Conditions: COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 178
Healthy volunteers: no

Brief summary:
In this study invetigators propose to administer clazakizumab to patients with life-threatening COVID-19 infection manifest by pulmonary failure and a clinical picture consistent with a cytokine storm syndrome. This is a double-blinded randomized multi-center trial designed as a phase II dose-finding three arm trial with seamless adaptive transition to a phase III efficacy trial. For phase II, patients were randomized 1:1:1 ratio to three study arms and received clazakizumab at a dose of 12.5 mg, 25 mg or placebo.

Based on interim analysis, the low dose arm was dropped and the phase III portion of the study continued to enroll patients randomized 1:1 to high dose clazakizumab or placebo.

Based on interim analysis, the remaining 10 subjects at NYU will be randomly assigned to a 1:1 ratio to two arms that will receive clazakizumab at a dose of 25 mg or placebo. The NYU site will serve as the central data management site for other centers who undertake this protocol. Other sites will enroll patients based on the two arm 1:1 randomization. 60 patients at outside sites are expected to enroll.

Detailed description:
The limited understanding of the clinical behavior of patients infected with SARS-CoV-2 (the viral organism responsible for COVID-19 disease) is evolving on a daily basis. Reports from China indicate that a subset of patients with the worst clinical outcomes may manifest cytokine storm syndrome. Hypotheses that excess cytokines may trigger a secondary hemophagocytic lymphhistiocytosis (sHLH) have been proposed. Indeed, cytokine profiles consistent with this picture were observed in Chinese patients with severe pulmonary involvement. Specifically, elevated ferritin and interleukin-6 (IL-6) were associated with fatalities among the infected patients. A role for targeted anti-inflammatory and anti-cytokine therapies in the treatment of pulmonary hyperinflammation has been proposed.

Clazakizumab is a genetically engineered humanized IgG1 monoclonal antibody (mAb) that binds with high affinity to human IL-6. This investigational agent is currently being studied as a treatment for chronic active antibody mediated rejection of renal allografts.

In this study investigators propose to administer clazakizumab to patients with life-threatening pulmonary failure secondary to COVID-19 disease.

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: Clazakizumab 25 mg intervention 2: Clazakizumab 12.5 mg intervention 3: Placebo
Intervention descriptions: intervention 1: The first dose will be administered as soon as possible after the patient is enrolled and randomized into the Clazakizumab 25 mg arm. The route of administration will be intravenous. Each dose will be administered as an infusion that is run over 30 minutes. Serum CRP will be evaluated at baseline and on days 1 and 2 following clazakizumab administration. If the CRP does not decrease by 50% within 36-48 hours after the first dose, a second dose of 25 mg clazakizumab will be given no later than day 3. intervention 2: The first dose will be administered as soon as possible after the patient is enrolled and randomized into the Clazakizumab 12.5 mg arm. The route of administration will be intravenous. Each dose will be administered as an infusion that is run over 30 minutes. Serum CRP will be evaluated at baseline and on days 1 and 2 following clazakizumab administration. If the CRP does not decrease by 50% within 36-48 hours after the first dose, a second dose of 12.5 mg clazakizumab will be given no later than day 3. intervention 3: The first dose will be administered as soon as possible after the patient is enrolled and randomized into the Placebo arm. The route of administration will be intravenous. Each dose will be administered as an infusion that is run over 30 minutes. Serum CRP will be evaluated at baseline and on days 1 and 2 following clazakizumab administration. If the CRP does not decrease by 50% within 36-48 hours after the first dose, a second dose of placebo will be given no later than day 3.

Protocol document:
Prot_SAP_000.pdf: 
Study number: s20-00392  
 
Page 1 
Version: 1.12 (VERSION DATE 16SEP2020) 
 
 
A RANDOMIZED PLACEBO-CONTROLLED SAFETY AND DOSE-FINDING STUDY FOR THE USE OF 
THE IL-6 INHIBITOR CLAZAKIZUMAB IN PATIENTS WITH LIFE-THREATENING COVID-19 
INFECTION 
 
Principal Investigator: 
 
Bonnie Lonze MD PHD  
Assistant Prof of Surgery 
Vice Chair for Research, Transplant Institute 
550 First Ave, Suite 7A 
New York, NY 10016 
212-263-3865 
Additional Investigators: 
 
 
Elaina Weldon, ACNP 
Rebecca Dieter, PharmD 
Vasishta Tatapudi, MD 
Tyler Lewis, PharmD 
Robert Montgomery, MD, DPhil 
Holly Foote, DO 
Steven Cohen, DO 
Andrea B. Troxel, ScD 
Irfana Soomro, MD 
Aprajita Mattoo, MD 
Peter Spiegler, MD 
Shalinee Chawla, MD 
Shilpa DeSouza, MD 
Manju Pillai, MD 
Amith Shenoy, MD 
Michael Bender, MD 
Priya Agarwala, MD 
Sarun Thomas, DO 
Diane Johnson, MD 
Martin Backer, MD 
Nikki Lawson, RN 
NYULMC Study Number: 
s20-00392 
Study Sponsor:  
NYULH Transplant Institute 
IND/IDE Number:  
149176 
IP Manufacturer: 
Vitaeris Inc.,  
1500 – 355 Burrard St. 
Vancouver, BC 
Canada 
V6C 2G8 
Study Product: 
Clazakizumab 
Study Product Provider:  
Investigational drug to be supplied by Vitaeris 
ClinicalTrials.gov Number     NCT04343989 
 
Initial version: 
March 24, 2020 
Revised:  
March 25, 2020 
Revised:  
March 27, 2020 
Revised:  
April 3, 2020 
Revised: 
April 13, 2020 
Revised: 
April 17, 2020 
Revised: 
May 1, 2020 
Revised:  
May 2, 2020  
Revised:  
May 20, 2020 
Revised: 
June 5, 2020 
Revised: 
July 19, 2020 
Revised: 
August 16, 2020 


Revised 
September 16, 2020 
 
 
 


Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other applicable 
US government research regulations, and institutional research policies and procedures. The International 
Conference on Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) (sometimes referred to 
as “ICH-GCP” or “E6”) will be applied only to the extent that it is compatible with FDA and DHHS regulations. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 
 
 


 
Table of Contents 
LIST OF ABBREVIATIONS .......................................................................................................................... 7 
PROTOCOL SUMMARY ............................................................................................................................... 8 
1 
KEY ROLES ........................................................................................................................................ 11 
2 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ..................... 15 
2.1 
BACKGROUND INFORMATION AND RELEVANT LITERATURE .............................................................. 15 
2.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL AGENT ............................................................. 15 
2.2.1 
Preclinical Data ...................................................................................................................... 15 
2.2.2 
Clinical Data to Date .............................................................................................................. 16 
2.2.3 
Dose Rationale ....................................................................................................................... 16 
2.3 
RATIONALE ................................................................................................................................... 16 
2.4 
POTENTIAL RISKS & BENEFITS ...................................................................................................... 17 
2.4.1 
Known Risks........................................................................................................................... 17 
2.4.2 
Potential Risks ....................................................................................................................... 18 
2.4.3 
Known Potential Benefits ....................................................................................................... 18 
3 
OBJECTIVES AND PURPOSE .......................................................................................................... 18 
3.1 
PRIMARY OBJECTIVE ..................................................................................................................... 18 
3.2 
SECONDARY OBJECTIVES.............................................................................................................. 18 
4 
STUDY DESIGN AND ENDPOINTS .................................................................................................. 18 
4.1 
DESCRIPTION OF STUDY DESIGN ................................................................................................... 18 
4.2 
STUDY ENDPOINTS ....................................................................................................................... 19 
4.2.1 
Primary Study Endpoints........................................................................................................ 19 
4.2.2 
Secondary Study Endpoints ................................................................................................... 19 
5 
STUDY ENROLLMENT AND WITHDRAWAL ................................................................................... 19 
5.1 
INCLUSION CRITERIA ..................................................................................................................... 19 
5.2 
EXCLUSION CRITERIA .................................................................................................................... 19 
5.3 
VULNERABLE SUBJECTS ................................................................................................................ 20 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION .......................................................................... 20 
5.5 
DURATION OF STUDY PARTICIPATION ............................................................................................. 20 
5.6 
TOTAL NUMBER OF PARTICIPANTS AND SITES ................................................................................ 20 
5.7 
PARTICIPANT WITHDRAWAL OR TERMINATION ................................................................................ 20 
5.7.1 
Reasons for Withdrawal or Termination ................................................................................ 20 
5.7.2 
Handling of Participant Withdrawals or Termination .............................................................. 21 
5.8 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................................................. 21 
6 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE ETC.) AND/OR PROCEDURAL 
INTERVENTION .......................................................................................................................................... 21 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION .............................................................................. 21 
6.1.1 
Acquisition .............................................................................................................................. 21 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ............................................................. 21 
6.1.3 
Product Storage and Stability ................................................................................................ 22 
6.1.4 
Preparation ............................................................................................................................. 22 
6.1.5 
Dosing and Administration ..................................................................................................... 22 
6.1.6 
Route of Administration .......................................................................................................... 22 
6.1.7 
Dosing schedule ..................................................................................................................... 23 
6.1.8 
Dose Adjustments/Modifications/Delays ................................................................................ 23 
6.1.9 
Duration of Therapy ............................................................................................................... 23 


6.1.10 
Tracking of Dose ................................................................................................................ 23 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES .............................................................................. 23 
6.2.1 
Initial Shipment of Products ................................................................................................... 23 
6.2.2 
Re-supply ............................................................................................................................... 24 
6.2.3 
Destruction of Investigational Product ................................................................................... 24 
7 
RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES ............................................... 24 
7.1 
RANDOMIZATION ........................................................................................................................... 24 
7.2 
BLINDING ...................................................................................................................................... 24 
8 
STUDY PROCEDURES AND SCHEDULE ........................................................................................ 25 
8.1 
STUDY PROCEDURES/EVALUATIONS .............................................................................................. 25 
8.1.1 
Study Specific Procedures ..................................................................................................... 25 
8.1.2 
Standard of Care Study Procedures ...................................................................................... 25 
8.2 
LABORATORY PROCEDURES/EVALUATIONS .................................................................................... 25 
8.2.1 
Clinical Laboratory Evaluations .............................................................................................. 25 
8.2.2 
Specimen Preparation, Handling, and Storage ..................................................................... 26 
8.3 
STUDY SCHEDULE ........................................................................................................................ 26 
8.3.1 
Withdrawal/Early Termination Visit ........................................................................................ 27 
8.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES .................................................... 27 
9 
ASSESSMENT OF SAFETY .............................................................................................................. 27 
9.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................................... 27 
9.1.1 
Definition of Adverse Events (AE).......................................................................................... 28 
9.1.2 
Definition of Serious Adverse Events (SAE) .......................................................................... 28 
9.1.3 
Definition of Unanticipated Problems (UP) ............................................................................ 28 
9.2 
CLASSIFICATION OF AN ADVERSE EVENT........................................................................................ 29 
9.2.1 
Severity of Event .................................................................................................................... 29 
9.2.2 
Relationship to Study Agent ................................................................................................... 29 
9.2.3 
Expectedness ......................................................................................................................... 30 
9.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP .................................... 30 
9.4 
REPORTING PROCEDURES BY THE SPONSOR – NOTIFYING THE IRB BY THE INVESTIGATOR .............. 31 
9.4.1 
Adverse Event Reporting ....................................................................................................... 31 
9.4.2 
Serious Adverse Event Reporting .......................................................................................... 31 
9.4.3 
Unanticipated Problem (UPs) Reporting ................................................................................ 31 
9.4.4 
Reporting of Pregnancy ......................................................................................................... 31 
9.5 
REPORTING PROCEDURES – NOTIFYING VITAERIS .......................................................................... 31 
9.6 
REPORTING PROCEDURES – NOTIFYING THE FDA.......................................................................... 32 
9.7 
TREATMENT HALTING RULES ......................................................................................................... 32 
9.8 
SAFETY OVERSIGHT ...................................................................................................................... 32 
9.8.1 
Data Safety Monitoring Board (DSMB) .................................................................................. 32 
10 
CLINICAL MONITORING ................................................................................................................... 33 
11 
STATISTICAL CONSIDERATIONS ................................................................................................... 33 
11.1 
STATISTICAL AND ANALYTICAL PLANS (SAP) .................................................................................. 33 
11.1.1 
Phase II: ............................................................................................................................. 33 
11.1.2 
Phase III: ............................................................................................................................ 34 
11.2 
INTERIM ANALYSES ....................................................................................................................... 35 
11.2.1 
Phase II .............................................................................................................................. 35 
11.2.2 
Phase III ............................................................................................................................. 36 
12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 36 
13 
QUALITY ASSURANCE AND QUALITY CONTROL ........................................................................ 37 
14 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 37 


