A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition
Phase: PHASE2
Conditions: Chronic Kidney Diseases, Inflammation
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03926117 
Sponsor trial ID: 
NN6018-4779 
Official title of study: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Trial to Evaluate REduction in Inflammation in PatientS with 
advanced Chronic Renal Disease Utilizing Antibody MEdiated 
IL-6 inhibition (RESCUE) 
Document date 
23 December 2019 
 
 

A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
Amendment No. 5
Corvidia Therapeutics Inc.  
 
Page 1 of 142 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial to 
Evaluate REduction in Inflammation in PatientS with advanced 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition 
(RESCUE) 
DRUG NAME: 
Ziltivekimab (human monoclonal antibody to IL-6) 
PROTOCOL 
NUMBER: 
COR-001-02 
PHASE: 
2 
IND: 
140,097 
TRIAL SPONSOR: 
Corvidia Therapeutics Inc. 
35 Gatehouse Drive 
Waltham MA 02451 
MEDICAL 
MONITOR: 
 
 
Corvidia Therapeutics Inc. 
Phone: 
 
Email:
 
DOCUMENT DATES: Original: 05 November 2018 
Protocol Amendment 1: 05 December 2018 
Protocol Amendment 2: 24 January 2019 
Protocol Amendment 3: 16 April 2019 
Protocol Amendment 4: 25 June 2019 
Protocol Amendment 5: 23 December 2019 
Confidentiality Statement 
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Redacted protocol 
Includes redaction of personal identifiable information only. 
. 

A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 2 of 142 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “A Phase 2, Randomized, Double-Blind, 
Placebo-Controlled Trial to Evaluate REduction in Inflammation in PatientS with 
advanced Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition 
(RESCUE)” and agree to abide by all provisions set forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable Food and Drug Administration 
(FDA) regulations/guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312 and all locally 
applicable laws. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation without 
the prior written consent of Corvidia Therapeutics Inc. 
 
 
 
 
 
Signature of Principal Investigator 
 
 
 
 
 
Name of Principal Investigator (Print) 
 
Date (DD Month YYYY) 
 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 4 of 142 
TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT .........................................................................................2 
SPONSOR APPROVAL PAGE ................................................................................................3 
TABLE OF CONTENTS ...........................................................................................................4 
LIST OF TABLES .....................................................................................................................9 
LIST OF FIGURES .................................................................................................................10 
PROTOCOL SYNOPSIS ........................................................................................................11 
LIST OF ABBREVIATIONS, DEFINITIONS AND TERMS ...............................................22 
1 
INTRODUCTION .................................................................................................26 
1.1 
Background ......................................................................................................26 
1.1.1 
Atherosclerotic Cardiovascular Disease (ASCVD) in Patients with 
CKD .....................................................................................................26 
1.1.1.1 
Study of Heart and Renal Protection (SHARP) ..........................26 
1.1.1.2 
CANTOS (Canakinumab Anti-inflammatory Thrombosis 
Outcome Study) ..........................................................................27 
1.1.1.3 
CANTOS hs-CRP Threshold Analysis .......................................27 
1.1.1.4 
CANTOS Patients with Moderate CKD .....................................28 
1.1.1.5 
Modulation of the interleukin-6 signaling pathway and 
incidence rates of atherosclerotic events and all-cause 
mortality in CANTOS .................................................................28 
1.1.2 
Congestive Heart Failure, Primarily Heart Failure with Preserved 
Ejection Fraction (HFpEF) ..................................................................29 
1.1.3 
Functional Iron Deficiency (the Anemia of Chronic Disease) ............31 
1.1.4 
Malnutrition-Inflammation-Cachexia Syndrome including 
hypoalbuminemia .................................................................................32 
1.2 
Description of Ziltivekimab .............................................................................33 
1.3 
Summary of Relevant Nonclinical Experience with Ziltivekimab ..................34 
1.4 
Summary of Relevant Clinical Experience with Ziltivekimab ........................34 
1.4.1 
Phase 1 Study in Rheumatoid Arthritis Patients (D4430C00001) .......34 
1.4.2 
Phase 1 Study in Patients with CKD (COR-001-SC1) ........................35 
1.4.3 
Phase 1/2 Study in CKD Patients on Hemodialysis (COR-001-01) ....36 
1.4.4 
Conclusions on Ziltivekimab Treatment of Anemia in CKD ..............38 
2 
STUDY GOAL AND OBJECTIVES ....................................................................39 
2.1 
Primary objective: ............................................................................................39 
2.2 
Secondary objectives: ......................................................................................39 
2.3 
Pharmacokinetic objectives: ............................................................................39 
2.4 
Safety objectives: .............................................................................................39 
2.5 
Exploratory objectives: ....................................................................................39 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 5 of 142 
3 
INVESTIGATIONAL PLAN ................................................................................41 
3.1 
Overall Study Design and Plan: Description ...................................................41 
3.1.1 
Pharmacokinetic and PK-PD Modeling ...............................................41 
3.1.2 
Safety Endpoints ..................................................................................42 
3.1.3 
Pharmacodynamic Endpoints ...............................................................42 
3.1.3.1 
Primary ........................................................................................42 
3.1.3.2 
Secondary ....................................................................................42 
3.1.3.3 
Exploratory .................................................................................43 
3.2 
Study Schematic...............................................................................................46 
3.3 
Blinding and Randomization ...........................................................................46 
3.3.1 
Randomization .....................................................................................46 
3.3.2 
Blinding................................................................................................46 
3.3.3 
Unblinding ...........................................................................................46 
3.4 
Duration of the Study ......................................................................................47 
3.5 
Discussion of Study Design, Including Choice of Control Arm .....................47 
3.5.1 
Study Population and Control Arm......................................................47 
3.5.2 
Rationale for Dosing and Length of Safety Evaluation .......................47 
3.5.3 
Rationale for the Efficacy Endpoints ...................................................48 
3.5.4 
Rationale for the Dose Regimens ........................................................49 
3.5.4.1 
Pharmacokinetic modeling..........................................................50 
3.5.4.2 
Correspondence of proposed doses to those used in prior 
clinical studies.............................................................................50 
3.5.4.3 
Exposure for proposed doses relative to IL-6 binding ................51 
3.5.4.4 
Exposures for proposed doses relative to the exposures at 
NOAEL dose in the toxicology study .........................................51 
3.5.4.5 
Exposures for proposed doses relative to the exposures 
associated with clinically meaningful PD changes in prior 
clinical studies.............................................................................51 
3.6 
Safety Plan and Monitoring .............................................................................52 
3.7 
Benefit and Risk Assessment ...........................................................................52 
4 
SELECTION OF STUDY POPULATION AND CRITERIA FOR 
WITHDRAWAL....................................................................................................53 
4.1 
Inclusion Criteria .............................................................................................53 
4.2 
Exclusion Criteria ............................................................................................53 
4.3 
Criteria for Discontinuation of Study Drug .....................................................56 
4.4 
Anaphylaxis Study Stopping Rule ...................................................................56 
4.5 
Temporary Discontinuation of Study Intervention ..........................................57 
4.6 
Participant Discontinuation/Withdrawal from the Study .................................57 
4.7 
Lost-to-Follow-up ............................................................................................58 
4.8 
Study Completion ............................................................................................58 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 6 of 142 
5 
ENROLLMENT AND STUDY PROCEDURES .................................................59 
5.1 
Screening Visit Procedures (Up to 2 weeks, Days -14 to -7) – Initial 
Screening..........................................................................................................63 
5.2 
Screening Visit Procedures (Week -1; Days -7 to -1) – Full Screening ..........63 
5.3 
Treatment Period (Study Weeks 1 - 21) ..........................................................64 
5.3.1 
Visit 1, Week 1, Day 1 (Pre-Dose) ......................................................64 
5.3.2 
Visit 1, Week 1, Day 1 (Dosing/Post-Dose) ........................................65 
5.3.3 
Visit 2, Week 2, Day 8 .........................................................................66 
5.3.4 
Visit 3, Week 4, Day 22 .......................................................................66 
5.3.5 
Visit 4, Week 5 ....................................................................................66 
5.3.6 
Visit 5, Week 7 ....................................................................................67 
5.3.7 
Visits 6 through 9, Weeks 9 through 21 ..............................................67 
5.3.8 
Visits 6 through 9, Weeks 9 through Week 21 (Dosing/Post-Dose) ...69 
5.3.9 
Visit 10, Week 23 and Visit 11, Week 24/ET......................................69 
5.4 
Safety Follow-Up Visits 12 and 13 Procedures (Study Weeks 28 and 32) .....70 
5.5 
Unscheduled Visit ............................................................................................70 
5.6 
Early Termination Visit ...................................................................................71 
6 
DRUG SUPPLIES AND DOSING .......................................................................72 
6.1.1 
Dosing and Administration ..................................................................72 
6.1.2 
Storage .................................................................................................73 
6.1.3 
Formulation and Packaging .................................................................73 
6.2 
Drug Accountability and Compliance .............................................................74 
7 
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS ..........75 
7.1 
Prior Medications and Treatments ...................................................................75 
7.2 
Concomitant Medications and Treatments ......................................................75 
8 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS .......................................76 
8.1 
Serious Infections.............................................................................................76 
8.2 
Injection-Related Reactions, Hypersensitivity, and Anaphylaxis....................76 
9 
ADVERSE EVENT REPORTING........................................................................77 
9.1 
Adverse Event Definitions ...............................................................................77 
9.2 
Serious Adverse Event Definition ...................................................................78 
9.3 
Adverse Events of Special Interest ..................................................................79 
9.4 
Assessment of Causal Relationship .................................................................79 
9.5 
Assessment of Severity ....................................................................................80 
9.6 
Adverse Event Reporting .................................................................................80 
9.7 
Reporting of Serious Adverse Events and Adverse Events of Special 
Interest..............................................................................................................81 
9.8 
Pregnancy Reporting ........................................................................................82 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 7 of 142 
10 
STUDY ASSESSMENTS .....................................................................................83 
10.1 
Pharmacodynamic Assessments ......................................................................83 
10.1.1 
CKD symptoms, Fatigue, and Health-Related Quality of Life ............83 
10.1.2 
Laboratory Assessments ......................................................................83 
10.2 
Safety Assessments (other than Adverse Events) ............................................83 
10.2.1 
Vital Signs ............................................................................................83 
10.2.2 
12-lead ECG.........................................................................................83 
10.2.3 
Physical Examination...........................................................................84 
10.2.4 
Clinical Laboratory Testing .................................................................84 
11 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ........................85 
11.1 
Sample Size ......................................................................................................85 
11.2 
Randomization .................................................................................................85 
11.3 
General Statistical Considerations and Definitions .........................................85 
11.3.1 
General Statistical Methods .................................................................85 
11.3.2 
Analysis Populations ............................................................................85 
11.3.3 
Analysis Windows and Baseline ..........................................................86 
11.3.4 
Missing Data Handling ........................................................................86 
11.4 
Statistical Analyses ..........................................................................................86 
11.4.1 
Demographic and Background Characteristics ....................................86 
11.4.2 
Study Drug and Concomitant Medications ..........................................86 
11.4.3 
Efficacy Analysis .................................................................................87 
11.4.4 
Efficacy Variables ................................................................................87 
11.4.4.1 
Primary ........................................................................................88 
11.4.4.2 
Secondary ....................................................................................88 
11.4.4.3 
Exploratory .................................................................................88 
11.4.4.4 
Multiple Comparisons Procedure for Primary Efficacy and 
Secondary Endpoints ..................................................................93 
11.4.5 
Safety Analysis ....................................................................................93 
11.4.5.1 
Adverse Events ...........................................................................93 
11.4.5.2 
Laboratory Tests .........................................................................94 
11.4.5.3 
Vital Signs ...................................................................................94 
11.4.5.4 
12-lead ECG................................................................................95 
11.4.5.5 
Physical Examination..................................................................96 
11.4.5.6 
Antibodies to Ziltivekimab .........................................................96 
11.4.5.7 
Bleeding Events ..........................................................................96 
11.4.6 
Pharmacokinetic Analysis and Pharmacokinetic/Pharmacodynamic 
Analysis................................................................................................96 
11.4.6.1 
Pharmacokinetic Data .................................................................96 
11.4.6.2 
Pharmacokinetic/Pharmacodynamic Analysis ............................97 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 8 of 142 
11.4.7 
Exploratory Analyses of Efficacy and Safety Endpoints Based on 
Baseline Hemoglobin (≥11 or <11 g/dL). ............................................97 
11.5 
Interim Analyses ..............................................................................................97 
12 
STUDY COMMITTEES .......................................................................................98 
12.1 
Clinical Events Committee ..............................................................................98 
12.2 
Safety Assessment Committee (SAC) .............................................................98 
13 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS .....................99 
13.1 
Institutional Review Board or Independent Ethics Committee .......................99 
13.2 
Informed Consent.............................................................................................99 
13.3 
Supplementary Documentation ........................................................................99 
13.4 
Data Reporting and Case Report Forms ........................................................100 
13.5 
Retention of Data ...........................................................................................100 
13.6 
Deviation from the Protocol...........................................................................100 
13.7 
Study Monitoring ...........................................................................................101 
13.8 
Drug Accountability.......................................................................................101 
13.9 
Disclosure of Data..........................................................................................101 
14 
REFERENCES ....................................................................................................102 
15 
APPENDICES .....................................................................................................109 
15.1 
Appendix A Exclusionary Drugs ...................................................................109 
15.2 
Appendix B PROMIS® (Patient-Reported Outcomes Measurement 
Information System) ......................................................................................110 
15.3 
Appendix C Optum SF-36 v2® Health Survey .............................................112 
15.4 
Appendix D Corvidia ePRO ..........................................................................116 
15.5 
Appendix E PGIS and PGIC ..........................................................................137 
15.6 
Appendix F EurQol-5D-5L (EQ-5D-5L) .......................................................139 
15.7 
Appendix G Guidance on Contraception .......................................................141 
 
 
 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 9 of 142 
LIST OF TABLES 
Table 1 
Summary of IV doses used in Study COR-001-01 with SC doses that 
represent corresponding exposure..............................................................51 
Table 2 
SCHEDULE OF PROCEDURES..............................................................60 
Table 3 
Planned Ziltivekimab Doses and Administered Volumes .........................73 
Table 4 
Composition for Ziltivekimab for Injection, Amount per mL (7.5 
mg/Vial, 15 mg/Vial, 30 mg/Vial, and Placebo) .......................................73 
Table 5 
Severity Assessment for AEs and Abnormal Laboratory Values ..............80 
Table 6 
Pre-defined Threshold Value for Vital Signs .............................................95 
Table 7 
Pre-defined Threshold Value for ECG ......................................................95 
Table 8 
TIMI Bleeding Classification ....................................................................96 
 
 
 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 10 of 142 
LIST OF FIGURES 
Figure 1 
A conceptual framework of contributors to the cardiovascular disease 
burden in patients with advancing CKD ....................................................30 
Figure 2 
A model for the influence of genetic variation on IL-6 –mediated 
cellular iron handling .................................................................................34 
Figure 3 
Percentage of CKD patients treated with Ziltivekimab or Placebo who 
achieved an hs-CRP level of < 2.0 mg/L from Baseline to Week 32 ........35 
Figure 4 
Ziltivekimab causes Dose-Dependent Decreases in hs-CRP from 
Baseline in ESRD Patients .........................................................................37 
Figure 5 
Study Flow .................................................................................................46 
 
 
 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 11 of 142 
PROTOCOL SYNOPSIS 
Title 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial to 
Evaluate REduction in Inflammation in PatientS with advanced 
Chronic Renal Disease Utilizing Antibody MEdiated IL6 
Inhibition (RESCUE) 
Study Number 
COR-001-02 
Study Phase 
2 
Objectives 
Patients with non-dialysis-dependent chronic kidney disease (NDD-
CKD), who have evidence of systemic inflammation with increased 
cardiovascular risk, will be enrolled into this trial. The purpose of 
this trial is to determine a dose to select for a potential 
cardiovascular outcome trial with Ziltivekimab. 
Primary objective: 
x 
To evaluate the effects of Ziltivekimab compared to placebo on 
markers of inflammation (i.e. high-sensitivity C-reactive protein 
[hs-CRP]). 
Secondary objectives: 
x 
To evaluate the effects of Ziltivekimab compared to placebo on 
markers of inflammation and cardiovascular risk: serum 
amyloid A (SAA) and fibrinogen. 
Pharmacokinetic objectives: 
x 
To evaluate the pharmacokinetics (PK) and PK-
Pharmacodynamic (PK-PD) modeling of Ziltivekimab following 
multiple doses at three different levels. 
Safety objectives: 
x 
To evaluate the safety of three dose levels of Ziltivekimab 
compared to placebo. 
Exploratory objectives:   
x 
To evaluate the effects of Ziltivekimab compared to placebo on 
markers of anemia (hemoglobin). 
x 
To evaluate the effects of Ziltivekimab compared to placebo on 
markers of inflammation-malnutrition (i.e. albumin). 
x 
To evaluate the effects of Ziltivekimab compared to placebo on 
markers of cardiovascular risk (i.e. N-terminal prohormone-B-
type natriuretic peptide [NT-pro-BNP]). 
x 
To evaluate the effects of Ziltivekimab compared to placebo on 
additional markers of cardiovascular risk (suppression of 
tumorigenicity 2 [ST2]). 
x 
To evaluate the effects of Ziltivekimab compared to placebo on 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 12 of 142 
markers of atherosclerosis risk: LDL-C, triglycerides, ApoB, 
ApoA1, ApoB/ApoA1, lipid profile by nuclear magnetic 
resonance (NMR) spectroscopy, and Lp(a).  
x 
To evaluate the effects of Ziltivekimab compared to placebo on 
markers of kidney function, (i.e. cystatin C, estimated GFR) and 
kidney damage, (i.e. urine albumin-to-creatinine ratio [UACR]). 
x 
To evaluate the effects of three dose levels of Ziltivekimab 
compared to placebo on patient reported outcomes (PRO): 
Patient-Reported Outcomes Measurement Information System 
(PROMIS®) Fatigue 13a short form, selected items from the 
PROMIS fatigue item bank, the Optum SF-36 v2® Health 
Survey, a Corvidia PRO, the PROMIS interest in sexual activity 
item, the patient global impression of change (PGIC), patient 
global impression of severity (PGIS), and the EQ-5D-5L.  
x 
To evaluate the psychometric properties of the PROMIS Fatigue 
13a short form and selected items from the PROMIS fatigue item 
bank, and the Corvidia electronic PRO (ePRO) items in CKD 
patients. 
x 
To evaluate the effects of Ziltivekimab on systemic iron 
availability:  transferrin saturation (TSAT), reticulocyte 
hemoglobin content (CHr) and total iron binding capacity 
(TIBC), systemic iron stores (serum ferritin), serum iron and 
systemic iron regulation (serum hepcidin). 
x 
To evaluate the effects of Ziltivekimab compared to placebo on 
markers of cardiovascular risk (i.e. NT-pro-BNP) in patients with 
baseline NT-pro-BNP > 250 pg/mL. 
x 
To evaluate the effects of Ziltivekimab compared to placebo on 
markers of anemia in patients with baseline hemoglobin < 11 
g/dL.  
x 
To evaluate the effects of Ziltivekimab compared to placebo on 
markers of inflammation-malnutrition (i.e. albumin) in patients 
with baseline albumin < 4.0 g/dL. 
Study Design 
This is a randomized, double-blind, placebo-controlled trial designed 
to evaluate the efficacy, safety, and pharmacokinetics of Ziltivekimab 
at three dose levels (7.5 mg, 15 mg or 30 mg) compared to placebo in 
patients with stage 3-5 CKD, not on dialysis, who have evidence of 
inflammation with high cardiovascular risk.  
Patients will undergo a Screening Period of up to 14-days during 
which inclusion and exclusion criteria will be evaluated. Patients 
who meet all inclusion criteria and no exclusion criteria will be 
randomized to one of three Ziltivekimab dose levels (7.5 mg, 15 mg 
or 30 mg) or placebo for a 24-week Treatment Period. Patient 
randomization will be stratified by baseline hemoglobin (≥11 or <11 
g/dL) and CKD stage (3, 4 or 5).  
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
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Page 13 of 142 
Approximately 240 patients will be randomized 1:1:1:1 (60 per 
group) into the trial. All patients must meet the inclusion/exclusion 
criteria. After the Screening Period, randomized patients will be 
dosed every 28 days out to Week 21. The primary, secondary and 
exploratory endpoints will be analyzed after 13 weeks of treatment 
and then followed for additional exploratory efficacy analyses 
through Week 24. Selected efficacy endpoints and safety 
assessments will evaluated in the Follow-up Period Week 25 though 
Week 32 (Figure 5). 
The patient will be randomized on Day 1 and the first dose of study 
drug should be administered after all assessments are conducted.  
Doses of study drug will be administered every 28-days for a total of 
6 treatments (Weeks 1, 5, 9, 13, 17, and 21). Study visits will follow 
the schedule of events (Table 2). 
Study Periods: 
The study will consist of three periods:  Screening, Treatment 
Period, and Safety Follow-Up Period. The total study duration for an 
individual patient will be approximately 8-9 months. 
Screening Period: up to 2 weeks [Days -14 to -1]  
x 
Starts with the first date that Initial Screening procedures 
were performed. The first procedure also defines the initial 
screening visit date 
Treatment Period: 24 weeks [Week 1, Day 1 through Week 24 
x 
Starts with the first administration of study 
drug/randomization (Day 1) 
Safety Follow-Up Period: 8 weeks [Weeks 25 through 32] 
x 
Safety period starts 4-weeks after last treatment dose 6. 
Inclusion Criteria: 
After signing an informed consent form approved by the 
Investigator’s Institutional Review Board (IRB) or Independent 
Ethics Committee (IC) to be eligible, potential study patients must 
meet all of the following criteria: 
1) Age ≥18 years at the time of signing of the Informed Consent 
Form (ICF).   
2) Stage 3-5 NDD-CKD, i.e. estimated glomerular filtration rate 
(eGFR) >10 and <60 mL/min/1.73 m2 using the CKD-EPI 
Creatinine Equation (www.kidney.org/content/ckd-epi-creatinine-
equation-2009).  
3) Serum hs-CRP level t2.0 mg/L measured during the Screening 
Period. (Note: Targeting patients with a history of advanced stage 
CKD, atherosclerotic cardiovascular disease, anemia, metabolic 
syndrome, diabetic retinopathy and diabetes for screening will help 
increase the chances of identifying patients with CRP ≥2.0) 
4) The patient agrees to comply with the contraception and 
reproduction restrictions of the study (Appendix G): 
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a) Women of childbearing potential must be using a method of 
contraception, that is “highly effective” (i.e., <1% failure 
rate) for at least 3 months following the last dose of study 
drug; 
b) Postmenopausal women must have had no menstrual bleeding 
for at least 1 year before initial dosing and either be over the 
age of 60-years or have an elevated plasma follicle-
stimulating hormone (FSH) level (i.e., >40 mIU/mL) at 
Screening; 
c) Women of childbearing potential must have a documented 
negative pregnancy test result at Screening. Patients with 
elevated β-HCG levels believed to be due to end-stage renal 
disease may be enrolled if documented to not be pregnant; 
AND 
d) All male patients, from the day of dosing until the final study 
visit, unless surgically sterile, must be willing to use a 
condom with a partner (male patients with partners of 
childbearing potential must be willing to use 2 effective 
methods of birth control, 1 should be condom with 
spermicide) to prevent pregnancy and drug exposure of a 
partner, and refrain from donating sperm or fathering a child. 
Exclusion Criteria: 
Participants are excluded from the study if any of the following 
criteria apply: 
Laboratory Values 
1. 
Absolute neutrophil count <2.0 x 109/L during screening. 
2. 
Platelet count <120 x 109/L during screening. 
3. 
Spot urine protein to creatinine ratio >4000 mg/g, or 4.0 
g/g. 
4. 
Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >2.5x ULN during screening. 
5. 
Positive testing for tuberculosis (TB) during screening. 
Blood testing (e.g., QuantiFERON) is preferred but a 
purified protein derivative (PPD) skin test read within 
48-72 hours by a qualified healthcare professional may 
also be performed. If a patient is PPD positive but 
QuantiFERON negative the patient is eligible.  
6. 
Evidence of human immunodeficiency virus-1 (HIV-1) 
or HIV-2 infection by serology measured during 
screening. 
7. 
Hepatitis B or C by serology (e.g. hepatitis B surface 
antigen or hepatitis C antibody positive) measured during 
screening. 
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Medical Conditions or Diseases 
8. 
Expected to require blood transfusion within 12-weeks 
post-randomization. 
9. 
Thromboembolic event within 12-weeks prior to 
randomization. 
10. 
Clinical evidence or suspicion of active infection. 
11. 
History of peptic ulcer disease or gastrointestinal 
ulceration in the 12-months prior to randomization. 
12. 
History of active diverticulitis in the 12-months prior to 
randomization. 
13. 
History of inflammatory bowel disease that has been 
clinically active during the 12-months prior to 
randomization. 
14. 
Uncontrolled hypertension (defined as an average SBP 
>160 mmHg or an average diastolic blood pressure 
(DBP) >100 mmHg during screening.  Patients may be 
re-evaluated within 2 weeks, at the discretion of the 
investigator for this criterion if anti-hypertensive therapy 
has been started or increased as a result of initial 
screening blood pressure being above these limits. 
15. 
Planned coronary revascularization (PCI or CABG) or 
any other major surgical procedure. 
16. 
Major cardiac surgical, non-cardiac surgical or major 
endoscopic procedure within the past 6 months prior to 
Randomization. 
17. 
History of New York Heart Association Class IV 
congestive heart failure within 12-weeks prior to 
randomization. 
18. 
Actively treated or active malignancy during the 1-year 
prior to randomization with the exception of successfully 
treated nonmetastatic basal cell or squamous cell 
carcinomas of the skin and/or local carcinoma in situ of 
the cervix. 
19. 
History of bone marrow or solid organ transplant or 
anticipated to receive an organ transplant during the time 
frame of the study. 
20. 
Known allergy to the study drug or any of its ingredients. 
Prior or Current Medications 
21. 
Received an investigational drug within 30-days prior to 
screening visit. 
22. 
Received a live vaccine product within 14 days of study 
drug administration (Day 1) or expect to receive live 
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vaccine during the Treatment Period (receiving a live 
vaccine within 14 days prior to enrollment is allowed). 
23. 
Treatment with a hypoxia-inducible factor (HIF) 
stabilizer (e.g., molidustat, roxadustat) or an 
erythropoietin-mimetic, e.g., erythropoietin alpha or 
beta, darbopoietin alpha, or continuous erythropoiesis 
receptor activator (CERA), within 6-weeks prior to 
randomization or during treatment period. 
24. 
Expected to receive any investigational drug or any of the 
exclusionary drugs listed in Section 15.1 during the 
Treatment Period or Safety Follow-Up Period. 
25. 
Chronic use of systemic immunosuppressive drugs 
during the screening period or anticipated use of such 
drugs any time during the study. Note: Use of otic, 
ophthalmic, inhaled, and topical corticosteroids or local 
corticosteroid injections are not exclusionary. Oral 
prednisone up to 5 mg per day is (or equivalent) is 
permitted if dose has been stable for at least 4 weeks 
prior to screening, and no dose changes are planned 
during study participation. 
26. 
Use of systemic antibiotics, systemic antivirals, or 
systemic antifungals during the screening period 
(“Systemic” is defined as oral or intravenous drugs that 
are absorbed into the circulation). 
27. 
Requiring an indwelling catheter of any type. 
General Exclusions 
28. 
Currently breastfeeding. 
29. 
Any condition that could interfere with, or for which the 
treatment might interfere with, the conduct of the study 
or interpretation of the study results, or that would in the 
opinion of the investigator increase the risk of 
participating in the study. 
Test Product, Dose and 
Mode of 
Administration 
The test product dose regimens to be examined in this study are:  
x Dose #1: Ziltivekimab, 7.5 mg per injection, administered 6 times 
(every 28-days) on Weeks 1, 5, 9, 13, 17, and 21, as a 
subcutaneous injection. 
x Dose #2: Ziltivekimab, 15 mg per injection, administered 6 times 
(every 28-days) on Weeks 1, 5, 9, 13, 17, and 21, as a 
subcutaneous injection. 
x Dose #3: Ziltivekimab, 30 mg per injection, administered 6 times 
(every 28-days) on Weeks 1, 5, 9, 13, 17, and 21, as a 
subcutaneous injection. 
Patients should receive 6 injections of their assigned dose during the 
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trial.  The total cumulative dosage will be 45 mg for those patients 
randomized to 7.5 mg per injection, 90 mg for those patients 
randomized to 15 mg per injection, and 180 mg for those patients 
randomized to 30 mg per injection. 
Reference Therapy, 
Dose, and Mode of 
Administration 
The reference dose regimens to be examined in this study are: 
x Matched placebo injections administered subcutaneously 6 times 
(every 28 days) at the same frequency as the active treatment in a 
given dose cohort, on Weeks 1, 5, 9, 13, 17 and 21. 
Pharmacokinetics and 
PK-PD Modeling: 
x Serum trough levels (Cmin) of Ziltivekimab will be measured at all 
visits. On dosing Weeks 1, 5, 9, 13, 17, and 21, trough PK 
samples to be collected within approximately -0.5 h pre-dose. 
Single PK blood samples will also be collected on Weeks 2, 4, 7, 
23, 24/ET, 28, and 32/ET around the same time as the pre-dose 
samples were collected on previous dosing visits. 
x The total IL-6 AUC will be described. 
x The relationship between trough Ziltivekimab levels and primary 
pharmacodynamic endpoints, specifically total plasma IL-6 and 
hs-CRP, will be described. 
Safety Endpoints: 
 
