hg or greater; 
x 
A reduction of mean ambulatory DBP of 4 mm Hg or greater. 
8.3.2. 
Change in seated office SBP or DBP after 12, 24, and 36 weeks 
treatment of bexagliflozin  
Summary statistics as in section 8.3.1 will be provided for seated office SBP or DBP.  
The proportion of subjects who achieve defined goals will be summarized after 12, 24, 
and 36 weeks treatment with bexagliflozin using frequency, percentage and 95% 
binomial confidence interval.  These goals will include: 
x 
The proportion of subjects who achieve a mean seated office SBP of 140 mm Hg 
or less at week 12. 
x 
The proportion of subjects who achieve a mean seated office DBP of 90 mm Hg 
or less at week 12. 
8.3.3. 
Cumulative mean change from baseline in seated office SBP and 
DBP as a function of time (including all scheduled office visits) for 
subjects exposed to bexagliflozin  
Summary tables will be presented for seated office SBP and DBP by treatment sequence 
for all subjects in 603B ITT population.  Table will include baseline, actual value and 
change from baseline at cumulative weeks 6, 12, 18, 24, and 36.  Baseline is defined as 
the last non-missing value before the first dose of bexagliflozin in 603A.  A by-sequence 
plot of change from baseline will include mean and standard error.  
9. 
SAFETY 
All analyses described in this section will be performed separately for each study and 
integrated analysis. The analysis set used for safety analyses will be the safety analysis 


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set for 603A, safety analysis set for withdrawal period for 603B, safety analysis set for 
603B run-in period, and integrated safety analysis set for integrated analysis.  Safety 
data include AEs; physical examination results; vital signs, including blood pressures; 
ECG results; and clinical laboratory results, including serum chemistry, hematology, 
serum lipids, and urinalysis.  
9.1. 
EXTENT OF EXPOSURE 
Study drug exposure will include: 
x 
Treatment duration by treatment group 
x 
Total dose received by treatment group 
Treatment duration (in weeks) is calculated as (the date of the last dose of study drug - 
the date of the first dose of study drug + 1) / 7 and rounded to 1 decimal place.  Total 
dose consumed will be calculated as number of tablets dispensed on the first day after 
randomization – number of tablets returned on the last day of the period.  If any of the 
bottles dispensed are not returned, it will not be possible to compute the total dose 
consumed.  In this case, the number of tablets consumed will be considered as missing.   
Exposure will be summarized for study 603A, 603B, and integrated.   
Summary statistics for treatment duration (in weeks) and total dose consumed, as well 
as a frequency summary of treatment duration categories (e.g., < 1, 1 - < 3 weeks), will 
be provided. 
9.2. 
TREATMENT COMPLIANCE  
Subjects will be provided with dosing instructions each time study medication is 
dispensed.  Subjects will also be instructed to bring their medication with them to every 
visit.   Treatment compliance will be summarized by treatment for 603A and 603B.   
Compliance in studies 603A, 603B, and integrated will be calculated as follows: 
x 
Percent compliance = (number of tablets consumed / number of tablets that should 
have been taken) x 100. 
x 
Number of tablets consumed is computed as in Section 9.1. 
x 
Number of tablets should have taken = number of exposure days. 
x 
Number of exposure days = last dose date – first dose date + 1. 
If any of the bottles dispensed are not returned, the number of tablets consumed and 
compliance will be considered as missing.  Compliance will be summarized for each 
period by actual treatment for safety analysis set.  A separate table for overall 
compliance will be presented without treatment arms.  A frequency summary of 
compliance will also be presented with the following categories: < 75%, 75-<100%, 


