Clinical trial NCT04347226
Conditions: Solid Tumor Sars-CoV2 Hematological Malignancy
Keywords: COVID-19 coronavirus corona virus COVID
Sponsor: Columbia University
Start date: 2020-04-16; Completion date: 2021-03-01
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is for patients that are hospitalized for Coronavirus Disease 2019 (COVID-19). The purpose of this study is to see whether neutralizing interleukin-8 (IL-8) with BMS-986253 can help improve the health condition of participants infected with COVID-19. This is the first in-human study of this investigational product specifically in patients with severe COVID-19. Currently there are no FDA approved medications that improve the chance of survival in patients diagnosed with COVID-19. However there are usual treatments currently being used to help treat COVID-19 patients and BMS-986253 will be compared to these standard of care treatments in this study.

Detailed description:
This is a single center, randomized, open-label, phase 2 trial to evaluate the time-to-improvement in the 7 point ordinal scale following treatment with anti-IL-8 therapy (BMS-986253) compared to standard of care in hospitalized patients with COVID-19 respiratory disease. Patients will be randomized 2:1 to receive either BMS-986253 or standard of care. Patients randomized to treatment with BMS-986253 will receive between 1-3 doses of therapy depending on their clinical status. Participants will be assessed daily while in the hospital and with then be followed for up to 1 year after discharge.

Arms: arm 1: BMS-986253 2400mg IV arm 2: Usual treatment of COVID-19 per study physician discretion
Interventions: intervention 1: BMS-986253
Intervention descriptions: intervention 1: BMS-986253 2400mg IV at 0 and 2 weeks (if patient is still hospitalized) and then 4 weeks (only if still hospitalized with continued severe respiratory disease).

Protocol documents:
Prot_SAP_000.pdf: 
Anti-IL-8 for Hospitalized Patients with COVID-19 
CUMC IRB# - AAAS9881 
Version date: 13Feb2023 
Page 1 of 70 
 
 
 
 
 
 
 
 
 
 
Herbert Irving Comprehensive Cancer Center 
Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Anti-IL-8 for Hospitalized Patients with COVID-19 
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CUMC IRB#: AAAS9881 
Version Date: 13 February 2023 NCT04347226 
 
TITLE: A randomized phase 2 study of anti-IL-8 therapy versus standard of care in the 
treatment of hospitalized patients with severe COVID-19 
 
Coordinating Center: 
Columbia University Medical Center 
 
Principal Investigator: 
Mark Stein, MD 
1130 St Nicholas Ave, 217A 
New York, NY 10032 
Phone: 212-305-5874 
Fax: 212-304-6330 
Mcd2187@cumc.columbia.edu 
 
Co-Investigators: 
Matthew Baldwin, MD 
Phone: 212-305-6539 
mrb45@columbia.edu 
 
Statistician: 
Cody Chiuzan, PhD 
722 West 168th St, Room 646, New York, NY 10032 
Phone: 212-305-9107 
cc3780@cumc.columbia.edu 
 
Regulatory Sponsor: 
Columbia University Medical Center 
Division of Hematology and Oncology 
177 Fort Washington Avenue 
Milstein Hospital Building, suite 6GN-435 
New York, NY 10032 
Phone: 212-305-2055 
Fax: 212-305-3035 
Funding Source: 
Bristol-Myers Squibb 
Route 206 & Province Line Road 
Lawrenceville, NJ 08543 
BMS reference number: CA025-013 
Study Agents: 
BMS-986253 (HuMax IL8, anti-IL8 mAb) 
Other Agent: 
None 


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IND Status: 
IND #: 
IND Sponsor: 
 
 
Affiliate Institutions: 
N/A 
 
 
Amendment: 13 February 2023 
Amendment: 07 October 2020 
Amendment: 24 April 2020 
Amendment: 20 April 2020 
Amendment: 14 April 2020 
Amendment: 10 April 2020 (FDA Study May Proceed granted) 
Amendment: 5 April 2020 (not approved) 
Initial version: 31 March 2020 (not approved 


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Instructions to Principal Investigator: Sign and Date this signature page and print your name. 
Return the original, completed and signed to the Clinical Protocol & Data Management Office. 
Retain a copy in the regulatory binder. 
Protocol Signature Page 
 
 
 
I confirm that I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practices, and the applicable federal, state, and local 
laws, rules, and regulations relating to the conduct of the protocol. I have read and understand 
the information in the Investigators’ Brochure (or Manufacturer’s Brochure) regarding the risks 
and potential benefits. I will promptly submit the protocol to the applicable IRB for review and 
approval. Once the protocol has been approved by the IRB, I understand that any modification 
made during the course of the study must first be approved by the IRB, prior to implementation 
except when such modification is made to remove an immediate hazard to the subject. I certify 
that I, and the study staff, have received the requisite training to conduct this research protocol. I 
agree to maintain adequate and accurate records in accordance with Columbia University and 
Herbert Irving Comprehensive Cancer Center policies, Federal, state and local laws and 
regulations. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
 
 
 
 
 
Signature of Principal Investigator 
Date 
 
 
 
 
 
Principal Investigator Name (Print) 
 
 
 
 
 
Name of Institution 


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Protocol Synopsis 
 
Title 
A randomized phase 2 study of anti-IL-8 therapy versus standard of 
care in the treatment of hospitalized patients with severe COVID-19 
Short Title 
Anti-IL-8 for patients with COVID-19 
Protocol Number 
AAAS9881 
Phase 
Phase 2 
Methodology 
Randomized, open label, phase 2 study 
Study Duration 
12 months (estimated) 
Study Center(s) 
single-center 
Objectives 
Primary: 
• To determine the time to improvement in the 7-point ordinal 
scale in patients treated with anti-IL-8 therapy compared to 
standard of care/controls. 
o Measured from baseline to 2 point or greater 
improvement in 7-point ordinal scale. 
Secondary: 
• To evaluate the time to death in patients treated with anti-IL-8 
therapy compared to controls. 
• To evaluate the mortality 1 month after start of treatment in 
patients treated with anti-IL-8 therapy compared to controls. 
• To determine the time to intubation in patients treated with 
anti-IL-8 therapy compared to controls. 
o Measured from time of disease onset to time of 
intubation. 
• To estimate the time to improvement in oxygenation in 
patients treated with anti-IL-8 therapy compared to controls.. 
o Measured as time from start of treatment until ≥ 30% 
decrease in oxygen requirement compared to baseline 
• To measure the proportion of patients requiring ICU 
admission at 1 month in patients treated with anti-IL-8 therapy 
compared to controls. 
o Measured as the number of patients requiring ICU 
admission over their hospitalization over the number of 
evaluable patients. 


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• To compare the raw 7-point ordinal scale scores at day 14 in 
patients treated with anti-IL-8 therapy versus controls. 
• To assess the safety and tolerability defined as adverse events 
graded by CTCAE v5.0 in patients treated with anti-IL-8 
therapy compared to controls. 
• To assess the duration of hospitalization in patients treated 
with anti-IL-8 therapy compared to controls. 
o Measured as time from admission to time of discharge. 
Exploratory: 
• To assess the change in LDH, D-Dimer, CRP, ESR, NLR and 
absolute lymphocytes before and after treatment and over time 
(every 2 days for duration of hospitalization). 
• To assess the change in sIL-6 before and after treatment and 
over time. 
• To evaluate radiological response by comparing % of lung 
fields with infiltrates on chest imaging (CXR and CT) through 
independent radiology review. 
• To measure time on ventilation measured from time of 
intubation to time of definitive extubation 
• To measure time to improvement in NEWS2 score to ≤ 2 
• To evaluate the change in NEWS2 from baseline. 
• To measure proportion of patients with multi-organ failure at 
1 month. 
• To assess whether IL-8 and other key cytokines (TNF, IL-1b, 
IL-6) at baseline and during treatment are predictive of 
treatment efficacy by quantification of circulating IL-1b, IL8, 
TNFalpha and IL-6 levels over time. 
• To quantify changes in humoral immune responses by 
antibody profiling at baseline and following treatment. 
• To characterize PK of BMS-986253 in cancer patients with 
severe COVID-19. 
Number of Subjects 
This trial will enroll 138 patients randomized 2:1 (anti IL8: control). 


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Diagnosis and Main 
Inclusion Criteria 
Main Inclusion Criteria 
• Confirmed diagnosis of SARS-CoV-2 infection 
• Inpatient hospitalization due to SARS-CoV-2 infection 
• Severe (oxygen saturation ≤93% on room air or 
requires ≥2L oxygen by NC in order to maintain SaO2 
≥93%) OR critical respiratory disease (ICU, ventilatory 
support, HFNC) 
• Non-COVID-related life expectancy > 2 months 
• Willingness to provide informed consent 
Study Product, 
Dose, Route, 
Regimen 
BMS-986253 2400mg IV at 0 and 2 weeks (if patient is still 
hospitalized) and then 4 weeks (only if continued severe respiratory 
disease). 
Duration of 
administration 
Every 2 weeks x 1-3 doses. 
Reference therapy 
Standard of care management 
Statistical 
Methodology 
This is a single center, randomized, open-label, phase 2 trial to 
evaluate the time-to-improvement in the 7 point ordinal scale 
following treatment with BMS-986253 compared to standard of care 
in hospitalized patients with COVID-19 respiratory disease. 
With a sample of 138 patients (N=92 patients randomized to the 
treatment arm and N=46 patients assigned to the control/standard of 
care arm), the study will have 80% power to detect an increase in the 
median time to improvement from 5 days (control) to 2 days (anti-IL- 
8 arm) with one-sided alpha of 0.025. The sample size was estimated 
based on a hazard ratio (HR) of 0.40 assuming an exponential 
survival. 
Interim Analysis 
One interim analysis is planned once 17 (40% of the total 41 events) 
have been observed using O'Brien and Fleming stopping boundary 
using the Lan-DeMets spending function and inflation for drop-outs. 
The intent-to-treat (ITT) principle is applied to the analysis, and 
therefore, we inflated the sample size by 5% to safeguard against 
drop-outs/lost-to-follow-up. 


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Protocol Schema: 


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Contents 
Protocol Signature Page ...................................................................................................................4 
1. 
Introduction ........................................................................................................................12 
2. 
Study Objectives ................................................................................................................12 
Primary Objective ..............................................................................................................12 
Secondary Objectives .........................................................................................................12 
2.1 
Exploratory Objectives ..........................................................................................13 
3. 
Background ........................................................................................................................13 
3.1 
Disease Background ...............................................................................................13 
3.2. 
IL-8 is a key cytokine in the pathogenesis of coronavirus-associated 
ARDS .....................................................................................................................14 
3.3. 
Rationale for anti-IL-8 therapy in hospitalized patients with severe 
COVID-19..............................................................................................................15 
Investigational AgentS ...................................................................................................................15 
3.4 
BMS-986253 ..........................................................................................................15 
4. 
Study Design ......................................................................................................................20 
4.1 
General Design .......................................................................................................20 
4.2 
Number of Subjects ................................................................................................21 
5. 
Subject Selection and Withdrawal .....................................................................................21 
5.1 
Inclusion Criteria ...................................................................................................21 
5.2 
Exclusion Criteria .................................................................................................23 
5.3 
Inclusion of Women and Minorities ........................................................................23 
5.4 
Subject Recruitment .................................................................................................23 
5.5 
Early Withdrawal of Subjects ..................................................................................24 
6. 
REGISTRATION PROCEDURES ...................................................................................25 
6.1 
CUMC Research Participant Registration .............................................................25 
6.2 
Informed Consent Procedures ................................................................................26 
7. 
TREATMENT PLAN ........................................................................................................27 
7.1 
Agent Administration.............................................................................................27 
7.2 
Management of Infusion Reactions: ......................................................................28 
7.3 
General Concomitant Medication and Supportive Care Guidelines ......................29 
7.4 
Treatment Compliance ...........................................................................................29 
7.5 
Randomization and Blinding .................................................................................29 
7.6 
Duration of Therapy ...............................................................................................30 
7.7 
Duration of Follow Up ...........................................................................................30 
7.8 
Criteria for Removal from Study ...........................................................................30 
DOSING DELAYS/ DOSE MODIFICATIONS...........................................................................30 
7.9 
Criteria and Procedures for Dose Modifications and Interruptions .......................30 


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8. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................32 
8.1 
Adverse events .......................................................................................................32 
8.2 
Definitions..............................................................................................................33 
Women in the following categories are not considered WOCBP ..................................................35 
8.3 
Recording of Adverse Events ................................................................................41 
8.4 
Reporting of Serious Adverse Events ....................................................................41 
8.5 
Reporting Process ..................................................................................................45 
9. 
PHARMACEUTICAL INFORMATION ..........................................................................45 
9.1 
BMS-986253 ..........................................................................................................45 
9.2 
Subject Compliance Monitoring ............................................................................48 
10. 
STUDY CALENDAR .......................................................................................................49 
10.1 
Screening/Pretreatment Evaluation ........................................................................50 
10.2 
During Hospitalization: ..........................................................................................51 
10.3 
Follow-Up After Discharge ...................................................................................51 
11. 
MEASUREMENT OF EFFECT ........................................................................................52 
11.1 
Primary Endpoint ...................................................................................................52 
11.2 
Secondary Endpoints .............................................................................................52 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................55 
12.1 
Data Collection ......................................................................................................55 
12.2 
Data Reporting .......................................................................................................56 
12.3 
Data and Safety Monitoring Committee ................................................................56 
12.4 
Quality Control and Quality Assurance .................................................................56 
12.5 
Confidentiality .......................................................................................................57 
12.6 
Source Documents .................................................................................................58 
12.7 
Case Report Forms .................................................................................................58 
12.8 
Records Retention ..................................................................................................58 
13 
STATISTICAL CONSIDERATIONS...............................................................................58 
13.1 
Study Design and Sample Size ..............................................................................58 
13.2 
Study Endpoints and Analysis Plan .......................................................................59 
13.3 
Subgroup Analysis ...........................................................................................60 
13.4 
Interim analyses ..............................................................................................60 
13.6 
Safety Analysis ......................................................................................................62 
14 
Protection of Human Subjects ...........................................................................................62 
15. Study Finances ..........................................................................................................................63 
15.1 
Conflict of Interest .................................................................................................63 
16 
Publication Plan .................................................................................................................63 
17 
References ..........................................................................................................................64 


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18 
Attachments .......................................................................................................................64 
Appendix A:  common toxicity criteria, version 5.0 .....................................................................65 
Appendix B:  National early warning score 2 (NEWS2) ...............................................................66 
Appendix C:  KATZ INDEX OF INDEPENDENCE IN ACTIVITIES OF DAILY LIVING .....67 
Appendix D:  LAWTON INSTRUMENTAL ACTIVITIES OF DAILY LIVING SCALE ........68 
Appendix E: Consent Guidance .....................................................................................................69 


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1. INTRODUCTION 
 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Columbia University Medical Center institutional research policies and procedures. 
 