x Proportion of patients with AEs, SAEs, severe hematologic AEs, 
severe non-hematologic AEs, and AEs leading to discontinuation. 
x Proportion of subjects with thrombolysis in myocardial infarction 
(TIMI) major bleeding event. 
x Description and frequency of events of special interest by 
treatment group: 
o 
Serious infections. 
o 
Severe injection-related reactions. 
o 
Gastrointestinal perforations. 
o 
Hypersensitivity reaction during study drug administration.  
o 
Anaphylaxis occurring at any time, even if considered 
unrelated to the study drug. A CRF for the collection of the 
details of such reactions will be available in the electronic 
data capture (EDC) system. 
o 
Neutrophil <500/mm3 (severe), or neutrophil <1000/mm3 
(severe) with evidence of concurrent infection. These events 
will be separately summarized by treatment group and dose. 
o 
Thrombocytopenia (platelet count <50,000/mm3 [severe]) or 
platelet count <75,000/mm3 (moderate) with evidence of 
concurrent TIMI major bleeding. These events will be 
separately summarized by treatment group and dose. 
o 
Malignancies. 
x Description of additional safety assessments by treatment group 
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and dose: vital signs, electrocardiogram (ECG), clinical 
laboratory, and anti-drug antibodies (binding and neutralizing). 
Primary Endpoint: 
x Difference in percent change in hs-CRP levels from Baseline 
(average of the hs-CRP value prior to randomization and Day 1) 
to Week 13 between each active group and placebo. 
Secondary Endpoints: 
 
x Difference in change in SAA from Baseline to Week 13 between 
each active group and placebo. 
x Difference in percent change in fibrinogen from Baseline to 
Week 13 between each active group and placebo. 
Exploratory 
Endpoints: 
 
x Difference in change in SAA from Baseline to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in percent change in fibrinogen from Baseline to End 
of Treatment (Week 24) between each active group and placebo. 
x Difference in percent change in hs-CRP levels from Baseline to 
End of Treatment (Weeks 23 through 24) between each active 
group and placebo. 
x Difference in percent change in serum NT-pro-BNP from 
Baseline (average of the NT-pro-BNP value prior to 
randomization and Day 1) to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in change in hemoglobin from Baseline (average of 
the two most recent hemoglobin values prior to randomization 
and Day 1) to Week 13 and to End of Treatment (Weeks 23 
through 24) between each active group and placebo. 
x Difference in change in serum albumin from Baseline (average 
of the two most recent serum albumin values prior to 
randomization and Day 1) to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Proportion of patients achieving hs-CRP response at Week 13 
and to End of Treatment (Weeks 23 through 24), defined as hs-
CRP <2.0 mg/L in each active group and placebo. 
x Difference in change in ST2 from Baseline to Week 13 and to 
End of Treatment (Week 24) between each active group and 
placebo. 
x Difference in percent change in Lp(a) from Baseline to Week 13 
and to End of Treatment (Weeks 23 through 24) between each 
active group and placebo. 
x Difference in percent change in LDL-C, triglycerides, ApoB, 
ApoA1, ApoB/ApoA1, and lipid profile by NMR spectroscopy 
from Baseline to Week 13 and to End of Treatment (Weeks 23 
through 24) between each active group and placebo. 
x Difference in change of creatinine based eGFR and cystatin C-
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based eGFR from Baseline to Week 13 and to the End of 
Treatment (Weeks 23 through 24) between each active group 
and placebo. 
x Difference in change of UACR from Baseline to Week 13 and to 
End of Treatment (Weeks 23 through 24) between each active 
group and placebo. 
x Difference in change of the total fatigue score (PROMIS Fatigue 
13a short form and selected items from the PROMIS Fatigue 
item bank) from Baseline to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in change of the PROMIS interest in sexual activity 
item from Baseline to Week 13 and to End of Treatment (Week 
24) between each active group and placebo. 
x Difference in change of the Corvidia ePRO items from Baseline 
to Week 12 and to End of Treatment (Weeks 23 through 24) 
between each active group and placebo. 
x Difference in change of the PGIS index from Baseline to Week 
12 and to End of Treatment (Week 24) between each active 
group and placebo. 
x Descriptive analyses of the PGIC index at Weeks 5, 13 and End 
of Treatment (Week 24) in each active group and placebo. 
x Difference in change of the Optum SF-36 v2® Health Survey 
physical component summary (PCS), mental component 
summary (MCS) and domain scores from baseline to Week 13 
and to End of Treatment (Weeks 23 through 24) between each 
active group and placebo. 
x Difference in change of the EQ-5D-5L index from Baseline to 
Week 12 and to End of Treatment (Week 24) between each 
active group and placebo. 
x Evaluation of the psychometric properties of the PROMIS Fatigue 
13a short form and selected items from the PROMIS Fatigue item 
bank and the Corvidia ePRO items in CKD patients – to be 
described in a PRO psychometric analysis plan. 
x Descriptive analyses by dose and treatment may be conducted on 
samples stored for analysis of exploratory biomarkers, genomic 
and transcriptomic analysis. 
x Difference in change in TSAT from Baseline to peak level, Week 
13 and End of Treatment (Weeks 23 through 24), between each 
active group and placebo. 
x Difference in change in CHr from Baseline to peak level, Week 
13 and to End of Treatment (Week 24) between each active group 
and placebo. 
x Difference in change in TIBC from Baseline to Week 13 and to 
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End of Treatment (Weeks 23 through 24) between each active 
group and placebo. 
x Difference in change in serum ferritin from Baseline to Week 13 
and to End of Treatment (Weeks 23 through 24) between each 
active group and placebo. 
x Difference in change in serum iron from Baseline to Week 13 and 
to End of Treatment (Weeks 23 through 24) between each active 
group and placebo. 
x Difference in change in serum hepcidin from Baseline to Week 13 
and to End of Treatment (Week 24) between each active group 
and placebo. 
x Difference in percent change in serum NT-pro-BNP from 
Baseline to Week 13 and to End of Treatment (Weeks 23 through 
24) between each active group and placebo in patients with 
baseline NT-pro-BNP > 250 pg/mL. 
x Difference in change in hemoglobin from Baseline (average of the 
two most recent hemoglobin values prior to randomization and 
Day 1) to Week 13 and to End of Treatment (Weeks 23 through 
24) between each active group and placebo in patients with 
baseline hemoglobin < 11 g/dL. 
x Difference in change in serum albumin from Baseline (average of 
the two most recent serum albumin values prior to randomization 
and Day 1) to Week 13 and to End of Treatment (Weeks 23 
through 24) between each active group and placebo in patients 
with baseline albumin < 4.0 g/dL. 
Sample Size 
Approximately 240 (60 per group). 
Statistical Methods 
Analysis 
The following analysis Populations are defined for the different types 
of data analysis: 
x 
Intent-to-treat (ITT) analysis population: all patients randomized. 
x 
Per-protocol (PP) analysis population: all patients randomized 
who completed the study and did not incur a significant protocol 
violation. 
x 
Pharmacokinetics (PK) analysis population: all patients 
randomized and who received at least one dose of Test or 
Reference product and who had at least one post-dose PK blood 
sample. 
x 
Safety analysis population: all patients randomized and who 
received at least one dose of Test or Reference product. 
All study-collected data will be summarized by treatment group for 
the appropriate analysis population, using descriptive statistics, 
graphs, and/or raw data listings. Descriptive statistics for continuous 
variables will include number of patients (n), mean, standard 
deviation (SD), median, quartiles (Q1 and Q3), minimum (min) and 
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maximum (max) values for the observed value and change from 
baseline will be reported. Analysis of categorical variables will 
include frequency and percentage. 
For efficacy variables, the difference between each active group and 
placebo will be presented. A mixed model for repeated measures 
(MMRM) will be used for this purpose, with baseline hemoglobin 
(≥11 or <11 g/dL), CKD stage (3, 4 or 5), treatment groups, visit and 
treatment group-by-visit interaction as categorical fixed effects, 
baseline value and baseline-by-visit interaction will be included as 
covariates. The least square means for each dose, the least square 
mean differences from placebo along with the associated 95% 
confidence intervals (CIs) and p-values will be presented. If the 
normality assumption is not met, a nonparametric test will be selected 
for efficacy analysis.  
Study Centers 
Approximately 50-60 study sites 
Sponsor 
Corvidia Therapeutics Inc.  
 
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LIST OF ABBREVIATIONS, DEFINITIONS AND TERMS 
Term 
Definition 
ACR 
Albumin to creatine ratio  
AE 
Adverse event 
ALT 
Alanine aminotransferase 
 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
β-hCG 
β -Human chorionic gonadotropin hormone 
BMP 
Bone morphogenic protein 
BMPR 
Bone morphogenic protein receptor 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CEC 
Clinical Events Committee (CEC)  
CERA 
Continuous erythropoiesis receptor activator  
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CHr 
Reticulocyte hemoglobin content 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration formula  
Cmax/min 
Maximum/minimum observed concentration 
Ziltivekimab 
Monoclonal antibody to IL-6 
CRF 
Case report forms 
CRO 
Contract research organization 
CV 
Cardiovascular 
CV 
Coefficient of variation  
CVD 
Cardiovascular disease 
ECG 
Electrocardiogram 
EDC 
Electronic data capture  
ESA  
Erythropoiesis-stimulating agent 
eGFR 
estimated glomerular filtration rate 
ePRO 
Electronic Patient-Reported Outcomes 
EQ-5D-5L  
(EuroQol-5D-5L 
ERI 
ESA resistance index (ESA weekly dose/targeted dry weight in 
kg*hemoglobin in g/dL) 
ESRD 
End stage renal disease 
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Term 
Definition 
FDA 
Food and Drug Administration 
FPN 
Ferroportin 
FSH 
Follicle stimulating hormone 
FWER 
Familywise error rate  
GCP 
Good Clinical Practice 
GCV 
Geometric CV 
GLP 
Good Laboratory Practices 
HAMP 
Hepcidin gene 
Hct 
Hematocrit 
HDL 
High density lipoprotein 
HFpEF 
Heart Failure with Preserved Ejection Fraction  
Hgb 
Hemoglobin 
HIF 
Hypoxia-inducible factor  
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
HRadj 
Adjusted hazard ratio  
HRQoL 
Health-related quality of life 
hs-CRP 
High sensitivity C-Reactive Protein 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IL1RL-1  
interleukin 1 receptor-like 1  
IL-6 
Interleukin-6 
IL-6R 
IL-6 receptor 
IND 
Investigational new drug 
INR 
International normalized ratio 
iPTH 
Intact parathyroid hormone 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IWRS 
Interactive Web-Response System 
kg 
Kilogram 
KDIGO 
Kidney Disease: Improving Global Outcomes  
LAV 
Left atrial volume 
LDL 
Low density Lipoprotein 
LHD 
Low Hemoglobin density 
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Term 
Definition 
LLN 
Lower Limit of Normal 
LVEF 
Left ventricular ejection fraction  
LVH 
Left ventricular hypertrophy 
LVMI 
Left Ventricular Mass Index 
MCS 
Mental component summary  
MCV 
Mean corpuscular hemoglobin 
mg 
Milligram 
MI 
Myocardial infarction 
MICS 
Malnutrition-inflammation-cachexia syndrome 
min 
Minute 
mL 
Milliliter 
MMRM 
Mixed Model Repeated Measures 
NDD-CKD 
Non-dialysis-dependent chronic kidney disease  
NMR 
Nuclear magnetic resonance 
NOAEL 
No observed adverse effect level 
NT-pro-BNP 
N-terminal prohormone-B-type natriuretic peptide 
PAP 
Psychometric analysis plan  
PBO 
Placebo 
PCS 
Physical component summary 
PD 
Pharmacodynamic 
PEW 
protein-energy wasting  
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PPD 
Purified Protein Derivative 
PRO 
Patient-Reported Outcomes 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PROSAP 
PRO statistical analysis plan  
PT 
Prothrombin Time 
PTH 
Parathyroid Hormone 
RBC 
Red Blood Cell 
RDW 
Red cell distribution width 
RR 
Respiratory Rate 
RSf 
Red cell size factor  
SAA 
Serum amyloid A 
SAE 
Serious adverse event  
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Term 
Definition 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SOP 
Standard Operating Procedure 
ST2 
Suppression of tumorigenicity 2 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Half-life 
TB 
tuberculosis 
TBD 
To be determined 
TIBC 
Total iron binding capacity 
TIMI 
Thrombolysis in Myocardial Infarction 
TMP 
Transmembrane Pressure 
TSAT 
Transferrin saturation 
UACR 
Urine albumin-to-creatinine ratio 
UFR 
Ultrafiltration Rate 
ULN 
Upper limit of normal 
WBC 
White blood cells 
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1 
INTRODUCTION 
1.1 
Background 
Ziltivekimab (COR-001), formerly MEDI5117, is an extended half-life human IgG1κ 
anti-human interleukin 6 (IL-6) monoclonal antibody designed with three amino acid 
substitutions (“YTE”) in the CH2 region of the Fc domain to decrease clearance and thereby 
dosing frequency. Ziltivekimab is being developed for the treatment of patients with the 
inflammatory sequalae of advanced chronic kidney disease (CKD). Inflammatory sequelae 
specifically include the following: 
x Atherosclerotic Cardiovascular Disease (ASCVD) 
x Congestive Heart Failure, Primarily Heart Failure with Preserved Ejection Fraction 
(HFpEF) 
x Functional Iron Deficiency Anemia 
x Malnutrition-Inflammation-Cachexia Syndrome  
1.1.1 
Atherosclerotic Cardiovascular Disease (ASCVD) in Patients with CKD 
Patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) are 10 times more 
likely to die of atherosclerotic cardiovascular disease (ASCVD) than the general population 
(Gregg 2018). However, cardiovascular disease is frequently underdiagnosed and 
undertreated in patients with CKD. Inflammation is highly prevalent in patients with 
chronic kidney disease (CKD) and is consistently associated with cardiovascular morbidity 
and mortality. Markers of inflammation, including plasma C-reactive protein (CRP), are 
associated with an increased risk of cardiovascular disease, and it has been suggested that 
this association is causal. An abundance of biologic, epidemiologic, and clinical trial data 
have demonstrated that inflammation is a key driver of atherosclerosis (Aday 2019). 
Circulating biomarkers of inflammation, including high-sensitivity C-reactive protein (hs-
CRP) and interleukin-6 (IL-6), are associated with increased risk of cardiovascular events 
independent of cholesterol and other traditional risk factors. Randomized trials have shown 
that statins reduce hs-CRP, and the magnitude of hs-CRP reduction is proportional to the 
reduction in cardiovascular risk (Aday 2019; Ridker 2018a; Arici 2001). 
1.1.1.1 
Study of Heart and Renal Protection (SHARP)  
The Study of Heart and Renal Protection (SHARP) assessed the associations between 
circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular 
outcomes (Storey 2018).  Higher baseline CRP was associated with an increased risk of 
major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). 
Higher baseline LDL cholesterol was also associated with an increased risk of major vascular 
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events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher 
baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 
1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and 
non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with 
simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar 
irrespective of CRP concentration at baseline however risk of increased CV events were 
significantly greater in patients who had elevated CRP on treatment. This "residual 
inflammatory risk" has increasingly become a viable pharmacologic target. 
1.1.1.2 
CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) 
To further assess the potential benefits of reducing residual  inflammation as determined by 
hs-CRP reduction, CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) 
was a randomized, double-blind trial of 3 SC doses of canakinumab (50, 150, and 300 mg) in 
10,061 patients with previous myocardial infarction (MI) and an hs-CRP level of ≥2 mg/L 
(Ridker 2017). The primary efficacy endpoint CANTOS was nonfatal MI, nonfatal stroke, or 
cardiovascular death. At 48 months the median reductions in hs-CRP levels compared to 
placebo were 26% (50 mg), 37% (150 mg), and 41% (300 mg) with all comparisons being 
statistically significant (p<0.0001). For the primary objective of CANTOS, the incidence rate 
of the predefined cardiovascular events was 4.50 events per 100 years for placebo, 4.11 
events per 100 years for 50 mg, 3.86 events per 100 years for 150 mg, and 3.90 events per 
100 years for 300 mg.  Compared to placebo, the 150 mg dose displayed a significant effect 
on the primary endpoint outcomes (hazard ratio [HR] vs placebo 0.85; p=0.02075; threshold 
p=0.02115). The 300 mg dose displayed a similar hazard ratio vs placebo (HR vs placebo 
0.86), but did not reach significance versus placebo (p=0.03140; threshold p=0.01058).  In 
addition, the 50 mg canakinumab dose did not reach significance compared to placebo for the 
primary endpoint.  Similar results were seen for the key secondary cardiovascular endpoint of 
the primary endpoint plus hospitalization for unstable angina leading to urgent 
revascularization. CANTOS showed that directly reducing inflammation with an IL-1β 
antagonist reduces cardiovascular event rates independent of LDL-C (Aday 2019). 
1.1.1.3 
CANTOS hs-CRP Threshold Analysis 
In the CANTOS trial, an additional prespecified secondary analysis of major cardiovascular 
events, cardiovascular mortality, and all-cause mortality was performed in hs-CRP subgroups 
< 2.0 mg/L and ≥ 2.0 mg/L (Ridker 2018a). During the CANTOS trial, patients who were 
treated with canakinumab and achieved an on treatment hs-CRP level < 2.0 mg/L had a 25% 
reduction in major cardiovascular events (adjusted HR 0.75, 95% confidence intervals [CI] 
0.66 - 0.85; p<0.0001).  Patients who had on treatment hs-CRP levels ≥ 2.0 mg/L did not 
display a significant reduction in major cardiovascular events (adjusted HR 0.90; 95% CI 
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0.79 - 1.02; p=0.11).  Similar significant reductions (31%) in cardiovascular mortality 
(adjusted HR 0.69; 95% CI 0.56 - 0.85; p=0.0004) and all-cause mortality (adjusted HR 0.69; 
95% CI 0.58 - 0.81; p<0.0001) were observed in patients who achieved the hs-CRP 
threshold, and no significant reductions in both cardiovascular and all-cause mortality were 
observed in patients who did not achieve the hs-CRP threshold. These results suggest that the 
reduction in hs-CRP levels during initial dosing of canakinumab may provide a method to 
identify patients who may have the largest benefit from treatment. 
1.1.1.4 
CANTOS Patients with Moderate CKD 
Patients in the CANTOS trial had serial monitoring of eGFR, creatinine, the urine to albumin 
ratio (UACR), and renal and urinary AE monitoring (Ridker 2018b).  Of the 10,061 
CANTOS patients, 18.6% (1875 patients) had a baseline eGFR of < 60 ml/min/1.73 m2 
indicative of moderate CKD. Patients in this group had higher incidence rates of major 
vascular events compared with those patients who had a baseline eGFR ≥ 60 ml/min/1.73 m2 
(6.92 vs 4.13 per 100 person years; p<0.0001). Among those patients with moderate CKD, 
treatment with canakinumab reduced the risk of major cardiovascular events by 18% (HR 
0.82; 95% CI 0.68 - 1.00; p=0.05).  However, the largest of these effects occurred in patients 
with moderate CKD who achieved on treatment hs-CRP levels < 2 mg/L after taking an 
initial dose of canakinumab (HR 0.68; 95% CI 0.53 - 0.86; p=0.0015). The primary endpoint 
of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death in the placebo-
treated CKD patients had an event rate of 7.92 (per 100 person years) while the event rate in 
canakinumab-treated CKD patients who achieved an hs-CRP level below 2 mg/L was 5.35 
on , representing a 32% relative risk reduction between placebo and active which correlated 
to a number needed to treat (NNT) of eight.  
1.1.1.5 
Modulation of the interleukin-6 signaling pathway and incidence rates of 
atherosclerotic events and all-cause mortality in CANTOS 
Based on the results and additional analyses from the hs-CRP/IL-6/IL-1 pathway discussion 
and the CANTOS trial described in the above sections, moving downstream from IL-1β 
inhibition to IL-6 inhibition may be a more effective target for the reduction of hs-CRP 
expression and ultimately improved atheroprotection (Ridker 2016).  
In the CANTOS trial, 4833 patients had IL-6 levels measured before randomization and after 
treatment (Ridker 2018c). Compared with those allocated to placebo, CANTOS participants 
receiving canakinumab who achieved on-treatment IL-6 levels below the study median value 
of 1.65 ng/L experienced a 32% reduction in major adverse cardiovascular events [MACE, 
multivariable adjusted hazard ratio (HRadj) 0.68, 95% confidence interval (CI) 0.56-0.82; 
P < 0.0001], a 30% reduction in MACE plus the additional endpoint of hospitalization for 
unstable angina requiring urgent revascularization (MACE+, HRadj 0.70, 95% CI 0.59-0.84; 
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P < 0.0001), a 52% reduction in cardiovascular mortality (HRadj 0.48, 95% CI 0.34-0.68; 
P < 0.0001), and a 48% reduction in all-cause mortality (HRadj 0.52, 95% CI 0.40-0.68; 
P < 0.0001) with prolonged treatment. In contrast, those with on-treatment IL-6 levels equal 
to or above 1.65 ng/L after taking the first dose of canakinumab had no significant benefit for 
any of these endpoints. CANTOS provides proof of concept evidence in humans that 
modulation of the IL-6 signaling pathway, at least with canakinumab, associates with 
reduced cardiovascular event rates, independent of lipid lowering.  
1.1.2 
Congestive Heart Failure, Primarily Heart Failure with Preserved Ejection 
Fraction (HFpEF) 
Cardiovascular disease (CVD) is the primary driver of morbidity and mortality in chronic 
kidney disease (CKD) at all stages, (US Renal Data System. 2002, Locatelli 2000). In end 
stage renal disease (ESRD), CVD mortality rate is up to 20 times higher than that of the 
general population (Foley 1998). While the severity of renal impairment is linked to CVD 
risk, accumulating evidence indicates that inflammation plays a key role in the progression of 
many forms of CKD and independently accounts for at least part of the increased risk of 
cardiac events in CKD patients (Go 2004). 
In cardiovascular disease, C-reactive protein (CRP) has been established as a pathognomonic 
measure of systemic inflammation, whose elevation connotes risk, and whose lowering 
confers benefit.  This relationship holds in the CKD population.  As recently reported in the 
SHARP trial (Study of Heart and Renal Protection), which randomized 9270 patients with 
CKD to low-density lipoprotein cholesterol (LDL-C) lowering therapy or placebo, CRP was 
independently associated with both vascular (atherosclerotic) and non-vascular CVD (Storey 
2018).  In the AURORA trial (A study to evaluate the Use of Rosuvastatin in subjects On 
Regular haemodialysis: an Assessment of survival and cardiovascular events), 2773 patients 
on hemodialysis, CRP and albumin were significant predictors of CV events independent of 
traditional risk factors (Solbu 2018). The CANTOS trial (Canakinumab Anti-Inflammatory 
Thrombosis Outcomes Study) evaluated the effects of an IL-1beta inhibitor, canakinumab, on 
CV events in patients with existing cardiovascular disease.  The majority of overall mortality 
benefit was driven by the subset of patients with CKD, and the largest benefits accrued 
among those who had the most robust anti-inflammatory response, specifically these who 
achieved on-treatment CRP levels <2 mg/L (Ridker 2018a).The CRP lowering effect of 
canakinumab is mediated by inhibiting the IL-1β stimulation of IL-6 (Ridker 2016).  
Interleukin-6 is the major inflammatory cytokine responsible for stimulating the hepatic 
synthesis of C-reactive protein (Castell 1990). These data support the thesis that 
inflammation, systemically measured as increased CRP, is a surrogate for the effector 
molecule IL-6 which drives cardiovascular risk in CKD. 
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As CKD progresses to end-stage, cardiovascular risk shifts from atherosclerotic (as studied 
in the trials noted above) to non-atherosclerotic, specifically that of ventricular disease 
manifesting as arrhythmia, sudden cardiac death and heart failure, which has been termed 
“uremic cardiomyopathy” or “Cardio-Renal Syndrome Type 4” (Figure 1, Herzog 2014 and 
Ronco 2008). 
Figure 1 
A conceptual framework of contributors to the cardiovascular 
disease burden in patients with advancing CKD 
 