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100-120%, and > 120%. 
9.3. 
ADVERSE EVENTS 
Adverse events will be collected and recorded after a subject is enrolled in the study to 
the last scheduled contact.  Any new serious adverse events (SAE) reported by the 
subject to the investigator that occur after the last scheduled contact, and are 
determined by the investigator to be reasonably associated with the use of the 
investigational product, will be included in the analysis.  
For all AEs, preferred AE terms and system organ class (SOC) will be coded using 
terminology from the Medical Dictionary for Regulatory Activities (MedDRA), version 
19.0 or above.    
A treatment-emergent adverse event (TEAE) is defined as an AE that begins (or an 
existing condition that worsens) after the first administration of double-blind study 
medication in study 603A).  TEAE will be summarized separately for periods: study 603A 
and study 603B after randomization, dependent upon in which period the event started.  
TEAE summary for all periods combined will include all bexagliflozin TEAEs started on or 
after the first dose of bexagliflozin and before the last dose of bexagliflozin.     
Drug-related AEs will be considered those to be possibly, probably and definitely related 
to bexagliflozin administration based on the investigator’s assessment. 
Unless otherwise specified, AEs will be summarized by SOC and PT, with SOCs and PTs 
within SOCs presented in descending order of subject incidence. 
9.3.1. 
Derived Data 
AE onset day is calculated as (date of AE start – date of first double-blind dose of each 
study + 1).   
9.3.2. 
Data Summarization  
The AE summaries will include: 
x 
An overall summary of the number and percentage of subjects reporting any 
TEAEs, serious TEAEs, treatment-related TEAEs, serious treatment-related TEAE, 
any TEAEs leading to treatment discontinuation, any TEAEs leading to subject 
withdrawal and TEAEs leading to death.   
x 
TEAEs overall and by SOC and PT 
x 
TEAEs by severity, overall and by SOC and PT 


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x 
Serious TEAEs, overall and by system organ class and preferred term 
x 
TEAEs by relationship to study treatment, overall and by system organ class and 
preferred term 
x 
TEAEs leading to treatment discontinuation, overall and by SOC and PT 
x 
TEAEs leading to study withdrawal, overall and by SOC and PT 
x 
Common TEAEs.  Common TEAEs are as TEAEs that occur in > 5% of the subjects 
in either of the treatment groups.  
Except for common TEAEs, each data summary will be presented for the 603A period, 
for the 603B period after randomization, and for the integrated bexagliflozin treatment 
periods. Common TEAEs will be presented for the integrated bexagliflozin treatment 
period. Tables for the 603A will be summarized by treatment received in 603A and 
overall. The summary table for the 603B period after randomization will contain 2 
layers: 1) 603B treatment, and 2) split 603B treatment by 603A treatment groups.  
Tables for integrated bexagliflozin treatment periods will present number and 
percentage of subjects with event, and exposure adjusted AE rate (i.e. rate per 100 
patient years of bexagliflozin).  Events will be summarized according to the actual 
treatment when the event starts.  The denominator for percentage calculations will be 
the total number of subjects who receive at least one dose of the specified treatment.  
All subjects should have received at least one dose of bexagliflozin unless they were 
withdrawn from study 603A. 
All AE summary tables will be prepared by actual treatment arm for the safety analysis 
set.  For summary tables, subjects having more than 1 event with the same PT in the 
period will be counted once for that term.  Subjects having more than 1 event with the 
same SOC in the period will be counted once for each event and once for that SOC.  For 
tabulations by severity, only a subject’s most severe event within the category (e.g. 
overall, SOC, PT) in the period will be counted; similarly, for tabulations by 
relationship, only a subject’s most related event within a category in the period will be 
counted.  The denominator for percentages will be the number of subjects in the safety 
analysis set for the given treatment group.   
Listings will be provided for all AEs and the following subsets: 
x 
All TEAEs at least possibly related to bexagliflozin 
x 
Serious AEs 
x 
AEs leading to treatment discontinuation 
x 
AEs with outcome of death.  
Additional information will be collected in the event diabetic ketoacidosis (DKA) is 


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suspected or observed.  These data will be listed. 
9.3.3. 
AEs of Special Interest 
AEs of special interest include, but are not limited to, diuretic effects, urinary tract 
infections (UTI), genital mycotic infections (GMI), hypoglycemia, hepatotoxicity, major 
adverse cardiovascular events (MACE), diabetic ketoacidosis (DKA), hypotension 
episodes, malignancies, fractures, renal failure events, hypersensitivity reactions, rash, 
pyelonephritis or urosepsis, and events may be associated with SGLT2 inhibition, 
including amputations, , and Fournier’s gangrene.  These AEs of special interest, except 
for MACE, will be prospectively identified based on the MedDRA PTs in the AEs log by a 
medical expert prior to the data base lock and unblinding of the individual subject 
treatment assignment. The list of AEs of special interest will be confirmed in a peer 
review process.  MACE and hypoglycemia events by severity will be summarized 
separately.  All AEs of special interest will be presented for 603A, 603B run-in, 603B 
post-randomization, and all periods combined in the same format as in Section 9.3.2.   
9.3.3.1. AE of Special Interest Identified by PTs 
The number and percentage of subjects experiencing TEAEs of special interest will be 
summarized for each treatment group by type of event. The incidence rate of AE of 
special interest per 100 patient years will also be summarized.  Each category of events 
will be displayed in a separate listing.   
9.3.3.2. Hypoglycemic Events 
Hypoglycemic event categories include: 
Category 
Description 
Severe 
Assistance required and blood glucose ≤70 mg/dL or no value 
available but responded to glucose treatment 
Documented 
Symptomatic 
Blood glucose ≤70 mg/dL and typical symptoms of hypoglycemia 
Asymptomatic 
Blood glucose ≤70 mg/dL and no typical symptoms of hypoglycemia 
Probable 
Symptomatic 
Typical symptoms of hypoglycemia and no value available but 
responded to glucose treatment 
Relative 
Typical symptoms of hypoglycemia and blood glucose >70 mg/dL 
 