14.1 
ETHICAL STANDARD ...................................................................................................................... 37 
14.2 
INSTITUTIONAL REVIEW BOARD ..................................................................................................... 37 
14.3 
INFORMED CONSENT PROCESS ..................................................................................................... 37 
14.3.1 
Consent/Assent and Other Informational Documents Provided to Participants ............... 37 
14.3.2 
Consent Procedures and Documentation ......................................................................... 37 
14.4 
PARTICIPANT AND DATA CONFIDENTIALITY ..................................................................................... 39 
14.4.1 
Research Use of Stored Human Samples, Specimens, or Data....................................... 40 
15 
DATA HANDLING AND RECORD KEEPING ................................................................................... 40 
15.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 40 
15.2 
STUDY RECORDS RETENTION........................................................................................................ 40 
15.3 
PROTOCOL DEVIATIONS ................................................................................................................ 41 
15.4 
PUBLICATION AND DATA SHARING POLICY ..................................................................................... 41 
16 
STUDY FINANCES ............................................................................................................................. 41 
16.1 
FUNDING SOURCE ........................................................................................................................ 41 
16.2 
COSTS TO THE PARTICIPANT ......................................................................................................... 41 
16.3 
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................................................................. 41 
17 
CONFLICT OF INTEREST POLICY ................................................................................................... 41 
18 
REFERENCES .................................................................................................................................... 42 
19 
ATTACHMENTS ................................................................................................................................. 43 
20 
SCHEDULE OF EVENTS ................................................................................................................... 45 
 
 
 
 


List of Abbreviations 
 
ADL 
Activity of daily living 
AE 
Adverse Event/Adverse Experience 
AKI 
Acute Kidney Injury 
ARDS 
Acute Respiratory Distress Syndrome 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data and Safety Monitoring Board 
FFR 
Federal Financial Report 
FWA 
Federal wide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IL-6 
Interleukin-6 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office of Human Subjects Research 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
RRT 
Renal Replacement Therapy 
sHLH 
Secondary hemophagocitic lymphhistiocytosis 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
US 
United States 


Protocol Summary 
Title 
A randomized placebo-controlled safety and dose-finding study for the use of 
the IL-6 inhibitor clazakizumab in patients with life-threatening COVID-19 
infection 
Short Title 
N/A 
Brief Summary 
In this study we propose to administer clazakizumab to patients with life-
threatening COVID-19 infection manifest by pulmonary failure and a clinical 
picture consistent with a cytokine storm syndrome. This is a single-center 
randomized, double-blind, placebo-controlled trial in which 80 patients will be 
enrolled and randomly assigned in a 1:1:1 ratio to three study arms and 
received clazakizumab at a dose of 12.5 mg, 25 mg or placebo. Based on 
interim analysis, all remaining subjects across all sites will be randomly 
assigned to a 1:1 ratio to two arms that will receive clazakizumab at a dose of 
25 mg or placebo. The NYU site will serve as the central data management 
site for other centers who undertake this protocol.  Other sites will enroll 
patients based on the two arm 1:1 randomization. A minimum of 150 patients 
across all sites are expected to enroll. 
Phase 
2-3 
Objectives 
The primary objective is to assess the safety of clazakizumab treatment in 
COVID-19 infected patients with respiratory failure due to hyperinflammation 
related to cytokine storm.  
  
The primary outcomes will be to assess the efficacy by evaluating the 
mechanical ventilation free survival at 28 days, and the rate of WHO 11 
points scale status at 14 and 28 days 
Methodology 
Randomized, double-blind, placebo-controlled, single-center trial 
Endpoint 
The primary safety endpoint for the Phase II portion is the rate of 
hypersensitivity reactions in the patients receiving clazakizumab compared to 
those receiving placebo. The primary efficacy endpoint is the rate of levels 6-
10 status on the WHO 11 points scale at day 14. The primary endpoint for the 
Phase III portion is 28-day survival free from ventilation. 
Study Duration 
12 Months 
Participant Duration 
60 Days 
Duration 
of 
IP 
administration 
Single dose (If second dose is necessary, administered within 2 days) 
Population 
Patients with known COVID-19 disease, male or female, 18 years of age or 
older, who are critically ill with respiratory failure and do not have any 
evidence of irreversible injury deemed non-survivable. 
Study Sites 
NYU Langone Health, New York, New York, United States  External sites  to 
be determined as single center investigator initiated trials with data 
contribution in a centralized EDC system managed by NYULH 
Number of participants 
150-180 patients 
Description of Study 
Agent/Procedure 
Clazakizumab is a humanized monoclonal antibody that binds to human IL-6.  
The patients randomized to the investigational arms will be given either a 
single intravenous dose of clazakizumab 25mg or placebo. Patients who fail 
to achieve the expected decrease in inflammatory markers following the first 
dose will have the day 1 dose repeated (clazakizumab 25 mg or placebo) on 
day 3.  Clazakizumab will be administered by intravenous infusion over 30 
minutes. 
Reference Therapy 
Placebo (NS infusion) 


Key Procedures 
Clazakizumab infusions and blood draws 
Statistical Analysis 
Estimation of the likelihood of superiority of one or more active treatments 
over placebo at each interim analysis point on the basis of the Phase III 
endpoints. 
 
 
 


Schematic of Study Design 
 
 


1 Key Roles 
 
Principal investigator 
Bonnie Lonze MD PHD 
NYU Langone Health, Transplant Institute 
550 First Ave, Suite 7A 
New York NY 10016 
212-263-8365 
Bonnie.Lonze@nyulangone.org 
 
Sub-investigators 
Elaina Weldon, ACNP 
NYU Langone Health, Transplant Institute 
403 E 34th St, 4th Floor 
New York, NY 10016 
212-263-3786 
Elaina.Weldon@nyulangone.org 
 
Rebecca Dieter, PharmD 
NYU Langone Health, Transplant Institute 
403 E 34th St, 4th Floor 
New York, NY 10016 
212-263-3786 
Rebecca.Dieter@nyulangone.org 
 
Vasishta Tatapudi, MD 
NYU Langone Health, Transplant Institute 
403 E 34th St, 2nd Floor 
New York, NY 10016 
212-263-2428 
Vasishta.Tatapudi@nyulangone.org 
 
Tyler Lewis, PharmD 
NYU Langone Health, Transplant Institute 
545 First Avenue, GBH-SC2-097 
New York, NY 10016 
646-501-6978  
Tyler.Lewis@nyulangone.org 
 
Robert A. Montgomery, MD, DPhil 
NYU Langone Health, Transplant Institute 
550 First Ave, Suite 7A 
New York NY 10016 
646-501-2418 
Robert.Montgomery@nyulangone.org 
 
Holly C. Foote, DO, MS 
NYU Langone Health Transplant Institute 
550 First Ave, Suite 7A 
New York NY 10016 
646-501-2418 
Holly.Foote@nyulangone.org 
 
 
 


Steven Mitchell Cohen D.O., F.A.C.S. 
530 First Avenue 
HCC, Suite 6-C 
New York, NY 10016 
212-263-7302 
steven.cohen@nyumc.org 
 
Irfana Soomro, MD 
317 East 34th Street 8th Floor 
New York, New York 10016 
314-566-7191 
Irfana.Soomro@nyulangone.org 
 
Aprajita Mattoo, MD 
317 East 34th Street 8th Floor 
New York, New York 10016 
516-547-0555 
Aprajita.Mattoo@nyulangone.org 
 
Cecilia Deterville, MA, CCRC 
NYU Langone Health, Transplant Institute 
403 E 34th St, 4th Floor 
New York, NY 10016 
212-263-3620 
Cecilia.Deterville@nyulangone.org 
 
Jennifer Michael, MS 
NYU Langone Health, Transplant Institute 
403 E 34th St, 4th Floor 
New York, NY 10016 
Jennifer.Michael@nyulangone.org 
 
Nikki Lawson, BSN, RN 
NYU Langone Health, Transplant Institute 
403 E 34th St, 4th Floor 
New York, NY 10016 
Nikki. Lawson@nyulangone.org 
 
Andrea B. Troxel, ScD 
NYU Langone Health, Department of Population Health 
Division of Biostatistics  
180 Madison Ave, Suite 5-55 
New York NY 10016 
646-501-3654 
Andrea.Troxel@nyulangone.org 
 
Peter Spiegler, MD 
NYU Winthrop Hospital 
Pulmonary & Critical Care / Sleep Medicine 
222 Station Plaza North, Suite 400 
Mineola, New York   11501 
T 516-663-8952 / 516-663-2004 option #2 
 
Shalinee Chawla, MD 
NYU Winthrop Hospital 
Pulmonary & Critical Care / Sleep Medicine 


222 Station Plaza North, Suite 400 
Mineola, New York   11501 
T 516-663-8952 / 516-663-2004 option #2 
Shalinee.Chawla@nyulangone.org 
 
Shilpa DeSouza, MD 
NYU Winthrop Hospital 
Pulmonary & Critical Care / Sleep Medicine 
222 Station Plaza North, Suite 400 
Mineola, New York   11501 
T 516-663-8952 / 516-663-2004 option #2 
Shilpa.DeSouza@nyulangone.org 
 
Manju Pillai, MD 
NYU Winthrop Hospital 
Pulmonary & Critical Care / Sleep Medicine 
222 Station Plaza North, Suite 400 
Mineola, New York   11501 
T 516-663-8952 / 516-663-2004 option #2 
Manju.Pillai@nyulangone.org 
 
Mangalore Amith Shenoy, MD 
NYU Winthrop Hospital 
Pulmonary & Critical Care / Sleep Medicine 
222 Station Plaza North, Suite 400 
Mineola, New York   11501 
T 516-663-8952 / 516-663-2004 option #2 
MangaloreAmith.Shenoy@nyulangone.org 
 
Michael Bender, MD 
NYU Winthrop Hospital 
Pulmonary & Critical Care / Sleep Medicine 
222 Station Plaza North, Suite 400 
Mineola, New York   11501 
T 516-663-8952 / 516-663-2004 option #2 
Michael.Bender@nyulangone.org 
 
Priya Agarwala, MD 
NYU Winthrop Hospital 
Pulmonary & Critical Care / Sleep Medicine 
222 Station Plaza North, Suite 400 
Mineola, New York   11501 
T 516-663-8952 / 516-663-2004 option #2 
Priya.Agarwala@nyulangone.org 
 
Suran Thomas, MD 
NYU Winthrop Hospital 
Pulmonary & Critical Care / Sleep Medicine 
222 Station Plaza North, Suite 400 
Mineola, New York   11501 
T 516-663-8952 / 516-663-2004 option #2 
Sarun.Thomas@nyulangone.org 
 
Martin Backer, MD 
222 Station Plaza North, Suite 432 
Mineola, NY 11501 


Martin.Backer@NYULangone.org 
1-516-663-2505 
 
Diane H. Johnson, MD 
NYU Winthrop Hospital, Clinical Center,  
101 Mineola Blvd, Suite 3-002, NY 11501 
Diane.Johnson@nyulangone.org 
516-663-9582 
 
Kimberly Byrnes, LPN 
NYU Winthrop Hospital 
Clinical Trials Center 
101 Mineola Blvd, Suite 3-002 
Mineola, NY 11501 
(516) 663-9582 Tel 
Kimberly.Byrnes@nyulangone.org 
 
Anita Farhi, RN 
NYU Winthrop Hospital 
Clinical Trials Center 
101 Mineola Blvd, Suite 3-002 
Mineola, NY 11501 
(516) 663-9582 Tel 
Anita.Farhi@nyulangone.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 Introduction, Background Information and Scientific Rationale 
 
2.1 Background Information and Relevant Literature 
The limited understanding of the clinical behavior of patients infected with SARS-CoV-2 (the viral 
organism responsible for COVID-19 disease) is evolving on a daily basis. Reports from China indicate 
that a subset of patients with the worst clinical outcomes may manifest cytokine storm syndrome. 
Hypotheses that excess cytokines may trigger a secondary hemophagocytic lymphhistiocytosis (sHLH) 
have been proposed. Indeed, cytokine profiles consistent with this picture were observed in Chinese 
patients with severe pulmonary involvement (1). Specifically, elevated ferritin and interleukin-6 (IL-6) were 
associated with fatalities among the infected patients. A role for targeted anti-inflammatory and anti-
cytokine therapies in the treatment of pulmonary hyperinflammation and acute kidney injury has been 
proposed.   
 