 
Numerous studies have revealed a relationship between IL-6 driven inflammation, left 
ventricular hypertrophy and fibrosis, and an increase incidence in cardiovascular events in 
CKD (Barreto 2010, Rao 2005, Pecoits-Filho 2002a), with the level of inflammation as 
measured by CRP and IL-6 correlated with left ventricular hypertrophy as well as clinical 
outcomes (Park 2002, Spoto 2015).   
The mechanisms by which IL-6 driven inflammation may be causal to the marked cardiac 
ventricular morbidity evident in advanced CKD populations can be described by two general 
themes: 
1. Hepcidin-independent direct IL-6 mediated cardiac myocyte hypertrophy and tissue 
fibrosis 
2. Hepcidin-dependent IL-6 mediated myocyte iron dysregulation. 
In vitro studies show that IL-6 exerts a direct effect on the cardiac ventricle, inducing 
myocyte hypertrophy and tissue fibrosis, possibly through a macrophage-induced, 
aldosterone-dependent mechanism via activation of cardiac fibroblasts (Meléndez 2010, Ma 
2012, Chou 2018).  In a more recent line of investigation, the Sponsor’s unpublished data 
further suggests that cardiac myocytes are susceptible to IL-6 mediated iron dysregulation 
which is exacerbated by ischemia-reperfusion (see Section 4.2.1.2).  Specifically, a 
synergistic increase in hepcidin expression by IL-6 and bone morphogenic protein (BMP) is 
potentiated by hypoxia, and in aggregate notably increases cellular susceptibility to 
ischemia-reperfusion.   
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B-type natriuretic peptide (BNP) is a hormone produced by the myocardium. N-terminal 
(NT)-pro hormone BNP (NT-pro-BNP) is a non-active prohormone that is released from the 
same molecule that produces BNP. Both BNP and NT-pro-BNP are released in response to 
changes in pressure inside the heart. N-Terminal pro-B-type natriuretic peptide (NT-pro-
BNP) level predicts underlying heart disease in the general population. The association 
between NT-pro-BNP level and coronary artery disease (CAD) and left ventricular 
hypertrophy (LVH) was determined in 207 ambulatory patients with CKD not on dialysis 
therapy. NT-pro-BNP levels were elevated in 116 patients (56%), and 67 patients (33%) had 
experienced prior CAD events (myocardial infarction or revascularization). After adjustment 
for glomerular filtration rate, cTnT level, age, and diabetes, NT-pro-BNP remained an 
independent indicator of prior CAD events for patients with echocardiograms, NT-pro-BNP 
level predicted prior CAD events independent of LVH. NT-pro-BNP level elevation in 
asymptomatic patients with CKD reflects underlying ischemic heart disease and hypertrophy 
independent of renal function in a population with anticipated high cardiac morbidity 
(DeFilippi 2005). The longitudinal Cardiovascular and Renal Outcome in CKD 2-4 Patients-
The Fourth Homburg Evaluation Study, prospectively studied 496 patients with CKD stages 
G2-G4. Left ventricular mass index, left atrial volume index, diastolic left ventricular 
function, and systolic left ventricular function were assessed echocardiographically as well 
as levels of NT-pro-BNP.  During a mean follow-up of 4.5 years, 104 patients suffered 
decompensated heart failure or all-cause mortality, and 127 patents had atherosclerotic 
events or all-cause mortality.  NT-pro-BNP remained an independent predictor for both end 
points in multivariate analysis, whereas left ventricular mass index, left atrial volume index, 
and diastolic left ventricular function did not. This data confirmed that NT-pro-BNP is an 
independent predictor of adverse outcomes in patients with CKD (Understellar 2016). 
1.1.3 
Functional Iron Deficiency (the Anemia of Chronic Disease) 
Anemia is nearly universal among patients with advancing renal disease unless treated with 
erythropoiesis stimulating agents (ESAs) and supplemental iron (Biggar 2017).  The etiology 
of this anemia is that of EPO deficiency alongside IL-6 driven inflammation, which 
stimulates the production of the protein hepcidin (Wrighting 2006, Babitt 2012). Hepcidin, a 
peptide hormone which is mainly synthesized in the liver, reduces extracellular iron in the 
body by several mechanisms: 1) it lowers dietary iron absorption by reducing iron transport 
across gut mucosal cells (enterocytes); 2) it reduces iron exit from macrophages, the main 
site of iron storage; and 3) it reduces iron exit from the liver (Reichert 2017, Sun 2012).  This 
pathophysiologic state represents an inefficiency of erythropoiesis, as evident by the need for 
initiation of ESAs and iron supplementation prior to the loss of EPO-synthetic capacity by 
the kidney, in order to maintain serum hemoglobin at an acceptable value (Mercadal 2012).   
These high doses of ESAs and the maintenance of a high ferritin level are associated with 
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increased risk of cardiovascular complications, the former of which is highlighted by the 
Agency’s boxed warning on ESA product labeling advising conservative serum hemoglobin 
targets.  Furthermore, the Sponsor’s unpublished data describes a novel, intermediate 
hormonal mechanism which may be causal in driving this observed erythropoietin-mediated 
cardiac injury. 
Randomized controlled trials of ESA therapy studying normalization of Hb have failed to 
demonstrate any beneficial effect on cardiovascular outcomes or death. Instead, these trials 
have indicated some potential harmful effects (Singh 2006, Besarab 1998). On the basis of 
this evidence, the recommended Hb initiation level for ESA use in the Kidney Disease 
Improving Global Outcomes (KDIGO) guidelines has been modified from 11 to <10 g/dL 
with the statement that it is no longer recommended to maintain Hb values above 11.5 g/dL 
(KDIGO 2012). The suggested target level by the European Renal Best Practice group is 10-
12 g/dL and recommend not letting Hb fall below 10 g/dL (Locatelli 2013). In addition, the 
FDA and EMA recommend that ESA should be used at the lowest possible dose to control 
anemia and avoid blood transfusions; see Information for Healthcare Professional: 
Erythropoiesis Stimulating Agents (ESA) US FDA 2011. 
Pre-clinically, IL-6 has been shown to affect the described derangements in iron handling 
(MacDougall 2005, Sun 2012), and clinically anti-IL-6 therapies improve anemia in 
non-renal inflammatory conditions.  Specifically, anti-IL-6 therapies have been shown to 
reduce serum hepcidin and increase serum hemoglobin in Multicentric Castleman’s Disease, 
Rheumatoid Arthritis, as well as advanced pulmonary malignancy (Song 2010, Song 2013, 
Bayliss 2011).  In hemodialysis, the Sponsor’s investigation (NCT02868229) has shown that 
neutralizing IL-6 increases iron availability and ESA sensitivity. Therefore, the Sponsor 
proposes that in the inflammatory milieu of CKD, anti-IL-6 therapy would release iron from 
tissue stores, enabling its availability to erythroid precursors, enhancing red blood cell 
production, and improving anemia independent of the need for exogenous ESA or iron 
administration.  Given the strong, direct relationship between ESA dose and cardiovascular 
complications, as well as the risk of iron overload with chronic administration of IV iron, the 
Sponsor believes that Ziltivekimab would fulfill a clear, present and pervasive need in the 
treatment of anemia in the CKD setting. 
1.1.4 
Malnutrition-Inflammation-Cachexia Syndrome including 
hypoalbuminemia 
Persistent inflammation in CKD is also one of the key players in the development of 
malnutrition/protein-energy wasting (PEW), which led to the description of the malnutrition-
inflammation-cachexia syndrome (MICS) in CKD (Kalantar-Zadeh 2003, Kalantar-Zadeh 
2005).  Hypoalbuminemia is strongly associated with mortality in dialysis patients (Kalantar-
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Zadeh 2005b) as well as non-dialysis dependent CKD, which when included as part of a 
“malnutrition inflammation score” with IL-6 and CRP strongly predicts 36-month mortality 
(Jagadeswaran 2018). Although historically hypoalbuminemia has been attributed to 
malnutrition, the recent lack of effect of oral nutritional supplementation on serum albumin 
strongly suggest that inflammation is the causal factor in hypoalbuminemia, especially when 
placed in the context of a direct link between IL-6 and hepatic albumin synthesis, and 
clinically, anti-IL-6 therapy can raise serum albumin in non-renal patients (Benner 2018, de 
Mutsert 2009, Ohsugi 2007). At this time, no therapy is indicated to improve 
hypoalbuminemia in patients with CKD. 
1.2 
Description of Ziltivekimab 
Ziltivekimab is an extended half-life anti-IL-6 antibody (human IgG1κ anti-human IL-6 
monoclonal antibody) with three amino acid substitutions (“YTE”) in the CH2 region of the 
Fc domain designed to decrease clearance, and thereby dosing frequency. Additional 
information about the mechanism and structure of Ziltivekimab can be found in the 
Ziltivekimab Investigator’s Brochure (IB).  
Alleviation of inflammatory anemia with anti-IL-6 therapy comes from published work 
regarding the use of said therapy in humans in non-renal inflammatory conditions. 
Tocilizumab (Roche) and clazakizumab (Alder Biopharmaceuticals) have both shown ability 
to raise hemoglobin in rheumatoid arthritis, Castleman’s disease and advanced malignancy 
(Song 2010, Song et al 2013, Bayliss 2011).  By example, the administration of tocilizumab 
(anti-IL-6 receptor antibody) reverses signs of inflammation, improves iron availability, and 
increases hemoglobin in Castleman’s patients. 
Although anti-IL-6 therapies have not been tested in dialysis patients to date, published and 
Sponsor’s unpublished data in a large prevalent dialysis population documents a correlation 
between serum IL-6 levels and the degree of ESA hypo-responsiveness (i.e., erythropoietin 
dose requirement divided by achieved serum hemoglobin) (Won 2012 and see Section 2 of 
the Ziltivekimab IB). 
However, the influence of IL-6 is not universal, and appears over-represented in a specific, 
genotypically defined subpopulation.  Based on non-clinical study and retrospective review 
of dialysis populations (data on file), it appears a genotypic variation in the iron-control 
system of mammalian cells can render tissues more or less susceptible to IL-6 based 
inflammation  and dictate the influence of this inflammation on clinical outcomes (Figure 2). 
 
 
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Figure 2 
A model for the influence of genetic variation on IL-6 –mediated cellular 
iron handling   
 
 
Matriptase-2 (TMPRSS6) = serine protease suppressor of HAMP (hepcidin gene) mRNA expression; 736V = normal allele; 
736A = risk allele; BMPR = BMP receptor; IL-6R = IL-6 receptor; FPN = ferroportin; Fe = iron 
 
1.3 
Summary of Relevant Nonclinical Experience with Ziltivekimab 
For information regarding nonclinical pharmacology, pharmacokinetics in animals, and 
nonclinical toxicology and safety, please refer to the Ziltivekimab IB. 
1.4 
Summary of Relevant Clinical Experience with Ziltivekimab 
1.4.1 
Phase 1 Study in Rheumatoid Arthritis Patients (D4430C00001) 
This study was a Phase 1, double-blind, placebo-controlled single ascending dose study in 
rheumatoid arthritis patients (Study D4430C00001) which completed in February 2014.  This 
study was a dose-escalation from 30 mg, with provisional doses of 90, 270, and 600 mg 
thereafter.  After 4 patients were enrolled (3 receiving Ziltivekimab 30 mg IV (single dose) 
and 1 receiving placebo), the study was terminated due to difficulties with recruitment.  
Further details surrounding this study can be found in the Ziltivekimab IB. 
Less susceptible to IL-6
HAMP
TMPRSS6
A/G or G/G
BMPR 
IL- 6R
IL- 6 Low 
Fe
Fe
IL -6 High 
Fe
Fe
Fe
Fe
Matriptase-2 ( TMPRSS6 ) 736A
HAMP
TMPRSS6
A/A 
BMPR
IL 
L- 6R 
Fe
Fe
Fe 
Matriptase-2 (TMPRSS6 ) 736V 
Fe Fe 
FPN 
More susceptible to IL-6
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1.4.2 
Phase 1 Study in Patients with CKD (COR-001-SC1) 
This study was a Phase 1 Randomized, Double-Blind, Placebo-Controlled, Cohort Dose-
Escalation Study in Patients with CKD to Assess the Safety, Pharmacokinetics, and 
Pharmacodynamics of a Single Dose of Ziltivekimab. The study population had moderate-to-
severe CKD (i.e., eGFR 20-60 mL/min/1.73 m2) who had serum CRP levels >2 mg/L over 
2 consecutive measurements. The primary objective evaluated the safety of single SC doses 
of Ziltivekimab (5, 15, 50 and 100 mg). The main secondary objective evaluated single-dose 
PK of SC Ziltivekimab and the effects of Ziltivekimab on CRP and serum amyloid A (SAA). 
After SC administration, Ziltivekimab concentrations reached peak levels by 7 to 17 days 
after dosing, on average, and serum Ziltivekimab concentrations remained quantifiable up to 
217 days post dose in all patients. Ziltivekimab concentrations increased in a dose dependent 
manner. Terminal slopes (half-life) appeared similar for 5 and 15 mg doses, suggesting linear 
PK. High intersubject variability among the three patients in the highest dose cohort (50 mg) 
confounded the interpretation for that dose. One patient in the 50 mg dose cohort had levels 
2- to 3-fold higher than the other two patients so that it appeared that the latter patients 
displayed a less than dose proportional increase, while the former showed a greater than dose 
proportional increase in Ziltivekimab serum levels.  
Mean hs-CRP levels were comparable and elevated at Baseline across placebo and the 
Ziltivekimab treatment groups suggesting systemic inflammation. Figure 3 presents the 
percentage of patients who achieved an hs-CRP level of < 2.0 mg/L from Baseline to Week 
32. A consistent decrease in hsCRP levels was observed in the Ziltivekimab dose groups 
throughout the first eight weeks post randomization, while levels in the placebo group 
increased over time. 
Figure 3 
Percentage of CKD patients treated with Ziltivekimab or Placebo who 
achieved an hs-CRP level of < 2.0 mg/L from Baseline to Week 32 
 
50 mg
15 mg
5 mg
Placebo
0%
20%
40%
60%
80%
100%
hsCRP Responder Rate
(on treatment hsCRP < 2  mg/L)
100%
100%
33%
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During the study, 33 AEs were reported by 12 subjects. The only adverse event reported by 
more than one subject (n=3) was upper respiratory tract infection. Other than one report of 
diarrhea, none of the other AEs were considered related to the study product. During the 
study, one subject on placebo reported an SAE (acute cardiac failure), there were no deaths 
and no subject discontinued the study as of February 01, 2018. 
1.4.3 
Phase 1/2 Study in CKD Patients on Hemodialysis (COR-001-01) 
This study was a Phase 1/2 Randomized, Double-Blind, Placebo-Controlled, Cohort Dose-
Escalation Study in Hemodialysis Patients to Assess the Safety, Pharmacokinetics, and 
Pharmacodynamics of Multiple IV Doses of Ziltivekimab. The target population was 
composed of hemodialysis patients who had a predefined genetic makeup, and who displayed 
high serum IL-6 levels and high ESA requirements.  
After IV administration, COR-001 concentrations increased in a dose-related manner and 
appeared to decline in a biphasic manner. The terminal half-life of Ziltivekimab ranged from 
38 to 44 days and there was no evidence of body weight as a covariate. Exposure levels were 
unaffected by hemodialysis and there was no pattern of altered PK to suggest neutralizing 
antibodies. Further details of this study may be found in the IB. 
 
 
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Figure 4 
Ziltivekimab causes Dose-Dependent Decreases in hs-CRP from Baseline 
in ESRD Patients  
 
Abbreviations:  hs-CRP = high-sensitivity C-reactive protein; N = number of subjects 
Note: Ziltivekimab (2 mg, 6 mg or 20 mg IV) Q2 weeks; Data from Pharmacodynamic Analysis Population. 
Note: After checking the data normality, the parameter was shown as Median (Q1/Q3). 
Source: Protocol No: COR-001-01 Final Analysis 
 
There was a greater incidence of Treatment Emergent Adverse Events (TEAE) in each of the 
Ziltivekimab groups than in the placebo group, there was not a clear dose response. The 6 mg 
COR-001 dose group had the greatest incidence of patients with at least one TEAE, and the 
two TEAEs that occurred at the highest incidence in the trial were reported in this treatment 
group (congestive cardiac failure and dyspnea which each occurred in 4 patients). 
Serious adverse events (SAEs) occurred at a higher rate in the 6 and 20 mg dose groups than 
in the placebo and 2 mg groups. The 6 mg group had the greatest incidence of SAEs (7 
patients reporting a total 14 SAEs), and all 4 of the congestive cardiac failure events in the 6 
mg group were considered serious. None of the SAEs in any group were assessed as 
treatment related. There were 4 patients who had SAEs with a fatal outcome; sepsis (Patient 
) and sudden cardiac death (Patient 
) in the 6 mg group and sepsis (
) and 
cardiac arrest (
) in the 20 mg group. None of the deaths were attributed to study drug; 
more information on the Safety results from study COR-001-01 can be found in the 
Investigator Brochure.       
 
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1.4.4 
Conclusions on Ziltivekimab Treatment of Anemia in CKD 
Ziltivekimab is a potent and highly selective fully-human anti-IL-6 antibody in development 
for the treatment of anemia in CKD patients. Ziltivekimab has shown marked reductions in 
hs-CRP levels (inflammation) within the first weeks of administration and continuing 
throughout the treatment period. In summary, the clinical evidence presented here supports 
investigating Ziltivekimab as a product to reduce hs-CRP based inflammation and an 
ultimate reduction in anemia-associated CVD in the proposed patient population. 
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2 
STUDY GOAL AND OBJECTIVES 
Patients with NDD-CKD, who have evidence of systemic inflammation with increased 
cardiovascular risk, will be enrolled into this trial. The purpose of this trial is to determine 
a dose to select for a potential cardiovascular outcome trial with Ziltivekimab. The current 
trial will determine which dose of Ziltivekimab will have a significant reduction in hs-CRP 
with acceptable increases in LDL-C or triglycerides and without clinically meaningful 
reductions in neutrophils and platelet counts. Doses to be tested will be 7.5 mg, 15 mg and 
30 mg subcutaneous monthly compared to placebo for six months.   
2.1 
Primary objective: 
To evaluate the effects of Ziltivekimab compared to placebo on markers of inflammation (i.e. 
hs-CRP). 
2.2 
Secondary objectives: 
To evaluate the effects of Ziltivekimab compared to placebo on markers of inflammation and 
cardiovascular risk: serum amyloid A (SAA) and fibrinogen. 
2.3 
Pharmacokinetic objectives: 
To evaluate the pharmacokinetics (PK) and PK-Pharmacodynamic (PK-PD) modeling of 
Ziltivekimab following multiple doses at three different levels. 
2.4 
Safety objectives: 
To evaluate the safety of three dose levels of Ziltivekimab compared to placebo. 
2.5 
Exploratory objectives:   
To evaluate the effects of Ziltivekimab compared to placebo on markers of anemia 
(hemoglobin). 
To evaluate the effects of Ziltivekimab compared to placebo on markers of inflammation-
malnutrition (i.e. albumin). 
To evaluate the effects of Ziltivekimab compared to placebo on markers of cardiovascular 
risk (i.e. N-terminal prohormone-B-type natriuretic peptide [NT-pro-BNP]). 
To evaluate the effects of Ziltivekimab compared to placebo on additional markers of 
cardiovascular risk (suppression of tumorigenicity 2 [ST2]). 
To evaluate the effects of Ziltivekimab compared to placebo on markers of atherosclerosis 
risk: LDL-C, triglycerides, ApoB, ApoA1, ApoB/ApoA1, lipid profile by nuclear magnetic 
resonance (NMR) spectroscopy, and Lp(a).  
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To evaluate the effects of Ziltivekimab compared to placebo on markers of kidney function, 
(i.e. cystatin C, estimated GFR) and kidney damage, (i.e. urine albumin-to-creatinine ratio 
[UACR]). 
To determine Ziltivekimab trough drug levels following multiple Ziltivekimab doses at three 
different dose levels. 
To evaluate the effects of three dose levels of Ziltivekimab compared to placebo on patient 
reported outcomes (PRO): Patient-Reported Outcomes Measurement Information System 
(PROMIS®) Fatigue 13a short form, selected items from the PROMIS fatigue item bank, the 
Optum SF-36 v2® Health Survey, a Corvidia PRO, the PROMIS interest in sexual activity 
item, the patient global impression of change (PGIC), patient global impression of severity 
(PGIS), and the EQ-5D-5L.  
To evaluate the psychometric properties of the PROMIS Fatigue 13a short form and selected 
items from the PROMIS fatigue item bank, and the Corvidia electronic PRO (ePRO) items in 
CKD patients. 
To evaluate the effects of Ziltivekimab on systemic iron availability:  transferrin saturation 
(TSAT), reticulocyte hemoglobin content (CHr) and total iron binding capacity (TIBC), 
systemic iron stores (serum ferritin), serum iron and systemic iron regulation (serum 
hepcidin). 
To evaluate the effects of Ziltivekimab compared to placebo on markers of cardiovascular 
risk (i.e. NT-pro-BNP) in patients with baseline NT-pro-BNP > 250 pg/mL. 
To evaluate the effects of Ziltivekimab compared to placebo on markers of anemia in patients 
with baseline hemoglobin < 11 g/dL.  
To evaluate the effects of Ziltivekimab compared to placebo on markers of inflammation-
malnutrition (i.e. albumin) in patients with baseline albumin < 4.0 g/dL. 
 