While each event meeting the criteria above will be entered into the hypoglycemia log, 
only critical (severe) hypoglycemia, documented symptomatic hypoglycemia, 
asymptomatic hypoglycemia, and probable hypoglycemia will be entered as AEs.  
The number and percentage will be summarized for the integrated bexagliflozin 
treatment period: 


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x 
Each category of hypoglycemic event; 
x 
Any severe or documented hypoglycemic events. 
9.3.3.3. Major Adverse Cardiovascular Events 
Cardiovascular events considered to be potential MACE by the investigator will be 
submitted to an independent CEC for adjudication.  The events of interest include 
cardiovascular mortality, MI, stroke, hospitalization for acute coronary syndromes, 
urgent revascularization procedures, and other possible serious cardiovascular events.  
The number, percentage and incidence rate per 100 patient years of  adjudicated MACE 
will be summarized for each treatment group.  Adjudicated MACE will be further 
summarized by PTs. 
9.4. 
LABORATORY EVALUATIONS 
Laboratory tests will include hematology panel, chemistry panel, serum lipids, and 
urinalysis testing. Hematology, HbA1c, chemistry, serum lipids, and urinalysis will be 
performed at the following time points: at the screening visit (Week - 12), on Day -1 
visit, and at cumulative week 12, 24, and 36.  A list of laboratory tests is included in 
Table 3. 
Low density lipoprotein cholesterol (LDL-C) will be calculated by the Friedewald 
equation. If triglycerides are > 400 mg/dL, the calculated LDL-C value is invalid by this 
equation and will be set as missing. Direct LDL-C will be determined in subjects whose 
triglycerides are > 350 mg/dL at screening visit. All subsequent LDL-C of these subjects 
will be determined by the same direct LDL-C measurements only.  If triglycerides are 
>350 mg/dL, a reflex test will be performed based on direct LDL measurement.  The 
following algorithm will be used to obtain LDL-C values for the analyses: 
1. Select subjects (based on the SI unit) who had screening triglycerides >3.4 or 
>350 based on the conventional unit 
2. Take the LDL – direct measurement values only, throughout the study visits for 
those subjects 
3. If screening triglycerides > 350 and no direct LDL-C values have been 
determined, take the calculated.   
Among those subjects who have screening triglycerides >350 and have both calculated 
and direct LDL values, only the direct LDL will be analyzed. 
Urinalysis microscopy will be conducted if the subject has a positive result on the 
leukocyte esterase or nitrite dipstick tests to clarify the significance of the finding. 
Results of glucose measurement in the urinalysis must be suppressed from the 
laboratory reports so the sponsor, investigators, study coordinators, pharmacists, study 
subjects, and the CEC members will remain blinded to the dosing assignment.  


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All scheduled and unscheduled results will be considered in tables that assess maximum 
severity.   
Observed values (in SI units) and change from baseline over time will be summarized for 
each scheduled visit and the end of the study visit.  Laboratory data will be classified as 
low, normal, or high relative to the parameter’s reference range. Laboratory 
abnormalities for each treatment will also be summarized with shift tables for selected 
parameters.  All summary tables will be presented by treatment group and for each visit 
for study 603A and 603B. In addition, summaries based on assessments from both 
studies (603A and 603B) will also be presented by weeks of exposure of bexagliflozin 
(12 weeks, 24 weeks, and 36 weeks).   
All continuous variables will be summarized by number of subjects [n], mean, SD, Q1, 
median, Q3, minimum and maximum and categorical variables will be summarized by 
frequency and percentage. For hematology, chemistry, and serum lipids, columns will 
be included for normal ranges and individual abnormal laboratory values will be flagged 
and clinical significance will be indicated.  A listing for the microscopic examination will 
be provided for subjects who have a positive result from the urinalysis dipstick 
evaluation.  