2. STUDY OBJECTIVES 
 
Primary Objective 
 
• To determine the time to improvement in the 7-point ordinal scale in patients treated 
with anti-IL-8 therapy compared to standard of care/controls. 
o Measured from baseline to 2 point or greater improvement in 7-point ordinal scale. 
 
Secondary Objectives 
• To evaluate the time to death in patients treated with anti-IL-8 therapy compared to 
controls. 
 
• To evaluate the mortality 1 month after start of treatment in patients treated with anti-IL- 
8 therapy compared to controls. 
 
• To determine the time to intubation in patients treated with anti-IL-8 therapy compared 
to controls. 
o Measured from time of disease onset to time of intubation. 
 
• To estimate the time to improvement in oxygenation in patients treated with anti-IL-8 
therapy compared to controls. 
o Measured as time from start of treatment until ≥ 30% decrease in oxygen 
requirement compared to baseline 
 
• To measure the proportion of patients requiring ICU admission at 1 month in patients 
treated with anti-IL-8 therapy compared to controls. 
o Measured as the number of patients requiring ICU admission over their 
hospitalization over the number of evaluable patients. 
 
• To assess the safety and tolerability defined as adverse events graded by CTCAE v5.0 in 
patients treated with anti-IL-8 therapy compared to controls. 
 
• To assess the duration of hospitalization in patients treated with anti-IL-8 therapy 
compared to controls. 
o Measured as time from admission to time of discharge. 
 
• 
 To compare the raw 7-point ordinal scale scores at day 14 in patients treated with anti- 
IL-8 therapy versus controls. 


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2.1 Exploratory Objectives 
 
• To assess the change in LDH, D-Dimer, CRP, ESR, NLR and absolute lymphocytes 
before and after treatment and over time (every 2 days for duration of hospitalization). 
 
• To assess the change in sIL-6 before and after treatment and over time. 
 
• To evaluate radiological response by comparing % of lung fields with infiltrates on chest 
imaging (CXR and CT) through independent radiology review. 
 
• To measure time on ventilation measured from time of intubation to time of definitive 
extubation 
 
• To measure time to improvement in NEWS2 score to ≤ 2 
 
• To evaluate the change in NEWS2 from baseline. 
 
• To measure proportion of patients with multi-organ failure at 1 month. 
 
• To assess whether IL-8 and other key cytokines (TNF, IL-1b, IL-6) at baseline and 
during treatment are predictive of treatment efficacy by quantification of circulating 
IL-1b, IL8, TNFalpha and IL-6 levels over time. 
 
• To quantify changes in humoral immune responses by antibody profiling at baseline and 
following treatment. 
 
• To characterize PK of BMS-986253 in cancer patients with severe COVID-19. 
3. BACKGROUND 
 
3.1 Disease Background 
 
Coronavirus disease 2019 (COVID-19) represents an emerging public health crisis that is 
caused by infection with the novel coronavirus, severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2), which is associated with high transmissibility and 
mortality.1 The World Health Organization (WHO) has defined COVID-19 as a pandemic. 
Symptoms include fever, cough, myalgias, shortness of breath and are most commonly 
mild in severity. However approximately 14% of patients with COVID-19 will develop 
severe disease (defined as dyspnea, respiratory frequency ≥30/minute, blood oxygen 
saturation ≤93%, PaO2/FiO2 ratio <300, and/or lung infiltrates >50% of the lung field 
within 24-48 hours).2 Although the overall mortality appears <1%, patients with severe 
disease have a mortality of approximately 20-25% across multiple studies reported to 
date.3-5 Medical co-morbidities also appear associated with particularly poor outcomes.3 
Particular, in cancer patients, reports suggest a mortality as high as 7%. Cancer patients 
also appear to have a dramatically increased rate of severe events (invasive ventilation or 


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death), with a rate of 40% in a small study from China.6 Novel strategies to address 
respiratory failure in COVID patients generally and cancer patients in particular represents 
an urgent and critical need. 
 
 
 
Figure 1 Clinical Course of Patients with COVID-19 
 
 
3.2. IL-8 is a key cytokine in the pathogenesis of coronavirus-associated ARDS 


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The primary causes of death in patients infected with SARS-CoV-2 is acute respiratory 
distress syndrome (ARDS), which is primarily a cytokine-mediated process that leads 
to profound lung injury. In addition, coronavirus spike protein-encoding plasmids 
can induce IL-8 production in lung cells.7 Innate immunity with neutrophil, 
macrophage and dendritic cell mediated lung injury plays a central role in the 
pathophysiology of ARDS. In ARDS, alveolar macrophages can trigger a robust pro- 
inflammatory response and secretion of interleukin-8 (IL-8) recruits neutrophils.8,9 This 
aberrant inflammatory response results in the accumulation of alveolar edema with 
resultant hypoxia and respiratory failure. Numerous clinical studies demonstrate that IL- 
8 is dramatically increased in both bronchoalveolar fluid and plasma in patients with 
ARDS compared to healthy controls and is associated with poor clinical outcomes.10-13 
In particular, prior data show that elevated IL-8 is associated with increased mortality 
rate in patients developing ARDS after infection with a similar virus (MERS-CoV).14 
Neutrophil-lymphocyte ratio (NLR) also appears to be associated with poor outcomes 
in ARDS and NLR is known to correlate with IL-8 levels.15 Therefore, IL-8 may 
represent a key upstream mediator of inflammation in ARDS that makes it an attractive 
therapeutic target. 
 
3.3. Rationale for anti-IL-8 therapy in hospitalized patients with severe COVID-19 
 
 
BMS-986253 (also referred to as anti-IL8 mAb or HuMax IL8) is a fully human- 
sequence IgG1κ mAb directed against human interleukin-8 (IL-8) also known as 
CXCL8. IL-8 is a well-described pro-inflammatory cytokine orchestrating the 
recruitment of neutrophils in tissue injuries. BMS-986253 potently binds to and 
neutralizes the various biological activities of IL-8. BMS-986253 was initially 
investigated for the treatment of inflammatory skin diseases and demonstrated an 
excellent tolerability and safety. More recently, BMS-986253 has been developed as a 
cancer immunotherapy and is currently in late-stage phase 1 testing. Results from these 
studies show excellent safety and tolerability at a dose of 2400mg every 2 weeks in a 
cancer patient population. 
 
Given the central role of IL-8 in the pathophysiology of ARDS, the increased morbidity 
and mortality of patients who develop severe COVID pneumonia and the excellent 
safety profile of BMS-986253, we believe there is an urgent need to evaluate this agent 
in patients who develop respiratory failure in the setting of SARS-CoV-2 infection. As 
a New York City based hospital, we believe we are well placed to rapidly evaluate 
BMS-986253 in this patient population. 
 
INVESTIGATIONAL AGENTS 
 
3.4 
BMS-986253 
 
3.4.1 
Pharmaceutical and Therapeutic Background 


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BMS-986253 (also known as Humax-IL8 and formerly referred to as Humax-Inflam) is a 
fully human immunoglobulin subclass G1 kappa monoclonal antibody (mAb) directed 
against IL-8, also known as CXCL8. IL-8 is a well-described proinflammatory cytokine. 
BMS-986253 potently binds free IL-8. Disruption of the IL-8:CXCR1/2 signaling axis may 
inhibit recruitment of neutrophils to sites of injury. 
 
The drug was initially investigated for the treatment of inflammatory skin diseases under 
the name Humax-Inflam. HuMax-Inflam was in a Phase 1/2 dose-escalation, safety, and 
efficacy trial in patients with palmoplantar pustulosis (PPP). The antibody demonstrated a 
tolerable profile and sign of activity based on a reduced inflammation index at doses up to 
8 mg/kg weekly. 
 
Subsequently, the product is now being developed for the treatment of cancer under the 
product code BMS-986253. The clinical development strategy for BMS-986253 as an 
anticancer agent will be in combination with other therapeutic approaches such as immune 
checkpoint inhibitors. 
 
The transition from hybridoma-derived to Chinese hamster ovary (CHO) cell-derived 
BMS-986253 was accomplished by the cloning and expression of the heavy and light 
chains of the antibody cDNAs in CHO cells to produce BMS-986253. A comparability 
exercise between CHO cell-derived material and hybridoma material has not revealed any 
significant differences in antigen-binding fragment (Fab) to IL-8 and other critical quality 
attributes, but has demonstrated a more complete processing and decreased heterogeneity 
in isoelectric point with the CHO cell-derived BMS-986253. Based on molecular 
characterization, the main difference between the hybridoma-derived and CHO cell- 
derived materials is glycosylation patterns. 
 
BMS-986253 was tested as monotherapy in 15 participants with advanced solid tumors 
(Study CA027-001) and demonstrated a tolerable profile at doses up to 32 mg/kg Q2W. Of 
these 15 participants, 11 had a best overall response of stable disease (SD) and 4 had a best 
overall response of progressive disease. In an ongoing Phase 1/2a study of BMS-986253 
in combination with nivolumab in advanced cancers (N=92 treated as of Jan 2020), 
safety data from patients treated to date suggest that the drug is extremely well 
tolerated at the maximum dose tested (2400mg Q2W) and does not lead to significant 
neutropenia. 
 
3.4.2 
Pre-clinical and Clinical Data 
 
Pre-clinical Data: 
The pharmacokinetics (PK) of BMS-986253 and HuMax-Inflam evaluated in cynomolgus 
monkeys showed that BMS-986253 and HuMax-Inflam have similar PK upon intravenous 
(IV) administration. 
 
After a single IV dose of HuMax-Inflam in monkeys (2 and 20 mg/kg doses), HuMax 
Inflam exhibited typical antibody PK characteristics: low total body serum clearance 
(CLTs, 0.001 to 0.003 mL/min/kg), limited volume of distribution at steady-state (Vss, 


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0.041 to 0.067 L/kg), and a long apparent elimination half-life (T-HALF) of 249 to 672 
hours. HuMax-Inflam exhibited a generally dose-proportional increase in exposure 
between 2 and 20 mg/kg doses. The exposure was generally similar in males and females 
at the 2 mg/kg and 20 mg/kg dose levels. 
 
After IV dosing of BMS-986253 to monkeys, the systemic exposure of BMS-986253 
increased in a dose-proportional manner between 20 and 160 mg/kg. The T-HALF was 204 
and 286 hours at 20 and 160 mg/kg, respectively. 
 
The nonclinical safety of BMS-986253 and HuMax-Inflam was evaluated in vitro in a 
human tissue cross-reactivity study, and in vivo was evaluated in exploratory single-dose 
and repeat IV dose studies in cynomolgus monkeys. 
 
In a Good Laboratory Practice (GLP)-compliant tissue cross reactivity study in normal 
human tissues, there was no specific staining of biotin labeled HuMax-Inflam (produced 
in hybridoma cells) indicating that BMS-986253 did not demonstrate cross reactivity with 
the human tissues examined. 
 
The cynomolgus monkey was selected as the toxicology species because 1) HuMax-Inflam 
stained intracellular IL-8 in lipopolysaccharide (LPS) stimulated whole blood cells from 
cynomolgus monkeys and rhesus monkeys, 2) amino acid sequence of cynomolgus IL-8 is 
identical to rhesus IL-8, and 3) BIAcore analysis confirmed that HuMax-Inflam cross 
reactivity to rhesus IL-8 (KD= 2.56 x 10-10 M) is comparable to human IL-8 (KD = 1.68 x 
10-10 M). BIAcore analysis of BMS-986253 to cynomolgus IL-8 has not been performed. 
 
Single dose IV tolerability studies demonstrated tolerability up to the highest doses tested 
of 20 mg/kg HuMax-Inflam (sex combined mean AUC[0-T] = 162,196 µg·h/mL) and 160 
mg/kg BMS-986258 (mean male AUC[INF] = 709,000 µg·h/mL). In GLP-compliant 
repeat-dose toxicity studies in cynomolgus monkeys, based on the lack of BMS-986253- 
related adverse effects, the NOAEL was considered to be the highest HuMax-Inflam dose 
of 20 mg/kg QW x 4 (sex combined mean AUC[0-T] = 93,500 µg·h/mL) in the 4-week 
study and the highest BMS-986253 dose of 160 mg/kg QWx12 (sex combined mean 
AUC[0-T] = 569,500 µg·h/mL) in the 12-week study. This dose was 5x higher than the 
proposed maximum dose tested in humans (32 mg/kg) with a corresponding AUC multiple 
of 3.6x the projected human AUC (approximately 159,934 µg·h/mL). 
 
Overall, the nonclinical toxicology assessment of BMS-986253 has demonstrated an 
acceptable safety profile with a lack of BMS-986253-related adverse effects, supporting 
clinical use in oncology patients 
 
Clinical Data: 
 
The clinical experience with BMS-986253 is based on the 4 completed and 1 ongoing 
clinical studies outlined in Table 2. In the HuMax-Inflam-001 study administration of 
HuMax-Inflam in a single dose of up to 8 mg/kg and up to 4 mg/kg in 4 weekly doses was 
safe and well tolerated by participants with PPP. Approximately 50% of reported AEs (45 


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of 85) were judged attributable to the study drug. The most frequent AEs were nausea, 
nasopharyngitis, and headache. In cancer patients, experience is based on the completed 
Phase 1 dose escalation study CA027-001, in which BMS-986253 monotherapy was 
assessed in a classical 3+3 design, as well as preliminary data from 92 participants in the 
ongoing Phase 1/2a study CA027-002 treated with varying doses of BMS-986253 in 
combination with a flat dose of 480-mg nivolumab Q4W: 600 mg Q4W (N = 16), 1,200 
mg Q4W (N = 15), 2,400 mg Q4W (N = 18), 1,200 mg Q2W (N = 12), and 2,400 mg Q2W 
(N = 31). In the CA027-001 study, AEs leading to discontinuation were reported in 3 
(20.0%) participants, and all were considered not related to BMS-986253. AEs leading to 
discontinuation included Grade 3 increased blood alkaline phosphatase (ALP), Grade 2 
increased blood creatinine, Grade 3 hypertension, Grade 3 fall, and Grade 3 back pain. 1 
patient reported “white blood cell decreased” (grade 1) at a dose of 16mg/kg Q2W. 
In the CA027-002 study combining BMS-986253 with nivolumab, 1 participant treated 
with Q2W BMS-986253 2,400mg experienced Grade 3 neutropenia on Cycle 2 Day 1; 
this participant was asymptomatic without evidence of infection, and the episode 
resolved without intervention in < 2 weeks. Overall, based on the available data as of 16- 
Jan-2020, no significant safety trends were identified. In CA027-001, BMS-986253 
reduced baseline serum IL-8 levels at all dose levels. The PD effect in tissue was not 
analyzed, and PK analysis showed an approximate linear correlation between increasing 
dose and exposure. 
 