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3 
INVESTIGATIONAL PLAN  
3.1 
Overall Study Design and Plan: Description 
This is a randomized, double-blind, placebo-controlled trial designed to evaluate the 
efficacy, safety, and pharmacokinetics of Ziltivekimab at three dose levels (7.5 mg, 15 mg 
or 30 mg) compared to placebo in patients with stage 3-5 CKD, not on dialysis, who have 
evidence of inflammation with high cardiovascular risk.  
Patients will undergo a Screening Period of up to 14-days during which inclusion and 
exclusion criteria will be evaluated. Patients who meet all inclusion criteria and no 
exclusion criteria will be randomized to one of three Ziltivekimab dose levels (7.5 mg, 15 
mg or 30 mg) or placebo for a 24-week Treatment Period. Patient randomization will be 
stratified by baseline hemoglobin (≥11 or <11 g/dL) and CKD stage (3, 4 or 5).  
Approximately 240 patients will be randomized 1:1:1:1 (60 per group) into the trial. All 
patients must meet the inclusion/exclusion criteria. After the Screening Period, randomized 
patients will be dosed every 28 days out to Week 21. The primary, secondary and exploratory 
endpoints will be analyzed at 13 weeks of dosing and then followed for additional 
exploratory efficacy analyses through Week 24, and then selected efficacy endpoints and 
safety assessments will evaluated in the Follow-up Period Week 25 though Week 32 
(Figure 5). The primary, secondary, and exploratory endpoint evaluation will take place at the 
end of Week 13, and the additional exploratory evaluations will take place at the End of 
Treatment (Weeks 23 and 24).    
The patient will be randomized on Day 1 and the first dose of study drug should be 
administered after all assessments are conducted.  Doses of study drug will be 
administered every 28-days for a total of 6 treatments (Weeks 1, 5, 9, 13, 17 and 21). 
Study visits will follow the schedule of events (Table 2). 
3.1.1 
Pharmacokinetic and PK-PD Modeling 
x Serum trough levels (Cmin) of Ziltivekimab will be measured at all visits. On dosing 
Week 1, 5, 9, 13, 17, and 21, trough PK samples to be collected within 
approximately -0.5 h pre-dose.  Single PK blood samples will also be collected on Weeks 
2, 4, 7, 23, 24/ET, 28, and 32/ET around the same time as the pre-dose samples were 
collected on previous dosing visits.  
x The total IL-6 AUC will be described. 
x The relationship between trough Ziltivekimab levels and primary pharmacodynamic 
endpoints, specifically total plasma IL-6 and hs-CRP, will be described. 
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3.1.2 
Safety Endpoints 
x Proportion of patients with AEs, SAEs, severe hematologic AEs, severe non-hematologic 
AEs, and AEs leading to discontinuation. 
x Proportion of subjects with thrombolysis in myocardial infarction (TIMI) major bleeding 
event. 
x Description and frequency of events of special interest by treatment group: 
o 
Serious infections. 
o 
Severe injection-related reactions. 
o 
Gastrointestinal perforations. 
o 
Hypersensitivity reaction during study drug administration.  
o 
Anaphylaxis occurring at any time, even if considered unrelated to the study drug. A 
CRF for the collection of the details of such reactions will be available in the 
electronic data capture (EDC) system. 
o 
Neutrophil <500/mm3 (severe) or neutrophil <1000/mm3 (severe) with evidence of 
concurrent infection. These events will be separately summarized by treatment group 
and dose. 
o 
Thrombocytopenia (platelet count <50,000/mm3 [severe]) or platelet count 
<75,000/mm3 (moderate) with evidence of concurrent TIMI major bleeding. These 
events will be separately summarized by treatment group and dose. 
o 
Malignancies 
x Description of additional safety assessments by treatment group and dose: vital signs, 
electrocardiogram (ECG), clinical laboratory, and anti-drug antibodies (binding and 
neutralizing). 
3.1.3 
Pharmacodynamic Endpoints 
3.1.3.1 
Primary 
x Difference in percent change in hs-CRP levels from Baseline (average of the hs-CRP 
value prior to randomization and Day 1) to Week 13 between each active group and 
placebo. 
3.1.3.2 
Secondary  
All secondary and exploratory analyses will be performed with the Intent-to-Treat (ITT) 
population. 
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x Difference in change in SAA from Baseline to Week 13 between each active group and 
placebo. 
x Difference in percent change in fibrinogen from Baseline to Week 13 between each 
active group and placebo. 
3.1.3.3 
Exploratory 
x Difference in percent change in hs-CRP levels from Baseline to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in percent change in serum NT-pro-BNP from Baseline (average of the NT-
pro-BNP value prior to randomization and Day 1) to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in change in SAA from Baseline to End of Treatment (Weeks 23 through 
24) between each active group and placebo. 
x Difference in percent change in fibrinogen from Baseline to End of Treatment (Week 
24) between each active group and placebo. 
x Difference in change in hemoglobin from Baseline (average of the two most recent 
hemoglobin values prior to randomization and Day 1) to Week 13 and to End of 
Treatment (Weeks 23 through 24) between each active group and placebo. 
x Difference in change in serum albumin from Baseline (average of the two most recent 
serum albumin values prior to randomization and Day 1) to Week 13 and to End of 
Treatment (Weeks 23 through 24) between each active group and placebo. 
x Proportion of patients achieving hs-CRP response at Week 13 and to End of Treatment 
(Weeks 23 through 24), defined as hs-CRP <2.0 mg/L in each active group and placebo. 
x Difference in change in ST2 from Baseline to Week 13 and to End of Treatment (Week 
24) between each active group and placebo. 
x Difference in percent change in Lp(a) from Baseline to Week 13 and to End of 
Treatment (Weeks 23 through 24) between each active group and placebo. 
x Difference in percent change in LDL-C, triglycerides, ApoB, ApoA1, ApoB/ApoA1, 
and lipid profile by NMR spectroscopy from Baseline to Week 13 and to End of 
Treatment (Weeks 23 through 24) between each active group and placebo. 
x Difference in change of creatinine based eGFR and cystatin C-based eGFR from 
Baseline to Week 13 and to the End of Treatment (Weeks 23 through 24) between each 
active group and placebo. 
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x Difference in change of UACR from Baseline to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in change of the total fatigue score (PROMIS Fatigue 13a short form and 
selected items from the PROMIS Fatigue item bank) from Baseline to Week 13 and to 
End of Treatment (Weeks 23 through 24) between each active group and placebo. 
x Difference in change of the PROMIS interest in sexual activity item from Baseline to 
Week 13 and to End of Treatment (Week 24) between each active group and placebo. 
x Difference in change of the Corvidia ePRO items from Baseline to Week 12 and to End 
of Treatment (Weeks 23 through 24) between each active group and placebo. 
x Difference in change of the PGIS index from Baseline to Week 12 and to End of 
Treatment (Week 24) between each active group and placebo. 
x Descriptive analyses of the PGIC index at Weeks 5, 13 and End of Treatment (Week 
24) in each active group and placebo. 
x Difference in change of the Optum SF-36 v2® Health Survey physical component 
summary (PCS), mental component summary (MCS) and domain scores from baseline 
to Week 13 and to End of Treatment (Weeks 23 through 24) between each active group 
and placebo. 
x Difference in change of the EQ-5D-5L index from Baseline to Week 12 and to End of 
Treatment (Week 24) between each active group and placebo. 
x Evaluation of the psychometric properties of the PROMIS Fatigue 13a short form and 
selected items from the PROMIS Fatigue item bank and the Corvidia ePRO items in 
CKD patients – to be described in a PRO psychometric analysis plan. 
x Descriptive analyses by dose and treatment may be conducted on samples stored for 
analysis of exploratory biomarkers, genomic and transcriptomic analysis. 
x Difference in change in TSAT from Baseline to peak level, Week 13 and End of 
Treatment (Weeks 23 through 24), between each active group and placebo. 
x Difference in change in CHr from Baseline to peak level, Week 13 and to End of 
Treatment (Week 24) between each active group and placebo. 
x Difference in change in TIBC from Baseline to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in change in serum ferritin from Baseline to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
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x Difference in change in serum iron from Baseline to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in change in serum hepcidin from Baseline to Week 13 and to End of 
Treatment (Week 24) between each active group and placebo. 
x Difference in percent change in serum NT-pro-BNP from Baseline to Week 13 and to 
End of Treatment (Weeks 23 through 24) between each active group and placebo in 
patients with baseline NT-pro-BNP > 250 pg/mL. 
x Difference in change in hemoglobin from Baseline (average of the two most recent 
hemoglobin values prior to randomization and Day 1) to Week 13 and to End of 
Treatment (Weeks 23 through 24) between each active group and placebo in patients with 
baseline hemoglobin < 11 g/dL. 
x Difference in change in serum albumin from Baseline (average of the two most recent 
serum albumin values prior to randomization and Day 1) to Week 13 and to End of 
Treatment (Weeks 23 through 24) between each active group and placebo in patients with 
baseline albumin < 4.0 g/dL. 
  
 
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3.2 
Study Schematic  
Figure 5 
Study Flow 
 
Ziltivekimab Dose Level 1, 2 or 3 (N=180); N=60 in each level 
 
 
 
Placebo (N=60) 
 
 
Screening 
Treatment Period 
Safety F/Up 
Visit 
Number 
-2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11/ET 
12 
13/ET 
Visit Day 
Window 
-14 
-7 
1 
8 
22 29-35 43-49 57-63 85-91 113-
119 
141-
147 
155-
161 
162-
168 
190-196 218-224 
Visit 
Window 
 
r2 
1 r2 r2 
 
 
 
 
 
 
 
 
 
 
Visit 
Week 
-2 
-1 
1 
2 
4 
5 
7 
9 
13 
17 
21 
23 24/ET 
28 
32/ET 
 
3.3 
Blinding and Randomization 
3.3.1 
Randomization 
Treatments will be assigned to randomized patients via an interactive web-response system 
(IWRS).  Patients (N=240) will be randomized in 1:1:1:1 ratio to Ziltivekimab Dose #1 (7.5 
mg), Ziltivekimab Dose #2 (15 mg), Ziltivekimab Dose #3 (30 mg) or matching Placebo, as 
they meet all entry criteria. Patients will be stratified by baseline hemoglobin (≥11 or <11 
g/dL) and CKD stage (3, 4 or 5).  Note that CKD stage is stratified into two categories: (1) 
stage 3 and (2) stages 4 or 5. 
3.3.2 
Blinding 
This study is double-blind. The patients, investigators, site personnel, site monitors and 
Sponsor and the Contract Research Organization (CRO) clinical operational personnel will 
be blinded to the treatment assignment (see Section 12.2 for details). Ziltivekimab and 
matching placebo will be provided as a liquid for subcutaneous injection.  
The randomization list will be generated by a CRO statistician not otherwise involved in the 
study. 
3.3.3 
Unblinding 
In case of a medical emergency or medical situation in which the treatment assignment is 
necessary for proper patient management, the Investigator may obtain the treatment 
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assignment from the IWRS.  The Investigator should make every reasonable attempt to 
contact the Medical Monitor before unblinding a patient.  In all cases, the Investigator must 
submit a written report, including all pertinent details, to the Medical Monitor within 
24 hours of the unblinding. 
3.4 
Duration of the Study 
The study will consist of three periods:  Screening, Treatment Period, and Safety Follow-
Up Period. The total study duration for an individual patient will be approximately 8-9 
months.  The study period durations are as follows: 
Screening Period: up to 2 weeks [Days -14 to -1]  
x 
Starts with the first date that Initial Screening procedures were performed. The 
first procedure also defines the initial screening visit date 
Treatment Assessment Period: 24 weeks [Week 1, Day 1 through Week 24, ] 
x 
Starts with the first administration of study drug/randomization (Day 1) 
Safety Follow-Up Period: 8 weeks [Weeks 25 through 32] 
x 
Safety period starts 4-weeks after last treatment dose 6.  
3.5 
Discussion of Study Design, Including Choice of Control Arm  
The study is a randomized, double-blind, placebo-controlled trial.  Randomization and 
double-blinding are being used to minimize bias. The treatment duration (Weeks 1 through 
24) was chosen as the shortest duration needed to evaluate the pharmacodynamic effect of 
said doses on the proposed inflammatory, hematologic and cardiovascular endpoints.  Sample 
size calculations were performed for several pharmacodynamics endpoints and these are 
presented in Section 11.1. 
3.5.1 
Study Population and Control Arm 
As there are currently no drugs approved for the treatment of functional iron deficiency and 
reduction of hs-CRP, there are no options for an active comparator.  
The study is being conducted in the target population because the pharmacodynamic 
endpoints (inflammation, functional iron deficiency, and increased cardiovascular risk) 
cannot be evaluated in healthy volunteers.  
3.5.2 
Rationale for Dosing and Length of Safety Evaluation 
Inhibition of free IL-6 greater than 90% is needed to achieve biologic effect, because growth 
factors and soluble cytokines in general are able to elicit signaling with receptor occupancies 
of less than 10%.  A basic logarithmic dose escalation scheme was used after modeling of 
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IL-6 binding and the PK-PD (hs-CRP) relationship from the concluded Phase 1 trial in RA 
patients (Study D4430C00001).  Based on the clearance of Ziltivekimab (dictated by the 
“YTE” Fc mutation), the duration of safety monitoring and follow-up for PK, IL-6, and 
antibody testing to 32 weeks is planned. 
3.5.3 
Rationale for the Efficacy Endpoints 
The inflammatory pharmacodynamic endpoint of hs-CRP was chosen as the primary 
endpoint because it is a direct measure of IL-6 function (specifically hs-CRP genes are 
induced by IL-6). The inflammatory biomarker hs-CRP has been shown to be a strong 
component in the prediction of cardiovascular risk to an extent approximately equivalent to 
total and high-density cholesterol (HDL) levels.  Further data support that hs-CRP levels 
while on statin therapy are a large predictor of cardiovascular risk to a similar extent to those 
seen with LDL (Ridker 2016).  However, CRP has a short circulating half-life of 
approximately 19 hours in which the plasma concentration is largely impacted by the rate of 
production through the biochemical pathway. Thus, CRP has not previously been considered 
an adequate target for intervention. 
The biochemical pathway of CRP production is downstream regulated by IL-6 expression 
which is itself regulated by the downstream expression of IL-1, specifically the inhibition of 
the 
IL-1β-producing 
NOD-like 
receptor 
family 
pyrin 
domain 
containing 
3 
inflammasome.  Thus, hs-CRP levels can be considered downstream surrogate biomarkers of 
both IL-6 and IL-1 expression when evaluating compounds which regulate their specific 
respective actions. Inhibition of IL-6 or IL-1 expression for the ultimate outcome of a 
reduction in circulating hs-CRP levels has been undertaken in several recent clinical studies 
(Ridker 2016).  
The secondary endpoints include evaluations of fibrinogen and serum amyloid A (SAA). 
Fibrinogen is an acute phase reactant and a mediator of coagulation and therefore a marker of 
cardiovascular risk and a predictor of future cardiovascular risk (Ridker 2012). The 
difference in percent change in fibrinogen will be evaluated from Baseline to Week 13 
between each active group and placebo. SAA is another acute phase reactant that was 
selected as an additional secondary endpoint because it is persistently elevated in chronic 
inflammatory conditions and elevated levels predict cardiovascular risk in humans (Shridas 
2019). The difference in change in SAA will be evaluated from Baseline to Week 13 between 
each active group and placebo. 
The exploratory endpoints include evaluations of NT-pro-BNP, ST2, albumin and 
hemoglobin. Serum NT-pro-BNP is a marker of cardiovascular risk and a predictor of future 
cardiovascular risk. Percent change in serum NT-pro-BNP will be evaluated from Baseline to 
Week 13 and to End of Treatment between each active group and placebo. Suppression of 
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tumorigenecity 2 (ST2) is a prognostic marker for heart failure with preserved and reduced 
ejection fraction. ST2 is a member of the interleukin 1 receptor family, also known as 
interleukin 1 receptor-like 1 (IL1RL-1). High circulating level of ST2 is associated to 
increased cardiovascular disease mortality and markers of metabolic dysfunction in subjects 
with atherosclerotic disease.  
Serum albumin was selected as an additional exploratory endpoint because it is also closely 
negatively correlated with inflammation in the CKD population and is therefore also being 
analyzed as a marker of inflammation. Changes in serum albumin will be evaluated from 
Baseline to Week 13 and to End of Treatment between each active group and placebo. 
Hemoglobin was selected as an exploratory endpoint because of its sensitivity to IL-6.  
Changes in hemoglobin will be evaluated from Baseline to Week 13 and to End of Treatment 
between each active group and placebo. 
In the inflammatory state, through the direct action of IL-6 there is overproduction of “the 
master iron regulator” hepcidin, a protein which prohibits cellular iron transport via 
degradation of ferroportin, the only known iron export channel in humans. This elicits a 
functional iron blockade that leads to anemia. Changes in serum hepcidin will be evaluated 
from Baseline to Week 13 and to End of Treatment between each active group and placebo.  
Additional hematologic pharmacodynamic endpoints chosen include TSAT, CHr, TIBC, 
iron, and ferritin. These endpoints are intended to evaluate the effects of reducing 
inflammation on functional iron deficiency anemia.  It is hypothesized that CHr will increase 
as iron is released from tissue stores. TSAT is also expected to increase over time as more 
iron is mobilized, until iron is utilized for erythropoiesis (reflected in rising hemoglobin). 
Supportive pharmacodynamic endpoints include LDL-C, triglycerides, ApoB, ApoB/A1, and 
Lp(a). Biomarkers for CKD will be evaluated including cystatin C, creatinine, and UACR. 
Finally, inflammation is known to affect systemic symptoms, notably fatigue and skeletal 
muscle strength; assessments will be made for selected items from the  PROMIS Fatigue and 
13a short form, Optum SF-36 v2® Health Survey, Corvidia ePRO, PGIS, PGIC, and EQ-5D-
5L. 
3.5.4 
 Rationale for the Dose Regimens 
The main goal of Ziltivekimab dosing in the planned Phase 1/2 CKD patient study is to attain 
and maintain serum Ziltivekimab concentrations sufficient for ≥90% IL-6 binding over the 
treatment period, with a secondary goal of reducing hs-CRP to below 2 mg/L while keeping 
the highest planned dose more than 20-fold below the no adverse effect level (NOAEL) 
observed in primates. 
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3.5.4.1 
Pharmacokinetic modeling 
To date, the Ziltivekimab clinical program is comprised of 2 studies, both of which are 
placebo-controlled ascending dose studies.  In the first of these studies (Study COR-001-01), 
patients with ESRD were administered intravenous (IV) infusions of study drug every 2 
weeks for a total of 6 doses. Ten patients per cohort were randomized in a 1:4 ratio to 
placebo or Ziltivekimab (2, 6, and 20 mg).   
In the second study (Study COR-001-SC1), patients with CKD were administered single 
subcutaneous (SC) doses of study drug.  Four patients per cohort were randomized in a 1:3 
ratio to placebo or Ziltivekimab (5, 15, and 50 mg).   
The PK parameters are generally consistent with those expected for a monoclonal antibody.  
Absolute bioavailability (F) of SC administered Ziltivekimab is 69%, and the mean time of 
occurrence for peak serum Ziltivekimab concentrations (tmax) after SC dosing ranged from 8 
to 15 days, with an absorption half-life of 3 days. Terminal elimination half-lives (t1/2,z) 
differed between the ESRD patients (mean t1/2,z ranging from 38 to 44 days) and CKD 
patients (mean t1/2,z ranging from 48 to 56 days).  While these results suggest that the rate of 
Ziltivekimab elimination may increase with decreasing renal function, a prior observation in 
rheumatoid arthritis patients that Ziltivekimab clearance is much slower than the glomerular 
filtration rate implies that the apparent elimination rate difference is not due to renal function 
per se, but more likely other physiological changes that accompany decreased renal function. 
3.5.4.2 
Correspondence of proposed doses to those used in prior clinical studies 
Based on the clinical PK for Ziltivekimab described above, especially the F of 69.3% for SC 
dosing, the correspondence of proposed SC doses can be derived. Table 1 provides a 
summary of the SC doses that would correspond to the Ziltivekimab doses used in prior 
studies. From this perspective, the proposed 7.5 and 15 mg q4w x 6 regimens are well within 
the range of exposures considered safe in the prior clinical study, and the proposed 30 mg 
q4w x 6 regimen is less than the exposure associated with adverse changes in laboratory 
parameters in the prior clinical study. 
 
 
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Table 1 
Summary of IV doses used in Study COR-001-01 with SC doses that 
represent corresponding exposure 
 
IV Dosing 
SC Dosing 
COR-001-01 
Dose 
q2w 
(mg) 
q4wa 
(mg) 
Cumulative Doseb 
(mg) 
q4wc 
(mg) 
Cumulative Dosec 
(mg) 
Monthly Dosed 
(mg) 
2 mg q2w x12 
2 
4 
24 
5.8 
34.6 
5.8 
6 mg q2w x12 
6 
12 
72 
17.3 
103.9 
17.3 
20 mg q2w x12 
20 
40 
240 
57.7 
346.3 
57.7 
Abbreviations:  IV, intravenous;  SC, subcutaneous;  q2w, every 2 weeks;  q4w, every 4 weeks. 
a 
Cumulative dose administered every 4 weeks, i.e., the total of 2 q2w doses given within a 4 week period. 
b 
Cumulative dose over the duration of the study, i.e., the total of 12 q2w doses given during the study. 
c 
Corresponding SC dose, assuming bioavailability (F) of 69.3%. 
d 
Monthly SC dose for 6 monthly doses that corresponds to the SC cumulative dose, i.e., SC cumulative dose 
divided by 6. 
 
3.5.4.3 
Exposure for proposed doses relative to IL-6 binding 
In the planned study, median trough serum Ziltivekimab concentrations for the 6th dose of 
723, 1446, and 2892 ng/mL are expected to be attained with the proposed 7.5, 15, and 30 mg 
q4w doses, respectively.  Those concentrations are sufficient to ensure >99% of plasma IL-6 
would be bound (i.e., <1% free IL-6).  It is reasonable to expect that this magnitude of IL-6 
binding would be associated with perturbation of inflammatory processes. 
3.5.4.4 
Exposures for proposed doses relative to the exposures at NOAEL dose in the 
toxicology study 
COR-001-02 will utilize SC doses of 7.5, 15, and 30 mg administered q4w for a total of 6 
months.  Based on the clinical PK for Ziltivekimab described above, exposures for the 
planned doses were estimated.  Those exposures were then compared to those attained in a 
26-week Good Laboratory Practice (GLP)-compliant toxicology study in cynomolgus 
monkeys (Study 20134998) to determine the safety factors for the planned clinical study 
doses. 
For these planned doses, safety factors relative to the exposures at the NOAEL SC dose in 
the 26-week monkey study are at least 76-fold for the Cmax after the 6th dose, and at least 118-
fold for the cumulative AUC0-∞ for the 6 doses. 
3.5.4.5 
Exposures for proposed doses relative to the exposures associated with clinically 
meaningful PD changes in prior clinical studies 
In the prior clinical studies, hs-CRP has been found to be a sensitive response to Ziltivekimab 
exposure, with clinically meaningful decreases even at the lowest doses tested.  Decreases 
were attained soon after the first dose, and the decreases were more prolonged as the 
Ziltivekimab dose is increased. Therefore, it is reasonable to expect that clinically 
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meaningful hs-CRP reduction can be attained with the proposed SC 7.5, 15, and 30 mg q4w 
x 6 regimens. 
3.6 
Safety Plan and Monitoring 
Please see the Guidance to Investigators section of the IB for a description of safety findings 
from other IL-6 monoclonal antibodies and guidance for clinical monitoring. 
3.7 
Benefit and Risk Assessment 
Despite the fact that the concept of inflammatory risk in renal patients has been in the public 
domain for decades, with an active basic research and clinical investigational community 
focused on its remediation, no therapy has been specifically designed or developed to address 
it.  The advancement of an anti-inflammatory therapy for CKD patients should offer the 
benefit of myocardial protection and potential treatment of heart failure in this otherwise 
vulnerable population. 
As for the risks associated with administration of Ziltivekimab, nonclinical toxicology 
studies established the NOAEL by the maximal dose administered (see the Ziltivekimab IB).  
Both in terms of local and systemic effects, Ziltivekimab was well tolerated, with no apparent 
adverse findings.  Of note, the highest Ziltivekimab dose planned for study allows an over 
20-fold margin to NOAEL in the non-clinical toxicology program.  
Available data for anti-IL6R (tocilizumab) and anti-IL6 (siltuximab) therapies suggest 
neutralization of IL-6 have acceptable safety and tolerability profiles for the indications 
studied.  Injection-related and life-threatening hypersensitivity reactions are rare with these 
agents.  Anti-inflammatory therapies in general run the risk of inducing immune suppression 
and promoting the emergence of infections, sometimes serious in nature.  Although anti-IL-6 
therapies lower neutrophil counts and may induce frank neutropenia, their rates of infectious 
complications appear to be similar to other immune-modulatory biologic agents when 
accounting for patient-specific factors (Sakai 2015, Sanofi 2016).  Gastrointestinal 
perforation has been associated with anti-IL-6 therapy, however data suggests proper 
exclusion criteria may mitigate these risks (Tanaka 2014). 
On balance then, the Sponsor proposes the potential risks to patients in this study are 
justifiable and the benefit-to-risk ratio positive.  Patients will be consented as to the potential 
risks and will be required to sign an ICF documenting their understanding of these risks and 
willingness to participate in the study. 
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4 
SELECTION OF STUDY POPULATION AND CRITERIA FOR 
WITHDRAWAL 
4.1 
Inclusion Criteria 
After signing an informed consent form approved by the Investigator’s Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) to be eligible, potential 
study patients must meet all of the following criteria: 
1) Age ≥18 years at the time of signing of the Informed Consent Form (ICF). 
2) Stage 3-5 NDD-CKD, i.e. estimated glomerular filtration rate (eGFR) >10 and <60 
mL/min/1.73 m2 using the CKD-EPI Creatinine Equation (www.kidney.org/content/ckd-
epi-creatinine-equation-2009).  
3) Serum hs-CRP level t2.0 mg/L measured during the Screening Period. (Note: C-reactive 
protein may not be commonly measured in patients with CKD. Targeting patients with a 
history of advanced stage CKD, ASCVD, anemia, metabolic syndrome, diabetic retinopathy 
and diabetes for screening will help increase the chances of identifying patients with CRP 
≥2.0) 
4) The patient agrees to comply with the contraception and reproduction restrictions of the 
study (Appendix G): 
a) Women of childbearing potential must be using a method of contraception, that is 
“highly effective” (i.e., <1% failure rate) for at least 3 months following the last dose 
of study drug; 
b) Postmenopausal women must have had no menstrual bleeding for at least 1 year 
before initial dosing and either be over the age of 60-years or have an elevated plasma 
follicle-stimulating hormone (FSH) level (i.e., >40 mIU/mL) at Screening; 
c) Women of childbearing potential must have a documented negative pregnancy test 
result at Screening. Patients with elevated β-HCG levels believed to be due to end-
stage renal disease may be enrolled if documented to not be pregnant; 
AND 
All male patients, from the day of dosing until the final study visit, unless surgically 
sterile, must be willing to use a condom with a partner (male patients with partners of 
childbearing potential must be willing to use 2 effective methods of birth control, 1 
should be condom with spermicide) to prevent pregnancy and drug exposure of a partner, 
and refrain from donating sperm or fathering a child.  
4.2 
Exclusion Criteria 
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Participants are excluded from the study if any of the following criteria apply: 
Laboratory Values 
1. Absolute neutrophil count <2.0 x 109/L during screening. 
2. Platelet count <120 x 109/L during screening. 
3. Spot urine protein to creatinine ratio >4000 mg/g, or 4.0 g/g. 
4. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5x ULN 
during screening. 
5. Positive 
testing 
for 
tuberculosis 
(TB) 
during 
screening. 
Blood 
testing 
(e.g., QuantiFERON) is preferred but a purified protein derivative (PPD) skin test 
read within 48-72 hours by a qualified healthcare professional may also be 
performed. If a patient is PPD positive but QuantiFERON negative the patient is 
eligible.  
6. Evidence of human immunodeficiency virus-1 (HIV-1) or HIV-2 infection by 
serology measured during screening. 
7. Hepatitis B or C by serology (e.g. hepatitis B surface antigen or hepatitis C antibody 
positive) measured during screening. 
Medical Conditions or Diseases 
8. Expected to require blood transfusion within 12-weeks post-randomization. 
9. Thromboembolic event within 12-weeks prior to randomization. 
10. Clinical evidence or suspicion of active infection. 
11. History of peptic ulcer disease or gastrointestinal ulceration in the 12-months prior to 
randomization. 
12. History of active diverticulitis in the 12-months prior to randomization. 
13. History of inflammatory bowel disease that has been clinically active during the 
12-months prior to randomization. 
14. Uncontrolled hypertension (defined as an average SBP >160 mmHg or an average 
diastolic blood pressure (DBP) >100 mmHg during screening.  Patients may be re-
evaluated within 2 weeks, at the discretion of the investigator for this criterion if anti-
hypertensive therapy has been started or increased as a result of initial screening 
blood pressure being above these limits. 
15. Planned coronary revascularization (PCI or CABG) or any other major surgical 
procedure. 
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16. Major cardiac surgical, non-cardiac surgical or major endoscopic procedure within 
the past 6 months prior to Randomization. 
17. History of New York Heart Association Class IV congestive heart failure within 12-
weeks prior to randomization. 
18. Actively treated or active malignancy during the 1-year prior to randomization with 
the exception of successfully treated nonmetastatic basal cell or squamous cell 
carcinomas of the skin and/or local carcinoma in situ of the cervix. 
19. History of bone marrow or solid organ transplant or anticipated to receive an organ 
transplant during the time frame of the study. 
20. Known allergy to the study drug or any of its ingredients. 
Prior or Current Medications 
21. Received any investigational drug within 30-days prior to screening visit. 
22. Received a live vaccine product within 14 days of study drug administration (Day 1) 
or expect to receive live vaccine during the Treatment Period (receiving a live 
vaccine within 14 days prior to enrollment is allowed). 
23. Treatment with a hypoxia-inducible factor (HIF) stabilizer (e.g., molidustat, 
roxadustat) or an erythropoietin-mimetic, e.g., erythropoietin alpha or beta, 
darbopoietin alpha, or continuous erythropoiesis receptor activator (CERA), within 
6-weeks prior to randomization or during treatment period. 
24. Expected to receive any investigational drug or any of the exclusionary drugs listed in 
Section 15.1 during the Treatment Period or Safety Follow-Up Period. 
25. Chronic use of systemic immunosuppressive drugs during the screening period or 
anticipated use of such drugs any time during the study. Note: Use of otic, 
ophthalmic, inhaled, and topical corticosteroids or local corticosteroid injections are 
not exclusionary. Oral prednisone up to 5 mg per day is (or equivalent) is permitted if 
dose has been stable for at least 4 weeks prior to screening, and no dose changes are 
planned during study participation. 
26. Use of systemic antibiotics, systemic antivirals, or systemic antifungals during the 
screening period (“Systemic” is defined as oral or intravenous drugs that are absorbed 
into the circulation). 
27. Requiring an indwelling catheter of any type. 
General Exclusions 
28. Currently breastfeeding. 
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29. Any condition that could interfere with, or for which the treatment might interfere 
with, the conduct of the study or interpretation of the study results, or that would in 
the opinion of the investigator increase the risk of participating in the study. 
 