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Table 3 
List of Laboratory Tests 
Hematology: 
• 
Hematocrit (Hct) 
• 
Hemoglobin (Hgb) 
• 
Mean corpuscular hemoglobin (MCH) 
• 
Mean corpuscular hemoglobin 
concentration (MCHC) 
• 
Mean corpuscular volume (MCV) 
• 
Platelet count 
• 
Red blood cell (RBC) count  
• 
White blood cell (WBC) count with 
differential  
 
Urinalysis:  
• 
Appearance 
• 
Bilirubin 
• 
Color 
• 
Glucose 
• 
Ketones 
• 
Microscopic examination of sediment  
• 
Nitrite  
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
 
Pregnancy test: 
Urine human chorionic gonadotropin (hCG) 
(only for females who are not diagnosed as 
postmenopausal) 
Serum Chemistry: 
• 
Albumin (ALB) 
• 
Alkaline phosphatase (ALK-P) 
• 
Alanine aminotransferase (ALT) 
• 
Aspartate aminotransferase (AST) 
• 
creatinine kinase (CK) 
• 
Blood urea nitrogen (BUN) 
• 
Calcium (Ca) 
• 
Bicarbonate (HCO3) 
• 
Chloride (Cl) 
• 
Creatinine 
• 
Glucose 
• 
Magnesium (Mg) 
• 
Phosphorus 
• 
Potassium (K) 
• 
Sodium (Na) 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Total cholesterol 
• 
HDL-cholesterol 
• 
LDL-cholesterol 
• 
Total protein 
• 
Triglycerides 
• 
Uric acid 
 
Glycemic control 
• 
HbA1c 
Population PK Sampling 
• 
Bexagliflozin plasma level 
9.5. 
VITAL SIGNS  
Vital signs will be measured at the screening visit (Week -12), on Day -1, Day 1, 
cumulative week 6, 12, 12 + 1 Day, 18, 24, 24 + 1 Day, 36 and 36 + 1 Day. Measurements 
of vital signs will include measurement of supine and standing blood pressure (BP) 
measurements, and heart rate.  Heart-rate in seated position will also be summarized. 
Orthostatic systolic and diastolic BP will be calculated as supine measurement – 
standing measurement.  Summary tables will be provided by treatment group and visit 
for study 603A and 603B.  An overall summary based on integrated data will be 
presented at 6, 12, 18, 24, and 36 weeks of bexagliflozin treatment.   


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Vital sign assessment on the clinical visit day is scheduled to be before the dosing of 
study medication.  Study level baseline will be defined as the last non-missing 
measurement on or prior to the first dose of double-blind study medication.  For 
integrated summary by weeks from first exposure of bexagliflozin, baseline is defined as 
the last non-missing measurement on or prior to the first exposure to bexagliflozin.   
For BP, pulse rate, and respiration rate, observed values and change from baseline will 
be summarized using descriptive statistics (n, mean and median, standard deviation, 
Q1, and Q3, minimum and maximum) at each scheduled visit and the end of the study 
visit.  For BP, supine, standing, and orthostatic BP will be summarized for safety 
analysis set.   
9.6. 
ELECTROCARDIOGRAM  
A 12-lead electrocardiogram (ECG) will be conducted at the screening visit (Week - 12), 
on Day -1, and at cumulative week 12, 24, and 36. ECG parameters measured will be 
the RR interval, PR interval, QRS duration, and QT interval. Each ECG should also be 
assessed by the investigator for signs of ischemia, clinically significant hypertrophy, and 
clinically significant T-wave abnormalities or arrhythmia. 
For each abnormal ECG result, the investigator shall ascertain if the observation 
represents a clinically significant change from the screening ECG for that individual 
subject.  This determination does not need to be made the first time an abnormal result 
is observed. The investigator may repeat the ECG to verify the results of the original 
result. If the ECG result is determined to be a clinically significant and abnormal change 
from baseline for that subject, it is considered an AE. 
For the ECG parameters, observed values and change from baseline from scheduled 
visits will be summarized with descriptive statistics by treatment group and overall at 
each visit for each study.   
In addition, an integrated summary table will be presented for 12 weeks, 24 weeks, and 
36 weeks of exposure to bexagliflozin. 
9.7. 
PHYSICAL EXAMINATION 
A complete physical examination will be conducted at the Day -1. The examination will 
include measurement of body weight, and a general assessment of all body systems 
including the skin, head, eyes, ears, nose, throat, neck, heart, lungs, abdomen, lymph 
nodes, and extremities.  An abbreviated physical examination will be conducted at 
screening visit 1 (Week -12) and at cumulative week 12, 24, and 36.  The examination 
will include body weight and height (height will be measured only at screening), and 
general assessment of the skin, heart, lungs and abdomen.  