Previously, three clinical studies were conducted with HuMax-Inflam. In the Humax 
Inflam-001 trial, intravenous infusion of repeated doses up to 4 mg/kg weekly for 4 weeks 
after single dose up to 8mg/kg were safe and well tolerated by 6 patients diagnosed with 
PPP, the MTD was not reached. The study indicated biologic and clinical activity, 
achieving reduction of IL-8 in the targeted tissue along with decrease in inflammatory 
scores. In the two subcutaneous studies, HuMax-Inflam-302 and -303, the drug was well 
tolerated with one injection site reaction noted in Study HuMax-Inflam-303 (n=7) as 
moderate pruritus. Overall these studies have not elicited any strong evidence for any 
adverse events of concern with an anti-IL8 antibody and are in support of further clinical 
development. See Table 2 below for summary of anti-IL8 clinical studies (see 
Investigator’s Brochure for additional details). Of note there was no clinically significant 
neutropenia in any of the trials conducted to date, including an ongoing study at 
Columbia testing BMS-986253 in patients with high-risk prostate cancer. 
 
Table 2 
anti-IL8 Clinical Trials 


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3.4.3 
Rationale for Dose Selection/Regimen 
 
Based on safety, PK, and PD findings, a combination of BMS-986253 2400mg Q2W was 
selected for testing. 
 
BMS-986253 trough serum concentrations in oncology subjects who received a 32 mg/kg 
Q2W (equivalent to 2400 mg flat dose) dose exceeded the IC90 concentrations for both 
CXCR1 and CXCR2 binding of IL-8 resulting in target engagement and the mean Cmax 
of this dose was 300 times higher than the IC50 for chemotaxis in vitro (IC50 of 0.3 μg/ml). 
Based on the safety data observed in oncology subjects as well as from healthy subjects, 
and PPP subjects, doses up to 2400mg Q2W were well tolerated with no MTD reached. 
 
In the ongoing Phase 1/2a Study CA027-002, the combination of BMS-986253 and 
nivolumab is being evaluated in advanced cancers. An ELISA assay is being used to detect 
serum free IL-8 (IL-8 that is not bound to therapeutic antibody). The serum free IL-8 results 
(as of the data cut-off date 16-Jan-2020) for 17 participants who were treated with BMS- 
986253 at a dose of 2400mg Q2W in combination with nivolumab 480 mg Q4W are 
presented in Figure 3. All participants displayed a rapid decrease in free serum IL-8 at the 
earliest time point assessed (Cycle 1 Day 2). The data suggest that BMS-986253 
 
Figure3 
Free serum IL-8 concentration after treatment with BMS-986253 


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decreases free serum IL-8 in a dose and frequency dependent manner. The 2,400 mg 
Q2W dosing provides the deepest and most durable free serum IL-8 suppression as 
well as robust suppression of IL-8 in tumor tissue. 
 
 
 
4. STUDY DESIGN 
 
4.1 
General Design 
 
This is a single-center, randomized, open-label phase 2 study comparing the time-to-improvement 
in 7 point ordinal scale in hospitalized patients with severe COVID-19 treated with BMS-986253 
(anti-IL-8) to standard of care/control. Patients will be recruited from the inpatient hospital at 
NYP/Columbia University Irving Medical Center. 
 
Study Interventions: Eligible patients will be randomized 2:1 to receive BMS-986253 IV every 
2 weeks x 1-3 doses (with 2nd dose given if patient still hospitalized and 3rd dose optional for 
patients with continued severe COVID-19 requiring hospitalization) versus standard of care. 
 
Schedule of Evaluations: During treatment patients will have safety assessments including 
routine bloodwork and routine physical examinations daily. (See Section 10 for detailed study 
evaluations and the study schedule). Safety evaluations will also occur by phone monthly 
following discharge until 100 days after the last treatment doses. 
 
The primary endpoint is time to improve in clinical status: the time (days) required from the start 
of treatment to the improvement of clinical status (2 points) assessment from baseline based on 
the 7-point ordinal scale. 


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Laboratory assessments including CBC with differential, basic metabolic panel, hepatic panel and 
coagulation studies will be performed daily during hospitalization. Inflammatory markers 
including D-Dimer, LDH, s-IL-6, neutrophil-to-lymphocytes ratio (NLR) and absolute 
lymphocyte count will be measured every other day during hospitalization. Imaging with CXR or 
CT scan will be done at baseline and after 7 days of treatment as clinically indicated. Serum for 
research purposes will be collected at baseline and then weekly during hospitalization if feasible. 
For patients ready for discharge prior to day 8, a serum sample should be collected, when feasible, 
prior to discharge. Post-discharge follow up will be conducted by phone and will be done monthly 
until 100 days following the last dose of treatment and then every 3 months for up to 1 year. 
Toxicity evaluation will utilize CTCAE v5.0 criteria. 
 
Duration of Treatment: Subjects randomized to receive BMS-986253 will receive treatment for 
up to 4 weeks while hospitalized or intolerable toxicity or side effects. Patients who are discharged 
prior to 2 weeks after the first treatment, will not receive additional doses of therapy. Patients still 
with severe respiratory symptoms and hospitalized at 4 weeks may receive an additional treatment 
dose. Subjects randomized to the control arm will receive standard of care therapy as determined 
by their treating physician. 
 
PK assessments and Correlative Studies: Serum will be collected at baseline and then weekly 
during hospitalization if feasible. For patients ready for discharge prior to day 8, a serum sample 
should be collected, when feasible, prior to discharge. 
 
Duration of Follow up: Toxicity and laboratory tests will be graded using the NCI CTCAE v5.0 
scoring system. Adverse events will be assessed continuously from the inpatient medical record 
during the study and for 100 days after the last dose of treatment. Laboratories as outlined in 
Section 11 will be collected daily during hospitalization. Post-discharge medical history and 
survival will be assessed monthly until 100 days following the last dose of therapy and then every 
3 months for up to 1 year. 
 
4.2 
Number of Subjects 
 
This study will enroll a total of 138 subjects randomized 2:1 (anti-IL-8: standard of care). 
 
5. 
SUBJECT SELECTION AND WITHDRAWAL 
 
Subjects will include patients hospitalized with confirmed SARS-CoV-2 who have developed 
severe COVID-19. Both patients with severe disease defined as oxygen saturation ≤ 93% on room 
air or critical disease defined as requiring non-rebreather, non-mechanical/mechanical ventilation, 
high-flow nasal cannula, or ICU admission will be recruited. Subjects will be identified and 
recruited through inpatient units at NYP/Columbia University Irving Medical Center. 
 
5.1 
Inclusion Criteria 
• Male or female adult ≥ 18 years of age at time of enrollment. 
• Confirmed diagnosis of SARS-CoV-2 infection ≤ 14 days prior to registration. 


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• Inpatient hospitalization (or documentation of a plan to admit to the hospital if the 
patient is in the emergency department) 
• Evidence of pneumonia by chest radiographs, chest CT OR chest auscultation 
(rales, crackles). 
• Severe respiratory disease (oxygen saturation ≤93% on room air or requires ≥2L 
oxygen by NC in order to maintain SaO2 ≥93%) OR critical respiratory disease 
(requiring non-rebreather, non-mechanical/mechanical ventilation, high-flow 
nasal cannula, ICU admission). 
• Patients can continue their anti-cancer therapy at the discretion of the treating 
physician. 
• Adequate laboratory tests including: 
o ANC >500 cells/mm3 
o Platelet count >20,000 cells/mm3 
o Serum total bilirubin <1.5 × ULN 
o ALT <5 × ULN 
o AST <5 × ULN 
 
• Age and Reproductive Status 
a) Males and females, aged at least 18 years old 
b) Women of childbearing potential (WOCBP) must have a negative 
serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of human chorionic gonadotropin) within 24 hours prior to the start 
of study treatment. 
c) Women must not be breastfeeding. 
d) WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of study treatment plus for a total of 155 
days post treatment completion. Local laws and regulations may require 
use of alternative and/or additional contraception methods. 
e) WOCBP who are continuously not heterosexually active are also 
exempt from contraceptive requirements, but should still undergo 
pregnancy testing as described in this section. 
f) Males who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception during study treatment with 
BMS-986253 for a total of 215 days post-treatment completion. 
g) Azoospermic males are exempt from contraceptive requirements. 
WOCBP who are continuously not heterosexually active are also exempt 
from contraceptive requirements, and still must undergo pregnancy testing 
as described in this section. 
• 
Willingness to provide written informed consent and HIPAA authorization for the release 
of personal health information, and the ability to comply with the study requirements 


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(note: HIPAA authorization will be included in the informed consent). In cases of 
partial impairment, impairment that fluctuates over time, or complete impairment 
due to dementia, stroke, traumatic brain injury, developmental disorders 
(including mentally disabled persons), serious mental illness, delirium, medical 
sedation, or intubation, a subject may be enrolled if the subject’s legally 
authorized representative consents on the subject’s behalf. 
5.2 
Exclusion Criteria 
 
• Treatment with anti-IL-6, anti-IL-6R antagonists or Janus kinase inhibitor (JAKi) 
within 48 hours of first dose of study treatment. 
• No other investigational therapies as part of another clinical trial with the intent to 
treat the patient’s COVID-19 can be administered while the patient is enrolled in 
the study. 
o Exception is remdesivir, hydroxychloroquine, convalescent plasma or 
other treatments being used as compassionate use or under Emergency 
Use Authorization (EUA) for COVID-19 per Investigator discretion. 
• Expected non-COVID-related survival of < 2 months. 
• Receipt of non-oncology vaccines containing live virus for prevention of 
infectious diseases within 4 weeks prior to first dose of study treatment 
• History of severe hypersensitivity reaction to any mAb 
• Multi-organ failure requiring vasopressors or continuous veno-venous 
hemofiltration (CVVH) or extracorporeal membrane oxygenation. 
• No active systemic bacterial or fungal infection 
o Excludes patients with positive blood cultures not infections like empiric 
pneumonia, antibiotic coverage, UTIs, etc. 
o Patients with a history of positive bacterial or fungal cultures but on 
enrollment do not have suspected or known active systemic bacterial or 
fungal infections are permitted. 
 
5.3 
Inclusion of Women and Minorities 
 
All genders, races and ethnic groups are eligible for this trial. 
 
5.4 
Subject Recruitment 
 
Subjects will be recruited from the inpatient units at NYP/Columbia University Irving 
Medical Center. Patients will not receive payment or reimbursement for participation. 
Every effort will be made to include patients of racial and ethnic minorities who fulfill the 
eligibility criteria. 
A member of the patient’s treatment team, the protocol investigator, or research team at 
NYP/Columbia University Irving Medical Center will identify potential research 


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participants. If the investigator is a part of the treatment team, s/he will screen the patient 
as to eligibility, and will discuss the study and the possibility of enrollment in the research 
study with the patient. The preliminary screen of eligibility will be inpatient hospitalization 
and confirmed SARS-CoV-2 infection. 
 
Potential subjects that meet these basic criteria will be referred by their treating physician 
to the investigator, co-investigators, or research staff of the study. Minority patients are 
well represented at NYP/Columbia University Irving Medical Center, and we expect that 
they will be well represented in the trial accrual. The principal investigator, Mark Stein, 
MD will be available to all patients for further questions and information through the 
contact number that will be provided on the consent form. 
 
During the initial conversation between the investigator/research staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. The investigator/research staff may also review portions of their medical 
records in order to further assess eligibility. They will use the information provided by the patient 
and/or medical record to confirm that the patient is eligible and to contact the patient regarding 
study enrollment. If the patient turns out to be ineligible for the research study, the research staff 
will destroy all information collected on the patients during the initial conversation and medical 
records review, except for any information that must be maintained for screening log purposes 
 
5.5 
Early Withdrawal of Subjects 
 
5.5.1 When and How to Withdraw Subjects 
 
• If at any time the patient develops unacceptable toxicity (e.g. a severe infusion 
reaction), as determined in consultation with the PI, he/she will be removed from the 
study treatment but should continue to be followed on the study for clinical outcomes 
including safety, intubation and mortality. 
• If the patient withdraws consent for continued participation, he will be removed from 
study. 
 
5.5.2 
Data Collection and Follow-up for Withdrawn Subjects 
 
If subjects withdraw prematurely from the study, follow-up will continue for all 
subjects. Subjects withdrawn because of unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. An attempt will be 
made to obtain survival information for all subjects for a period of at least 1 year 
following the time of registration or until death, whichever comes first. This will 
include attempts to contact subjects via telephone and by certified letter using 
information available to the investigators and the study team. When possible, at 
least two attempts will also be made to contact the subject’s next of kin to obtain 
such information while observing relevant privacy laws, when applicable. 


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6. REGISTRATION PROCEDURES 
6.1 
CUMC Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures, along with applicable institutional policies and federal regulations. 
 
Only Investigators/Research personnel properly trained and delegated to consent subjects for this 
protocol will participate in the consenting process. Furthermore, properly delegated/trained 
Physician Investigators (e.g., MD, MD PhD) are required to sign/verify a protocol specific 
Eligibility Checklist for each subject enrolled on the study, in addition to providing the relevant 
source documentation confirmation subject eligibility. 
 
All participants must be centrally registered through the Central Registration Office 
within Herbert Irving Comprehensive Cancer Center at CUMC prior to initiation of study 
treatment. 
 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST (excluding 
holidays and weekends). Same day patient registrations (and after hour registrations) will be 
accommodated on a case by case basis provided that the study team has expressed all time 
sensitive registration concerns/cases in a timely manner to the Central Registration Office. 
 
CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent (excluding holidays and weekends), a completed/signed 
IRB approved informed consent HIPAA form, and demographics forms must be submitted to the 
CPDM Central Registration Office via an email to CPDMRegistration@cumc.columbia.edu or 
fax to 212.304.6330, with the subject line “AAAS9881 Pending Subject Registration Request 
(PHI)”. Upon receipt, applicable subject information as well as a “pending eligibility” status will 
be entered into HICCC’s institutional database. This status will remain until further source 
documentation is made available to confirm overall patient eligibility. Required materials for all 
pending registration submissions are as follows: 
 
• 
Completed/signed IRB approved/stamped Informed Consent Forms, including additional 
study ICFs (e.g., tissue, DNA, etc.), as applicable. 
• 
The completed/signed IRB approved HIPAA Authorization form 
• 
Completed/signed CPDM ICF checklist 
• 
Completed/signed HICCC personal census form 
• 
Completed/signed CPDM Demographics Note to File 
In order to confirm eligibility status, Investigators/designees (e.g., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation to the 
Central Registration Office via email or fax: 


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• 
The completed/signed study specific Eligibility Checklist (signed by a Physician level 
Investigator) 
• 
Copies of source documentation necessary for each item to be verified on the CPDM 
specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) or other appropriate medical records capturing the consent process 
information, along with providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms (e.g., positive 
investigator statements of unique eligibility items not captured via other direct source 
documentation, concomitant medication lists, etc.) 
o Protocol deviation/waiver approvals (if applicable) 
• 
Please note: subject line of email or fax should include the following: “AAAS9881 
Complete Subject Registration Request (PHI)”. 
Upon receipt of the above mentioned documentation, participant eligibility information will be 
verified by a qualified Central Registration Registrar. If any questions arise during the review 
process, queries in the form of emails will be addressed to the applicable study team personnel 
for clarification prior to enrollment. All applicable finalized registration/eligibility information 
will then be entered into HICCC’s institutional CTMS database by the Central Registration 
Registrar. Upon completion, an official subject registration notification email will be sent to the 
PI/research team which will include eligibility/enrollment status, as well as subject ID 
information. Protocol therapy may not be initiated prior to receipt of this notification from the 
Central Registration Office. 
 
All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be 
required within the corresponding submissions. 
 
6.2 
Informed Consent Procedures 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must review the IRB/PB-approved consent form and indicate 
their consent to participate. This consent form meets the requirements of the Code of Federal 


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Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following: 
 
1. 
The nature, objectives, potential risks and benefits of the intended study. 
2. 
The length of study and the likely follow-up required. 
3. 
Alternatives to the proposed study. This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive care for 
therapeutic studies. 
4. 
The name of the investigator(s) responsible for the protocol. 
5. 
The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
The participant must receive a copy of the signed informed consent form. 
Remote Consenting 
Patient will be consented remotely as part of this study either by phone. 
 
During this phone call, or subsequent phone calls if necessary, the PI/treating physician will 
perform remote consent. The remote consent discussion will be documented in the medical record. 
Upon receipt/confirmation of the signed/dated consent form (if applicable), the authorized 
consenter will subsequently sign/date the scanned copy of the consent/HIPAA document, and 
provide documentation regarding the delay in signature, so documentation is clear and self-evident 
upon any audit or QA review. Further guidance regarding the consent process can be found in 
Appendix E: Consent Guidance. 
 
7. 
TREATMENT PLAN 
 
7.1 Agent Administration 
 
Treatment will be administered on an inpatient basis. Reported adverse events and 
potential risks for BMS-986253 are described in Section 10. Appropriate dose 
modifications for BMS-986253 are described in section 9. No investigational therapies 
other than those described below may be administered with the intent to treat the 
patient's COVID-19 while the patient is enrolled in the study. 
 
REGIMEN DESCRIPTION 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule+ 
Cycle 
Length 
BMS-986253 No specific 
premedications 
or precautions 
2400mg 
IV over 120 minutes 
(+/- 10 minutes)* 
Days 1, 15, 
29 
6 weeks 


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*Infusion time will be 180 minutes (+/- 10 minutes) for patients <35kg. 
+ Day 15 dose will be given if still hospitalized; day 29 dose is optional and will be given if 
patient hospitalized with severe respiratory symptoms. 
7.2 Management of Infusion Reactions: 
 
Since BMS-986253 contains only human Ig protein sequences, it is unlikely to induce 
hypersensitivity reactions. In the CA027-001 study, an infusion reaction (Grade 1) was observed 
in 1 patient and in the CA027-002 study 2 patients experienced infusions reactions (1 patient with 
Grade 2; 1 patient with Grade 4). If such a reaction were to occur, it might manifest with fever, 
chills, rigors, headache, rash, pruritus, arthralgia, hypotension, hypertension, bronchospasm, or 
other allergic-like reactions. All serious infusion reactions should be reported to BMS. All Grade 
3 or 4 infusion reactions should be reported within 24 hours (excluding holidays and weekends) to 
the CUMC Sponsor-Investigator and BMS Medical Monitor and reported as an SAE. Infusion 
reactions should be graded according to NCI CTCAE v5.0 guidelines. 
 
Treatment recommendations for infusion reactions are provided below and may be modified based 
on local treatment standards and guidelines, as appropriate. 
 
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
 
• Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic pre-medications are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or acetaminophen/paracetamol 325 mg to 1000 mg at least 30 
minutes before study treatment administrations. 
 
For Grade 2 symptoms (moderate reaction requiring therapy or infusion interruption but 
responding promptly to symptomatic treatment such as antihistamines, non-steroidal anti- 
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids, or prophylactic 
medications indicated for ≤ 24 hours): 
 
• Stop the study treatment infusion, begin an IV infusion of 0.9% sodium chloride and treat 
the 
participant 
with 
diphenhydramine 
50 
mg 
IV 
(or 
equivalent) 
and/or 
acetaminophen/paracetamol 325 mg to 1000 mg; remain at bedside and monitor participant 
until resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% 
of the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor 
participant closely. If symptoms recur, then no further BMS-986253 will be administered 
at that visit. 
 
• For future infusions, the following prophylactic pre-medications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 mg to 
1000 mg should be administered at least 30 minutes before study treatment infusions. If 
necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used. 


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For Grade 3 or 4 symptoms (severe reaction, Grade 3: prolonged [i.e., not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [e.g., renal impairment, 
pulmonary infiltrates]; Grade 4: Life-threatening; pressor or ventilatory support indicated): 
 
• Immediately discontinue infusion of study treatment. Begin an IV infusion of 0.9% sodium 
chloride and treat the participant as follows: recommend bronchodilators, epinephrine 0.2 
mg to 1 mg of a 1: 1,000 solution for subcutaneous administration or 0.1 mg to 0.25 mg of 
a 1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 mg 
IV with methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be 
monitored until the investigator is comfortable that the symptoms will not recur. Study 
treatment will be permanently discontinued except for a Grade 3 infusion reaction that 
returns to Grade 1 in less than 6 hours. Investigators should follow their institutional 
guidelines for the treatment of anaphylaxis. Remain at bedside and monitor participant 
until recovery of the symptoms. 
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids). 
 
7.3 
General Concomitant Medication and Supportive Care Guidelines 
 
7.3.1 
Concomitant Therapy 
 
The following medications are prohibited during the study if the subject is randomized to 
the investigational therapy arm (unless utilized to treat a drug related AE): 
 
• anti-IL-6, anti-IL-6R antagonists or Janus kinase inhibitor (JAKi) 
 
7.3.2 
Other Restrictions and Precautions 
 
Patients being treated with anti-cancer immunotherapy are permitted. 
 
7.4 
Treatment Compliance 
 
Treatment compliance with all study-related medications should be emphasized to the 
subject by the site personnel. Compliance with BMS-986253 will be documented in the 
medical record and monitored by the principal investigator of its designee. 
 
7.5 
Randomization and Blinding 
 
Patients will be randomized 2:1 (anti-IL8: standard of care) in “real-time”. If the 
subject’s eligibility status is confirmed, the statistician will send the randomization 
assignment based on the pre-generated randomization scheme. 
 
This is an open-label study. 


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7.6 
Duration of Therapy 
 
In the absence of treatment discontinuation due to adverse events, treatment may continue for 
up to 4 weeks or until one of the following criteria applies: 
 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse events(s) 
• Patient decides to withdraw from the study 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• Patient has been discharged from the hospital 
At the end of the study period, Bristol-Myers Squibb Company will not continue to supply study 
drug to subjects/investigators unless the Sponsor-Investigator chooses to extend their study and 
such extension is approved by Bristol Myers Squibb Company. The investigator is responsible to 
ensure that the subject receives appropriate standard of care or other appropriate treatment in the 
independent medical judgement of the Investigator to treat the condition under study. 
 
7.7 
Duration of Follow Up 
 
Following completion of therapy, patient will have follow up by phone every 30 days for the first 
100 days following the last dose of therapy. Patients will then have follow up by phone every 90 
days (+/- 30 days) for up to 1 year. In addition, patients will be assessed 28 days (+/- 2 days) 
following start of treatment whether they are discharged or in the hospital. Participants who 
discontinue study treatment must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section 4.1 until death or the conclusion of the study. 
 
7.8 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 8.6 applies. The 
reason for study removal and the date the patient was removed will be documented in the Case 
Report Form. 
 
DOSING DELAYS/ DOSE MODIFICATIONS 
 
7.9 
Criteria and Procedures for Dose Modifications and Interruptions 
 
Dose escalation/reduction is not permitted in this study in order to allow better evaluation of the 
safety and efficacy. However, if toxicities occur, subsequent doses of BMS-986253 should 
following the below guidelines: 
 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing of 
Treatment 
Restart 
Dose Schedule for 
Treatment 
Restart 
Discontinue Subject 
1, 2 
No 
N/A 
N/A 
N/A 


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Hematologic 
Toxicity 
3, 4 
Yes 
Toxicity resolves to 
≤ Grade 1 or 
baseline 
Restart at same dose. 
However, for all Grade 4 
hematologic toxicities, 
treatment may not be 
restarted. 
Toxicity does not resolve to 
≤ Grade 1 or baseline by the 
time of next treatment dose. 
Permanent discontinuation 
should be considered for any 
severe or life-threatening event. 
Non-Hematologic 
Toxicity 
Note: Exception to be 
treated similar to Grade 1 
toxicity: 
- Grade 2 fatigue 
- Grade 3 rash in patients 
who have not 
experienced a grade 3 
drug-related skin AE 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
holding for 
persistent 
symptoms 
Toxicity resolves to 
≤ Grade 1 or 
baseline 
Restart at same dose 
Toxicity does not resolve to 
≤ Grade 1 or baseline by the 
time of next treatment dose. 
Permanent discontinuation 
should be considered for any 
severe or life-threatening event 
3 
Yes 
Toxicity resolves to 
≤ Grade 1 or 
baseline 
Restart at same dose 
Toxicity does not resolve to 
≤ Grade 1 or baseline by the 
time of next treatment dose. 
Permanent discontinuation 
should be considered for any 
severe or life-threatening event 
4 
Yes 
Discontinue 
treatment 
Treatment may not be 
restarted 
Yes. 
 
Criteria to resume treatment: 
 
Subsequent dosing with study therapy may resume once AEs resolve to Grade 1 or baseline. 
 
Participants experiencing AEs not meeting criteria for permanent discontinuation as outlined in 
Section 5.5 may resume treatment with study medication under the following criteria: 
 
• Participants may resume treatment with study treatment when the drug-related AE(s) 
resolve to Grade  1 or baseline value, with the following exceptions: 
o Participants may resume treatment in the presence of Grade 2 fatigue. 
o Participants who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity. 
o Participants with Grade 2 uveitis, episcleritis, iritis, eye pain, or blurred vision 
(except for patients that do not respond to topical therapy and does not improve to 
Grade 1 severity within the re-treatment period OR requires systemic treatment). 
• For participants with Grade 2 AST, ALT, or total bilirubin elevations, dosing may resume 
when laboratory values return to baseline and management with corticosteroids (if needed) 
is complete. 
• Participants with combined Grade 2 AST/ALT and total bilirubin values with symptomatic 
liver inflammation (eg, right upper quadrant tenderness, jaundice) should have treatment 
permanently discontinued. 
Exceptions to permanent discontinuation criteria: 
 
The following exceptions to permanent discontinuation will apply: 
 
• Grade 3 diarrhea, nausea, vomiting, or abdominal pain that returns to Grade 1 or baseline 
within 3 days with medical intervention. 


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• Grade 3 pruritus or rash that returns to Grade 1 or baseline within 7 days with medical 
intervention. 
• Isolated Grade 3 or 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management within 
3 days of their onset. 
• Grade 4 neutropenia < 7 days in duration. 
• Grade 4 lymphopenia or leukopenia. 
• Grade 3 or 4 increase in amylase or lipase that is not associated with clinical or radiographic 
evidence of pancreatitis. 
• Grade 3 infusion reactions that return to Grade 1 in < 6 hours. 
• Grade 3 fever not associated with hemodynamic compromise (eg, hypotension, clinical, or 
laboratory evidence of impaired end-organ perfusion). 
• Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to sites of known or 
suspected tumor). 
• Grade 3 fatigue. 
• Grade 3 or 4 drug-related endocrinopathy AEs, such as adrenal insufficiency, 
adrenocorticotropic hormone, hyper- or hypothyroidism, or glucose intolerance, which 
resolve or adequately controlled with physiologic hormone replacement (corticosteroids, 
thyroid hormones) or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the Sponsor-Investigator. 
• Any AE, laboratory abnormality, or concurrent illness, which, in the judgment of the 
investigator, presents a substantial clinical risk to the participant with continued study 
treatment dosing. 
Even if the criteria to resume treatment are met, the consideration to re-initiate study therapy under 
the following exception will be made on a case by case basis after considering the overall 
benefit/risk profile, and in consultation between the investigator and the Sponsor. Any AE with 
clinical risk will be assessed on a case by case basis with the investigator and the BMS Medical 
Monitor, to determine the risks and benefits of continuing on therapy following resolution versus 
discontinuing therapy permanently. 
 
All participants who discontinue IP should comply with protocol specified follow-up procedures 
as outlined in Section 5.5. The only exception to this requirement is when a participant withdraws 
consent for all study procedures including post treatment study follow-up or loses the ability to 
consent freely (e.g., imprisonment, involuntarily incarceration for the treatment of either a 
psychiatric or physical illness). If study treatment is discontinued prior to the participant’s 
completion of the study, the reason for the discontinuation must be documented in the participant’s 
medical records and entered on the appropriate case report form (CRF) page. 
 
8. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
8.1 
Adverse events 
 
See Investigator’s brochure for BMS-986253 and Section 11 for details. 


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8.2 
Definitions 
 
Adverse Event: 
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of investigational product, whether or not considered 
related to the investigational product. 
 
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The casual relationship can be one of the following: 
 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
 
Not related: There is not a reasonable causal relationship between study drug administration and 
the AE. 
 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
Serious Adverse Event: 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening (defined as an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.) 
• Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE. 


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Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
 
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
− a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
− elective surgery, planned prior to signing consent 
− admissions as per protocol for a planned medical/surgical procedure 
− routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
− Medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases. 
− Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
− Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols) 
Non-serious Adverse Event: 
• Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or 
final study reports as specified in the agreement or, if a regulatory requirement [eg, IND 
US trial] as part of an annual reporting requirement. 
 
