Clinical trial NCT04026165
Conditions: Diabetic Kidney Disease
Sponsor: Gilead Sciences
Start date: 2019-07-24; Completion date: 2021-09-03
Enrollment: 384 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this study is to evaluate whether selonsertib (SEL) can slow the decline in kidney function in participants with moderate to advanced diabetic kidney disease (DKD).

Detailed description:
Following the screening period, eligible participants will enroll into a Run-in period of at least 5 weeks and receive placebo to match SEL for at least 1 week and then SEL for at least 4 weeks. After completing Run-in period, eligible participants will be randomized and receive either SEL or placebo to match SEL for at least 48 weeks.

Arms: arm 1: Run-in Period (5 Weeks): Participants will receive placebo-to-match SEL for at least one week and then SEL 18 mg for at least 4 weeks.

Randomized Period: Participants will be randomized to receive SEL 18 mg for at least 48 weeks. arm 2: Run-in Period (5 Weeks): Participants will receive placebo-to-match SEL for at least one week and then SEL 18 mg for at least 4 weeks.

Randomized Period: Participants will be randomized to receive placebo-to-match SEL for at least 48 weeks.
Interventions: intervention 1: SEL intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet administered orally once daily intervention 2: Tablet administered orally once daily

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
MOSAIC - A Phase 2b, Randomized, Double-Blind, Placebo-
Controlled, Parallel Group, Multicenter Study Evaluating the 
Efficacy and Safety of Selonsertib in Subjects with Moderate to 
Advanced Diabetic Kidney Disease
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
Clinical Trials.gov 
Identifier:
117513 
NCT04026165
Indication:
Diabetic Kidney Disease
Protocol ID:
GS-US-223-1017
Protocol Version/Date:
Original:
01 February 2019
Amendment 1:
10 June 2019
Amendment 2: 
13 April 2020
This study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312); however, sites located in the European Economic Area and Switzerland are 
not included under the IND and are considered non-IND sites.
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
(rJ GILEAU 


Selonsertib 
Protocol GS-US-223-1017 
Gilead Sciences, Inc. 
Final 
Amendment 2 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 5 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 5 
PROTOCOL SYNOPSIS .............................................................................................................................................. 6 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 18 
1. 
INTRODUCTION .............................................................................................................................................. 21 
1.1. 
Backgrowid ............................................................................................................................................ 21 
1.2. 
Investigational Medicinal Product Selonsertib ....................................................................................... 22 
1. 2 .1. 
General Infonnation ............................................................................................................. 22 
1.2.2. 
Preclinical Phannacology and Toxicology ........................................................................... 23 
1.2.3. 
Clinical Trials ofSelonsertib ................................................................................................ 27 
1.3. 
Rationale for This Study ........................................................................................................................ 35 
1.4. 
Rationale for Dose Selection of Selonse1tib ........................................................................................... 36 
1.5. 
Rationale for Placebo Use ...................................................................................................................... 38 
1.6. 
Risk/Benefit Assessment for the Study .................................................................................................. 38 
1.7. 
Compliance ............................................................................................................................................ 39 
2. 
OBJECTIVES ..................................................................................................................................................... 40 
3. 
STUDY DESIGN ................................................................................................................................................ 41 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
3.6. 
Endpoints ............................................................................................................................................... 41 
Study Design .......................................................................................................................................... 42 
Duration ofTreatinent ............................................................................................................................ 43 
Discontinuation of Study D1ug .............................................................................................................. 43 
Discontinuation Criteria from Study ...................................................................................................... 44 
End of Stud ........................................................................................................................................... 45 
4. 
SUBJECT POPULATION .................................................................................................................................. 47 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 47 
4.2. 
Inclusion Criteria .................................................................................................................................... 47 
4.3. 
Exclusion Criteria ................................................................................................................................... 49 
4.4. 
Eligibility Criteria for Randomization ................................................................................................... 51 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................................... 52 
5.1. 
Rando1nization, Blinding and Treatment Codes .................................................................................... 52 
5.1.1. 
Procedures for Breaking Treatinent Codes ........................................................................... 53 
5.2. 
Description and Handling of Selonse1tib (SEL) ..................................................................................... 53 
5.2.1. 
Foimulation .......................................................................................................................... 53 
5.2.2. 
Packaging and Labeling ....................................................................................................... 54 
5. 2. 3. 
Storage and Handling ........................................................................................................... 54 
5.3. 
Dosage and Administrntion of Selonse1tib / Placebo-to-Match ............................................................. 54 
5.3.1. 
Doselnte1n1ption .................................................................................................................. 55 
5.4. 
Prior and Concoinitant Medications ....................................................................................................... 55 
5.5. 
Accowitability for Study Diug ............................................................................................................... 57 
5.5.1. 
Investigational Medicinal Product Retum or Disposal.. ....................................................... 57 
CONFIDENTIAL 
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Gilead Sciences, Inc. 
Final 
Amendment 2 
6. 
STUDY PROCEDURES .................................................................................................................................... 58 
6.1. 
Info1med Consent ................................................................................................................................... 58 
6.2. 
Subject Enrollinent ................................................................................................................................. 58 
6.3. 
Randomization and Treatment Assignment ........................................................................................... 59 
6.4. 
Study Procedw·e Descriptions ................................................................................................................ 59 
6.4.1. 
Medical Histo1y & Medication Hist01y ................................................................................ 59 
6.4.2. 
Concomitant Medications ..................................................................................................... 59 
6.4.3. 
Physical Examination ........................................................................................................... 60 
6.4.4. 
Vital Si s ............................................................................................................................ 60 
6.4.7. 
6.4.8. 
6.4.9. 
6.4.10. 
6.4.11. 
6.4.12. 
6.4.13. 
6.5. 
Assessme 
Pregnancy T estmg ................................................................................................................ 61 
Electi·ocardiograin ................................................................................................................ 61 
Clinical Outco1ne Assess1nents ............................................................................................ 62 
Laborato1y Assess1nents ....................................................................................................... 63 
Urine Albu1nin to Creatinine Ratio ...................................................................................... 63 
Estimated Glomemlar Filtration Rate .................................................................................. 63 
6.6 
Assessments for Discontinuation of Study Thug ................................................................................... 66 
6. 7. 
Post End of Treatlnent Follow-up Assessments ..................................................................................... 66 
6. 7 .1. 
Full Assessments .................................................................................................................. 66 
6. 7 .2. 
Limited Assessments ............................................................................................................ 66 
6.7.3. 
Re1note Assessments ............................................................................................................ 67 
6.8. 
Unscheduled Visits ................................................................................................................................. 67 
6.9. 
Sample Storage ....................................................................................................................................... 68 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 69 
7.1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 69 
7 .1.1. 
Adverse Events ..................................................................................................................... 69 
7.1.2. 
Serious Adverse Events ........................................................................................................ 69 
7.1.3. 
Clinical Laborat01y Abnonnalities and Other Abno1mal Assessments as 
Adverse Events or Serious Adverse Events ......................................................................... 70 
7 .2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 70 
7.2.1. 
Assessment of Causality for Study Drngs and Procedw-es ................................................... 71 
7.2.2. 
Assess1nent of Severity ........................................................................................................ 71 
7.3. 
Investigator Requirements and Instiuctions for Reporting Adverse Events and Serious 
Adverse Events to Gilead ....................................................................................................................... 72 
7 .3 .1. 
Adverse Events ..................................................................................................................... 72 
7.3.2. 
Serious Adverse Events ........................................................................................................ 72 
7.4. 
Gilead Reporting Requirements ............................................................................................................. 74 
7.5. 
Toxicity Management ............................................................................................................................ 75 
7 .5 .1. 
Grades 1 and 2 Laborat01y Abnonnality or Clinical Event.. ................................................ 7 5 
7.5.2. 
Grade 3 Laborato1y Abno1mality or Clinical Event.. ........................................................... 76 
7.5.3. 
Grade 4 Laborato1y Abno1mality or Clinical Event.. ........................................................... 76 
7.5.4. 
Liver Enzy1nes ...................................................................................................................... 77 
7.5.5. 
eGFRDecline ....................................................................................................................... 77 
7.6. 
Special Situations Repo1ts ...................................................................................................................... 78 
7.6.1. 
Definitions of Special Situations .......................................................................................... 78 
7 .6.2. 
Instluctions for Reporting Special Situations ....................................................................... 79 
8. 
STATISTICALCONSIDERATIONS ................................................................................................................ 81 
CONFIDENTIAL 
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Final 
Amendment 2 
8.1. 
8.2. 
8.3. 
8.4. 
8.5. 
8.6. 
I 
8.9. 
8.10. 
8.11. 
Analysis Objectives and Endpoint.s ........................................................................................................ 81 
8.1.1. 
Analysis Objectives .............................................................................................................. 81 
8.1.2. 
Pri1nruy Endpoint. ................................................................................................................. 81 
8.1.3. 
Seconda1 End oint. ............................................................................................................. 82 
.
ysis Convent.Ions ............................................................................................................................. 83 
8.2.1. 
Analysis Sets ........................................................................................................................ 83 
Data Handling Conventions ................................................................................................................... 83 
Demographic Data and Baseline Chru·act.eristics ................................................................................... 84 
Efficacy Analysis ................................................................................................................................... 84 
8.5.1. 
Pri1nruy Analysis .................................................................................................................. 84 
8.5.2. 
Seconda1 Anal ses ............................................................................................................. 85 
-
8.5.4. 
Mu hp 1c1ty A JUstment ....................................................................................................... 88 
Safety Analysis ....................................................................................................................................... 88 
8.6.1. 
Extent ofExposw·e ............................................................................................................... 88 
8.6.2. 
Adverse Events ..................................................................................................................... 89 
8.6.3. 
Laborato1y Evaluations ........................................................................................................ 89 
Other Safe Evaluations ...................................................................................................... 89 
Samp e Size ............................................................................................................................................ 90 
8.9 .1. 
Sample Size Detennination .................................................................................................. 90 
Data Monitoring Committee .................................................................................................................. 90 
Endpoint Adjudication ........................................................................................................................... 90 
8.11.1. 
Events for Adjudication ........................................................................................................ 91 
9. 
RESPONSIBILITIES .......................................................................................................................................... 92 
9 .1. 
Investigator Responsibilities .................................................................................................................. 92 
9 .1.1. 
Good Clinical Practice .......................................................................................................... 92 
9.1.2. 
Financial Disclosure ............................................................................................................. 92 
9 .1. 3. 
Institutional Review Board (IRB )/Independent. Ethics Committee (IEC) 
Review and Approval ........................................................................................................... 92 
9 .1.4. 
Info1med Consent ................................................................................................................. 92 
9 .1. 5. 
Confidentiality ...................................................................................................................... 93 
9.1.6. 
Study Files and Retention of Records .................................................................................. 93 
9.1.7. 
Case Report Fo1ms ............................................................................................................... 94 
9.1.8. 
Investigational Medicinal Product Accountability and Retwn ............................................. 95 
9.1.9. 
Inspections ............................................................................................................................ 95 
9.1.10. 
Protocol Compliance ............................................................................................................ 95 
9.2. 
Sponsor Responsibilities ........................................................................................................................ 95 
9.2.1. 
Protocol Modifications ......................................................................................................... 95 
9.2.2. 
Study Repo1t and Publications ............................................................................................. 96 
9.3. 
Joint Investigator/Sponsor Responsibilities ........................................................................................... 96 
9 .3 .1. 
Payment Repo1ting ............................................................................................................... 96 
9.3.2. 
Access to Info1mation for Monitoring .................................................................................. 96 
9.3.3. 
Access to Info1mation for Auditing or Inspections .............................................................. 97 
9 .3 .4. 
Study Discontinuation .......................................................................................................... 97 
10. REFERENCES ................................................................................................................................................... 98 
11. APPENDICES .................................................................................................................................................. 102 
Appendix 1. 
Investigator Signatw·e Page .................................................................................................. 103 
CONFIDENTIAL 
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Gilead Sciences, Inc. 
Amendment 2
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Appendix 2.
Study Procedures Table........................................................................................................104
Appendix 3.
Clinical Laboratory Analytes................................................................................................113
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v5.0....................................114
Appendix 5.
Management of Clinical and Laboratory Adverse Events....................................................115
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................116
LIST OF IN-TEXT TABLES
Table 1-1.
Estimated Exposure Margins For SEL After Oral Administration.........................................27
Table 1-2.
GS-US-223-1015: Estimated Glomerular Filtration Rate (MDRD) Decline Rate 
from Week 4 to Week 48 (Posthoc Analysis) ........................................................................31
Table 1-3.
GS-US-223-1015: Overall Summary of Adverse Events (Safety Analysis Set) ....................32
Table 1-4.
GS US-223-1015: Adverse Events Occurring in ≥5% of Subjects in Any Treatment 
Group by Preferred Term (Safety Analysis Set).....................................................................32
Table 1-5.
GS-US-223-1015: Serious Adverse Events Occurring in ≥ 2 Subjects in Any 
Treatment Group by Preferred Term (Safety Analysis Set) ...................................................34
Table 1-6.
GS-US-223-1015: Grade 3 or 4 Laboratory Abnormalities (Safety Analysis Set).................35
Table 5-1.
Examples of Medications that are Prohibited or to be Used with Cautiona............................56
Table 7-1.
Guidelines for Grading of Adverse Event Severity................................................................71
LIST OF IN-TEXT FIGURES
Figure 1-1.
ASK-1 Signaling in DKD.......................................................................................................22
Figure 1-2.
GS-US-223-1015: Adjusted Mean (95% CI) of Estimated Glomerular Filtration 
Rate (MDRD) Change from Baseline by Visit (Primary Analysis) (Full Analysis 
Set) .........................................................................................................................................30
Figure 1-3.
GS-US-223-1015: Estimated Glomerular Filtration Rate (MDRD) Decline Rate 
Using a Piecewise Linear Random Slope Model (Posthoc Analysis) ....................................30
Figure 1-4.
PK/PD Relationships for SEL Exposure (AUCtau) and %p-p38 or %p-ASK-1 
(Study GS-US-223-1015).......................................................................................................37
Figure 3-1.
Study Design Schema.............................................................................................................42
CCI-


Selonsertib 
Protocol GS-US-223-1017 
Gilead Sciences, Inc. 
Study Title: 
IND Number: 
Clinical Trials.gov 
Identifier: 
Study Centers 
Planned: 
Objectives: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
Final 
Amendment2 
MOSAIC - A Phase 2b, Randomized, Double-Blind, Placebo-
Controlled, Parallel Group, Multicenter Study Evaluating the 
Efficacy and Safety of Selonse1iib in Subjects with Moderate to 
Advanced Diabetic Kidney Disease 
117513 
NCT04026165 
Approximately 190 centers globally 
The prima1y objective of this study is as follows: 
• 
To evaluate whether selonse1iib (SEL) can slow the decline in 
kidney function 
The secondaiy objectives of this study ai·e as follows: 
• 
To evaluate whether SEL can reduce the risk of kidney failure, or 
reduce the risk of death due to kidney disease in subjects with 
diabetic kidney disease (DKD) 
• 
To assess the safety and tolerability of SEL in subjects with DKD 
Page6 
13 April 2020 


Selonsertib
Protocol GS-US-223-1017
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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Study Design:
This is a Phase 2b, randomized, double-blind, placebo-controlled, 
parallel group, multicenter study evaluating the efficacy and safety of 
SEL in subjects with type 2 diabetes mellitus (T2DM) and moderate 
to advanced DKD.
Following the screening period, eligible subjects will enroll into a
Run-in period of at least 5 weeks. During the Run-in period, all 
subjects will receive placebo-to-match (PTM) for at least 
7 consecutive days. Subsequently, all subjects will receive SEL 
(18 mg) for at least 4 weeks. 
After completing the Run-in period, subjects eligible for 
randomization will be randomized in a 1:1 ratio to receive SEL 
(18 mg) or PTM, orally once daily. Randomization will be stratified 
by estimated glomerular filtration rate (eGFR), urine albumin to 
creatinine ratio (UACR), and concomitant use of sodium-glucose 
co-transporter-2 (SGLT-2) inhibitors.  
Subjects will continue to receive SEL or PTM in a double-blind 
fashion until death, study drug discontinuation, kidney failure 
(dialysis performed for at least 4 weeks, kidney transplantation, or 
confirmed decrease in eGFR to < 15 mL/min/1.73 m2 for subjects 
without dialysis or kidney transplantation), or the global study end 
date. 
Study Design Schema
Abbreviations: EOS = End of Study, EOT = End of Treatment, PTM = placebo to match, 
SEL = Selonsertib 
a
Prior to randomization, subjects must have at least 7 consecutive daily doses of study 
drug immediately prior to Visit C and Randomization (Visit 1)
b
Post-run-in baseline eGFR is defined as the average of Visit C and Visit 1 eGFR values.  
Pre-run-in baseline is defined as the average of Visit A and Visit B eGFR values. 
c
If kidney failure is reached, subjects should discontinue study drug and remain on 
study. 
d
If a subject permanently discontinues study drug, there will be a 30 Day EOT 
Follow-up visit. Subjects who permanently discontinue study drug prior to the global 
study end date will have an EOT visit and a 30 Day (±7 days) EOT Follow-up visit.
Subjects are encouraged to complete all remaining study visits until the global study 
end date.
e
The global study end date will occur when the last randomized subject reaches 
48 weeks and/or all subjects on study have completed end of study assessments and the 
30 Day EOS Safety Follow-up visit. 
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Selonsertib
Protocol GS-US-223-1017
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 8
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Number of Subjects 
Planned:
Approximately 300 randomized subjects
Target Population:
Subjects with T2DM and eGFR ranging from ≥20 mL/min/1.73 m²
to < 60 mL/min/1.73 m² with albuminuria receiving standard of care
(SOC) therapy (angiotensin converting enzyme inhibitor [ACEi], or 
angiotensin receptor blocker [ARB], or intolerant to both ACEi and 
ARB)
Duration of 
Treatment:
At least 52 weeks (4 weeks during the Run-in period and at least 
48 weeks post randomization)
Diagnosis and Main 
Eligibility Criteria:
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be 
eligible for enrollment in this study:
1) Male or female between 18 (or ≥ age of majority in each 
jurisdiction if different than 18) and 80 years of age, inclusive
2) Prior diagnosis of T2DM with diagnostic modalities as per local 
guidelines. Must have hemoglobin A1c (HbA1c) > 6% within
30 days prior to Enrollment (Visit A) or be on active treatment for 
T2DM for at least 6 weeks prior to Enrollment (Visit A)
3) eGFR value calculated by central laboratory utilizing samples 
collected during Screening and prior to Enrollment (Visit A) of 
≥20 mL/min/1.73 m² to < 60 mL/min/1.73 m² with albuminuria 
as measured by UACR
a) eGFR values will be calculated using the Chronic Kidney 
Disease Epidemiology (CKD-EPI) Creatinine Equation 
(2009); UACR will be determined by urine collection, 
preferably early morning void. Subjects can have up to 
3 eGFR and 3 UACR collections during the Screening 
period. Any one of the eGFR values and any one of the 
UACR values collected during Screening may be used to 
satisfy this inclusion criterion. Qualifying eGFR and UACR 
values do not need to be collected on the same day  
b) eGFR and UACR must meet criteria a, b, or c  
Criteria
eGFR (mL/min/1.73 m²)
UACR (mg/g)
a
≥ 45 to < 60
≥ 600 to 5000
b
≥ 30 to < 45
≥ 300 to 5000
c
≥20 to < 30
≥ 150 to 5000


Selonsertib
Protocol GS-US-223-1017
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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4) Treatment with either an ACEi or ARB as a single agent at the 
maximum labeled or tolerated dose deemed appropriate for the 
subject by the investigator and/or per local SOC for at least 
6 weeks prior to Enrollment, with a stable dose for at least 
2 weeks prior to Enrollment 
a) Subjects not receiving an ACEi or ARB may be enrolled if 
there is documented intolerance to ACEi and ARB 
b) Subjects receiving less-than-maximal dose of an ACEi or 
ARB may be enrolled if there is a documented reason that the 
maximum labeled dose of ACEi and ARB could not be 
reached  
5) Subjects already receiving SGLT-2 inhibitors must be on a stable 
dose at least 2 weeks prior to Enrollment
6) For females of childbearing potential (unless permanently sterile 
or post-menopausal, as described in Appendix 6), a negative 
serum pregnancy test at Screening
7) For male and female subjects of childbearing potential who 
engage in heterosexual intercourse, agreement to abstain or use 
protocol specified method(s) of contraception as described in 
Appendix 6
8) Male subjects must refrain from sperm donation from the 
Screening visit through 30 days following the last dose of study 
drug
9) Female subjects must refrain from egg donation or harvest from 
the Screening visit through 30 days following the last dose of 
study drug 
10) Subjects must refrain from blood product donation from the 
Screening visit through 30 days following the last dose of study 
drug
11) Mean systolic blood pressure (SBP) must be < 160 mmHg and 
mean diastolic blood pressure (DBP) must be < 100 mmHg taken 
at two time-points at least five minutes apart within 30 days prior
to Enrollment (Visit A)


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12) Required baseline laboratory data, analyzed by central laboratory,
within 30 days prior to Enrollment (Visit A) as shown in the table 
below
Organ System
Parameter
Required Value
Hematologic
WBC, neutrophil, 
lymphocyte, and 
platelet count
≥0.75 x LLN to ≤ 1.5 x ULN
Hepatic
Serum total 
bilirubin
≤ 1.5 × ULN
Serum ALT
Serum AST
Pregnancy
-HCGa
Negative
Infection
HIVb
Negative HIV antibody
HBV
Negative HBsAg and negative HBc 
antibody or
positive HBc and negative for HBV 
DNA by quantitative PCR
HCV
Negative HCV antibody or negative 
viral RNA (if HCV antibody is 
positive)
a
For women of childbearing potential only; serum -HCG must be negative during 
Screening
b
If screening test is positive, a negative confirmatory test will be required for eligibility
Abbreviations: -HCG = beta human chorionic gonadotropin, ALT = alanine 
aminotransferase, AST = aspartate aminotransferase, DNA = deoxyribonucleic acid, 
LLN = lower limit of normal, HBc antibody = anti-hepatitis B core antibody, 
HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HCV = hepatitis C virus, 
HIV = human immunodeficiency virus, PCR = polymerase chain reaction, 
RNA = ribonucleic acid, ULN = upper limit of normal, WBC = white blood count
13) Have either a normal 12-lead electrocardiogram (ECG) or an 
ECG with abnormalities that are not considered to be clinically 
significant by the investigator within 30 days prior to Enrollment 
(Visit A)
14) In the judgment of the investigator, participation in the study 
offers an acceptable benefit to risk ratio, taking into consideration 
the subject’s current DKD status, medical condition, and the 
potential benefits and risks of alternative treatments for DKD
15) Willing and able to comply with scheduled visits, drug 
administration plan, laboratory tests, other study procedures, and 
study restrictions
16) Willing and able to give informed consent prior to any study 
specific procedures being performed


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Amendment 2
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Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to 
be enrolled in this study:
1)
HbA1c > 12.0% within 30 days prior to Enrollment (Visit A) 
2)
In the investigator’s opinion, a condition other than T2DM is the 
primary etiology of DKD  
3)
Subjects with diagnosis of type 1 diabetes mellitus (T1DM) or 
maturity onset diabetes of the young (MODY) 
4)
Body mass index (BMI) > 50 kg/m2 at Enrollment (Visit A) 
5)
UACR > 5000 mg/g on any measurement during Screening
6)
End stage kidney disease (ESKD) (i.e., chronic hemodialysis, 
chronic peritoneal dialysis, or history of kidney transplantation)
7)
Anticipated progression to ESKD (need for chronic 
hemodialysis, chronic peritoneal dialysis or receipt of kidney 
transplant) within 3 months after Enrollment (Visit A)
8)
Unstable CV disease as defined by any of the following:
a) Myocardial infarction (MI), coronary artery bypass graft 
surgery, or coronary angioplasty within 3 months prior to 
Enrollment (Visit A)
b) Transient ischemic attack or cerebrovascular accident within 
3 months prior to Enrollment (Visit A)
c) Hospitalization for heart failure within 3 months prior to 
Enrollment (Visit A)
d) New York Heart Association (NYHA) Class IV congestive 
heart failure
9)
Diagnostic or interventional procedure that requires intravenous 
or intra-arterial iodinated contrast agent within 30 days prior to 
Enrollment (Visit A) and/or planned during the study Run-in
period
10) History of a malignancy within 5 years prior to Enrollment 
(Visit A). However, the following are not exclusions, and 
subjects may enroll if there is any history of: 
a) Carcinoma in situ of the cervix, or
b) Basal or squamous cell cancer or other localized 
non-melanoma skin cancer that has been adequately treated 
11) Pregnant or lactating females or planning to become pregnant or 
breastfeed during the study


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12) Concurrent use of either 
a)
ACEi and ARB or
b) Mineralocorticoid receptor antagonist (MRA) or direct renin 
inhibitor (DRI) in combination with an ACEi or ARB for at 
least 2 weeks prior to Enrollment
13) Requiring chronic administration of prohibited medications as 
per protocol 
14) Participation in another investigational study within 1 month or 
within 5 half-lives of the prior investigational agent (whichever 
is longer) prior to Enrollment (Visit A) 
15) Concurrent participation in another therapeutic clinical study
16) Prior participation in any clinical trial of SEL 
17) Known hypersensitivity to the study drug (SEL/placebo-to-
match), the metabolites, or formulation excipients
18) Prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, ECG finding, or laboratory 
abnormality that, in the investigator’s opinion, could adversely 
affect the safety of the subject or impair the assessment of study 
results
19) Presence of any condition that could, in the opinion of the 
investigator, compromise the subject’s ability to participate in the 
study, such as history of substance abuse, alcoholism, or a 
psychiatric condition
Randomization 
Eligibility Criteria: 
Subjects must meet all of the following criteria to be eligible for
randomization: 
1)
eGFR ≥15 mL/min/1.73 m² at all central laboratory assessments 
during the Run-in period prior to Randomization (Visit 1)
2)
At least 7 consecutive daily doses of SEL, without interruption,
immediately prior to Visit C and prior to Randomization (Visit 1)
3)
Subject did not permanently discontinue study drug during the 
Run-in period 
4)
Subject did not withdraw consent 
5)
Subject did not initiate, change dose, or discontinue SGLT-2 
inhibitor during the Run-in period or is not anticipated to initiate, 
change dose or discontinue SGLT-2 inhibitor within 12 weeks 
after Randomization (Visit 1)  
6)
Negative urine pregnancy test for female subjects of childbearing
potential


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7)
No ongoing clinically significant illness, medical condition, 
surgical history, physical finding, or laboratory abnormality that, 
in the investigator’s opinion, could adversely affect the safety of 
the subject or impair the assessment of study results
Stratification 
Factors:

eGFR Strata:  
eGFR (mL/min/1.73 m²)
≥ 45
≥30 to < 45
≥15 to < 30

Albuminuria Strata: UACR < 1500 mg/g vs. ≥1500 mg/g

Concomitant SGLT-2 Inhibitor Use Strata: Yes vs. No
Randomization will be stratified by the average eGFR values from 
Visit A and Visit B; the average values of UACR from Visit A and 
Visit B; and concomitant use of SGLT-2 inhibitors assessed at 
Visit 1. Visit A and B values for eGFR and Albuminuria will be 
transferred directly from the central laboratory to the interactive web 
response system (IWRS) for stratification but eGFR values will not 
be released to sites, investigators, or the sponsor. 
Study Procedures/
Frequency:
Subjects who meet eligibility criteria at Screening will enroll into the 
Run-in period. Starting at Visit A, subjects will receive PTM once 
daily for at least 7 consecutive days. Starting at Visit B, subjects will
begin to receive SEL (18 mg) once daily for at least 4 weeks.
During the Run-in period, subjects will be monitored for safety and 
study drug compliance. After Enrollment (Visit A), subjects will be 
required to return to the study site on Visit B (7-14 days after 
Visit A), Visit C (21-28 days after Visit B), and Visit 1 (7-14 days 
after Visit C). Immediately prior to Visit C and Visit 1, subjects must 
be on SEL for at least 7 consecutive days. Visit windows are 
provided in the unlikely event that a subject misses a dose within 
7 days prior to Visit C and Visit 1. 
Following the Run-in period, eligible subjects will be randomized at 
the study site on Visit 1 to enter the blinded treatment phase. Subjects 
will have study visits on Weeks 4, 8, 12, 24, 36, 48, and every 
12 weeks thereafter. SEL/PTM will continue to be administered until 
kidney failure (dialysis performed for at least 4 weeks, kidney 
transplantation, or confirmed decrease in eGFR to <15 mL/min/1.73
m2 for subjects without dialysis or kidney transplantation), death, 
study drug discontinuation (e.g., unacceptable toxicity, subject’s 
refusal of treatment, kidney transplantation), or the global study end 
date.


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Test Product, Dose, 
and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
CONFIDENTIAL 
Final 
Amendment2 
Subjects who pe1manently discontinue study drng prior to the global 
study end date will have an EOT visit and a 30 Day (±7 days) EOT 
Follow-up visit. They will then resume all study visits per the 
schedule of procedures and attend all subsequent study visits in the 
same manner as subjects who are still receiving study diug. 
Subjects who pe1manently discontinue study diug can have limited 
follow-up as defined in the schedule of procedures table, if requested. 
If full consent has not been withdi·awn, subjects who pennanently 
discontinue study di11g and are no longer willing or able to attend 
clinic visits in-person will be asked to continue study paiticipation via 
remote assessments. Subjects will be contacted approximately eve1y 
24 weeks until the global study end date. Subjects who have reached 
kidney failure will be followed via remote assessments as well. 
The global study end date will occur when the last randomized 
subject reaches 48 weeks and/or all subjects on study have completed 
end of study assessments and the 30 Day EOS Safety Follow-up visit. 
SEL 18 mg or PTM to be taken orally once daily 
The safety of SEL will be assessed during the study through the 
repo1ting of adverse events (AEs) and serious adverse events (SAEs), 
physical exaininations (PEs), clinical laborato1y tests, vital sign 
assessments, concomitant medications, and ECGs at various time 
points during the study. 
A data monitoring committee (DMC) will meet regularly to evaluate 
all available safety data accumulated during the study. In addition, 
endpoints of interest (kidney and CV events) will be reviewed and 
adjudicated. 
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Efficacy: 
CONFIDENTIAL 
Final 
Amendment2 
Prima1y efficacy endpoint: 
• 
eGFRcr slope from treatment-specific baselines 
Seconda1y endpoints: 
• 
Proportion of Kidney Clinical Events at Week 48 defined as any 
of the following events: 
Confmned 40% decline in eGFRcr from pre-nm-in baseline, 
or 
Kidney failure ( dialysis perfo1med for at least 4 weeks, kidney 
transplantation, or confomed decrease in eGFRcr to 
< 15 mUmin/1.73 m2 for subjects without dialysis or kidney 
transplantation), or 
Death due to kidney disease 
• 
Time from randomization to first occunence of a Kidney Clinical 
Event 
• 
eGFRcys slope from pre-nm-in baseline 
I 
I 
I 
I 
I 
I 
I 
I 
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Statistical Methods:
Primary Efficacy 
Analyses
Analysis Methods
The primary analysis set for efficacy analyses is the ITT Analysis Set, 
which includes all subjects who were randomized in the study. 
Definition of Baseline
Baseline eGFRcr is defined as below for the primary analysis:

SEL arm (Arm A): The average of the measurements at Visit C
and Visit 1. This baseline will also be referred to as post-run-in
baseline. 

Placebo arm (Arm B): The average of the measurements at Visit 
A (Enrollment) and Visit B. This baseline will also be referred to 
as pre-run-in baseline.
The primary analysis of eGFRcr slope will be performed after all 
subjects in the ITT Analysis Set complete the Week 48 visit or 
discontinue from the study. Pre-run-in baseline eGFRcr and post-run-
in baseline eGFRcr will be used for the placebo and SEL arms, 
respectively. Baseline eGFRcr as well as all on- and off-treatment 
eGFRcr values collected after Visit 1 through time of the analysis for 
all subjects with available data will be included. eGFRcr slope will be 
compared between SEL and placebo using a random slope model. 
The random slope model will have eGFRcr values starting from 
Baseline as the outcome and will include terms for pre-run-in 
baseline eGFRcr as a continuous variable, pre-run-in baseline UACR 
category (< 1500 mg/g vs. ≥1500 mg/g), concomitant use of SGLT-2 
inhibitors, treatment group, visit, and treatment-by-visit interaction.
The difference in eGFRcr slope between SEL and placebo groups will 
be estimated and tested.
Multiplicity 
Adjustment
The primary endpoint and each secondary endpoint will be evaluated 
at a one-sided Type 1 error level of 0.15. No formal multiplicity 
adjustment will be performed.
Sample Size 
Determination
With a sample size of 300 subjects (150 per treatment arm), power to 
detect a difference in eGFRcr decline rate of 3.7 mL/min/1.73 m2/year 
(common SD = 10 mL/min/1.73 m2/year) between SEL 18 mg and 
placebo-to-match using a two-sample t-test is 99% at a 1-sided 
significance level of 0.15. Assuming 15% dropout, with a sample size 
of 254 (127 per arm), the power is 97%. 