Clazakizumab is a genetically engineered humanized IgG1 monoclonal antibody (mAb) that binds with 
high affinity to human IL-6. This investigational agent is currently being studied as a treatment for chronic 
active antibody mediated rejection of renal allografts (2-4).  Vitaeris holds INDs 134376 and 108525 for 
the ongoing clinical investigations of this agent.  
 
In this study we propose to administer clazakizumab to patients with life-threatening pulmonary failure 
secondary to COVID-19 disease.  A new IND request has been submitted and the study team has 
received safe-to-proceed correspondence from the FDA.  The IND assigned to this protocol is 149176. 
 
2.2 Name and Description of the Investigational Agent  
Investigational agent: clazakizumab  
Supplier of clazakizumab: Vitaeris Inc, Vancouver, BC, Canada 
Manufacturer: Ajinomoto Althea Bio-Pharma, Inc, San Diego CA, USA 
 
Clazakizumab is a genetically engineered humanized mAb directed against the human cytokine IL-6. 
Clazakizumab is a soluble protein consisting of 4 polypeptide chains that include 2 identical heavy chains 
of 450 amino acids each and 2 identical light chains of 217 amino acids each. Its molecular weight is 
145,239 Daltons.  It is clear to slightly opaque, colorless to yellow colored in solution.  The pH in solution 
is 5.5-6.5.  
 
This is an investigational drug which is currently under Phase 3 investigations for patients with chronic 
active antibody mediated rejection after kidney transplantation. Vitaeris holds INDs for these studies but 
the drug does not currently have an FDA-approved indication.  Existing INDs will be cross-referenced for 
this study. 
 
2.2.1 Preclinical Data 
Clazakizumab was shown to be a potent inhibitor of IL-6-induced acute phase proteins. In 
pharmacokinetic and pharmacodynamic (PD) studies, a single dose of clazakizumab resulted in full 
inhibition of IL-6 activity as measured by the inhibition of IL-6-induced phosphorylated STAT3 (pSTAT3) 
activity in whole blood treated ex vivo with IL-6. The results of this functional PD assay correlated with 
drug exposures where full inhibition of pSTAT3 activity was observed when drug levels exceeded 50 
ng/mL (approximately 0.3 nM). In a tissue cross-reactivity study, tissue binding of clazakizumab was 
observed in multiple tissues in both human and cynomolgus monkey, was generally cytoplasmic in 
nature, and was consistent with the known expression of IL-6 by cells and tissues. Results from both 
single- and repeat-dose nonclinical toxicology studies of up to 6 months in cynomolgus monkeys 
demonstrated an acceptable safety profile for clazakizumab. In a preliminary enhanced pre- and post-
natal development study conducted in cynomolgus monkeys, an increase in the number of monkeys with 
retention of the placenta at parturition was observed at clazakizumab doses of 3 mg/kg (n=2) and 30 


mg/kg (n=3), corresponding to doses 34 and 340 a human dose of 12.5 mg once every 4 weeks (Q4W). 
There were no other safety findings of clinical concern. Preclinical data are described in detail in the 
Investigator’s Brochure (5). 
 
2.2.2 Clinical Data to Date 
Clinical studies have been conducted in healthy subjects and in the following patient populations: 
rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, graft-versus-host disease, and oncology. These 
completed clinical studies include a total of 1,223 subjects, of which 1,056 subjects were exposed to 
clazakizumab for up to 175 weeks (including open-label, long-term extension phases) with doses ranging 
from 1 mg to 640 mg, given by either IV or subcutaneous (SC) injection.  
 
In addition, preliminary safety data are available from the ongoing pivotal Study VKTX01 (IMAGINE) in 
renal transplant recipients with chronic active antibody-mediated rejection and 3 ongoing Investigator-
initiated trials (IITs) in the kidney transplant setting including highly-human leukocyte antigen 
(HLA)-sensitized subjects awaiting a kidney transplant; subjects with CABMR; and subjects with late, 
active ABMR. 
 
Further details of these clinical trials are described in detail in the Investigator’s Brochure (5). 
2.2.3 Dose Rationale  
The proposed doses of 25 mg and 12.5 mg IV in the planned COVID-19 infection trial are based on a 
rational dose justification taking into account the results of the clazakizumab nonclinical program, the 
safety and efficacy data from completed clinical trials where repeat dosing was studied, preliminary safety 
results from the ongoing pivotal study VKTX01 and 3 ongoing IITs in the kidney transplant setting, and 
comparison with the experience with tocilizumab, an anti-IL-6R mAb, approved for use in rheumatoid 
arthritis and recently investigated with promising results in a small observational study of severe/critical 
Chinese COVID-19 patients. The completed clinical trials provide an extensive drug exposure experience 
to define the safety profile of clazakizumab, which is primarily associated with its IL-6 blocking effects. 
The AEs observed with clazakizumab have been described with other mAbs that block IL-6 signaling, 
such as tocilizumab and sarilumab. Further details can be found in the dose selection rationale document 
(in Attachments). 
 
An intravenous route of administration is proposed for this study.  Apart from the bioavailability being 
about 40% less by the subcutaneous route compared to intravenous, the most notable difference 
between the two routes is the median time to Tmax.  Tmax was achieved after 1 week in patients 
receiving a subcutaneous dose, compared to at the end of infusion for patients receiving an intravenous 
dose. Given that the study subject enrolled here is critically ill, any beneficial effect of the IP will need to 
be imparted immediately. The patient may not survive long enough to see the effect of a drug that 
achieves Tmax at one week. For this reason, the route of administration will be intravenous. 
 
Eighty subjects were enrolled with the aforementioned dose rationale. Based on interim analysis the 
DSMB has recommended discontinuing the low-dose 12.5 mg clazakizumab arm.  They have advised 
that all subsequent enrollments should be carried out based on a 1:1 randomization for high-dose 25 mg 
of clazakizumab versus placebo.   
2.3 Rationale 
 
As of March 20, 2020, the novel 2019-coronavirus has infected nearly 250,000 people resulting in over 
10,000 deaths. There is no known treatment for this disease. Among the subset of patients who develop 
critical illness, evidence points towards the development of a cytokine storm syndrome that is similar to 
what is observed in secondary hemophagocytic lymphhistiocytosis (sHLH).  Clinical and laboratory features 
of sHLH include high fevers, elevated ferritin, elevated triglycerides, low fibrinogen, and cytopenias.  About 
half of the patients with sHLH develop ARDS which carries a high mortality (1). In China, hypercytokinemia 
was observed in patients with severe COVID disease and one study published online associated elevations 


in ferritin and IL-6 with greater mortality risk in these patients (6). It is reasonable to postulate that the 
pulmonary involvement may be the result of unchecked hyperinflammation, and that there may be a benefit 
to immunosuppressive, specifically, anti-cytokine therapies.  Currently a multicenter randomized trial to 
evaluate the IL-6 receptor blocker tocilizumab is rolling out in China.  Vitaeris Inc manufactures a direct IL-
6 inhibitor, clazakizumab, which is currently under phase 3 investigations for patients with chronic active 
antibody mediated rejection after kidney transplantation.  Recognizing, based on its mechanism of action, 
clazakizumab is hypothesized to have benefit for patients with life-threatening COVID-disease, Vitaeris is 
willing to provide drug for this investigator initiated trial for use in patients who are at greatest risk of dying 
from COVID-19 disease.  This study is a prospective, randomized, double-blind, placebo-controlled trial of 
clazakizumab to prevent death from respiratory and multi-organ failure in COVID-19 disease. An under-
recognized co-morbidity in SARS-CoV-2 infected patients is acute kidney injury (AKI) occurring in up to 
30% of critically ill patients, and contributing to fluid retention, worsening oxygenation, and the need for 
renal replacement therapy. While multiple etiologies may be at play, the effects of systemic and possibly 
local inflammation are highly likely to be significant contributing factors. Improving renal function via IL-6 
inhibition would be a substantial clinical benefit. 
2.4 Potential Risks & Benefits 
2.4.1 Known Risks 
 
Identified risks associated with clazakizumab based on experience in Phase 1-3 clinical trials include: 
infections, liver function test abnormalities, hematologic derangements (neutropenia and 
thrombocytopenia), dyslipidemia, gastrointestinal perforations, injection site reactions. 
 
Infections: as IL-6 is a component of innate and adaptive immunity, IL-6 blockade can potentially promote 
infections.  Since this study does not propose longitudinal administration of clazakizumab, the likelihood 
of prolonged immune compromise related to IL-6 inhibition is low. 
 
Liver function tests: treatment with clazakizumab is associated with transaminitis. Liver function tests will 
be monitored in the study subject as outlined in the study procedures below. Transaminitis may be 
confounded by liver insults that occur as a result of hypotension and hypoperfusion in critically ill patients 
such as the study subject enrolled. 
 
Gastrointestinal perforations: Three cases of bowel perforations were seen in patents with Crohn’s 
disease.  Cases of perforated diverticulitis were also observed in one patient with head and neck cancer 
and in two patients with antibody mediated rejection of kidney transplants.  Patients with active 
inflammatory bowel disease or active untreated diverticulitis will be excluded from participation in this 
study. 
 
Hematologic derangements: clazakizumab is associated with the development of neutropenia and 
thrombocytopenia. Cytopenias are known to be associated with severe COVID-19 infections and 
therefore the etiology of hematologic derangements may be difficult to discern. Blood cell counts will be 
monitored as outlined in the study procedures below and supportive maneuvers instituted as deemed 
clinically appropriate. 
 
Dyslipidemia: Moderate increases in total cholesterol and triglyceride levels have been observed in 
patients receiving serial doses of clazakizumab.  As these were observed to occur early (after the first 
dose) lipid panels will be measured as outlined in the study procedures below. 
 
Injection site reactions: These occurred most commonly with subcutaneous injection and the route of 
administration in this study will be intravenous. 
 
There is a risk that administration of the investigational product may afford the patient no benefit, and that 
the patient may continue to clinically deteriorate and may expire. This may be either because there is no 


therapeutic effect of the investigational product, or that the investigational product may have been 
administered too late in the patient’s course to enable clinical recovery. 
 
There are no known active metabolites of clazakizumab. Metabolism studies have not been performed for 
clazakizumab, which is a mAb. Metabolism studies are generally not performed for therapeutic proteins, 
such as mAbs, which are degraded to their component amino acids which are then recycled into other 
proteins. Since it is an immunoglobulin, no formal drug-drug interaction studies have been performed (5). 
2.4.2 Potential Risks 
Infusion reactions including hypersensitivity type reactions: This type of reaction has not been observed 
with clazakizumab to date, however has the potential to occur with IV administration of antibody products. 
These can manifest as fevers, tachycardia, shortness of breath/tachypnea, hemodynamic derangements 
such as hypotension or hypertension. Cardiopulmonary and hemodynamic monitoring will be continuous in 
the critically ill patients who will be enrolled in this study. Suspected infusion reaction will be managed by 
pausing or discontinuing the infusion, and supportive therapy with corticosteroid and/or epinephrine as 
appropriate. 
2.4.3 Known Potential Benefits 
There are no certain benefits to this study.  We are proposing an experimental use of an agent with a 
similar mechanism to a drug that showed promise in a small cohort of Chinese patients who developed 
life-threatening pulmonary failure after acquiring COVID-19 disease.  On that basis, there is potential that 
receiving clazakizumab could rapidly abrogate the hyperinflammatory syndrome that may otherwise lead 
to respiratory failure and death in COVID-19 disease.  Extremely limited literature exists on this topic. A 
recent correspondence in the Lancet summarizes the experience to date (1). 
 