4.3 
Criteria for Discontinuation of Study Drug  
It may be necessary for a participant to permanently discontinue study intervention. If study 
intervention is permanently discontinued, the participant shall remain in the study to be 
evaluated on all early termination and safety follow-up procedures per the Schedule of 
Assessments (SOA) in Section 5.3.9 and Section 5.6. Study drug may be prematurely 
discontinued for a number of reasons, including: 
x An intercurrent illness at the discretion of the investigator; 
x Any intolerable AE that cannot be ameliorated by appropriate medical intervention or 
that in the opinion of the Medical Monitor or Investigator would lead to undue risk if 
the patient were to continue on treatment; 
x In the event of severe injection related reactions,  anaphylaxis, or hypersensitivity 
(Section 8.2 and Section 4.5); 
x If at any point during the study, >10% of subjects enrolled experience anaphylaxis, 
additional enrollment will stop in the study, and all patients in the study will 
discontinue receiving study drug (Section 8.2 and Section 4.4); 
x Pregnancy; 
x Organ transplantation or development of another indication for chronic 
immunosuppression; 
Reasons for all withdrawals/discontinuations of Study Drug will be recorded, and the 
Medical Monitor should be informed of all such cases as they occur. Temporary 
discontinuation of study intervention and restarts may be performed per Section 4.5. 
4.4 
Anaphylaxis Study Stopping Rule  
If at any point during the study ≥10% of participants experience an anaphylaxis event, the 
anaphylaxis study stopping rule will be executed. The study stopping rule will halt any 
additional enrollment into the study for safety purposes. Additionally, all randomized 
participants currently receiving study drug will immediately discontinue further study drug 
administration. The remaining study procedures and visits may be performed if deemed 
necessary by the Sponsor. 
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4.5 
Temporary Discontinuation of Study Intervention 
Participants may have their study drug administration temporarily suspended during the 
course of the study. Study drug administration should be temporarily withheld if the 
participant experiences one or more of the following: 
x ALT >3x ULN (moderate)  
x Neutrophils <1000/mm3 (severe) 
x Platelet count <50,000/mm3 (severe) 
x Platelet count <75,000/mm3 (moderate) with evidence of concurrent TIMI major 
bleeding.  
Laboratory measures should be present on two independent assessments.  After a temporary 
suspension of study drug has been performed, study drug may be restarted provided the 
participant has met the following criteria: 
x Neutrophils ≥1500/mm3, and 
x Platelets ≥100,000/mm3 
No ongoing clinical sequalae attributable to neutropenia or thrombocytopenia, respectively. 
If, after restarting study drug, the event causing temporary discontinuation reoccurs study 
drug should be discontinued permanently.  
4.6 
Participant Discontinuation/Withdrawal from the Study 
The following are descriptions of participant discontinuation and withdrawal from the study.  
This is not an exhaustive list, and each instance should be evaluated on a case-by-case basis. 
x Withdrawal of consent. A participant may elect to withdraw consent to treatment at 
any time. 
x Participants withdrawing their consent for all study procedures must be given the 
option to continue to give consent for passive follow-up (i.e., by means of chart 
review) for AEs. 
x Participants discontinuing study drug treatment after receiving any amount of study 
drug should undergo all early termination and safety follow-up study procedures per 
the SOA (Section 5.3.9 and Section 5.6) unless the participant also explicitly 
withdraws consent for these procedures as mentioned above.  The study drug has a 
long pharmacodynamic effect. Therefore, continued monitoring for 
pharmacodynamic effects and safety is prudent.  
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x A participant may be withdrawn at any time at the discretion of the investigator for 
safety, behavioral, compliance, or administrative reasons. Participation in the early 
termination and safety follow-up procedures will be evaluated on a case-by-case 
basis.  If possible, participants should take part in the early termination and safety 
follow-up procedures in the SOA (Section 5.3.9 and Section 5.6). 
x If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
x If a participant withdraws from the study, the participant may request destruction of 
any samples taken and not tested.  The investigator must document this in the site 
study records. 
4.7 
Lost-to-Follow-up 
A participant will be considered lost to follow-up if they repeatedly fail to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return for any required study 
visit: 
x The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible.  If possible, the site should attempt to reschedule the missed visit 
within any allowed visit or treatment window. 
o The site should advise the participant that it is important to adhere to the assigned 
visit schedule. 
o The site shall attempt to ascertain whether or not the participant wishes to and/or 
should continue in the study. 
x Prior to a participant being deemed lost-to-follow-up, the investigator or designee 
must make every effort to regain contact with the participant.  All attempts to regain 
contact with the participant must be recorded in the participant’s medical record. 
If the participant continues to be unreachable, the participant will be 
considered to have withdrawn from the study. 
4.8 
Study Completion 
Primary study completion is defined as the completion of the Week 24 visit, even if one or 
more interim visits or procedures was/were missed. 
Completion of the Safety Follow-Up is defined by the completion of the Week 32 visit even 
if one or more interim visits or procedures was/were missed. 
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5 
ENROLLMENT AND STUDY PROCEDURES 
Table 2 presents the procedures and assessments at each of the scheduled visits. Details of 
each visit are provided in Section 5.1 through Section 5.6. 
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Table 2 
SCHEDULE OF PROCEDURES 
Screening1 
Treatment Period 
Safety F/Up 
Visit Number 
-2 
-1 
1 
2 
3 
4 
5 
6 
N/A 
7 
8 
9 
10 
11/ET 
12 
13/ET 
Visit Day Window 
-14 
-7 
1 
8 
22 
29-35 43-49 57-63 78-84 85-91 113-119 141-147 155-161 162-168 190-196 218-224 
Visit Window 
 
r2 
 
r2 
r2 
 
 
 
 
 
 
 
 
 
 
 
Visit Week 
-2 
-1 
1 
2 
4 
5 
7 
9 
12 
13 
17 
21 
23 
24/ET 
28 
32/ET 
ICF signed 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Update 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administered (post-
assessments) 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
Concomitant and Prior Medications 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs2 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
BMI 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Hematology3 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Lipids (fasting 8 hours)4 
 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
Chemistry5 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Spot urine protein-creatinine ratio 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Urinalysis (including albumin) 6 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Iron Indices7 
X 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
Serum Hepcidin 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
TMPRSS6 Genotype test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious Disease Screen8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Special RBCs9 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
Screening (total) IL-6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IL-610 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
hs-CRP 11 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy, FSH 12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ziltivekimab trough PK13 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ADA14 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
CKD Biomarkers16 
 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
NT-pro-BNP 
 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Lp(a), ApoB, ApoA1 (fasting 8 
hours)4 
 
X 
X 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
 
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Table 2 
SCHEDULE OF PROCEDURES 
Screening1 
Treatment Period 
Safety F/Up 
Visit Number 
-2 
-1 
1 
2 
3 
4 
5 
6 
N/A 
7 
8 
9 
10 
11/ET 
12 
13/ET 
Visit Day Window 
-14 
-7 
1 
8 
22 
29-35 43-49 57-63 78-84 85-91 113-119 141-147 155-161 162-168 190-196 218-224 
Visit Window 
 
r2 
 
r2 
r2 
 
 
 
 
 
 
 
 
 
 
 
Visit Week 
-2 
-1 
1 
2 
4 
5 
7 
9 
12 
13 
17 
21 
23 
24/ET 
28 
32/ET 
Lipid Profile by NMR spectroscopy 
(fasting 8 hours)4 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Cardiac Risk Biomarker17 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Storage samples for Exploratory 
Biomarkers and RNA Testing18 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
DNA Testing (Stored Blood 
Samples) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examination19 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
INR20 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
PROMIS® 13a and Fatigue Items21 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
PROMIS® Sexual Interest Items21 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
CARES (Corvidia ePRO)22 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
PGIS23 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
PGIC24  
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Optum SF-36 v2®25 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
EQ-5D-5L26 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
ET = Early Termination; F/Up = Follow-up.  
 
1. If a Screening laboratory (excluding hematology) result is outside inclusion criteria parameters screening may be extended up to one week to allow for 
retesting of lab test(s) that did not meet inclusion criteria. 
2. Vital signs include temperature, respiratory rate, heart rate, and blood pressure (patients may be re-evaluated within 2 weeks, at the discretion of the PI 
if anti-hypertensive therapy has been started or increased as a result of initial screening blood pressure).  Whenever possible, vital signs will be obtained 
after at least 5 minutes resting in the supine position or, when necessary, in a semi-recumbent position. Vital signs will be done prior to ECG recordings. 
3. Hematology:  hemoglobin, hematocrit, reticulocyte count, red blood count (RBC) indices (e.g., mean corpuscular volume (MCV), red cell distribution 
width (RDW), platelets, white blood count (WBC), WBC differential.  
4. Lipids and subfractions (fasting 8 hours): total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL), and 
triglycerides; Lp(a), ApoB, ApoA1. 
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5. Chemistry: sodium, potassium, chloride, bicarbonate (or CO2), calcium, phosphate, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), blood urea nitrogen (BUN) creatinine, total bilirubin, direct bilirubin, alkaline phosphatase, albumin, glucose and eGFR calculated by 
CKD-EPI Creatinine Equation (https://www.kidney.org/content/ckd-epi-creatinine-equation-2009). 
6. At Weeks 1 and 24, a portion of urine will be stored frozen for future analysis. 
7. Iron Indices: TSAT, ferritin, iron, total iron binding capacity (TIBC). 
8. Infectious Disease Screen:  HIV 1 and 2, Hepatitis B surface antigen, Hepatitis B surface antibody, Hepatitis C antibody, mycobacterium tuberculosis 
test (e.g., QuantiFERON) is preferred, but a purified protein derivative (PPD) skin test read within 48-72 hours by a qualified healthcare professional 
can be performed. If the test comes back unable to perform analysis or indeterminate or confirmatory testing is required, the screening window is 
extended until central laboratory results are available. (https://www.cdc.gov/tb/publications/factsheets/testing/skintesting.htm). 
9. Special RBC: reticulocyte hemoglobin content (CHr). 
10. IL-6: Interleukin-6. Pre-dose sampling. 
11. hs-CRP: high-sensitivity C-reactive protein. Test can be repeated once prior to randomization visit.  Results after screening will be blinded after the first 
dose. 
12. Pregnancy: E-hCG; FSH: Follicle Stimulating Hormone. 
13. On dosing Weeks 1, 5, 9, 13, 17, and 21, trough PK samples to be collected within approximately -0.5 h pre-dose. Single PK blood samples will also 
be collected on Weeks 2, 4, 7, 23, 24/ET, 28, and 32/ET around the same time as the pre-dose samples were collected on previous dosing visits. 
14. On dosing weeks 1, 5, 9, 13, 17, and 21, ADA: Anti-drug antibodies specimens to be collected within approximately 0.5 h pre-dose. 
15. Standard 12-lead ECG will be recorded in the supine position (or with the patient as flat as possible) after vital signs assessments.  The ECG will be 
locally read by the Investigator. 
16. Chronic Kidney Disease (CKD) Biomarkers: cystatin C and UACR. 
17. Cardiac Risk marker: SSA, fibrinogen and ST2. 
18. Exploratory storage samples will be two 5-ml tubes of plasma, two 5-ml tubes of serum, and two 5-mL tubes of whole blood (PBMC testing at 
Screening, Week 13 and Week 24). 
19. Limited physical exam to include skin, oropharynx, lungs, heart, abdomen, extremities (including feet), and any areas suggested by symptoms, with 
particular attention to signs of infection.  May be performed by a physician-investigator or mid-level provider.  Record abnormal findings in the source 
documents. 
20. INR performed by a local laboratory on Warfarin patients only. 
21. PROMIS (Appendix B), to be done on subjects’ device at the clinic PRIOR to dosing. 
22. CARES Corvidia ePRO (Appendix D), 7 day at home assessment on subject’s personal device; the questionnaire will be answered daily for 7 days prior 
to dose (Screening Day -7 to Day -1 prior to Dose 1 (Visit 1), Dose 2 (Visit 4), Dose 4 (Visit 7), and the last 2 weeks after Dose 6 (Visit 23-24). 
CARES: Daily recall 
(starts with Visit -1) = baseline average of the 7 consecutive assessments (Day -7 to Day -1) prior to Dose 1  
(starts with Visit 3) = end of month of Dose 1 
(no visit) = end of month of Dose 3  
(starts with Visit 10 and Visit 11) = starts 2 weeks after Dose 6 
23. PGIS (Appendix E), to be done on subjects’ device on the last day of CARES assessment. 
24. PGIC (Appendix E), to be done on subjects’ device at the clinic PRIOR to dosing. 
25. Optum SF-36 v2® Health Survey (Appendix C), to be done on subjects’ device at the clinic PRIOR to dosing. 
26. EQ-5D-5L (Appendix F), to be done on subjects’ device at the clinic PRIOR to dosing.
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After signing the ICF, patients should be registered into the electronic data capture system to 
obtain a patient identification number for the study. 
5.1 
Screening Visit Procedures (Up to 2 weeks, Days -14 to -7) – Initial 
Screening 
Screening will be conducted in a stepwise manner. If a Screening laboratory result is outside 
inclusion criteria parameters screening may be extended up to one week to allow for retesting 
of lab test(s) that did not meet inclusion criteria.   
Prior to conducting any study procedures informed consent will be obtained from the patient 
by the investigator (or other study staff who are conducting the informed consent interview).  
The Initial Screening procedures will be conducted after informed consent has been obtained. 
The following will be performed according to Table 2. 
x ICF signed 
x Hematology 
x Chemistry 
x Iron Indices 
x TMPRSS6 Genotype  
x hs-CRP (may be repeated once up to randomization) 
x Screening IL-6 (total) 
 
5.2 
Screening Visit Procedures (Week -1; Days -7 to -1) – Full Screening  
Every effort should be made to obtain the blood tests for each visit on the same day of the 
week (e.g. on Wednesdays).  
The following list summarizes the procedures for Week -1.  Please see Table 2 for full 
details. 
x Medical History 
x Concomitant and Prior Medications 
x Vital Signs  
x Hematology 
x Lipids (fasting 8 hours) 
x Chemistry  
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x Spot urine protein-creatinine ratio  
x Infectious Disease Screen (If the test comes back unable to perform analysis or 
indeterminate or confirmatory testing is required, the screening window is extended 
until central laboratory results are available) 
x Serum Pregnancy, FSH  
x 12-lead ECG  
x CKD Biomarkers  
x NT-pro-BNP 
x Lp(a), ApoB, ApoA1 (fasting 8 hours) 
x Storage samples for Exploratory Biomarkers and RNA Testing (PBMC testing)  
x DNA Testing – Stored Blood Samples  
x Limited Physical Examination 
x CARES Corvidia ePRO 
x PGIS 
The following sections summarize the procedures for the Treatment Period. Please see Table 
2 for full details.  
5.3 
Treatment Period (Study Weeks 1 - 21) 
Important: Study Visits during which Study Drug injections are required should be planned 
for the same day of the week so that Study Drug administration can occur on a schedule of 
every 28 days.  See Section 6.1.1 for guidance on missed doses. 
5.3.1 
Visit 1, Week 1, Day 1 (Pre-Dose) 
x Medical History (update if necessary) 
x Randomization (may occur on Day -1 if needed) 
x Concomitant and Prior Medications 
x Vital Signs 
x BMI 
x Hematology 
x Lipids (fasting 8 hours) 
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x Chemistry 
x Urinalysis (including albumin); portion stored frozen 
x Iron indices  
x Serum hepcidin  
x Special RBCs 
x IL-6 (pre-dose) 
x hs-CRP 
x Ziltivekimab trough PK 
x ADA (pre-dose) 
x CKD Biomarkers 
x NT-pro-BNP 
x Lp(a), ApoB, ApoA1 (fasting 8 hours) 
x Lipid profile by NMR spectroscopy (fasting 8 hours) 
x Cardiac Biomarkers: SSA, fibrinogen and ST2 
x Coagulation (INR): Patients on warfarin only 
x Adverse Events 
x PROMIS® 13a and Fatigue Items 
x PROMIS® Sexual Interest Items 
x Optum SF-36 v2® Health Survey 
x EQ-5D-5L  
 
5.3.2 
Visit 1, Week 1, Day 1 (Dosing/Post-Dose) 
Administration of the first dose of Study Drug will continue to define Study Day 1. 
Prepare the Study Drug prior to the anticipated time of administration (see Section 6.1.1 and 
Pharmacy Manual). 
x Study Drug (after all assessments) 
 
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5.3.3 
Visit 2, Week 2, Day 8 
x Concomitant and Prior Medications 
x Hematology 
x Chemistry 
x Ziltivekimab trough PK 
x ADA 
x Coagulation (INR): Patients on warfarin only 
x Adverse Events 
 
5.3.4 
Visit 3, Week 4, Day 22 
x Concomitant and Prior Medications 
x Vital Signs 
x Hematology 
x Chemistry 
x IL-6 
x hs-CRP 
x Ziltivekimab trough PK 
x ADA (pre-dose) 
x Coagulation (INR): Patients on warfarin only 
x Adverse Events 
x CARES Corvidia ePRO 
x PGIS 
 
5.3.5 
Visit 4, Week 5 
x Study drug administered (after all assessments) 
x Concomitant and Prior Medications 
x Vital Signs 
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x Hematology 
x Chemistry 
x IL-6 (pre-dose) 
x hs-CRP 
x Ziltivekimab trough PK 
x ADA (pre-dose) 
x Coagulation (INR): Patients on warfarin only 
x Adverse events 
x PROMIS® 13a and Fatigue Items 
x PROMIS® Sexual Interest Items 
x PGIC 
x Optum SF-36 v2® Health Survey 
x EQ-5D-5L  
 
5.3.6 
Visit 5, Week 7 
x Concomitant and Prior Medications 
x Hematology 
x Chemistry 
x Ziltivekimab trough PK 
x ADA 
x Coagulation (INR): Patients on warfarin only 
x Adverse Events 
 
5.3.7 
Visits 6 through 9, Weeks 9 through 21 
x Concomitant and Prior Medications (not Week 12) 
x Vital Signs (not Week 12) 
x BMI (Week 13 only) 
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x Hematology (not Week 12) 
x Lipids (fasting 8 hours; Week 13 only) 
x Chemistry (not Week 12) 
x Spot urine protein-creatinine ratio (Week 13 only) 
x Urinalysis (including albumin) (Week 13 only) 
x Iron Indices (Week 13 only) 
x Serum hepcidin (Week 13 only) 
x Special RBCs (Week 13 only) 
x IL-6 (pre-dose) (not Week 12) 
x hs-CRP (not Week 12) 
x Ziltivekimab trough PK (not Week 12) 
x ADA (pre-dose) (not Week 12) 
x CKD Biomarkers (Week 13 only) 
x NT-pro-BNP (Week 13 only) 
x Lp(a), ApoB, ApoA1 (fasting 8 hours; Weeks 9 and 13 only) 
x Lipid profile by NMR spectroscopy (fasting 8 hours; Week 13 only) 
x Cardiac Risk Biomarkers: SSA, fibrinogen and ST2 (Week 13 only) 
x Storage samples for Exploratory Biomarkers and RNA Testing (Week 13 only) 
x Coagulation (INR): Patients on warfarin only (not Week 12) 
x Adverse Events (not Week 12) 
x PROMIS® 13a and Fatigue Items (Week 13 only) 
x PROMIS® Sexual Interest Items (Week 13 only) 
x CARES Corvidia ePRO (Week 12 only) 
x PGIS (Week 12 only) 
x PGIC (Week 13 only) 
x EQ-5D-5L  (Week 13 only) 
x Optum SF-36 v2 (Week 13 only) 
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5.3.8 
Visits 6 through 9, Weeks 9 through Week 21 (Dosing/Post-Dose) 
x Study Drug (after all assessments) (not Week 12) 
 
5.3.9 
Visit 10, Week 23 and Visit 11, Week 24/ET 
x Concomitant and Prior Medications 
x Vital Signs 
x BMI (Week 24 only) 
x Hematology 
x Lipids (fasting 8 hours) 
x Chemistry 
x Urinalysis (including albumin); portion stored frozen at Week 24 only 
x Iron Indices  
x Serum hepcidin (Week 24 only) 
x Special RBCs (Week 24 only) 
x IL-6 
x hs-CRP 
x Ziltivekimab trough PK 
x ADA  
x 12-lead ECG (Week 24 only) 
x CKD Biomarkers 
x NT-pro-BNP 
x Lp(a), ApoB, ApoA1 (fasting 8 hours) 
x Lipid profile by NMR spectroscopy (fasting 8 hours) 
x Cardiac Biomarker: SSA, fibrinogen and ST2 (Week 24 only) 
x Storage samples for Exploratory Biomarkers and RNA Testing (Week 24 only) 
x Limited Physical Examination (Week 24 only) 
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x Coagulation (INR): Patients on warfarin only 
x Adverse Events 
x PROMIS® 13a and Fatigue Items 
x PROMIS® Sexual Interest Items (Week 24 only) 
x CARES (Corvidia ePRO) [2 weeks after Week 21 (Dose 6) for 14 consecutive days] 
x PGIS (Week 24 only) 
x PGIC (Week 24 only) 
x Optum SF-36 v2® 
x EQ-5D-5L (Week 24 only) 
 
5.4 
Safety Follow-Up Visits 12 and 13 Procedures (Study Weeks 28 and 32) 
x Concomitant and Prior Medications 
x Vital Signs 
x Hematology 
x Lipids (fasting 8 hours) 
x Chemistry 
x Iron Indices  
x Special RBCs 
x IL-6 
x hs-CRP 
x Ziltivekimab trough PK  
x ADA  
x Adverse Events 
 
5.5 
Unscheduled Visit 
Additional clinical visits may be scheduled at the Investigators’ discretion in order to follow 
or evaluate AEs.  The reason for a given unscheduled visit will be recorded.  
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The following must be performed at any unscheduled visit occurring prior to Week 32: 
x Record adverse events 
x Record any medication changes. 
5.6 
Early Termination Visit 
There are two possible types of Early Termination visits: 
Early Termination Visit 1 (ET-1): Randomized patients terminating from the study 
prematurely prior to Study Week 24 should undergo an Early Termination Visit during which 
Week 24 procedures are performed. 
Early Termination Visit 2 (ET-2): Randomized patients terminating from the study 
prematurely after Study Week 24 visit, but before Week 32 should undergo an early 
termination visit during which Week 32 procedures are performed. 
Criteria for discontinuation of Study Drug can be found in Section 4.3. 
Patients may be withdrawn from the study for a number of reasons, including those outlined 
below: 
x Patients withdrawing their consent for all study procedures.  Patients must be given 
the option to continue to give consent for passive follow-up (i.e. by means of chart 
review) for adverse events through Study Week 21. 
x Discontinuation of the study by the Sponsor. 
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6 
DRUG SUPPLIES AND DOSING 
6.1.1 
Dosing and Administration 
The dose of Ziltivekimab for subcutaneous (SC) injection must be prepared using aseptic 
techniques.  Drug Product is presented as a single use vial and any unused portion must be 
discarded. 
Ziltivekimab is supplied as a liquid for injection.   
The rationale for the planned doses in the study is described in Section 3.5.4. Details on the 
dosing and administration are provided in Table 3, and the composition for Ziltivekimab for 
injection and amount per mL are provided in Table 4.  
Personnel responsible for study drug preparation should have an appropriate background 
(i.e., physician, pharmacist, pharmacy technician, nurse, or other personnel approved by the 
Sponsor) and has been appropriately trained.  Please see Pharmacy Manual for full details. 
The final required volume of Ziltivekimab is provided in Table 3. 
Please see the Pharmacy Manual for instructions on preparing and administering the Study 
Drug and storage of prepared Study Drug. 
Special Situations 
Patients who miss a dose of Study Drug may receive the missed Study Drug up to 15 days 
later. 
If the missed dose cannot be administered within this time frame, the dose should be 
considered “missed” and the next dose administered at the next study visit as planned. 
In the above special situations, please ensure that blood testing and PK sampling that is timed 
with the administered dose must be adhered to. 
 