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Safety Analysis 
Final 
Amendment2 
Safety analyses include summaries of extent of exposme, AEs, 
laborato1y evaluations, and vital sign assessments. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents. 
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
ACEi
angiotensin converting enzyme inhibitor
AE
adverse event
ALT
alanine aminotransferase
ARB
angiotensin receptor blocker
ASK1
apoptosis signal-regulating kinase 1
AST
aspartate aminotransferase
BCRP
breast cancer resistance protein
BLQ
below the limit of quantitation
BMI
body mass index
Cmax
maximum concentration
CI
confidence interval
CKD EPI equation
Chronic Kidney Disease Epidemiology Collaboration equation
CMH
Cochran-Mantel-Haenszel
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
CV
cardiovascular
CXCL1
chemokine (C-X-C motif) ligand 1
CYP
cytochrome P450 enzyme
DBP
diastolic blood pressure
DDI
drug-drug interaction
DKD
diabetic kidney disease
DRI
direct renin inhibitors
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EOS
end of study
EOT
end of treatment
ESKD
end stage kidney disease
EU
European Union
FDA
United States Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCV
Hepatitis C virus


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HIV
Human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
IB
Investigator's Brochure
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
institutional review board
ITT
Intent-to-treat
IWRS
interactive web response system
JNK
c-Jun N-terminal kinase
LLN
lower limit of normal
LLOQ
lower limit of quantitation
MAPK
mitogen activated protein kinase
MATE1
multidrug and toxin extrusion protein 1
MATE2K
multidrug and toxin extrusion protein 2
MDRD
modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
mGFR
measured glomerular filtration rate
MI
myocardial infarction
MRA
mineralocorticoid receptor antagonist
MODY
maturity onset diabetes of the young
mmHg
millimeter of mercury
NASH
nonalcoholic steatohepatitis 
NYHA
New York Heart Association
OATP
organic anion-transporting polypeptide
OCT
organic cation transporter
P-gp
P-glycoprotein
PAH
pulmonary hypertension
PBMC
peripheral blood mononuclear cell
PE
physical examination
PK
pharmacokinetics
PT
preferred term
PTM
placebo to match
PVE
Pharmacovigilance & Epidemiology
QT
electrocardiographic interval between the beginning of the Q wave and
termination of the T wave, representing the time for both ventricular
depolarization and repolarization to occur
QTc
QT interval corrected for heart rate
ROS
reactive oxygen species


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SAE
serious adverse event
SBP
systolic blood pressure
SD
standard deviation
SEL
selonsertib
SGLT-2
sodium-glucose co-transporter-2 
SOC
system organ class
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TDAR
T-cell-dependent antibody response
T1DM  
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
cTnI
troponin
Trx
thioredoxins
UACR
urine albumin to creatinine ratio
UGT1A1
uridine diphosphate glucuronosyltransferase 1A1
ULN
upper limit of normal
VAS
visual analog scale


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1.
INTRODUCTION
1.1.
Background
Apoptosis signal-regulating kinase 1 (ASK1) is an important signaling node through which 
oxidative stress promotes inflammation, proliferation, apoptosis, and fibrosis (Figure 1-1). The 
ASK1 protein is ubiquitously expressed and normally bound and repressed by thiol-containing 
antioxidant proteins, including thioredoxins (Trx) in the cytosol and mitochondria {Borroni 
2013, Derkay 2013, Fujino 2007}. In settings of elevated oxidative stress and/or reactive oxygen 
species (ROS), Trx undergoes oxidation and dissociation from ASK1 leading to trans-
autophosphorylation of ASK1 homodimers at threonine 845 within the activation loop {Tobiume 
2002}.
Threonine (Thr) 845-phosphorylated ASK1 (pASK1) has increased catalytic activity and 
phosphorylates mitogen activated protein kinase kinases (MAPKKs) 3, 4, 6, and 7, which in turn 
phosphorylate and activate the mitogen activated protein kinases (MAPKs) p38 and c-Jun 
N-terminal kinase (JNK) {Fujisawa 2007, Sturchler 2010}. In response to pathological oxidative 
stress, ASK1 activation of p38 and JNK mediates diverse stress response pathways in cell type–
and context-dependent manners. For example, in experimental models of acute and chronic 
kidney disease, these downstream MAPKs drive inflammation, fibrosis, and apoptosis, and are 
implicated as contributors to kidney disease in humans {Liles 2018}. ASK1, p38 and JNK 
activity are all increased in the glomerulus, and tubulointerstitium of kidneys from diabetic and 
nondiabetic patients with chronic kidney disease (CKD) and associated with driving progression 
through apoptosis, inflammation and fibrosis {Adhikary 2004, Liles 2018, Verzola 2007}. 
Notably, ASK1 is required for sustained activation of p38 and JNK; therefore, ASK1 serves as a 
mechanistic link between oxidative stress and the downstream pathological processes mediated 
by these 2 kinases {Tobiume 2001}. In pathological settings of oxidative stress, ASK1 is 
required for sustained activation of p38 and JNK, which mediate diverse cellular responses by 
phosphorylating both cytosolic substrates and nuclear transcription factors {Tobiume 2001}. The 
ASK1 pathway promotes the expression of inflammatory cytokines (eg, interleukin [IL]-1β, 
IL-2, and IL 6), chemokines (eg, monocyte chemotactic protein 1 [MCP-1], chemokine ligand 1 
[CXCL1], and chemokine ligand 2 [CXCL2]), and matrix remodeling genes (i.e., transforming 
growth factor beta [TGF – β], tissue inhibitor of metalloproteinase [TIMP], plasminogen 
activator inhibitor-1 [PAI-1]) (Figure 1-1) {Matsuzawa 2005, Mnich 2010, Nakamura 2009, 
Takeda 2008, Terada 2007, Yokoi 2006}.


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Figure 1-1.
ASK-1 Signaling in DKD
In vivo, mice that are ASK1 deficient (ASK1−/−) develop normally, have no histological 
evidence of abnormality under controlled standard laboratory settings, and possess normal 
wound healing responses {Osaka 2007, Yamaguchi 2003}. In settings of diabetes, obesity, 
hypertension, and ischemia, ASK1−/−mice are protected from pathological organ remodeling and 
fibrosis, and display decreased cell loss by apoptosis, decreased macrophage infiltration into 
tissues, decreased vascular intimal hyperplasia, and improved vascular function {Kataoka 2011, 
Nakagawa 2008, Nakamura 2009, Terada 2007, Watanabe 2005, Yamaguchi 2003, Yamamoto 
2008, Yamashita 2007, Yokoi 2006}.
1.2.
Investigational Medicinal Product Selonsertib
1.2.1.
General Information
Selonsertib (SEL; GS-4997) is a new chemical entity and is a first-in-class small molecule 
inhibitor of ASK1 being developed by Gilead Sciences, Inc. Selonsertib is a potent and selective 
inhibitor of ASK1, a critical serine/threonine signaling kinase through which oxidative stress 
promotes inflammation, apoptosis, and fibrosis {Fujisawa 2007, Liles 2018, Ma 2014, Takeda 
2008, Terada 2007, Tesch 2015, Tobiume 2001, Watanabe 2005}. Pathological imbalances in 
cellular redox homeostasis and the resultant activation and dysregulation of downstream ASK1 
signaling have been implicated in the pathogenesis of diseases such as diabetic kidney disease 
Podocyte 
1' Apoptosis 
Oxidative Stress 
Tubular Epithelium 
1' Apoptosis 
1' Cytokines 
1' Myofibroblast 
recruitment 
Macrophage 
1' Cytokines 
1' Accumulation 


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(DKD), nonalcoholic steatohepatitis (NASH), alcoholic hepatitis (AH), heart failure, and 
rheumatoid arthritis. ASK1 may also be involved in other diseases such as select solid tumors, 
idiopathic pulmonary fibrosis, and asthma {Chibon 2004, Hayakawa 2012, Hikoso 2007, 
Izumiya 2003, Noguchi 2014, Takada 2013, Taki 2008, Terada 2007, Watanabe 2005, 
Yamaguchi 2003, Yamaguchi 2004, Yamamoto 2008}. Clinical studies have been conducted in 
subjects with NASH, AH, DKD, and pulmonary hypertension (PAH); SEL is currently being 
developed for the treatment of DKD and as a component in combination therapy for the 
treatment of NASH.
In DKD, ASK1 may have a key role in maintaining the pathological cycle between oxidative 
stress and inflammation, leading to progressive disease noted by increased apoptosis and fibrosis, 
and associated damage in the kidney with a decline in glomerular filtration rate (GFR). Through 
inhibition of ASK1, SEL is expected to slow or halt the progression of kidney disease and the 
rate of GFR decline, thereby delaying dialysis and death in patients with DKD.  Furthermore, 
ASK1 has been shown to be a key mediator of oxidative stress-induced apoptosis and fibrosis in 
the heart, suggesting that improvement in cardiovascular outcomes may also be observed with 
SEL {Gerczuk 2012, Hikoso 2007, Tobiume 2002, Toldo 2012, Yamaguchi 2003}.
The safety, tolerability, and pharmacokinetics (PK) of SEL has been evaluated in Phase 1 studies 
in healthy volunteers and in Phase 2 and Phase 3 studies in subjects with NASH, AH, DKD, and 
PAH, and potential risks based on the findings from these studies and nonclinical studies, are 
summarized in the Summary of Data and Guidance for the Investigator section of the 
Investigator’s Brochure (IB).
For further information on SEL, refer to the current investigator’s brochure for SEL.
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Nonclinical Pharmacology
Selonsertib is a potent and selective adenosine triphosphate (ATP) competitive inhibitor of the 
kinase ASK1. The potency of SEL to inhibit ASK1 activation and signaling was characterized in 
cellular assays and in vivo models of oxidative stress. In human kidney cell line 2 (HK2) human 
kidney proximal tubular epithelial cells, SEL inhibited auranofin induced ASK1 
autophosphorylation and inhibited the downstream phosphorylation of p38 and JNK. Selonsertib 
efficacy was similar to that obtained when ASK1 expression was reduced by small interfering 
Ribonucleic Acid (siRNA). The potency of SEL to inhibit auranofin induced p38 activation in 
human HK2 cells (EC50 10.5 ± 1.3 nM) and human peripheral blood mononuclear cells (PBMCs)
(EC50 10.8 ± 1.3 nM) were congruent with the potency of SEL to inhibit ASK1 in a biochemical 
assay (1.76 ± 0.85 nM). Selonsertib inhibited auranofin induced production of the 
proinflammatory chemokine CXCL1 in human whole blood and in isolated human PBMCs with 
mean EC50 values of 131 ± 70 and 32 ± 13 nM, respectively. The approximate 4 fold difference 
in potency observed between whole blood and isolated PBMCs is likely due to plasma protein 
binding; the free fraction of SEL in human plasma is approximately 5%.


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The inhibition of ASKl by SEL or a close stmctural analog (GS-444217) was efficacious and 
well tolerated in a number of kidney in vivo efficacy models, which together reflect the 
pathophysiology of human DKD. In a rat model of acute oxidative sti·ess induced by auranofin 
administration, SEL dose dependently inhibited activation of ASKl and ASKl signaling in the 
kidney and inhibited the downsti·eam expression of cytokines and chemokines in the kidney. In 
the unilateral ureteral obsti11ction (UUO) model, SEL dose dependently inhibited ASKl pathway 
activation in the kidney and was efficacious in reducing both biochemical and histological 
indices of kidney tubulointerstitial fibrosis. In addition, SEL decreased collagen IV deposition 
and reduced the expression of a-smooth muscle actin ( a-SMA), a marker of myofibroblasts 
activation. At doses :::: 10 mg/kg, SEL h'eatment reduced collagen IV levels to sham conti·ol 
group levels; at 10 mg/kg, the mean protein free level of SEL in plasma was 8.7 nM at Cmin. 
GS-444217 was evaluated in the mouse db/db eNos-1-model ofDKD, which is phenotypically 
similar to advanced human DKD {Mohan 2008, Zhao 2006}. Treatment with GS-444217 in this 
model markedly slowed disease progression as assessed by GFR and reduced the severity of 
glomemlosclerosis, proteinuria, and apoptosis in the kidney. 
In safety phannacology studies, SEL inhibited the human ether-a-go-go-related gene (hERG) 
channel in viti·o with a concenh'ation at which 50% inhibition occurs (ICso) of 5.9 µg/mL and, 
based on in vivo animal studies, has the potential to prolong QT interval coITected for heaii rate 
(QTc) and decrease systemic blood pressure at exposures (free Cmax) that are approximately 
11- and 3-fold, respectively, higher than the exposure observed at the maximum human dose of 
18 mg/day. 
Overall, the results from these phaimacology studies demonsh'ate that SEL is a potent and 
selective inhibitor of the ASKl kinase, a key mediator of oxidative stress induced injmy. 
Collectively, the data indicate that SEL has the potential to ameliorate the progression of DKD in 
patients. 
1.2.2.2. 
Non clinical Phaimacokinetics 
Consistent with the moderate to high bioavailability seen in nonclinical species, SEL shows high, 
concenti·ation-independent fo1wai·d pe1meability across Caco-2 monolayers, with low efflux. 
Although SEL is a subsh'ate for P-glycoprotein (P-gp) and breast cancer resistance protein 
CRP this is unlikel to be of relevance durin abso1 tion due to its hi h enneabili . 
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Amendment2 
Selonse1i ib has a moderate volume of distribution, close to that of total body water. Selonsertib 
is unlikely to cross the blood-brain banier, likely through the action of efflux transporters at the 
blood-brain banier. Systemic clearance in nonclinical species is well predicted from the rates of 
metabolism by hepatic microsomal fractions and hepatocytes. Selonse1iib has good metabolic 
stability with human hepatic material in vitro and low clearance in vivo. In vitro, the main route 
of metabolism of SEL involves N-dealkylation, resulting in loss of the isopropyl group 
. However, other routes of metabolism were detected in the rat, 
including oxidation (with subsequent glucuronidation) and hydrolysis of the amide. Of the 
major cytochrome P450 en 
e CYP enz 
es tested, only CYP3A4 had the ability to 
metabolize SEL 
, consistent with results in a clinical drng interaction 
study (Study GS-US-223-1434). 
Selonse1i ib is unlikely to cause clinical interactions through inhibition of CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Substrate-dependent inhibition was observed for 
CYP3A, and inhibition of uridine di hos hate lucuronos ltransferase l Al 
GTlAl also was 
observed. 
A clinical study found little effect of SEL (30 mg 
As evaluated using in vitro studies, SEL is a weak inhibitor of BCRP and P-gp with ICso values 
of > 10 µM and 3 .4 µM, respectively. A Phase I clinical drng interaction study using the probe 
substrate digoxin (GS-US-223-1434) demonstrated that co-administration of a once-daily dose of 
SEL (20 mg) with digoxin (0.5 mg) resulted in a modest increase of the maximum concentration 
(Cmax) and area under the concentration-time curve (AUCINF) of digoxin (35% and 24%, 
respectively) with no change to the half-life. SEL was a weak inhibitor of intestinal P-gp in vivo. 
Selonse1i ib was detennined to be an in vitro inhibitor for hepatic transpo1iers OATPlBl 
(ICso = 9.9 µM), OATP1B3 (ICso > 10 µM), and organic cation transpo1i er (OCT) 1 
(ICso = 2.8 µM). Based on the regulato1y guidelines for detennining potential DDis and the 
nature of high protein binding(> 95%), SEL is unlikely to be a relevant inhibitor of these 
transpo1i ers in vivo. 
In in vitro experiments, SEL was identified as an inhibitor of the kidney transporters OCT2 
(ICso= 5.5 µM), multidrng and toxin extrusion protein 1 (MATEl) (ICso = 2.4 µM), and 
multidrng and toxin extrusion protein 2 (MATE2K) (ICso = 0.94 µM). Based on in vivo plasma 
exposure and the 2017 FDA Guidance for Industry- In Vitro Metabolism-and Transpo1ier-
Mediated Drng-Drng Interaction studies, at clinical doses, SEL is predicted to be an in vivo 
inhibitor ofMATEl and MATE2K ( Imax, ul[ICsoJ 2:: 0.02; [Imax,u]l[ICso] = 0.02 and 0.05, 
respectively) but not OCT2 (Imax, ul[ICso] 
0.1; Imax, ul[ICso] = 0.008). A Phase I study was 
conducted to evaluate the effect of SEL or placebo on kidney function using iohexol as an 
exogenous marker of GFR (GS-US-223-3973). Small, dose-dependent and reversible increases 
in sernm creatinine with resulting decreases in calculated creatinine clearance (Cockcroft-Gault) 
were observed, a finding consistent with the inhibition of kidney transpo1i ers by SEL. 
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The metabolite was a 
slightly more potent inhibitor of MATE1 (IC50 = 6.4 µM) and MATE2K (IC50 = 3.4 µM), but 
based on the regulatory guidelines (Imax,u/ IC50 = 0.01) and the high plasma protein binding 
(~99% bound), the inhibition of these transporters by the metabolite is unlikely to be relevant in 
vivo.
Selonsertib 
 are not expected to be clinically relevant inducers of human drug 
metabolizing enzymes and drug transporters through activation of either aryl hydrocarbon 
receptor (AhR) or pregnane X receptor (PXR).
Elimination of SEL and its metabolites is likely to occur through a mixture of urinary, biliary, 
and intestinal excretion.
1.2.2.3.
Nonclinical Toxicology
Target organs/tissues identified in the repeat-dose rat and monkey toxicity studies with SEL were 
the gastrointestinal, kidney, hematopoietic tissue, lymphoid tissue (cynomolgus monkey only), 
adrenal (rat only), and lung (monkey only). In general, findings were reversible, monitorable, 
and only occurred at doses that exceeded the projected exposure (AUC24h) at the proposed 
maximum human dose by at least 4-fold. Selonsertib was nongenotoxic in in vitro and in vivo 
assays and noncarcinogenic in transgenic RasH2 mice. In Sprague-Dawley rats, there was a 
reduction in the latency period for pituitary adenomas (a common spontaneous tumor in 
Sprague-Dawley rats) that resulted in an increased incidence of pituitary adenomas at doses 
associated with exposures ≥ 13-fold higher than the exposure in NASH subjects at the 18 mg 
dose. There was no effect of SEL on phototoxicity, ocular or skin irritation, or skin sensitization. 
In addition, there were no effects of SEL on fertility, early embryonic or peri- and postnatal 
development. However, there were embryofetal effects during organogenesis including a few 
visceral and/or skeletal malformations in rats and rabbits at maternally toxic doses. Therefore, 
appropriate precautions to prevent pregnancy should be taken in women of child-bearing 
potential as discussed in the Investigator Brochure (IB). There was a reduced T-cell-dependent 
antibody response (TDAR) in monkeys; however, this is unlikely to be clinically relevant 
because the TDAR finding was observed at a dose above the dose associated with systemic 
toxicity. 
The no observed adverse effect level (NO[A]EL) (repeat-dose toxicity and immunotoxicity 
studies) or no observed effect level (NOEL) (reproductive toxicity studies) from key studies and 
exposure margins are presented in the IB. The exposure margins are based on preliminary 
population PK estimates of exposures from the NASH Phase 2 study (GS-US-384-1497).
CCI
CCI


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Table 1-1.
Estimated Exposure Margins For SEL After Oral Administration
Study Type
Species
Duration of Dosing
NO(A)EL 
(mg/kg/day)
SEL 
AUC24h 
(μg•h/mL)
SEL Exposure
Marginsa
Repeat-dose 
toxicity
Rat
26 weeks
15
164
18
Monkey
39 weeks
5
11
1
Carcinogenicity
Mouse
26 weeks
M: 30
F: 100
M: 206
F: 194
M: 22
F: 21
Rat
up to 96 weeks
M: 5
F: 3
M: 45.4
F: 49.5
M: 5
F: 5
Fertility
Rat
4 (males) and 2 (females)
weeks prior to mating
75
—
—
Embryofetal 
development
Rat
Gestation Days 6 to 17
15
109
12
Rabbit
Gestation Days 7 to 19
10
30.7
3
Peri- and 
postnatal 
development
Rat
F0: Gestation Day 6 to
Lactation Day 10
30
F0: 118
F1: 18
F0: 13
F1: 2
Immunotoxicity
Monkey
4 weeks
15
59.5
6
F = female; F0 = initial generation (dams); F1 = first generation (pups); M = male; NO(A)EL = no observed (adverse) effect level
a
Margins of exposure were calculated using the exposure (AUC24h of 9.2 μg•h/mL) observed in NASH subjects at the 18 mg 
QD dose based on preliminary population PK data from the Phase 2 NASH study (GS-US-384-1497).
Source: Studies TX-223-2011, TX-223-2012, TX-223-2026, TX-223-2016, TX-223-2018 and TX-223-2027
1.2.3.
Clinical Trials of Selonsertib
As of 17 July 2019, 10 Phase 1, 6 Phase 2, and 3 Phase 3 clinical studies have been 
conducted/are ongoing in which 390 healthy subjects, 248 subjects with DKD, an estimated 
40 subjects with CKD, 1473 subjects with NASH, 50 subjects with AH, and 145 subjects with 
PAH have been dosed with SEL Across these studies, SEL was generally well tolerated. No 
adverse drug reactions with SEL have been identified to date.
Information on the completed and ongoing clinical studies can be found in the IB. Brief 
summaries of an additional Phase 1b study and the completed Phase 2 study relevant to this 
protocol are provided below.
1.2.3.1.
A Phase 1b, Randomized, Blinded, Placebo-Controlled Study to Evaluate the 
Effect of Selonsertib on Renal Function as Assessed by Markers of Glomerular 
Filtration Rate in Subjects with Chronic Kidney Disease (GS-US-223-0110)
Study GS-US-223-0110 is a Phase 1b, blinded, randomized, placebo-controlled study that 
evaluated the effect of SEL on kidney function in subjects with CKD using markers of estimated 
(eGFRcr) and measured GFR (mGFR, as assessed by iohexol clearance). Subjects (n = 82) with 
CKD (eGFRcr 20 to < 60 mL/min/1.73 m2) were randomized 1:1 to receive SEL 18 mg or 
placebo once daily for 28 days followed by a 28-day washout period. After adjusting for baseline 


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eGFRcr and placebo treatment, a 4.8% decrease in mGFR on Day 7 and a decrease of 5.7% 
(approximately 2 mL/min/1.73 m2) on Day 28 in the SEL treatment group was observed. This 
acute decrease in mGFR was reversible and deemed not clinically significant, as evidenced by no 
decrease in the SEL treatment group relative to placebo on Day 56. Compared with mGFR 
changes, there was a slightly larger decrease in eGFRcr in the SEL treatment group relative to 
placebo on Days 7 and 28 (7.0% and 6.5%, respectively) that was reversible on Day 56. Study 
conduct is currently complete and writing of the clinical study report is ongoing. 
The results of this Phase 1b study are discordant with those of the previous Phase 1 study of SEL 
in healthy subjects (GS-US-223-3973). Numerically small changes in mGFR were observed 
during the on-treatment period in subjects with CKD that had not been observed in healthy 
subjects. The decrease in mGFR indicates there may be a secondary mechanism in addition to 
kidney transporter inhibition that is responsible for the changes in mGFR and eGFRcr observed 
in subjects with CKD. The rapid reversibility of the decrease in mGFR indicates there is no 
evidence of a nephrotoxic effect, and the safety profile of SEL was favorable in the Phase 1b 
study. Overall, the mechanism of decrease in mGFR in this population warrants further 
investigation with analyses ongoing while the totality of data from Study GS-US-223-0110 
continues to support the development of SEL in subjects with kidney disease.
1.2.3.2.
A Phase 2, Double-Blind, Placebo-Controlled, Dose-Ranging Study Evaluating 
the Efficacy, Safety, and Tolerability of SEL in Subjects with Diabetic Kidney 
Disease (GS-US-223-1015)
1.2.3.2.1.
Study Design
Study GS-US-223-1015 is a completed Phase 2, double-blind, placebo-controlled, dose-ranging 
study that evaluated the efficacy, safety, and tolerability of SEL in subjects with DKD. A total of 
334 subjects with type 2 diabetes mellitus (T2DM) and Stage 3 or Stage 4 kidney impairment 
and albuminuria receiving standard of care treatment for DKD were randomized (1:1:1:1) to 1 of 
4 treatment groups: SEL 2, 6, or 18 mg, or matching placebo administered once daily for 
48 weeks. The primary objective of this study was to determine the effect of SEL on eGFR 
decline in subjects with DKD.
1.2.3.2.2.
Subject Disposition
Of the 334 randomized subjects, 333 subjects received at least 1 dose of study drug: 85 subjects 
received placebo and 248 subjects received SEL (81, 84, and 83 subjects received SEL 2, 6, and 
18 mg, respectively).
A total of 256 subjects (76.9%) completed treatment and 76 subjects (22.8%) discontinued study 
drug (19 subjects [22.4%] in the placebo group and 57 subjects [23.0%] in the pooled SEL group 
[18.5%, 21.4%, and 28.9% for SEL 2, 6, and 18 mg, respectively]). The most frequent reason for 
discontinuation of study drug was due to an adverse event ([AE], 4 subjects [4.7%] in the 
placebo group and 18 subjects [7.3%] in the pooled SEL group), followed by progression to end 
stage kidney disease (ESKD) (4 subjects [4.7%] in the placebo group and 13 subjects [5.2%] in 
the pooled SEL group), and withdrawal of consent (3 subjects [3.5%] in the placebo group and 
13 subjects [5.2%] in the pooled SEL group).


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1.2.3.2.3.
Activity and Efficacy Results
In the prespecified primary efficacy analysis, subjects receiving SEL had similar mean decreases 
from baseline in eGFR compared with the placebo group at Week 48 (mean [SE] difference from 
placebo: 0.38 [1.21] mL/min/1.73 m2 for the SEL 2 mg group, 0.84 [1.22] mL/min/1.73 m2 for 
the SEL 6 mg group, and −0.87 [1.23] mL/min/1.73 m2 for the SEL 18 mg group; p > 0.4 for all 
pair-wise comparisons) (Figure 1-2). Differences in eGFR at Week 48 were confounded by acute 
effects of SEL on creatinine. Subjects receiving SEL 18 mg had a larger acute decrease in eGFR 
(approximately 10% of the baseline value at Week 4) than the other SEL dose groups or placebo 
group, which may be due, in part, to greater inhibition of the kidney transporters involved in the 
secretion of creatinine by SEL at this higher dose (Studies GS-US-223-0102 and GS-US-223-
3973).
To evaluate the potential treatment effect of SEL in a future DKD study population, posthoc 
analyses were performed with 2 changes to the analysis population. First, posthoc analyses 
excluded data from 20 subjects enrolled at 2 study sites that were audited and found to have 
compliance violations, anomalous data, or both. Second, posthoc analyses excluded subjects with 
baseline eGFR < 20 mL/min/1.73 m2 (n = 50 in the Full Analysis Set excluding subjects from the 
2 sites described above) to reduce the probability of subjects experiencing an immediate 
decrease in eGFR to the threshold that defines kidney failure (eGFR < 15 mL/min/1.73 m2).
Two dose-dependent effects were observed that correspond to acute and chronic effects: a 
greater decline in eGFR acutely from Weeks 0 to 4 (creatinine transport effect [inhibition of 
tubular secretion of creatinine by SEL]), and a smaller decline in eGFR chronically from 
Weeks 4 to 48 (therapeutic effect) (Figure 1-3). Between Weeks 4 and 48, the rate of eGFR 
decline in the SEL 18 mg group was significantly slower than that in the placebo group (mean 
difference from placebo: 3.70 mL/min/1.73 m2 annualized over 1 year, or 75% reduction in 
eGFR decline rate compared with placebo; nominal p = 0.036) (Table 1-2 and Table 1-3)


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Figure 1-2.
GS-US-223-1015: Adjusted Mean (95% CI) of Estimated Glomerular 
Filtration Rate (MDRD) Change from Baseline by Visit (Primary 
Analysis) (Full Analysis Set)
Figure displays adjusted mean (95% CI) eGFR change in randomized subjects who received at least 1 dose of study drug 
(N = 333). Results were obtained from mixed-effect model repeated measures (MMRM) with baseline eGFR, treatment group, 
visit, and treatment-by-visit interaction included in the model. MDRD = modification of diet in renal disease
Figure 1-3.
GS-US-223-1015: Estimated Glomerular Filtration Rate (MDRD) 
Decline Rate Using a Piecewise Linear Random Slope Model 
(Posthoc Analysis)
Figure displays observed and fitted eGFR change values (ml/min/1.73 m2) from a piecewise linear random slope model in 
randomized subjects who received at least 1 dose of study drug, were not from the 2 excluded sites, and had a baseline eGFR 
≥20 ml/min/1.73 m2 (N = 263). The piecewise linear random slope model had a turning point at Week 4, with baseline eGFR, 
treatment group, week, and treatment-by-week interaction included in the model. MDRD = modification of diet in renal disease
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Table 1-2.
GS-US-223-1015: Estimated Glomerular Filtration Rate (MDRD) 
Decline Rate from Week 4 to Week 48 (Posthoc Analysis)
SEL 18 mg
(N = 67)
SEL 6 mg
(N = 65)
SEL 2 mg
(N = 67)
Placebo
(N = 64)
eGFR decline rate (mL/min/1.73 m2/year)
Adjusted Mean (SE)
−1.27 (1.28)
−2.05 (1.23)
−3.90 (1.18)
−4.97 (1.21)
95% CI
−3.78, 1.24
−4.46, 0.37
−6.22, −1.59
−7.35, −2.59
Difference in eGFR decline rate from Placebo
Adjusted Mean (SE)
3.70 (1.76)
2.93 (1.72)
1.07 (1.69)
—
95% CI
0.25, 7.16
−0.46, 6.31
−2.25, 4.39
—
p-value
0.036
0.090
0.528
—
CI = confidence interval; MDRD = modification of diet in renal disease; SE = standard error 
Posthoc analysis was performed for subjects who received at least 1 dose of study drug, were not from the 2 excluded sites, and 
had a baseline eGFR ≥ 20 ml/min/1.73 m2 (N = 263)
eGFR (MDRD) was calculated as 175 * serum creatinine-1.154 * age at laboratory collection-0.203 * 1.212 (if black) * 0.742 
(if female)
Adjusted means for rate of eGFR decline from Week 4 to Week 48 were estimated from a piecewise linear random slope model 
in randomized subjects who received at least 1 dose of study drug. The model had a turning point at Week 4, with baseline eGFR, 
treatment group, week, and treatment-by-week interaction included in the model
Difference from placebo was the difference in adjusted eGFR decline rate between each SEL group and placebo
1.2.3.2.4.
Safety Results
Table 1-3 presents the overall summary of AEs by treatment group. Overall, 80.8% of subjects 
experienced an AE: 83.5% in the placebo group and 79.8% in the pooled SEL group 
(79.0%, 84.5%, and 75.9% for SEL 2, 6, and 18, respectively). Adverse events related to study 
drug occurred in 9.4% (8 subjects) in the placebo group and 12.5% (31 subjects) in the pooled 
SEL group (8.6%, 11.9%, and 16.9% for SEL 2, 6, and 18 mg, respectively). Adverse events 
leading to study drug discontinuation occurred in 9.4% (8 subjects) in the placebo group 
compared with 12.1% (30 subjects) in the pooled SEL group (8.6%, 13.1%, and 14.5% for 
SEL 2, 6, and 18 mg, respectively). Overall, 4 deaths occurred (1.2%), with a frequency of 1.2% 
in the placebo group and 1.2% in the pooled SEL group (1.2%, 1.2%, and 1.2% for SEL 2, 6, and 
18 mg, respectively). Three of the deaths were nontreatment emergent, i.e., occurred more than 
30 days after the last dose of study drug.


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Table 1-3.
GS-US-223-1015: Overall Summary of Adverse Events 
(Safety Analysis Set)
Number (%) of Subjects With Any
SEL 2 mg
(N = 81)
SEL 6 mg
(N = 84)
SEL 18 mg
(N = 83)
SEL Pooled
(N = 248)
Placebo
(N = 85)
AE
64 (79.0%)
71 (84.5%)
63 (75.9%)
198 (79.8%)
71 (83.5%)
Grade ≥3 AE
21 (25.9%)
20 (23.8%)
21 (25.3%)
62 (25.0%)
15 (17.6%)
AE Related to Study Drug
7 (8.6%)
10 (11.9%)
14 (16.9%)
31 (12.5%)
8 (9.4%)
Grade ≥3 AE Related to Study Drug
0
3 (3.6%)
0
3 (1.2%)
1 (1.2%)
SAE
24 (29.6%)
20 (23.8%)
20 (24.1%)
64 (25.8%)
16 (18.8%)
SAE Related to Study Drug
0
2 (2.4%)
0
2 (0.8%)
1 (1.2%)
AE Leading to Temporary 
Interruption of Study Drug
14 (17.3%)
8 (9.5%)
10 (12.0%)
32 (12.9%)
7 (8.2%)
AE Leading to Study Drug 
Discontinuation
7 (8.6%)
11 (13.1%)
12 (14.5%)
30 (12.1%)
8 (9.4%)
AE Leading to Death
0
1 (1.2%)
0
1 (0.4%)
0
All Deaths During Study
1 (1.2%)
1 (1.2%)
1 (1.2%)
3 (1.2%)
1 (1.2%)
Adverse events were mapped according to MedDRA Version 19
Treatment-emergent AEs are those started on or after first study dose date up to and including 30 days after permanent 
discontinuation, or led to premature study drug discontinuation
Toxicity grades (1=Mild, 2=Moderate, 3=Severe, 4=Life-Threatening, 5=Death) were from modified CTCAE Version 4.03
Table 1-4 presents a summary of AEs reported for ≥ 5% of subjects in any treatment group by 
preferred term. The most common AEs in the pooled SEL group were upper respiratory tract 
infection, hypertension, hyperkalemia, diarrhea, constipation, and hypoglycemia, with no 
dose-dependent toxicity noted.
Table 1-4.
GS US-223-1015: Adverse Events Occurring in ≥5% of Subjects in 
Any Treatment Group by Preferred Term (Safety Analysis Set)
SEL 2 mg
(N = 81)
SEL 6 mg
(N = 84)
SEL 18 mg
(N = 83)
SEL Pooled
(N = 248)
Placebo
(N = 85)
Number (%) of Subjects 
Experiencing Any AE
64 (79.0%)
71 (84.5%)
63 (75.9%)
198 (79.8%)
71 (83.5%)
Upper respiratory tract infection
5 (6.2%)
5 (6.0%)
8 (9.6%)
18 (7.3%)
9 (10.6%)
Hypertension
9 (11.1%)
6 (7.1%)
3 (3.6%)
18 (7.3%)
6 (7.1%)
Hyperkalaemia
6 (7.4%)
4 (4.8%)
8 (9.6%)
18 (7.3%)
4 (4.7%)
Diarrhoea
8 (9.9%)
2 (2.4%)
7 (8.4%)
17 (6.9%)
4 (4.7%)
Anaemia
4 (4.9%)
6 (7.1%)
5 (6.0%)
15 (6.0%)
5 (5.9%)
Oedema peripheral
2 (2.5%)
5 (6.0%)
4 (4.8%)
11 (4.4%)
8 (9.4%)
Constipation
6 (7.4%)
7 (8.3%)
3 (3.6%)
16 (6.5%)
2 (2.4%)


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SEL 2 mg
(N = 81)
SEL 6 mg
(N = 84)
SEL 18 mg
(N = 83)
SEL Pooled
(N = 248)
Placebo
(N = 85)
Nausea
8 (9.9%)
5 (6.0%)
1 (1.2%)
14 (5.6%)
4 (4.7%)
Acute kidney injury
3 (3.7%)
6 (7.1%)
6 (7.2%)
15 (6.0%)
2 (2.4%)
Back pain
3 (3.7%)
6 (7.1%)
6 (7.2%)
15 (6.0%)
2 (2.4%)
Hypoglycaemia
7 (8.6%)
5 (6.0%)
4 (4.8%)
16 (6.5%)
1 (1.2%)
Urinary tract infection
6 (7.4%)
1 (1.2%)
5 (6.0%)
12 (4.8%)
5 (5.9%)
Dyspnoea
1 (1.2%)
5 (6.0%)
6 (7.2%)
12 (4.8%)
3 (3.5%)
End stage kidney disease
2 (2.5%)
4 (4.8%)
3 (3.6%)
9 (3.6%)
6 (7.1%)
Chronic kidney disease
2 (2.5%)
5 (6.0%)
3 (3.6%)
10 (4.0%)
4 (4.7%)
Arthralgia
6 (7.4%)
1 (1.2%)
1 (1.2%)
8 (3.2%)
5 (5.9%)
Blood creatinine increased
6 (7.4%)
1 (1.2%)
3 (3.6%)
10 (4.0%)
2 (2.4%)
Cardiac failure congestive
3 (3.7%)
2 (2.4%)
5 (6.0%)
10 (4.0%)
2 (2.4%)
Cellulitis
1 (1.2%)
3 (3.6%)
6 (7.2%)
10 (4.0%)
1 (1.2%)
Dizziness
1 (1.2%)
1 (1.2%)
5 (6.0%)
7 (2.8%)
4 (4.7%)
Hyperglycaemia
6 (7.4%)
1 (1.2%)
3 (3.6%)
10 (4.0%)
1 (1.2%)
Metabolic acidosis
3 (3.7%)
1 (1.2%)
5 (6.0%)
9 (3.6%)
2 (2.4%)
Bronchitis
1 (1.2%)
1 (1.2%)
3 (3.6%)
5 (2.0%)
5 (5.9%)
Cough
3 (3.7%)
2 (2.4%)
5 (6.0%)
10 (4.0%)
0
Gout
3 (3.7%)
5 (6.0%)
0
8 (3.2%)
1 (1.2%)
Abdominal pain
0
5 (6.0%)
1 (1.2%)
6 (2.4%)
0
Adverse events were mapped according to MedDRA Version 19
Treatment-emergent AEs are those started on or after first study dose date up to and including 30 days after permanent 
discontinuation, or led to premature study drug discontinuation
Multiple AEs were counted once per subject for each PT. PTs are presented by descending order of the total frequency 
(all treatment groups combined)
Table 1-5 presents a summary of serious adverse events (SAEs) occurring in ≥ 2 subjects in any 
treatment group by preferred term. In the placebo group, 18.8% (16 subjects) experienced an 
SAE compared with 25.8% (64 subjects) in the pooled SEL group (29.6%, 23.8%, and 24.1% for 
SEL 2, 6, and 18 mg, respectively). The most common SAEs were acute kidney injury, 
congestive cardiac failure, pneumonia, chest pain, fluid overload, and hypertension, with no 
dose-dependent toxicity noted.