3 Objectives and Purpose 
3.1 Primary Objective 
The primary objective is to assess the safety of clazakizumab treatment in COVID-19 infected patients 
with respiratory failure due to hyperinflammation related to cytokine storm   
3.2 Secondary Objectives  
The secondary objectives are to assess efficacy by evaluating the incidence and duration of mechanical 
ventilation, the length of ICU stay, severity and duration of acute renal failure and patient survival in 
patients who receive IP at two different doses versus placebo. 
 
4 Study Design and Endpoints 
4.1 Description of Study Design 
 
This is a randomized, double-blind, placebo-controlled, adaptive seamless Phase II/III design (ASD). We 
propose the administration of an investigational drug in patients with high predicted short-term mortality 
secondary to COVID-19 disease. 80 patients were randomly assigned in a 1:1:1 ratio to three study arms 
that will receive clazakizumab at a dose of 12.5 mg, 25 mg or placebo. Interim analyses have occurred 
every 7 days since the enrollment of the first 30 patients. Based on week 4 interim analysis the DSMB 
has recommendation discontinuing the low-dose 12.5 mg of clazakizumab arm.   The DSMB has advised 
continuing enrollment in the placebo and high-dose 25 mg of clazakizumab arms in a 1:1 randomization. 
 


4.2 Study Endpoints 
4.2.1 Primary Study Endpoints 
The primary Phase II endpoint is patient safety as determined by freedom from Category A adverse 
events, defined as death, intubation, need for pressors, and need for mechanical ventilation.  The primary 
Phase III endpoint is survival, free from mechanical ventilation, at 28 days. 
4.2.2 Secondary Study Endpoints 
The secondary endpoints are: incidence of intubation, time to extubation, length of ICU stay, trend in C-
reactive protein, severity of AKI, need for RRT, duration of RRT and patient survival at 28 and 60 days. 
5 Study Enrollment and Withdrawal 
5.1 Inclusion Criteria 
In order to be eligible to participate in this study, the patients must meet all of the following criteria: 
1. At least 18 years of age 
2. Confirmed COVID-19 disease (by Cobas SARS-CoV-2 real time RT-PCR using nasopharyngeal 
swab sample, or equivalent test available to be performed by the NYU Langone clinical laboratory). 
Effort will be made to have the confirmatory test result <72 hours prior to enrollment however given 
overall clinical demand this may not be feasible in all cases. 
3. Respiratory failure manifesting as: Acute Respiratory Distress Syndrome (defined by a P/F ratio of 
<200), OR SpO2 < 90% on 4L (actual or expected given higher O2 requirement) OR increasing 
O2 requirements over 24 hours, PLUS 2 or more of the following predictors for severe disease: 
• 
CRP > 35 mg/L 
• 
Ferritin > 500 ng/mL 
• 
D-dimer > 1 mg/L 
• 
Neutrophil-Lymphocyte Ratio > 4 
• 
LDH > 200 U/L 
• 
Increase in troponin in patient w/out known cardiac disease 
4. Has a consent designee willing to provide informed consent on behalf of the patient (this assumes 
that a mechanically ventilated patients lacks capacity to consent on his/her own behalf. Should it be 
deemed that the patient has capacity to consent, consent may be obtained from the patient.) 
5. Women of childbearing potential must be willing and able to use at least one highly effective 
contraceptive method for a period of 5 months following the study drug administration. In the 
context of this study, an effective method is defined as those which result in low failure rate (i.e. 
less than 1% per year) when used consistently and correctly such as: 
a. combined (estrogen and progestogen containing) hormonal contraception combined 
(estrogen and progestogen containing) hormonal contraception (oral, intravaginal, or 
transdermal) 
b. progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, implantable) 
c. intrauterine device (IUD) 
d. intrauterine hormone-releasing system (IUS) 
e. vasectomized partner 
f. 
bilateral tubal occlusion 
g. true abstinence. when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence, such as calendar, ovulation, symptothermal, postovulation methods, 
and withdrawal are not acceptable methods of contraception. 
6. Men must be willing to use a double-barrier contraception from enrollment until at 5 months after 
the last dose of study drug, if not abstinent. 
5.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 


1. Evidence of irreversible injury deemed non-survivable even if the pulmonary failure recovers (for 
example severe anoxic brain injury) 
2. Known active inflammatory bowel disease 
3. Known active, untreated diverticulitis 
4. Known untreated bacteremia 
5. Pregnancy. (The protocol will exclude pregnant subjects given the lack of overall data on use of 
clazakizumab in pregnancy however the study team would consider a protocol revision should 
more than 3 potential pregnant study subjects be excluded on this basis). 
6. Known hypersensitivity to the clazakizumab  
5.3 Vulnerable Subjects 
Vulnerable subjects will not be excluded. This study is designed to include any patients deemed at risk for 
imminent death, and the opportunity to enroll will not be withheld provided the subject meets the above 
inclusion and exclusion criteria. 
5.4 Strategies for Recruitment and Retention 
The patients enrolled have been identified by the members of the NYULH COVID-19 inpatient team who 
have identified the potential subject as critically ill and failing all available medical and supportive 
therapies. 
 
Patient recruitment will be by direct communication between the COVID-19 inpatient team and the study 
team. 
5.5 Duration of Study Participation 
The entire duration of study participation is 60 days. Study specific laboratory tests will be performed 
within the first 14 days of study initiation.  Beyond 14 days, all data collected will be that which is acquired 
for purposes of clinical care. Patients will be followed for the survival endpoint for 60 days. 
 
5.6 Total Number of Participants and Sites  
80 patients were enrolled in the phase II study and randomized 1:1:1 between placebo, low-dose 12.5mg 
and high-dose 25mg clazakizumab.   Based on DSMB recommendations, all subsequent subjects 
enrolled will be randomized 1:1 to receive placebo or high dose 25mg clazakizumab.   
 
NYU will serve as the central data managing site for additional external sites where this protocol will be 
implemented. Total enrollment is expected to be a minimum of 150 patients across three sites.  This 
includes the 80 patients enrolled at NYU in the former three-arm randomization scheme. At least 70 and 
up to 100 additional patients are expected to be enrolled and randomized 1:1.  A maximum of 180 
patients will be enrolled. 
 
The external sites will contribute de-identified data to a central dataset but the conduct of their trials will 
be overseen by local IRB at their respective sites. 
5.7 Participant Withdrawal or Termination 
5.7.1 Reasons for Withdrawal or Termination 
The predicted mortality rate for patients with COVID-19 and ARDS is in excess of 50% (7).  As such we 
anticipate there will be mortality amongst some of the participants. Death will constitute withdrawal from 
the trial.  Otherwise we would not anticipate premature withdrawal from the study as the patients are 
expected to remain hospitalized (likely in an ICU setting) for the entire duration of the 14-day period 
where study specific data are collected. If the patient is discharged before day 28 survival status will be 
obtained by patient lookup in the electronic medical record.  For discharged patients in whom there is no 
definitive record documenting patient status (alive or dead) after 28 days have elapsed, the study team 


will contact the patient or patient’s family by phone to assess patient survival and to assess for the 
occurrence of any interim AEs/SAEs. At end of study (day 60), a phone call will also take place to assess 
patient survival and again asses for interim AEs/SAEs. The IP administration will occur over a maximum 
of 3 days following enrollment. Study specific laboratory tests will be performed in the first two weeks and 
if a patient (or consent designee should the patient lack capacity) wishes to withdraw from participation 
and refuse these laboratory studies, they will be free to do so.  
 
An investigator may terminate participation in the study if: 
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
5.7.2 Handling of Participant Withdrawals or Termination 
Should a patient (or consent designee) withdraw from the study by choice, no further study specific 
laboratory tests will be drawn. The study team would continue to follow the patient for the primary 
outcome of patient survival and for secondary outcomes that would be measurable by tests and 
assessments done for routine clinical care.  The overall clinical care of this patient will not change as a 
result of participation in this study nor will it change should the patient be withdrawn for any reason. 
5.8 Premature Termination or Suspension of Study 
Patient deaths are expected among study subjects given that the expected mortality of the enrolling 
patient population exceeds 50%.  All deaths and related SAEs within the study period will be reviewed by 
the DSMB (see section 9.8, Safety Monitoring).  The DSMB will determine whether unblinding of the 
deceased subject is warranted. The decision to stop or suspend the study will be made the DSMB after 
considering the totality of the data and the benefit-risk of continuing the study.  
6 Study Agent (Study drug, device, biologic, vaccine etc.) and/or 
Procedural Intervention  
6.1 Study Agent(s) and Control Description 
Clazakizumab is provided as a preservative-free solution for IV administration, contained in a single-dose 
2-cc Type I flint glass vial that is stoppered with a 13-mm stopper and sealed with an aluminum seal. 
Each vial contains clazakizumab Drug Substance (25 mg/mL), 25 mM histidine buffer (L-histidine, L-
histidine monohydrochloride), 250 mM sorbitol, and 0.015% (w/w) polysorbate-80 at pH 6.0. An overfill is 
included to ensure a 1.0 mL (25 mg) withdrawable volume. In these vials, clazakizumab has a clear, 
colorless appearance. 
 
Placebo will be sourced locally at the study site from commercially available saline. The placebo will 
contain 0.9% sodium chloride as a sterile solution. There are no excipients. 
6.1.1 Acquisition 
Vitaeris, Inc. will ship investigational product directly to the NYU Langone Investigational Pharmacy. The 
study team will enter an order for the IP in the Epic system.  Once the order is received, the medication 
will be prepared by the pharmacy and delivered to the patient’s bedside. 
Placebo (normal saline) will be sourced locally at the study site from commercially available saline. 
6.1.2 Formulation, Appearance, Packaging, and Labeling 
Clazakizumab is manufactured by Ajinomoto Althea Bio-Pharma, Inc., San Diego, CA, USA.  The product 
will be provided a cartons containing single-use glass vials of clazakizumab (25 mg/mL). Vials are 2 mL, 
containing a minimum of 1.1 mL clazakizumab. The kits will be labeled with an Annex 13 compliant label. 


 
This product is not commercially available and will be shipped directly from the manufacturer to the NYU 
Langone Investigational Pharmacy for purposes of this study only.    
 
The placebo will contain 0.9% sodium chloride as a sterile solution and will be sourced locally by the 
study site. 
6.1.3 Product Storage and Stability 
Clazakizumab vials should be stored at ≤–20°C ± 5°C (≤–4°F ± 9°F) with protection from light. 
Prepared infusion bags may be stored for up to 12 hours in a refrigerator, 2°C to 8°C (36°F to 46°F), or at 
controlled room temperature, 15°C to 25°C (59°F to 77°F) and should be protected from light. 
 
The placebo should be stored at conditions specified in the product labeling.  
6.1.4 Preparation 
Investigational drug (clazakizumab or placebo) will be prepared and dispensed in identical infusion bags by 
an unblinded pharmacist/qualified personnel at the investigational site. Each infusion bag will contain a 
label with details including protocol number, subject ID, and date dispensed. The pharmacist will record the 
vial number dispensed for each subject, including the date and time of dispensing on an accountability log.  
 