A non-serious adverse event is an AE not classified as serious. 
 
Non-serious Adverse Event Collection and Reporting 
 
The collection of serious and non-serious AE information should begin at initiation of study drug. 
All serious non-serious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 100 days following the 
last dose of study treatment. 
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. 
 
Laboratory Test Abnormalities 
 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported to BMS as such. 
 
The following laboratory abnormalities should be documented and reported appropriately: 


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• any laboratory test result that is clinically significant or meets the definition of an SAE 
• any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
• any laboratory abnormality that required the subject to receive specific corrective therapy. 
 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value). 
 
Potential Drug Induced Liver Injury (DILI) 
 
All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs. 
Potential drug induced liver injury is defined as: 
 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND 
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
 
Pregnancy 
 
DEFINITIONS 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
WOMEN IN THE FOLLOWING CATEGORIES ARE NOT CONSIDERED WOCBP 
• Premenarchal 
• Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
• Postmenopausal female 
− A postmenopausal state is defined as 12 months of amenorrhea  in  a  woman  over  
age 45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level 


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> 40 mIU/mL to confirm menopause. 
 
Note: Women treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout periods indicated below are suggested guidelines, and the investigators should use 
their judgement in checking serum FSH levels. 
• 1 week minimum for vaginal hormonal products (rings, creams, gels) 
• 4 week minimum for transdermal products 
• 8 week minimum for oral products 
 
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal. 
 
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL 
 
One of the highly effective methods of contraception listed below is required during study 
duration 
and until the end of relevant systemic exposure, which is defined as 105 days after completion of 
study treatment for monotherapy treatment and 155 days after completion of combination 
therapy treatment. 
 
Local laws and regulations may require use of alternative and/or additional contraception methods. 
 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
− oral 
− intravaginal 
− transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
− oral 
− injectable 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b 
• Intrauterine devicec 
• Intrauterine hormone-releasing systemc 
• 
Bilateral tubal occlusion 


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• 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
• It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
• WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests. 
• Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence. 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method. Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous. In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness 
 
 
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly. 
• Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal Sponge with spermicide 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action 
Unacceptable Methods of Contraception 


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• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• 
Withdrawal (coitus interruptus). 
• 
Spermicide only 
• 
Lactation amenorrhea method 
• 
 
Any pregnancy that occurs in a female or female partner of a male study participant should be 
reported to BMS. All pregnancy cases should be reported, within 5 months after the last exposure 
to BMS-986253. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form. In order for Sponsor or designee to collect any pregnancy surveillance information from the 
female partner, the female partner must sign an informed consent form for disclosure of this 
information. 
 
Contraception Guidance for Male Participants with Partner(s) of Child Bearing Potential 
 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure. 
• Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator. 
• Male participants are required to use a condom for study duration and until the end of 
relevant systemic exposure defined as 7 months Relevant Exposure after the end of 
treatment in the male participant. 
• Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months Relevant 
Exposure after the end of treatment in the male participant. 
• Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment and until 7 months Relevant Exposure after the end of 
treatment. 
• Refrain from donating sperm for the duration of the study treatment and for 7 months after 
the end of treatment. 
Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
 
Other Safety Considerations 
 
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not these 


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procedures are required by the protocol, should also be recorded as a non-serious or serious AE, 
as appropriate, and reported accordingly. 
 
Adverse Events of Special Interest: 
 
An AESI is an event of scientific and medical interest or concern to the Sponsor’s product or 
program, for which ongoing monitoring and rapid communication to the Sponsor could be 
appropriate. It may be a serious or non-serious AE, which may require further investigation in 
order to characterize and understand it. 
 
AESI will include the following: 
• Grade 3 or greater infusion reaction including CRS; and, 
• 
Immune related AE of Grade 3 or greater suggestive of an autoimmune process, including, 
but not limited to, glomerulonephritis. 
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. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious events should be regarded as 
non-serious adverse events. 
 
Unanticipated Problem: 
 
An unanticipated problem is any incident, experience or outcome involving risks to subjects or 
others in any human subjects research that meets all of the following criteria: 
• Unexpected (in terms of nature, severity or frequency) given (a) the research procedures 
that are described in the IRB-approval protocol and informed consent document, and (b) the 
characteristics of the subject population being studied; 
• Related or possibly related to participation in such research (e.g., there is a reasonable 
possibility that the incident, experience or outcome may have been caused by the procedures 
involved in such research); and 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic or social harm) than was previously known or recognized. 
Adverse Event Reporting Period 
 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures (e.g., after the first dose of study treatment) to the end 
of the study treatment (e.g., last dose of study treatment) and/or follow-up. For this study, the 
study treatment follow-up is defined as 100 days following the last administration of study 
treatment. 


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Baseline/Preexisting Condition 
 
A baseline/preexisting condition is one that is present at the start of the study. A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or if the character of 
the condition worsens during the study period. 
General Physical Examination Findings 
 
At screening, any clinically significant abnormality should be recorded as a preexisting condition. 
At the end of the study, any new clinically significant findings/abnormalities that meet the 
definition of an adverse event must also be recorded and documented as an adverse event. 
Post-study Adverse Event 
 
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. 
Abnormal Laboratory Values 
 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met: 
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management (e.g., change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc.). 
Hospitalization, Prolonged Hospitalization or Surgery 
 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in this 
protocol. Any condition responsible for surgery should be documented as an adverse event if the 
condition meets the criteria for an adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
• Hospitalization for >24 hours or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition. Surgery should not be reported as an outcome of an 
adverse event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 


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• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
 
8.3 
Recording of Adverse Events 
 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events should 
be recorded immediately in the source document, and also in the appropriate adverse event module 
of the case report form (CRF). All clearly related signs, symptoms, and abnormal diagnostic 
procedures results should be recorded in the source document, though should be grouped under 
one diagnosis. 
 
All adverse events occurring during the study period must be recorded. The clinical course of each 
event should be followed until resolution, stabilization, or until it has been determined that the 
study treatment or participation is not the cause. Serious adverse events that are still ongoing at 
the end of the study period must be followed up to determine the final outcome. Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the study 
treatment or study participation should be recorded and reported immediately. 
 
8.4 
Reporting of Serious Adverse Events 
 
8.4.1 
IRB Notification by Sponsor-Investigator 
Reports of all events (including follow-up information) that meet the definition of an unanticipated 
problem posing risk to subjects or others must be submitted to the IRB within one week (5 business 
days) following the occurrence of the unanticipated problem or the principal investigator’s 
acquiring knowledge of the unanticipated problem in accordance with IRB policy. Additionally, 
the sponsor-investigator will submit a summary of all Unanticipated problems that occurred since 
the beginning of the study at the time of continuing review. Copies of each report and 
documentation of IRB notification and receipt will be kept in the Regulatory binder. 
 
8.4.2 
FDA Notification by Sponsor-Investigator 
The Columbia University Medical Center Sponsor-Investigator, as holder of the IND, will be 
responsible for all communication with the FDA. Columbia University Medical Center Principal 
Investigator will report to the FDA, regardless of the site of occurrence, any adverse event that is 
serious, unexpected and there is evidence to suggest a causal relationship between the drug and 
the adverse event. These must be reported to the FDA and any affiliate sites as soon as possible, 
but in no case later than 15 calendar days after the sponsor determines that the information 
qualifies for reporting. The Sponsor-Investigator will also submit an IND annual report to the 
FDA in accordance with 21.CFR 312.33. 
 
The Columbia University Medical Center Sponsor Investigator must report to the FDA and any 
affiliate site investigators as follows: 
• Any unexpected fatal or life-threatening event must be reported as soon as possible, but no 
later than 7 calendar days after the sponsor investigator initial receipt of the information 


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• Any findings from epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND, and whether or not conducted by the 
sponsor-investigator, that suggest a significant risk in humans exposed to the drug must be 
reported as soon as possible but no later than 15 calendar days after the sponsor-investigator 
determines that the information qualifies for reporting 
• Any findings from animal or in vitro testing whether or not conducted under an IND, and 
whether or not conducted by the sponsor-investigator, that suggest a significant risk in 
humans exposed to the drug must be reported as soon as possible but no later than 15 
calendar days after the sponsor-investigator determines that the information qualifies for 
reporting 
• Any clinically important increase in the rate of a serious suspected adverse reactions over 
that listed in the protocol or Investigator Brochure 
• Expected SAEs and AEs will be included in the IND Annual Reports. 
Follow-up information to a safety report should be submitted as soon as the relevant information 
is available. However, if the results of a sponsor’s investigation show that an adverse drug 
experience not initially determined to be reportable are so reportable, the sponsor investigator 
must report such experience as soon as possible, but no later than 15 calendar days after the 
determination is made. 
 
All other serious unexpected experiences associated with the use of the study treatment will be 
reported to FDA as soon as possible but in no event later than 15 calendar days after initial 
receipt of the information. 
 
8.4.3 DSMC Reporting by the Sponsor Investigator 
Serious adverse events not constituting unanticipated problems are to be reported to the HICCC 
DSMC. Reporting should occur within 24 hours of knowledge of the SAE occurring at our 
institution or affiliate sites. 
 
8.4.4 Reporting to Drug Manufacturers by Sponsor-Investigator 
The Sponsor-Investigator will report to investigational agent manufacturers any serious adverse 
events that meet the reporting criteria to the Institutional Review Board as described in section 
10.4 and/or to the FDA as described in section 10.4 within 3 days of becoming aware of it, so 
that these reports can be evaluated and included in the Investigator’s Brochure and for IND 
safety submissions per regulations. Reporting will occur by sending the reporting form along 
with any additional documentation sent to the regulatory authorities. 
 
At the time of IRB renewal or at the request of the manufacturer, the Sponsor- Investigator will 
submit a summary of all Serious Adverse Events that have occurred inclusive of all sites to 
manufacturer. 
 
All Serious Adverse Events (SAEs) that occur following the subject’s treatment start date to 
participate in the study through 100 days of discontinuation of dosing must be reported to BMS 
Worldwide Safety and to Ferring Safety, whether related or not related to study drug. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a 
follow-up skin biopsy). 


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Following the subject’s treatment start date, all SAEs, whether related or not related to study 
drug, are collected, including those thought to be associated with protocol-specified procedures. 
The investigator should report any SAE occurring after these aforementioned time periods, 
which is believed to be related to study drug or protocol-specified procedure. 
 
• An SAE report should be completed for any event where doubt exists regarding its 
seriousness; 
• If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the narrative 
section of the SAE Report Form. 
 
An appropriate SAE form (e.g. ex-US = CIOMS form or USA = Medwatch form)/ or equivalent 
(HICCC DSMC SAE Form) should be used to report SAEs to BMS. Note: Please include the 
BMS Protocol number on the SAE form or on the cover sheet with the SAE form transmission. 
 
o The CIOMS form is available at: http://www.cioms.ch/index.php/cioms-form-i 
o The MedWatch form is available at: MedWatch 3500 Form 
• 
• SAE reporting to BMS: 
• The Sponsor will reconcile the clinical database AE cases (case level only) transmitted to 
BMS Global Pharmacovigilance (Worldwide.Safety@bms.com). 
▪ The Investigator will request from BMS GPV&E, 
aepbusinessprocess@bms.com the SAE reconciliation report and include 
the BMS protocol number every 3 months and prior to data base lock or 
final data summary 
▪ GPV&E will send the investigator the report to verify and confirm all 
SAEs have been transmitted to BMS GPV&E. 
▪ The data elements listed on the GPV&E reconciliation report will be used 
for case identification purposes. If the Investigator determines a case was 
not transmitted to BMS GPV&E, the case should be sent immediately to 
BMS (Worldwide.Safety@bms.com). 
 
In addition to the Sponsor Investigator’s responsibility to report events to their local HA, 
suspected serious adverse reactions (whether expected or unexpected) shall be reported by 
BMS to the relevant competent health authorities in all concerned countries according to 
local regulations (either as expedited and/or in aggregate reports). 
 
• In accordance with local regulations, BMS will notify investigators of all reported SAEs 
that are suspected (related to the investigational product) and unexpected (ie, not previously 
described in the IB). An event meeting these criteria is termed a Suspected, Unexpected 


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Serious Adverse Reaction (SUSAR). Investigator notification of these events will be in the 
form of a SUSAR Report. 
o Other important findings which may be reported by BMS as an Expedited Safety 
Report (ESR) include: increased frequency of a clinically significant expected SAE, an 
SAE considered associated with study procedures that could modify the conduct of the 
study, lack of efficacy that poses significant hazard to study subjects, clinically 
significant safety finding from a nonclinical (eg, animal) study, important safety 
recommendations from a study data monitoring committee, or sponsor decision to end 
or temporarily halt a clinical study for safety reasons. 
o Upon receiving an ESR from BMS, the investigator must review and retain the ESR 
with the IB. Where required by local regulations or when there is a central IRB/IEC 
for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. The 
investigator should also comply with the IRB/IEC procedures for reporting any other 
safety information. 
o In addition to the Sponsor Investigator’s responsibility to report events to their local 
HA, suspected serious adverse reactions (whether expected or unexpected) shall be 
reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate 
reports). 
 
SAEs, whether related or not related to study drug, and pregnancies, must be reported to BMS 
within 24 hours of becoming aware of the event. SAEs must be recorded on either CIOMS, 
MedWatch, or approved site SAE form. 
• Pregnancies must be reported and submitted to BMS on any of the following form(s): 
• 1. MedWatch or, CIOMS or 
• 2. BMS Pregnancy Surveillance Form or, 
• 3. Approved site SAE form 
 
SAE Email Address: Worldwide.Safety@BMS.com 
 
SAE Facsimile Number: +1 609-818-3804 
 
• If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.) 
• If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours 
(excluding holidays and weekends) to BMS using the same procedure used for 
transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization. 
 
Adverse Event Reporting to BMS 


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Adverse Events that are routinely collected according to GCP shall be submitted to BMS 
every three (3) months by the last working day of the third month. 
 
The Adverse Event information required to be sent to BMS is noted in an ‘Bristol-Myers 
Squibb Early Asset Investigator Sponsored Research (ISR) Import Plan’ which describes 
the method of collection and submission to BMS via the mailbox: 
 
MG-RD-GPVE-PHARMACOVIGILANCE@bms.com 
 
When the file is submitted to BMS, it must be noted that the file contains all Non Serious 
Adverse Events (only adverse events not previously submitted to BMS within the 3 
months). 
 
The HICCC CPDM Multicenter Trials Core will submit on behalf of CUMC and all 
affiliate sites. 
 
8.5 
Reporting Process 
 
Adverse events may be submitted on FDA Form 3500A, the HICCC DSMC Serious Adverse 
Event Reporting 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 10. 
 