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Table 1-5.
GS-US-223-1015: Serious Adverse Events Occurring in ≥ 2 Subjects 
in Any Treatment Group by Preferred Term (Safety Analysis Set)
SEL 2 mg
(N = 81)
SEL 6 mg
(N = 84)
SEL 18 mg
(N = 83)
SEL Pooled
(N = 248)
Placebo
(N = 85)
Number (%) of Subjects 
Experiencing Any SAE
24 (29.6%)
20 (23.8%)
20 (24.1%)
64 (25.8%)
16 (18.8%)
Acute kidney injury
3 (3.7%)
3 (3.6%)
1 (1.2%)
7 (2.8%)
2 (2.4%)
Cardiac failure congestive
2 (2.5%)
1 (1.2%)
4 (4.8%)
7 (2.8%)
2 (2.4%)
Pneumonia
3 (3.7%)
2 (2.4%)
1 (1.2%)
6 (2.4%)
0
Chest pain
1 (1.2%)
2 (2.4%)
1 (1.2%)
4 (1.6%)
1 (1.2%)
Fluid overload
2 (2.5%)
1 (1.2%)
1 (1.2%)
4 (1.6%)
0
Hypertension
3 (3.7%)
0
1 (1.2%)
4 (1.6%)
0
Acute myocardial infarction
1 (1.2%)
2 (2.4%)
0
3 (1.2%)
0
Chronic obstructive pulmonary 
disease
3 (3.7%)
0
0
3 (1.2%)
0
Dyspnoea
0
2 (2.4%)
1 (1.2%)
3 (1.2%)
0
Bradycardia
2 (2.5%)
0
0
2 (0.8%)
1 (1.2%)
Cardiac failure acute
2 (2.5%)
0
0
2 (0.8%)
1 (1.2%)
Hypovolaemia
2 (2.5%)
0
0
2 (0.8%)
0
kidney failure
2 (2.5%)
0
0
2 (0.8%)
0
Cerebrovascular accident
0
0
0
0
2 (2.4%)
Adverse events were mapped according to MedDRA Version 19
Treatment-emergent AEs are those started on or after first study dose date up to and including 30 days after permanent 
discontinuation, or led to premature study drug discontinuation
Preferred terms are presented by descending order of the total frequency (all treatment groups combined)
Table 1-6 presents a summary of subjects with Grade 3 or 4 laboratory abnormalities. In the 
placebo group, 51.8% (44 subjects) experienced a Grade 3 or 4 laboratory abnormality compared 
with 51.2% (127 subjects) in the pooled SEL group (44.4%, 52.4%, and 56.6% for SEL 2, 6, and 
18 mg respectively). The most common Grade 3 or 4 laboratory abnormalities were 
hyperglycemia and fasting hyperglycemia.


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Table 1-6.
GS-US-223-1015: Grade 3 or 4 Laboratory Abnormalities (Safety 
Analysis Set)
SEL 2 mg
(N = 81)
SEL 6 mg
(N = 84)
SEL 18 mg
(N = 83)
SEL Pooled
(N = 248)
Placebo
(N = 85)
Subjects with Post-baseline Value
81
84
83
248
85
Maximum Post-baseline Toxicity Grade
Grade 3 or 4
36 (44.4%)
44 (52.4%)
47 (56.6%)
127 (51.2%)
44 (51.8%)
Grade 3
32 (39.5%)
39 (46.4%)
44 (53.0%)
115 (46.4%)
42 (49.4%)
Grade 4
4 (4.9%)
5 (6.0%)
3 (3.6%)
12 (4.8%)
2 (2.4%)
Toxicity grades (1=Mild, 2=Moderate, 3=Severe, 4=Life-Threatening, 5=Death) were from modified CTCAE Version 4.03
For maximum post-baseline toxicity grade, the most severe graded abnormality from all tests was counted for each subject
For each individual laboratory test, the most severe graded abnormality for that test was counted for a subject
A treatment-emergent laboratory abnormality was defined as an increase of at least 1 toxicity grade from baseline at any time 
post-baseline up to and including the date of last study drug dose plus 30 days
1.2.3.2.5.
Conclusion
This study did not meet the predefined efficacy endpoints, which did not account for the acute 
effects of SEL on eGFR. In post-hoc analyses, SEL demonstrated a dose-dependent reduction in 
decline of kidney function in subjects with advanced DKD. Differences in eGFR slope between 
Weeks 4 and 48 indicate that SEL may be efficacious in slowing the progression of DKD
{Chertow 2019}.
Treatment with SEL was well tolerated and no dose-limiting toxicity was observed.
1.3.
Rationale for This Study
Diabetes mellitus is the leading cause of CKD in the developed world, accounting for half of all 
incident cases of ESKD, the latter of which is associated with a 5-year survival of less than 40%. 
Approximately 13 million people in the United States (US) and European Union (EU) have 
concomitant CKD and T2DM. Approximately 10 million of these patients have CKD Stage 2-4 
and the prevalence continues to increase in step with the increasing prevalence of T2DM and 
metabolic syndrome. Current standard of care (SOC) therapies for DKD (angiotensin converting 
enzyme inhibitors [ACEi] and angiotensin receptor blockers [ARB]) target glomerular 
hypertension and do not address the underlying pathological processes of chronic inflammation 
and oxidative stress that persist and drive disease progression through fibrosis. The continual 
decline in eGFR that occurs in many patients with DKD despite treatment with these approved 
therapies highlights the large unmet medical need.
Selonsertib is a potent and selective once daily, orally administered inhibitor of ASK1 that has 
the potential to improve pathological sequelae in the kidney leading to GFR decline. SEL is 
expected to delay the time to development of serious adverse clinical outcomes such as kidney 
transplantation, dialysis, and death in patients with DKD.  SEL has demonstrated clinical activity 
and a favorable safety and tolerability profile in a Phase 2 study in subjects with Stage 3 and 4 
DKD. 


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In the Phase 2 study in subjects with Stage 3 and 4 DKD, subjects receiving SEL 18 mg had a 
larger acute decrease in eGFR (approximately 10% of the baseline value at Week 4) than the 
other SEL dose groups or placebo group, which may be due, in part, to greater inhibition of the 
kidney transporters involved in the secretion of creatinine by SEL at this higher dose (Studies 
GS-US-223-0102 and GS-US-223-3973). In a Phase 1b study in subjects with CKD with a eGFR 
between 20 to < 60 mL/min/1.73 m2 (GS-US-223-0110), acute reversible decreases for both 
eGFR and mGFR were observed with SEL 18 mg, indicating a potential secondary mechanism 
involved in the acute decrease observed in eGFR upon initiation of SEL.
Due to this acute (potentially artefactual) effect observed in prior studies, this Phase 2b study has 
incorporated a Run-in design to account for the acute eGFR effect in order to better characterize 
the chronic (long-term) effect of SEL on eGFR. To maintain the integrity of the study, other than 
eGFR values < 15 mL/min/1.73 m², eGFR results collected at Visits A, B, C, and Visit 1 will not 
be released to subjects, investigators or sponsor before study unblinding. All eGFR values 
starting at week four will be released to subjects, investigators and the sponsor for safety 
monitoring and treatment decisions. 
1.4.
Rationale for Dose Selection of Selonsertib
A SEL dosing regimen of 18 mg once daily was selected for evaluation in this Phase 2b DKD 
study based on results from the dose-ranging Phase 2 studies in subjects with DKD, NASH, and 
PAH and an examination of pharmacokinetic/pharmacodynamic (PK/PD) relationships between 
SEL exposure and response. 
Across the clinical development program, SEL administered for up to 48 weeks has been well 
tolerated with no clear exposure relationship for the incidence or severity of adverse events or 
laboratory abnormalities. Collectively, the efficacy, safety, and PK/PD data support evaluation of 
a single dose of SEL 18 mg in the proposed Phase 2b study in subjects with DKD.
Dose selection for SEL in the Phase 2bDKD study was based on results from the dose-ranging 
Phase 2 study in subjects with DKD indicating near maximal inhibition of p38 phosphorylation 
in blood cells, and near maximal slowing of the chronic rate of eGFR decline between week 4 
and 48 of treatment. In addition, the percent change from baseline in phosphorylation of ASK-1 
was measured in whole blood lysates with a sandwich immunoassay using anti-phospho-ASK-1 
antibody to capture phospho-ASK-1 (p-ASK-1) and anti-ASK-1 antibody for detection. This was 
determined at Week 12 with all remaining samples from study GS-US-223-1015 (N = 126: 35, 
28, 33, 30 from the placebo, 2 mg, 6 mg, and 18 mg daily SEL treatment arms, respectively) and 
provides additional data supporting the 18 mg dose of SEL. As the p-ASK-1 analysis was 
conducted on a subset of samples from the dataset previously presented in the IB, PK/PD 
analyses for both % phospho-p38 (p-p38) and p-ASK-1 have been reconstructed in this subset 
for a direct comparison to the observed p-ASK-1 results (Figure 1-4).
Across the range of SEL doses evaluated, a consistently greater degree of inhibition of the more 
proximal measure of ASK-1 engagement, %p-ASK-1, is observed compared to %p-p38 
(Figure 1-4). Pharmacokinetic/pharmacodynamic model fits for %p-ASK-1 and %p-p38 in this 
analysis set indicate the maximum predicted inhibition of ASK-1 and p-38 phosphorylation to be 


Selonsertib 
Protocol GS-US-223-1017 
Gilead Sciences, Inc. 
Final 
Amendment2 
89.6% and 75.8%, respectively, with SEL exposure resulting in half-maximal inhibition of 
185 hr*ng/mL and 1520 hr*ng/mL, respectively. These analyses of ASK-1 engagement suppo1i 
dose selection of 18 mg SEL which provides near maximal effect and any finiher increased dose 
of SEL is not expected to provide meaningfully greater PD response, or increased efficacy. 
Figure 1-4. 
50 
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PK/PD Relationships for SEL Exposure (AUCtau) and %p-p38 or 
o/op-ASK-1 (Study GS-US-223-1015) 
%p-p38 and ¾p-ASK-1 Percent Change Vs. SEL AUCtau 
• PBO n=35 
• 2 mg n=28 
• 6mg n=33 
-
0/op-ASK-1 Model Fit 
0 
2000 
4000 
6000 
8000 
10000 
Mean (95%CI) SEL AUC1au (hr .. ng/ml) 
Similar to p38 phospho1ylation, in the Phase 2 DKD study, a dose- and exposure 
(AUCtau)-dependent response relationship was observed for the rate of eGFR decline (slope) 
from Week 4 to 48. The mean eGFR slope in the 18 mg group was -1.27 mL/min/1. 73 m2 /year, 
significantly smaller than the placebo group slope (-4.97 mL/min/1.73 m2/year), and residing on 
the flat portion of the dose- and exposure-response curves. Additionally, the relationship between 
p-p38 inhibition and chronic eGFR slope by dose group showed a trend in improved efficacy 
with increasing dose of SEL with minimal overlap between SEL 18 mg and placebo. 
In the Phase 2 DKD study, there was a small difference in change in eGFR between the 6 mg and 
18 mg doses of SEL that trended in favor of the 18 mg dose at 48 weeks but was not statistically 
significant. This improvement with the 18 mg dose in slowing the rate of eGFR decline may be 
clinically significant over longer periods of time. For example, for patients staiiing with an eGFR 
of 30 ml/rnin/1. 73 m2, this difference between doses would increase time to kidney failure from 
approximately 4 yeai·s with SEL 6 mg to approximately 6 yeai·s with SEL 18 mg. In the context 
of such lai·ge therapeutic differences and a disease course that spans many yeai·s, SEL 18 mg is 
the optimal dose for the long-te1m prevention of kidney failure among patients with moderate to 
advanced DKD. 
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Amendment 2
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Across the clinical development program, SEL administered for up to 48 weeks has been well 
tolerated with no clear exposure relationship for the incidence or severity of adverse events or 
laboratory abnormalities. Collectively, the efficacy, safety, and PK/PD data support evaluation of 
SEL 18 mg in this Phase 2b study in subjects with DKD.
1.5.
Rationale for Placebo Use
All subjects, including those randomized to the placebo arm, will continue to receive standard of 
care therapy (e.g., ACEi, ARB, etc.) as part of their treatment for T2DM and moderate to 
advanced DKD. Thus, the use of placebo will not interfere with their current treatment plan.
1.6.
Risk/Benefit Assessment for the Study
Chronic kidney diseases, including DKD, are serious diseases that have broad and negative 
public health, social, and economic impacts. New agents that prevent long-term decreases in 
kidney function are needed to improve the efficacy, safety, and tolerability of treatments for 
these diseases.
This study will provide additional information regarding the safety and efficacy of SEL in 
patients with T2DM and moderate to severe DKD. Transient increases in serum creatinine have
been observed in a dose-dependent manner with SEL and are consistent with the inhibitory effect 
of SEL on transporters involved in tubular creatinine secretion (MATE1 and MATE2K, 
IC50 = 2.4 µM and 0.94 µM). The potential benefits of SEL for the treatment of DKD were 
shown in the Phase 2 study GS-US-223-1015. SEL appeared to be safe and well-tolerated 
without significant dose-related toxicity and demonstrated a clinically meaningful reduction in 
decline of kidney function among subjects with advanced DKD. Differences in eGFR slope
between SEL and placebo from 4 to 48 weeks demonstrate that SEL is expected to slow the 
progression of DKD. These data support further evaluation of the 18 mg dose in a Phase 2b 
study. No events considered to be adverse drug reactions (ADRs) to SEL have been identified in 
the clinical studies conducted to date. Thus, at this time, no significant clinical risks are expected 
with administration of SEL. 
Potential risks of this study include those related to the fact that SEL is a new chemical entity. 
Although a long term safety profile has yet to be established, SEL, administered at doses up to 
100-mg in Phase 1 studies and up to 18 mg in Phase 2 studies in subjects with NASH, AH, DKD, 
or PAH, appears to be well tolerated. 
A concentration QT analysis demonstrated that SEL at doses up to 100-mg did not cause 
clinically relevant prolongation of the QTc interval. To mitigate the potential risk of liver injury, 
subjects are monitored closely; defined rules for close observation and drug cessation due to 
elevated liver tests are specified in the protocols. In addition, embryofetal toxicity was observed 
in nonclinical studies; therefore to prevent potential fetal exposure, adherence to highly effective 
methods of contraception will be required. 


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Gilead Sciences, Inc. 
Amendment 2
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Additional risks to study subjects include those attributable to study participation in general, 
including risks associated with frequent clinic visits and laboratory blood draws, and the 
associated pain and discomfort of phlebotomy. Strategies to mitigate these risks include close 
monitoring of lab values as well as AEs. Parameters for discontinuation of the study drugs due to 
AEs and non-kidney laboratory abnormalities are also defined and will be closely followed.
For this study, frequent assessments of kidney function will be performed from the collection of 
both blood and urine samples. Parameters for discontinuation of the study drugs due to adverse 
events are defined in this study protocol and will be closely followed.
While the potential benefits and risks described above must be confirmed, available data in DKD 
subjects treated for 48 weeks, as well as the favorable safety profile seen across the Phase 2 
studies in NASH, DKD, and PAH, provide strong rationale for a favorable benefit/risk ratio in
support of the study in subjects with DKD.
1.7.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


Selonsertib 
Protocol GS-US-223-1017 
Gilead Sciences, Inc. 
2. 
OBJECTIVES 
The prima1y objective of this study is: 
• 
To evaluate whether SEL can slow the decline in kidney function 
The secondaiy objectives of this study ai·e: 
Final 
Amendment2 
• 
To evaluate whether SEL can reduce the risk of kidney failure, or reduce the risk of death 
due to kidney disease in subjects with diabetic kidney disease (DKD) 
• 
To assess the safety and tolerability of SEL in subjects with DKD 
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Selonsertib 
Protocol GS-US-223-1017 
Gilead Sciences, Inc. 
3. 
STUDY DESIGN 
3.1. 
Endpoints 
Primary efficacy endpoint: 
eGFRcr slope from treatment-specific baselines 
The secondaiy endpoints of this study are: 
Final 
Amendment2 
• 
Proportion of Kidney Clinical Events at Week 48 defined as any of the following events: 
Confomed 40% decline in eGFRcr from pre-nm-in baseline, or 
Kidney failure ( dialysis perfo1m ed for at least 4 weeks, kidney transplantation, or 
confinned decrease in eGFRcr to < 15 mL/min/1. 73 m2 for subjects without dialysis or 
kidney transplantation), or 
Death due to kidney disease 
• 
Time from randoinization to first occmTence of a Kidney Clinical Event 
• 
eGFRcys slope from pre-nm-in baseline 
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Final 
Amendment2 
I 
I 
3.2. 
Study Design 
This is a Phase 2b, randomized, double-blind, placebo-contrnlled, parallel group, multicenter 
study evaluating the efficacy and safety of SEL in subjects with T2DM and moderate to 
advanced DKD. 
Subjects meeting the study's entiy criteria after signing the info1med consent will emoll into a 
Run-in period of at least 5 weeks and receive at least one week of placebo to match (PTM) and 
then SEL (18 mg) for at least 4 weeks. After completing the Run-in period, subjects meeting 
eligibility will be randomized in a 1: 1 ratio to receive SEL (18 mg) or PTM orally once daily. 
Subjects must be on SEL for at least 7 consecutive doses prior to Visit C and Visit 1 in order to 
randomize. 
The overall study design is presented graphically in Figure 3-1. 
Figure 3-1. 
Study Design Schema 
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Abbreviations: EOS = End of Study, EOT = End of Treatment, P1M = placebo-to-match to match, SEL= Selonsertib 
a 
Prior to randomization, subjects must have at least 7 consecutive daily doses of study dmg immediately prior to Visit C and 
Randomization (Visit I) 
b 
Post-nm-in baseline eGFR is defined as the average of Visit C and Visit I eGFR values. Pre-nm-in baseline is defined as 
the average of Visit A and Visit B eGFR values. 
c 
If kidney faihu·e is reached, subjects should discontinue study dmg and remain on study. 
d 
If a subject permanently discontinues study dmg, there will be a 30 Day EOT Follow-up visit. Subjects who penuanently 
discontinue study dmg prior to the global study end date will have an EOT visit and a 30 Day (±7 days) EOT Follow-up 
visit. Subjects are encotu·aged to complete all remaining study visits until the global study end date. 
e 
The global study end date will occtu· when the last randomized subject reaches 48 weeks and/or all subjects on study have 
completed end of study assessments and the 30 Day EOS Safety Follow-up visit. 
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Amendment 2
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Randomization will be stratified by average eGFR values from Visit A and Visit B, average 
urine albumin to creatinine ratio (UACR) values from Visit A and B, and concomitant use of 
sodium-glucose co-transporter-2 (SGLT-2) inhibitors at Visit 1. 
Subjects will continue to receive SEL or PTM in a double-blind fashion until death, study drug 
discontinuation, kidney failure (dialysis performed for at least 4 weeks, kidney transplantation, 
or confirmed decrease in eGFR to < 15 mL/min/1.73 m2 for subjects without dialysis or kidney 
transplantation), or the global study end date. 
3.3.
Duration of Treatment
At least 52 weeks (4 weeks during the Run-in period and at least 48 weeks post randomization)
3.4.
Discontinuation of Study Drug
Selonsertib or PTM should be discontinued for any of the following reasons in consultation with 
the Gilead Medical Monitor and/or sponsor designee: 

Death 

Kidney failure (dialysis performed for at least 4 weeks, kidney transplantation, or confirmed 
decrease in eGFR to < 15 mL/min/1.73 m2 for subjects without dialysis or kidney 
transplantation)

Pregnancy during the study; refer to Appendix 6

Participation in another therapeutic clinical study

Clinically significant adverse event in the opinion of the subject or investigator 

Significant protocol violation that impacts subject safety

Significant subject noncompliance with study drug administration, study procedures, or study 
requirements per judgement of the investigator

Intercurrent illness that would, in the judgment of the investigator, permanently affect 
assessments of clinical status to a significant degree 

Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Study blinding is intentionally broken by the subject or the study site 

Discontinuation of the study at the request of Gilead, a regulatory agency, or an institutional 
review board or independent ethics committee (IRB/IEC)


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Amendment 2
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Subjects who permanently discontinue study drug will have an end of treatment (EOT) visit 
scheduled as soon as possible after the decision to discontinue study drug is made. If an ECG, 
STS was conducted at a previous visit within 24 weeks of the EOT visit, the assessment does not 
need to be performed at the EOT visit. In addition to the EOT visit, subjects who permanently 
discontinue study drug prior to global study end date will have a 30 day (±7 days) EOT Follow-
up visit which will include an assessment of eGFR and UACR.
Every attempt should be made to keep these subjects in the study and complete all subsequent 
study visits in the same way as subjects who are still on study drug. If this is not possible, 
subjects off study drug will have the option to be followed via limited assessments as defined in 
Section 6.7.2.
Subjects who have permanently discontinued study drug, reached kidney failure, or are no longer 
able to continue to attend clinic visits in-person, and have not withdrawn full consent will be 
asked to continue to participate in this study via remote assessments as defined in Section 6.7.3.
3.5.
Discontinuation Criteria from Study
Subjects may discontinue from study for the following reasons: 

Death

Pregnancy during the study; refer to Appendix 6

Participation in another therapeutic clinical study

Withdrawal of consent and refusal to allow any subsequent data collection, including passive 
methods. If a subject is amenable to any degree of limited follow-up or data collection, 
including passive methods, the subject must not be discontinued from the study

Significant subject noncompliance with study drug administration, study procedures, or study 
requirements per judgement of the investigator

The subject is lost to follow-up after exhaustion of all contact efforts until the global study 
end date; see Section 6.7.3.

Investigator’s decision to remove the subject from the study

Discontinuation of the study by the Sponsor, a Regulatory Agency, or an IRB or EC
For subjects who discontinue from study for reasons other than death, withdrawal of full consent
or loss to follow-up, the subject should complete the end of study (EOS) visit. Subjects who 
permanently discontinue study drug and study on the same day should complete the EOT visit 
and return to clinic for their EOT Follow-up visit 30 days (±7 days) for assessments. If an ECG
or STS was conducted at a previous visit within 24 weeks of the EOT/EOS visit, the assessment 
does not need to be performed at the EOT/EOS visit.


Selonsertib 
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3.6. 
End of Study 
Final 
Amendment2 
The primary analysis of eGFRcr slope will be perfo1med after all subjects in the ITT Analysis Set 
complete the Week 48 visit or discontinue from the study. The global study end date is defined 
as when the last randomized subject reaches 48 weeks and/or all subjects on study have 
completed end of study assessments and the 30 Day EOS Safety Follow-up visit. 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
This study will enroll approximately 300 subjects with T2DM and eGFR ranging from
≥20 mL/min/1.73 m² to < 60 mL/min/1.73 m² with albuminuria receiving standard of care 
therapy (ACEi or ARB, or intolerant to ACEi and ARB).
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in this 
study:
1) Male or female between 18 (or ≥ age of majority in each jurisdiction if different than 18) and 
80 years of age, inclusive
2) Prior diagnosis of T2DM with diagnostic modalities as per local guidelines. Must have 
hemoglobin A1c (HbA1c) > 6% within 30 days prior to Enrollment (Visit A) or be on active 
treatment for T2DM for at least 6 weeks prior to Enrollment (Visit A)
3) eGFR value calculated by central laboratory utilizing samples collected during Screening and 
prior to Enrollment (Visit A) of ≥20 mL/min/1.73 m² to < 60 mL/min/1.73 m² with 
albuminuria as measured by UACR
a) eGFR values will be calculated using the Chronic Kidney Disease Epidemiology (CKD-
EPI) Creatinine Equation (2009); UACR will be determined by urine collection, 
preferably early morning void. Subjects can have up to 3 eGFR and 3 UACR collections 
during the Screening period. Any one of the eGFR values and any one of the UACR 
values collected during Screening may be used to satisfy this inclusion criterion.
Qualifying eGFR and UACR values do not need to be collected on the same day  
b) eGFR and UACR must meet criteria a, b, or c  
Criteria
eGFR (mL/min/1.73 m²)
UACR (mg/g)
a
≥ 45 to < 60
≥ 600 to 5000
b
≥ 30 to < 45
≥ 300 to 5000
c
≥ 20 to < 30
≥ 150 to 5000


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4) Treatment with either an ACEi or ARB as a single agent at the maximum labeled or tolerated 
dose deemed appropriate for the subject by the investigator and/or per local SOC for at least 
6 weeks prior to Enrollment, with a stable dose for at least 2 weeks prior to Enrollment 
a) Subjects not receiving an ACEi or ARB may be enrolled if there is documented 
intolerance to ACEi and ARB 
b) Subjects receiving less-than-maximal dose of an ACEi or ARB may be enrolled if there is 
a documented reason that the maximum labeled dose of ACEi and ARB could not be 
reached  
5) Subjects already receiving SGLT-2 inhibitors must be on a stable dose at least 2 weeks prior 
to Enrollment
6) For females of childbearing potential (unless permanently sterile or post-menopausal, as 
described in Appendix 6), a negative serum pregnancy test at Screening
7) For male and female subjects of childbearing potential who engage in heterosexual 
intercourse, agreement to abstain or use protocol specified method(s) of contraception as 
described in Appendix 6
8) Male subjects must refrain from sperm donation from the Screening visit through 30 days 
following the last dose of study drug
9) Female subjects must refrain from egg donation or harvest from the Screening visit through 
30 days following the last dose of study drug 
10) Subjects must refrain from blood product donation from the Screening visit through 30 days 
following the last dose of study drug
11) Mean systolic blood pressure (SBP) must be < 160 mmHg and mean diastolic blood pressure 
(DBP) must be < 100 mmHg taken at two time-points at least five minutes apart within 
30 days prior to Enrollment (Visit A)
12) Required baseline laboratory data, analyzed by central laboratory, within 30 days prior to 
Enrollment (Visit A) as shown in the table below
Organ System
Parameter
Required Value
Hematologic
WBC, neutrophil, 
lymphocyte, and platelet 
count
≥0.75 x LLN to ≤ 1.5 x ULN
Hepatic
Serum total bilirubin
≤ 1.5 × ULN
Serum ALT
Serum AST


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Organ System
Parameter
Required Value
Pregnancy
-HCGa
Negative
Infection
HIVb
Negative HIV antibody
HBV
Negative HBsAg and negative HBc antibody or
positive HBc and negative for HBV DNA by
quantitative PCR
HCV
Negative HCV antibody or negative viral RNA (if HCV 
antibody is positive)
a
For women of childbearing potential only; serum -HCG must be negative during Screening
b
If screening test is positive, a negative confirmatory test will be required for eligibility
Abbreviations: -HCG = beta human chorionic gonadotropin, ALT = alanine aminotransferase, 
AST = aspartate aminotransferase, DNA = deoxyribonucleic acid, LLN = lower limit of normal, HBc antibody = anti-hepatitis B 
core antibody, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = human 
immunodeficiency virus, PCR = polymerase chain reaction, RNA = ribonucleic acid, ULN = upper limit of normal, 
WBC = white blood count
13) Have either a normal 12-lead electrocardiogram (ECG) or an ECG with abnormalities that 
are not considered to be clinically significant by the investigator within 30 days prior to 
Enrollment (Visit A)
14) In the judgment of the investigator, participation in the study offers an acceptable benefit to 
risk ratio, taking into consideration the subject’s current DKD status, medical condition, and 
the potential benefits and risks of alternative treatments for DKD
15) Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, 
other study procedures, and study restrictions
16) Willing and able to give informed consent prior to any study specific procedures being 
performed
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) HbA1c > 12.0% within 30 days prior to Enrollment (Visit A) 
2) In the investigator’s opinion, a condition other than T2DM is the primary etiology of DKD  
3) Subjects with diagnosis of type 1 diabetes mellitus (T1DM) or maturity onset diabetes of the 
young (MODY)   
4) Body mass index (BMI) > 50 kg/m2 at Enrollment (Visit A) 
5) UACR > 5000 mg/g on any measurement during Screening 


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6) End stage kidney disease (ESKD) (i.e., chronic hemodialysis, chronic peritoneal dialysis, or 
history of kidney transplantation)
7) Anticipated progression to ESKD (need for chronic hemodialysis, chronic peritoneal dialysis 
or receipt of kidney transplant) within 3 months after Enrollment (Visit A)
8) Unstable CV disease as defined by any of the following:
a) Myocardial infarction (MI), coronary artery bypass graft surgery, or coronary angioplasty 
within 3 months prior to Enrollment (Visit A)
b) Transient ischemic attack or cerebrovascular accident within 3 months prior to 
Enrollment (Visit A)
c) Hospitalization for heart failure within 3 months prior to Enrollment (Visit A)
d) New York Heart Association (NYHA) Class IV congestive heart failure
9) Diagnostic or interventional procedure that requires intravenous or intra-arterial iodinated 
contrast agent within 30 days prior to Enrollment (Visit A) and/or planned during the study 
Run-in period
10) History of a malignancy within 5 years prior to Enrollment (Visit A). However, the following 
are not exclusions, and subjects may enroll if there is any history of: 
a) Carcinoma in situ of the cervix, or
b) Basal or squamous cell cancer or other localized non-melanoma skin cancer that has been 
adequately treated 
11) Pregnant or lactating females or planning to become pregnant or breastfeed during the study
12) Concurrent use of either
a) ACEi and ARB or
b) Mineralocorticoid receptor antagonist (MRA) or direct renin inhibitor (DRI) in 
combination with an ACEi or ARB for at least 2 weeks prior to Enrollment
13) Requiring chronic administration of prohibited medications as per protocol  
14) Participation in another investigational study within 1 month or within 5 half-lives of the 
prior investigational agent (whichever is longer) prior to Enrollment (Visit A) 
15) Concurrent participation in another therapeutic clinical study
16) Prior participation in any clinical trial of SEL 


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17) Known hypersensitivity to the study drug (SEL/placebo-to-match), the metabolites, or 
formulation excipients
18) Prior or ongoing clinically significant illness, medical condition, surgical history, physical 
finding, ECG finding, or laboratory abnormality that, in the investigator’s opinion, could 
adversely affect the safety of the subject or impair the assessment of study results
19) Presence of any condition that could, in the opinion of the investigator, compromise the 
subject’s ability to participate in the study, such as history of substance abuse, alcoholism, or 
a psychiatric condition
4.4.
Eligibility Criteria for Randomization
Subjects must meet all of the following criteria to be eligible for randomization: 
1) eGFR ≥15 mL/min/1.73 m² at all central laboratory assessments during the Run-in period 
prior to Randomization (Visit 1)
2) At least 7 consecutive daily doses of SEL, without interruption, immediately prior to Visit C 
and prior to Randomization (Visit 1)
3) Subject did not permanently discontinue study drug during the Run-in period
4) Subject did not withdraw consent
5) Subject did not initiate, change dose, or discontinue SGLT-2 inhibitor during the Run-in 
period or is not anticipated to initiate, change dose or discontinue SGLT-2 inhibitor within 
12 weeks after Randomization (Visit 1)  
6)
Negative urine pregnancy test for female subjects of childbearing potential
7) No ongoing clinically significant illness, medical condition, surgical history, physical 
finding, or laboratory abnormality that, in the investigator’s opinion, could adversely affect 
the safety of the subject or impair the assessment of study results


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
An Interactive Web Response System (IWRS) will be used to maintain a central log 
documenting screening, enrollment and randomization and study drug bottle numbers. It is the 
investigator's responsibility to ensure that the subject is eligible for the study prior to enrollment 
and randomization. Subjects will be assigned a screening number at the time of consent. Once 
eligibility for enrollment has been confirmed, the subjects will be assigned a unique subject 
number via IWRS and enter the Run-in period. During the Run-in, treatment will be unblinded 
and subjects will receive PTM for at least 7 consecutive days and SEL for at least 4 weeks.
Subjects must be on SEL for at least 7 consecutive doses prior to Visit C and Visit 1 in order to 
randomize. 
Subjects who meet randomization eligibility criteria will be randomized in a 1:1 ratio to either 
SEL or PTM. Randomization will be stratified by average eGFR values from Visit A and 
Visit B, average UACR values from Visit A and B, and concomitant use of SGLT-2 inhibitors at 
Visit 1. The unique subject number assigned at enrollment will remain the same in the 
randomized phase of the study. 

eGFR Strata:  
eGFR strata (mL/min/1.73 m²)
≥45
≥ 30 to < 45
≥ 15 to < 30

Albuminuria Strata: UACR < 1500 mg/g vs. ≥1500 mg/g

Concomitant SGLT-2 Inhibitor Use Strata: Yes vs. No
During the randomized phase, subjects and all personnel directly involved in the conduct of the 
study will be blinded to treatment assignment. Study drug will be dispensed in a blinded fashion 
to the subjects. Additionally, to maintain the blinding of treatment assignment, serum creatinine 
and eGFR results collected at Visits A, B, C, and 1 will not be released to subjects, investigators 
or sponsor before study unblinding, with the exception of eGFR values < 15 mL/min/1.73 m². 
The IWRS will be utilized to maintain the blinding of eGFR values required for stratification. A 
third party vendor, who is independent of Gilead, or Biometrics personnel at Gilead who are not 
associated with the study team will be unblinded to baseline eGFR values in order to monitor and 
calculate the decrease in eGFR of ≥ 40% relative to baseline.


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Other specified Gilead personnel or independent vendors may be unblinded based on their study 
role. The Pharmacokinetics File Administrator, or designee, in Bioanalytical Operations and/or 
Clinical Data Management, who facilitates the data transfer of PK files between Gilead and 
vendors, will remain unblinded. Individuals in Clinical Packaging & Labeling or Clinical 
Supply Management who have an Unblinded Inventory Manager role in the IXRS system for 
purposes of IMP inventory management will remain unblinded. Individuals in PVE responsible 
for safety signal detection, IND safety reporting and/or expedited reporting of suspected 
unexpected serious adverse reactions (SUSARs) may be unblinded to individual case data and/or 
group level summaries. External (ie, contract research organizations) biostatisticians and 
programmers will be unblinded for data monitoring activities. Regulatory Compliance personnel 
may also be unblinded for purposes of identifying subjects for whom study drug concentrations 
are to be determined for blinded studies in which Quality Assurance audits of bioanalytical or 
research reports are necessary.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject (refer to the IWRS Site User Manual for unblinding instruction). Gilead 
recommends but does not require that the investigator contact the Gilead Medical Monitor and/or 
sponsor designee before breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessary to determine subject emergency medical care. The rationale for 
unblinding must be clearly explained in source documentation and on the electronic case report 
form (eCRF), along with the date on which the treatment assignment was obtained. The 
investigator is requested to contact the Gilead Medical Monitor and/or sponsor designee
promptly in case of any treatment unblinding, and retain this information at the study site team 
level only.
Blinding of study drug is critical to the integrity of this clinical study and therefore, if a subject’s 
treatment assignment is disclosed to the investigator, during the blinded treatment phase, the 
subject will have study drug discontinued. All subjects will be followed until the global study 
end date unless consent to do so is specifically withdrawn by the subject.
Gilead Pharmacovigilance & Epidemiology (PVE) may independently unblind cases for 
expedited reporting of suspected unexpected serious adverse reactions (SUSARs).
5.2.
Description and Handling of Selonsertib (SEL)
5.2.1.
Formulation
SEL 18 mg tablets will be supplied as round, film-coated gray tablets debossed with an 
underscored “18” on one side and “GSI” on the other side. The tablets are approximately 
7.14 mm in diameter. In addition to the active ingredient, SEL 18 mg tablets contain the 
following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, and 
iron oxide black.