Preparation of 25 mg dose from 25 mg/mL vials:  
To prepare the clazakizumab IP solution for infusion, remove one 25 mg/mL vial from the freezer and 
allow the vial to thaw at ambient temperature, protected from light, until all vial contents have liquefied 
(this should take approximately 15–20 minutes). During the thaw process, occasionally, gently swirl the 
vial. Do not attempt to speed up the warming process in any way such as using a microwave or placing 
the vial in warm water. Once the clazakizumab vial is at ambient temperature, remove the plastic cap on 
the vial and wipe the septum as well as the minibag port with the alcohol swab. Remove and discard 
overfill (5 mL) + volume of IP dose from the 50 mL 0.9% sodium chloride bag. Using a single use, sterile 
needle and syringe, draw up 1 mL of the contents from the vial. Inject into the minibag containing 50mL 
sterile injectable 0.9% sodium chloride.  Apply investigational study label. Transport in a light protected 
bag to the patient’s bedside for administration.   
 
 
Preparation of Placebo:  
To prepare the placebo solution for infusion, remove one vial of 0.9% sodium chloride sterile solution from 
local supply at the study site. In order to be consistent with preparation of the IP solution, wait 15-20 
minutes before preparing. Then remove the plastic cap on the vial and wipe the septum as well as the 
minibag port with the alcohol swab. Remove and discard overfill (5 mL) + volume of IP dose from the 50 
mL 0.9% sodium chloride bag. Using a single use, sterile needle and syringe, draw up 1 mL of the 
contents from the vial. Inject into the minibag containing 50mL sterile injectable 0.9% sodium chloride.  
Apply investigational study label. Transport in a light protected bag to the patient’s bedside for 
administration.   
6.1.5 Dosing and Administration 
Once the patient is consented and enrolled in the trial, the first dose of 25 mg of clazakizumab or placebo 
will be given as soon as possible thereafter.  No premedications will be given prior to the investigational 
product. Serum CRP will be evaluated at baseline and on days 1 and 2 following clazakizumab or 
placebo administration to assess response.  If the CRP does not decrease by 50% by day 3, a second 
dose of 25mg clazakizumab or placebo (an identical dose to the day 1 dose) will be given no later than 
day 3. All doses will be administered in a blinded fashion.  
6.1.6 Route of Administration 
The route of administration will be intravenous. Each dose will be administered as an infusion that is run 
over 30 minutes. 


6.1.7 Dosing schedule 
Patients will be dosed according to the randomization schedule with 25mg of clazakizumab or placebo.  
Should the patient fail to demonstrate a 50% decrease in CRP by day 3, a second dose will be given. 
Patients whose CRP decreases by 50% or more by day 3 will not be redosed. Patients with CRP failing to 
decrease 50% or more will receive a second dose, identical to the first dose (25mg clazakizumab or 
placebo) on day 3. All doses will be administered in a blinded fashion. 
6.1.8 Dose Adjustments/Modifications/Delays 
Changes in timing between dose 1 and dose 2 (if dose 2 is determined to be indicated) might occur 
based on the laboratory turnaround time for the CRP test.  We expect that this test will result within 24 
hours of being sent. Lab reporting delays could potentially result in a delay in the administration of the 
second dose.  In the event that the CRP lab test is delayed due to laboratory backlog, then clinical 
judgment of the investigators will be used to determine if a second dose is to be given.  Lack of clinical 
improvement, in the absence of a resulted CRP test, will prompt a second dose.  
 
A second dose, even if deemed indicated, would be held if there was suspicion of any serious adverse 
reaction deemed likely related to the first dose. 
6.1.9 Duration of Therapy 
All IP administration is expected to be completed within 2 days of the first dose. It may be the case that 
only a single dose of clazakizumab is given, in which case all IP administration will be complete after the 
first infusion. 
6.1.10 Tracking of Dose 
All doses will be administered in the acute care or intensive care unit.  Patients will not have any 
responsibility for medication self-administration. Standard of care medication administration charting will 
be performed to ensure that the medication is administered. 
6.2 Study Agent Accountability Procedures 
Once the site has been approved to receive investigational drug, Vitaeris Inc. will ship clazakizumab directly 
to the NYU Langone Investigational Pharmacy. Clazakizumab will then immediately be stored in a secured 
area, accessible only to authorized site personnel. Clazakizumab will be stored, handled, and prepared 
according to the instructions specified in the Pharmacy Manual.  
 
The Investigator is ultimately responsible for accountability of investigational drug supplies. The 
Investigational/designee will ensure that an accurate and current accounting of the dispensing of 
investigational drug for each participant is maintained on an ongoing basis by the study site unblinded 
pharmacist/designee. The Investigator is ultimately responsible for ensuring that only study participants 
receive investigational drug.  
 
The amount of investigational drug received, dispensed, and returned/destroyed by the Investigator (or 
designated site staff) will be recorded on an IP Accountability Log.  
 
The IP accountability records will be made available, upon request, for inspection by the designated 
representatives of Vitaeris, Inc., representatives of the US Food and Drug Administration (FDA), or other 
governing regulatory authorities.  
6.2.1 Initial Shipment of Products 
Once regulatory approval to the study site has been given, the initial shipment of clazakizumab 
investigational product will be shipped by Vitaeris, Inc. to the NYU Langone Health Investigational 
Pharmacy. Placebo (normal saline) will be sourced locally by the study site using commercially available 
saline. 


6.2.2 Re-supply 
The need for drug resupply will be assessed on a regular basis taking into account the number of subjects 
enrolled and the number of subjects in screening.  
6.2.3 Destruction of Investigational Product 
Every vial must be clearly accounted for in writing from receipt through return/destruction. For this study, 
partially or fully used clazakizumab vials will be destroyed on-site per site standard destruction practices 
for hazardous biologics. Any unused clazakizumab vials will be accounted for and destroyed as outlined in 
the Pharmacy Manual. 
7 Randomization, Blinding and Unblinding Procedures 
7.1 Randomization 
All enrolled subjects will be assigned a unique subject number, and the Investigator will maintain a list of 
subject numbers and subject names.  
 
Eighty subjects have been randomized (via an IRT) 1:1:1 into the 3 treatment arms using a stratified block 
randomization scheme: 20-50 subjects in the clazakizumab 12.5mg group, 20-50 subjects in the 
clazakizumab 25mg group, and 20-50 subjects in the placebo group.   
 
All subsequent enrolled patients will be randomized 1:1 into the placebo arm or the high-dose 25mg 
clazakizumab arm.   
 
The randomization schema will be pre-prepared by a blinded statistician and will be made available only 
to the investigational pharmacy.  All study investigators and clinical staff administering study drug will be 
blinded to the content of the dose.   
 
As the study transitions to Phase III, randomization in Phase III will follow the same 1:1 format.   
7.2 Blinding 
This study is double-blind and therefore neither the Investigator, the subject and its representatives, nor 
other designated study site personnel involved in running of the study will be aware of the identification of 
the investigational drug administered to each subject. To maintain blinding, interim analyses will be 
conducted by the designated Data Safety Monitoring Board. Detailed procedures for maintaining the blind 
are specified below.  
 
Given that clazakizumab and placebo are packaged differently, investigational drug will be prepared and 
dispensed by an unblinded pharmacist/qualified personnel at each investigational site. To maintain 
blinding during the study, the pharmacist/designated staff will dispense either clazakizumab or placebo 
into identical infusion bags, according to each subject’s randomized treatment allocation, and all subjects 
will receive each dose of investigational drug (clazakizumab or placebo) as an intravenous infusion. 
  
The pharmacist/designated staff will ensure that blinded personnel will not have access to drug supply 
records.  
 
7.3 Unblinding 
  
In the event that an AE occurs for which knowledge of the identity of the investigational drug administered 
is necessary to manage the subject’s condition and/or for regulatory reporting of a suspected unexpected 
serious adverse reaction (SUSAR), the blinding code for that subject may be broken by the Investigator 
and the treatment identified.  
 


Should emergency unblinding be required, the Investigator should call and discuss the patient with the 
DSMB chair before unblinding wherever possible; however, the Investigator is responsible for the medical 
care of the individual trial subject and does not require the agreement of the DSMB Chair before 
unblinding. The reason for unblinding must be documented. The information on investigational drug 
should only be used for decision making in the subject’s further treatment. Details on unblinded treatment 
assignments should not be shared with the site personnel, or project team unless necessary for care of 
the subjects. 
  
In case of an emergency, the following process will occur after the DSMB Chair is made aware, if time 
permits. The Investigator will notify the unblinded Investigational Pharmacist who will serve as the source 
for emergent unblinding information. The Investigational Pharmacist will be responsible for the following:  1) 
providing unblinding information to the Investigator only for the specific Subject affected, 2) documenting 
the provision of unblinding information in the pharmacy records and 3) confirming with the DSMB Chair of 
the unblinding occurrence and rationale for unblinding. 
 
8 Study Procedures and Schedule 
8.1 Study Procedures/Evaluations 
8.1.1 Study Specific Procedures 
8.1.2 Standard of Care Study Procedures 
All critical care interventions will be performed by the clinical care team independent of the study team. 
 
These include but are not limited to: 
• 
Ventilator management and determination of when to extubate (or perform tracheostomy)  
• 
Hemodynamic support (fluid and vasoactive drug administration) 
• 
Mechanical circulatory support if needed (e.g. ECMO) 
• 
Renal replacement therapy 
• 
Enteral or parenteral nutrition 
• 
Surveillance for and management of infections 
8.2 Laboratory Procedures/Evaluations 
8.2.1 Clinical Laboratory Evaluations 
 
• 
Complete blood count with differential: hemoglobin, hematocrit, white blood cells (WBC) with 
differential count, platelet count. 
• 
Complete metabolic panel: creatinine, total bilirubin, alanine aminotransferase (ALT), aspartate 
• 
aminotransferase (AST) 
• 
C-reactive protein (CRP) 
• 
Interleukin 6 (IL-6) 
• 
Lipid panel: total cholesterol, triglycerides 
• 
Ferritin 
• 
Fibrinogen 
• 
Pregnancy test (only for women of childbearing potential), to be done at screening 24 hours 
prior to study intervention and results must be available prior to administration of study product. 
• 
D-Dimer 
• 
LDH 
• 
Troponin 


8.2.2 Specimen Preparation, Handling, and Storage 
No specimens will be collected or maintained for purposes of this study. 
8.3 Study Schedule 
A detailed Schedule of Events is outlined in Section 20. 
Screening (Days -5 to 1): 
 
Inclusion and exclusion criteria verified 
 
Informed consent signed 
Medical history and physical exam documented (physical examination as conducted by subject’s   
 
clinical care team) 
 
Concomitant medications documented 
 
Calculation of baseline H-score (see attached documents) for scoring sheet 
Baseline study labs drawn (CRP must be drawn on same day as infusion of Investigational 
Product; prior to infusion of Investigational Product) 
Collection of clinical data (vital signs, respiratory and hemodynamic support parameters) 
 
Day 1:  
Day 1 laboratory studies (CRP, if screening and Day 1 are not performed on the same day) 
Physical examination (as conducted by subject’s clinical care team) 
Infusion of clazakizumab 25mg or placebo IV 
Collection of clinical data (vital signs, respiratory and hemodynamic support parameters) 
Record baseline (at time of first infusion) WHO clinical outcome score 
 
Day 2 No window: 
 
Day 2 laboratory studies 
 
Physical examination (as conducted by subject’s clinical care team) 
Collection of clinical data (vital signs, respiratory and hemodynamic support parameters) 
 
Day 3 No window: 
 
Day 3 laboratory studies 
 
Physical examination (as conducted by subject’s clinical care team) 
 
Assessment of eligibility for repeated clazakizumab dose 
Infusion of clazakizumab 25mg or placebo IV if criteria met 
Collection of clinical data (vital signs, respiratory and hemodynamic support parameters) 
 
Day 4 No window: 
 
Day 4 laboratory studies 
 
Day 5 No window: 
 
Day 5 laboratory studies 
 
Day 6 No window: 
 
Day 6 laboratory studies 
 
Day 7 +/-1: (this visit pertains only to subjects who remain inpatient at this time) 
Day 7 laboratory studies 
Collection of clinical data (vital signs, hemodynamic parameters, respiratory parameters) 
 
Day 14 +/- 2:  
 
Day 14 laboratory studies – only for those who remain inpatient 
Collection of clinical data (vital signs, hemodynamic parameters, respiratory parameters) – only 
for those who remain inpatient 
Assess WHO clinical outcome score - for patients discharged prior to this day, WHO score will be 
recorded as the score at the time of discharge, with patients considered to be Ambulatory. 
Documentation of WHO score will constitute the visit. 