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10. 
INTERIM ANALYSIS 
An interim non-binding futility analysis when half (i.e., 300) patients have completed 
the first 12 weeks of the treatment period was conducted. Using an interpolated 
spending function of Type II error, i.e., with 0.5 proportion of Type II error being spent 
at the interim look, the study could have stopped for futility when the test statistics (Z 
score) was less than 0.656 (or p-value > 0.512). The overall power for the first primary 
endpoint was maintained at >95% with this interim look. The interim analysis was 
conducted by an independent group that was not part of the study management team.  
All study subjects were to continue to receive the investigational products during the 
data cleaning and analysis time.  Results from the interim analysis were reviewed by an 
independent Data Monitoring Committee (DMC).  The data extraction and transfer 
methods and measures for preservation of blinding/access to interim results followed 
the rules described in the DSMB SAP. 
11. 
DATA AND SAFETY MONITORING BOARD 
An independent data and safety monitoring board (DSMB) has been charged with 
reviewing descriptive summaries of accumulating safety, subject disposition and limited 
efficacy data every 6 months, or at a frequency recommended by the DSMB.   
A designated statistician who is not involved with the study operation has been assigned 
to hold the treatment codes. The unblinded treatment information can be provided to 
the DSMB to facilitate the evaluation of any clinically important increase in the rate of a 
serious suspected adverse reaction or to the designated safety contact when the 
treatment information is required to determine if an expedited safety report must be 
submitted to regulatory agencies. The data for DSMB review will be prepared by an 
unblinded team. Personnel involved in the conduct of the study will not participate in 
the preparation of the data and will not receive the data, or participate in the 
unblinded portions of the DSMB meetings. Additional details can be found in the DSMB 
charter and DSMB SAP. 
12. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
Wilcoxon rank sum tests were added to both primary endpoints as sensitivity analysis. 
Protocol specified that if < 64 BP readings (51 day time and 13 night time BP readings) 
are recorded, ABPM is considered as invalid and is repeated. In SAP, the validity criteria 
has been relax to include more subjects (section 8.1.1.1).   
Additional exploratory endpoints are added in sections 4.1.3 and 4.2.3. 


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Baselines for efficacy endpoints are defined as the last measurement prior to the first 
dose of double-blind study medication, not prior to randomization per protocol. 
Randomization date is only used if subject is not dosed. 
Adverse events occurred during 603B run-in period will not be summarized separately as 
stated in the protocol, instead, adverse events occurred during bexagliflozin treatment 
period will be summarized based on integrated safety analysis set. Some tables are only 
prepared for integrated safety analysis set due to lack of event occurrences. 
 
 
 


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13. 
PROGRAMMING CONSIDERATIONS 
The following conventions will hold for programming of outputs: 
• 
SAS® Version 9.3 or higher will be used for programming and production 
• 
The format of the table shells will be followed as closely as possible; however, in 
the course of programming and familiarization with the database, some changes may 
become necessary.  All changes will be documented.  Major changes will be documented 
through a formal amendment to this document.  
• 
Patients in this study will be identified as “Subjects.” 
• 
Descriptive statistics will be displayed in the following order: 
n 
Mean 
Standard deviation (SD) 
Q1 
Median 
Q3 
Minimum  
Maximum  
 
• 
Decimal places: For summary statistics, the minimum and maximum will be 
reported with the same number of decimal places as the collected measure, the mean, 
LS mean (if applicable) and median will have 1 more decimal place than the measure 
collected, and the SD and confidence interval (CI) will have 2 more decimal places than 
the collected measure.  For frequency distributions, percentages will be reported to 1 
decimal place.  For p-values, 4 decimal places will be reported or the SAS® p-value 
format of “< 0.0001” or “> 0.9999” will be reported.  
• 
Unless otherwise noted, the denominator for percentages is the number of 
subjects in the applicable analysis population and treatment group.  
• 
If the frequency for a particular table cell is zero, then “0”, properly aligned, 
will be displayed (i.e. “0 (0.0%)” will not be displayed.) 
• 
Non-numeric values:  Where variables are recorded using < (e.g., “< 10” or “≤ 
10”) the numeric portion of the result will be used (e.g., < 10 and ≤ 10 becomes 10) for 
summary; where variables are recorded using > (e.g., “> 10” or “ ≥ 10”) the numeric 
portion of the result will be used (e.g. > 10 and ≥ 10 become 10) for summary; the 
actual recorded results, (e.g. “< 10” or “> 10”) will appear in listings. 