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PTM 18 mg tablets are available for blinding purposes. Each placebo-to-match tablet is identical 
to SEL 18 mg tablets in their size, shape, and appearance and contains the same inactive 
ingredients.
5.2.2.
Packaging and Labeling
SEL and PTM tablets are packaged in white, high-density polyethylene (HDPE) bottles. Each 
bottle contains 30 tablets, silica gel desiccant and polyester packing material. Each bottle is 
capped with a child-resistant polypropylene screw cap fitted with an induction-sealed, 
aluminum-faced liner.
Study drugs to be distributed to centers in the United States (US) and other participating 
countries shall be labeled to meet applicable requirements of the US Food and Drug 
Administration (FDA), European Union (EU) Guideline to Good Manufacturing Practice -
Annex 13 (Investigational Medicinal Products), and/or other local regulations.
5.2.3.
Storage and Handling
SEL 18 mg and PTM tablets should be stored at controlled room temperature of 25°C (77°F); 
excursions are permitted between 15°C and 30°C (59°F and 86°F). Storage conditions are 
specified on the label. Until dispensed to the subjects, all bottles of study drug should be stored 
in a securely locked area, accessible only to authorized site personnel. To ensure the stability and 
proper identification, study drug should not be stored in a container other than the containers in 
which they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.3.
Dosage and Administration of Selonsertib / Placebo-to-Match 
The administration of study drug will be recorded in the source documentation and in the eCRF. 
Study drug will be self-administered by the subject orally once daily at approximately the same 
time each day. The study drug should be swallowed whole with water and may be taken with or 
without food. A dose is considered missed if the subject cannot take the dose within 12 hours of 
their regular dosing time. If a subject misses a dose, the subject should take their next dose at the 
regular dosing time.
Following completion of screening assessments, eligible subjects will enroll into the Run-in 
period. Subjects will self-administer PTM orally once daily from Enrollment (Visit A) to Visit B 
for at least 1 week, at approximately the same time each day. Following Visit B subjects will 
receive at least 4 weeks of SEL (18 mg) orally once daily at approximately the same time each 
day. 
After completing the Run-in period, subjects meeting randomization eligibility criteria will be 
randomized 1:1 to receive either SEL 18 mg or PTM orally once daily.


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5.3.1.
Dose Interruption
The Gilead Medical Monitor and/or sponsor designee should be consulted prior to study drug 
interruption when medically feasible. Prior to resumption of study drug, the investigator should 
discuss the case with the Gilead Medical Monitor and/or sponsor designee. Study drug 
interruption should be considered in the following situations:  

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator

Subject is scheduled for elective or emergency procedures that require nothing by mouth; 
timing of study drug pause should be determined in consultation with the Gilead Medical 
Monitor and/or sponsor designee

See Section 7.5 for dose interruptions related to toxicity including liver enzyme 
abnormalities and eGFR decline 

If study drug is withheld, restart study drug as soon as clinically appropriate and check eGFR 
at next scheduled visit, preferably with study drug taken for at least 7 consecutive days.
NOTE: While study drug is interrupted for any of the above reasons, the subject may continue to 
have study visits and to take part in procedures and assessments, if deemed medically 
appropriate by the investigator.
5.4.
Prior and Concomitant Medications
All concomitant medications will be recorded in the source documents and eCRFs. This includes 
concomitant medications taken within 30 days prior to Screening; concomitant medications of 
interest, as defined in Section 6.4.2, up to 1 year prior to Screening; and any taken during the 
study through the 30 Day EOS Safety Follow-up visit or until subjects are being followed via 
remote assessments as defined in Section 6.7.3.
The following medications are prohibited:

Any investigational medication or device within 30 days or within 5 half-lives of the prior 
investigational agent (whichever is longer) prior to Enrollment and throughout the study

Concurrent use of study drug with both an ACEi and ARB   

Strong cytochrome P4503A4 (CYP3A4) inducers may decrease the exposure of SEL and 
could lead to decreased efficacy. Use of strong CYP3A4 inducers is prohibited from 2 weeks 
prior to Enrollment through end of treatment

Inhibitors of kidney transporter-mediated creatinine secretion may impact the assessment of 
efficacy. Use of inhibitors of creatinine secretion is prohibited from 2 weeks prior to 
Enrollment through end of study


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Caution should be exercised when co-administering sensitive P-gp substrates with narrow 
therapeutic index with SEL as it may increase the concentrations of these agents. Investigators 
should refer to the full prescribing information for additional guidance on use of concomitant 
medication with a P-gp inhibitor.
Examples of representative medications that are prohibited 2 weeks prior to enrollment or which 
should be used with caution starting at enrollment are listed in Table 5-1. This is not an 
exhaustive list of medications that are prohibited or to be used with caution. If there are 
questions about concomitant medications, please contact the Gilead Medical Monitor or Sponsor 
Designee. 
Table 5-1.
Examples of Medications that are Prohibited or to be Used with 
Cautiona
Drug Class
Agents Prohibited
Prohibited 2 weeks prior to enrollment through the end of study
Antianginalsb
ranolazinec
Antiarrhythmicsb
amiodaroned, dronedaronec, dofetilidec
Antibioticsb
trimethoprim
Antifungalsb
isavuconazolec
Antiparasiticsb
pyrimethaminec
Direct renin inhibitors (DRI)e
aliskirenf
H2 Blockersb,i
cimetidine, famotidine
Mineralocorticoid receptor antagonists 
(MRA)e
spironolactone, eplerenone 
Nuclear factor erythroid 
2–related factor 2 (Nrf2) activator 
bardoxolonec
Drug Class
Agents Prohibited
Prohibited 2 weeks prior to enrollment through the end of treatment
Anticonvulsantsg
phenobarbital, phenytoin
Antimycobacterialsg
rifampin
Herbal/Natural Supplementsg
St. John’s Wort


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Category
Agents to be used with caution
Use with caution from enrollment through end of treatment 
Cardiac Medicationsf
digoxinh, dabigatran etexilate, flecainide 
Antineoplastic/immunosuppressantf
methotrexate
a
Not all of these example medications may be approved in each of the countries where the study is being conducted; please 
refer to local product information 
b
May increase serum creatinine and decrease eGFR. 
c
Not approved in Japan
d
Due to the long half-life of amiodarone, prohibited 90 days prior to enrollment through end of the study
e
Disallowed if concurrent use with ACEi or ARB for at least 2 weeks prior to Enrollment. If subject cannot tolerate ACEi or 
ARB, subject may use either a DRI OR an MRA as a single agent. If medically necessary after Week 12, concurrent use of 
MRA with ACEi or ARB is permitted. However, concurrent use with ACEi or ARB is associated with risk of hyperkalemia, 
so caution must be exercised. Please refer to full prescribing information for additional guidance.
f
SEL may increase the exposure of these medications and must be used with caution. Please refer to the full prescribing 
information for additional guidance
g
May result in a decrease in the concentration of SEL
h
Digoxin level should be measured at Visit C and Week 4. PI may continue checking after Week 4 as part of digoxin 
management as needed. Monitor and adjust digoxin dose as necessary based on prescribing information
i
Permissible H2 blockers include ranitidine, nizatidine, roxatidine, and lafutidine.
5.5.
Accountability for Study Drug
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug bottles. This includes acknowledgement of receipt of each shipment of study drug (quantity 
and condition). All used and unused study drug bottles dispensed to subjects must be returned to 
the site, and any study drug losses must be explained.
Study drug accountability records will be provided to each study site to:

Record the date received and quantity of SEL/PTM bottles

Record the date, subject number and the SEL/PTM bottle numbers dispensed

Record the date, quantity of used and unused SEL/PTM bottles returned, along with the 
initials of the person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
The study drug (SEL/PTM) should be retrieved from each subject at the end of each dispensing 
interval. The quantity of study drug and the date returned by the subject should be recorded in 
the subject’s study drug accountability records. All study drug returned by the subject should be 
retained for review by the study site monitor prior to return of study drug to Gilead Sciences or 
destruction at the site. 
Please see Section 9.1.8 for more information.


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The study procedures to be conducted for each subject enrolled in the study are presented in the 
Study Procedures Table (Appendix 2) and described in the text below. 
In the event a study visit is delayed, all attempts should be made to complete a visit as close as 
possible to the missed visit. All subsequent visits should be completed on the original schedule 
based on time from randomization. If a subject is on a drng hold or pennanently off study drng, 
they should still return for regular assessments according to the schedule of procedures. 
If a subject experiences chug intenuption or is unable to undergo study assessments at their site 
due to an SAE or other emergent reasons (e.g., pandemic, natural disasters or other reasons 
including recommendations by national, state, or local authorities, site institution or 
investigator), document the deviation from the protocol along with the reason in source 
documentation and consult with the sponsor on a case-by-case basis. Sites should attempt 
alternative means (such as phone calls, text messages, e-mails, or other suitable means) to 
maintain contact with subjects to follow up on assessments including AEs, IP, and concomitant 
medication usage. 
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO). 
6.1. 
Informed Consent 
All subjects must sign and date the most recent Institutional Review Board/Institutional Ethics 
Committ 
· 
are 
relative or friend of the subject. This infonnation will be stored at the site, and not shared with 
the sponsor or sponsors representatives, but used for remote assessments as defined in protocol 
Section 6.7.3. 
6.2. 
Subject Enrollment 
Entry into screening does not guarantee enrollment into the study. To manage the total study 
enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any site or 
study-wide at any time. 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within the 30 day screening window for enrollment into the study. 
Any consented subject who is excluded from the study before enrollment will be considered a 
screen failure. All screen failures must be documented along with an adequate description of the 
reason the subject was considered a screen failure. If available, info1m ation should be provided 
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as to why the subject did not meet eligibility criteria, withdrew consent, experienced an 
intercurrent illness, or had other events that precluded enrollment. Of note, subjects may be 
rescreened only once for study eligibility under a new screening number.
From time of obtaining informed consent and prior to study drug initiation, the following 
type of events should be reported on the eCRFs: all SAEs and AEs which are related to 
protocol-mandated procedures. All other untoward medical occurrences observed during the 
Screening period, including exacerbation or changes in medical history are to be captured on 
the medical history eCRF. See Section 7 Adverse Events and Toxicity Management for 
additional details.
6.3.
Randomization and Treatment Assignment
After the Run-in period, subjects who meet randomization eligibility will be randomized to SEL 
or PTM based on a randomization schedule prepared by Gilead and/or a designee before the start 
of the study. Any consented subject who is excluded from the study before randomization will be 
considered a Run-in failure.
Eligible subjects will be centrally randomized via IWRS. See Section 5.1 Randomization, 
Blinding and Treatment Codes for additional details.
6.4.
Study Procedure Descriptions
6.4.1.
Medical History & Medication History
A complete medical and surgical history will be obtained prior to Enrollment (Visit A) and 
recorded on the eCRF, including a history of the subject’s DKD.
Medical history should include, but not be limited to (as applicable): T2DM, DKD, diabetic 
neuropathy, diabetic retinopathy, diabetic gastroparesis, congestive heart failure NYHA 
(Class I, II, IIIa, IIIb), valvular heart disease, coronary artery disease, coronary revascularization 
(coronary artery bypass graft, percutaneous coronary intervention), dyslipidemia, stroke, PVD, 
peripheral revascularization, NASH, fatty liver disease, gout, kidney stones, cancer, and history 
of smoking tobacco.
6.4.2.
Concomitant Medications
Concomitant medications include prescription medication, over-the-counter preparations, and 
herbal/homeopathic remedies and therapies used within 30 days prior to Screening, concomitant 
medications of interest up to 1 year prior to Screening, and any taken during the study through 
the 30 Day EOS Safety Follow-up visit or until subjects are being followed via remote 
assessments as defined in Section 6.7.3.


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Concomitant medications of interest on this study are defined as the following categories of 
medications:
a) Glucose-lowering (oral and injectable medications)
b) Cardiovascular risk reduction: blood pressure and/or heart failure (e.g., calcium channel 
blockers, beta blockers, diuretics, other medications for blood pressure and/or heart failure); 
lipid-lowering (e.g., statins, fibrates, PCSK9 inhibitors, other lipid-lowering medications); 
blood thinners (anti-platelets, anti-thrombotics, anti-coagulants); anti-arrhythmics 
c) Kidney disease risk reduction: renin-angiotensin-aldosterone system inhibitors [RAASi] 
(e.g., angiotensin converting enzyme inhibitors [ACEi], angiotensin receptor blockers 
[ARB], and other medications); sodium-glucose cotransporter 2 [SGLT2] inhibitors
d) Kidney disease complications: potassium binders, bicarbonate, erythropoiesis-stimulating 
agents, hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), iron, phosphate 
binders, vitamin D analogs, calcimimetics, etc.
6.4.3.
Physical Examination
A complete physical examination (PE) will be performed at Screening and End of Treatment. 
The PE will be performed by a physician, physician’s assistant, or nurse practitioner qualified to 
perform the assessment.
A complete PE should include source documentation of general appearance and the following 
body systems including head, neck, and thyroid; eyes, ears, nose, throat, mouth, and tongue; 
chest (excluding breasts); respiratory; CV; lymph nodes; abdomen; musculoskeletal; 
neurological.
At each subsequent visit where a complete PE is not scheduled, a symptom-driven PE may be 
performed if necessary, if a new symptom or a worsening symptom is reported by the subject or 
is identified upon assessment by the physician, physician’s assistant or nurse practitioner, or 
qualified. Significant changes should be recorded as AEs, if applicable.
Height, waist circumference and body mass index will be collected at specified time points.
6.4.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, temperature and weight performed by a qualified designee as per standard institutional 
guidelines at each study visit.
Screening Subjects must meet Inclusion Criteria #11: Mean systolic blood pressure (SBP) must 
be < 160 mmHg and mean diastolic blood pressure (DBP) must be < 100 mmHg taken at two 
time-points at least five minutes apart within 30 days prior to Enrollment (Visit A).


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Blood pressure is to be obtained when the subject has been seated for::::: 5 minutes with feet flat 
on the floor and measurement aim supported so that the midpoint of the manometer cuff is at 
hea1t level. The subject's position during blood pressure assessments should remain consistent 
and a consistent aim should be used throughout the study. Measure and record the blood pressure 
to the neai·est 2 millimeter of mercmy (mmHg) mai·k on the manometer or to the nearest whole 
number on an automatic device. 
-
-
6.4.7. 
Pregnancy Testing 
All females of childbeai·ing potential as defined in Appendix 6 will have a serum pregnancy test 
at Screening and urine pregnancy tests at Visit B during the Run-in period, Visit 1 and eve1y 
4 weeks thereafter until the 30 Day EOT Follow-up visit. After Week 4, eve1y 4 week pregnancy 
testing may be perfo1med at home in between clinic visits, where possible, or in clinic, if at home 
pregnancy tests ai·e unavailable. Pregnancy testing will continue eve1y 4 weeks through the 
30 Day EOT Follow-up visit. At home pregnancy testing kits will be provided. Females of 
childbeai·ing potential who perfo1m at home pregnancy tests will be contacted by the site at 
4 week intervals and asked to repo1t the result of the at home pregnancy test. 
In the event of a positive urine home pregnancy result, subjects will be instructed to stop study 
drng immediately (if applicable) and retmn to the clinic as soon as possible for a sernm 
pregnancy test. 
6.4.8. 
Electrocardiogram 
A single 12-lead ECG will be collected at Screening, eve1y 48 weeks, and at EOT and EOS 
visits. Collection of additional ECGs for routine safety monitoring at additional time points or 
days is at the discretion of the Investigator based on GCP. 
ECGs should always be collected prior to PK (or any other blood draw) if they are to be 
collected at the same nominal time point. Subjects should be resting quietly and free of 
disti·action (e.g., television, conversation) for 10 minutes prior to and during the ECG collection. 
ElectI'ocardiograms will be recorded using the site's standard ECG equipment and will include 
ventI'iculai· rate, PR interval, QRS interval and QT interval. ECGs will be inte1preted by the 
investigator ( or qualified designee) for clinical significance and results will be entered into the 
eCRF. 
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Clinical Outcome Assessments 
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Clinical outcome assessments 
should be completed at the staii 
of the study visit and prior to the clinical and laborato1y assessments. Questionnaires should be 
administered prior to conducting 
test when perfo1med on the same day. 
-
-
-
-
-
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6.4.10.
Laboratory Assessments
All blood and urine samples for laboratory assessments will be sent to the central laboratory for 
analysis. Specific instructions for collection, processing, labeling and shipping samples will be 
provided in a central laboratory manual. Laboratory samples will be collected as specified in 
Appendix 2. A list of clinical laboratory analytes to be collected are listed in Appendix 3.
For fasting laboratory visits, subjects should abstain from all food for at least 8 hours prior to 
laboratory draw. Water is allowed.
6.4.11.
Urine Albumin to Creatinine Ratio
Collection of the first urine void after the subject awakes from sleep is the preferred urine 
collection option because more concentrated urine allows for enhanced detection of analytes in 
small quantities. When possible, the subject should capture the first morning void and bring the 
sample to the clinic within 1 hour of collection. If that is not possible, the specimen should be 
refrigerated and brought in within 12 hours of collection. As the first morning void may be 
difficult to obtain, an early morning or early waking sample is accepted in situations where the 
subject cannot collect a first void.
Subjects can have up to 3 UACR collections during the Screening period. Any one of the UACR 
values and any one of the eGFR values collected during Screening may be used to satisfy the 
inclusion criterion. Qualifying eGFR and UACR values do not need to be collected on the same 
day. UACR stratification will be the average of Enrollment (Visit A) and Visit B measurements.
6.4.12.
Estimated Glomerular Filtration Rate

Screening: Subjects can have up to 3 eGFR collections during the Screening period. Any one 
of the eGFR values and any one of the UACR values collected during Screening may be used 
to satisfy the inclusion criteria. Subjects must have an eGFR value calculated by central 
laboratory utilizing samples collected during Screening and prior to Enrollment (Visit A) of
≥ 20 mL/min/1.73 m² to < 60 mL/min/1.73 m².

Run-in period: Other than eGFR values < 15 mL/min/1.73 m², eGFR and serum creatinine
results collected at Visit A, B, C, and Visit 1 will not be released to subjects, investigators or 
sponsor before study unblinding. Local labs assessing eGFR or creatinine should not be 
collected during the Run-in period or during the time after the Run-in period leading up to 
the Week 4 visit unless required for safety. 

Run-in prior to Week 4: If there is a ≥50% decline in eGFR compared to Screening during 
the Run-in period prior to Week 4, a central laboratory flag will be issued to notify the site of 
this drop. Sites will be notified of the ≥50% eGFR decline but will continue to be blinded to
the eGFR values. Local labs assessing eGFR or creatinine should not be collected during the 
Run-in period or during the time after the Run-in period leading up to the Week 4 visit unless 
required for safety. 


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• 
Randomization: Subjects must have eGFR values of~ 15 mL/min/1.73 m2 at all central 
laborato1y assessments dming the Run-in period to satisfy randomization eligibility. 
• 
Stratification: eGFR will be the average ofEmollment (Visit A) and Visit B measurements. 
This value will be transfened directly from the central laborato1y to the IWRS system for 
stratification. 
A clinical endpoint event is a confnmed decrease in eGFR to < 15 mL/min/1.73 m2 for subjects 
who remain asymptomatic without initiation of dialysis or kidney transplantation. The eGFR 
confinnato1y measure will be collected at the next scheduled study visit but at least 4 weeks after 
the index measurement. 
Another clinical endpoint event is a confnmed change in eGFR 40% decline from pre-nm-in 
baseline. The 
40% decline confnmato1y measure will be collected at the next scheduled study 
visit but at least 4 weeks after the index measurement. A third party vendor, who is independent 
of Gilead, or Biometrics personnel at Gilead who are not associated with the study or study team, 
will be unblinded to baseline eGFR values to provide the calculation of decrease in eGFR of 
40% relative to baseline. 
Only eGFR values from the central laborato1y will be utilized for efficacy assessments. 
Following randomization, eGFR calculations will be confmned by Gilead. 
6.4.12.1. 
eGFR Calculations 
eGFR will be calculated from measured semm creatinine using the CKD-EPI Creatinine 
Equation (2009). 
The CKD-EPI (mL/min/1.73 m2) Creatinine Equation (2009) is: 
S 
a 
S 
-1.209 
eGFR = 141 X min ( ;r, 1) 
X max ( ;r, 1) 
X Q_993A9 e X 1.018[if female] 
x 1.159[if Black] 
Ser = standardized semm creatinine (mg/dL) 
K = 0.7 (females) or 0.9 (males) 
a = -0.329 (females) or -0.411 (males) 
min indicates the minimum of Scr/K or 1 
max indicates the maximum of Scr/K or 1 
age m years 
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For secondaiy 
analyses, eGFR may be calculated from measured cystatin C 
using the CKD-EPI cystatin C Equation (2012) as below: 
S 
-0.499 
S 
-1.328 
eGFR = 133 X min ( cys, 1) 
X max ( cys, 1) 
X 0.996Ao" X 0.932(i/ female] 
0.8 
0.8 
Seys = standai·dized sernm cystatin C (mg/L) 
min indicates the minimum of ScyJ 0.8 or 1 
max indicates the maximum of ScyJ 0.8 or 1 
age m yeai·s 
6.4.13. 
Digoxin Testing 
Digoxin should be administered with caution from emollment through end of treatment. Digoxin 
levels should be assessed at Visit C, Week 4, and per investigator discretion. Digoxin levels will 
continue to be checked during the study period per investigator discretion. Investigators should 
monitor and adjust digoxin dose as necessaiy based on prescribing info1mation. 
-
-
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6.5.
Assessments for Subjects who Reach Kidney Failure While on Study Drug
Subjects who reach kidney failure will be instructed to discontinue study drug, complete the 
EOT and 30 Day (±7 days) EOT Follow-up visits, which will include an assessment of eGFR 
and UACR. Following the 30 Day EOT Follow-up visit, subjects who reach kidney failure will 
continue on study, followed via remote assessments per Section 6.7.3, but no longer followed for 
the primary efficacy endpoint.
6.6
Assessments for Discontinuation of Study Drug
Prior to premature study drug discontinuation, the Gilead Medical Monitor and/or sponsor 
designee should be consulted. Subjects who permanently discontinue from study drug (see
Section 3.4) will complete an EOT visit and return to clinic for a 30 Day (± 7) EOT Follow-up 
visit. If a subject has completed a 12-lead ECG, or the STS test within 24 weeks prior to the EOT 
visit, these assessments do not need to be performed. 
6.7.
Post End of Treatment Follow-up Assessments
Following permanent study drug discontinuation, subjects should remain on study and continue 
to attend all subsequent study visits in the same manner as subjects who are still on study drug 
for full assessments (see Section 6.7.1).
Alternative follow-up visits and assessments have been defined to ensure subjects remain on 
study through the global study end date. If a subject indicates the assessments or in-clinic visits 
have become burdensome, an alternative follow-up method should be implemented (see 
Sections 6.7.2 and 6.7.3). 
6.7.1.
Full Assessments
For subjects who prematurely discontinue from study drug, all efforts should be made for the 
subject to remain on study to complete all assessments through the global end of study. If the 
subject following study drug discontinuation remains on study, the subject should resume study 
visits as per the Study Procedures Table (see Appendix 2). 
6.7.2.
Limited Assessments
Subjects who permanently discontinue study drug will be encouraged to continue all study visits 
according to the same schedule and continue the same assessments as subjects still receiving 
study drug. However, if a subject requests limited follow up, at a minimum, the following 
assessments must be performed every 12 weeks to follow the subject for kidney and 
cardiovascular outcomes (see Appendix 2).

Complete physical exam (symptom driven)

Vital signs including weight

AE and SAE collection per protocol Section 7


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
Concomitant Medications

eGFR

Chemistry and Hematology 
6.7.3.
Remote Assessments
Subjects who have permanently discontinued study drug, reached kidney failure, or are no longer 
able to continue to attend clinic visits in-person, and have not withdrawn full consent will be 
asked to continue study participation through remote contact, without in-clinic study visits. 
Subjects will be contacted approximately every 24 weeks until the global study end date. At a 
minimum, subjects will be contacted at the global study end date. 
Subjects will be contacted via telephone, email, or other contact methods through friends or 
family. Details regarding discussions via telephone, email, or other contact must be properly 
documented by the site in the source records, including the responses from the subject. The 
investigator will make every effort to contact the subject or a close relative or caretaker by phone 
to collect information. The investigator should show due diligence by documenting in the source 
documents steps taken to contact the subject (e.g., dates of phone calls, registered letters, etc.).
Follow-up for survival, kidney outcomes, and safety will continue until reasons listed in protocol 
Section 3.5 are met or until the global study end date. 
Information gathered will include:

Survival status 

Death details, if applicable

Receipt of kidney transplant 

Dialysis initiation post study drug discontinuation 

AE and SAE collection per protocol Section 7
6.8.
Unscheduled Visits
Unscheduled visits may occur at any time while the subject is enrolled and on study. 
Unscheduled procedures, including but not limited to, vital signs, laboratory assessments, 
12-lead ECG and health-related quality of life questionnaires may be conducted. Data generated 
during an unscheduled visit will be collected on the eCRF.


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Sample Storage 
Final 
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Residual biological samples from all visits may be frozen and stored if specific consent is 
obtained. These stored samples may be used by Gilead or research partners of Gilead to help 
answer questions about the study diugs, DKD, and its associated conditions, or clinical 
laborato1y testing to provide additional safety data. No human enetic testin will be erf01m ed 
without ex ress written consent of stud sub· ects. 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
product, which does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product.
AEs may also include pre- or post-treatment complications that occur as a result of protocol 
specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or occupational 
exposure. Preexisting events that increase in severity or change in nature during or as a 
consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen. Situations where an untoward medical occurrence has not 
occurred (eg, hospitalization for elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
eCRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” 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 that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity


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
A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is reportable under 
expedited reporting rules. 
Examples of medically important events include:
Intensive treatment in an emergency room or at home for allergic bronchospasm
Blood dyscrasias or convulsions that do not result in hospitalization
Development of drug dependency or drug abuse 

For the avoidance of doubt, infections resulting from contaminated medicinal product will be
considered a medically important event and subject to expedited reporting requirements
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or discontinuation must be recorded as an AE, as well as 
an SAE, if applicable. In addition, laboratory or other abnormal assessments 
(eg, electrocardiogram, x-rays, vital signs) that are associated with signs and/or symptoms must 
be recorded as an AE or SAE if they meet the definition of an AE or SAE as described in 
Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (ie, anemia), not the laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
For adverse events associated with laboratory abnormalities, the event clinical severity should be 
graded in the context of the underlying conditions; this may or may not be in agreement with the 
grading of the laboratory abnormality.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.


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7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study drug. For 
SAEs, an alternative causality must be provided (eg, pre-existing condition, underlying 
disease, intercurrent illness, or concomitant medication)

Yes: There is reasonable possibility that the event may have been caused by the study drug
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be graded using a modified version of the Common Terminology 
Criteria for Adverse Events (CTCAE), Version 5.0, November 27, 2017 (see Appendix 4). For 
each event, the highest severity grade attained should be reported. The modifications to the 
CTCAE criteria are the addition of a Grade 1 upper respiratory infection and a revision of the 
Hyperglycemia grading scale (reference Appendix 4 for grading scales).
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to 
describe the maximum severity of the AE. For purposes of consistency with the CTCAE, these
severity grades are defined in Table 7-1. 
Table 7-1.
Guidelines for Grading of Adverse Event Severity
Grade
Adjective
Description*
Grade 1
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only, intervention 
not indicated
Grade 2
Moderate
Minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (preparing meals, shopping, using telephone, 
managing money, etc.)
Grade 3
Severe
Medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living (bathing, dressing, and undressing, feeding self, using toilet, taking medications, 
and not bedridden)
Grade 4
Life-threatening
Life-threatening consequences; urgent intervention indicated
Grade 5
Fatal
Death related to adverse event
*
A semi-colon indicates 'or' within the description of the grade.


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The distinction between the seriousness and the severity of an AE should be noted. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met one of 
the criteria for serious events listed in Section 7.1.2.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead 
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the eCRFs: all SAEs and adverse events related to protocol-mandated 
procedures.
7.3.1.
Adverse Events
Following initiation of study drug and throughout the duration of the study, including the 30 Day 
EOS Safety Follow-up period, collect all AEs, regardless of causal relationship. AEs must be 
collected and reported to the eCRF database as instructed.
Regarding subjects who permanently discontinue study drug but remain on study, AEs are 
collected as follows:

Full Assessments (per Section 6.7.1): Subjects continuing on study and completing full 
assessments, AEs are collected throughout the duration of the study including the 30 Day 
EOS Safety Follow-up period.

Limited Assessments (per Section 6.7.2): Subjects continuing on study and completing 
limited assessments, AEs are collected throughout the duration of the study including the 
30 Day EOS Safety Follow-up period.

Remote Assessments (per Section 6.7.3): Subjects continuing on study and completing 
survival outcome assessments, AEs are collected through the 30 Day EOT Follow-up period.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow-up 
period.
7.3.2.
Serious Adverse Events
All SAEs, regardless of causal relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the 30 Day EOS Safety Follow-up period, must be reported to the eCRF 
database and Gilead PVE as instructed. This also includes any SAEs resulting from 
protocol-associated procedures performed after informed consent is signed.


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If the investigator learns of any SAEs that occur after study paiiicipation has concluded and the 
event is deemed relevant to the use of IMP, he/she should promptly document and repo1i the 
event to Gilead PVE. 
Regarding subjects who prematurely discontinue study diug but remain on study, SAEs are 
collected as follows: 
• 
Full Assessments (per Section 6.7.1): subjects continuing on study and completing full 
assessments, SAEs are collected throughout the duration of the study including the 30 Day 
EOS Safety Follow-up period. 
• 
Limited Assessments (per Section 6.7.2): subjects continuing on study and completing 
limited assessments, SAEs are collected throughout the duration of the study including the 
30 Day EOS Safety Follow-up period. 
• 
Remote Assessments (per Section 6.7.3): subjects continuing on study and completing 
survival outcome assessments, SAEs are collected through the 30 Day EOT Follow-up 
period. 
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Repo1iing Process 
• 
Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
infonnation to Gilead PVE within 24 hours of the investigator's knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines 
• If for any reason it is not possible to record the SAE infonnation electr·onically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
fo1m and submit within 24 hours to: 
Gilead PVE: 
• 
As soon as it is possible to do so, any SAE reported via paper must be tr·anscribed into the 
eCRF database according to instructions and within timelines outlined in the eCRF 
completion guidelines 
• If an SAE has been repo1ied via a paper fonn because the eCRF database has been locked, no 
fuither action is necessaiy 
• 
For fatal or life-threatening events, copies of hospital case repo1is, autopsy repo1is, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the tr·aceability of a document to the subject identifiers 
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
Additional information may be requested to ensure the timely completion of accurate safety 
reports

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
SUSARs. In accordance with the EU Clinical Trials Directive (2001/20/EC), Gilead or a 
specified designee will notify worldwide regulatory agencies and the relevant IEC in concerned 
Member States of applicable SUSARs as outlined in current regulations.
In the intended study population, Gilead anticipates the occurrence of SAEs that would not be 
meaningful to report on an individual basis to regulatory agencies in an expedited fashion. These 
events include SAEs that are manifestations of the underlying disease, commonly occur in the 
study population independent of drug exposure, or are components of the study endpoints. The 
following SAEs will not be reported to regulatory agencies in an expedited fashion throughout 
the conduct of this clinical trial unless they are life-threatening or fatal, or if reporting is 
specifically requested by any regulatory agencies:

Kidney impairment

Chronic kidney disease

Diabetic nephropathy

Diabetes mellitus 

Hypertension

Hyperkalaemia

Hypoglycaemia

Hyperglycaemia

Blood creatinine abnormal

Blood creatinine increased

Glomerular filtration rate abnormal

Glomerular filtration rate decreased 


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
Albuminuria

Proteinuria

Kidney failure

End stage kidney disease

Dialysis

Dialysis device insertion

Kidney transplant 

Acute myocardial infarction

Cardiac failure congestive

Cardiac failure acute

Cerebrovascular accident 

Atrial fibrillation
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Toxicity Management 
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in the Management of Clinical and Laboratory Adverse Events (Appendix 5).
For study-specific discontinuation and interruption criteria, refer to Section 3.4 and 
Section 5.3.1. Specific toxicity discontinuation criteria in Section 3.4 supersede general toxicity 
guidelines, and in general, where discrepancy is present, the more conservative criteria apply.
The Gilead Medical Monitor and/or sponsor designee should be consulted prior to study drug 
discontinuation when medically feasible.
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
For Grades 1 and 2 laboratory abnormalities or clinical events not specified in Sections 3.4
or Section 5.3.1, continue study drug at the discretion of the investigator.


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7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event
For Grade 3 laboratory abnormalities or clinical events not specified in Sections 3.4 or 
Section 5.3.1, the following toxicity management guidelines apply:

For a Grade 3 clinically significant laboratory abnormality or clinical event, study drug may 
be continued if the event is considered to be unrelated to study drug

For a Grade 3 clinical event or clinically significant laboratory abnormality confirmed by
repeat testing, that is considered to be related to study drug, study drug should be withheld 
until the toxicity returns to ≤ Grade 2

If a laboratory abnormality or clinical event recurs to ≥ Grade 3 following re-challenge with 
study drug and is considered related to study drug, then study drug should be permanently 
discontinued and the subject managed according to local clinical practice. Recurrence of 
laboratory abnormalities considered unrelated to study drug may not require permanent 
discontinuation and study drug may be continued at the discretion of the investigator
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event
For Grade 4 laboratory abnormalities or clinical events not specified in Sections 3.4 or 5.3.1, the 
following toxicity management guidelines apply:

For a Grade 4 clinical event or clinically significant laboratory abnormality, confirmed by 
repeat testing, that is considered to be related to study drug, study drug should be 
permanently discontinued and the subject managed according to local practice. The subject 
should be followed as clinically indicated until the laboratory abnormality returns to baseline 
or is otherwise explained, whichever occurs first. A clinically significant Grade 4 laboratory 
abnormality that is not confirmed by repeat testing should be managed according to the 
algorithm for the new toxicity grade

Study drug may be continued without dose interruption for a clinically non-significant
Grade 4 laboratory abnormality (eg, Grade 4 creatine kinase after strenuous exercise or 
non-fasting triglyceride elevation that can be medically managed) or a clinical event 
considered unrelated to the study drug
Grade 4 treatment-emergent toxicities will be noted by the investigator and brought to the
attention of the Gilead Medical Monitor and/or sponsor designee, who will discuss with the 
investigator and determine the appropriate course of action. All subjects experiencing AEs must 
be monitored periodically until symptoms subside, any abnormal laboratory values have resolved 
or returned to baseline levels or they are considered irreversible, or until there is a satisfactory 
explanation for the changes observed.


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7.5.4.
Liver Enzymes
To mitigate the potential risk of liver injury, subjects are monitored closely; defined rules for 
close observation and drug cessation due to elevated liver tests are specified. 
After becoming aware of any of the following abnormal laboratory values, an unscheduled visit 
(ie, sequential visit) should occur to retest within 3 to 7 days of receipt of the original test results. 
Retest may be obtained sooner if medically indicated per investigator judgement.
If ALT and/or AST:

> 3 – 5 x ULN (Grade 2):  Monitor at least weekly until < or equal to 1.5 x ULN

> 5 – 20 x ULN (Grade 3):  Withhold study drug. Monitor at least weekly until ALT/AST are 
< or equal to 1.5 x ULN, then may resume study drug. If Grade 3 recurrence, withhold study 
drug. Monitor at least weekly until ALT/AST < or equal to 1.5 x ULN, then may resume
study drug. If Grade 3 recurrence, discontinue study drug permanently

> 20 x ULN (Grade 4):  Withhold study drug until ALT/AST < or equal to 1.5 x ULN, then 
may resume study drug. If Grade 4 recurrence, discontinue study drug permanently
7.5.5.
eGFR Decline
SEL is associated with an acute decline in eGFR after study drug initiation, and in the phase 2 
study of SEL in DKD (GS-US-223-1015), the median acute eGFR decline associated with SEL 
18 mg at Week 4 was 10%. We observed that approximately 25% of subjects had an acute eGFR 
decline of 19% or greater (25th percentile), and 75% of subjects had an acute eGFR decline of 
4% or greater (75th percentile).
However, acute declines in eGFR are expected to occur in subjects with moderate to advanced 
DKD and may not necessarily be associated with SEL. If acute eGFR decline occurs after the 
period following study drug initiation, refer to the below instructions:

If clinically indicated, evaluate for alternative etiologies of eGFR decline and address 
reversible factors

Avoid withholding or discontinuation of study drug in the setting of eGFR decline to the 
extent possible

Consult with Gilead Medical Monitor and/or sponsor designee prior to withholding or 
discontinuing study drug 

If study drug is withheld, restart study drug as soon as clinically appropriate and check eGFR 
at next scheduled visit, preferably with study drug taken for at least 7 consecutive days. 