 
 
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Table 3 
Planned Ziltivekimab Doses and Administered Volumes 
 
Dose Cohort 1 
Dose Cohort 2 
Dose Cohort 3 
Dose Cohort 4 
Intervention 
Name 
Ziltivekimab 
Ziltivekimab 
Ziltivekimab 
PBO 
Type 
Active Drug 
Active Drug 
Active Drug 
Comparator 
Dose 
7.5 mg 
15 mg 
30 mg 
N/A 
Dose 
Administration 
7.5 mg in 1 mL 
injection 
15 mg in 1 mL 
injection 
30 mg in 1 mL 
injection  
1 mL PBO 
injections\ 
Route of 
Administration 
SC injections 
SC injections 
SC injections 
SC injections 
Frequency 
Every 28 days per 
SOA 
Every 28 days per 
SOA 
Every 28 days per 
SOA 
Every 28 days per 
SOA 
Abbreviations: PBO = placebo; SC = subcutaneous; SOA = schedule of activities 
 
The date and time of administration of Study Drug must be recorded in the appropriate 
sections of the CRFs. 
6.1.2 
Storage 
Ziltivekimab and placebo must be stored at 2 to 8 °C in the original container and must not 
be frozen. 
6.1.3 
Formulation and Packaging 
Table 4 
Composition for Ziltivekimab for Injection, Amount per mL (7.5 
mg/Vial, 15 mg/Vial, 30 mg/Vial, and Placebo) 
Component 
Amount per mL 
(7.5 mg vial) 
Amount per mL 
(15 mg vial) 
Amount per mL 
(30 mg vial) 
Amount per mL 
(Placebo vial) 
Ziltivekimab 
7.5 mg 
15 mg 
30 mg 
0 mg 
Trehalose dihydrate 
50.00 mg 
50.00 mg 
50.00 mg 
50.00 mg 
L-Arginine 
monohydrochloride 
14.75 mg 
14.75 mg 
14.75 mg 
14.75 mg 
L-Methionine 
1.49 mg 
1.49 mg 
1.49 mg 
1.49 mg 
L-Histidine 
1.55 mg 
1.55 mg 
1.55 mg 
1.55 mg 
L-Histidine mono-
hydrochloride monohydrate 
2.10 mg 
2.10 mg 
2.10 mg 
2.10 mg 
Polysorbate 80 
0.70 mg 
0.70 mg 
0.70 mg 
0.70 mg 
Water for Injection 
q.s. to 1.0 mL 
q.s. to 1.0 mL 
q.s. to 1.0 mL 
q.s. to 1.0 mL 
Abbreviations:  q.s. = quantum satis 
 
 
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6.2 
Drug Accountability and Compliance 
The dispensing pharmacist or designated qualified individual will write the date dispensed, 
dose dispensed, and the patient’s identification number, and initials on the Drug 
Accountability Source Documents.  All medication supplied will be accounted for on the 
Drug Accountability Record.  All partially used or unused drug supplies will be destroyed at 
the site in accordance with approved written site procedures or returned to Corvidia 
Therapeutics.  The Investigator will maintain a record of the amount and dates when unused 
supplies were either destroyed or returned to Corvidia Therapeutics.  All records will be 
retained as noted in Section 13.5. 
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7 
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS 
7.1 
Prior Medications and Treatments 
See Section 4.1 and Section 4.2 for restrictions on prior medications and treatments. 
7.2 
Concomitant Medications and Treatments 
Patients with cardiovascular disease should be treated according to published guidelines 
throughout the trial; in addition, patients may receive concomitant medications as clinically 
indicated with the following restrictions: 
Systemic immunosuppressive drugs (i.e., such as cyclosporine, tacrolimus, sirolimus, 
mycophenolate, oral and intravenous glucocorticoids other than prednisone [or equivalent] 
up to a dose of 5 mg per day) may not be prescribed at any time during Study.  Topical use 
(e.g., cyclosporine eye drops) is not restricted 
Note: Use of otic, ophthalmic, inhaled, and topical corticosteroids or local 
corticosteroid injections are not restricted.  Short-term systemic glucocorticoid use 
(e.g., less than 5 consecutive days) for managing acute illnesses is also not restricted. 
Narrow therapeutic window medications that are influenced by CYP enzymatic pathways 
(See list in Appendix A) may not be prescribed at any time during Study.  
x 
Warfarin is permitted, but the INR must be monitored closely and, at minimum, 
according to the protocol Schedule of Events (see Table 2). 
 
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8 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS  
8.1 
Serious Infections 
Study drug treatments should be withheld if patients experience a serious infection until the 
infection is believed to have completely resolved.  The Investigator should contact the 
Medical Monitor to discuss whether the patient should return to Study Drug treatment. 
8.2 
Injection-Related Reactions, Hypersensitivity, and Anaphylaxis 
Signs of a possible injection-related reaction include fever, chills, pruritus, and urticaria.   
Anaphylaxis is a severe, potentially fatal, systemic allergic reaction that occurs suddenly 
after contact with an allergy-causing substance, such as an investigational product. 
For the purposes of this study, a hypersensitivity reaction is defined as an acute onset of an 
illness with involvement of the skin, mucosal tissue, or both during injection of the Study 
Drug (but does not meet the definition of anaphylaxis described above). 
If signs and symptoms of injection-related reactions are observed and the patient’s 
cardiovascular status is stable:  
x If the patient continues to show signs and symptoms of hypersensitivity, administer 
an SC dose of antihistamine, if the Investigator believes this is appropriate.   
x In patients who have experienced mild or moderate injection reactions during prior 
Study Drug administrations, antihistamines and/or acetaminophen may be 
administered prophylactically prior to subsequent injections, at the discretion of the 
Investigator. 
x In patients who experience severe injection-related reactions, anaphylaxis, or 
hypersensitivity (see definition and grading below): 
x Permanently discontinue the Study Drug 
x Treat the patients as for an anaphylactic reaction with IV antihistamines, 
corticosteroids, epinephrine, inhaled bronchodilators, and other measures as 
necessary  
x Obtain a blood sample for the presence of anti-drug antibodies 
The patient should remain in the study for continued follow-up, but should receive no further 
Study Drug. 
 
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9 
ADVERSE EVENT REPORTING 
9.1 
Adverse Event Definitions  
An AE is any undesirable event or any untoward medical occurrence that occurs to a 
participant during the course of a study, or the protocol-defined time after study termination, 
whether or not that event is considered Study Drug-related. 
Examples include: 
x Any treatment emergent signs and symptoms (events that are marked by a change 
from the patient’s baseline/entry status [e.g., an increase in severity or frequency of 
pre-existing abnormality or disorder]);  
x All reactions from Study Drug, abuse of drug, withdrawal phenomena, sensitivity or 
toxicity to Study Drug; 
x Apparently unrelated illnesses; 
x Injuries or accidents (e.g., for a fall secondary to dizziness, record “dizziness” as the 
event and include the information about the fall in the comment/narrative section and 
information about any injury secondary to the fall as part of the “outcome”); 
x Exacerbations (increase in frequency or severity) of symptomatology, subjective 
patient-reported events, new clinically significant abnormalities in clinical laboratory, 
physiological testing or physical examination; 
x Abnormal laboratory findings considered by the Investigator to be clinically 
significant.  In general, an abnormal laboratory value should not be recorded as an 
adverse event unless: 
o It is associated with clinical signs or symptoms, 
o Requires an intervention, results in a serious adverse event, or  
o Results in study termination or interruption/discontinuation of study 
treatment.  
However, if none of the above applies, but the laboratory abnormality is considered clinically 
significantly worsened, it should be reported as a laboratory AE (e.g., “increased white blood 
cell count”).  When recording an adverse event resulting from a laboratory abnormality, the 
resulting medical condition rather than the abnormality itself should be recorded (e.g., record 
“anemia” rather than “low hemoglobin”). 
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9.2 
Serious Adverse Event Definition 
An SAE is any AE, occurring at any dose and regardless of causality, that: 
x Results in death; 
x Is life-threatening.  Life-threatening means that in the opinion of the Investigator or 
Study Sponsor, the patient was at immediate risk of death from the reaction as it 
occurred, (i.e., it does not include a reaction that hypothetically might have caused 
death had it occurred in a more severe form); 
x Requires inpatient hospitalization or prolongation of existing hospitalization. 
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period, but planned before the signing for the ICF, are not considered AEs if the 
illness or disease existed before the patient was enrolled in the trial, provided that it 
did not deteriorate in an unexpected manner during the trial (e.g., surgery performed 
earlier than planned); 
x Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions; 
x Is a congenital anomaly/birth defect; 
x Is an important medical event.  An important medical event is an event that may not 
result in death, be life-threatening, or require hospitalization but may be considered 
an SAE when, based upon appropriate medical judgment, it may jeopardize the 
patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions for SAEs.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
A distinction should be made between the terms “serious” and “severe” since they are not 
synonymous.  The term “severe” is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as severe headache).  This is not the same 
as “serious,” which is based on patient/event outcome or action criteria usually associated 
with events that pose a threat to a patient’s life or functioning.  A severe adverse event does 
not necessarily need to be considered serious.  For example, persistent nausea of several 
hours duration may be considered severe nausea but not an SAE if the event does not meet 
the serious criteria.  On the other hand, a stroke resulting in only a minor degree of disability 
may be considered mild, but would be defined as an SAE based on the above noted serious 
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criteria.  Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
9.3 
Adverse Events of Special Interest  
The following adverse events of special interest must be reported to the Sponsor within 
24 hours of the Investigator’s awareness, even if not meeting the definition of a serious 
adverse event: 
x Serious infections. 
x Severe injection-related reactions. 
x Gastrointestinal perforations. 
x Hypersensitivity reaction during study drug administration. 
x Anaphylaxis occurring at any time, even if considered unrelated to the study drug. A 
CRF for the collection of the details of such reactions will be available in the EDC. 
x Neutrophil <500/mm3 (severe), or neutrophil <1000/mm3 (severe) with evidence of 
concurrent infection. These events will be separately summarized by treatment group 
and dose. 
x Thrombocytopenia (platelet count <50,000/mm3 (severe)) or platelet count 
<75,000/mm3 (moderate) with evidence of concurrent TIMI major bleeding. These 
events will be separately summarized by treatment group and dose. 
x Malignancies 
x Description of additional safety assessments by treatment group and dose: vital signs, 
ECG, clinical laboratory, and anti-drug antibodies (binding and neutralizing). 
9.4 
Assessment of Causal Relationship 
The causal association of AEs to Study Drug administration should be determined as follows: 
The following categories should be used in the causality assessment of suspected adverse 
reactions: 
Probable  
The AE follows a reasonable temporal sequence from the time of Study Drug administration; 
and/or follows a known response pattern to the Study Drug; and was unlikely to have been 
produced by other factors such as the patient’s clinical state, therapeutic intervention or 
concomitant therapy. 
Possible 
The AE follows a reasonable temporal sequence from the time of Study Drug administration; 
and/or follows a known response pattern to the Study Drug; but could have been produced by 
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other factors such as the patient’s clinical state, therapeutic intervention or concomitant 
therapy. 
Unlikely  
The AE does not follow a reasonable temporal sequence from the time of Study Drug 
administration; and was most likely produced by other factors such as the patient’s clinical 
state, therapeutic intervention or concomitant therapy. 
Unrelated 
This category is applicable to those AEs that are judged to be clearly and incontrovertibly 
due only to extraneous causes (the patient’s clinical state, therapeutic intervention or 
concomitant therapy) and do not meet the criteria for Study Drug relationship listed under 
Probable, Possible, or Unlikely.  
An AE with causal relationship not initially determined will require follow-up to assign 
causality. 
9.5 
Assessment of Severity 
The Investigator must determine the severity of the event or laboratory value according to 
Table 5 (refer to laboratory manual for guidance); severity describes the intensity of the 
adverse event or lab value. 
Table 5 
Severity Assessment for AEs and Abnormal Laboratory Values  
Mild 
Awareness of sign or symptom, but easily tolerated; lab value mildly 
outside normal reference range but not clinically significant 
Moderate 
Discomfort enough to cause interference with normal daily activities; 
lab value moderately outside normal reference range and clinically 
significant 
Severe 
Inability to perform normal daily activities; lab value severely outside 
normal reference range and clinically significant 
 
9.6 
Adverse Event Reporting 
The AE reporting period starts with randomization and continues through the Week 32 study 
visit.  Patients in this study who experience a drug-related AE or SAE will be followed until 
the AE or SAE is resolved or stabilizes per the Investigator’s judgment, even if this occurs 
after the final study visit.  All AEs spontaneously reported by the patient and/or in response 
to an open question from study personnel or revealed by observation, physical examination, 
or other diagnostic procedures will be recorded and reported on the appropriate CRF.  When 
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a unifying diagnosis has been made that accounts for several possible signs and/or symptoms, 
the unifying diagnosis should be selected as the AE term.  For example, the combination of 
general malaise, mild fever, headache, and rhinitis should be described as “upper respiratory 
syndrome” if this diagnosis has been made, rather than reporting the individual symptoms as 
separate events. 
If any laboratory test is newly abnormal during the treatment or safety follow-up period, it 
will be followed at the discretion of the Investigator.  Abnormalities of laboratory tests which 
are, in the opinion of the Investigator, clinically significantly worse compared to baseline, or 
for which a medical intervention is initiated, should be reported as AEs on the AE CRF. 
9.7 
Reporting of Serious Adverse Events and Adverse Events of Special 
Interest  
The SAE reporting period is the same as the AE reporting period.  All SAEs that occur 
during the reporting period and regardless of causality must be reported by the Investigator to 
 by completing the SAE Form in the EDC system.  Any pertinent source documents 
should also be submitted as soon as they are available.  Do not withhold submission of an 
SAE even if complete information about the event is not available at the time of the initial 
report.  Follow-up information on the SAE should be sent promptly by the Investigator when 
any additional relevant information about the event becomes known to the Investigator, or as 
requested by 
 or Corvidia Therapeutics. 
SAE and Pregnancy Reporting Contact Information 
 
 
Telephone: 
 
Facsimile: 
 
e-mail:
 
 
 