 
Day 28 +/- 3: 
 
If outpatient: phone visit for documentation of survival status and assessment of interval AE/SAEs 
Assess WHO clinical outcome score 
If inpatient: WHO score will be extracted by review of patient electronic medical record and this 
will constitute the visit. 
 
Day 60 +/- 5: 
If outpatient: phone visit for documentation of survival status and assessment of interval AE/SAEs 
Assess WHO clinical outcome score 
If inpatient: WHO score will be extracted by review of patient electronic medical record and this 
will constitute the visit. 
 
 
Additional clinical data to be collected: 
 
Date of symptom onset 
Date of intubation (if performed) 
Date of extubation (if performed) 
Date of tracheostomy (if performed) 
Use and duration of prone positioning (if performed) 
Date of ICU discharge (if occurs) 
Date of hospital discharge (if occurs) 
Date of death (if occurs) 
 
Additional data to be collected if testing becomes available during the conduct of this trial: 
Assessment of SARS-CoV-2 viral load by quantitative RT-PCR in blood.  This would be tested at 
enrollment and on day7 if this assay becomes available and able to be performed in the NYU clinical 
laboratory.  
8.3.1 Withdrawal/Early Termination Visit 
Should the patient choose to withdraw from the study before the 60 day study duration has elapsed, the 
patient’s choice to withdraw will be documented. The patient will be followed by the medical record to 
collect clinical data obtained for standard clinical care as pertains to the study outcomes, but no further 
study-specific blood draws will take place. 
8.4 Concomitant Medications, Treatments, and Procedures 
All concomitant prescription medications being administered at enrollment and during the inpatient stay 
up to the first 28 days of study participation will be recorded. This will include any investigational drugs 
(such as antivirals) the patient may have received. For this protocol, a prescription medication is defined 
as a medication that can be prescribed only by a properly authorized/licensed clinician. Medications to be 
reported in the CRF are concomitant prescription medications, over-the-counter medications and non-
prescription medications. 
9 Assessment of Safety 
9.1 Specification of Safety Parameters  
Patients will be monitored for the manifestations of adverse events related to clazakizumab infusion.  
Both the nature of the event and the timing related to infusion will be considered. Given the baseline 
laboratory and physiologic abnormalities of the patient being enrolled in this study, assessments of 
clinical deterioration will be difficult to attribute with certainty to the underlying disease versus the study 
drug infusion.  The known risks associated with clazakizumab will be considered in determining likelihood 
of association of AEs with the drug. We will only report adverse events which are deemed more than 


probably related or related to the clazakizumab infusion by the Principal Investigator. Any new infection 
that occurs in a study subject once dosing has commenced, regardless of the infecting agent will be 
captured as either an AE or an SAE as appropriate. The site of infection and source of the culture (BAL, 
tracheal aspirate, sputum, blood, urine, etc) will also be recorded.  AEs and SAEs will be captured and 
graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0) scale. 
9.1.1 Definition of Adverse Events (AE) 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
9.1.2 Definition of Serious Adverse Events (SAE) 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. 
 
It is important to acknowledge that the patient being enrolled in this study has a high risk of mortality at 
the time of enrollment in the study and there is a chance that the patient may die of COVID-19 disease 
despite rather than because of the clazakizumab administration.  In the event of mortality, every effort will 
be made on the part of the investigators to assess whether there was any probable association between 
the study drug and the patient death. 
 
In the event of patient death, the study team will consult with the clinical critical care team in an effort to 
determine whether the patient death was related to the underlying clinical condition (COVID-19 infection) 
or whether the death was unexpected given the patient’s condition between the time of study drug 
infusion and the patient’s death. 
 
9.1.3 Definition of Unanticipated Problems (UP) 
 
 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 


• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
9.2 Classification of an Adverse Event 
9.2.1 Severity of Event 
 
CTCAE (v5.0) definitions will be used to describe severity. Grade refers to the severity of the AE. The 
CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on 
this general guideline:  
 
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
• 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activity of daily living (ADL).  
• 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL.  
• 
Grade 4 Life-threatening consequences; urgent intervention indicated.  
• 
Grade 5 Death related to AE. 
 
9.2.2 Relationship to Study Agent 
 
The clinician’s assessment of an AE's relationship to study agent is part of the documentation process, 
but it is not a factor in determining what is or is not reported in the study. If there is any doubt as to 
whether a clinical observation is an AE, the event should be reported. All AEs must have their relationship 
to study agent assessed. In a clinical trial, the study product must always be suspect. To help assess, the 
following guidelines are used. 
 
• Related – The AE is known to occur with the study agent, there is a reasonable possibility that the 
study agent caused the AE, or there is a temporal relationship between the study agent and event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between the 
study agent and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study agent 
caused the event, there is no temporal relationship between the study agent and event onset, or 
an alternate etiology has been established. 
 
For all collected AEs, the clinician who examines and evaluates the participant will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below. 
 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the drug 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the drug, is unlikely to be attributed to concurrent disease 
or other drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 


• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related,” as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to drug administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the trial medication) and in 
which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
9.2.3 Expectedness 
The PI will be responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information described in the current version of the Investigator Brochure (Section 7.3.3). 
9.3 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits. All AEs 
including local and systemic reactions not meeting the criteria for SAEs, but deemed to have relation to 
the Investigational product will be captured on the appropriate CRF. Information to be collected includes 
event description, date and time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. Unanticipated problems will be recorded in the data collection 
system throughout the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The PI will record all reportable events related to the Infusion of the Investigational Product with start 
dates occurring any time after informed consent is obtained until 7 (for non-serious AEs and SAEs)  after 
the last day of study participation. At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit. Events will be followed for outcome information until resolution or 
stabilization.  
 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.  The 
investigator should notify Vitaeris of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be related to this study.  Vitaeris 
should also be notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that has participated in this study.  
 


9.4 Reporting Procedures by the Sponsor – Notifying the IRB by the Investigator  
9.4.1 Adverse Event Reporting 
The IRB and DSMB will be notified within 24 hours if a patient dies during the 60-day study period.   
9.4.2 Serious Adverse Event Reporting 
The IRB and DSMB will be notified within 24 hours of any SAEs that are determined by the study team 
and the patient’s clinical providers to be probably or more than probably related to the investigational 
product. 
9.4.3 Unanticipated Problem (UPs) Reporting 
It is the site investigator’s responsibility to report UPs to their IRB and to the DSMB. The UP report will 
include the following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• UPs that are SAEs will be reported to the IRB and to the drug manufacturer (Vitaeris) within 24 
hours of the investigator becoming aware of the event. 
• Any other UP will be reported to the IRB and to the drug manufacturer (Vitaeris) within 72 hours of 
the investigator becoming aware of the problem. 
9.4.4 Reporting of Pregnancy 
Should the study subject become pregnant within the study period this will be reported within 72 hours to 
the IRB and to the drug manufacturer (Vitaeris). Given that the patient at enrollment is critically ill, we 
anticipate the likelihood of new pregnancy (patient or partner) to be exceptionally low. 
 
Clazakizumab was evaluated in pregnant monkeys. In these animals there was an increase in the 
number of monkeys with retention of the placenta at parturition observed at clazakizumab doses of 3 
mg/kg Q2W (n=2) and 30 mg/kg Q2W (n=3), corresponding to doses 17 and 170 times a human dose of 
25 mg Q4W, or 34 and 340 times a human dose of 12.5 mg Q4W (based on a 70 kg adult). These doses 
far exceed what would be administered in this study.  No other pregnancy, parturition, or post-delivery 
issues in the monkeys were reported in this study, and all 5 infants born from the mothers with retained 
placentas were normal. No retained placentas were seen in the control group. No adverse effect of 
clazakizumab was noted on infant post-delivery survival or growth and development assessed by clinical 
observations, body weights, examination for external abnormalities, morphology measurements, 
neurobehavioral test battery, grip strength, skeletal examination, clinical chemistry, hematology, and 
immunology. 
9.5 Reporting Procedures – Notifying Vitaeris 
 
Vitaeris Inc. is not the sponsor for this study. Vitaeris is supplying investigational product for this 
investigator initiated trial. Nonetheless the study team will inform Vitaeris of patient death should it occur. 
Patient death, whether related or unrelated to clazakizumab will be reported to Vitaeris within 72 hours of 
the death.  SAEs deemed related to clazakizumab will be reported to Vitaeris within 24 hours of the study 
team being made aware. 
 


The FDA will be notified of patient death, whether deemed related or unrelated to the investigational 
product, within 72 hours of the patient death. 
9.6 Reporting Procedures – Notifying the FDA  
The IND holder is required to report certain study events in an expedited fashion to the FDA.  These 
written notifications of adverse events are referred to as IND/IDE safety reports.  
 
The following describes the IND safety reporting requirements by timeline for reporting and associated 
type of event: 
 
• Within 7 calendar days (via notification to IND) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit this 
criteria for reporting (reporting within 7 calendar days from when event was deemed 
reportable). 
 
• Within 15 calendar days (via notification to IND) 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit this 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
 
Additional reporting requirements 
The investigator/designee is also required to identify in IND safety reports all previous reports concerning 
similar adverse events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A (MEDWATCH Form), or in a narrative format. If 
supplied as in a narrative format, the minimum information to be supplied is noted above at the beginning 
of section 8.3. The contact information for submitting IND safety reports is noted below: 
9.7 Treatment Halting Rules 
If a treatment related SAE occurs following the first dose, additional dosing may be halted at the 
discretion of the DSMB or investigator based on a benefit risk assessment.  Data collection for safety 
would not be affected and would continue provided the patient does not elect to withdraw from the study. 
9.8 Safety Oversight  
9.8.1  Data Safety Monitoring Board (DSMB) 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan. Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 


Safety oversight will be under the direction of the NYULH COVID-19 DSMB. This DSMB committee for this 
study will be comprised of individuals with expertise across the broad range of disciplines. The DSMB 
Charter, which outlines DSMB roles and responsibilities are forthcoming.  
 
The DSMB will be notified of all AEs and SAEs as outlined above in sections 9.4.1 and 9.4.2.  It will 
be the responsibility of the DSMB to evaluate cumulative participant safety data and make 
recommendations regarding the safe continuation of the study. The DSMB will convene a planned 
meeting after the first 10 patients have enrolled. Subsequent meetings will be at the discretion of 
the DSMB chair and the principal investigator. 
 
The DSMB will hold emergency meetings in the event of patient deaths to discuss whether unblinding 
is warranted. The DSMB will hold emergency meetings if the DSMB chair deems this is warranted 
based on any reported AE or SAE. Emergency meetings will occur within 2 business days of the 
precipitating event occurring or being recognized. Any event that prompts an emergency DSMB-study 
team meeting will be reported to the IRB and to Vitaeris within 24 hours of the event occurring or being 
recognized. 
 
There are planned interim analyses after every 30 patients have 14-day data available on Category A 
events. The DSBM will review the data in light of the planned interim analysis procedure and determine 
whether particular arms should be closed, or whether the study should be stopped for efficacy or futility. 
The DSMB may request to see safety and/or efficacy data in an unblinded fashion; if this occurs, the 
DSMB statistician will be provided with the randomization codes in order to effect unblinding for the 
DSMB only.  
  
10 Clinical Monitoring  
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with 
applicable regulatory requirement(s). 
11 Statistical Considerations 
11.1 Statistical and Analytical Plans (SAP) 
11.1.1 Phase II: 
Descriptive statistics for the safety endpoints will be used. With 20 patients, the 95% confidence interval 
(CI) around the rate of SAEs will be no more than 0. 46 units wide.  With 40 patients (combining the low-
dose and high-dose groups), the 95% CI will be no more than 0.33 units wide. When 30 patients have 
been enrolled and treated, the DSMB will conduct a comprehensive analysis of safety and efficacy. 
 