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Additionally, progressive decline in kidney function is expected to occur in subjects with 
moderate to advanced DKD. SEL is hypothesized to slow progression of DKD, and study drug 
should not be discontinued in the setting of expected progressive decline of underlying kidney 
disease.
Specific toxicity interruption and discontinuation criteria listed above supersede general toxicity 
guidelines, and in general, where discrepancy is present, the more conservative criteria apply.
NOTE: During the time of the study drug interruption for any of the above, the subject may 
continue to have study visits and to take part in procedures and assessments, if deemed medically 
appropriate.    
In addition, embryofetal toxicity was observed in SEL nonclinical studies; therefore to prevent 
potential fetal exposure, adherence to highly effective methods of contraception will be required.
Please see Appendix 6 for more details.
Any questions regarding toxicity management should be directed to the Gilead Medical Monitor
and/or sponsor designee. 
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE and an AE in an infant following the potential exposure from breastfeeding and 
occupational exposure with an AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
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Occupational exposure is defined as exposure to a medicinal product as a result of one’s
professional or non-professional occupation. Please refer to the Material Safety Sheet for product 
handling guidelines.
Infant exposure from breastfeeding that is associated with an AE is also considered a special 
situation report.
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study drug and throughout the study, including the post study drug follow-up period, 
to Gilead PVE using the pregnancy report form within 24 hours of becoming aware of the 
pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead PVE. Gilead PVE contact information is as follows: 
Email:
 and Fax: 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead PVE using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead PVE, 
fax number
 or email 
Refer to Appendix 6 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
PPD
PPD
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7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y objective of this study is: 
• 
To evaluate whether SEL can slow the decline in kidney function 
The secondaiy objectives of this study ai·e: 
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• 
To evaluate whether SEL can reduce the risk of kidney failure, or reduce the risk of death 
due to kidney disease in subjects with diabetic kidney disease (DKD) 
• 
To assess the safety and tolerability of SEL in subjects with DKD 
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Primary Endpoint 
The prima1y efficacy endpoint of this study is: 
• 
eGFRcr slope from treatment-specific baselines 
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8.1.3. 
Secondary Endpoint 
Secondary endpoints are: 
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• 
Propo1t ion of Kidney Clinical Events at Week 48 defined as any of the following events: 
Confomed:::: 40% decline in eGFRcr from pre-nm-in baseline, or 
Kidney failure ( dialysis perfo1m ed for at least 4 weeks, kidney transplantation, or 
confin ned decrease in eGFRcr to < 15 mL/min/1. 73 m2 for subjects without dialysis or 
kidney transplantation), or 
Death due to kidney disease 
• 
Time from randomization to first occmTence of a Kidney Clinical Event 
• 
eGFRcys slope from pre-nm-in baseline 
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8.2. 
8.2.1. 
8.2.1.1. 
Analysis Conventions 
Analysis Sets 
Efficacy Analysis Set 
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The final analysis set for efficacy analysis is the Intent-to-treat (ITT) Analysis Set, which 
includes all subjects who were randomized in the study. 
8.2.1.2. 
Safety Analysis Set 
The final analysis set for safety analyses is the Safety Analysis Set, which includes all subjects 
who receive at least one dose of study drng. All data collected during ti·eatment will be included 
in the safety summaries. 
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8.2.1.4. 
Biomarker Analysis Set 
The Biomarker Analysis Set will include data from subjects in the Safety Analysis Set who have 
the necessaiy baseline and on-study measurements to provide interpretable results for the 
specific pai·ameters of interest. 
8.3. 
Data Handling Conventions 
Values for missing safety laborato1y data will not be imputed. However, a missing baseline result 
will be replaced with a screening result, if available. If no pre-ti·eatment laborato1y value is 
available, the baseline value will be assumed to be nonnal (i.e, no grade [Grade O]) for the 
summary of graded laborato1y abnonnalities. If safety laborato1y results for a subject ai·e missing 
for any reason at a time point, the subject will be excluded from the calculation of summaiy 
statistics for that time point. 
Values for missing vital sign data will not be imputed. However, a missing baseline result will be 
replaced with a screening result, if available. 
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PK concentration values and PK parameter values below the limit of quantitation (BLQ) will be 
presented as “BLQ” in the data listings. BLQ values that occur prior to the first dose will be 
treated as 0, BLQ values at all other time points will be treated as 1/2 of the lower limit of 
quantitation (LLOQ).
Laboratory data that are continuous in nature but are less than the LLOQ or above the upper limit 
of quantitation will be imputed to the value of the lower or upper limit minus or plus one 
significant digit, respectively (e.g., if the result of a continuous laboratory test is < 20, a value of 
19 will be assigned; if the result of a continuous laboratory test is < 20.0, a value of 19.9 will be 
assigned).
Procedures for handling missing data for eGFR will be described in the statistical analysis plan 
(SAP).
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized by treatment group using standard 
descriptive statistics (n, mean, standard deviation [SD], median, 1st quartile [Q1], 3rd quartile 
[Q3], minimum, maximum for continuous variables and number and percentage of subjects for 
categorical variables) for the ITT Analysis Set.
Demographic summaries will include sex, race/ethnicity, and age.
Baseline characteristics may include eGFR, UACR, height, weight, BMI, concomitant use of 
SGLT-2 inhibitors, prior use of ACEi and/or ARB, and other variables of interest.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The Primary Analysis Set for efficacy analyses is the ITT Analysis Set, which includes all 
subjects who were randomized in the study. 
8.5.1.1.
Analysis of eGFR Slope 
Definition of Baseline
Baseline eGFRcr for the primary analysis is defined as below:

SEL arm (Arm A): The average of the measurements at Visit C and Visit 1. This baseline 
will also be referred to as post-run-in baseline. 

Placebo arm (Arm B): The average of the measurements at Visit A (enrollment) and Visit B. 
This baseline will also be referred to as pre-run-in baseline.


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The primary analysis of eGFRcr slope will be performed after all subjects in the ITT Analysis Set 
complete the Week 48 visit or discontinue from the study. Pre-run-in baseline eGFRcr and 
post-run-in baseline eGFRcr will be used for the placebo and SEL arms, respectively. Baseline 
eGFRcr as well as all on- and off-treatment eGFRcr values collected after Visit 1 through time of 
the analysis for all subjects with available data will be included. eGFRcr slope will be compared 
between SEL and placebo using a random slope model. The random slope model will have 
eGFRcr values starting from Baseline as the outcome, and will include terms for pre-run-in 
baseline eGFRcr as a continuous variable, pre-run-in baseline UACR category (< 1500 mg/g vs. 
≥1500 mg/g), concomitant use of SGLT-2 inhibitors, treatment group, visit, and 
treatment-by-visit interaction. The difference in eGFRcr slope between SEL and placebo 
groups will be estimated and tested. 
8.5.2.
Secondary Analyses
The Secondary Analysis Set for efficacy analyses is the ITT Analysis Set.
8.5.2.1.
Analysis of proportion of Kidney Clinical Events at Week 48
Kidney Clinical Event is defined as any of the following events:

Confirmed ≥40% decline in eGFRcr from baseline, or 

Kidney failure (dialysis performed for at least 4 weeks, kidney transplantation, or confirmed 
decrease in eGFRcr to < 15 mL/min/1.73 m2 for subjects without dialysis or kidney 
transplantation), or 

Death due to kidney disease
The ≥ 40% decline in eGFRcr from baseline and sustained decrease in eGFRcr to 
< 15 mL/min/1.73 m2 components need to be confirmed at the next scheduled visit but at least 
4 weeks after the index measurement. Events of eGFRcr < 15 mL/min/1.73 m2 or eGFRcr decline 
> 40% from baseline without confirmation due to study discontinuation (e.g., death or lost to 
follow-up) will be included in the analysis.
The analysis of proportion of Kidney Clinical Events will be conducted when all subjects in the 
ITT Analysis Set reach Week 48 Visit or discontinue from the study. Number and proportion of 
subjects who experience a Kidney Clinical Event will be summarized. The Cochran-Mantel-
Haenszel (CMH) approach adjusting for stratification factors will be used for hypothesis testing 
of Kidney Clinical Events.
Number and proportion of subjects who experienced each component of the Kidney Clinical 
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8.5.2.2. 
Analysis of time from randomization to a Kidney Clinical Event 
The 
40% decline in eGFRcr from baseline and sustained decrease in eGFRcr to 
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< 15 mL/min/1.73 m2 components need to be confmned at the next scheduled visit but at least 
4 weeks after the index measm ement. Events of eGFRcr < 15 mL/min/1. 73 m2 or eGFRcr decline 
40% from baseline without confinnation due to study discontinuation (e.g., death or lost to 
follow-up) will be included in the analysis. The date the first sample meets the threshold will be 
used as the date in the analysis. 
If a subject has not experienced any Kidney Clinical Events at the time of global study end 
date/early discontinuation of the study, this subject will be censored at the time of the last 
assessment of kidney function. 
The analysis of time from randomization to a Kidney Clinical Events will be conducted when all 
subjects in the ITT Analysis Set reach Week 48 or discontinue from the study. Baseline as well 
as all on- and off-ti·eatment eGFRcr values collected after Visit 1 through the end of the study 
will be included in the evaluation of the endpoint. The comparison will be perfo1med between 
the SEL and placebo aims using a su-atified log-rank test, sti·atified by randomization 
sti·atification factors. Median survival times and 95% Confidence Intervals (Cis) for the SEL and 
placebo anns will be estimated using Kaplan-Meier method. Hazai·d ratio (HR) and 95% CI 
compai·ing the SEL and placebo aims will be estimated using a su-atified Cox propo1iional 
hazai·d model, sti·atified by randomization sti·atification factors. 
8.5.2.3. 
Analysis of eGFRcys slope from pre-nm-in baseline 
The analysis of eGFRcys slope from pre-nm-in baseline will be perfo1med after all subjects in the 
ITT Analysis Set complete the Week 48 visit or discontinue from the study. Pre-nm-in baseline 
eGFRcys will be used for both placebo and SEL aims. Baseline eGFRcys as well as all on- and off-
ti·eatment eGFR.cys values collected after Visit 1 through time of the analysis for all subjects with 
available data will be included. eGFRcys slope will be compai·ed between SEL and placebo using 
a random slope model. The random slope model will have eGFR.cys values staiting from pre-nm-
in Baseline as outcome, and include te1ms for pre-nm-in baseline eGFRcys as a continuous 
variable, pre-nm-in baseline UACR catego1y (< 1500 mg/g vs.~ 1500 mg/g), concomitant use of 
SGLT-2 inhibitors, ti·eatment group, visit, and ti·eatment-by-visit interaction. The difference in 
eGFRcys slope between SEL and placebo groups will be estimated and tested using the random 
slope model. 
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Multiplicity Adjustment 
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The prima1y endpoint and each seconda1y endpoint will be evaluated at a one-sided Type 1 enor 
level of 0.15. No fonnal multiplicity adjustment will be perfo1med. 
8.6. 
Safety Analysis 
Safety will be assessed during the study through the reporting of AEs, and by clinical laborato1y 
tests and vital sign assessments at various time points during the study. Concomitant medication 
usage will also be assessed throughout the study. 
All safety data collected on or after the date that SEL or PTM was first dispensed up to the date 
of last dose of SEL or PTM plus 30 days, including data collected during the Run-in period, will 
be summarized by treatment group (according to the study dmg received). 
8.6.1. 
Extent of Exposure 
A subject's extent of exposure will be generated from the study dmg administration eCRF. 
Exposure data will be summarized by treatment group. 
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8.6.2. 
Adverse Events 
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Clinical and laborato1y adverse events will be coded using the Medical Dictionaiy for 
Regulato1y Activities (MedDRA). System Organ Class (SOC), High-Level Group Te1m 
(HLGT), High-Level Te1m (HLT), Prefe1Ted Te1m (PT), and Lower-Level Te1m (LLT) will be 
attached to the clinical database. 
Events will be sUllllnai·ized on the basis of the date of onset for the event. Treatment-emergent 
adverse events (TEAEs) ai·e defined as one or both of the following: 
• 
Any AEs with an onset date on or after the study drng staii date and no later than 30 days 
after pennanent discontinuation of study diug 
• 
Any AEs leading to premature discontinuation of study diug. Summaries (number and 
percentage of subjects) ofTEAEs (by SOC, and PT) will be provided by treatment group. 
TEAEs will also be sUllllnarized by relationship to study di11g and severity. In addition, 
TEAEs leading to premature discontinuation of study diug will be summarized and listed. 
8.6.3. 
Laboratory Evaluations 
Selected laborato1y data (using conventional units) will be sUllllnai·ized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized by treatment 
group and study visit. 
Graded laborato1y abno1malities will be defined using the grading scheme in CTCAE version 5.0 
(Appendix 4). 
Incidence of treatment-emergent laborato1y abnonnalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to and including the date of last 
dose of study diug plus 30 days, will be summarized by treatment group. 
8.6.4. 
Other Safety Evaluations 
Vital sign measurements will be summai·ized by treatment aim and listed by subject. 
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8.9. 
8.9.1. 
Sample Size 
Sample Size Determination 
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With a sample size of 300 subjects (150 per treatment aim), power to detect a difference in 
eGFRcr decline rate of 3. 7 mL/min/1. 73 m2/yeai· ( common SD = 10 mL/min/1. 73 m2/year) 
between SEL 18 mg and placebo using a two-sample t-test is 99% at a I-sided significance level 
of0.15. Assuming 15% dropout, with a sample size of254 (127 per aim), the power is 97%. 
8.10. 
Data Monitoring Committee 
An external multidisciplinaiy data monitoring committee (DMC) will review the progress of the 
study and perfo1m interim reviews of safety data and provide recommendation to Gilead whether 
the nature, frequency, and severity of adverse effects associated with study dmg wa1Tant the 
early te1mination of the study in the best interests of the paiiicipants, whether the study should 
continue as planned, or the study should continue with modifications. The DMC may also 
provide recommendations as needed regai·ding study design. 
The initial DMC meeting will occur after approximately 300 subjects reach Week 12 or 
discontinue from the study. Following this, subsequent meetings will occur approximately once 
every 6 months. The DMC's specific activities will be defined by a mutually agreed chaiier, 
which will define the DMC's membership, conduct and meeting schedule. 
While the DMC will be asked to advise Gilead regai·ding future conduct of the study, including 
possible eai·ly study tennination, Gilead retains final decision-making authority on all aspects of 
the study. 
8.11. 
Endpoint Adjudication 
Endpoint adjudication will be perfo1med for major adverse kidney and CV events. If a subject 
has a clinical event, the data should be entered into the case report fo1m to trigger adjudication. 
The adjudication may require additional source documents to suppo1i the review. The 
adjudication of these events will be perfo1med in a blinded fashion for the purposes of data 
analysis. Detailed definitions for each event will be used in the adjudication process. 
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8.11.1.
Events for Adjudication 
Adjudicated events include, but are not limited to the following:

Kidney failure
Dialysis performed for at least 4 weeks
Kidney transplantation

Death due to kidney disease defined as death determined to be caused by kidney failure 
(eGFR less than 15 mL/min/1.73 m2) and no other cause of death is determined via 
adjudication

CV death 

Non-fatal MI

Non-fatal stroke

Hospitalization for heart failure 

Atrial fibrillation 
Subjects who experience one of these confirmed clinical events will stay on study drug until
kidney failure, global study end date, treatment discontinuation due to AE or other reasons.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with ICH E6 (R2) Good 
Clinical Practices and applicable laws and regulations.
9.1.2.
Financial Disclosure
The investigator and subinvestigators will provide documentation of their financial interest or 
arrangements with Gilead, or proprietary interests in the investigational drug under study. This 
documentation must be provided prior to the investigator’s (and any subinvestigator’s) 
participation in the study. The investigator and subinvestigator agree to notify Gilead of any 
change in reportable interests during the study and for 1 year following completion of the study. 
The global study end date is defined as the date when the last subject completes the 
protocol-defined activities.
9.1.3.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.4.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC-approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 
and dated by the subject and the person conducting the consent discussion, and also by an 
impartial witness if required by IRB/IEC or local requirements. The consent form will inform 
subjects about genomic testing and sample retention, and their right to receive clinically relevant 
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9.1.5.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any form 
or biological sample submitted to the Sponsor, IRB/IEC, or laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The investigator 
must keep a screening log showing codes, names, and addresses for all subjects screened and for 
all subjects enrolled in the study. Subject data will be processed in accordance with all applicable 
regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, study drug, and any other study information, remain 
the sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.6.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, eCRF and query forms,
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, year of birth, gender)

Documentation that subject meets eligibility criteria, ie, history, PE, and confirmation of 
diagnosis (to support inclusion and exclusion criteria)

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number)

Study discussed and date of informed consent


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
Dates of all visits

Documentation that protocol specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity)

Concomitant medication (including start and end date, dose if relevant; dose changes)

Date of end of study and reason for early discontinuation, if it occurs
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (i.e., United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.7.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed as per site contract, to enable the sponsor to perform central monitoring of safety 
data. The Eligibility Criteria eCRFs should be completed only after all data related to eligibility 
have been received. Subsequent to data entry, a study monitor will perform source data 
verification within the electronic data capture (EDC) system. Original entries as well as any 
changes to data fields will be stored in the audit trail of the system. Prior to database lock (or any 
interim time points as described in the clinical data management plan), the investigator will use 
his/her log in credentials to confirm that the forms have been reviewed, and that the entries 
accurately reflect the information in the source documents. The eCRF capture the data required 


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per the protocol schedule of events and procedures. System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or internal 
Gilead staff, who routinely review the data for completeness, correctness, and consistency. The 
site coordinator is responsible for responding to the queries in a timely manner, within the 
system, either by confirming the data as correct or updating the original entry, and providing the 
reason for the update (e.g. data entry error). At the conclusion of the study, Gilead will provide 
the site with a read-only archive copy of the data entered by that site. This archive must be stored 
in accordance with the records retention requirements outlined in Section 9.1.6.
9.1.8.
Investigational Medicinal Product Accountability and Return
Where possible, study drug should be destroyed at the site. If the site has an appropriate SOP for 
drug destruction as determined by Gilead, the site may destroy used (empty or partially empty) 
and unused study drug supplies in accordance with that site’s approved SOP. A copy of the site’s 
approved SOP will be obtained for central files. If study drug is destroyed on site, the 
investigator must maintain accurate records for all study drug destroyed, the method of 
destruction, and the person who disposed of the study drug. Upon the global study end date, 
copies of study drug accountability records must be filed at the site. Another copy will be 
returned to Gilead.
If the site does not have an appropriate SOP for drug destruction, used and unused study drug 
supplies are to be sent to the designated disposal facility for eventual destruction. The study 
monitor will provide instructions for return.
The study monitor will review study drug supplies and associated records at periodic intervals.
9.1.9.
Inspections
The investigator will make available all source documents and other records for this study to 
Gilead’s appointed study monitors, to IRB/IEC, or to regulatory authority or health authority 
inspectors.
9.1.10.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented.


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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies. Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead in an abstract, manuscript, or presentation form or the study has been completed at 
all study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.5).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.


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9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Medical Monitor and/or sponsor designee immediately. 
The investigator agrees to provide to representatives of a regulatory agency or Gilead access to 
records, facilities, and personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
Adhikary L, Chow F, Nikolic-Paterson DJ, Stambe C, Dowling J, Atkins RC, et al. Abnormal 
p38 mitogen-activated protein kinase signalling in human and experimental 
diabetic nephropathy. Diabetologia 2004;47 (7):1210-22.
Borroni G, Cazzaniga M, Andreoletti M, Ceriani R, Guerzoni P, Omazzi B, et al. Low 
glomerular filtration rate is a risk factor for ribavirin-associated anaemia in old 
patients with chronic hepatitis C. J Viral Hepat 2013;20 (4):e90-5.
Chertow GM, Pergola PE, Chen F, Kirby BJ, Sundy JS, Patel UD, et al. Effects of Selonsertib in 
Patients with Diabetic Kidney Disease. J Am Soc Nephrol 2019.
Chibon F, Mariani O, Derre J, Mairal A, Coindre JM, Guillou L, et al. ASK1 (MAP3K5) as a 
potential therapeutic target in malignant fibrous histiocytomas with 12q14-q15 
and 6q23 amplifications. Genes, chromosomes & cancer 2004;40 (1):32-7.
CV Outcomes Inc. The Kansas City Cardiomyopathy Questionnaire (KCCQ). Available at: 
https://cvoutcomes.org/pages/3214.  December, 2015.
Derkay CS, Volsky PG, Rosen CA, Pransky SM, McMurray JS, Chadha NK, et al. Current use 
of intralesional cidofovir for recurrent respiratory papillomatosis. Laryngoscope 
2013;123 (3):705-12.
Fujino G, Noguchi T, Matsuzawa A, Yamauchi S, Saitoh M, Takeda K, et al. Thioredoxin and 
TRAF family proteins regulate reactive oxygen species-dependent activation of 
ASK1 through reciprocal modulation of the N-terminal homophilic interaction of 
ASK1. Mol Cell Biol 2007;27 (23):8152-63.
Fujisawa T, Takeda K, Ichijo H. ASK family proteins in stress response and disease. Molecular 
biotechnology 2007;37 (1):13-8.
Gerczuk PZ, Breckenridge DG, Liles JT, Budas GR, Shryock JC, Belardinelli L, et al. An 
apoptosis signal-regulating kinase 1 inhibitor reduces cardiomyocyte apoptosis 
and infarct size in a rat ischemia-reperfusion model. J Cardiovasc Pharmacol 
2012;60 (3):276-82.
Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and Evaluation of the Kansas 
City Cardiomyopathy Questionnaire: A New Health Status Measure for Heart 
Failure. J Am Coll Cardiol 2000;35 (5):1245-55.
Hayakawa Y, Hirata Y, Sakitani K, Nakagawa H, Nakata W, Kinoshita H, et al. Apoptosis 
signal-regulating kinase-1 inhibitor as a potent therapeutic drug for the treatment 
of gastric cancer. Cancer science 2012;103 (12):2181-5.


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Gilead Sciences, Inc. 
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Hays RD, Kallich JD, Mapes DL, Coons SJ, Carter WB. Development of the Kidney Disease 
Quality of Life (KDQOL^TM) Instrument. Qual Life Res 1994;3:329-38.
Hikoso S, Ikeda Y, Yamaguchi O, Takeda T, Higuchi Y, Hirotani S, et al. Progression of heart 
failure was suppressed by inhibition of apoptosis signal-regulating kinase 1 via 
transcoronary gene transfer. J Am Coll Cardiol 2007;50 (5):453-62.
Izumiya Y, Kim S, Izumi Y, Yoshida K, Yoshiyama M, Matsuzawa A, et al. Apoptosis signal-
regulating kinase 1 plays a pivotal role in angiotensin II-induced cardiac 
hypertrophy and remodeling. Circ Res 2003;93 (9):874-83.
Kataoka K, Tokutomi Y, Yamamoto E, Nakamura T, Fukuda M, Dong YF, et al. Apoptosis 
signal-regulating kinase 1 deficiency eliminates cardiovascular injuries induced 
by high-salt diet. J Hypertens 2011;29 (1):76-84.
Liles JT, Corkey BK, Notte GT, Budas GR, Lansdon EB, Hinojosa-Kirschenbaum F, et al. 
ASK1 Contributes to Fibrosis and Dysfunction in Models of Kidney Disease. J 
Clin Invest 2018.
Ma LN, Ding XC, Liu XY, Xu CQ, Liu SW, Yan X. De novo combination therapy adefovir plus 
lamivudine as a treatment for women of child-bearing age with HBeAg-positive 
chronic hepatitis B before pregnancy. J Med Virol 2014;86 (3):433-6.
Matsuzawa A, Saegusa K, Noguchi T, Sadamitsu C, Nishitoh H, Nagai S, et al. ROS-dependent 
activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-
mediated innate immunity. Nature immunology 2005;6 (6):587-92.
Mnich SJ, Blanner PM, Hu LG, Shaffer AF, Happa FA, O'Neil S, et al. Critical role for apoptosis 
signal-regulating kinase 1 in the development of inflammatory K/BxN serum-
induced arthritis. Int Immunopharmacol 2010;10 (10):1170-6.
Mohan S, Reddick RL, Musi N, Horn DA, Yan B, Prihoda TJ, et al. Diabetic eNOS knockout 
mice develop distinct macro- and microvascular complications. Lab Invest 
2008;88 (5):515-28.
Nakagawa H, Maeda S, Hikiba Y, Ohmae T, Shibata W, Yanai A, et al. Deletion of apoptosis 
signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by 
inhibiting c-Jun N-terminal kinase activation. Gastroenterology 2008;135 
(4):1311-21.
Nakamura T, Kataoka K, Fukuda M, Nako H, Tokutomi Y, Dong YF, et al. Critical role of 
apoptosis signal-regulating kinase 1 in aldosterone/salt-induced cardiac 
inflammation and fibrosis. Hypertension 2009;54 (3):544-51.


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Gilead Sciences, Inc. 
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Noguchi H, Yamada S, Nabeshima A, Guo X, Tanimoto A, Wang KY, et al. Depletion of 
apoptosis signal-regulating kinase 1 prevents bile duct ligation-induced 
necroinflammation and subsequent peribiliary fibrosis. Am J Pathol 2014:1-18.
Osaka N, Takahashi T, Murakami S, Matsuzawa A, Noguchi T, Fujiwara T, et al. ASK1-
dependent recruitment and activation of macrophages induce hair growth in skin 
wounds. J Cell Biol 2007;176 (7):903-9.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and
activity impairment instrument. Pharmacoeconomics 1993;4 (5):353-65.
Shlipak MG, Lash JP, Yang W, Teal V, Keane M, Cappola T, et al. Symptoms Characteristic of 
Heart Failure Among CKD Patients Without Diagnosed Heart Failure. Journal of 
cardiac failure 2011;17 (1):17-23.
Sturchler E, Feurstein D, McDonald P, Duckett D. Mechanism of Oxidative Stress-Induced 
ASK1-Catalyzed MKK6 Phosphorylation. Biochemistry 2010;49 (19):4094-102.
Takada E, Furuhata M, Nakae S, Ichijo H, Sudo K, Mizuguchi J. Requirement of apoptosis-
inducing kinase 1 for the induction of bronchial asthma following stimulation 
with ovalbumin. International archives of allergy and immunology 2013;162 
(2):104-14.
Takeda K, Noguchi T, Naguro I, Ichijo H. Apoptosis signal-regulating kinase 1 in stress and 
immune response. Annu Rev Pharmacol Toxicol 2008;48:199-225.
Taki K, Shimozono R, Kusano H, Suzuki N, Shinjo K, Eda H. Apoptosis signal-regulating 
kinase 1 is crucial for oxidative stress-induced but not for osmotic stress-induced 
hepatocyte cell death. Life Sci 2008;83 (25-26):859-64.
Terada Y, Inoshita S, Kuwana H, Kobayashi T, Okado T, Ichijo H, et al. Important role of 
apoptosis signal-regulating kinase 1 in ischemic acute kidney injury. Biochem 
Biophys Res Commun 2007;364 (4):1043-9.
Tesch GH, Ma FY, Han Y, Liles JT, Breckenridge DG, Nikolic-Paterson DJ. ASK1 Inhibitor 
Halts Progression of Diabetic Nephropathy in Nos3-Deficient Mice. Diabetes 
2015;64 (11):3903-13.
Tobiume K, Matsuzawa A, Takahashi T, Nishitoh H, Morita K, Takeda K, et al. ASK1 is 
required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO 
reports 2001;2 (3):222-8.
Tobiume K, Saitoh M, Ichijo H. Activation of apoptosis signal-regulating kinase 1 by the stress-
induced activating phosphorylation of pre-formed oligomer. Journal of cellular 
physiology 2002;191 (1):95-104.


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Gilead Sciences, Inc. 
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Toldo S, Breckenridge DG, Mezzaroma E, Tassell BW, Shryock J, Kannan H, et al. Inhibition of 
apoptosis signal-regulating kinase 1 reduces myocardial ischemia-reperfusion 
injury in the mouse. Journal of the American Heart Association 2012;1 
(5):e002360.
Verzola D, Gandolfo MT, Ferrario F, Rastaldi MP, Villaggio B, Gianiorio F, et al. Apoptosis in 
the kidneys of patients with type II diabetic nephropathy. Kidney Int 2007;72 
(10):1262-72.
Watanabe T, Otsu K, Takeda T, Yamaguchi O, Hikoso S, Kashiwase K, et al. Apoptosis signal-
regulating kinase 1 is involved not only in apoptosis but also in non-apoptotic 
cardiomyocyte death. Biochem Biophys Res Commun 2005;333 (2):562-7.
Yamaguchi O, Higuchi Y, Hirotani S, Kashiwase K, Nakayama H, Hikoso S, et al. Targeted 
deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular 
remodeling. Proc Natl Acad Sci U S A 2003;100 (26):15883-8.
Yamaguchi O, Watanabe T, Nishida K, Kashiwase K, Higuchi Y, Takeda T, et al. Cardiac-
specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. 
J Clin Invest 2004;114 (7):937-43.
Yamamoto E, Dong YF, Kataoka K, Yamashita T, Tokutomi Y, Matsuba S, et al. Olmesartan 
prevents cardiovascular injury and hepatic steatosis in obesity and diabetes, 
accompanied by apoptosis signal regulating kinase-1 inhibition. Hypertension 
2008;52 (3):573-80.
Yamashita T, Yamamoto E, Kataoka K, Nakamura T, Matsuba S, Tokutomi Y, et al. Apoptosis 
signal-regulating kinase-1 is involved in vascular endothelial and cardiac 
remodeling caused by nitric oxide deficiency. Hypertension 2007;50 (3):519-24.
Yokoi T, Fukuo K, Yasuda O, Hotta M, Miyazaki J, Takemura Y, et al. Apoptosis signal-
regulating kinase 1 mediates cellular senescence induced by high glucose in 
endothelial cells. Diabetes 2006;55 (6):1660-5.
Zhao HJ, Wang S, Cheng H, Zhang MZ, Takahashi T, Fogo AB, et al. Endothelial nitric oxide 
synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc 
Nephrol 2006;17 (10):2664-9.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Clinical Laboratory Analytes
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Appendix 5.
Management of Clinical and Laboratory Adverse Events
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
CCI-


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
MOSAIC - A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, 
Multicenter Study Evaluating the Efficacy and Safety of Selonsertib in Subjects with Moderate 
to Advanced Diabetic Kidney Disease 
GS-US-223-101 7 Amendment 2, 13 April 2020 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
_
j_PPD 
,_P_D ______ (Printed) 
Signat ... 
Author 
Date 
INVESTIGATOR STATEMENT 
T have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
1 will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
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Appendix 2.
Study Procedures Table
Study Procedures Table – Screening to Randomization
Period
Screening
Enrollment
Run-In
Randomization
Visit
A
Ba
Cb
1b
Visit Window (days)
30 day 
screening 
period
7 – 14 days 
after visit A
21 – 28 days 
after visit B
7 – 14 days 
after visit C
Clinical Assessments
Written Informed Consent
X
Medical History & Demographics
X
Complete Physical Examinationc
X
Vital Signs including Weightd
X
X
X
X
X
Height
X
Waist Circumference
X
12 Lead ECG
X
Adverse Events
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
Study Drug Dispensing
X
X
X
X
Study Drug Dosing
X
X
X
X
Study Drug Bottle Return
X
X
X
CCI
CCI


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Period
Screening
Enrollment
Run-In
Randomization
Visit
A
Ba
Cb
1b
Visit Window (days)
30 day 
screening 
period
7 – 14 days 
after visit A
21 – 28 days 
after visit B
7 – 14 days 
after visit C
Laboratory Assessments
Subject Fastingg
X
X
eGFRh
X
X
X
X
X
Early Morning Void Urine ACR & Urinalysisi
X
X
X
X
X
Chemistry & Hematology
X
X
X
X
X
HbA1c
X
HIV-1, HBV, HCV Serology  
X
Blood Biomarkers
X
X
Prothrombin Time
X
Insulin, Lipid, c-peptide
X
X
Nt-proBNP
X
X
cTnI
X
X
Digoxink
X
Pregnancy Testingl
X
X
X
FSH Testingm
X
Urine Biomarkers
X
X
a.
Samples to be collected pre-dose
b.
Subject can have no missed doses of study drug during the 7 consecutive days immediately prior to Visit C and Visit 1
c.
On visits without a scheduled complete physical examination, a symptom-driven physical examination may be performed if necessary
d.
Vital signs include resting blood pressure, pulse, respiratory rate, temperature and weight. Measurements of blood pressure should be taken per institutional guidelines. Subject 
position should be consistent for each subsequent measure
e.
Subject-reported outcomes should be completed at the start of the study visit and prior to the clinical and laboratory assessments. The subject should read the questionnaires by 
himself/herself and record the answers by himself/herself. 
CCI
CCI