9. 
PHARMACEUTICAL INFORMATION 
 
STUDY DRUGS 
 
9.1 
BMS-986253 
 
9.1.1 
Dispensing of BMS-986253 
 
The investigator or designee will calculate the number of BMS-986253 vials needed, pull 
the appropriate number of vials to prepare the infusion solution, and enter the vials used 
into the eCRF and drug accountability log. The Principal Investigator must keep accurate 
and up-to-date dispensation records. Any discrepancies between the amounts of Study drug 
dispensed and returned must also be explained in writing. All such records of drug 
accountability must be entered on the corresponding Subject CRFs. 
 
9.1.2 
Packaging and Formulation 
 
Product 
Description / Class 
and Dosage Form 
Potency 
IP/Non 
-IMP 
Blinded or 
Open 
Label 
Packaging / 
Appearance 
Storage 
Conditions 
(per label) 


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BMS-986253 for 
injection 
1000mg/vial 
(100mg/mL) 
IP 
Open Label 
Vial 
Refer to the 
label on 
container 
 
For additional details refer to the Investigator’s Brochure. 
 
9.1.3 
Storage 
 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. 
 
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
9.1.4 
Administration 
 
Administer intravenously over 120 minutes. Do not co-administer other drugs through the 
same infusion line. See Section 8.1 for details on BMS-986253 administration. 
 
9.1.5 
Disposal 
 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from BMS or designee, the amount dispensed to and returned by the subjects and 
the amount remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, 
state, local and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
 
9.1.6 
Drug Interactions and Concomitant Therapy 
 
The expected in vivo degradation of mAbs is via biochemical pathways that are 
independent of typical small molecule drug metabolizing enzymes. Consequently, typical 
mAbs, such as BMS-986253 or HuMax-Inflam, are not expected to have interactions with 
molecules that are metabolized by these enzymes. 
 
No formal pharmacokinetic drug interaction studies have been conducted with BMS- 
986253. 


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9.1.7 
Adverse Events 
 
Potential adverse events are summarized in the Investigator’s Brochure. 
Study HuMax-Inflam-001: Safety in Participants with PPP 
Within the dose range up to 8 mg/kg as a single-dose administration, the MTD of 
HuMaxInflam was not reached. Administration of HuMax-Inflam in a single dose of up to 
8 mg/kg and up to 4 mg/kg in 4 weekly doses was safe and well tolerated by participants 
with PPP. Approximately 50% of reported AEs (45 of 85) were judged attributable to the 
study drug. The most frequent AEs were nausea, nasopharyngitis, and headache. There was 
no increase in the frequency of AEs with increasing dose. Administration of HuMax-Inflam 
did not lead to formation of antibodies against HuMax-Inflam. 
 
Study CA027-001: Safety with BMS-986253 Monotherapy in Participants with Cancer 
 
Multiple ascending doses of BMS-986253 were well tolerated across the dose range of 4 
to 32 mg/kg Q2W in 15 adults with advanced tumors treated in Study CA027-001. AEs 
leading to discontinuation were reported in 3 (20.0%) participants, and all were considered 
not related to BMS-986253. AEs leading to discontinuation included Grade 3 increased 
blood alkaline phosphatase (ALP), Grade 2 increased blood creatinine, Grade 3 
hypertension, Grade 3 fall, and Grade 3 back pain. There were no deaths due to AEs in this 
study. The MTD was not reached, and no DLTs were observed. There was 1 death due to 
disease progression within 48 days of the last dose of BMS-986253. 
 
Five of the 15 participants were considered by the Investigator to have experienced AEs 
related toBMS-986253 monotherapy. All TRAEs were Grade 1 or Grade 2 in severity. The 
most common TRAEs were nausea (N = 2) and fatigue (N = 2). 1 patient treated at 16mg/kg 
with grade 1 “reduced white blood cells” related to study drug. 
 
Study CA027-002: BMS-986253 plus Nivolumab in Advanced Cancers 
 
In the ongoing Study CA027-002 (data cut-off date of 16-Jan-2020), 92 participants have 
been treated with varying doses of BMS-986253 in combination with a flat dose of 480- 
mg nivolumab Q4W: 600 mg Q4W (N = 16), 1,200 mg Q4W (N = 15), 2,400 mg Q4W (N 
= 18), 1,200 mg Q2W (N = 12), and 2,400 mg Q2W (N = 31). Of these 92 participants, 9 
received treatment as part of a safety lead-in: 5 received 2,400-mg BMS-986253 Q4W and 
480-mg nivolumab Q4W, and 4 received 2,400-mg BMS-986253 Q2W and 480-mg 
nivolumab Q4W. All 9 participants dosed cleared a 28-day DLT period, with no DLTs 
observed. Overall, based on the available data as of 16-Jan-2020, no significant safety 
trends were identified. 
 
Thirty of 92 (32.6%) participants experienced AEs related to the study drug combination. 
The most common TRAEs (N > 2) were Grade 1/2 fatigue (N = 9), Grade 1/2 nausea (N = 
7), Grade 1 rash (N = 3), and Grade 1/2 decreased appetite (N = 3). Most TRAEs were 
Grade 1/2, and based on the available data, no dose-dependent TRAEs were identified. Of 


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note, 1 participant treated with Q2W BMS-986253 2,400mg experienced Grade 3 
neutropenia on Cycle 2 Day 1; this participant was asymptomatic without evidence of 
infection, and the episode resolved without intervention in < 2 weeks. 2 patients 
experienced infusion reactions (1 patient grade 2 reaction and 1 patient with grade 4 
infusion reaction). 
 
9.2 
Subject Compliance Monitoring 
 
Study treatments will be administered by healthcare professionals under the 
supervision of the Investigators. Records of study treatment dose calculation, 
administration, and dosing regimen will be accurately maintained by site staff. The 
monitor will review dose calculation, administration and regimen as well as medication 
accountability during investigational site visits and at the completion of the study. 


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10. 
STUDY CALENDAR 
 
Every effort should be made to keep visits, tests, and procedures on schedule. Acceptable 
deviations are listed below. 
 
Screening 
Evaluation a 
During Hospitalization (daily 
unless indicated) 
Day 29 and Follow-up (after 
discharge)f 
Informed consent 
X 
Medical history (including 
baseline ECOG) 
X 
X 
Review of medications 
X 
X 
X 
Physical assessmentk 
X 
X 
Vital signs (including 
Sp02/FIO2 if on 
supplemental oxygen) 
X 
(3 times per day)i 
Height and weight 
X 
Laboratory studiesb 
X 
X 
Inflammatory markersj 
X 
Every 2 days 
NLR and absolute 
lymphocyte count 
X 
X 
Serumc 
X 
Every 7 days (+/- 2 days)c 
NEWS2 score d 
X 
X 
7-point ordinal scalel 
X 
X 
Chest imaging (optional) e 
X 
Every 7 days (+/- 2 days) e 
BMS-986253 dose 
Every 2 weeks for 1-3 dosesg 
Toxicity assessment 
X 
Xh 
a: 
The screening (pre-treatment) evaluation should be conducted within 1 day prior to dose of BMS-986253. If screening done on same day as 
treatment then treatment day 1 assessments do not need to be repeat (screening assessments will suffice) 
b: 
Laboratories should include hemoglobin, hematocrit, white blood cell count with differential (including absolute eosinophil count), platelets, 
sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, glucose, calcium, albumin, total protein, bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase. Prothrombin time (PT/INR), activated partial 
thromboplastin time (APTT) will be drawn at baseline and then as clinically indicated. 
c: 
Serum samples should be collected for cytokine and PK analysis at screening, day 8, 15, 22, 29, and EOT if possible (not required). Should be 
collected prior to the treatment dose of day 15 and 29. For patients ready for discharge prior to day 8, a serum sample should be collected, 
when feasible, prior to discharge. 
d: 
NEWS2 score is calculated considering respiratory rate, oxygen saturation, systolic blood pressure, pulse rate, level of 
consciousness/confusion, temperature. 
e: 
CT chest or CXR at baseline (within 2 days of enrollment) and after 7 days (+/- 2 days) if clinically indicated. 
f: 
Can be done by phone: at day 29 (+/- 1 day) and every 1 month (+/- 1 week) (until 100 days following last dose of treatment), then every 3 
months (+/- 1 month) from registration to up to 1 year follow up. 
g: 
If randomized to anti-IL-8 therapy, BMS-986253 will be given every 2 weeks (+/- 2 days). 2nd dose will be given if patient is still 
hospitalized. 3rd dose is optional and will be given if patient still hospitalized with severe COVID-19. If randomized to control, patients will 
receive standard of care as determined by their treating physician. 
h: 
Follow-up for toxicity will be done until 100 days following last dose of treatment 
i: 
Vitals sings should include temperature, heart rate, blood pressure, respiratory rate and oxygen saturation and FI02 if on supplemental oxygen 
j: 
Inflammatory markers will include: LDH, D-Dimer, CRP, sIL-6 (+/- 1 day). 
k: 
Documented physical exam from primary treatment team will be sufficient with chart review by research team. 
l: 
7-point ordinal scale scored as follows: (1) death, (2) hospitalized on invasive mechanical ventilation or extracorporeal membrane 
oxygenation, (3) hospitalized, requiring non-invasive ventilation or high flow nasal cannula, (4) hospitalized, requiring supplemental 
oxygenation (5) hospitalized, not requiring supplemental oxygenation and requiring ongoing medical care (COVID-19 related or otherwise) 
(6) Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care, (7) not hospitalized. 


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10.1 
Screening/Pretreatment Evaluation 
 
Before initiating any screening activities, the scope of the study should be explained to 
each patient. Patients should be advised of any known risks inherent in the planned 
procedures, any alternative treatment options, their right to withdraw from the study at 
any time and for any reason, and their right to privacy. After this explanation, patients 
should be asked to sign and date an IRB-approved informed consent form that meets 
the requirements of the Code of Federal Regulations (Federal Register Vol. 46, No. 17, 
January 27, 1981, part 50). 
The pretreatment/screening visit will determine patient eligibility according to the 
inclusion and exclusion criteria. All subjects must undergo a number of baseline 
evaluations as part of this screening visit, as detailed below. All of these evaluations 
should be conducted within 1 day of starting the protocol. This information is also 
summarized in the Study Calendar (Table 1). 
• informed consent 
• demographic information 
• medical history, including review of systems and baseline ECOG score. 
• physical assessment 
• vital signs: temperature, pulse, blood pressure, respiratory rate, oxygen saturation 
and FIO2 and SpO2/FIO2 
• height and weight 
• current medication list, including drug allergies/adverse events 
• hematological laboratories (hemoglobin, hematocrit, white blood cell count with 
differential [including absolute eosinophil count], platelets) 
• coagulation profile (INR, aPTT) 
• serum chemistry (sodium, potassium, chloride, bicarbonate, urea, creatinine, 
glucose, calcium, albumin, protein, bilirubin, ALT, AST, alkaline phosphatase) 
• CRP, D-Dimer, LDH, sIL-6 level 
• Neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count 
• NEWS2 score 
• 7-point ordinal score 
• CT or CXR of the chest (optional) 
• Sera for biomarker and PK analysis. 
After all relevant screening information is documented, registration should be finalized 
and appropriate documents (i.e., signed informed consent, supporting source 
documentation for eligibility) should be faxed or emailed to CPDM Central 
Registration Office for review. 
Information on patients who do not meet eligibility criteria to participate in this study 
(i.e., screening failures) should also be captured. 


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10.2 
During Hospitalization: 
The following must be performed during hospitalization (if screening assessments done 
<1 day prior to first treatment dose, they do not need to be repeated on Day 1 of 
treatment). 
• review of medication list daily 
• review of toxicity/adverse events daily 
• vital signs (pre- and post-infusion of BMS-986253) and three times per day 
including temperature, heart rate, blood pressure, respiratory rate, oxygen 
saturation and FIO2 and SpO2/FIO2 if on supplementation oxygen. 
• physical exam daily 
• hematological laboratories (hemoglobin, hematocrit, white blood cell count with 
differential [including absolute eosinophil count], platelets) daily 
• coagulation profile (INR, aPTT) as clinically indicated. 
• serum chemistry profile (sodium, potassium, chloride, bicarbonate, urea, 
creatinine, glucose, calcium, albumin, total protein, bilirubin, ALT, AST, alkaline 
phosphatase) daily 
• CRP, D-Dimer, LDH, sIL-6 level every other day 
• Neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count daily 
• NEWS2 score daily 
• 7-point ordinal score daily 
• CT or CXR of the chest weekly (+/- 2 days) (optional) 
• 
Sera for biomarker and PK analysis day 8, 15, 22, 29, and EOT (+/- 2 days). Where 
possible, the Day 15 and 29 PK samples should be collected just prior to dosing. 
(optional). For patients ready for discharge prior to day 8, a serum sample should be 
collected, when feasible, prior to discharge. 
• Patients randomized to anti-IL-8 therapy will receive BMS-986253 every 2 weeks 
(+/- 2 days) x 1-3 doses, with 2nd dose given if patient still hospitalized and then 
3rd dose optional if patient still hospitalized with severe COVID-19. Patients 
randomized to control will receive standard of care. 
10.3 
Follow-Up After Discharge: 
Following completion of therapy, patient will have follow up by phone every 30 days 
for the first 100 days following the last dose of therapy. Patients will then have follow 
up by phone every 90 days (+/- 30 days) for up to 1 year. In addition, patients will be 
assessed 28 days (+/- 2 days) following start of treatment whether they are discharged 
or in the hospital. These assessments will include: 
• review of medication list 
• review of toxicity/adverse events (for up to 100 days following last dose of 
treatment) 
• Evaluation of Katz basic ADLs and Lawton IADLs (Appendix C and D) 


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• assessment for survival 
 
Patients withdrawing from the study early because of adverse events should be 
followed until the adverse event has either resolved or stabilized. Reasons for 
premature withdrawal should be determined and documented. 
11. 
MEASUREMENT OF EFFECT 
 
11.1 
Primary Endpoint 
11.1.1 
Time to improvement (2 points) in 7-point ordinal scale 
 
The time to improvement (2 points) will be defined as the time (days) required from 
the start of treatment to the improvement of clinical status (2 points) assessment from 
baseline based on the 7-point ordinal scale. Patients for whom there was no event will 
be censored from this analysis. 7-point ordinal scale will be calculated as follows: (1) 
death, (2) hospitalized on invasive mechanical ventilation or extracorporeal membrane 
oxygenation, (3) hospitalized, requiring non-invasive ventilation or high flow nasal 
cannula, (4) hospitalized, requiring supplemental oxygenation (5) hospitalized, not 
requiring supplemental oxygenation and requiring ongoing medical care (COVID-19 
related or otherwise) (6) Hospitalized, not requiring supplemental oxygen – no longer 
requires ongoing medical care, (7) not hospitalized. 
 