Regarding the secondary outcome of patient survival, too little is known about the expected clinical behavior 
of these patients to make meaningful projections about expected changes in mortality given drug efficacy.  
The table below summarizes approximate power for the projected sample size (N=20 in each arm) to detect 
various reductions in mortality from the expected 50% rate in the placebo group, for various levels of Type 
I error (alpha) assuming use of a two-sided test.  For example, we have approximately 68% power to detect 
a reduction in the mortality rate of 80%, from 0.5 in the placebo group to 0.1 in the treated group, assuming 
20 patients per group, at the usual Type I error rate of 0.05.  While power is admittedly low with the planned 
sample size of 60 patients, the trial’s primary outcome is safety and the estimates of mortality will provide 
an important signal of efficacy for future investigations.  
 
Mortality Rate 
Reduction (%) 
N=20 per group 
α=5% 
α=10% 
α=20% 


5% 
-90 
0.84 
0.91 
096 
10% 
-80 
0.68 
0.80 
0.89 
15% 
-70 
0.52 
0.65 
0.78 
20% 
-60 
0.36 
0.49 
0.64 
25% 
-50 
0.24 
0.35 
0.49 
30% 
-40 
0.14 
0.23 
0.35 
35% 
-30 
0.08 
0.14 
0.23 
40% 
-20 
-- 
-- 
-- 
 
In Phase II the safety and efficacy of 12.5mg and 25mg clazakizumab will be monitored. Depending upon 
the safety and efficacy profiles of the two doses. The DSMAB will recommend one of the following 
actions: 
1. Continue into Phase III with the same study design if there is no evidence for any safety 
issues with either dose, and compare efficacy of the two doses of clazakizumab. 
2. Continue into Phase III with only placebo and 12.5mg dose, if there is evidence of safety 
issues with 25mg dose. 
3. Continue into Phase III with only placebo and 25mg dose, if there is no evidence for any 
safety issues and there is evidence for higher efficacy with 25mg dose. 
4. Stop the study if there is evidence for safety issues with both clazakizumab doses. 
11.1.2 Phase III: 
If after Phase II the DSMB recommends continuation into Phase III, we expect that we will be able to activate 
additional recruitments sites.If other institutions join the protocol, they will each enroll up to 30 patients in a 
1:1 randomization ratio, with 15 patients each on clazakizumab 25mg and placebo.  At these other sites, 
with 15 patients, the 95% confidence interval (CI) around the rate of SAEs will be no more than 0.52 units 
wide.   
 
If three other institutions join the protocol, for a total planned enrollment of 150 subjects, the power to detect 
treatment effects will increase considerably. The table below summarizes approximate power for the 
projected sample size in the placebo and 25 mg clazakizumab groups (N=60 in each arm) to detect various 
reductions in mortality from the expected 50% rate in the placebo group, for various levels of Type I error 
(alpha) assuming use of a two-sided test.  For example, we have approximately 82% power to detect a 
reduction in the mortality rate of 50%, from 0.5 in the placebo group to 0.25 in the treated group, assuming 
60 patients per group, at the usual Type I error rate of 0.05. If each external site enrolls the full 30 patients, 
a maximum of 180 patients will be enrolled. 
 
 
Mortality Rate 
Reduction (%) 
N=60 per group 
α=5% 
α=10% 
α=20% 
5% 
-90 
0.99 
0.99 
0.99 
10% 
-80 
0.99 
0.99 
0.99 
15% 
-70 
0.99 
0.99 
0.99 
20% 
-60 
0.94 
0.97 
0.99 
25% 
-50 
0.82 
0.89 
0.95 
30% 
-40 
0.61 
0.73 
0.84 
35% 
-30 
0.38 
0.51 
0.65 
40% 
-20 
0.19 
0.29 
0.43 
 
 


 
11.2 Interim Analyses 
11.2.1 Phase II 
Given the nature of the COVID-19 pandemic and the rapid surges of infections in different locations, the 
DSMB Chair (EA) and statistician (EP) will make real time decisions about additional interim analyses based 
on deaths and intubation outcomes. Pairwise treatment groups (1:high dose vs. placebo and 2:low dose 
vs. placebo and 3:low vs. high does) will be compared with respect to status at levels 6-10 on the 11 points 
WHO scale at day 14 pot first dose. The following actions can be taken: 
a) stopping for safety 
b) continue the study as is 
c) transition to Phase III of this adaptive seamless Phase 2-3 study 
d) eliminating a treatment arm 
 
Efficacy 
A “bad event” is defined as having a status of 6-10 on the 11 point WHO scale: 
6 
Hospitalized; oxygen by NIV or High flow 
7 
Intubation & mechanical ventilation, pO2/FiO2>/=150 or SpO2/FiO2>/=200 
8 
Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2<200) or vasopressors 
9 
Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO 
10 
Dead 
 
q: probability a patient is at level 6-10 on WHO 11 points scale at day 14. 
In this study without treatment (or treatment = placebo) the expected rate is 50%, or qpbo = 0.5. 
 
Odds(q): q/(1-q) 
The odds ratio for the bad event of a given clazakizumab dose X compared to placebo is denoted by 
OR(doze x/placebo) = odds(qdose x) / odds(qpbo) 
 
Bayesian rules 
The Bayesian stopping rules are based on the posterior distribution of OR, given the data. The efficacy rule 
are as follows: 
 
Dose X will continue into Phase III of this adaptive seamless Phase II/III study, if the 
Prob{OR(doze x/placebo) < 1} >0.95 using uninformative prior distribution for the parameter of interest 
(log(OR) will be taken to be N(0, 106)). 
 
Dose X will be discontinued, if 
Prob{OR(doze x/placebo) < 1} < 0.5 using uninformative prior distribution for the parameter of interest 
(log(OR) will be taken to be N(0, 106)). 
 
Safety 
Safety events are those associated with clazakizumab. A safety event will be considered any that is ruled 
to be probably related to clazakizumab. Hypersensitivity reactions are expected to be clazakizumab-related. 
Bayesian stopping guidelines will be applied as follows: 
 
Doze X will be stopped for safety, if the odds ratio associated with safety events 
Prob{OR(doze x/placebo) > 1} > 0.75 using uninformative prior distribution for the parameter of interest. 
 
We plan interim analyses for efficacy and futility after every 30 patients have accrued 14-day information 
on the Phase II outcome, occurrence of Category A adverse events (death, intubation, need for pressors, 
need for mechanical ventilation).  We will follow the approach of Stallard and incorporate information on 
these shorter-term events into the interim analyses to determine which arm(s) should continue to the 
Phase III portion of the study.  Assuming standardized effect sizes of 0.3 and 0.6 for the low- and high-


dose arms, respectively, compared to placebo, we have more than 95% probability of selecting the 
higher-performing active arm to continue from Phase II to Phase III. In addition, we have more than 85% 
power to detect a significant improvement of at least one active arm at the Phase III analysis. 
11.2.2 Phase III 
The Phase III part of this adaptive seamless Phase II/III study is a double-blind placebo-controlled trial for 
evaluating the efficacy of 25mg clazakizumab. The primary outcome is mechanical ventilation free survival 
at day 28. The efficacy will be monitored based on Bayesian logistic regression, modeling the primary 
outcome (survival free of mechanical ventilation, a good event) as a function of treatment, and controlling 
for: i) age; ii) sex; iii) duration of symptoms prior to study enrollment; iv) baseline WHO 11 point scale 
measure; and v) BMI at baseline. 
 
Efficacy 
A skeptical prior will be used for the regression coefficient for the treatment effect in the logistic regression 
βtrt: 
Prob{βtrt > ln(2)} < 0.025 and Prob{βtrt < ln(0.5)} <0.025, 
where “ln” indicates the natural logarithm with base e=2.718. 
The DSMB would consider stopping the study for efficacy if Prob{ βtrt > 0} > 0.95. This would correspond to 
Prob(OR(25mg claza/placebo)) > 0.95. 
 
Harm 
The DSMB will consider stopping for harm if Prob{ βtrt < 0} > 0.75, using the same model as described 
above in section Efficacy. In this case, however, an uninformative prior for the βtrt coefficient will be used, 
i.e.,Normal(mean=0,variance=100). 
 
Safety 
Safety events are those associated with clazakizumab. A safety event will be considered any that is ruled 
to be probably related to clazakizumab. Hypersensitivity reactions are expected to be clazakizumab-related. 
The DSMB will consider stopping the study for safety, if the odds ratio associated with safety events 
Prob{OR(25mg claza/placebo) > 1} > 0.75. Uninformative prior will be used for the safety monitoring: the 
prior distribution for ln(OR) will be taken to be Normal(mean=0,variance=100). 
12 Source Documents and Access to Source Data/Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. It is acceptable to use CRFs as source 
documents. If this is the case, it should be stated in this section what data will be collected on CRFs and 
what data will be collected from other sources. 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is 
left blank because the procedure was not done or the question was not asked, write “N/D”.  If the item is 
not applicable to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any 
entry error has been made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR 
WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it. 
 
Access to study records will be limited to IRB-approved members of the study team. The investigator will 
permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, government 


regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
13 Quality Assurance and Quality Control 
 
QC procedures will be implemented beginning with the data entry system and data QC checks that will be 
run on the database will be generated. Any missing data or data anomalies will be communicated to the 
site(s) for clarification/resolution. 
 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by Vitaeris, and inspection by local and regulatory 
authorities. 
14 Ethics/Protection of Human Subjects 
14.1 Ethical Standard 
 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6. 
14.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must be 
obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether previously consented participants 
need to be re-consented. 
14.3 Informed Consent Process 
14.3.1 Consent/Assent and Other Informational Documents Provided to Participants 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product. The informed consent document is submitted with this protocol. 
14.3.2 Consent Procedures and Documentation 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families. In order to limit exposure of 
the study team to potential COVID-19 infection, the consent process may be undertaken by phone or 
video chat between the study team and the patient. Consent forms will be IRB-approved and the 


participant will be asked to read and review the document. The investigator will explain the research study 
to the participant and answer any questions that may arise. All participants will receive a verbal 
explanation in terms suited to their comprehension of the purposes, procedures, and potential risks of the 
study and of their rights as research participants. Participants will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. The participants should have the opportunity 
to discuss the study with their surrogates or think about it prior to agreeing to participate. The participant 
will sign the informed consent document prior to any procedures being done specifically for the study. The 
participants may withdraw consent at any time throughout the course of the trial. A copy of the signed 
informed consent document will be given to the participants for their records. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
 
A signed informed consent document will be stored in the subject’s research record. The consent 
process, including the name of the individual obtaining consent, will be thoroughly documented in the 
subject’s research record.  
 
FOR PATIENTS WHO LACK CAPACITY TO CONSENT 
Some patients eligible to enroll will not have the capacity to sign consent, due to life-threatening critical 
illness and respiratory failure requiring mechanical ventilation.  A consent designee will be contacted to 
consent for enrollment on behalf of the patient. Since visitors are currently prohibited in the NYULH 
system hospitals the consent conversation with the consent designee will be held either by phone or by 
video chat. Written consent will be obtained either digitally (via RedCAP e-consent process) or by fax, 
email, or the transmission of a digital image of the signed consent form. 
 
If the consent designee does not speak English, a phone interpreter will be used to read the full consent 
form, and a short form of the consent will be signed by one of the digital processes outlined above.  The 
interpreter’s full name and/or ID number will be documented on a printed copy of the signed consent form 
by the study team. 
 
A copy of the signed consent form will be retained by the study team.  A copy of the signed consent form 
will be provided to the consent designee by email or postal mail unless obtained in RedCAP. Consents 
obtained in RedCAP are considered available to the individual signing the consent.   
 