Selonsertib 
Protocol GS-US-223-1017 
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I 
g. 
Su 1ects s ou a stam ·om a 
oo 
or at east 8 1om·s pnor to 
oratory araw, water is allowed 
Final 
Amendment2 
h. 
eGFR value to be calculated by the Chronic Kidney Disease Epidemiology Creatinine Equation (2009); if eGFR value at Screening does not meet inclusion criteria, subject 
may repeat 2 additional times during Screening and prior to Elll'olhuent (Visit A). Subject must have eGFR :C:: 15 mL/min/1.73 m2 at all central laboratory assessments during 
the Run-in period prior to Randomization (Visit 1) 
I. 
First moming void collection is prefe!l'ed when possible, but early moming void is accepted. Bring sample to clinic within 1 hotu·, if not possible, refrigerate and bring to clinic 
within 12 hours. IfUACR value at Screenino does not meet inclusion criteria, sub'ect ma re eat 2 additional times durino Screening and rior to Elll'olhnent 
isit A 
I' 
k. 
For su 1ects ta 
g 1goxm o y, 1goxin level should be measm·ed at Visit C and Week 4. PI may continue checking after Week 4 as part of digoxin management as needed. 
Monitor and adjust digoxin dose as necessa1y based on prescribing info1mation. 
I. 
Females of childbearing potential as defmed by protocol only (refer to Appendix 6): Semm pregnancy test at Screening and m-ine pregnancy test at Visit B, Randomization and 
eve1y 4 weeks through the 30 Day EOT Follow-up visit. 
m. FSH testing to dete1mine female subject's postmenopausal state as described in Appendix 6. 
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Study Procedures Table – Week 4 to Week 48+
Period
On Treatment
Visit
2
3
4
5
6
7
q12 weeksl
Week
4
8
12
24
36
48
Visit Window (days)
±5
±5
±5
±5
±5
±5
±5
Clinical Assessments
Complete Physical Examinationa
Vital Signs including Weightb
X
X
X
X
X
X
X
Waist Circumference
X
12 Lead ECG
X
Adverse Events
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Study Drug Dispensing
X
X
X
X
X
X
X
Study Drug Dosing
X
X
X
X
X
X
X
Study Drug Bottle Return
X
X
X
X
X
X
X
CCI
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Period 
Visit 
Week 
Visit Window (days) 
Subject Fastinge 
Early Moming Void Urine ACR & Urinalysisg 
Chemist:iy & Hematology 
HbAlc 
2 
3 
4 
8 
±5 
±5 
X 
X 
X 
X 
X 
X 
On Treatment 
4 
5 
6 
7 
12 
24 
36 
48 
±5 
±5 
±5 
±5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Biomarkers 
X 
Insulin, Lipid, c-peptide 
X 
Final 
Amendment2 
q12 
weeks1 
±5 
X 
X 
X 
X 
; 
1-N_t-_p1_·o_B_NP 
_____________________ +----------+-----------+--X ______ _ 
a. 
b. 
I 
I 
e. 
f. 
cTnI 
X 
0 
..J 
Digoxinh 
X 
CRP 
X 
Sparse PK; 
X 
X 
X 
X 
Pregnancy Testingk 
X 
X 
X 
X 
X 
X 
X 
Urine Biomarkers 
X 
X 
X 
On visits without a scheduled complete physical examination, a symptom-driven physical examination may be performed if necessary 
Vital signs include resting blood pressure, pulse, respirato1y rate, temperattu·e and weight. Measurements of blood pressure should be taken per institt1tional guidelines. 
Sub· ect osition should be consistent for each subse uent measm·e 
w, water is allowed 
eGFR value to be calculated by the Chronic Kidney Disease Epidemiology Creatinine Equation (2009) 
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g. 
Fit·st moming void collection is prefe!l'ed when possible, but early moming void is accepted. Bring sample to clinic within 1 hotu·, if not possible, refrigerate and bring to 
clinic within 12 hotu-s 
h. 
For subjects taking digoxin only, digoxin level should be measm·ed at Visit C and Week 4. PI may continue checking after Week 4 as pait of digoxin management as needed. 
Monitor and adjust digoxin dose as necessary based on prescribing info,mation. 
1. 
S arse PK sam !es should on! be collected for randomized sub'ects on stud dru!l; 
I 
k. 
nay occtu· at home, where 
possible, in between in clinic visits or in clinic. At home pregnancy testing kits will be provided. Females of childbearing-potential performing at home pregnancy testing will 
be contacted every 4 weeks to repo1t the result of the at home pregnancy tests until the 30 Day EOT Follow-up visit. 
I. 
Repeat every 12 weeks until global study end date. 
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Study Procedures Table – EOT to 30 Day EOS Safety Follow-up
Period
EOTa
30 Day EOT 
Follow-upb
Limited 
Assessmentsc
EOSd
30 Day EOS Safety 
Follow-upe
Visit
Week
Visit Window (days)
±7
±7
±7
±7
±7
Clinical Assessments
Complete Physical Examinationf
X
Vital Signs including Weightg
X
X
X
Waist Circumference
X
12 Lead ECG
X
X
Adverse Events
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
Study Drug Dispensing
Study Drug Dosing
Study Drug Bottle Return
X
CCI
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Period
EOTa
30 Day EOT 
Follow-upb
Limited 
Assessmentsc
EOSd
30 Day EOS Safety 
Follow-upe
Visit
Week
Visit Window (days)
±7
±7
±7
±7
±7
Laboratory Assessments
Subject Fastingj
eGFRk
X
X
X
X
Early Morning Void Urine ACR & Urinalysisl
X
X
X
Chemistry & Hematology
X
X
X
X
HbA1c
Blood Biomarkers
X
X
X
Blood Glucose
Insulin, Lipid, c-peptide
Nt-proBNP
cTnI
CRP
Sparse PKm
X
Pregnancy Testingn
X
X
X
Urine Biomarkers
X
X
X
a.
EOT assessments should be completed for subjects who meet criterion for study drug discontinuation in Section 3.4. These assessments should be completed as soon as
possible after the decision is made. Every attempt should be made to keep the subject in the study to complete all remaining study visits for outcome assessment. If an ECG or 
STS was conducted at a previous visit within 24 weeks of the EOT visit, the assessment does not need to be performed at the EOT visit
b.
Subjects who permanently discontinue study drug must also return to clinic for a 30 Day EOT Follow-up visit 30 days (±7 days) after study drug discontinuation
c.
Subjects who permanently discontinue study drug are encouraged to continue all study visits per schedule of procedures. However, if a subject requests limited assessments,
they may perform these procedures every 12 weeks
d.
EOS assessments should be completed for subjects who meet criterion for study discontinuation in Section 3.5. If the subject discontinues study drug and discontinues from 
the study on the same day, assessments for EOT visit should be completed. The subject will still need to return to clinic 30 days (±7 days) for a 30 Day EOT Follow-up visit
and complete the 30 Day EOS Safety Follow-up visit. 
e.
This visit may be conducted in clinic or via telephone


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f. 
On visits without a scheduled complete physical examination, a symptom-driven physical examination may be performed if necessary 
Final 
Amendment2 
g. 
Vital signs include resting blood pressure, pulse, respirato1y rate, temperattu·e and weight. Meastu·ements of blood presstu·e should be taken per institt1tional guidelines. 
Sub· ect osition should be consistent for each subse uent measm·e 
I 
I 
J. 
u 1ects s ou a stam om a 
oo 
or at east 
1om·s pnor to a oratory oraw, water is allowed 
k. 
eGFR value to be calculated by the Chronic Kidney Disease Epidemiology Creatinine Equation (2009) 
I. 
First moming void collection is prefe!l'ed when possible, but early moming void is accepted. Bring sample to clinic within 1 hotu·, if not possible, refrigerate and bring to 
clinic within 12 hotu-s 
m. 
Sparse PK testing should be pe1fon11ed for all randomized subjects while on stt1dy diug. Spa1-se PK testing does not need to be collected after stlldy dmg is discontinued. 
n. 
Females of childbearing potential as defmed by protocol only (refer to Appendix 6): Starting after Week 4, eve1y 4 week pregnancy testing may occtu· at home where 
possible, in between in clinic visits, or in clinic. At home pregnancy testing kits will be provided. Females of childbearing potential pe1fon11ing at home pregnancy testing will 
be contacted eve1y 4 weeks to repo1t the result of the at home pregnancy tests tu1til the 30 Day EOT Follow-up visit 
CONFIDENTIAL 
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Appendix 3.
Clinical Laboratory Analytes
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Hemoglobin
Platelet count
Red Blood Cell (RBC) 
count
White Blood Cell (WBC) 
count
Differentials (absolute and 
percentage), including:
Lymphocytes
Monocytes
Neutrophils
Eosinophils
Basophils
Mean Corpuscular 
Volume (MCV)
Alkaline phosphatase (ALP)
Aspartate aminotransferase 
(AST)
Alanine aminotransferase (ALT)
Gamma-Glutamyl 
Transpeptidase (GGT)
Total bilirubin
Direct and indirect bilirubin
Total protein
Albumin
Bicarbonate
Blood Urea Nitrogen (BUN)
Calcium
Chloride
CPK
Cystatin-C
Serum creatinine
Fasting Glucose
Phosphorus
Magnesium
Potassium
Sodium
Serum Uric Acid (screening and 
yearly)
eGFR using estimating equations 
(e.g., CKD-EPI Creatinine 
(2009); CKD-EPI Creatinine-
Cystatin C (2012); CKD-EPI 
Cystatin C (2012); MDRD Study 
Equation)
Appearance
Blood
Color
Glucose
Leukocyte esterase
Nitrites
pH
Protein
Specific gravity
Urobilinogen
Reflex to microscopic 
urinalysis if dipstick result is 
abnormal
Urine albumin, urine 
creatinine, and UACR (early
morning void on days when 
eGFR value is obtained)
C-reactive protein 
(hsCRP)
Digoxin
HIV-1, HBV, HCV 
Serology  
Nt-proBNP
Pharmacokinetics 
(PK)
Prothrombin time
Cardiac troponin I 
(cTnI)
Endocrine
Pregnancy
Hemoglobin A1c
Fasting Insulin
c-peptide
FSH (for women only)
In females of childbearing 
potential:
Serum β-hCG (Screening and 
if positive urine β-hCG)
Urine β-hCG (all other visits)*
Fasting Lipids
Triglycerides
Total Cholesterol 
High-density lipoprotein 
(HDL)
Low-density lipoprotein 
(LDL)
*
Females of childbearing potential as defined by protocol: Starting after Week 4, every 4 week pregnancy testing may occur 
at home, where possible, in between in clinic visits or in clinic. At home pregnancy testing kits will be provided by the 
sponsor. Females of childbearing potential performing at home pregnancy testing will be contacted every 4 weeks to report 
the result of the at home pregnancy tests through 30 day EOT Follow-up visit.


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Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Please refer to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, 
which can be found at:
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
The modifications to the CTCAE v5.0 criteria include a revision of the Hyperglycemia grading 
scale and the addition of a Grade 1 upper respiratory infection as follows:
Appendix Table 1.
Hyperglycemia Grading Scale
CHEMISTRY
CTCAE v. 
5.0*modification
Grade 1
Grade 2
Grade 3
Grade 4
Hyperglycemia, 
Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
* 
CTCAE Version 5.0 currently has no provision for serum glucose levels that correlate with hyperglycemia toxicity grades. 
The language here represents a Gilead modification to the CTCAE Version 5.0 term ‘Hyperglycemia’.
Appendix Table 2.
Upper Respiratory Infection Grading Scale
CTCAE
V5.0 Term
Grade 1*
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v5.0
AE Term
Definition
Upper 
respiratory 
infection
Mild symptoms; 
symptomatic 
relief (cough 
suppressant, 
decongestant, 
etc.)
Moderate 
symptoms; 
oral 
intervention 
indicated 
(e.g., 
antibiotic, 
antifungal, 
antiviral)
IV antibiotic, 
antifungal, or 
antiviral 
intervention 
indicated; 
invasive 
intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder 
characterized by an 
infectious process 
involving the upper 
respiratory tract 
(nose, paranasal 
sinuses, pharynx, 
larynx, or trachea).
*
CTCAE currently has no provision for Grade 1 upper respiratory infection. The language here represents a Gilead 
modification to the CTCAE.
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.


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Appendix 5. 
Management of Clinical and Laboratory Adverse Events 
Grade 1 
Grade 2 
Grade3 
Grade4 
May continue dosing at 
the discretion of the 
investigator 
Repeat lab to confirm 
toxicity grade 
Repeat lab to confirm 
toxicity grade 
, 
If confirmed and possibly or 
probably related to study drug, 
discontinue study drug dosing 
permanently and follow at 
least weekly until a return to 
baseline or otherwise 
explained 
If confirmed and possibly and/or probably related to 
study drug: 
1. Withhold study drug until s Grade 2 
2. Restart study drug at full dose 
If Grade 3 or 4 recurrence that is confirmed and 
possibly or probably related to study drug, 
discontinue study drug dosing permanently 
* 
Refer to Section 7.5 for details 
CONFIDENTIAL 
r 
If confirmed and unrelated to study 
drug, dosing may continue at the 
discretion of the investigator 
If Grade 3 or 4 recurrence that Is considered 
unrelated to study drug, continue all study drug at 
the same dose at the discretion of the investigator 
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Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are ≥54 years of age with 
cessation of previously occurring menses for ≥12 months without an alternative cause. In 
addition, women of any age with amenorrhea of ≥12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchiectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
SEL is contraindicated in pregnancy as a malformation effect is suspected, based on non-clinical 
data. In rats and rabbits, SEL administration was associated with effects on embryofetal
development at maternally toxic doses. 
Preclinical and clinical drug-drug interaction (DDI) data indicate that SEL is unlikely to alter the 
exposure of hormonal contraceptives through induction of human drug metabolizing enzymes or 
drug transporters. Please refer to the latest version of the IB for additional information.


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b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test at Visit B and Visit 1. Pregnancy tests will be performed at 4 week 
intervals thereafter through the 30 Day EOT Follow up visit. Female subjects must agree to one 
of the following from Screening until 30 days following the last dose of study drug:

Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below:
Intrauterine device (IUD) with a failure rate of < 1% per year
Tubal sterilization
Vasectomy in the male partner (provided that the partner is the sole sexual partner and
had confirmation of surgical success 3 months after procedure)
The above described methods are considered preferred methods of highly effective contraception
in this protocol.
Should female subjects wish to use a hormonally based method; use of a male condom by the 
female subject’s male partner is required. Subjects who utilize a hormonal contraceptive as one 
of their birth control methods must have used the same method for at least three months prior to 
study dosing. Hormonally-based contraceptives permitted for use in this protocol are as follows:

Hormonal methods associated with inhibition of ovulation (each method must be used with a 
condom in the male partner):
Oral contraceptives (either combined or progesterone only)
Injectable progesterone*
Subdermal contraceptive implant*
Transdermal contraceptive patch*
Contraceptive vaginal ring*


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Not all of these methods may be approved in each of the countries where the study is being 
conducted. Please refer to local product information. Additional local regulatory requirements
may apply.
NOTE: * Not approved in Japan
Female subjects must also refrain from egg donation or harvest during treatment and until at least 
30 days after the last dose of study drug.
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid. Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 30 days after the
last dose of study drug. Female partners of male study subjects are asked to select one of the 
above methods. 
Male subjects must also refrain from sperm donation from the screening visit through 30 days
following the last dose of study drug.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg. calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM). Female condom and male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Male subjects whose 
partner has become pregnant or suspects she is pregnant during the study or within 30 days of 
last study drug dose must report the information to the investigator. Instructions for reporting 
pregnancy, partner pregnancy, and pregnancy outcome are outlined in Section 7.6.2.


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SAP_001.pdf: 
  
STATISTICAL ANALYSIS PLAN
Study Title:
MOSAIC - A Phase 2b, Randomized, Double-Blind, 
Placebo-Controlled, Parallel Group, Multicenter Study 
Evaluating the Efficacy and Safety of Selonsertib in Subjects 
with Moderate to Advanced Diabetic Kidney Disease
Name of Test Drug:
Selonsertib 
Study Number:
GS-US-223-1017
Protocol Version (Date):
Original:
01 February 2019
Amendment 1:
10 June 2019
Amendment 2: 
13 April 2020
Analysis Type:
Final Analysis 
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
03 December 2021
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(rJ GILEAU 


Selonsertib 
GS-US-223-1017 
Statistical Analysis Plan - Final Analysis 
Version 1.0 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................................................ 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ .4 
LIST OF IN-TEXT FIGURES ........................................................................................................................................ 5 
LIST OF ABBREVIATIONS ......................................................................................................................................... 6 
PHARMACOKINETICABBREVIATIONS ................................................................................................................. 8 
1. 
INTRODUCTION .................................................................................................................................................. 9 
1. 1. 
Study Objectives ........................................................................................................................................ 9 
1.2. 
Study Design ............................................................................................................................................. 9 
1.3. 
Saniple Size and Power ........................................................................................................................... 10 
2. 
TYPE OF PLANNED ANALYSIS ...................................................................................................................... 11 
2.1. 
Interi1n Analyses ...................................................................................................................................... 11 
2.1. 1. 
DMC Analysis ....................................................................................................................... 11 
2.2. 
Final Analysis .......................................................................................................................................... 11 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................. 12 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
3.6. 
3.7. 
3.8. 
Analysis Sets ........................................................................................................................................... 12 
3.1. 1. 
All Enrolled Analysis Set ...................................................................................................... 12 
3.1.2. 
All Randomized Analysis Set ................................................................................................ 13 
3.1.3. 
Full Analysis Set. ................................................................................................................... 13 
3.1.4. 
Per-Protocol Analysis Set ...................................................................................................... 13 
3.1.5. 
Safe Anal sis Set ................................................................................................................ 15 
Su ~ect Grouping ..................................................................................................................................... 16 
Strata and Covariates ............................................................................................................................... 16 
Examination of Subject Subgroups ......................................................................................................... 17 
Multiple Co1nparisons ............................................................................................................................. 18 
Missing Data and Outliers ....................................................................................................................... 18 
3.6.1. 
Missing Data .......................................................................................................................... 18 
3. 6. 2. 
Outliers .................................................................................................................................. 18 
Data Handling Conventions and Transfo1mations .................................................................................. 18 
Analysis Visit Windows .......................................................................................................................... 20 
3.8.1. 
Definition of Study Day ........................................................................................................ 20 
3.8.2. 
Analysis Visit Windows ........................................................................................................ 20 
3.8.2.1. 
Analysis Visit Windows for the Run-in Phase ................................................ 20 
3.8.2.2. 
Analysis Visit Windows for the Randomization Phase ................................... 20 
3.8.3. 
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window ................................................................................................................................. 23 
4. 
SUBJECT DISPOSITION ................................................................................................................................... 24 
4.1. 
Subject Enrollinent and Disposition ........................................................................................................ 24 
4.2. 
Extent of Study Thug Exposme and Adherence ...................................................................................... 25 
4.2.1. 
Duration of Exposw·e to Study Thug ..................................................................................... 25 
4.2.2. 
Adherence to Study D1ug ...................................................................................................... 26 
4.2.2.1. 
On-Treatinent Adherence ................................................................................ 26 
4.3. 
Protocol Deviations ................................................................................................................................. 26 
4.4. 
Assess1nent of COVID-19 Impact ........................................................................................................... 27 
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Statistical Analysis Plan - Final Analysis 
Version 1.0 
4.4.1. 
Study Thug or Study Discontinuation Due to COVID-19 ..................................................... 27 
4.4.2. 
Protocol Deviations Due to COVID-19 ................................................................................ 27 
4.4.3. 
Missed and Virtual Visits due to COVID-19 ........................................................................ 27 
4.4.4. 
Adverse Events Due to COVID-19 ....................................................................................... 28 
4.4.5. 
Overall Assessment of COVID-19 Pandemic Impact ........................................................... 28 
5. 
BASELINE CHARACTERISTICS ..................................................................................................................... 29 
5.1. 
Demographics and Baseline Characteristics ........................................................................................... 29 
5.2. 
Other Baseline Characteristics ................................................................................................................ 29 
5.3. 
Medical Histo1y ....................................................................................................................................... 29 
6. 
EFFICACY ANALYSES ..................................................................................................................................... 30 
6.1. 
Pri1nruy Endpoint. .................................................................................................................................... 30 
6.1. 1. 
Definition of the Prima1y Endpoint ....................................................................................... 30 
6.1.2. 
Statisical Hypothesis of the Prima1y Endpoint ...................................................................... 30 
6.1.3. 
Analysis of the Priina1y Endpoint ......................................................................................... 30 
6.2. 
Secondruy Endpoints ............................................................................................................................... 32 
6.2.1. 
Definition of Seconda1y Endpoints ....................................................................................... 32 
6.2.2. 
Analysis of Secondruy Endpoints .......................................................................................... 33 
6.2.2.1. 
Analysis of proportion of Kidney Clinical Events .......................................... 33 
6.2.2.2. 
Analysis of time from randomization to a Kidney Clinical 
Event ................................................................................................................ 34 
--
7. 
SAFETY ANALYSES ........................................................................................................................................ .42 
7. I. 
Adverse Events and Deaths .................................................................................................................... .42 
7.1. 1. 
Adverse Event Dictiona1y .................................................................................................... .42 
7.1.2. 
Adverse Event Severity ........................................................................................................ .42 
7.1.3. 
Relationship of Adverse Events to Study Dmg .................................................................... .42 
7.1.4. 
Serious Adverse Events ........................................................................................................ .42 
7.1.5. 
Treatinent-Emergent Adverse Events ................................................................................... .42 
7 .1.5.1. 
Definition of Trea.tinent-Emergent Adverse Events ....................................... .42 
7.1.5.2. 
Inco1nplete Dates ............................................................................................ .43 
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Statistical Analysis Plan - Final Analysis 
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7.1.6. 
Summaries of Adverse Events and Deaths ............................................................................ 43 
7. 1.6.1. 
Calculation of Treatment Exposw-e ................................................................. 44 
7.1.6.2. 
Calculation ofExposw-e-Adjusted AE Incidence Rate ................................... 44 
7 .1.6.3. 
Summaries of Exposure-Adjusted AE Incidence Rate ................................... .45 
7.1. 7. 
Additional Analysis of Adverse Events ............................................................................... .46 
7 .2. 
La.borato1y Evaluations .......................................................................................................................... .46 
7.2.1. 
Summaries of Numeric Labora.t01y Results ......................................................................... .47 
7.2.2. 
Graded Labora.to1y Values ................................................................................................... .47 
7.2.2.1. 
Treatment-Emergent La.borato1y Abnonnalities ............................................ .48 
7 .2.2.2. 
Treatment-Emergent Marked La.bora.t01y Abno1malities ............................... .48 
7.2.2.3. 
Sw-nmaries of Laborat01y Abnonnalities ....................................................... .49 
7.2.3. 
Liver-related La.borat01y Evaluations ................................................................................... .49 
7.3. 
Vital Signs and BMI ................................................................................................................................ 50 
7 .4. 
Prior and Concolllitant Medications ........................................................................................................ 50 
7.4.1. 
Prior Medications ................................................................................................................. 50 
7.4.2. 
Conco1nitant Medica.tions ...................................................................................................... 51 
7.5. 
Electrocardiogra1n Results ....................................................................................................................... 52 
7 .5. 1. 
Investigator Electrocardiogram Assessment ......................................................................... 52 
7 .5.2. 
Co1Tected QT Intervals .......................................................................................................... 52 
7.5.3. 
PR and QRS Interva.ls ............................................................................................................ 53 
7.6. 
Other Safety Measw-es ............................................................................................................................ 53 
7 .6.1. 
Pregnancy Repo1t .................................................................................................................. 53 
7.6.2. 
HIV-1, HBV, and HCV Serology .......................................................................................... 54 
7.6.3. 
Digoxin and C-Peptide Testing Results ................................................................................ 54 
7.7. 
Changes From Protocol-Specified Safety Analyses ................................................................................ 54 
I 
9. 
REFERENCES ..................................................................................................................................................... 58 
10. SOFTWARE ......................................................................................................................................................... 59 
11. SAP REVISION ................................................................................................................................................... 60 
12. APPENDICES ...................................................................................................................................................... 61 
Appendix 1. 
Appendix 2. 
Appendix 3. 
Appendix 4. 
Table 3-1. 
Table 3-2. 
Table 3-3. 
CONFIDENTIAL 
Schedule of Assessments ......................................................................................................... 62 
Adjustment of On-Treatment eGFRc, Values .......................................................................... 71 
Prohibited Medications That May Impact SEL Treatment Efficacy or Decrease SEL 
Dn1g Level ............................................................................................................................... 72 
Data Collection of COVID-19 Data ........................................................................................ 73 
LIST OF IN-TEXT TABLES 
Analysis Visit Windows for Visits in the Run-in Phase .......................................................... 20 
Analysis Visit Windows for eGFR, UACR, Vita.I Signs, Hematology Tests, 
Chemistiy Tests and Pregnancy Tests in the Randomization Phase ....................................... 21 
Analysis Visit Windows for HbAlc in the Randomization Phase ......................................... 22 
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Table 3-4.
Analysis Visit Windows for Insulin, Lipid, c-peptide, Nt-proBNP, cTnI, CRP, 
sTNFR1, Waist Circumference, ECG, KDQOL-36, KCCQ, Work Productivity and 
Activity Impairment, and Sit-to-Stand Tests in the Randomization Phase .............................22
Table 7-1.
Methods in Selecting Preferred Terms for Specified AE of Interest Categories.....................46
Table 8-2.
PK Parameters for Each Analyte.............................................................................................56
Table 12-1.
Example Search Terms for “COVID-19” and “Virtual” Used to Identify 
Missed/Virtual Visits...............................................................................................................73
LIST OF IN-TEXT FIGURES
Figure 1-1.
Study Design Schema..............................................................................................................10
CCI-


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LIST OF ABBREVIATIONS
ACEi
angiotensin converting enzyme inhibitor
AE
adverse event
ANCOVA
analysis of covariance
ARB
angiotensin receptor blocker
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
COVID-19
coronavirus disease 2019
CRF
case report form
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
DKD
diabetic kidney disease
DMC
data monitoring committee
EAIR
exposure-adjusted incidence rate
ECG
Electrocardiogram
EOS
end of study
EOT 
end of treatment
eGFR
estimated glomerular filtration rate
eGFRcr
estimated glomerular filtration rate calculated by CKD-EPI Creatinine Equation (2009)
eGFRcys
estimated glomerular filtration rate calculated by CKD-EPI Cystatin C Equation (2012)
ESKD
end stage kidney disease
FAS
Full Analysis Set
GLP1-RA
glucagon-like peptide-1 receptor agonists
GLPS
Global Patient Safety
HbA1c
hemoglobin A1c 
HLT
high-level term
IXRS
interactive voice or web response system
LTT
lower-level term
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effect model repeated measures
PP
per protocol
PT
preferred term
PTM
placebo to match
PY
patient year
Q1, Q3
first quartile, third quartile


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QRS
electrocardiographic deflection between the beginning of the Q wave and termination of the 
S wave representing time for ventricular depolarization
QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave representing the time for both ventricular depolarization and repolarization to occur
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RR
electrocardiographic interval representing the time measurement between the R wave of one 
heartbeat and the R wave of the preceding heartbeat
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SEL
selonsertib
SGLT-2i
sodium-glucose co-transporter-2 inhibitors
SI (units)
international system of units
SOC
system organ class 
sTNFR1
soluble tumour necrosis factor receptor-1
T2DM
type 2 diabetes mellitus
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
UACR
urine albumin to creatinine ratio
ULN
upper limit of normal
VR
ventricular rate
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ctau
observed drug concentration at the end of the dosing interval
CLss/F
apparent oral clearance after administration of the drug:
at steady state: CLss/F = Dose/AUCtau , where “Dose” is the dose of the drug
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 
2 by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
phase of the concentration of drug versus time curve


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-223-1017. This SAP is based on the study protocol Amendment 2 dated 
13 April 2020 and the electronic case report form (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR.
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate whether selonsertib (SEL) can slow the decline in kidney function
The secondary objectives of this study are as follows:

To evaluate whether SEL can reduce the risk of kidney failure, or reduce the risk of death 
due to kidney disease in subjects with diabetic kidney disease (DKD)

To assess the safety and tolerability of SEL in subjects with DKD
1.2.
Study Design
This is a Phase 2b, randomized, double-blind, placebo-controlled, parallel group, multicenter 
study evaluating the efficacy and safety of SEL in subjects with type 2 diabetes mellitus (T2DM) 
and moderate to advanced DKD.
Subjects meeting the study’s entry criteria after signing the informed consent will enroll into a 
Run-in period of at least 5 weeks and receive at least one week of placebo to match (PTM) and 
then SEL (18 mg) for at least 4 weeks. After completing the Run-in period, subjects meeting 
eligibility will be randomized in a 1:1 ratio to receive SEL (18 mg) or PTM orally once daily. 
Subjects must be on SEL for at least 7 consecutive doses prior to Visit C and Visit 1 in order to 
randomize.
The overall study design is presented graphically in Figure 1-1.


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Figure 1-1.
Study Design Schema
Abbreviations: EOS = End of Study, EOT = End of Treatment, PTM = placebo-to-match to match, SEL= Selonsertib
a
Prior to randomization, subjects must have at least 7 consecutive daily doses of study drug immediately prior to Visit C and 
Randomization (Visit 1)
b
Post-run-in Baseline eGFR is defined as the average of Visit C and Visit 1 eGFR values.  Pre-run-in Baseline is defined as 
the average of Visit A and Visit B eGFR values. 
c
If kidney failure is reached, subjects should discontinue study drug and remain on study. 
d
If a subject permanently discontinues study drug, there will be a 30 Day EOT Follow-up visit. Subjects who permanently 
discontinue study drug prior to the global study end date will have an EOT visit and a 30 Day (±7 days) EOT Follow-up 
visit. Subjects are encouraged to complete all remaining study visits until the global study end date.
e
The global study end date will occur when the last randomized subject reaches 48 weeks and/or all subjects on study have 
completed end of study assessments and the 30 Day EOS Safety Follow-up visit. 
Randomization will be stratified by average estimated glomerular filtration rate calculated by 
CKD-EPI Creatinine Equation (2009) (eGFRcr) values from Visit A and Visit B, average urine 
albumin to creatinine ratio (UACR) values from Visit A and B, and concomitant use of 
sodium-glucose co-transporter-2 (SGLT-2) inhibitors at Visit 1. 
Subjects will continue to receive SEL or PTM in a double-blind fashion until death, study drug 
discontinuation, kidney failure (dialysis performed for at least 4 weeks, kidney transplantation, 
or confirmed decrease in eGFR to < 15 mL/min/1.73 m2 for subjects without dialysis or kidney 
transplantation), or the global study end date. 
1.3.
Sample Size and Power
With a sample size of 300 subjects (150 per treatment arm), power to detect a difference in 
eGFRcr decline rate of 3.7 mL/min/1.73 m2/year (common SD = 10 mL/min/1.73 m2/year) 
between SEL 18 mg and placebo using a two-sample t-test is 99% at a 1-sided significance level 
of 0.15. Assuming 15% dropout, with a sample size of 254 (127 per arm), the power is 97%. 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
2.1.1.
DMC Analysis
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of 
the study and perform interim reviews of the safety data in order to protect subject welfare and 
preserve study integrity. To ensure the best interests of the participants, the DMC will make 
recommendations to the sponsor if the nature, frequency, and severity of adverse effects 
associated with the study treatment warrant the early termination of the study, the continuation of 
the study, or the continuation of the study with modifications.
The initial review will be conducted after 300 randomized subjects have completed through 
Week 12 or discontinued from the study. Additional meetings will be scheduled approximately 
every 6 months.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
provided in a mutually agreed upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency.
No formal interim efficacy analysis, which may lead to early termination for efficacy or futility, 
is planned.
2.2.
Final Analysis
The unblinded final analysis will be performed after all subjects have completed the study, 
outstanding data queries have been resolved or adjudicated as unresolvable, and the data have 
been cleaned and finalized. The analysis of the primary endpoint will be conducted at the time of 
the final analysis and will be tested at 1-sided 0.15 significance level.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the Safety Analysis Set and sorted by 
subject ID number, visit date, and time (if applicable). Data collected on log forms, such as AEs, 
will be presented in chronological order within the subject. For randomized subjects, the 
treatment group to which subjects were randomized will be used in the listings. Age, sex at birth, 
race, and ethnicity will be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. Subjects included in each analysis set will be determined before the 
study blind is broken for analysis. The analysis set will be identified and included as a subtitle of 
each table, figure, and listing.
For each analysis set, the number and percentage of subjects eligible for inclusion, as well as the 
number and percentage of subjects who were excluded and the reasons for their exclusion, will 
be summarized by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis Set includes all subjects who were enrolled in the study.
Allowable Analysis Sets Naming Convention per GSI Standards 
Allowable 
Allowable 
Allowable 
Analysis Set5: 
Analysis Set5: 
Am1ly~i5 Sets: 
• Al I Randomized 
• ITT 
• All Enrolled 
- FAS 
- mITT 
- FAS 
- Safety 
- Safety 
- Safet,, 
- Per-Protocol 
- Per.Protocol 
- Per-Protocol 


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3.1.2.
All Randomized Analysis Set
The All Randomized Analysis Set includes all subjects who were randomized in the study.
3.1.3.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who were randomized in the study, and 
received at least one dose of study drug in the Randomization Phase.
This is the primary analysis set for the primary, secondary 
 efficacy analyses.
3.1.4.
Per-Protocol Analysis Set
The Per-protocol (PP) Analysis Set includes subjects who are in the Full Analysis Set, excluding 
subjects who met any of the following criteria:
Violated any of the following major inclusion criteria as determined by the 
Inclusion/Exclusion Criteria CRF page:
1) Male or female between 18 (or ≥ age of majority in each jurisdiction if different than 18) and 
80 years of age, inclusive
2) Prior diagnosis of T2DM with diagnostic modalities as per local guidelines. Must have 
hemoglobin A1c (HbA1c) > 6% within 30 days of Enrollment (Visit A) or be on active 
treatment for T2DM for at least 6 weeks prior to Enrollment (Visit A)
3) eGFR value calculated by central laboratory utilizing samples collected during Screening and 
prior to Enrollment (Visit A) of ≥ 20 mL/min/1.73 m² to < 60 mL/min/1.73 m² with 
albuminuria as measured by UACR
a) eGFR values will be calculated using the Chronic Kidney Disease Epidemiology 
(CKD-EPI) Creatinine Equation (2009); UACR will be determined by urine collection, 
preferably early morning void. Subjects can have up to 3 eGFR and 3 UACR collections 
during the Screening period. Any one of the eGFR values and any one of the UACR 
values collected during Screening may be used to satisfy this inclusion criterion. 
Qualifying eGFR and UACR values do not need to be collected on the same day  
b) eGFR and UACR must meet criteria a, b, or c  
Criteria
eGFR (mL/min/1.73 m²)
UACR (mg/g)
A
≥ 45 to < 60
≥ 600 to 5000
B
≥ 30 to < 45
≥ 300 to 5000
C
≥ 20 to < 30
≥ 150 to 5000
 
CCI


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4) Treatment with either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin 
receptor blocker (ARB) as a single agent at the maximum labeled or tolerated dose deemed 
appropriate for the subject by the investigator and/or per local standard of care for at least 
6 weeks prior to Enrollment, with a stable dose for at least 2 weeks prior to Enrollment 
a) Subjects not receiving an ACEi or ARB may be enrolled if there is documented 
intolerance to ACEi and ARB 
b) Subjects receiving less-than-maximal dose of an ACEi or ARB may be enrolled if there is 
a documented reason that the maximum labeled dose of ACEi and ARB could not be 
reached  
5) Mean systolic blood pressure (SBP) must be < 160 mmHg  and mean diastolic blood pressure 
(DBP) must be < 100 mmHg taken at two time-points at least five minutes apart within 30 
days prior to Enrollment (Visit A)
6) Subjects already receiving SGLT-2 inhibitors must be on a stable dose at least 2 weeks prior 
to Enrollment
Met any of the following major exclusion criteria as determined by the Inclusion/Exclusion 
Criteria CRF page:
1) Hemoglobin A1c (HbA1c) > 12.0% within 30 days prior to Enrollment (Visit A) 
2) In the investigator’s opinion, a condition other than T2DM is the primary etiology of DKD  
3) Subjects with diagnosis of type 1 diabetes mellitus (T1DM) or maturity onset diabetes of the 
young (MODY)
4) Body mass index (BMI) > 50 kg/m2 at Enrollment (Visit A)
5) UACR > 5000 mg/g on any measurement during Screening 
6) End stage kidney disease (ESKD) (i.e., chronic hemodialysis, chronic peritoneal dialysis, or 
history of kidney transplantation)
7) Anticipated progression to ESKD (need for chronic hemodialysis, chronic peritoneal dialysis 
or receipt of kidney transplant) within 3 months after Enrollment (Visit A)
8) Unstable cardiovascular (CV) disease as defined by any of the following:
a) Myocardial infarction (MI), coronary artery bypass graft surgery, or coronary angioplasty 
within 3 months prior to Enrollment (Visit A)
b) Transient ischemic attack or cerebrovascular accident within 3 months prior to 
Enrollment (Visit A)
c) Hospitalization for heart failure within 3 months prior to Enrollment (Visit A)
d) New York Heart Association (NYHA) Class IV congestive heart failure