Hypersensitivity reactions (see Section 8.2) occurring during the Study Drug injection and 
anaphylaxis occurring anytime during Weeks 1 – 21 of the study should be reported in the 
EDC as adverse or serious adverse events on the AE and SAE CRFs within 24 hours of the 
site’s awareness of the event.  Please submit as much information as is available with the 
initial report. 
Corvidia Therapeutics will immediately notify the Investigator about important safety or 
toxicology information as it becomes available.  It is the responsibility of the Investigator to 
promptly notify the IRB/ IEC about new and relevant safety information regarding the Study 
Drug, including serious adverse drug reactions involving risk to human subjects, in 
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accordance with the applicable policies.  An unexpected event is one that is not listed by 
nature or severity in the Investigator’s Brochure. 
9.8 
Pregnancy Reporting 
If a woman who is a study patient becomes pregnant or a woman suspects she is pregnant 
from a male study patient, the Investigator should be informed immediately.  The Sponsor 
must, in turn, also be notified by the Investigator immediately by completing a Pregnancy 
Form and faxing or emailing it to 
 (see Section 9.7).  The pregnancy must be 
followed up through delivery or other fetal outcome.  For any abnormal fetal outcome, 
including congenital anomaly or birth defect, spontaneous or therapeutic abortion, still birth, 
pre-mature birth, or other outcome other than live normal birth, the Investigator should 
promptly report to the Sponsor the abnormal fetal outcome on an SAE form. 
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10 
STUDY ASSESSMENTS 
10.1 
Pharmacodynamic Assessments 
10.1.1 
CKD symptoms, Fatigue, and Health-Related Quality of Life  
CKD symptoms, fatigue, and health-related quality of life will be assessed with the PROMIS 
Fatigue 13a short form and selected items from the PROMIS fatigue item bank (Appendix 
B), Optum SF-36 v2® Health Survey PCS, MCS, and domain scores (Appendix C), 
PROMIS interest in sexual activity item (Appendix B), the Corvidia ePRO (Appendix D), the 
patient global impression of severity (PGIS) and the patient global impression of change 
(PGIC) (Appendix E),  and the EQ-5D-5L (Appendix F). 
10.1.2 
Laboratory Assessments 
Evaluation of hs-CRP and hemoglobin are direct measure of IL-6 function. Serum albumin is 
also closely negatively correlated with inflammation. Key hematologic and iron metabolism 
assessments include Chr, TSAT, TIBC, ferritin, serum iron, and hepcidin. 
Biomarkers of inflammation and cardiovascular risk include serum SSA, fibrinogen, NT-pro-
BNP and ST2, which were chosen based on the documented detrimental effects of IL-6, and 
beneficial effects of anti-IL-6 therapies, on inflammation and on cardiac structure and 
function. 
Biomarkers for CKD will be evaluated including cystatin C, creatinine, and urine albumin-to-
creatinine ratio (UACR). 
10.2 
Safety Assessments (other than Adverse Events) 
10.2.1 
Vital Signs 
Vital signs include temperature, respiratory rate, heart rate, and blood pressure.  Whenever 
possible, vital signs will be obtained after at least 5 minutes resting in the supine position or, 
when necessary, in a semi-recumbent position. Vital signs will be done prior to ECG 
recordings. 
10.2.2 
12-lead ECG 
At specified time points, standard 12-lead ECG will be recorded in the supine position 
(or with the patient as flat as possible) after vital signs assessments.  The ECG will be locally 
read by the Investigator. 
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10.2.3 
Physical Examination 
Scheduled (limited) physical exams must include at a minimum an examination of the skin, 
oropharynx, lungs, heart, abdomen, extremities (including feet), and any areas suggested by 
symptoms, with particular attention to signs of infection. 
10.2.4 
Clinical Laboratory Testing 
Details on the collection, processing, storage, and shipment of central lab samples are 
contained in the Laboratory Manual.  Coagulation: INR (only for patients on warfarin) will 
be performed at the Local Laboratory. 
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11 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS 
The study design and objectives are described in Sections 2.0 and 3.0, respectively. Details of 
all planned analyses are provided in the Statistical Analysis Plan (SAP).  
11.1 
Sample Size 
The primary efficacy endpoint is percent change from baseline in hs-CRP (average of the 
hs-CRP value prior to randomization and Day 1) to Week 13 between each active group and 
placebo. Based on the observed treatment difference in percent change from baseline in 
hs-CRP of -60.74% between combined COR-001-01 active groups and placebo and the 
associated pooled SD of 16.893% in hs-CRP at Week 4 from the final analysis of study 
COR-001-SC1, a sample size of 54 per group yields more than 99% power with 2-sided 
alpha=0.05. Taking into consideration the dropout rate of 10% by the end of the study, a 
sample size of 60 per group is planned for this study 
Approximately 240 patients (60 per group) will be randomized.  
11.2 
Randomization 
Approximately 240 patients will be randomized 1:1:1:1 to Ziltivekimab Dose #1 (7.5 mg), 
Ziltivekimab Dose #2 (15 mg) or Ziltivekimab Dose #3 (30 mg) or Placebo as they became 
eligible to proceed with dosing on Day 1. Patient randomization will be stratified by baseline 
hemoglobin (≥11 or <11 g/dL) and CKD stage (3, 4 or 5). Approximately 240 patients will 
be randomized 1:1:1:1 (60 per group) into the trial. 
11.3 
General Statistical Considerations and Definitions 
11.3.1 
General Statistical Methods 
All study-collected data will be summarized by treatment group for the appropriate analysis 
population, using descriptive statistics, graphs, and/or raw data listings.  Descriptive statistics 
for continuous variables will include number of patients (n), mean, standard deviation (SD), 
median, quartiles (Q1 and Q3), minimum (min) and maximum (max) values.  Analysis of 
categorical variables will include frequency and percentage. 
11.3.2 
Analysis Populations 
Intent-to-Treat (ITT) analysis population: all patients randomized. 
The ITT analysis populations will be the primary population for the analyses of disposition 
and baseline data and efficacy endpoints. 
Per-Protocol analysis population: all patients randomized who completed the study and did 
not incur a significant protocol violation 
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For the ITT analysis populations and per-protocol populations, treatment classification will 
be based on the randomized treatment.   
Pharmacokinetics (PK) analysis population: all patients randomized and who received at 
least one dose of Test or Reference product and who had at least one post-dose PK blood 
sample 
Safety analysis population: all patients randomized and who received at least one dose of 
Test or Reference product. 
For the PK analysis population and safety population, treatment classification will be based 
on the treatment actually received.  
11.3.3 
Analysis Windows and Baseline 
If data are collected by visit, the data will be analyzed by visit based on the protocol-planned 
visits.  If multiple records are collected for a visit, the latest record will be used for the 
summary for that visit. 
The observational period for the study will start from informed consent and end with study 
completion (see Section 4.4 for the definition of study completion).  Any event occurring 
after the defined observational period, even if collected on the CRF, may not be included in 
the planned statistical analysis.  However, all data, including that reported after the defined 
observational period, will be included in the patient data listings.  
For evaluations that are collected at multiple occasions prior to initiation of Study Drug, the 
latest evaluation will be considered the "Baseline" evaluation for analysis, unless otherwise 
specified. 
11.3.4 
Missing Data Handling 
Unless otherwise specified, missing data will not be imputed and the analyses will be based 
on observed data only. 
11.4 
Statistical Analyses 
11.4.1 
Demographic and Background Characteristics 
Patient demographics and baseline characteristics will be summarized by treatment group 
using the ITT, per-protocol, and safety populations 
11.4.2 
Study Drug and Concomitant Medications 
Summaries of prior (pre-baseline) medications and concomitant (baseline or later) 
medications will be provided by treatment group using the safety population. Prior 
medications are defined as medications given before the first dose of study drug. 
Concomitant medications are defined as medications taken before and continuing after first 
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dose of study drug or initiated after first dose of study drug. Medications will be coded with 
World Health Organization (WHO) Drug Dictionary.  Patients will be counted only once by 
medication class or name. 
11.4.3 
Efficacy Analysis 
For all efficacy variables, the number of patients (n), mean, standard deviation (SD), median, 
quartiles (Q1 and Q3), minimum (min) and maximum (max) values for the observed value, 
change from baseline, or percent change from baseline (as applicable) will be reported. The 
difference (Ziltivekimab - Placebo) in changes or percent changes (as applicable) will be 
presented.  
A mixed model for repeated measures (MMRM) will be used to evaluate change or percent 
change from baseline. The model will include variables for baseline hemoglobin (≥ 11 or < 
11 g/dL), CKD Stage (3, 4 or 5), treatment group, visit and treatment group-by-visit 
interaction as categorical fixed effects, baseline value and baseline-by-visit interaction will 
be included as covariates. The least squares means for each dose, the least squares mean 
differences from placebo along with the associated 95% confidence intervals (CIs) and p-
values will be presented. If the normality assumption is not met, a nonparametric test will be 
selected for efficacy analysis. Details of normality test and nonparametric test will be 
provided in the Statistical Analysis Plan. 
An unstructured covariance matrix will be used to model the within-subject correlation. The 
Kenward-Roger approximation will be used to adjust the denominator degrees of freedom. 
The analysis will be performed based on all observed post-baseline scores without any 
imputation of missing data. In the case when the MMRM fails to converge using an 
unstructured covariance matrix in any stage, a less stringent covariance matrix (e.g., 
autoregressive 1) will be used. 
Sensitivity analyses will be conducted to explore the robustness of the result for primary 
efficacy endpoint based on MMRM. Full details will be pre-specified in SAP and 
documented prior to database lock of the study. 
The differences in proportions and 95% CIs will be based on the normal approximation to 
binomials. 
11.4.4 
Efficacy Variables 
The pharmacodynamic efficacy of three Ziltivekimab doses compared to placebo will be 
assessed by evaluating the following: 
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11.4.4.1 
Primary 
x Difference in percent change in hs-CRP levels from Baseline (average of the hs-CRP 
value prior to randomization and Day 1) to Week 13 between each active group and 
placebo. 
11.4.4.2 
Secondary  
x Difference in change in SAA from Baseline to Week 13 between each active group and 
placebo. 
x Difference in percent change in fibrinogen from Baseline to Week 13 between each 
active group and placebo. 
11.4.4.3 
Exploratory 
x Difference in percent change in hs-CRP levels from Baseline to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in percent change in serum NT-pro-BNP from Baseline (average of the NT-
pro-BNP value prior to randomization and Day 1) to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in change in SAA from Baseline to End of Treatment (Weeks 23 through 
24) between each active group and placebo. 
x Difference in percent change in fibrinogen from Baseline to End of Treatment (Week 
24) between each active group and placebo. 
x Difference in change in hemoglobin from Baseline (average of the two most recent 
hemoglobin values prior to randomization and Day 1) to Week 13 and to End of 
Treatment (Weeks 23 through 24) between each active group and placebo. 
x Difference in change in serum albumin from Baseline (average of the two most recent 
serum albumin values prior to randomization and Day 1) to Week 13 and to End of 
Treatment (Weeks 23 through 24) between each active group and placebo. 
x Proportion of patients achieving hs-CRP response at Week 13 and to End of Treatment 
(Weeks 23 through 24), defined as hs-CRP <2.0 mg/L in each active group and placebo. 
x Difference in change in ST2 from Baseline to Week 13 and to End of Treatment (Week 
24) between each active group and placebo. 
x Difference in percent change in Lp(a) from Baseline to Week 13 and to End of 
Treatment (Weeks 23 through 24) between each active group and placebo. 
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x Difference in percent change in LDL-C, triglycerides, ApoB, ApoA1, ApoB/ApoA1, 
and lipid profile by NMR spectroscopy from Baseline to Week 13 and to End of 
Treatment (Weeks 23 through 24) between each active group and placebo. 
x Difference in change of creatinine based eGFR and cystatin C-based eGFR from 
Baseline to Week 13 and to the End of Treatment (Weeks 23 through 24) between each 
active group and placebo. 
x Difference in change of UACR from Baseline to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in change of the total fatigue score (PROMIS Fatigue 13a short form and 
selected items from the PROMIS Fatigue item bank) from Baseline to Week 13 and to 
End of Treatment (Weeks 23 through 24) between each active group and placebo. 
x Difference in change of the PROMIS interest in sexual activity item from Baseline to 
Week 13 and to End of Treatment (Week 24) between each active group and placebo. 
x Difference in change of the Corvidia ePRO items from Baseline to Week 12 and to End 
of Treatment (Weeks 23 through 24) between each active group and placebo. 
x Difference in change of the PGIS index from Baseline to Week 12 and to End of 
Treatment (Week 24) between each active group and placebo. 
x Descriptive analyses of the PGIC index at Weeks 5, 13 and End of Treatment (Week 
24) in each active group and placebo. 
x Difference in change of the Optum SF-36 v2® Health Survey physical component 
summary (PCS), mental component summary (MCS) and domain scores from baseline 
to Week 13 and to End of Treatment (Weeks 23 through 24) between each active group 
and placebo. 
x Difference in change of the EQ-5D-5L index from Baseline to Week 12 and to End of 
Treatment (Week 24) between each active group and placebo. 
x Evaluation of the psychometric properties of the PROMIS Fatigue 13a short form and 
selected items from the PROMIS Fatigue item bank and the Corvidia ePRO items in 
CKD patients – to be described in a PRO psychometric analysis plan. 
x Descriptive analyses by dose and treatment may be conducted on samples stored for 
analysis of exploratory biomarkers, genomic and transcriptomic analysis. 
x Difference in change in TSAT from Baseline to peak level, Week 13 and End of 
Treatment (Weeks 23 through 24), between each active group and placebo. 
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x Difference in change in CHr from Baseline to peak level, Week 13 and to End of 
Treatment (Week 24) between each active group and placebo. 
x Difference in change in TIBC from Baseline to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in change in serum ferritin from Baseline to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in change in serum iron from Baseline to Week 13 and to End of Treatment 
(Weeks 23 through 24) between each active group and placebo. 
x Difference in change in serum hepcidin from Baseline to Week 13 and to End of 
Treatment (Week 24) between each active group and placebo. 
x Difference in percent change in serum NT-pro-BNP from Baseline to Week 13 and to 
End of Treatment (Weeks 23 through 24) between each active group and placebo in 
patients with baseline NT-pro-BNP > 250 pg/mL. 
x Difference in change in hemoglobin from Baseline (average of the two most recent 
hemoglobin values prior to randomization and Day 1) to Week 13 and to End of 
Treatment (Weeks 23 through 24) between each active group and placebo in patients with 
baseline hemoglobin < 11 g/dL. 
x Difference in change in serum albumin from Baseline (average of the two most recent 
serum albumin values prior to randomization and Day 1) to Week 13 and to End of 
Treatment (Weeks 23 through 24) between each active group and placebo in patients with 
baseline albumin < 4.0 g/dL. 
For the above efficacy variables, the observed values, changes from baseline, or percent 
changes from baseline (as applicable) will be summarized by treatment group using 
descriptive statistics using ITT.  
The PROMIS Fatigue 13a short form contains 13 items that assess symptoms and impacts of 
fatigue (Appendix B).  The total score of the PROMIS Fatigue 13a short form and selected 
items from the PROMIS fatigue item bank will be calculated as a raw score based on the 
average of the items. The observed value and change from baseline in total fatigue score will 
be summarized by treatment at each visit.  
The PROMIS Sexual Function and Satisfaction (PROMIS SexFS) is a customizable self-
reported set of measures that include 79 items in 11 domains, for the purpose of this protocol 
we are only using 1 item: interest in sexual activity, lubrication, vaginal discomfort, erectile 
function, global satisfaction with sex life, orgasm, anal discomfort, therapeutic aids, sexual 
activities, interfering factors, and screener questions. The PROMIS evaluations are to be 
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done on subjects’ device at the clinic PRIOR to dosing. The observed value and the change 
from baseline will be summarized by treatment at each visit.  
The Optum SF-36 v2® Health Survey is perhaps the most widely used health-related quality 
of life (HRQoL) survey instrument in the world today (Hays 2001). It is comprised of 36 
items that assess eight health concepts: physical functioning, role limitations caused by 
physical health problems, role limitations caused by emotional problems, social functioning, 
emotional well-being, energy/fatigue, pain, and general health perceptions (Appendix C). 
Physical and mental health summary scores are also derived from the eight Optum SF-36 
scales. The PCS, MCS, and domain scores will only be analyzed descriptively. The observed 
value and change from baseline in total Optum SF-36 v2® Health Survey score will be 
summarized by treatment. The Optum evaluations are to be done on subjects’ device at the 
clinic PRIOR to dosing. 
The CARES Corvidia ePRO is a new PRO instrument under development (Appendix D).  It 
consists of 19 symptom items, with a 24-hour recall, asking patients to report their worst 
level of that symptom in the past 24 hours on a numeric rating scale from 0 (no symptom) to 
10 (symptom as bad as I can imagine).    
Data will be collected at home on subject’s personal device or one provided by Corvidia; the 
questionnaire will be answered daily for 7 days prior to dose (Screening Day -7 to Day -1 
prior to Dose 1 (Visit 1), Dose 2 (Visit 4), Dose 4 (Visit 7), and the last 2 weeks after Dose 6 
(Visit 23-24). For each item, weekly scores will be derived as the average of the 7 
consecutive daily scores as follows: 
Baseline = average of Day -7 to Day -1 
Visit 4 = average of Day 22 to Day 28 
Visit 7 = average of Day 78 to Day 84 
If more than 4 daily scores out of the 7 days (>50%) within the weekly period are missing, 
then the score is set to missing. 
A bi-weekly score (the End of Treatment) will also be derived as the average of Day 155 to 
Day 168. If more than 8 daily scores out of the 14 days (>50%) within the bi-weekly period 
are missing, then the score is set to missing. 
Psychometric analyses will be conducted using the trial data to assess the psychometric 
properties of the CARES Corvidia ePRO instrument. The structural validity of CARES 
Corvidia ePRO instrument will be evaluated by means of exploratory factor analysis. A total 
summary scale or set of scales will be proposed in light of the factor loadings as well as 
clinical and conceptual considerations.  Additional details will be described in the PAP. The 
score(s) developed as psychometrically sound will be used to evaluate efficacy. 
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Summary measures of compliance at each analysis visit will be derived among those patients 
who are expected to have PRO assessments. The completion rate will be defined as the total 
number of actual completed diary entries divided by the expected number of diary entries in 
a given time period (total number of days X number of expected patients). 
The observed value and change from baseline on the developed scores will be summarized 
by treatment at each analysis visit. 
The Patients' Global Impression of Change (PGIC) scale and the Patients' Global Impression 
of Severity (PGIS) scale represent clinically relevant tools to assess perceived impact of 
disease management. The PGIC evaluates overall health status as perceived by the patient in 
a seven-point, single-item scale ranging from 'very much worse' to ‘no changes’ to 'very 
much improved’.  The PGIS is a 5-point scale (from no symptoms to very severe symptoms) 
and patients are asked to rate their overall severity of symptoms in the present (e.g., at each 
visit). The PGIC and PGIS are the most commonly used anchor based method of assessing 
clinically important change and severity in which the external judgment of meaningful 
change is made by the patient (Appendix E). The PGIC and PGIS evaluations will be done 
on subjects’ device at the clinic PRIOR to dosing. Descriptive statistics (counts and 
percentages) for each response option at each scheduled visit for both PGIC and PGIS 
(separately) will be provided. A stacked column chart showing the distribution of responses 
at each scheduled visit will also be provided. 
The EurQol-5D-5L (EQ-5D-5L) is a standardized measure of health status developed by the 
EuroQol Group in order to provide a simple, generic measure of health for clinical and 
economic appraisal (Appendix F). Applicable to a wide range of health conditions and 
treatments, it provides a simple descriptive profile and a single index value for health status 
that can be used in the clinical and economic evaluation of health care as well as in 
population health surveys. EQ-5D is designed for self-completion by respondents and is 
ideally suited for use in postal surveys, in clinics, and in face-to-face interviews. It is 
cognitively undemanding, taking only a few minutes to complete. Instructions to respondents 
are included in the questionnaire. 
The EQ-5D-5L is to be done on a subject’s device at the clinic PRIOR to dosing. EQ-5D-5L 
consists of two parts: 
x EQ-5D-5L descriptive system 
x Visual Analog Scale (VAS) with instant recall of “how you feel today”; scale goes 
from 0-100, where 100 means the best health you can imagine and 0, the worst one. 
The EQ-5D-5L descriptive system includes the basic domains common to each generic 
health status measure: mobility, self-care, usual activities, pain/discomfort and 
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anxiety/depression. The instrument includes one single question per domain. For each 
question, there are 5 levels of responses, corresponding to increasing levels of impairment 
(no problems, slight problems, moderate problems, severe problems, and extreme problems), 
and coded 1 to 5. 
Only descriptive analyses of the EQ-5D-5L results will be presented. Number and percentage 
of patients with each of five levels (no problems, slight problems, moderate problems, severe 
problems, and extreme problems) of response in each domain will be presented by treatment 
and visit. The observed value and change from baseline on the EQ-5D-5L VAS score will be 
summarized by treatment at each analysis visit. 
Additional exploratory analyses of the PROs collected in the study will be described in the 
PROSAP. 
11.4.4.4 
Multiple Comparisons Procedure for Primary Efficacy and Secondary Endpoints 
The overall familywise error rate (FWER) will be controlled at α = 0.05 using the sequential 
testing procedure for the primary efficacy endpoint comparing between the three dose levels 
of Ziltivekimab vs. placebo. The high dose (30 mg) will be compared with placebo at the 
beginning. If significant then the middle dose (15 mg) will be compared with placebo. If the 
middle dose is significant, then the low dose (7.5 mg) will be compared with placebo. The 
procedure stops whenever a nonsignificant test occurs. 
Secondary endpoints are not included in the multiplicity control. 
11.4.5 
Safety Analysis 
11.4.5.1 
Adverse Events 
The adverse event verbatim descriptions (investigator terms from the CRF) will be classified 
into medical terminology using the Medical Dictionary for Regulatory Activities (MedDRA).  
Adverse events will be coded to primary System Organ Class (SOC) and preferred term (PT) 
using MedDRA, Version 21.0.   
Treatment emergent adverse events (TEAEs) are defined as AEs that initiated or worsened 
on or after the date of first dose of study drug up to the end of safety-follow-up. For AEs 
occurring on the first dosing day, if the start time cannot be ascertained, the event will be 
counted as treatment-emergent. 
Safety events of special interest (Section 9.3) will be summarized by dose group and 
treatment assignment. 
An overview of AEs will be provided including counts and percentages of subjects with the 
following: 
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• 
Any TEAEs (overall and by maximum severity) 
• 
Any study drug related TEAEs (overall and by maximum severity) 
• 
Any TEAEs of special interest (overall and by maximum severity) 
• 
Any serious AEs (SAEs) 
• 
Any treatment-emergent serious AEs (TESAEs) 
• 
Any TEAEs leading to discontinuation of study drug 
• 
Any TEAEs leading to discontinuation of study 
• 
Any AEs leading to death 
• 
Any severe hematologic AEs (see Section 11.4.5.7) 
• 
Any severe non-hematologic AEs 
The number and percentage of patients reporting TEAEs and SAEs for each preferred term 
will be tabulated by system-organ class, by system- organ class and severity, and by system- 
organ class and relationship to Study Drug. If more than one event occurred with the same 
preferred term for the same patient, the patient will be counted only once for that preferred 
term using the most severe or related occurrence for the summary by severity, or relationship 
to study drug, respectively. 
Listings will be presented specifically for SAEs and TEAEs leading to discontinuation of 
study drug. 
11.4.5.2 
Laboratory Tests 
Laboratory values (excluding efficacy laboratory parameters) will be summarized by 
treatment group, including changes from baseline at each visit.  
11.4.5.3 
Vital Signs 
Vital signs and change from baseline in vital signs will be summarized descriptively at each 
visit by treatment group.  The number and percentage of patients with exceeding pre-defined 
absolute and relative threshold values will be summarized according to Table 6. 
When calculating the percentages for the criterion related to a threshold, the numerator will 
be the number of subjects with normal baseline with respect to the specific criterion and at 
least 1 post-baseline outlier value within the analysis period; and the denominator will be the 
number of subjects with a baseline and at least 1 post-baseline assessment within the analysis 
period. 
 
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Table 6 
Pre-defined Threshold Value for Vital Signs 
Parameter 
Criteria 
Systolic Blood Pressure (SBP) 
>25% mmHg increased or decreased from baseline 
SBP 
>160 mmHg 
SBP 
<90 mmHg 
Heart Rate (HR) 
>100 beats per minute 
HR 
<50 beats per minute 
Respiration Rate  
>24 breaths per minute 
BMI 
>10% increased from baseline 
BMI 
>10% decreased from baseline 
 
11.4.5.4 
12-lead ECG 
ECG interpretation (normal vs. abnormal) will be summarized using frequency and 
percentage at each visit by treatment group.  ECG intervals (PR, QT, HR, and QTcF) will be 
summarized descriptively at each visit.  The number and percentage of patients with 
exceeding pre-defined absolute and relative threshold values will be summarized (Table 7). 
When calculating the percentages for the criterion related to a threshold, the numerator will 
be the number of subjects with normal baseline with respect to the specific criterion and at 
least 1 post-baseline outlier value within the analysis period; and the denominator will be the 
number of subjects with a baseline and at least 1 post-baseline assessment within the analysis 
period. 
 
Table 7 
Pre-defined Threshold Value for ECG  
Parameter 
Criteria 
PR Interval 
>200 msec 
QTcF  
>450 msec 
QTcF 
>480 msec 
QTcF  
>500 msec 
QTcF  
Increase from baseline >30 msec 
QTcF 
Increase from baseline >60 msec 
 
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11.4.5.5 
Physical Examination  
Physical examination clinically significant new or worsening findings will be reported as 
adverse events and will therefore be summarized as described for adverse events. 
11.4.5.6 
Antibodies to Ziltivekimab 
The immunogenic potential of Ziltivekimab will be assessed by summarizing the number and 
percentage of patients who develop detectable anti-drug antibodies (ADA).  Anti-drug 
antibody titers will be summarized descriptively for ADA positive samples and the impact of 
ADA on PK will be assessed if data allows.   
11.4.5.7 
Bleeding Events 
Bleeding events will be classified using the TIMI Bleeding Classification in Table 8. 
 
 
Table 8 
TIMI Bleeding Classification  
Parameter 
Criteria 
Major 
Intracranial hemorrhage or a ≥5 g/dl decrease in the hemoglobin concentration or a 
≥15% absolute decrease in the hematocrit 
Minor 
Observed blood loss: ≥3 g/dl decrease in the hemoglobin concentration or ≥10% 
decrease in the hematocrit. No observed blood loss: ≥4 g/dl decrease in the hemoglobin 
concentration or ≥12% decrease in the hematocrit 
Minimal 
Any clinically overt sign of hemorrhage (including imaging) that is associated with a 
<3 g/dl decrease in the hemoglobin concentration or <9% decrease in the hematocrit 
All TIMI definitions take into account blood transfusions, so that hemoglobin and hematocrit values are 
adjusted by 1 g/dl or 3%, respectively, for each unit of blood transfused. Therefore, the true change in 
hemoglobin or hematocrit if there has been an intervening transfusion between two blood measurements is 
calculated as follows: Δ Hemoglobin = [baseline Hgb − post-transfusion Hgb] + [number of transfused units]; Δ 
Hematocrit = [baseline Hct − post-transfusion Hct] + [number of transfused units × 3]. 
TIMI = Thrombolysis In Myocardial Infarction. 
Source: Rao 2006 
 
11.4.6 
Pharmacokinetic 
Analysis 
and 
Pharmacokinetic/Pharmacodynamic 
Analysis 
11.4.6.1 
Pharmacokinetic Data 
A listing of PK blood sample collection times as well as derived sampling time deviations 
will be provided.  A patient listing of all serum concentration-time data for each dose group 
will be presented.  Ziltivekimab serum concentrations will be summarized by dose group and 
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nominal time point, using appropriate descriptive statistics (e.g., n, arithmetic mean, standard 
deviation (SD), coefficient of variation (CV), minimum, median, maximum, geometric mean, 
and geometric CV (GCV).  
For IL-6, results of PK parameters such as Cmax, AUC, and T1/2 will be summarized by dose 
group. 
Individual and mean concentration-time profiles will be presented graphically. 
The data from this study may be used in combination with data from other studies to develop 
a population PK model.  If performed, the plan for and results of such analysis will be 
documented separately. 
Pharmacokinetic analysis will be performed separately. 
11.4.6.2 
Pharmacokinetic/Pharmacodynamic Analysis 
Pharmacokinetic-pharmacodynamic (PK-PD) model parameters will be derived using plasma 
IL-6 levels to describe target engagement, with clinically meaningful PD variables that may 
include one or more of the following: C-reactive protein, serum amyloid A, transferrin 
saturation, hemoglobin, reticulocyte hemoglobin content, or reticulocyte count.  The specific 
model parameters to be estimated will be determined based on review of the observed data.  
The PD endpoints to be included in the PD analysis will be determined following review of 
the study data. 
A listing of PD blood sample collection times as well as derived sampling time deviations 
will be provided.  A patient listing of all PD results and their corresponding change from 
baseline value for each dose group will be presented.  The observed and change from 
baseline serum results will be summarized using descriptive statistics by dose group. 
Graphical presentations, as appropriate for PD variables, may include: individual observed 
and percent change from baseline serum concentration-time curves for each patient on linear 
scale; arithmetic mean serum concentration-time curves by dose group on linear scale. 
11.4.7 
Exploratory Analyses of Efficacy and Safety Endpoints Based on Baseline 
Hemoglobin (≥11 or <11 g/dL).  
Exploratory analyses may be performed for the primary and secondary efficacy endpoints 
with a stratified analysis by baseline hemoglobin (≥11 or <11 g/dL) and CKD stage (3, 4 or 
5). 
11.5 
Interim Analyses 
Interim analyses will not be conducted.  
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12 
STUDY COMMITTEES 
12.1 
Clinical Events Committee 
An independent external Clinical Events Committee (CEC) will not be established based on 
the low current event rates in this ongoing trial. 
12.2 
Safety Assessment Committee (SAC) 
A Safety Assessment Committee (SAC) will not be required because the study will be 
unblinded after 13 weeks for the primary analysis, and all safety data will be reviewed at that 
time by Sponsor including any potential changes to the ziltivekimab development program if 
necessary. At the 13-week analysis, only a small internal group of staff at Corvidia and the 
CRO who are uninvolved with running the study will know the results. The sites, Corvidia 
and CRO study teams, 
 study team, CRAs, Investigators and patients will remain 
blinded to treatment for the duration of the trial. 
 
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13 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS 
13.1 
Institutional Review Board or Independent Ethics Committee 
The protocol and informed consent for this study must be reviewed and approved by an 
appropriate IRB or IEC before patients are enrolled in the study.  It is the responsibility of the 
Investigator to assure that the study is conducted in accordance with current country and 
Local Regulations, International Conference on Harmonisation (ICH), GCP, and the 
Declaration of Helsinki.  A letter, documenting the approval that specifically identifies the 
protocol by number and title as well as the Investigator, must be received by Corvidia 
Therapeutics before initiation of the study.  Amendments to the protocol will be patient to the 
same requirements as the original protocol. 
After the completion or termination of the study, the Investigator will submit a report to the 
IRB or IEC. 
13.2 
Informed Consent 
Each potential subject must be provided with oral and written information from the 
investigator (or other study staff who are conducting the informed consent interview) to 
allow for an informed decision about participation in the clinical investigation, facilitating 
the potential subject’s comprehension of the information, providing adequate opportunity for 
the potential subject to ask questions and to consider whether to participate, obtaining the 
potential subject’s voluntary agreement to participate and continuing to provide information 
as the clinical investigation progresses or as the subject or situations requires. The process 
must provide sufficient time for subjects to consider the information and providing time and 
opportunity for the subjects to ask questions and have those questions answered. The 
investigator (or other study staff who are conducting the informed consent interview) and the 
subject should exchange information and discuss the contents of the informed consent. This 
process must occur under circumstances that minimize the possibility of coercion or undue 
influence. Each patient must be provided with oral and written information describing the 
nature and duration of the study and must sign a written ICF in a language in which the 
patient is fluent before study specific procedures are conducted.  The signed and dated ICF 
will be retained with the study records.  Each patient will also be given a copy of their signed 
ICF.  
13.3 
Supplementary Documentation 
Before initiation of the study, the Investigator must provide Corvidia Therapeutics with the 
following documents (copies of which must be maintained by the Investigator): 
1. Curriculum vitae of the Investigator and any sub-Investigators listed on the 1572 
form; 
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2. A signed copy of the IRB or IEC approval notice for protocol and informed consent; 
3. A copy of the IRB or IEC approved ICF; 
4. Laboratory certification with a list of normal values for laboratory tests that will be 
conducted at local laboratories; 
5. Completed financial disclosure form for the Investigator and any sub Investigators 
listed on the 1572 form. 
 