ASSESSMENT AND RE-ASSESSMENT OF CAPACITY TO CONSENT 
Any patient who is intubated, mechanically ventilated and/or sedated will automatically be determined to 
lack capacity to provide consent. Patients who are not intubated, and not on continuous intravenous 
infusions of sedating medications may have the capacity to provide consent. The study team member will 
assess consenting capacity by conversing with the patient (by phone or video chat).  In the event that the 
study team member determines that the patient does not have capacity to consent, the study team 
member will notify the patient that a consent surrogate will be contacted.  If a patient is deemed by the 
study team member to lack capacity to consent, documentation of failure to meet at least one of the 
following criteria will be made: 
 
• 
understand the study protocol and why it is being offered 
• 
express a clear choice to agree or decline to participate 
• 
express appreciation of the choice as it pertains to the patient’s own situation 
• 
be able to demonstrate reasoning for how they reached their choice 
If a subject who has capacity to consent at enrollment loses capacity the following will apply: 
• 
If capacity is lost after all study medication administration is complete (either after day 3 or after 
day 1 and the patient does not qualify for repeat dosing on day 3) no surrogate consent will be 
sought. Only laboratory tests as performed for standard of care will be collected. Assessment of 
survival will be performed at day 60. 
• 
If capacity is lost between days 1 and 3 and the patient qualifies for a repeat dose of the study 
medication, a surrogate consent will be sought. If the consent surrogate declines further study 
participation on the patient’s behalf, then the repeat dose of study medication on day 3 will not be 
given and only laboratory tests as performed for standard of care will be collected. Assessment of 
survival will be performed at day 60. 


• 
Since the study drug will be administered shortly after consent is obtained, we do not envision a 
scenario where a consenting patient would lose capacity to consent between signing a consent 
and the time that the study medication is ready to be given, However, in the event this were to 
occur, the study team would not proceed with administering the study drug. The study team 
would seek consent from a surrogate before proceeding with study medication administration.  
 
Subjects will be regularly assessed throughout the study with discussions with the clinical care team to 
determine whether or not they have regained or lost the capacity to consent. If subjects regain the capacity 
to consent during the study and decline to continue participation, they will be asked if previously collected 
data can still be used. If they decline, this data will be discarded. 
 
CONSENT SURROGATES 
If a study subject candidate lacks consenting capacity the study team would seek to obtain consent from a 
surrogate. The patient’s identified health care proxy will be the default surrogate. If no health care proxy 
has been designated then the study team will consider the following surrogates in the listed order of priority: 
spouse, adult child, parent, adult sibling, nearest living relative, close friend.  If a surrogate of higher priority 
wishes to defer surrogacy to a lower priority surrogate, the study team will document that both individuals 
agree upon the consent designee. 
14.4 Participant and Data Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. Except when 
required by law, subjects will not be identified by name, personal identification number (e.g. social security 
number, social insurance number), address, telephone number, or any other direct personal identifier in 
database records.  No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
 
Authorized representatives of the sponsor, representatives of the IRB or pharmaceutical company 
supplying study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records 
for the participants in this study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at NYU Langone Health. This will not include the participant’s contact or 


identifying information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by clinical sites 
and by NYU Langone Health research staff will be secured and password protected and are protected by 
a firewall. At the end of the study, all study databases will be de-identified and archived at the NYU 
Langone Health. 
14.4.1 Research Use of Stored Human Samples, Specimens, or Data 
No specimens will be collected and stored for purposes of this study.  Laboratory data collected for 
purposes of this study will be collected and maintained in the study binders. 
15 Data Handling and Record Keeping 
15.1 Data Collection and Management Responsibilities 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data. Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, 
cross out the original entry with a single line, and initial and date the change. DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the eCRF derived from source 
documents should be consistent with the source documents or the discrepancies should be explained 
and captured in a progress note and maintained in the participant’s official electronic study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into a 21 CFR Part 11-compliant password protected web-based 
electronic data capture (EDC) system with validated electronic records and electronic signatures 
provided by the NYULH. All investigational staff authorized to enter study data will receive training on 
the EDC system. Training records will be retained by the study team. 
 
The EDC includes internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. Any out-of-range values or missing key variables will be flagged 
at the site in real time during the data entry process. When a query is generated on a particular variable, 
an exclamation point will be present next to the item in the database enabling the system to track the 
queries and produce reports of outstanding queries. Queries can also be generated from manual review 
of the data forms. These queries will be entered into the database and tracked in the same manner as 
the computer-generated queries. Further cross-checking of the data will be performed and discrepant 
observations flagged will be appropriately resolved through a data query system. The data monitoring 
group will perform internal database quality-control checks, and data audits throughout the course of the 
trial. Clinical data will be entered directly from the source documents. 
15.2 Study Records Retention 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final 
reporting/publication, or 2 years after the last approval of a marketing application is approved for the drug 
for the indication for which it is being investigated or 2 years after the investigation is discontinued and 
FDA is notified if no application is to be filed or if the application has not been approved for such 


indication. No records will be destroyed without the written consent of the sponsor, if applicable. It is the 
responsibility of the sponsor to inform the investigator when these documents no longer need to be 
retained. 
15.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. 
 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site PI/study staff to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the scheduled 
protocol-required activity. 
 
All protocol deviations must be addressed in study source documents, reported to the NYULH IRB. 
 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. Further details about the handling of 
protocol deviations will be included in the MOP. 
15.4 Publication and Data Sharing Policy 
 
This study will comply with terms outlined in the agreement outlined between NYULH Investigators and 
Vitaeris Inc. 
16 Study Finances 
16.1 Funding Source 
There is no source of monetary funding associated with this study. Vitaeris, Inc. will supply the 
investigation product at no cost to the patient, investigators, or institution under an agreement mutually 
accepted by both Vitaeris Inc. and NYULMH. 
16.2 Costs to the Participant 
The patient will incur no costs associated with participation in this study. 
16.3 Participant Reimbursements or Payments 
No payments or reimbursements will be disbursed in exchange for participation in this study. 
17 Conflict of Interest Policy 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial.  
 


Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by the NYU 
Langone Conflict of Interest Management Unit (CIMU) with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study sponsor prior to participation in this study. All 
NYULMC investigators will follow the applicable conflict of interest policies. 
18 References 
 
1. Mehta P et al (2020). COVID-19:  consider cytokine storm syndromes and immunosuppression. 
The Lancet. Published online. Available at: 
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext 
2. Karkhur S et al (2019). Interleukin-6 inhibition in the management of non-infectious uveitis and 
beyond. J Ophthalmic Inflamm Infect. 2019 Sep 16;9(1):17. 
3. Weinblatt ME et al (2015). The Efficacy and Safety of Subcutaneous Clazakizumab in Patients 
With Moderate-To-Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate: 
Results From a Multinational, Phase IIb, Randomized, Double-Blind, Placebo/Active-Controlled, 
Dose-Ranging Study. Arthritis Rheumatol. 2015 Oct;67(10):2591-600. 
4. Eskandary F et al (2019). Clazakizumab in late antibody-mediated rejection: study protocol of a 
randomized controlled pilot trial. Trials. Jan 11;20(1):37. 
5. Vitaeris. Investigator’s Brochure: Clazakizumab. Version 1 Feb 2020 
6. Ruan Q et al (2020) Clinical predictors of mortality due to COVID-19 based on an analysis of data 
of 150 patients from Wuhan, China. Intensive Care Med. 2020 Mar 3.Epub. doi: 10.1007/s00134-
020-05991-x  
7. Arentz M (2020) Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in 
Washington State. JAMA. Published online March 19, 2020. doi:10.1001/jama.2020.4326. 
8. Stallard N. A confirmatory seamless phase II/III clinical trial design incorporating short-term 
endpoint information.  Statistics in Medicine 2010, 29 959—971. 
9. Nick Parsons a, Tim Friede b, Susan Toddc, Elsa Valdes Marquezd, Jeremy Chatawaye,f, 
Richard Nicholas e, Nigel Stallard. An R package for implementing simulations for seamless 
phase II/III clinical trials using early outcomes for treatment selection. Computational Statistics 
and Data Analysis 56 (2012) 1150–1160. 
 
 
 


19 Attachments 
These documents are relevant to the protocol, but they are not considered part of the protocol.  They are 
stored and modified separately. As such, modifications to these documents do not require protocol 
amendments. 
 
Attached are: 
H-score calculator 
Schedule of Events 
DSMB Charter 
Dose selection rationale 
Pharmacy manual 
Laboratory manual 
 
 
 


H-score calculator 
 
The above table was reproduced from Mehta et al (2020). The H-score can also be calculated using an 
online calculator found at http://saintantoine.aphp.fr/score/ 


Study number: s20-00392  
 
Page 45 
Version: 1.12 (VERSION DATE 16SEP2020) 
 
 
20  Schedule of Events 
Activity 
Screening 
(can occur on 
Day 1) 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Windows 
-5 Days 
No window 
No window 
No window 
No window 
No window 
No window 
Study team procedures 
  
  
  
 
  
  
  
Assess inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Consent obtained 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Exam 
X3 
X3 
X3 
X3 
 
 
 
Height 
X 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
Vitals signs  
X 
X 
X 
X 
 
 
 
Document respiratory and hemodynamic 
support (eg vent settings, vasopressors, 
circulatory support) 
X 
X 
X 
X 
 
 
 
Calculation of enrollment H-score 
X 
 
 
 
 
 
 
Dose 1 administered 
 
X 
 
 
 
 
 
Dose 2 administered if indicated 
 
 
 
X 
 
 
 
Documentation of patient survival status 
 
 
 
 
 
 
 
Phone visit (AE/SAE/survival assessment) – 
only if outpatient 
 
 
 
 
 
 
 
Documentation of WHO score 
 
X (at dose 1) 
 
 
 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
Comprehensive chemistry panel 
X 
 
 
 
 
 
 
CBC with differential 
X 
 
 
 
 
 
 
CRP 
X 
X 
X 
X 
X 
X 
X 
IL-6 
X 
 
 
 
 
 
 
Total cholesterol 
X 
 
 
 
 
 
 
Triglycerides 
X 
 
 
 
 
 
 
Ferritin 
X 
 
 
 
 
 
 
Fibrinogen 
X 
 
 
 
 
 
 
D-Dimer 
X 
 
 
 
 
 
 
LDH 
X 
 
 
 
 
 
 
Troponin 
X 
 
 
 
 
 
 
Quantitative SARS-CoV-2 viral load1 
X 
 
 
 
 
 
 
Pregnancy Test2 
X 
 
 
 
 
 
 
 
 


Activity 
Day 7 
(if still  
inpatient) 
Day 14 
(if still 
inpatient)  
Day 28  
Day 60  
Windows 
+/- 1 
+/- 2 
+/- 2 
+/- 5 
Study team procedures 
  
  
 
 
Assess inclusion/exclusion criteria 
 
 
 
 
Consent obtained 
 
 
 
 
Medical History 
 
 
 
 
Physical Exam 
 
 
 
 
Height 
 
 
 
 
Weight 
 
 
 
 
Vitals signs 
X 
X 
 
 
Document respiratory and hemodynamic 
support (eg vent settings, vasopressors, 
circulatory support) 
X 
X 
 
 
 
Calculation of enrollment H-score 
 
 
 
 
Dose 1 administered 
 
 
 
 
Dose 2 administered if indicated 
 
 
 
 
Documentation of patient survival status 
 
 
X 
X 
Phone visit (AE/SAE/survival assessment) – 
only if outpatient 
 
 
X 
X 
Documentation of WHO score 
 
X 
X 
X 
Laboratory Assessments 
 
 
 
 
Comprehensive chemistry panel 
X 
X 
 
 
CBC with differential 
X 
X 
 
 
CRP 
X 
X 
 
 
IL-6 
 
 
 
 
Total cholesterol 
X 
X 
 
 
Triglycerides 
X 
X 
 
 
Ferritin 
X 
X 
 
 
Fibrinogen 
X 
X 
 
 
D-Dimer 
 
 
 
 
LDH 
 
 
 
 
Troponin 
 
 
 
 
Quantitative SARS-CoV-2 viral load1 
 
 
 
 
Pregnancy Test2 
 
 
 
 
1 Only if this testing become available by NYU clinical laboratory over the course of the conduct of this study 
2 Only for women of childbearing potential3 Physical examination as conducted by subject’s clinical care team