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9) Histo1y of a malignancy within 5 years prior to Enrollment (Visit A). However, the following 
are not exclusions, and subjects may enroll if there is any histo1y of: 
a) Carcinoma in situ of the cervix, or 
b) Basal or squamous cell cancer or other localized non-melanoma skin cancer that has been 
adequately treated 
10) Requiring chronic administration of prohibited medications as per protocol 
Violated any of the following major randomization eligibility criteria as determined by 
central laboratory data, the Study Drug Administration and Concomitant Medication CRF 
pages: 
1) eGFR 
15 mL/min/1. 73 m2 at all central laborato1y assessments during the Run-in period 
prior to the day of Randoinization. 
2) At least 7 consecutive daily doses of SEL, without intenuption, immediately prior to the day 
of nominal Visit C and prior to the day of nominal Visit 1. If Run-in SEL is taken on the day 
of nominal Visit C or nominal Visit 1, it will be counted towards the 7 consecutive daily 
doses of SEL. The day of nominal Visit C ( or Visit 1) is the calendar day when Visit C ( or 
Visit 1) was perfo1med. 
3) Subject did not initiate, change dose, or discontinue SGLT-2 inhibitor during the Run-in 
period prior to the day of Randomization and did not initiate, change dose or discontinue 
SGLT-2 inhibitor within 12 weeks after the day of Randoinization. 
Had any of the following major protocol deviations: 
• 
Adherence to study diug is less than 80% in the Randoinization Phase as detennined by the 
Study Dmg Accountability CRF page. 
The PP Analysis Set is the seconda1y analysis set for selected efficacy endpoints. 
3.1.5. 
Safety Analysis Set 
The Safety Analysis Set includes all subjects who took at least 1 dose of Run-in SEL. This is the 
primaiy analysis set for safety analyses. 
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Subject Grouping 
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For analyses based on the Full Analysis Set, subjects will be grouped according to the treatment 
to which they were randomized. For analyses based on the PP Analysis Set, subjects will be 
grouped according to the actual treatment received in the Randomization phase. For exposure-
adjusted incidence rate (EAIR) analyses based on the Safety Analysis Set, subjects and events 
will be grouped according to exposure (SEL or placebo). Please refer to Section 7 for details on 
EAIR analyses. The actual treatment received will differ from the randomized treatment only 
when their actual ti·eatment differs from randomized ti·eatment for the entire ti·eatment duration. 
For the PK Analysis Set, subjects will be grouped according to the actual ti·eatment they 
received. 
3.3. 
Strata and Covariates 
Subjects will be randomly assigned to treatment groups via the interactive voice or web response 
system (IXRS) in a 1: 1 ratio using a sti·atified randomization schedule. Sti·atification will be 
based on the following variables: 
• 
eGFRa, Sti·ata: 
eGF~r (mL/min/1.73 m2) 
c:: 30 to < 45 
c:: 15 to < 30 
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
Albuminuria Strata: UACR < 1500 mg/g vs. ≥ 1500 mg/g

Concomitant SGLT-2 Inhibitor Use Strata: Yes vs. No 
Randomization will be stratified by the average eGFRcr values from Visit A and Visit B; the 
average values of UACR from Visit A and Visit B; and concomitant use of SGLT-2 inhibitors 
assessed at Visit 1. Visit A and B values for eGFRcr and Albuminuria will be transferred directly 
from the central laboratory to the IXRS for stratification but eGFRcr values will not be released 
to sites, investigators, or the sponsor.
If there are discrepancies in stratification factor values between the IXRS and the clinical 
database, the values recorded in the clinical database will be used for analyses. Additionally, 
stratification discrepancies will be reviewed and assessed. Based on the assessment of 
stratification discrepancies, a sensitivity analysis of the primary endpoint may be performed.
3.4.
Examination of Subject Subgroups
Subgroup analyses based on the following Baseline characteristics will be performed for primary 
and secondary endpoints:

Age (< 65 years and  65 years)

Sex (male and female)

Race (white and all other races)

Ethnicity (Hispanic and non-Hispanic)

Pre-run-in eGFRcr (mL/min/1.73m2) stratum (>=45, >= 30 to < 45, and >= 15 to < 30)

Pre-run-in eGFRcr (mL/min/1.73m2) and UACR (mg/g) stratum (45 <= eGFRcr < 60 and 
600 <= UACR < 5000, 30 <= eGFRcr < 45 and 300 <= UACR < 5000, 15 <= eGFRcr < 30 
and 150 <= UACR < 5000)

SGLT-2i use at Randomization (yes and no)

Glucagon-like peptide-1 receptor agonist (GLP1-RA) use at Randomization (yes and no)

Pre-run-in Baseline UACR categories (< 1500 mg/g and ≥ 1500 mg/g)

ACEi or ARB use at Randomization (yes)

Baseline N-terminal pro-B-type natriuretic peptide (Nt-proBNP) categories (Normal and 
High Normal)

Day 1 soluble tumour necrosis factor receptor-1 (sTNFR1) subgroups (<= 4.3 ng/mL and 
> 4.3 ng/mL)


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3.5.
Multiple Comparisons
The study has 1 primary efficacy endpoint: eGFRcr slope from treatment-specific Baselines. The 
primary endpoint and each secondary endpoint will be evaluated at a 1-sided Type 1 error level 
of 0.15. No formal multiplicity adjustment will be performed. All other efficacy endpoints will 
also be tested using 1-sided tests at the 0.15 significance level without multiplicity adjustment.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for 
prior and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:

If only month and year of birth is collected, then “15” will be imputed as the day of birth

If only year of birth is collected, then “01 July” will be imputed as the day and month of birth

If year of birth is missing, then date of birth will not be imputed.
In general, age collected at Randomization (in years) will be used for analyses and presented in 
listings. If age at Randomization is not available for a subject, then age derived based on date of 
birth and the Randomization visit date will be used instead. If an enrolled subject was not 
randomized, age collected at Enrollment will be used. For screen failures, the date the first 
informed consent was signed will be used for the age derivation. Age required for longitudinal 
and temporal calculations and analyses (e.g., estimates of creatinine clearance, age at date of AE) 
will be based on age derived from date of birth and the date of the measurement or event, unless 
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Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “ x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data or nonparametric analysis methods may be used, 
as appropriate.
Sparse PK concentration values that are below the limit of quantitation (BLQ) will be presented 
as “BLQ” in the data listing.
Natural logarithm transformation will be used for analyzing concentrations and PK parameters in 
intensive PK samples. Concentration values that are BLQ will be presented as “BLQ” in the 
concentration data listing. Values that are BLQ will be treated as 0 at predose time points, and 
one-half the value of the LOQ at postdose time points for summary purposes.
The following conventions will be used for the presentation of summary and order statistics for 
intensive PK concentrations: 

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
PK parameters that are BLQ will be imputed as one-half LOQ before log transformation or 
statistical model fitting.


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3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study Day will be calculated from the first dosing date of blinded SEL/placebo treatment and 
derived as follows:

For postdose study days: Assessment Date – First Blinded SEL/placebo Dosing Date  + 1

For days prior to the first dose: Assessment Date – First Blinded SEL/placebo Dosing Date 
Therefore, Study Day 1 is the day of first dose of blinded SEL/placebo administration.
3.8.2.
Analysis Visit Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
3.8.2.1.
Analysis Visit Windows for the Run-in Phase 
The analysis windows for the Run-in phase will be defined based on nominal visit date, as 
detailed in Table 3-1.
Table 3-1.
Analysis Visit Windows for Visits in the Run-in Phase
Analysis Visit Window Definition
Nominal Visit
Lower Limit
Upper Limit
Visit A
None
Earlier of (Nominal Visit B date – 4, Run-in 
SEL first dosing date – 1)
Visit B
Earlier of (Nominal Visit B date – 3, Run-in 
SEL first dosing date)
Run-in SEL first dosing date
Visit C
Run-in SEL first dosing date + 1
For randomized subjects: Earlier of (Nominal 
Visit C date + 5, DB SEL/placebo first dosing 
date – 1)
For not randomized subjects: None
3.8.2.2.
Analysis Visit Windows for the Randomization Phase 
The analysis windows  are provided in Table 3-2 through Table 3-4.


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Table 3-2.
Analysis Visit Windows for eGFR, UACR, Vital Signs, Hematology 
Tests, Chemistry Tests and Pregnancy Tests in the Randomization 
Phase 
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Day 1
1
Earlier of (Nominal Visit 
C date + 6, Study Day 1)
1
Week 4
29
2
43
Week 8
57
44
71
Week 12
85
72
127
Week 24
169
128
211
Week 36
253
212
295
Week 48
337
296
379
Week 60
421
380
463
Week 72
505
464
547
Week 84
589
548
631
Week 96
673
632
715
Week 108
757
716
799
Week 120
841
800
883
Week 132
925
884
967
Week 144
1009
968
1051
Week 156
1093
1052
1135
Week 168
1177
1136
1219
For eGFRcr and eGFRcys based on the CKD-EPI creatinine 2009 and CKD-EPI cystatin C 2012 
equations, the analysis visit windows will be the same as in  Table 3-2.


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Table 3-3.
Analysis Visit Windows for  HbA1c in the Randomization Phase
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Day 1
1
 Earlier of (Nominal Visit 
C date + 6, Study Day 1)
1
Week 24
169
2
239
Week 48
337
240
379
Week 60
421
380
463
Week 72
505
464
547
Week 84
589
548
631
Week 96
673
632
715
Week 108
757
716
799
Week 120
841
800
883
Week 132
925
884
967
Week 144
1009
968
1051
Week 156
1093
1052
1135
Week 168
1177
1136
1219
Table 3-4.
Analysis Visit Windows for Insulin, Lipid, c-peptide, Nt-proBNP, 
cTnI, CRP, sTNFR1, Waist Circumference, ECG, KDQOL-36, 
KCCQ, Work Productivity and Activity Impairment, and Sit-to-
Stand Tests in the Randomization Phase
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Day 1
1
Earlier of (Nominal 
Visit C date + 6, Study 
Day 1)
1
Week 48
337
2
None


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3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from Baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:

For pre-SEL-treatment values (Visit A and Visit B):
In general, the last nonmissing value on or prior to the first dosing date of Run-in SEL 
will be selected, unless specified differently. If there are multiple records with the same 
time or no time recorded on the same day, the Baseline value will be the average of the 
measurements for continuous data, or the measurement with the lowest severity (e.g., 
normal will be selected over abnormal for safety electrocardiogram (ECG) findings) for 
categorical data.
For eGFRcr, eGFRcys, UACR (including urine albumin, urine creatinine), serum 
creatinine and serum cystatin C, a single value within each of the Visit A and/or Visit B 
analysis window will be used to calculate pre-run-in and/or post-run-in Baselines. 
■
Within each analysis window, the latest record will be selected. 
■
If there is more than 1 record on the selected day, the record with the latest time will 
be selected. If all records have the same time, or time is missing for at least one 
record, the average will be taken. 

For post-SEL-treatment values (Visit C, Day 1 and post-Randomization visits):
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the record with the latest time will be 
selected. If all records have the same time, or time is missing for at least one record, the 
average will be taken. 
Definition of pre-run-in Baseline: The average of the measurements at Visit A and Visit B.
Definition of post-run-in Baseline: The average of the measurements at Visit C and Day 1.
Definition of treatment-specific Baselines: For subjects in the placebo arm, Baseline is defined as 
pre-run-in Baseline. For subjects in the SEL arm, Baseline is defined as post-run-in Baseline.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by randomization status and treatment group 
for each country, investigator within a country, and overall. The summary will present the 
number and percentage of subjects enrolled. For each column, the denominator for the 
percentage calculation will be the total number of subjects analyzed for that column.
A  table will be provided to summarize discrepancies in the value used for stratification 
assignment between the IXRS and the clinical database. The denominator for the percentage of 
subjects in the stratum will be the total number of randomized subjects. A listing of subjects with 
discrepancies in the value used for stratification assignment between the IXRS and the clinical 
database at the time of data finalization will be provided.
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of subject disposition will be provided by randomization status and treatment group. 
This summary will present the number of subjects screened, the number of subjects enrolled, the 
number of subjects randomized, and the number of subjects in each of the categories listed 
below:

All Enrolled Analysis Set 

Safety Analysis Set

All Randomized Analysis Set

Full Analysis Set

Of subjects in the All Enrolled Analysis Set:
Completed study drug 
Did not complete study drug with reasons for premature discontinuation of study drug
Completed study
Did not complete study with reasons for premature discontinuation of study
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the All Enrolled Analysis Set 
corresponding to that column. In addition, a flowchart will be provided to depict the disposition.


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A by-subject listings of reasons for premature discontinuation of study drug will be provided by 
subject identification (ID) number in ascending order. A similar listing of reasons for study 
discontinuation will also be provided. 
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence relative to the study drug regimen specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to study drug will be defined as last dosing date minus first dosing 
date plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (e.g., 4.5 weeks). 
If the last study drug dosing date is missing or partial (month and year available or only year 
available), the following rules will be used to impute the last dosing date:
For the purpose of calculating the duration of exposure, the last contact date is the latest clinical 
visit date (including follow-up phone calls when the site was able to reach the subject), 
laboratory sample collection date, or vital signs assessment date collected in the study. 
If the last study drug dosing date is missing, then the last contact date will be used. 
If the last study drug dosing date is partial: 

If the month and year are the same as the month and year of the last contact date (defined as 
above), then the last contact date will be used.

If the month and year are earlier than the month and year of the last contact date, the last day 
of the month (or the last day of the year if only year is available) will be used. 

There should not be any partial dosing date with the month and year later than the month and 
year of the last contact date.
The total duration of exposure to study drug will be summarized using descriptive statistics and 
using the number (i.e., cumulative counts) and percentage of subjects exposed through the 
following time periods: 1 day, 4 weeks, 8 weeks, and every 4 weeks after Week 8. Summaries will 
be provided by treatment group (for randomized subjects) and overall for the Safety Analysis Set, 
for Run-in and Randomization Phases separately.
No formal statistical testing is planned.


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4.2.2.
Adherence to Study Drug
In this study, the subjects will orally take 1 tablet of the study drug daily. The total number of 
tablets administered will be summarized using descriptive statistics. 
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:
Total Number of Tablets Administered =
No. of Tablets Dispensed ―
No. of Tablets Returned
4.2.2.1.
On-Treatment Adherence
The level of on-treatment adherence to the study drug regimen will be determined by the total 
amount of study drug administered relative to the total amount of study drug expected to be 
administered during a subject’s actual on-treatment period based on the study drug regimen.
The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Descriptive statistics for the level of on-treatment adherence with the number and percentage of 
subjects belonging to adherence categories (e.g., {< 75%, ≥ 75 to < 90%, ≥ 90%}) will be 
provided by treatment group for the Safety Analysis Set. 
No formal statistical testing is planned.
A by-subject listing of study drug administration and drug accountability will be provided by 
subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations 
Subjects who did not meet the eligibility criteria for study entry but enrolled in the study will be 
summarized regardless of whether they were exempted by the sponsor or not. The summary will 
present the number and percentage of subjects who did not meet at least 1 eligibility criterion and 
the number of subjects who did not meet specific criteria by randomization status and treatment 
group based on the All Enrolled Analysis Set. A by-subject listing will be provided for those 
subjects who did not meet at least 1 eligibility (inclusion or exclusion) criterion and enrolled. The 
listing will present the eligibility criterion (or criteria if more than 1 deviation) that subjects did not 
meet and related comments, if collected.
Total Amount of Study Drug Administered
On-Treatment Adherence (%) = 
 x 100
Study Drug Expected to be Administered on Treatment






) 


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A by-subject listing will also be provided for subjects who did not meet at least 1 randomization 
eligibility criterion and randomized. The listing will present the eligibility criterion (or criteria if 
more than 1 deviation) that subjects did not meet and related comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (e.g., nonadherence to study drug, violation of select inclusion/exclusion 
criteria) will be summarized by treatment group and randomization status for the Safety Analysis 
Set. A by-subject listing will be provided for those subjects with important protocol deviations.
4.4.
Assessment of COVID-19 Impact
This study was ongoing during the coronavirus disease 2019 (COVID-19) pandemic which has 
an impact on the study conduct. Some subjects were unable to attend onsite visits due to shelter 
in place guidelines, site closures, or other reasons. This section describes how special situations 
due to COVID-19 will be handled in the analysis.
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19
A by-subject listing of reasons for premature study drug or study discontinuation due to 
COVID-19 will be provided.
4.4.2.
Protocol Deviations Due to COVID-19
A by-subject listing will be provided for subjects with important protocol deviations related to 
COVID-19. A separate listing will be provided for subjects with non-important protocol 
deviations related to COVID-19.
4.4.3.
Missed and Virtual Visits due to COVID-19
A summary of subjects affected by the COVID-19 pandemic will be provided for each scheduled 
study visit by treatment group and overall. For each visit, the summary will present the number 
and percentage of subjects who missed the visit due to COVID-19 or had a virtual visit due to 
COVID-19. For each column, the denominator for the percentage calculation will be the total 
number of subjects in the Safety Analysis Set for that column.
An overall summary of the number and percentage of subjects with missed or virtual visits (e.g., 
at least 1, with 1, 2, 3 or more visits) due to COVID-19 will be provided by treatment group and 
overall. The denominator for the percentage calculation will be the total number of subjects in 
the safety population for that column.
A by-subject listing of subjects with missed or virtual visits due to COVID-19 will be provided 
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Information regarding missed or virtual visits due to COVID-19 will be collected as free text in 
the CRF comment fields. The determination of missed or virtual visits due to COVID-19 will be 
done using Natural Language Processing (NLP) to search the CRF comment fields.  A detailed 
explanation of the algorithm is given in Appendix 4.
4.4.4.
Adverse Events Due to COVID-19
AEs of COVID-19 will be included in analyses of AEs if applicable, which will be determined 
through COVID-19 SMQ narrow search. A by-subject listing of AEs of COVID-19 will be 
provided if applicable.
4.4.5.
Overall Assessment of COVID-19 Pandemic Impact
For subjects affected by COVID-19 infection and/or pandemic while participating in the study, a 
listing of the following individual COVID-19 related outcome categories will be provided:

Death due to COVID-19

Adverse event of COVID-19, as determined by COVID-19 SMQ narrow search 

Hospitalization (using data from AE eCRF) due to adverse event of COVID-19 as defined 
above

Tested positive for COVID-19

Study drug discontinuation due to COVID-19

Study discontinuation due to COVID-19

Missed visits due to COVID-19  

Missed key assessments due to COVID-19 (Key assessments are the central lab assessments 
of serum creatinine and/or serum cystatin C)
In addition, composite broad COVID-19 impact indicator will be derived based on the following 
individual categories defined above: death, adverse event, hospitalization, tested positive, study 
drug discontinuation, study discontinuation, missed visits, and missed key assessments. 
Composite specific COVID-19 impact indicator will be derived based on death and tested 
positive.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Subject demographic variables (i.e., age, sex, race, and ethnicity) and Baseline characteristics 
(body weight [in kg], height [in cm], body mass index [BMI; in kg/m2], systolic blood pressure, 
diastolic blood pressure, heart rate, ACEi or ARB medication use, and other variables of interest) 
will be summarized.
Demographic and Baseline characteristics will be summarized by randomized status, treatment 
group and overall using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) for continuous variables and using number and percentage of subjects for categorical 
variables. For Baseline body weight, height, and BMI, descriptive statistics will also be 
presented by sex in the same table. The summary of demographic data will be provided for the 
Safety Analysis Set. No formal statistical testing is planned.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other Baseline characteristics include serum creatinine, serum cystatin C, eGFRcr, eGFRcys, 
UACR, stage of disease (defined by eGFRcr and UACR), blood urea nitrogen, potassium, 
calcium, phosphorus, bicarbonate, fasting blood glucose, fasting blood insulin, and HbA1c. These 
Baseline characteristics will be summarized by randomization status, treatment group and overall 
using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for 
continuous variables and using number and percentage of subjects for categorical variables. The 
summary of these Baseline characteristics will be provided for the Safety Analysis Set. No formal 
statistical testing is planned.
A by-subject listing of other Baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
Medical history will be collected at screening for disease-specific and general conditions 
(i.e., conditions not specific to the disease being studied).
Disease-specific medical history will be summarized by treatment group and overall by the 
number and percentage of subjects with each prepopulated condition. A summary of disease-
specific medical history will be provided for the Safety Analysis Set. No formal statistical testing 
is planned.
General medical history data will not be coded but will be listed only.


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6.
EFFICACY ANALYSES
6.1.
Primary Endpoint
6.1.1.
Definition of the Primary Endpoint
The primary efficacy endpoint of this study is eGFRcr slope from treatment-specific Baselines 
through Week 84. The values for eGFRcr will be calculated using the CKD-EPI Creatinine 
Equation (2009):
𝑒𝐺𝐹𝑅
= 141 × min
𝑆𝑐𝑟
𝜅, 1
𝛼
× max
𝑆𝑐𝑟
𝜅, 1
― 1.209
× 0.993𝐴𝑔𝑒× 1.018[𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒] × 1.159[
𝑖𝑓 𝐵𝑙𝑎𝑐𝑘]
𝑆𝑐𝑟 = standardized serum creatinine (mg/dL)
𝜅 = 0.7 (females) or 0.9 (males)
𝛼 = -0.329 (females) or -0.411 (males)
min indicates the minimum of Scr/κ or 1
max indicates the maximum of Scr/κ or 1
age in years
6.1.2.
Statisical Hypothesis of the Primary Endpoint
The primary analysis will test the following null hypothesis (H0) that there is no difference in 
eGFRcr slope from treatment-specific Baselines between SEL and placebo versus the alternative 
hypothesis (H1) that eGFRcr slope in the SEL arm is larger than that in the placebo arm. 
Formally, 
𝐻0:𝛽𝑆𝐸𝐿= 𝛽𝑃𝐵𝑂 𝑣𝑠. 𝐻1:𝛽𝑆𝐸𝐿> 𝛽𝑃𝐵𝑂
where 𝛽𝑆𝐸𝐿 and 𝛽𝑃𝐵𝑂 denote the mean slope from treatment-specific Baselines for SEL and 
placebo, respectively.
Statistical testing will be conducted at a 1-sided Type 1 error level of 0.15.
6.1.3.
Analysis of the Primary Endpoint
The Primary Analysis Set for efficacy analyses is the Full Analysis Set. 
Definition of Baseline
Baseline eGFRcr for the primary analysis is defined as below:

SEL arm: The average of the measurements at Visit C and Visit 1. This Baseline will also be 
referred to as post-run-in Baseline. 
(-) 
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
Placebo arm: The average of the measurements at Visit A (enrollment) and Visit B. This 
Baseline will also be referred to as pre-run-in Baseline. 
Estimand
The Treatment Policy estimand is defined as follows. This is the primary estimand for the 
primary endpoint.
1) Population: Subjects in the FAS. See definition of the FAS in Section 3.1.3.
2) Variable: Primary endpoint (eGFRcr slope from treatment-specific Baselines through 
Week 84). See Section 6.1.1 for detailed definition of the primary endpoint.
3) Intercurrent events: Intercurrent events for this study include study treatment discontinuation 
and/or starting a concomitant medication (e.g. SGLT-2 inhibitors).
The occurrence of an intercurrent event is irrelevant. All observed values will be used 
regardless of occurrence of an intercurrent event.

All observed values will be used regardless of occurrence of an intercurrent event (i.e, All 
available data defined above)

If a subject is lost to follow up, treat data as missing from the point of loss to follow-up 
onward
4) Population-level summary: eGFRcr slope from treatment-specific Baselines through Week 84 
in each treatment arm, and difference in eGFRcr slope from treatment-specific Baselines 
through Week 84 between SEL and placebo treatment arms.
Main Estimator
A random slope model will be used to evaluate SEL treatment effect on eGFRcr slope from 
treatment-specific Baselines through Week 84. The random slope model will have 
eGFRcr change from treatment-specifc Baselines at Weeks 4, 8, 12, 24, 36, 48, 60, 72 and 84 as 
outcome, and will include terms for eGFRcr at treatment-specific Baselines as a continuous 
variable, pre-run-in Baseline UACR category (< 1500 mg/g vs. ≥ 1500 mg/g), concomitant use 
of SGLT-2 inhibitors at Randomization, treatment group, week, and treatment-by-week 
interaction. Within-subject variance covariance will be modeled as unstructured. If model 
convergence problems arise, other variance-covariance structures, such as Heterogeneous 
Toeplitz, will be considered and documented. 
Sensitivity analyses of the eGFRcr slope endpoint will include the following:

Sensitivity analysis of eGFRcr slope excluding off-treatment eGFRcr values from the SEL 
treatment group.


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
Sensitivity analysis of eGFRcr slope excluding eGFRcr values collected after the initiation of 
dialysis or kidney transplantation.

Sensitivity analysis to evaluate the impact of attenuation of the acute effect. For subjects in 
the SEL group, the on-treatment eGFRcr values will be adjusted using a regression model as 
described in Appendix 2, which takes into account attenuation of the acute treatment effect 
that may be due to the theoretical concern for loss of kidney function over time. For subjects 
in the placebo group, the observed eGFRcr values will be used. The analysis of eGFRcr slope 
will be performed using the same model as described in the primary analysis, except that 
pre-run-in Baseline eGFRcr will be used for both SEL and placebo arms.

Sensitivity analysis of eGFRcr slope in subjects who completed study treatment. 

Sensitivity analysis of eGFRcr slope excluding subjects with randomization stratification 
mismatch between IXRS and Clinical Database. 

Sensitivity analysis of eGFRcr slope excluding subjects who took prohibited medications that 
may affect SEL efficacy or decrease SEL drug level in the prohibited period as detailed in 
Appendix 3. 

Sensitivity analysis of eGFRcr slope from pre-run-in Baseline for both SEL and placebo 
arms.

Sensitivity analysis of eGFRcr slope from treatment-specific Baselines through Week 48.

Sensitivity analysis of eGFRcr slope from treatment-specific Baselines through Week 60.

Sensitivity analysis of eGFRcr slope from treatment-specific Baselines through Week 72.

Sensitivity analysis of eGFRcr slope from treatment-specific Baselines through Week 96.
6.2.
Secondary Endpoints
6.2.1.
Definition of Secondary Endpoints
Secondary endpoints for this study are:

Proportion of Kidney Clinical Events defined as any of the following events:
Confirmed ≥ 40% decline in eGFRcr from pre-run-in Baseline, or 
Kidney failure (dialysis performed for at least 4 weeks, kidney transplantation, or 
confirmed decrease in eGFRcr to < 15 mL/min/1.73 m2 for subjects without dialysis or 
kidney transplantation), or 
Death due to kidney disease


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The ≥ 40% decline in eGFRcr from Baseline and sustained decrease in eGFRcr to 
<15 mL/min/1.73 m2 components need to be confirmed at the next scheduled visit but at least 
4 weeks after the index measurement (i.e., the first measurement of  ≥ 40% decline in eGFRcr 
from Baseline or eGFRcr < 15 mL/min/1.73 m2 ). Events of eGFRcr decline > 40% from Baseline 
or eGFRcr < 15 mL/min/1.73 m2 without confirmation due to study discontinuation (e.g., death or 
lost to follow-up) will be included in the analysis and counted as events. Date of the index 
measurement will be used as the date of event in the analysis.

Time from randomization to first occurrence of a Kidney Clinical Event
If a subject has not experienced any Kidney Clinical Events at the time of global study end 
date/early discontinuation of the study, this subject will be censored at the time of the last 
assessment of kidney function. 

eGFRcys slope from pre-run-in Baseline through Week 84
The values for eGFRcys will be calculated using the CKD-EPI Cystatin C Equation (2012):
𝑒𝐺𝐹𝑅= 133 × min
𝑆𝑐𝑦𝑠
0.8 , 1
―0.499
× max
𝑆𝑐𝑦𝑠
0.8 , 1
―1.328
× 0.996𝐴𝑔𝑒× 0.932[𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒]
𝑆𝑐𝑦𝑠=  standardized serum cystatin C (mg/L)
min indicates the minimum of Scys/0.8 or 1
max indicates the maximum of Scys/0.8 or 1 
age in years
6.2.2.
Analysis of Secondary Endpoints
The Secondary Analysis Set for efficacy analyses is the Full Analysis Set.
6.2.2.1.
Analysis of proportion of Kidney Clinical Events 
Number and proportion of subjects who experience a Kidney Clinical Event will be summarized 
by treatment group. Number and proportion of subjects who experienced each component of the 
Kidney Clinical Events will also be summarized by treatment group.  95% exact CI based on the 
Santner-Snell method (Santner and Snell, 1980) will be presented for the difference in 
proportions between SEL and placebo arms for the Kidney Clinial Events endpoint, as well as 
each component of the Kidney Clinical Events.
P-value based on the Cochran-Mantel-Haenszel (CMH) approach adjusting for randomization 
stratification factors will be reported for the comparison of proportion of Kidney Clinical Events 
between treatment arms. In addition, p-value based on Fisher’s exact test without adjusting for 
randomization stratification factors will also be reported. P-values will not be reported for the 
comparison of each component of the Kidney Clinical Events endpoint between treatment arms.
Subjects who do not have sufficient measurements to determine whether or not they had a 
Kidney Clinical Event will be considered not having a Kidney Clinical Event.
(-) 
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6.2.2.2.
Analysis of time from randomization to a Kidney Clinical Event
A stratified log-rank test stratified by randomization stratification factors will be used to evaluate 
SEL treatment effect on time from randomization to a Kidney Clinical Event. Hazard ratio (HR) 
and 95% CI comparing the SEL and placebo arms will be estimated using a stratified Cox 
proportional hazard model, stratified by randomization stratification factors. Number and percent 
of subjects with event per treatment group, event rate, HR, 95% CI and p-value will be presented 
for analysis of time to the first Kidney Clinical Event, and time to each component of the Kidney 
Clinical Event endpoint. HR and 95% CI will only be reported for outcomes with more than 10 
events, and have at least 1 event in each treatment arm. Event rate will be calculated as the 
number of subjects with the event, divided by the total duration of follow-up across all subjects 
in a given treatment group. Follow-up time for each subject will be calculated as time from 
Randomization to the earliest of study completion, premature study discontinuation, death and 
event of interest for a given outcome. 
Sensitivity analyses will be performed based on different definition of events or population. 
The same approaches as described in Sections 6.2.2.1 and 6.2.2.2 will be used for hypothesis 
testing for Kidney Clinical Events for the following:

Sensitivity analysis where in the SEL group, a 40% reduction in eGFRcr will be calculated 
from the pre-run-in Baseline eGFRcr for off-treatment eGFRcr values and the post-run-in 
Baseline eGFRcr for on-treatment eGFRcr values. 

Sensitivity analysis to use treatment-specific Baselines to calculate eGFRcr percent decline. 
For all eGFRcr values in the SEL group, a 40% reduction in eGFRcr will be calculated using 
the post-run-in Baseline eGFRcr. 

Sensitivity analysis to evaluate the impact of attenuation of the acute effect. For subjects in 
the SEL group, the on-treatment eGFRcr values will be adjusted using a regression model as 
described in Appendix 2, which takes into account attenuation of the acute treatment effect 
that may be due to the theoretical concern for loss of kidney function over time. This 
adjusted on-treatment eGFRcr value will be compared with the pre-run-in Baseline eGFRcr to 
calculate an adjusted percent eGFRcr reduction. For subjects in the placebo group, percent 
eGFRcr reduction will be calculated by comparing observed eGFRcr values with the 
pre-run-in Baseline eGFRcr. 

Sensitivity analysis in subjects who completed study treatment.

Sensitivity analysis excluding subjects with randomization stratification mismatch between 
IXRS and Clinical Database.

Sensitivity analysis excluding subjects who took prohibited medications that may affect SEL 
efficacy or decrease SEL drug level in the prohibited period as detailed in Appendix 3. 


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
Sensitivity analysis where a 57% reduction in eGFRcr from pre-run-in Baseline will be used 
for the eGFRcr reduction component of the Kidney Clinical Events instead of 40% reduction. 

Sensitivity analysis for the Kidney Clinical Events based on eGFRcys. The Kidney Clinical 
Events endpoint will have the same definition as in Section 6.2.1, except that the eGFR 
reduction and eGFR < 15 components will be based on eGFRcys instead of eGFRcr. 
The same approaches as described in Sections 6.2.2.1 only will be used for hypothesis testing for 
Kidney Clinical Events for the following:

The proportion of Kidney Clinical Events by Week 48 will be compared between SEL and 
placebo treatment arms. Subjects who do not have sufficient measurements to determine 
whether or not they had a Kidney Clinical Event by Week 48 will be considered not having a 
Kidney Clinical Event by Week 48.
6.2.2.3.
Analysis of eGFRcys slope from pre-run-in Baseline 
A random slope model will be used to evaluate SEL treatment effect on eGFRcys slope from 
pre-run-in Baseline through Week 84. The random slope model will have change in 
eGFRcys values from pre-run-in Baseline at Weeks 4, 8, 12, 24, 36, 48, 60, 72, and 84 as 
outcome, and will include terms for pre-run-in Baseline eGFRcys as a continuous variable, 
pre-run-in Baseline UACR category (< 1500 mg/g vs. ≥ 1500 mg/g), concomitant use of SGLT-2 
inhibitors at Randomization, treatment group, week, and treatment-by-week interaction. 
Within-subject variance covariance will be modeled as unstructured. If model convergence 
problems arise, other variance-covariance structures, such as Heterogeneous Toeplitz, will be 
considered and documented. 
Sensitivity analyses of the eGFRcys slope endpoint will include the following:

Sensitivity analysis of eGFRcys slope excluding eGFRcys values collected after the initiation 
of dialysis or kidney transplantation.

Sensitivity analysis of eGFRcys slope in subjects who completed study treatment. 

Sensitivity analysis of eGFRcys slope excluding subjects with randomization stratification 
mismatch between IXRS and Clinical Database. 

Sensitivity analysis of eGFRcys slope excluding subjects who took prohibited medications 
that may affect SEL efficacy or decrease SEL drug level in the prohibited period as detailed 
in Appendix 3. 

Sensitivity analysis of eGFRcys slope from pre-run-in Baseline through Week 48.

Sensitivity analysis of eGFRcys slope from pre-run-in Baseline through Week 60.

Sensitivity analysis of eGFRcys slope from pre-run-in Baseline through Week 72.

Sensitivity analysis of eGFRcys slope from pre-run-in Baseline through Week 96.


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7.
SAFETY ANALYSES
Unless otherwise specified, summaries of safety data will be provided for the Safety Analysis Set 
and will include data collected up to the last dose of study drug plus 30 days.
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA. System organ class (SOC), high-level group term (HLGT), high-level term (HLT), 
preferred term (PT), and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to toxicity 
criteria specified in the protocol. The severity grade of events for which the investigator did not 
record severity will be categorized as “missing” for tabular summaries and data listings. The 
missing category will be listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Global Patient Safety 
(GLPS) Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events 
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as follows for SEL and placebo 
exposures, respectively.