11.2 
Secondary Endpoints 
 
11.2.1 
Time to death 
 
The time to death will be defined as the time from onset from symptoms until 
death from any cause. Patients who are alive or lost to follow-up at the cut-off date 
will be censored from this analysis. 
 
11.2.2 
Mortality at 1 month 
 
1-month mortality is defined as the percentage of patients who have died 1 month 
from the time of start of treatment. 
 
11.2.3 
Time to intubation 
 
The time to intubation will be defined as the time from symptom onset until time 
of intubation. Any patients already intubated at enrollment will be censored from 
this analysis. 
11.2.4 
Time to improvement in oxygenation 
 
The time to improvement in gas exchange will be defined as the time from time of 
start of treatment until a ≥ 30% decrease in oxygen requirement compared to 


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baseline [or elimination of oxygen requirement] without a decrease in SpO2 
sustained for at least 48hrs or until discharge. 
 
11.2.4 
Proportion of patients requiring ICU admission at 1 month. 
The proportion of patients requiring ICU admission will be calculated as the 
number of patients requiring ICU admission over the course of their 
hospitalization over the number of evaluable patients. 
 
11.2.5 
Safety and Toxicity 
 
All subjects receiving at least one dose of the study drug will be evaluated for safety 
by monitoring symptoms, physical examinations, and laboratory tests. Adverse 
events will be classified and graded according to the NCI Common Toxicity 
Criteria version 5.0 (see Appendix A). The absolute number and frequency of each 
adverse event will be reported, and subdivided according to toxicity grade. A 
description of adverse events by treatment arm will also be reported. A particular 
adverse event occurring more than once in the same subject will be counted only 
once and at its worse grade. 
 
11.2.6 
Duration of Hospitalization 
Duration of hospital admission will be measured from the time of admission until 
the time of discharge. 
 
11.2.7 
7-point Ordinal Scale Score 
 
The mean/medians of the 7-point ordinal raw scores at day 14 from the start of 
treatment will be computed and compared between the treatment and control 
groups. 
 
Exploratory Endpoints. 
11.2.8 
Change in inflammatory markers from baseline 
 
Changes in LDH, D-Dimer, CRP, ESR, NLR and absolute lymphocytes before and 
after treatment and over time with be measured every other day during 
hospitalization. 
 
11.2.9 
Change in circulating sIL-6 levels from baseline 
 
Change in sIL-6 levels before and after treatment and over time will be measured 
every other day during hospitalization. 
11.2.10 
Radiographic response 
Radiological response will be evaluated by comparing % of lung fields with 
infiltrates on chest imaging (CXR and CT) through independent radiology review 
between baseline and day 8) if available. 


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11.2.11 
Proportion of patients with multiorgan failure at 1 month 
 
The proportion of patients with multiorgan failure will be defined as the number of 
patients with multiorgan failure during their hospitalization measured at 1 month 
over the number of evaluable patients. 
11.2.12 
Time to improvement in NEWS2 score ≤ 2 
Determine the time to improvement in NEWS score will be defined as time from 
start of treatment until NEWS score ≤ 2 and maintained for at least 24hrs. The 
NEWS 2 score is calculated based respiratory rate, oxygen saturation, systolic 
blood pressure, pulse rate, level of consciousness/confusion and temperature. 
11.2.13 
To measure time on ventilation 
 
Measured from time of intubation to time of definitive extubation. Will censor 
for patients not requiring intubation. 
 
11.2.12 
Change in NEWS2 from baseline 
 
Changes in NEWS2 score will be reported at days 3, 5, 8, 11, 15, and 29. 
 
11.2.15 
Change in IL-8 and downstream cytokines. 
Circulating IL-8 and additional cytokines (IL1B, IL2, IL4, IL5, IL6, IL7, IL9, IL10, 
IFNgamma, TNFalpha and others) will be measured at baseline and at additional 
time points when possible (day 8, 15, 22, 29). 
 
11.2.16 
Change in humoral immune response 
The humoral immune response will be assessed by protein microarray antibody 
profiling at baseline and at additional time points when possible (day 8, 15, 22, 29). 
 
11.2.17 
To characterize PK of BMS-986253 
 
Will assess PK at screening, day 8, 15, 22, 29, and EOT by collection of serum at 
these time points when feasible. For patients ready for discharge prior to day 8, a 
serum sample should be collected, when feasible, prior to discharge. 
 
Stopping Rules 
 
The study may be discontinued by the data and safety monitoring committee 
(DSMC), the Food and Drug Administration (FDA), or other regulatory authorities. 
Any unforeseen deaths or serious adverse events may, after a discussion between 
the principal investigator, prompt an interruption to study accrual pending a full 
investigation into the circumstances surrounding the event. 


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Continuous Toxicity Monitoring 
 
As this trial will be the first time an anti-IL-8 will be tested in patients with severe 
COVID-19, safety will be monitored on a continual basis. Sequential 
boundaries will be used to monitor dose-limiting toxicity rate.16 The accrual will 
be halted if excessive numbers of dose-limiting toxicities are seen, that is, if the 
number of dose-limiting toxicities is equal to or exceeds bn out of n patients with 
full follow-up (see Table 3). This is a Pocock-type stopping boundary that yields 
the probability of crossing the boundary at most 0.05 when the rate of dose- 
limiting toxicity is equal to the acceptable rate of 30%. For the purposes of this 
stopping rule, dose-limiting toxicities will be defined as any treated related grade 
3 or 4 toxicity. 
 
Table 3. Toxicity Monitoring 
Number of 
Patients, n 
1 2 
3 
4 
5 
6- 
7 
8- 
9 
10- 
11 
12- 
14 
15- 
16 
17- 
18 
19- 
21 
22- 
23 
24- 
25 
26- 
28 
29- 
30 
31- 
33 
34- 
36 
37- 
38 
Boundary, bn* - 
- 
- 
4 
5 
6 7 8 9 
10 11 12 13 14 15 16 17 18 19 
Number of 
Patients, n 
39- 
41 
42- 
43 
44- 
46 
47- 
49 
50- 
51 
52- 
54 
55- 
57 
58- 
59 
60- 
62 
63- 
65 
66- 
67 
67- 
70 
71- 
73 
74- 
76 
77- 
78 
79- 
81 
82- 
84 
85- 
87 
98- 
90 
Boundary, bn* 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 
Number of 
Patients, n 
91- 
92 
Boundary, bn* 39 
*This boundary is equivalent to testing the null hypothesis, after each patient, that the event rate 
is equal to 30%, using a one-sided level 0.009 test. 
 
For example, based on the boundaries above, if 12 out of the first 20 patients 
enrolled in the anti-IL-8 arm experience dose-limiting toxicities, the trial will be 
stopped for safety. In this case, the 95% exact confidence interval will be (0.36, 
0.81), with the lower confidence limit exceeding the event rate (30%). 
 
12 DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10.0 
(Adverse Events: List and Reporting Requirements). The Data Safety Monitoring Plan is 
described in Section 14.3. 
 
12.1 
Data Collection 
 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials and data 
management system (CTMS) that will be used for data collection. CRFs for the study will be built 
into the CTMS for data entry. The system has full auditing capabilities which is web-based and 
housed on a server in a fully HIPAA compliant server room with restricted access and video 


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camera monitoring. All users must login with their own application username and password. 
Users off campus must first access the Virtual Private Network with their assigned campus 
username and password and then use their application credentials. Users are only able to see study 
information if they are indicated as study personnel in our electronic IRB system. Users are limited 
to access based on the role assigned in their corresponding protocol. Subject data is entered 
directly into the system, which (in the case of Columbia subjects) confirms the correct identity of 
patients via an interface with the electronic medical patient index. Staff with the appropriate IRB 
defined roles can run reports within the system for reporting purposes. 
 
12.2 
Data Reporting 
 
Case Report Forms will be completed for each subject enrolled into the clinical study through the 
CTMS. It is the investigator’s responsibility for ensuring that all clinical and laboratory data 
entered on the corresponding CRFs are complete, accurate and authentic. 
 
 
12.3 
Data and Safety Monitoring Committee 
 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving 
Comprehensive Cancer Center (HICCC) will monitor every subject who receives treatment on this 
protocol for toxicity. This protocol will adhere to the policies of the currently approved HICCC 
Data and Safety Monitoring Plan (DSMP), which is in accordance with NCI and CUMC-IRB 
policy and guidelines. The committee is chair is appointed by the HICCC Director. The committee 
consists of HICCC faculty and staff with expertise in oncology, research pharmacy, research 
nursing, and data management. The DSMC convenes twice a month to review patient safety and 
the conduct of the trial. The PI will submit data and safety monitoring reports to the DSMC at a 
frequency to be determined by the DSMC based on risk to the subjects. 
 
At the time of renewal, the study team will submit the most recent DSMC approval letter for safety 
review to the CUMC IRB. Any modifications that are required by the DSMC to ensure patient 
safety will be submitted to the IRB. All protocol deviations, violations, and eligibility waivers will 
be submitted to and approved by the DSMC prior to being reported to the IRB. All study data 
reviewed and discussed during these meetings will be kept confidential. 
 
12.4 
Quality Control and Quality Assurance 
 
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically by the CPDM Compliance Core on behalf of the HICCC DSMC. Additionally, the 
Compliance Oversight Committee of the IRB at Columbia University Medical Center may audit 
the study at any time per institutional policies and procedures. The investigator-sponsor and 
Columbia University Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
A risk-based approach will be used by the Compliance Core to determine the frequency, number 
of subject charts, and data elements to be monitored. The Compliance Coordinator will review the 


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study status and summarize enrollment, toxicities, SAEs/UPs, dose escalation, statistical endpoints 
(e.g., stopping rules), etc. for the full DSMC membership at the regularly scheduled meetings. 
 
Internal On-site Monitoring: 
 
• Initial, recurrent, and close-out on-site monitoring visits will also be conducted at remote 
clinical sites, as appropriate/feasible. Other sites will have monitoring performed remotely 
(see below for further details). 
 
• The Compliance Coordinator will communicate with the site coordinator/Site Principle 
Investigator to schedule the monitoring visit and arrange for access to study materials and 
documentation. 
 
• The assigned Compliance Coordinator will monitor IIT trials within 1 month after the first 
subject is enrolled and throughout the life of the study to ensure that the study is being 
conducted in accordance with the protocol, GCP, applicable federal and local regulations, 
and per all applicable SOPs. The Compliance Coordinator is responsible to notify the PI 
and CRNP/CRN/CRC of upcoming monitor visits and convey what information and 
documentation will be required for the visit(s). The Compliance Coordinator is 
responsible for verifying that informed consent is properly obtained, eligibility is met (via 
the central registration process), and all study procedures are conducted according to the 
study protocol. The Compliance Coordinator will also verify that the data reported in the 
CRF’s accurately reflect source documents, that all toxicities have been reported to date, 
and that all SAE’s/UPs/deviations/violations have been reported according to local IRB 
and HICCC DSMC requirements. The Compliance Coordinator will issue queries and 
ensure resolution in a timely and efficient manner. The Compliance Coordinator will also 
monitor for applicable regulatory compliance and research pharmacy compliance (if 
applicable) and communicate any deficiencies as appropriate. 
 
12.5 
Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (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 (e.g., that the subject is alive) at the end 
of their scheduled study period. 


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The subject binders will be maintained with in the CPDM offices, a secured floor within the 
Herbert Irving Pavilion and only the investigator and study staff will have access to the file. 
 
12.6 
Source 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. 
 
12.7 
Case Report Forms 
 
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”. 
 
12.8 
Records Retention 
 
Records relating to a specific research activity, including research records collected by 
investigators, must be maintained for at least three years after completion of the research (45 CFR 
46.115(b); 21 CFR 56.115(b); 21 CFR 312.62). This minimum retention period applies whether 
or not any subjects were enrolled in the study. If the research is FDA regulated, records should be 
retained for at least two years after approval of the investigational agent by FDA; if it is not 
approved, records should be retained at least two years after the study is terminated and FDA is 
notified (note the additional requirement below for clinical research studies); Clinical records, 
including consent forms that document clinical intervention or clinical diagnostic procedure 
research-related procedures, must be retained in medical records by the institution for at least seven 
years, per CUMC and NYP policy which is based on state law. 
 
13 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design and Sample Size 
 
This study is a single-center, randomized open-label phase 2 trial to evaluate 
the efficacy and safety of anti-IL-8 in hospitalized adults with severe or critical 
COVID-19. The primary endpoint is time to improvement in clinical status: the time 
(days) required from the start of treatment to the improvement of clinical status (2 
points) assessment from baseline based on the 7-point ordinal scale. Patients for 
whom there was no event will be censored. 


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Patients will be randomized in a 2:1 allocation ratio to either anti-IL-8 or standard of 
care. Patients will be assessed daily while hospitalized. Discharged patients will be 
contacted by telephone on Day 29 and then monthly up to one-year to assess status. In 
addition to these specific assessment times, one interim analysis is planned at and the 
DSMC will actively monitor interim data to make recommendations about early signs 
of overwhelming efficacy and futility/study closure (see Section 13.4.) 
 
With a sample size of 138 patients: N=92 patients randomized to the treatment arm 
and N=46 patients assigned to the standard of arm/control, the study will have 80% 
power to detect an increase in median time to improvement from 2 days (control) to 5 
days (treatment arm) with one-sided alpha of 0.025. The sample size was estimated 
based on a hazard ratio (HR) of 0.40 assuming an exponential survival distribution 
with inflation to account for one interim look and 5% drop-out rate. 
 
 
13.2 
Study Endpoints and Analysis Plan 
All subjects who receive at least one dose of study drug will be considered 
evaluable and included in the efficacy and safety analysis. 
Analytic plan for primary objective: 
The primary efficacy null hypothesis of the equality of time to improvement (2 
points) in clinical status curves will be tested with the log-rank test. The overall 
type I error for the primary analysis will be considered one-sided alpha of 0.025. 
Kaplan-Meier estimates will be reported for each of the two arms with median time 
to improvement and 95% confidence intervals (CI). Cox regression will be 
employed to estimate the treatment effect (HR) and 95% CI. 