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13.1. 
GENERAL CONSIDERATIONS 
x 
A separate SAS program will be created for each output. 
x 
Output files will be delivered in Word format. 
x 
Numbering of TFLs will follow ICH E3 guidance 
 
13.2. 
TABLE, LISTING, AND FIGURE FORMAT 
13.2.1. 
General 
x 
All TLFs will be produced in landscape format, unless otherwise specified. 
x 
All TLFs will be produced using the Courier New font, size 9  
x 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
x 
Headers and footers for figures will be in Courier New font, size 9. 
x 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
x 
TLFs will be in black and white (no color), unless otherwise specified 
x 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
x 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
x 
Mixed case will be used for all titles, footnotes, column headers, and 
programmer-supplied formats, as appropriate. 
 
13.2.2. 
Headers 
x 
All output should have the following header at the top left of each page: 
Theracos Sub, LLC 
Protocol Number: THR-1442-C-603       
x 
Draft or Final in top right corner. 
x 
All output should have Page n of N at the top of each page. TLFs should be internally 
paginated in relation to the total length (i.e., the page number should appear 
sequentially as page n of N, where N is the total number of pages in the table). 


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x 
The date output was generated should appear along with the program name as a 
footer on each page. 
13.2.3. 
Display Titles 
x 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination. A decimal system (x.y and x.y.z) should be 
used to identify TLFs with related contents. The title is centered. The analysis set 
should be identified on the line immediately following the title. The title and table 
designation are single spaced. A solid line spanning the margins will separate the 
display titles from the column headers. There will be 1 blank line between the last 
title and the solid line. 
 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Set 
 
13.2.4. 
Column Headers 
x 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
x 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values will be presented in a separate comparison column (if applicable).  
x 
For numeric variables, include “unit” in column or row heading when appropriate. 
x 
Analysis set sizes will be presented for each treatment group in the column heading 
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set. 
x 
The order of treatments in the tables and listings will be active treatment first, then 
placebo, followed by a total column (if applicable). 
13.2.5. 
Body of the Data Display 
13.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 


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• 
numbers containing fractional portions are decimal aligned. 
13.2.5.2. Table Conventions 
x 
Units will be included where available 
x 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
x 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 
x 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
x 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 
n 
  XX 
Mean 
XXX.X 
SD 
     X.XX 
Q1 
XXX.X 
Median 
XXX.X 
Q3 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
x 
P-values should be output in the format: “0.xxxx”, where xxxx is the value rounded 
to 4 decimal places. Any p-value less than 0.0001 will be presented as <0.0001.  If 
the p-value is returned as >0.9999 then present as >0.9999 
x 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). If the rounded 
percentage is 0.0, display as '<0.1'. Unless otherwise noted, for all percentages, the 
number of subjects in the analysis set for the treatment group who have an 


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observation will be the denominator. Percentages after zero counts should not be 
displayed and percentages equating to 100% should be presented as 100%, without 
any decimal places.  
x 
Tabular display of data for concomitant and rescue medications should be presented 
by treatment class with the highest occurrence in the total column in decreasing 
order.  Tabular display of data for medical history and adverse event data should be 
presented by the SOC using descending order.  Within the drug class and SOC, 
medical history (by preferred term), drugs (by ATC2 code), and adverse events (by 
preferred term) should be displayed in decreasing order in the total column. If 
incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics which cannot be estimated should be 
reported as “-”. 
x 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
x 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
x 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page.  The overall summary statistics for the subheading should only be 
output on the first relevant page. 
13.2.5.3. Listing Conventions 
x 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 
x 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
x 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
x 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 


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x 
Units will be included where available 
13.2.5.4. Figure Conventions 
x 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis. 
13.2.6. 
Footnotes 
x 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
x 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
x 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
x 
Subject specific footnotes should be avoided, where possible. 
x 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page.  
x 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’). 
14. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. INC Research SOP 03.010 
and 03.013 provide an overview of the development of such SAS programs. 
INC Research SOP 03.009 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the 
proper clinical trial output by checking for their logic, efficiency and commenting and 
by review of the produced output.  Details will be provided in a separate QC plan. 
 
 


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15. 
MOCK-UPS 
Shells for tables, figures, and listings are provided in a separate document.