SEL exposure: TEAEs are defined as 1 or both of the following:
Any AEs with an onset date on or after the Run-in SEL start date and no later than 
30 days after permanent discontinuation of SEL 
Any AEs leading to premature discontinuation of SEL


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
Placebo exposure: TEAEs are defined as any AEs with an onset date on or after Study Day 
31 (30 days after the Randomized placebo start date) and no later than 30 days after 
permanent discontinuation of Randomized placebo 
7.1.5.2.
Incomplete Dates
If the onset date of an AE is incomplete and the AE stop date is not prior to the first dosing date 
of Run-in SEL, then the month and year (or year alone if month is not recorded) of onset will 
determine whether an AE is treatment emergent. 
The event is considered treatment emergent to SEL exposure if both of the following 2 criteria 
are met:

The AE onset date is the same as or after the month and year (or year) of the first dosing date 
of Run-in SEL, and

The AE onset date is the same as or before the month and year (or year) of the 30th day after 
the last dosing date of SEL 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of Run-in SEL, will be considered to be treatment emergent 
to SEL expsoure. In addition, an AE with the onset date missing and incomplete stop date with 
the same or later month and year (or year alone if month is not recorded) as the first dosing date 
of Run-in SEL will be considered treatment emergent to SEL exposure.
The event is considered treatment emergent to placebo exposure if both of the following 2 
criteria are met:

The AE onset date is the same as or after the month and year (or year) of the 30th day after 
the first dosing date of Randomized placebo (Study Day 31), and

The AE onset date is the same as or before the month and year (or year) of the 30th day after 
the last dosing date of Randomized placebo 
7.1.6.
Summaries of Adverse Events and Deaths
Exposure-adjusted treatment-emergent AE incidence rates will be summarized based on the 
Safety Analysis Set, by exposure type (SEL or placebo) and overall. SEL exposure includes 
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7.1.6.1.
Calculation of Treatment Exposure
Treatment exposure will be calculated as follows, for SEL and placebo respectively:

SEL: Total exposure (Patient Year) is calculated as the sum of Run-in SEL and Randomized 
SEL exposure time (in years) for all subjects who have been exposed to Run-in SEL and/or 
Randomized SEL in the Safety Analysis Set, starting from the first dosing date of Run-in 
SEL to the last dosing date of SEL (Run-in SEL or Randomized SEL).
In other words,
𝑇𝑜𝑡𝑎𝑙 𝑆𝐸𝐿 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒
=  
𝑖∈{𝑆𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑒𝑑 𝑡𝑜 𝑆𝐸𝐿}
𝐸𝑥(𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑅𝑢𝑛𝑖𝑛 𝑆𝐸𝐿 𝑡𝑜 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑅𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑒𝑑 𝑆𝐸𝐿)𝑖
+
𝑖∈{𝑆𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑒𝑑 𝑡𝑜 𝑃𝑙𝑎𝑐𝑒𝑏𝑜}
𝐸𝑥(𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑅𝑢𝑛𝑖𝑛 𝑆𝐸𝐿 𝑡𝑜 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑅𝑢𝑛𝑖𝑛 𝑆𝐸𝐿)𝑖
+
𝑖∈{𝑆𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑛𝑜𝑡 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑒𝑑}
𝐸𝑥(𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑅𝑢𝑛𝑖𝑛 𝑆𝐸𝐿 𝑡𝑜 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑅𝑢𝑛𝑖𝑛 𝑆𝐸𝐿)𝑖

Placebo: Total exposure (Patient Year) is calculated as the sum of Randomized placebo 
exposure time (in years) for all subjects who exposed to Randomized placebo in the Safety 
Analysis Set, starting from Study Day 1 to the last dosing date of Randomized placebo.
In other words,
𝑇𝑜𝑡𝑎𝑙 𝑃𝑙𝑎𝑐𝑒𝑏𝑜 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒
=  
𝑖∈{𝑆𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑒𝑑 𝑡𝑜 𝑃𝑙𝑎𝑐𝑒𝑏𝑜}
𝐸𝑥(𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑅𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑒𝑑 𝑃𝑙𝑎𝑐𝑒𝑏𝑜 𝑡𝑜 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑅𝑎𝑛𝑑𝑜𝑚𝑧𝑖𝑒𝑑 𝑃𝑙𝑎𝑐𝑒𝑏𝑜)𝑖
7.1.6.2.
Calculation of Exposure-Adjusted AE Incidence Rate
EAIR for AEs will be calculated as follows for SEL and placebo exposure periods, respectively:
𝐸𝐴𝐼𝑅(𝑆𝐸𝐿)
= # 𝑜𝑓 𝑆𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑤ℎ𝑜 𝑒𝑥𝑝𝑒𝑟𝑖𝑒𝑛𝑐𝑒𝑑 𝑎𝑡 𝑙𝑒𝑎𝑠𝑡 1 𝑇𝐸𝐴𝐸 𝑜𝑓 𝑖𝑛𝑡𝑒𝑟𝑒𝑠𝑡 𝑡𝑜 𝑆𝐸𝐿 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒
𝑇𝑜𝑡𝑎𝑙 𝑆𝐸𝐿 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒
𝐸𝐴𝐼𝑅(𝑃𝑙𝑎𝑐𝑒𝑏𝑜)
= # 𝑜𝑓 𝑆𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑤ℎ𝑜 𝑒𝑥𝑝𝑒𝑟𝑖𝑒𝑛𝑐𝑒𝑑 𝑎𝑡 𝑙𝑒𝑎𝑠𝑡 1 𝑇𝐸𝐴𝐸 𝑜𝑓 𝑖𝑛𝑡𝑒𝑟𝑒𝑠𝑡 𝑡𝑜 𝑃𝑙𝑎𝑐𝑒𝑏𝑜 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒
𝑇𝑜𝑡𝑎𝑙 𝑃𝑙𝑎𝑐𝑒𝑏𝑜 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒


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7.1.6.3.
Summaries of Exposure-Adjusted AE Incidence Rate
A brief, high-level summary of the number of subjects who experienced at least 1 TEAE in the 
categories described below will be provided by exposure type (SEL or placebo) and overall. 
EAIRs (per 100 Patient Years) will also be presented. All deaths observed in the study, as well as 
EAIRs per 100 Patient Years will also be included in this summary by exposure type (SEL or 
placebo) and overall. 
The number subjects who experienced at least 1 TEAE in the AE categories described below will 
be provided and summarized by SOC, PT, by exposure type (SEL or placebo) and overall. 
EAIRs (per 100 Patient Years) for AEs in these categories will also be provided. 

TEAEs

TEAEs with Grade 3 or higher 

TE treatment-related AEs

TE treatment-related AEs with Grade 3 or higher 

TE SAEs

TE treatment-related SAEs 

TEAEs leading to premature discontinuation of study drug

TEAEs leading to temporary interruption of study drug

TEAEs leading to Death
Multiple events will be counted only once per subject per exposure type in each summary. 
Adverse events will be summarized and listed first in alphabetic order of SOC, and then by PT in 
descending order of total frequency within each SOC. For summaries by severity grade, the most 
severe grade will be used for those AEs that occurred more than once in an individual subject 
during one exposure type (SEL or placebo) during the study. 
In addition to the above summary tables, all TEAEs, TE SAEs, TE treatment-related AEs, and 
TE treatment-related SAEs will be summarized by PT only, in descending order of total 
frequency.
In addition, data listings will be provided for the following in the All Enrolled Analysis Set:

All AEs, indicating whether the event is treatment emergent

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
All SAEs

All Deaths

All AEs leading to premature discontinuation of study drug 

All AEs leading to temporary interruption of study drug
7.1.7.
Additional Analysis of Adverse Events
Categories of AEs of special interest will be summarized (number and percentage) by treatment 
group. Table 7-1 presents the method of selecting preferred terms for each specified AE 
category.
Table 7-1.
Methods in Selecting Preferred Terms for Specified AE of Interest 
Categories
AE of Interest Category
Methods in Selecting Preferred Terms
Cardiac failure
Broad Standardized MedDRA Query (SMQ) Cardiac Failure
Acute Renal Failure
Narrow SMQ Acute Renal Failure
COVID-19
Narrow SMQ COVID-19
7.2.
Laboratory Evaluations
Central laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of central laboratory data will be provided for 
the Safety Analysis Set and will include data collected up to the last dose of study drug plus 
30 days for subjects who have permanently discontinued study drug. The analysis will be based 
on values reported in conventional units. When values are below the LOQ, they will be listed as 
such, and the closest imputed value will be used for the purpose of calculating summary statistics 
as specified in Section 3.7. Hemolyzed test results will not be included in the analysis, but they 
will be listed in by-subject laboratory listings.
A by-subject listing for central laboratory test results will be provided by subject ID number and 
visit in chronological order for hematology, serum chemistry, and urinalysis separately. For 
central laboratory data, values falling outside of the relevant reference range and/or having a 
severity grade of 1 or higher on the CTCAE severity grade will be flagged in the data listings, as 
appropriate.
A by-subject listing for local laboratory test results will also be provided by subject ID number 
and collection date in chronological order. Test values and corresponding reference ranges 
reported by the local laboratories will be presented.
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7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by treatment group for each central laboratory test 
specified in the study protocol as follows:

Baseline values 

Values at each postbaseline visit

Change from Baseline at each postbaseline visit
A Baseline laboratory value will be defined as the last nonmissing measurement obtained on or 
prior to the date/time of first dose of Run-in SEL, with the exception that Baseline laboratory 
values for serum creatinine, serum cystatin C, eGFRcr, eGFRcys, urine albumin, urine creatinine 
and UACR will be defined as the average values of Visit A and Visit B measurements. Change 
from Baseline to a postbaseline visit will be defined as the visit value minus the Baseline value. 
The mean, median, Q1, Q3, minimum, and maximum values will be displayed to the reported 
number of digits; SD values will be displayed to the reported number of digits plus 1.
Median (Q1, Q3) of the change from Baseline values for white blood cells, neutrophis, 
lymphocytes, hemoglobin, platelet count, serum creatinine, eGFRcr, serum cystatin C, eGFRcys, 
UACR, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and 
alkaline phosphatase (ALP) will be plotted using a line plot by randomization status, treatment 
group and visit.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.
7.2.2.
Graded Laboratory Values
The modified CTCAE v5.0 criteria as specified in the protocol will be used for assigning toxicity 
grades (0 to 4) to central laboratory results for analysis. 
Severity grading for serum creatinine will be defined with the following criteria for reporting 
purposes. Any serum creatinine within the normal range should be grade 0 regardless of the 
criteria specified.
Grade 1
Grade 2
Grade 3
Grade 4
1.25 to  < 1.5 x Baseline
1.5 to  < 1.75 x Baseline
1.75  to < 3 x Baseline
>3 x Baseline
Severity grading for serum cystatin C will be defined with the following criteria for reporting 
purposes. Any serum cystatin C within the normal range should be grade 0 regardless of the 
criteria specified.
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Grade 1
Grade 2
Grade 3
Grade 4
1.25 to  < 1.5 x Baseline
1.5 to  < 1.75 x Baseline
1.75  to < 3 x Baseline
>3 x Baseline
Grade 0 includes all values that do not meet the criteria for an abnormality of at least Grade 1. 
For laboratory tests with criteria for both increased and decreased levels, analyses for each 
direction (ie, increased, decreased) will be presented separately. 
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as follows for SEL and placebo 
exposures, respectively. Treatment-emergent laboratory abnormalities will only be evaluated for 
central laboratory testing results.

SEL exposure: values that increase at least 1 toxicity grade from Baseline at any time point 
after the first dosing date of Run-in SEL, up to and including the date of last dose of SEL 
plus 30 days. 

Placebo exposure: values that increase at least 1 toxicity grade from Baseline at any time 
point on or after Study Day 31, up to and including the date of last dose of Randomized 
placebo plus 30 days. 
Baseline is defined as the last nonmissing value prior to the first dose of Run-in SEL.
If the relevant Baseline laboratory value is missing, any abnormality of at least Grade 1 observed 
within the time frame specified above will be considered treatment emergent.
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities
Treatment-emergent marked laboratory abnormalities are defined as follows for SEL and 
placebo exposures, respectively. Treatment-emergent marked laboratory abnormalities will only 
be evaluated for central laboratory testing results.

SEL exposure: values that increase at least 2 toxicity grades from Baseline at any time point 
after the first dosing date of Run-in SEL, up to and including the date of last dose of SEL 
plus 30 days. 

Placebo exposure: values that increase at least 2 toxicity grades from Baseline at any time 
point on or after Study Day 31, up to and including the date of last dose of Randomized 
placebo plus 30 days. 
Baseline is defined as the last nonmissing value prior to the first dose of Run-in SEL.
If the relevant Baseline laboratory value is missing, any Grade 2, 3 or 4 values observed within 
the time frame specified above will be considered treatment emergent.
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7.2.2.3.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at Baseline and each scheduled postbaseline visit.
The following summaries (number and EAIR per 100 Patient Years) for treatment-emergent 
central laboratory abnormalities will be provided by lab test and exposure type (SEL or placebo); 
subjects will be categorized according to the most severe postbaseline abnormality grade for a 
given lab test:

Treatment-emergent laboratory abnormalities

Treatment-emergent Grade 3 or 4 laboratory abnormalities

Treatment-emergent marked laboratory abnormalities
EAIR for treatment-emergent laboratory abnormalities will be calculated in the same manner as 
EAIR for TEAEs (Section 7.1.6.2).
A by-subject listing of treatment-emergent Grade 3 or 4 laboratory abnormalities  will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the lab test of interest, with all applicable 
severity grades displayed.
7.2.3.
Liver-related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and EAIR of subjects who were reported to have the following central 
laboratory test values for postbaseline measurements:

AST: (a) > 3 times of the upper limit of reference range (ULN); (b) > 5 x ULN; (c) > 10 x 
ULN; (d) > 20 x ULN

ALT: (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

AST or ALT: (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

Total bilirubin: (a) > 1 x ULN; (b) > 2 x ULN

ALP: > 1.5 x ULN

AST or ALT > 3 x ULN and (a) total bilirubin > 1.5 x ULN; (b) total bilirubin > 2 x ULN; 
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The summary will include data for the following exposure periods for SEL and placebo 
exposures, respectively:

SEL exposure: at any time point after the first dosing date of Run-in SEL, up to and 
including the date of last dose of SEL plus 30 days. 

Placebo exposure: at any time point on or after Study Day 31, up to and including the date of 
last dose of Randomized placebo plus 30 days. 
For individual laboratory tests, subjects will be counted once based on the most severe values in 
corresponding period. For both the composite endpoint of AST or ALT and total bilirubin, 
subjects will be counted once when the criteria are met at the same postbaseline visit date. A 
listing of subjects who met at least 1 of the above criteria will be provided.
7.3.
Vital Signs and BMI
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
by treatment group for vital signs and BMI as follows. Body weight will be summarized as 
described in Section 5.1. 

Baseline value

Value at each postbaseline visit

Change from Baseline at each postbaseline visit
A Baseline value will be defined as the last available value collected on or prior to the date of 
first Run-in SEL administration. Change from Baseline to a postbaseline visit will be defined as 
the postbaseline value minus the Baseline value. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.  No inferential statistics will be generated.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary.
7.4.1.
Prior  Medications
Prior medications are defined as any medications taken before a subject took the first Run-in 
SEL.
Prior  medications will be summarized by preferred name using the number and percentage of 
subjects for each treatment group and overall. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary will be ordered by preferred term in order of 
descending overall frequency. For drugs with the same frequency, sorting will be done 
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For the purposes of analysis, any medication with a start date prior to the first dosing date of 
Run-in SEL will be included in the prior medication summary regardless of when the stop date 
is. If a partial start date is entered the medication will be considered prior unless the month and 
year (if day is missing) or year (if day and month are missing) of the start date are after the first 
dosing date of Run-in SEL. Medications with a completely missing start date will be included in 
the prior medication summary, unless otherwise specified.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
All prior medications will be provided in a listing sorted by subject ID number and start date in 
chronological order.
Disease-specific prior medications (ACEi, ARB, and ARB or ACEi) will be summarized and 
listed in a similar manner.
Prior use of SGLT-2 inhibitors, statins and GLP1-RAs will also be summarized and listed in a 
similar manner. 
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by preferred name using the number and 
percentage of subjects for each treatment group and overall. A subject reporting the same 
medication more than once will be counted only once when calculating the number and 
percentage of subjects who received that medication. The summary will be ordered by preferred 
term in descending overall frequency . For drugs with the same frequency, sorting will be done 
alphabetically.
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of Run-in SEL and continued to be taken after the first dosing date, or started after the first 
dosing date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date of Run-in 
SEL or the last dosing date of study drug will also be considered concomitant. Medications with 
a stop date prior to the date of first dosing date of Run-in SEL or a start date after the last dosing 
date of study drug will be excluded from the concomitant medication summary. If a partial stop 
date is entered, any medication with the month and year (if day is missing) or year (if day and 
month are missing) prior to the date of first Run-in SEL administration will be excluded from the 
concomitant medication summary. If a partial start date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) after the study drug 
stop date will be excluded from the concomitant medication summary. Medications with 
completely missing start and stop dates will be included in the concomitant medication summary, 
unless otherwise specified. 
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.


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All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
Disease-specific concomitant medications (ACEi, ARB, and ARB or ACEi) will be summarized 
and listed in a similar manner.
Concomitant use of SGLT-2 inhibitors, statins and GLP1-RAs will also be summarized and 
listed in a similar manner. 
7.5.
Electrocardiogram Results
ECG analysis results are intended to identify meaningful changes in the QT interval. If potential 
abnormalities of interest are identified, further analyses may be conducted. Summaries of 
investigator assessment of ECG readings will be provided for the Safety Analysis Set for each 
scheduled time point. No formal statistical testing is planned.
7.5.1.
Investigator Electrocardiogram Assessment
A shift table of the investigators’ assessment of ECG results at each postbaseline visit compared 
with Baseline values will be presented by randomization status and treatment group using the 
following categories: normal; abnormal, not clinically significant; abnormal, clinically 
significant; or missing. Baseline ECG value will be defined as the last nonmissing value before 
the first dose of Run-in SEL. The number and percentage of subjects in each cross-classification 
group of the shift table will be presented. Subjects with a missing value at Baseline or 
postbaseline will not be included in the denominator for percentage calculation. No formal 
statistical testing is planned.
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order.
7.5.2.
Corrected QT Intervals
The QT interval (measured in millisecond [msec]) is a measure of the time between the start of 
the Q wave and the end of the T wave in the heart’s electrical cycle. The QT interval represents 
electrical depolarization and repolarization of the ventricles. The QT interval is affected by heart 
rate, and a number of methods have been proposed to correct QT for heart rate. 
Corrected QT (QTc) intervals will be derived using Fridericia’s correction (QTcF) as follows: 
𝑄𝑇𝑐𝐹= 𝑄𝑇
3 𝑅𝑅
where QT is measured in msec; RR = 60/Heart Rate (beats per min [bpm]) and RR is measured 
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The maximum postbaseline QTcF interval values obtained during the study will be summarized 
within the following categories: 

> 450 msec

> 480 msec

> 500 msec
The maximum postbaseline change in QTcF interval values obtained during the study will also 
be summarized within the following categories:

> 30 msec

> 60 msec
QTcF and uncorrected QT values at each visit and change from Baseline at each visit  will be 
summarized for the Safety Analysis Set by treatment group and randomization status using 
descriptive statistics.
7.5.3.
PR and QRS Intervals
The PR interval (measured in msec) is a measure of the time between the start of the P wave (the 
onset of atrial depolarization) and the beginning of the QRS complex (the onset of ventricular 
depolarization). The QRS interval measures the duration of the QRS complex. The maximum 
postbaseline ventricular rate (VR) and PR and QRS intervals observed during the study will be 
categorized. The number and percentage of subjects having values in the following ranges will 
be presented by treatment group and randomization status:

VR > 100 bpm

PR interval > 200 msec

QRS interval > 110 msec
In addition, VR, PR, RR, and QRS values at each visit and change from Baseline at each visit 
will be summarized for the Safety Analysis Set by treatment group and randomization status 
using descriptive statistics.
7.6.
Other Safety Measures
7.6.1.
Pregnancy Report
A data listing will be provided for subjects experiencing pregnancy during the study, from 
screening to subjects’ last study visit. 


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7.6.2.
HIV-1, HBV, and HCV Serology
Data for HIV-1, HBV, and HCV serology will be listed and summarized.
7.6.3.
Digoxin and C-Peptide Testing Results
A data listing will be provided for digoxin levels; a separate listing will be provided for 
C-peptide testing results.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8. 
PHARMACOKINETIC (PK) ANALYSES 
8.1. 
PK Sample Collection 
Version 1.0 
Sparse (single) PK samples will be collected at Weeks 4, 12, 24, 48 and EOT visit for PK 
analysis of SEL and metabolite(s), as applicable. Date and time of last dose of study chug prior to 
PK sample collection as well as date and time of PK sample collection will be recorded. 
Additionally, whether the previous dose of study chug was taken fed or fasted will be recorded. 
Sparse (single) PK samples will not be collected for subjects who pe1manently discontinue study 
chug and remain on study. 
A single PK blood sample will be collected at any time during each On-Treatment Visit for all 
subjects. 
Concentrations of SEL and GS-607509 in plasma will be dete1mined using validated 
bioanalytical assays. A population PK model will be developed to characterize the PK of SEL 
and its metabolite (as applicable). Data from this study (single PK 
) will be 
combined with data from other studies in a meta-population analysis using nonlinear mixed-
effects modeling techniques. Details of the population PK analysis will be provided in a separate 
population PK analysis repo1t. 
8.2. 
PK Analyses Related to Intensive PK Sampling 
Concentrations o SEL an 
will be 
dete1mined using validated bioanalytical assays. 
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8.2.1. 
Estimation of PK Parameters 
Version 1.0 
PK parameters will be estimated using Phoenix WinNonlin® software using standard 
noncompartmental methods. The linear up/log down rnle will be used in conjunction with the 
appropriate noncompartmental model, with input values for dose level, dosing time, plasma 
concentration, and conesponding real-time values, based on dmg dosing times whenever 
possible. 
All predose sample times before time-zero will be conve1ied to 0. 
For area under the curve (AUC), samples BLQ of the bioanalytical assays occmTing prior to the 
achievement of the first quantifiable concentration will be assigned a concentration value of O to 
prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will be 
treated as missing data in WinNonlin. The nominal time point for a key event or dosing interval 
('t) may be used to pennit direct calculation of AUC over specific time intervals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile 
basis. 
Phaimacokinetic pai·ameters such as AUCum, "A2 and t112 ai·e dependent on an accmate estimation 
of the te1minal elimination phase of drng. The appropriateness of calculating these parameters 
will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist. 
-
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9.
REFERENCES
Mallinckrodt CH, Sanger TM, Dube S, DeBrota DJ, Molenberghs G, Carroll RJ, et al. Assessing 
and interpreting treatment effects in longitudinal clinical trials with missing data. 
Biological psychiatry 2003;53 (8):754-60.
Santner, T. J., and Snell, M. K. Small-Sample Confidence Intervals for  and  in  Contingency 
Tables. Journal of the American Statistical Association 1980; 75:386–394.


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10.
SOFTWARE
SAS® Software Version 9.2. SAS Institute Inc., Cary, NC, USA.
East 6 Version 6.5. Copyright © Cytel Inc., 1994-2018


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision
3 DEC 2021
Original Version 1.0


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12.
APPENDICES
Appendix 1.
Schedule of Assessments
Appendix 2.
Adjustment of On-Treatment eGFRcr Values
Appendix 3.
Prohibited Medications That May Impact SEL Treatment Efficacy or Decrease SEL 
Drug Level
Appendix 4.
Data Collection of COVID-19 Data


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Appendix 1.
Schedule of Assessments
Study Procedures Table – Screening to Randomization
Period
Screening
Enrollment
Run-In
Randomization
Visit
A
Ba
Cb
1b
Visit Window (days)
30 day 
screening 
period
7 – 14 days 
after visit A
21 – 28 days 
after visit B
7 – 14 days 
after visit C
Written Informed Consent
X
Medical History & Demographics
X
Complete Physical Examinationc
X
Vital Signs including Weightd
X
X
X
X
X
Height
X
Waist Circumference
X
12 Lead ECG
X
Adverse Events
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
Study Drug Dispensing
X
X
X
X
Study Drug Dosing
X
X
X
X
Clinical Assessments
Study Drug Bottle Return
X
X
X
CCI


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Period
Screening
Enrollment
Run-In
Randomization
Visit
A
Ba
Cb
1b
Visit Window (days)
30 day 
screening 
period
7 – 14 days 
after visit A
21 – 28 days 
after visit B
7 – 14 days 
after visit C
Subject Fastingg
X
X
eGFRh
X
X
X
X
X
Early Morning Void Urine ACR & Urinalysisi
X
X
X
X
X
Chemistry & Hematology
X
X
X
X
X
HbA1c
X
HIV-1, HBV, HCV Serology  
X
Blood Biomarkers
X
X
Prothrombin Time
X
Insulin, Lipid, c-peptide
X
X
Nt-proBNP
X
X
cTnI
X
X
Digoxink
X
Pregnancy Testingl
X
X
X
FSH Testingm
X
Laboratory Assessments
Urine Biomarkers
X
X
a.
Samples to be collected pre-dose
b.
Subject can have no missed doses of study drug during the 7 consecutive days immediately prior to Visit C and Visit 1
c.
On visits without a scheduled complete physical examination, a symptom-driven physical examination may be performed if necessary
d.
Vital signs include resting blood pressure, pulse, respiratory rate, temperature and weight. Measurements of blood pressure should be taken per institutional guidelines. Subject 
position should be consistent for each subsequent measure
e.
Subject-reported outcomes should be completed at the start of the study visit and prior to the clinical and laboratory assessments. The subject should read the questionnaires by 
himself/herself and record the answers by himself/herself. The HRQoL questionnaires to be completed at Enrollment are KDQOL-36, KCCQ, and WPAI-GH
CCI


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I 
g. 
u 1ects s ou a stam om a 
oo 
or at east 
1om·s pnor to 
oratory ·aw, water is allowed 
Version 1.0 
h. 
eGFR value to be calculated by the Chronic Kidney Disease Epidemiology Creatinine Equation (2009); if eGFR value at Screening does not meet inclusion criteria, subject 
may repeat 2 additional times during Screening and prior to Enrolhnent (Visit A). Subject must have eGFR :;:: 15 mL/m.in/1. 73 m2 at all central laborato1y assessments dtuing 
the Run-in period prior to Randomization (Visit 1) 
1. 
First mom.ing void collection is preferred when possible, but early moming void is accepted. B,ing sample to clinic within 1 hotu·, if not possible, refrigerate and b,ing to clinic 
within 12 hours. IfUACR value at Scre.ening does not meet inclusion criteria sub'ect ma r eat 2 additional times durino Screenin and rior to Elll'olhuent 
isit A 
I' 
k. 
For su 1ects t mg 1goxm on y, 1goxin level should be measured at Visit C and Week 4. PI may continue checking after Week 4 as part of digoxin management as needed. 
Monitor and adjust digoxin dose as necessa,y based on prescribing info,mation. 
I. 
Females of childbea,ing potential as defmed by protocol only (refer to Protocol Appendix 6): Semm pregnancy test at Screening and mine pregnancy test at Visit B, 
Randomization and eve,y 4 weeks through the 30 Day EOT Follow-up visit. 
m. FSH testing to detemiine female subject's postmenopausal state as described in Protocol Appendix 6. 
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Study Procedures Table – Week 4 to Week 48+
Period
On Treatment
Visit
2
3
4
5
6
7
Week
4
8
12
24
36
48
q12 weeksl
Visit Window (days)
±5
±5
±5
±5
±5
±5
±5
Complete Physical Examinationa
Vital Signs including Weightb
X
X
X
X
X
X
X
Waist Circumference
X
12 Lead ECG
X
Adverse Events
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Study Drug Dispensing
X
X
X
X
X
X
X
Study Drug Dosing
X
X
X
X
X
X
X
Clinical Assessments
Study Drug Bottle Return
X
X
X
X
X
X
X
CCI


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Period 
Visit 
Week 
Visit Window (days) 
Subject Fasting• 
eGFRf 
Early Moming Void Urine ACR & Urinalysisg 
Chemist:iy & Hematology 
HbAlc 
Blood Biomarkers 
Insulin, Lipid, c-peptide 
Nt-proBNP 
cTnI 
Digoxinh 
CRP 
Sparse PKi 
Pregnancy Testingk 
Urine Biomarkers 
2 
4 
±5 
X 
X 
X 
X 
X 
X 
X 
X 
On Treatment 
3 
4 
5 
8 
12 
24 
±5 
±5 
±5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a. 
On visits without a scheduled complete physical examination, a symptom-driven physical examination may be performed if necessary 
Version 1.0 
6 
7 
36 
48 
q12 weeks1 
±5 
±5 
±5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
b. 
Vital signs include resting blood pressure, pulse, respiratory rate, temperattu·e and weight. Measurements of blood pressure should be taken per institutional guidelines. 
Sub· ect osition should be consistent for each subse uent measm·e 
I 
I 
e. 
f. 
is allowed 
eGFR value to be calculated by the Chronic Kidney Disease Epidemiology Creatinine Equation (2009) 
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g. 
Fit·st moming void collection is preferred when possible, but early moming void is accepted. Bring sample to clinic within 1 hour, if not possible, refrigerate and bring to 
clinic within 12 hours 
h. 
For subjects taking digoxin only, digoxin level should be meastu·ed at Visit C and Week 4. PI may continue checking after Week 4 as pait of digoxin management as needed. 
Monitor and adjust digoxin dose as necessa1y based on prescribing info1mation. 
1. 
S 
PK 
1 
h 
Id 
1 b 
11 t d £ 
d 
. d 
b' ts 
tt d dt 
I 
k. 
. 
. . 
. 
where possible, in between in clinic visits or in clinic. At home pregnancy testing kits will be provided. Females of childbearing-potential pe1fon11ing at home pregnancy 
testing will be contacted eveiy 4 weeks to repo1t the result of the at home pregnancy tests until the 30 Day EOT Follow-up visit. 
I. 
Repeat eveiy 12 weeks until global study end date. 
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Study Procedures Table – EOT to 30 Day EOS Safety Follow-up
Period
Visit
Week
EOTa
30 Day EOT 
Follow-upb
Limited 
Assessmentsc
EOSd
30 Day EOS 
Safety Follow-upe
Visit Window (days)
±7
±7
±7
±7
±7
Complete Physical Examinationf
X
Vital Signs including Weightg
X
X
X
Waist Circumference
X
12 Lead ECG
X
X
Adverse Events
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
Study Drug Dispensing
Study Drug Dosing
Clinical Assessments
Study Drug Bottle Return
X
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Period
Visit
Week
EOTa
30 Day EOT 
Follow-upb
Limited 
Assessmentsc
EOSd
30 Day EOS 
Safety Follow-upe
Visit Window (days)
±7
±7
±7
±7
±7
Subject Fastingj
eGFRk
X
X
X
X
Early Morning Void Urine ACR & Urinalysisl
X
X
X
Chemistry & Hematology
X
X
X
X
HbA1c
Blood Biomarkers
X
X
X
Blood Glucose
Insulin, Lipid, c-peptide
Nt-proBNP
cTnI
CRP
Sparse PKm
X
Pregnancy Testingn
X
X
X
Laboratory Assessments
Urine Biomarkers
X
X
X
a.
EOT assessments should be completed for subjects who meet criterion for study drug discontinuation in Protocol Section 3.4. These assessments should be completed as soon 
as possible after the decision is made. Every attempt should be made to keep the subject in the study to complete all remaining study visits for outcome assessment. If an ECG 
or STS was conducted at a previous visit within 24 weeks of the EOT visit, the assessment does not need to be performed at the EOT visit
b.
Subjects who permanently discontinue study drug must also return to clinic for a 30 Day EOT Follow-up visit 30 days (±7 days) after study drug discontinuation 
c.
Subjects who permanently discontinue study drug are encouraged to continue all study visits per schedule of procedures. However, if a subject requests limited assessments, 
they may perform these procedures every 12 weeks
d.
EOS assessments should be completed for subjects who meet criterion for study discontinuation in Protocol Section 3.5. If the subject discontinues study drug and 
discontinues from the study on the same day, assessments for EOT visit should be completed. The subject will still need to return to clinic 30 days (±7 days) for a 30 Day 
EOT Follow-up visit and complete the 30 Day EOS Safety Follow-up visit. 
e.
This visit may be conducted in clinic or via telephone 


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f. 
On visits without a scheduled complete physical examination, a symptom-driven physical examination may be performed if necessary 
Version 1.0 
g. 
Vital signs include resting blood pressure, pulse, respiratory rate, temperattu·e and weight. Measurements of blood pressure should be taken per institutional guidelines. 
Sub· ect osition should be consistent for each subse uent measm·e 
I 
I 
J. 
is allowed 
k. 
eGFR value to be calculated by the Chronic Kidney Disease Epidemiology Creatinine Equation (2009) 
I. 
Fit·st moming void collection is preferred when possible, but early moming void is accepted. Bring sample to clinic within I hotu·, if not possible, refrigerate and bring to 
clinic within 12 hours 
m. Sparse PK testing should be performed for all randomized subjects while on stt1dy dmg. Sparse PK testing does not need to be collected after study dmg is discontinued. 
n. 
Females of childbearing potential as defined by protocol only (refer to Protocol Appendix 6): Starting after Week 4, every 4 week pregnancy testing may occtu· at home where 
possible, in between in clinic visits, or in clinic. At home pregnancy testing kits will be provided. Females of childbearing potential perfomiing at home pregnancy testing will 
be contacted every 4 weeks to repo1t the result of the at home pregnancy tests m1til the 30 Day EOT Follow-up visit 
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Appendix 2.
Adjustment of On-Treatment eGFRcr Values 
For subjects in the SEL treatment group, the on-treatment eGFRcr values will be adjusted using a 
regression model. The statistical methods are described below. For subjects in the SEL treatment 
group whose off-treatment eGFRcr data are not collected, or who experience a decrease in eGFR 
of ≥ 40% relative to Baseline as a primary clinical endpoint event before treatment 
discontinuation, their eGFR values after treatment discontinuation will be imputed using a 
regression model. The statistical methods are described below.
The following linear regression model will be fitted for subjects in the SEL treatment group 
whose off-treatment eGFRcr values are collected in the study:
𝛿= 𝛼+ 𝛽𝑥+ 𝜖
Where δ is the change in eGFRcr values after treatment discontinuation defined as the first 
observed eGFRcr value at least 7 days after treatment discontinuation minus the last observed 
eGFRcr value before treatment discontinuation; x is the last observed eGFRcr value before 
treatment discontinuation, α is the intercept, β is the coefficient for x, and ϵ is the residual.
This model will then be used to predict the unobserved eGFRcr change after treatment 
discontinuation for subjects in the SEL treatment group. Specifically, the x term in the model is 
the observed eGFRcr value at each visit, and the outcome δ is the predicted eGFRcr change if 
subject hypothetically discontinue SEL treatment at each visit.
On-treatment eGFRcr values will then be as adjusted by adding δ to the observed eGFRcr values. 
These adjusted eGFRcr values will be used in the sensitivity analyses for primary and some 
secondary endpoints, as described in Sections 6.1.3 and 6.2.2.


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Appendix 3.
Prohibited Medications That May Impact SEL Treatment Efficacy or 
Decrease SEL Drug Level
Medication
Prohibited Period
Amiodarone
90 days prior to Enrollment through EOS
Bardoxolone 
2 weeks prior to Enrollment through EOS
Ranolazine 
2 weeks prior to Enrollment through EOS
Dronedarone
2 weeks prior to Enrollment through EOS
Dofetilide
2 weeks prior to Enrollment through EOS
Trimethoprim 
2 weeks prior to Enrollment through EOS
Isavuconazole 
2 weeks prior to Enrollment through EOS
Pyrimethamine 
2 weeks prior to Enrollment through EOS
Cimetidine
2 weeks prior to Enrollment through EOS
Famotidine
2 weeks prior to Enrollment through EOS
Phenobarbital
2 weeks prior to Enrollment through EOT
Phenytoin
2 weeks prior to Enrollment through EOT
Rifampin 
2 weeks prior to Enrollment through EOT
St. John’s wort 
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Appendix 4.
Data Collection of COVID-19 Data
This appendix describes the clinical trial site collection of COVID-19 data pertaining to 
missed/virtual visits and the data processing algorithm that will be used to determine which visits 
are missing and which visits are virtual.
Data Collection
A COVID-19 supplement to the eCRF Completion Guidelines (CCG) was provided by Clinical 
Data Management to instruct clinical trial sites with data entry expectations pertaining to 
scenarios related to the COVID-19 pandemic.  If a visit was missed, sites were instructed to enter 
“Visit missed due to COVID-19” and if an in-person visit was conducted virtually, sites were 
instructed to enter “Virtual visit due to COVID-19”.
Determination of Missed and Virtual Visits
Natural Language Processing (NLP) will be used to search the CRF comment fields to identify 
instances of “COVID-19”, “Virtual”, or synonyms (see Table 12-1).  The search terms will be 
maintained in a global lookup table and can be modified to tune the NLP model. Any comments 
with COVID-19 search terms, “Missed visit” or “Virtual visit” will be assigned as follows:
i)
If COVID-19 terms are identified through NLP and the visit date is missing, then result is 
“Missed Visit”
ii) If COVID-19 and Virtual terms are identified through NLP for a visit, then result is “Virtual 
Visit”. When there are multiple records for the same subject and the same visit, if one record 
could be categorized as “Virtual Visit”, all records associated with this subject and this visit 
will be categorized as “Virtual Visit”
iii) Otherwise result is missing
Table 12-1.
Example Search Terms for “COVID-19” and “Virtual” Used to 
Identify Missed/Virtual Visits.
Search Terms for “COVID-19”
Search Terms for “Virtual”
COVID19
CORONA
CORONAVIRUS
PANDEMIC
OUTBREAK
CRISIS
LOCKDOWN
QUARANTINE
SHELTER
VIRTUAL
TELEMED
TELEHEALTH
TELEPHONE
REMOTE
TELEMEDICINE 
TELECONSULTATION
TELEPHONICALLY
PHONE
HOME VISIT
ZOOM
SKYPE