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Analytic plan for secondary and exploratory objective: 
We will estimate the distributions of all time-to-event endpoints using the Kaplan- 
Meier method and if possible, provide medians (95% CI). Comparisons between 
survival curves will be assessed using log-rank tests and Cox regression models. 
For each arm, we will estimate the 1-month mortality rate and incidence of adverse 
events graded by CTCAE v5.0 using the exact 95% confidence intervals. 
Comparisons between the two arms will assessed using chi-squared or Fisher’s 
exact tests. The mean/medians of the 7-point ordinal scores at day 14 after the start 
of treatment will be computed and compared between the two groups using two- 
sample t-test or the equivalent non-parametric Wilcoxon Rank-Sum test if 
normality is not satisfied. 
Changes in exploratory endpoints (before and after treatment) will be quantified 
using means (95% CI) and/or medians (inter-quartile ranges) for non-normal data. 
Comparisons between the two arms will be made using two-sample independent t- 
tests or the non-parametric equivalent, Wilcoxon Rank-Sum test. The associations 
between baseline levels and/or changes over time of IL-8 and other key cytokines 
(TNF, IL-1b, IL-6) with outcomes will be assessed using regression models. 
 
13.3 
Subgroup Analysis 
 
A post-hoc, subgroup analysis will be employed to compare the primary and secondary 
endpoints for cancer vs non-cancer patients. 
 
A post-hoc, subgroup analysis based on severity of respiratory symptoms is also 
planned to investigate the consistency or heterogeneity of the treatment effect across 
the following pre-specified groups: 
 
1) Severe Respiratory Disease – defined as oxygen saturation ≤ 93% on 
room air, RR ≥ 24 or ≥50% lung involvement on imaging within 24 - 48hrs. 
 
2) Critical Respiratory Disease – defined as respiratory failure requiring 
non-rebreather, high-flow nasal cannula, ICU admission, non-invasive 
ventilation, invasive ventilation. 
 
13.4 
Interim analyses 
One interim analysis is planned after approximately 17 (40% of the total 41 events) have been 
observed using O'Brien and Fleming stopping boundary using the Lan-DeMets spending function 
at a nominal type I error of 0.025. The intent-to-treat (ITT) principle is applied to the analysis, and 
therefore, we inflated the sample size by 5% to safeguard against drop-outs. 
 
An independent Data Safety Monitoring Committee (DSMC) will serve as the primary reviewer 
of the results of the interim analyses of the study and will make recommendations for 
discontinuation of the study or protocol modifications. Stopping rules for overwhelming efficacy 
and/or futility are provided in Table 4 below. 


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Table 4. Efficacy and Boundaries and Properties for the Time to Improvement Analysis 
 
Analysis* 
Value 
Efficacy 
Futility 
IA1: 40% 
Nominal critical point Z-value 
3.3569 
0.0811 
N: 138 
p (1-sided) 
0.0004 
0.4677 
Events: 17 
~HR at bound 
0.1720 
0.9584 
Month: 2.6 
P(Cross) if HR=1 
0.0004 
0.5323 
P(Cross) if HR=0.4 
0.0599 
0.0427 
IA2: 100% 
Nominal critical point Z-value 
1.9622 
1.9622 
N: 138 
p (1-sided) 
0.0249 
0.0249 
Events: 41 
~HR at bound 
0.5217 
0.5217 
Month: 7 
P(Cross) if HR=1 
0.0240 
0.9760 
P(Cross) if HR=0.4 
0.8000 
0.2000 
*This column displays the number of events and percentage (%) of needed time to improvement events, the 
expected sample size (N), and the estimated months (Month) after first participant is randomized for each 
analysis. 
p (1-sided): the nominal α for testing. 
~HR at bound: the approximate hazard ratio required to reach the bound for overwhelming efficacy or futility 
stop. 
P (Cross if HR=1): the probability of crossing a bound at or before each analysis under the null hypothesis. 
P (Cross if HR=0.40): the probability of crossing a bound at or before each analysis under the alternative 
hypothesis. 
Abbreviations: HR = hazard ratio; IA = interim analysis. 
 
13.5 
Analysis Populations 
13.5.1 Intention-to- treat and per protocol population 
ITT population: The intention-to-treat (ITT) population includes all randomized 
patients who received at least one dose of the study drug. Analysis of the ITT 
population will be done according to the initial treatment assigned to the patient (as 
randomized). ITT population may be used for sensitivity analysis of the efficacy 
endpoints, as well as for analysis of data including (but not limited to) demographics 
and baseline characteristics. 
 
PP population: The per protocol population set (PPS) includes all ITT patients who did 
not have any relevant major protocol deviations, e.g., patients who are randomized and 
treated, but do not have laboratory-confirmed SARS-CoV-2 infection will be excluded 
from PPS. Analysis of the PPS will be done according to the treatment the patient 


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actually received (as treated). The PPS will be used for sensitivity analysis of the 
primary efficacy endpoint. 
 
13.5.2 Safety population 
The safety population includes all randomized patients who received at least one dose 
of the study drug. Analysis of the Safety population will be done according to the 
treatment received (as treated). 
 
13.6 
Safety Analysis 
 
All subjects receiving at least one dose of the study drug will be evaluated for safety 
by monitoring symptoms, physical examinations, and laboratory tests. Adverse 
events will be classified and graded according to the NCI Common Toxicity 
Criteria version 5.0 (see Appendix B). The absolute number and frequency of each 
adverse event will be reported, and subdivided according to toxicity grade. A 
description of adverse events by treatment arm will also be reported. A particular 
adverse event occurring more than once in the same subject will be counted only 
once and at its worse grade. At the end of study, the cumulative incidences of these 
events will be compared between the two treatment groups using Fisher’s exact 
test. 
 
13.4.1 Evaluation of adverse events 
Treatment-emergent adverse events will be translated from investigator terms to 
MedDRA version 22.1 terminology and summarized (number and percentage of 
patients) for all patients who receive at least one dose of the study drug(s). Adverse 
event summaries will be organized by body system, frequency of occurrence, 
intensity (i.e., severity grade), and causality or attribution. Patients who experience 
an adverse event more than once will be counted only once. The occurrence with 
the maximum severity will be used to calculate intensity. 
13.4.2 Evaluation of serious adverse events and premature withdrawals 
Adverse events deemed serious and those resulting in early treatment withdrawal 
or death will be summarized separately. Narrative paragraphs will be generated to 
describe the circumstances surrounding each SAE and each death. 
13.4.3 Evaluation of laboratory parameters and assays 
Abnormal laboratory parameters (e.g. electrolyte levels, liver function tests, renal 
function tests, complete blood counts) will be summarized, and clinically 
significant changes from baseline will be discussed. 
14 
PROTECTION OF HUMAN SUBJECTS 
This study is to be conducted in accordance with applicable government regulations and 
Institutional research policies and procedures. 


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This protocol and any amendments will be submitted to a properly constituted Institutional Review 
Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct. 
The decision of the IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be obtained before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study. The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure. This consent form must be signed 
by the subject or legally acceptable surrogate, as outlined in the IRB approved protocol, and the 
investigator-designated research professional obtaining the consent. 
 
The PI, co-investigators and research nurses will conduct a remote consent discussion with the 
subject. Eligible study participants will be given detailed information about the study purpose, 
procedures, and requirements. The research team will be available to answer all the patients' 
questions adequately before he/she decides to enroll in the study. It will be emphasized to patients 
that enrolling in the study may or may not directly benefit them, nor will choosing not to participate 
affect their treatment or care in any way. Patients will be informed that the information collected 
from their medical records, specimens, and blood samples will be kept confidential. Each patient 
will be assigned a study ID number to which all study information will be linked. Patients will be 
assured that the only document linking their personal identification information to this number will 
be kept in a locked secure location. We will enroll non-English speaking participants. Non-English 
speaking participants will be enrolled in accordance with the CUMC IRB enrollment of non- 
English speaking subjects’ policy. 
 
15. STUDY FINANCES 
 
15.1   Conflict of Interest 
 
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 Columbia University Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved prior to participation in this study. 
All CUMC investigators will follow the University conflict of interest policy. 
 
16 PUBLICATION PLAN 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor. Any investigator 
involved with this study is obligated to provide the sponsor with complete test results and all data 
derived from the study. 


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17 
REFERENCES 
1. 
Arshad Ali S, Baloch M, Ahmed N, Arshad Ali A, Iqbal A. The outbreak of 
Coronavirus Disease 2019 (COVID-19)-An emerging global health threat. J Infect Public Health 
2020. 
2. 
Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19): 
WHO; 2020. 
3. 
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult 
inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020. 
4. 
Li LQ, Huang T, Wang YQ, et al. 2019 novel coronavirus patients' clinical 
characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol 2020. 
5. 
Guan W-j, Ni Z-y, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 
in China. New England Journal of Medicine 2020. 
6. 
Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a 
nationwide analysis in China. Lancet Oncol 2020;21:335-7. 
7. 
Chang YJ, Liu CY, Chiang BL, Chao YC, Chen CC. Induction of IL-8 release in lung 
cells via activator protein-1 by recombinant baculovirus displaying severe acute respiratory 
syndrome-coronavirus spike proteins: identification of two functional regions. J Immunol 
2004;173:7602-14. 
8. 
Han S, Mallampalli RK. The acute respiratory distress syndrome: from mechanism to 
translation. J Immunol 2015;194:855-60. 
9. 
Williams AE, Jose RJ, Mercer PF, et al. Evidence for chemokine synergy during 
neutrophil migration in ARDS. Thorax 2017;72:66-73. 
10. 
Nieto-Torres JL, DeDiego ML, Verdia-Baguena C, et al. Severe acute respiratory 
syndrome coronavirus envelope protein ion channel activity promotes virus fitness and 
pathogenesis. PLoS Pathog 2014;10:e1004077. 
11. 
Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 
and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti- 
inflammatory strategies. J Biol Regul Homeost Agents 2020;34. 
12. 
Lau SKP, Lau CCY, Chan KH, et al. Delayed induction of proinflammatory 
cytokines and suppression of innate antiviral response by the novel Middle East respiratory 
syndrome coronavirus: implications for pathogenesis and treatment. J Gen Virol 2013;94:2679- 
90. 
13. 
Chen IY, Moriyama M, Chang MF, Ichinohe T. Severe Acute Respiratory Syndrome 
Coronavirus Viroporin 3a Activates the NLRP3 Inflammasome. Front Microbiol 2019;10:50. 
14. 
Alosaimi B, Hamed ME, Naeem A, et al. MERS-CoV infection is associated with 
downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated 
inflammatory innate immune response in the lower respiratory tract. Cytokine 2020;126:154895. 
15. 
Liu J, Liu Y, Xiang P, et al. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness 
Patients with 2019 Novel Coronavirus in the Early Stage. medRxiv 2020:2020.02.10.20021584. 
16. 
Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in 
oncology. Biometrics 2005;61:540-5. 
 
 
18 
ATTACHMENTS 


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APPENDIX A: COMMON TOXICITY CRITERIA, VERSION 5.0 
 
Adverse events will be described and graded using the NCI Common Toxicity Criteria (Version 
5.0).A copy of this document can be downloaded from the CTEP website 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). All treatment 
areas must have a copy of this document, or must be able to access a copy. 
 
In general, the grading system can be summarized as follows: 
 
Grade: 
Severity: 
Description: 
Grade 1 
Mild 
Mild; asymptomatic or mild symptom; clinical or diagnostic 
observation only; intervention not indicated. 
Grade 2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL. 
Grade 3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
Grade 4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death 
Death related to an adverse event. 


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APPENDIX B: NATIONAL EARLY WARNING SCORE 2 (NEWS2) 
 
 


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APPENDIX C: KATZ INDEX OF INDEPENDENCE IN ACTIVITIES OF DAILY 
LIVING 
 
 


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APPENDIX D: LAWTON INSTRUMENTAL ACTIVITIES OF DAILY LIVING SCALE 
 
 
 
 
 


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APPENDIX E: CONSENT GUIDANCE 
 
 
CONSENT GUIDANCE 
In light of COVID-19, extra precautions are being taken to ensure the safety of 
patients and staff. 
 
 
CONSENT PROCESS 
• Consent process will begin with a patient being identified. After preliminary 
prescreening is performed and the patient appears potentially eligible, the 
consent form will be given to nurse or provider caring for the patient to give to 
them to read. 
• Paper consent form will NOT be returned 
• All consent discussions will be held over the telephone. 
 
 
 
USE OF LEGALLY AUTHORIZED REPRESENTATIVE 
If it appears to the study physician that a potential subject lacks cognitive capacity 
to understand the ICF, then a physician not associated with the study will be 
consulted. 
 
If the independent consultant agrees, then an appropriate legally authorized 
representative (LAR) will be identified in accordance with CUMC IRB Informed 
Consent Policy (CUIRB Policy, Informed Consent, 26Oct2013, Section 4.F) and 
New York State Law. The LAR will sign the IRB-approved ICF and HIPAA 
authorization in lieu of the subject. 
 
If the potential subject regains capacity during the study in the opinion of both the 
study physician and an independent consulting physician, then the study 
procedures performed to date will be discussed with the subject who will provide 
re-consent before continuing study related procedures per IRB policy. 


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AN EMAIL WITH DOCU SIGN USING #ENCRYPT PHI 
1. A copy of the consent explaining the study will be emailed to the patient or LAR for review. 
2. The patient or LAR will be contacted via phone by an authorized consentor and the consent will 
be explained in detail to the patient or LAR. 
3. The patient or LAR will docu sign the consent which will be returned. Authorized consentor will 
sign and complete ICF checklist 
4. The ICF document will be scanned into the subject’s electronic medical record. 
5. The consent process will be documented by the authorized consentor who will complete the 
CPDM IC Process Checklist. 
AN EMAIL USING #ENCRYPT PHI 
1. A copy of the consent explaining the study will be emailed to the patient or LAR for review. 
2. The patient or LAR will be contacted via phone by an authorized consentor and the consent will 
be explained in detail to the patient or LAR. 
3. The patient or LAR will sign the consent then take a picture and email the picture to the 
authorized consentor. Authorized consentor will print and sign. 
4. The ICF document will be scanned into the subject’s electronic medical record 
5. The consent process will be documented by the authorized consentor who will complete the 
CPDM IC Process Checklist. 
TELEPHONE WITH NO ABILITY TO SIGN 
1. A copy of the consent will be provided to the patient for the patient to review explaining the 
study. 
2. The patient or LAR will be contacted via phone by an authorized consenter and the consent will 
be explained in detail to the patient. 
3. The patient or will provide verbal consent. This will be documented by the authorized consenter 
who will complete the CPDM IC Process Checklist. The following comments will be recorded: 
• Method of consent 
• Time of consent 
• Translator identity if applicable 
4. A signature from the patient or LAR will not be obtained. The authorized consentor will sign the 
consent form and note in the IC checklist that consent was obtained verbally. This document will 
be scanned into the subject’s electronic medical record. 
5. The consent process will be documented by the authorized consentor who will complete the 
CPDM IC Process Checklist. 
METHODS OF CONSENT