13.4 
Data Reporting and Case Report Forms 
Data for each patient will be entered into the CRF and verified by the Investigator. It is the 
Investigator’s responsibility to ensure the accuracy, completeness, legibility, and timeliness 
of the data reported on the patient’s CRF.  Source documentation supporting the CRF data 
should indicate the patient’s participation in the study and should document the dates and 
details of study procedures, AEs, and patient’s clinical status. 
The Investigator or designated representative should complete the CRF as soon as possible 
after information is collected, preferably on the same day that a study patient is seen for an 
examination, treatment, or any other study procedure.  Any outstanding entries must be 
completed immediately after the final examination.  CRF data will be processed in a US 21 
Code of Federal Regulations (CFR) Part 11-compliant system. 
13.5 
Retention of Data 
U.S. Federal regulations require that a copy of records (e.g., laboratory data slips, source 
documents, test article disbursement records), which support case records of this study, must 
be retained in the files of the responsible Investigator for a minimum of 2 years after 
notification by the Sponsor that the FDA has approved a marketing application for the drug 
and indication being investigated, or the investigation has been terminated. 
13.6 
Deviation from the Protocol 
The Investigator will not deviate from the protocol.  In medical emergencies, the Investigator 
will use medical judgment and will remove the patient from immediate hazard, and then 
notify the Corvidia Therapeutics Medical Monitor and the IRB or IEC immediately regarding 
the type of emergency and course of action taken.  Any action in this regard will be recorded 
on the appropriate CRF.  Any other changes or deviations in the protocol will be made as an 
amendment to the protocol and must be approved by Corvidia Therapeutics and the IRB or 
IEC — before the changes or deviations are implemented.  Corvidia Therapeutics will not 
assume any responsibility or liability for any deviation or change. 
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13.7 
Study Monitoring 
The Investigator will allow representatives of Corvidia Therapeutics to periodically audit 
(at mutually convenient times before, during, and after the study has been completed) all 
CRFs and relevant portions of office, clinical, and laboratory records for each patient.  
Appropriate source documents such as a record of the patient’s medical history and 
concomitant medications from the patient’s physician must be available to confirm eligibility 
for the study.  The monitoring visits provide Corvidia Therapeutics with the opportunity to 
evaluate the progress of the study; verify the accuracy and completeness of CRFs; assure that 
all protocol requirements, applicable regulations, and Investigator's obligations are being 
fulfilled; and resolve any inconsistencies in the study records. 
13.8 
Drug Accountability 
The Investigator must maintain accurate records of the amounts and dates Study Drugs were 
received from Corvidia Therapeutics and dispensed to the patients, including the remaining 
volume after dose administration.  All drug supplies must be accounted for at the termination 
of the study and a written explanation provided for any discrepancies.  All partially used or 
unused drug supplies will be destroyed at the site, in accordance with approved written 
procedures, or returned to Corvidia Therapeutics after written authorization is obtained from 
Corvidia Therapeutics.  The Investigator will maintain a record of the amount and dates 
when unused supplies were either destroyed or returned.  All records will be retained as 
noted in Section 13.5. 
13.9 
Disclosure of Data 
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties other than those noted below is prohibited.  Patient 
confidentiality will be further assured by utilizing patient identification code numbers to 
correspond to treatment data in the computer files.  The study personnel, employees of the 
regulatory agencies, including the U.S. FDA and the study sponsor, Corvidia Therapeutics, 
and its agents will need to review patient medical records in order to accurately record 
information for this study.  If results of this study are reported in medical journals or at 
meetings, the patient’s identity will remain confidential. 
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14 
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associated with improved survival in hemodialysis patients. Clin J Am Soc Nephrol 2008; 
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Cardiovascular disease in chronic renal failure: the challenge continues. Nephrol Dial 
Transplant. 2000;15(Suppl 5):69–80. 
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Locatelli F, Bárány P, Covic A, De Francisco A, Del Vecchio L, Goldsmith D, Hörl W, 
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inflammation. Eur J Clin Invest 2005; 35 Suppl 3:32-5. 
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myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats. Hypertension. 
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Vrtovsnik F, Stengel B, Froissart M; NephroTest Study Group. Timing and determinants of 
erythropoietin deficiency in chronic kidney disease. Clin J Am Soc Nephrol. 2012 
Jan;7(1):35-42. 
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Stenvinkel P. Circulating follistatin in patients with chronic kidney disease: implications for 
muscle strength, bone mineral density, inflammation, and survival. Clin J Am Soc Nephrol. 
2011 May;6(5):1001-8. 
Ohsugi Y. Recent advances in immunopathophysiology of interleukin-6: an innovative 
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Increased C-reactive protein following hemodialysis predicts cardiac hypertrophy in chronic 
hemodialysis patients. Am J Kidney Dis. 2002 Dec;40(6):1230-9. 
Pecoits-Filho R, Lindholm B, Stenvinkel P. The malnutrition, inflammation and 
atherosclerosis (MIA) syndrome-the heart of the matter. Nephrol Dial Transpl. 
2002;17(11):28–31. 
Rao M, Guo D, Perianayagam MC, Tighiouart H, Jaber BL, Pereira BJ, Balakrishnan VS. 
Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients. Am J Kidney 
Dis. 2005 Feb;45(2):324-33. 
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Rao SV, O'Grady K, Pieper KS, Granger CB, Newby LK, Mahaffey KW, Moliterno DJ, 
Lincoff AM, Armstrong PW, Van de Werf F, Califf RM, Harrington RA. A comparison of 
the clinical impact of bleeding measured by two different classifications among patients with 
acute coronary syndromes. J Am Coll Cardiol. 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26  
Reichert CO, da Cunha J, Levy D, Maselli LMF, Bydlowski SP, Spada C. Hepcidin: 
Homeostasis and Diseases Related to Iron Metabolism. Acta Haematol. 2017;137(4):220-
236. 
Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, Thuren T; CANTOS Pilot 
Investigative Group. Effects of interleukin-1β inhibition with canakinumab on hemoglobin 
A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, 
placebo-controlled trial. Circulation. 2012 Dec 4;126(23):2739-48.  
Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ; CANTOS Trial 
Group. Relationship of C-reactive protein reduction to cardiovascular event reduction 
following treatment with canakinumab: a secondary analysis from the CANTOS randomised 
controlled trial. Lancet. 2018 Jan 27;391(10118):319-328. (Ridker 2018a) 
Ridker PM, MacFadyen JG, Glynn RJ, Koenig W, Libby P, Everett BM, Lefkowitz M, 
Thuren T, Cornel JH. Inhibition of Interleukin-1β by Canakinumab and Cardiovascular 
Outcomes in Patients With Chronic Kidney Disease. J Am Coll Cardiol. 2018 May 
29;71(21):2405-2414. doi: 10.1016/j.jacc.2018.03.490. (Ridker 2018b) 
Ridker PM, Libby P, MacFadyen JG, Thuren T, Ballantyne C, Fonseca F, Koenig W, 
Shimokawa H, Everett BM, Glynn RJ. Modulation of the interleukin-6 signalling pathway 
and incidence rates of atherosclerotic events and all-cause mortality: analyses from the 
Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J. 
2018 Oct 7;39(38):3499-3507. doi: 10.1093/eurheartj/ehy310. (Ridker 2018c) 
Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, 
Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova 
R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, 
Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ; CANTOS Trial Group. 
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 
2017 Sep 21;377(12):1119-1131. doi: 10.1056/NEJMoa1707914. Epub 2017 Aug 27. 
Ridker PM. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To 
Identify Novel Targets for Atheroprotection. Circ Res. 2016 Jan 8;118(1):145-56. 
Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll 
Cardiol. 2008 Nov 4;52(19):1527-39. 
Sakai R, Cho S-KK, Nanki T, Watanabe K, Yamazaki H, Tanaka M, et al.: Head-to-head 
comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid 
arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients 
on biologics for long-term safety (REAL) registry. Arthritis Res Ther 2015 Jan 4;17:74. 
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Sanofi, Regeneron: Topline Results of Phase 3 Monotherapy Study Demonstrating 
Superiority of Sarilumab vs. Adalimumab in Patients with Active Rheumatoid Arthritis 2016 
Mar 11 
Shridas P, Tannock LR. Role of serum amyloid A in atherosclerosis. Curr Opin Lipidol. 2019 
Aug;30(4):320-325. 
Sieper J,  Braun J,  Kay J, Badalamenti S, Radin A,  Jiao L,  Fiore S,  et al.  Sarilumab for the 
treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-
controlled study (ALIGN). Ann Rheum Dis 2015; 74:1051–1057. 
Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D; CHOIR 
Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J 
Med. 2006 Nov 16;355(20):2085-98. 
Solbu MD, Mjøen G, Mark PB, Holdaas H, Fellström B, Schmieder RE, Zannad F, 
Herrington WG, Jardine AG. Predictors of atherosclerotic events in patients on 
haemodialysis: post hoc analyses from the AURORA study.Nephrol Dial Transplant. 2018 
Jan 1;33(1):102-112. 
Song SN, Iwahashi M, Tomosugi N, Uno K, Yamana J, Yamana S, Isobe T, Ito H, Kawabata 
H, Yoshizaki K. Comparative evaluation of the effects of treatment with tocilizumab and 
TNF-α inhibitors on serum hepcidin, anemia response and disease activity in rheumatoid 
arthritis patients. Arthritis Res Ther. 2013 Oct 2;15(5):R141. 
Song SN, Tomosugi N, Kawabata H, Ishikawa T, Nishikawa T, Yoshizaki K. Down-
regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody 
(tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood. 
2010 Nov 4;116(18):3627-34. 
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Parlongo RM, D'Arrigo G, Tripepi G, Mallamaci F, Zoccali C. Association of IL-6 and a 
functional polymorphism in the IL-6 gene with cardiovascular events in patients with CKD.  
Clin J Am Soc Nephrol. 2015 Feb 6;10(2):232-40. 
Stenvinkel P, Heimbürger O, Paultre F, Diczfalusy U, Wang T, Berglund L, Jogestrand T. 
Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal 
failure. Kidney Int. 1999 May;55(5):1899-911. 
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R, Fellström B, Wanner C, Landray MJ, Baigent C; SHARP Collaborative Group. Lowering 
LDL cholesterol reduces cardiovascular risk independently of presence of inflammation. 
Kidney Int. 2018 Apr;93(4):1000-1007.  
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treatment strategies for anemia of chronic disease and anemia of inflammation. Am J 
Hematol. 2012; 87(4):392-400. 
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Tanaka Y, Martin Mola E: IL-6 targeting compared to TNF targeting in rheumatoid arthritis: 
studies of olokizumab, sarilumab and sirukumab. Ann Rheum Dis 2014 Sep 1;73:1595–7. 
Untersteller K, Girerd N, Duarte K, Rogacev KS, Seiler-Mussler S, Fliser D, Rossignol P, 
Heine GH.  NT-proBNP and Echocardiographic Parameters for Prediction of Cardiovascular 
Outcomes in Patients with CKD Stages G2-G4. Clin J Am Soc Nephrol. 2016 Nov 
7;11(11):1978-1988. 
US Renal Data System, author. 2002 Annual Data Report. Bethesda, MD: The National 
Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2002.  
Won HS, Kim HG, Yun YS, Jeon EK, Ko YH, Kim YS, Kim YO, Yoon SA. IL-6 is an 
independent risk factor for resistance to erythropoiesis-stimulating agents in hemodialysis 
patients without iron deficiency. Hemodial Int. 2012 Jan;16(1):31-7. 
Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. 
Blood. 2006 Nov 1;108(9):3204-9. 
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15 
APPENDICES 
15.1 
Appendix A Exclusionary Drugs 
The following medications are metabolized by CYP450 enzymatic pathways and have a 
narrow therapeutic window.  The use of these medications from one day prior to 
Randomization (Day -1) through Study Week 24 is prohibited. 
digoxin 
theophylline 
terfenadine 
tizanidine 
quinidine 
phenytoin and its derivatives 
taxane chemotherapeutic agents 
cyclosporine 
mTOR inhibitors (e.g., sirolimus, tacrolimus) 
ergot alkaloids 
antipsychotic medications (specifically pimozide, thioridazine) 
fentanyl and derivatives (e.g., alfentanil and sufentanil) 
 
 
 
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15.2 
Appendix B PROMIS® (Patient-Reported Outcomes Measurement 
Information System) 
 
  
 
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FATEXP36: How exhausted were you on average?
FATEXP43: How physically drained were you on average?
FATIMP52: To what degree did your fatigue make you feel 
less alert?
During the past 7 days………………………………………..
I feel fatigued
I feel weak all over
I feel listless (“washed out”)
I feel tired
I have trouble starting things because I am tired
I have trouble finishing things because I am tired
I have energy
I am able to do my usual activities
I need to sleep during the day
I am too tired to eat
I need help doing my usual activities
I am frustrated by being too tired to do the things I want to do
I have to limit my social activity because I am tired
1
2
3
4
5 
Not at all
A little bit
Somewhat
Quite a bit
Very much
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
1
2
3
4
5 
PROMIS Items
PROMIS 
Short Form 
v1.0 –
Fatigue 
13a
PROMIS 
items 
(Item 
identifier 
in bold)
During the past 30 days………………………………………..
SFINT101: How interested have you been in sexual activity?
1
2
3
4
5 
Not at all
A little bit
Somewhat
Quite a bit
Very much
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15.3 
Appendix C Optum SF-36 v2® Health Survey  
 
 
 
 
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SF-36v2® Health Survey  1992, 2000, 2009 Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Standard, United States (English))
SF-36v2® Health Survey Single-Item Standard Recall for Handheld Device 
Item Name 
Question Text 
Answer 
Text 1 
Answer 
Text 2
Answer 
Text 3
Answer 
Text 4
Answer 
Text 5
Answer 
Text 6 
 
Your Health and Well-Being 
This survey asks for your views about 
your health.  This information will help 
keep track of how you feel and how 
well you are able to do your usual 
activities. Thank you for completing 
this survey! 
For each of the following questions, 
please select the one response that 
best describes your answer. 
 
 
 
 
 
 
SF36v2_GH1 
In general, would you say your health 
is: 
Excellent 
Very good 
Good 
Fair 
Poor 
 
SF36v2_HT 
Compared to one year ago, how 
would you rate your health in general 
now? 
Much
better
now than 
one year 
ago
Somewhat 
better now 
than one 
year ago 
About the 
same as 
one year 
ago
Somewhat 
worse 
now than 
one year 
ago
Much
worse 
now than 
one year 
ago
The following questions are about 
activities you might do during a typical 
day.  Does your health now limit you in 
these activities?  If so, how much? 
 
 
 
 
 
 
SF36v2_PF01 
Does your health now limit you in 
vigorous activities, such as running, 
lifting heavy objects, participating in 
strenuous sports?  If so, how much? 
Yes, 
limited a 
lot
Yes, 
limited a 
little 
No, not 
limited at 
all
  
  
 
SF36v2_PF02
Does your health now limit you in 
moderate activities, such as moving a 
table, pushing a vacuum cleaner, 
bowling, or playing golf?  If so, how 
much?
Yes, 
limited a 
lot
Yes, 
limited a 
little 
No, not 
limited at 
all
  
  
 
SF36v2_PF03
Does your health now limit you in 
lifting or carrying groceries?  If so, how 
much?
Yes, 
limited a 
lot
Yes, 
limited a 
little 
No, not 
limited at 
all
  
  
 
SF36v2_PF04
Does your health now limit you in 
climbing several flights of stairs?  If so, 
how much? 
Yes, 
limited a 
lot
Yes, 
limited a 
little 
No, not 
limited at 
all
  
  
 
SF36v2_PF05
Does your health now limit you in 
climbing one flight of stairs?  If so, 
how much? 
Yes, 
limited a 
lot
Yes, 
limited a 
little 
No, not 
limited at 
all
  
  
 
SF36v2_PF06
Does your health now limit you in 
bending, kneeling, or stooping?  If so, 
how much? 
Yes, 
limited a 
lot
Yes, 
limited a 
little 
No, not 
limited at 
all
  
  
 
SF36v2_PF07
Does your health now limit you in 
walking more than a mile?  If so, how 
much?
Yes, 
limited a 
lot
Yes, 
limited a 
little 
No, not 
limited at 
all
  
  
 
SF36v2_PF08
Does your health now limit you in 
walking several hundred yards?  If so, 
how much? 
Yes, 
limited a 
lot
Yes, 
limited a 
little 
No, not 
limited at 
all
  
  
 
SF36v2_PF09
Does your health now limit you in 
walking one hundred yards?  If so, 
how much? 
Yes, 
limited a 
lot
Yes, 
limited a 
little 
No, not 
limited at 
all
  
  
 
SF36v2_PF10
Does your health now limit you in 
bathing or dressing yourself?  If so, 
how much? 
Yes, 
limited a 
lot
Yes, 
limited a 
little 
No, not 
limited at 
all
  
  
 
During the past 4 weeks, how much of 
the time have you had any of the 
following problems with your work or 
other regular daily activities as a result 
of your physical health? 
 
 
 
 
 
 
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SF-36v2® Health Survey  1992, 2000, 2009 Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Standard, United States (English))
Item Name 
Question Text 
Answer 
Text 1 
Answer 
Text 2
Answer 
Text 3
Answer 
Text 4
Answer 
Text 5
Answer 
Text 6 
SF36v2_RP1
During the past 4 weeks, how much of 
the time have you cut down on the 
amount of time you spent on work or 
other activities as a result of your 
physical health? 
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_RP2
During the past 4 weeks, how much of 
the time have you accomplished less 
than you would like as a result of your 
physical health? 
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_RP3
During the past 4 weeks, how much of 
the time were you limited in the kind of 
work or other activities as a result of 
your physical health? 
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_RP4
During the past 4 weeks, how much of 
the time have you had difficulty 
performing the work or other activities 
as a result of your physical health (for 
example, it took extra effort)? 
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
During the past 4 weeks, how much of 
the time have you had any of the 
following problems with your work or 
other regular daily activities as a result 
of any emotional problems (such as 
feeling depressed or anxious)? 
 
 
 
 
 
 
SF36v2_RE1
During the past 4 weeks, how much of 
the time have you cut down on the 
amount of time you spent on work or 
other activities as a result of any 
emotional problems (such as feeling 
depressed or anxious)? 
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_RE2
During the past 4 weeks, how much of 
the time have you accomplished less 
than you would like as a result of any 
emotional problems (such as feeling 
depressed or anxious)? 
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_RE3
During the past 4 weeks, how much of 
the time have you done work or other 
activities less carefully than usual as a 
result of any emotional problems 
(such as feeling depressed or 
anxious)? 
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_SF1 
During the past 4 weeks, to what 
extent has your physical health or 
emotional problems interfered with 
your normal social activities with 
family, friends, neighbors, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
 
SF36v2_BP1 
How much bodily pain have you had 
during the past 4 weeks? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very 
severe 
SF36v2_BP2 
During the past 4 weeks, how much 
did pain interfere with your normal 
work (including both work outside the 
home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
These questions are about how you 
feel and how things have been with 
you during the past 4 weeks.  For 
each question, please give the one 
answer that comes closest to the way 
you have been feeling. 
 
 
 
 
 
 
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SF-36v2® Health Survey  1992, 2000, 2009 Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Standard, United States (English))
Item Name 
Question Text 
Answer 
Text 1 
Answer 
Text 2
Answer 
Text 3
Answer 
Text 4
Answer 
Text 5
Answer 
Text 6 
SF36v2_VT1
How much of the time during the past 
4 weeks did you feel full of life? 
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_MH1
How much of the time during the past 
4 weeks have you been very nervous?  
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_MH2
How much of the time during the past 
4 weeks have you felt so down in the 
dumps that nothing could cheer you 
up?   
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_MH3
How much of the time during the past 
4 weeks have you felt calm and 
peaceful?
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_VT2
How much of the time during the past 
4 weeks did you have a lot of energy?  
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_MH4
How much of the time during the past 
4 weeks have you felt downhearted 
and depressed?   
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_VT3
How much of the time during the past 
4 weeks did you feel worn out?   
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_MH5
How much of the time during the past 
4 weeks have you been happy?  
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_VT4 
How much of the time during the past 
4 weeks did you feel tired?  
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF36v2_SF2 
During the past 4 weeks, how much of 
the time has your physical health or 
emotional problems interfered with 
your social activities (like visiting with 
friends, relatives, etc.)? 
All of the 
time
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
How TRUE or FALSE is each of the 
following statements for you? 
 
 
 
 
 
 
 SF36v2_GH2 
I seem to get sick a little easier than 
other people. 
Definitely 
true 
Mostly 
true 
Don't know 
Mostly 
false
Definitely 
false
SF36v2_GH3
I am as healthy as anybody I know. 
Definitely 
true 
Mostly 
true 
Don't know 
Mostly 
false
Definitely 
false
SF36v2_GH4
I expect my health to get worse. 
Definitely 
true 
Mostly 
true 
Don't know 
Mostly 
false
Definitely 
false
SF36v2_GH5
My health is excellent. 
Definitely 
true 
Mostly 
true 
Don't know 
Mostly 
false
Definitely 
false
SF-36v2
® Health Survey  1992,
2000, 2009 Medical Outcomes Trust 
and QualityMetric Incorporated. 
All rights reserved. 
SF-36
® is a registered trademark of 
Medical Outcomes Trust. 
(SF-36v2
® Health Survey Standard, 
United States (English)) 
 
 
 
 
 
 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 116 of 142 
15.4 
Appendix D Corvidia ePRO 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
 
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Corvidia COR-001-02 ePRO Screenshots 
 
25-Feb-2019 
 
Symptom Inventory 
 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 137 of 142 
15.5 
Appendix E PGIS and PGIC 
 
 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 139 of 142 
15.6 
Appendix F EurQol-5D-5L (EQ-5D-5L) 
 
 
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EQ-5D-5L PDA version
English (USA)
Country (Language)
Health Questionnaire
Health Questionnaire
English version for the USA
Version (Target Language)
Version (English)
On the following screens please tap the statement that best describes your health TODAY.
Instruction
Your mobility TODAY
Mobility
I have no problems walking
MB1
I have slight problems walking 
MB2
I have moderate problems walking
MB3
I have severe problems walking
MB4
I am unable to walk
MB5
Your self-care TODAY
Self-care
I have no problems washing or dressing myself 
SC1
I have slight problems washing or dressing myself 
SC2
I have moderate problems washing or dressing myself 
SC3
I have severe problems washing or dressing myself 
SC4
I am unable to wash or dress myself 
SC5
Your usual activities TODAY (e.g. work, study, housework, family or leisure activities)
Usual Activities
I have no problems doing my usual activities 
UA1
I have slight problems doing my usual activities 
UA2
I have moderate problems doing my usual activities 
UA3
I have severe problems doing my usual activities 
UA4
I am unable to do my usual activities 
UA5
Your pain / discomfort TODAY
Pain / Discomfort
I have no pain or discomfort 
PD1
I have slight pain or discomfort 
PD2
I have moderate pain or discomfort 
PD3
I have severe pain or discomfort 
PD4
I have extreme pain or discomfort 
PD5
Your anxiety / depression TODAY
Anxiety / Depression
I am not anxious or depressed 
AD1
I am slightly anxious or depressed 
AD2
I am moderately anxious or depressed 
AD3
I am severely anxious or depressed 
AD4
I am extremely anxious or depressed 
AD5
We would like to know how good or bad your health is TODAY.
Vas Line 1
On the next screen you will see a scale numbered 0 to 100.
Vas Line 2
100 means the best health you can imagine.
Vas Line 3
0 means the worst health you can imagine.
Vas Line 4
Please tap on the scale to indicate how your health is TODAY.
Vas Line 5
The best health you can imagine
Top Scale
The worst health you can imagine
Bottom Scale
YOUR HEALTH TODAY
Box Health
© EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation
Disclaimer:  This is a preview of the EQ-5D instrument. It demonstrates the text, questions and response options included in 
this version. This preview does not represent the final product and should not be used as an official EQ-5D instrument.
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 141 of 142 
15.7 
Appendix G Guidance on Contraception 
Patients must agree to comply with the contraception and reproduction restrictions of the 
study: 
a) 
Women of childbearing potential must be using a method of contraception, that is 
“highly effective” (i.e., <1% failure rate)  
OR 
b) 
Postmenopausal women must have had no menstrual bleeding for at least 1 year 
before initial dosing and either be over the age of 60-years or have an elevated plasma 
follicle-stimulating hormone (FSH) level (i.e., >40 mIU/mL) at Screening;  
AND 
b) 
Postmenopausal • 
All female patients of childbearing potential must have a 
documented negative pregnancy test result at Screening. Patients with elevated β-HCG 
levels believed to be due to end-stage renal disease may be enrolled if documented to not be 
pregnant. 
For the purposes of the proposed study, “highly effective” contraceptive methods are 
defined as those, alone or in combination, that result in a low failure rate (i.e., less than 
1 percent per year) when used consistently and correctly, and include the following: 
x Surgical sterilization at least 6 months before Study Drug administration 
x Implants 
x LNG and Copper T IUDs 
x Sexual abstinence 
 
Patients who prefer methods which evidence a higher (6-9%) failure rate with typical use will 
be required to employ at least two methods of contraception concurrently.  These methods 
include the following: 
x Injectable hormone depots 
x Oral contraceptive pill 
x Hormone patch 
x Vaginal ring 
 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are NOT acceptable methods of contraception. 
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A Phase 2 Trial to Evaluate REduction in Inflammation in PatientS with advanced 
Protocol COR-001-02 
Chronic Renal Disease Utilizing Antibody MEdiated IL-6 inhibition (RESCUE) 
23 December 2019 
 
 
Amendment No. 5 
Corvidia Therapeutics Inc.  
 
Page 142 of 142 
All male patients, from the day of dosing until the final study visit, unless surgically sterile, 
must be willing to use a condom with a partner (male patients with partners of childbearing 
potential must be willing to use 2 effective methods of birth control, 1 should be condom 
with spermicide) to prevent pregnancy and drug exposure of a partner, and refrain from 
donating sperm or fathering a child.  
https://www.cdc.gov/reproductivehealth/contraception/index.htm 
Investigators may contact the Medical Monitor to discuss questions regarding appropriate 
contraception.  The guidance will follow that described in the document 
and 
will comply with FDA M3(R2). 
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