Phase 2, Randomized, Double-Blind Placebo Controlled Study of Intravenous Abatacept in the Treatment of Hospitalized COVID-19 Participants With Respiratory Compromise
Phase: PHASE2
Conditions: COVID-19, SARS-CoV-2
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
Phase 2, Randomized, Double-Blind Placebo Controlled Study of Intravenous Abatacept in the 
Treatment of Hospitalized COVID-19 Participants with Respiratory Compromise 
 
NCT Number: NCT04472494 
Document Date (Date in which document was last revised): December 18, 2020  

Page:
1
Protocol Number:
IM101873
Date:
20-May-2020
Revised Date
18-Dec-2020
REGULATORY AGENCY IDENTIFIER NUMBER(S)
IND: 150078
EudraCT: NA
NCT: 04472494
WHO: U1111-1250-4217
EUDAMED: NA
CLINICAL PROTOCOL IM101873
Phase 2, Randomized, Double-Blind Placebo Controlled Study of Intravenous Abatacept in the 
Treatment of Hospitalized COVID-19 Participants with Respiratory Compromise
Protocol Amendment 02
Short Title: Abatacept in the Treatment of COVID-19
Study Director/Medical Monitor
Medical Monitor
24-hr Emergency Telephone Number
USA: 
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
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authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 02
18-Dec-2020
Clarification of language for one inclusion and one 
exclusion criterion to address a recruitment barrier.
Revised Protocol 01
16-Jun-2020
The protocol was revised 
 
. See Summary of Key changes document for details.
Original Protocol
20-May-2020
Not applicable
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 02:
The purpose of this revision is to clarify an inclusion and exclusion criterion, and address minor 
inconsistencies throughout the protocol. The main issue being addressed is the apparent exclusion 
of participants being created by the current exclusion criterion for recent infections. As currently 
written, the exclusion criterion related to recent infection appears anchored on the use of antibiotic,
when the intent was to exclude participants with recent or active, confirmed and serious infections. 
One of the main inclusion criteria is the need to identify an abnormal chest image. As noted in 
Section 9.4.3, this was meant to include several forms of imaging but the language in the inclusion 
criterion limits imaging to chest X-ray only. Both of these criteria have been updated to clarify 
their intent and address apparent recruitment barriers.
Minor editorial, grammatical and typographical revisions are also addressed in this revision. 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 02
Section Number & Title
Description of Change
Brief Rationale
Section 2,
Table 2-1 Screening 
Procedural Outline 
(IM101873)
For Chest imaging procedure -
added computerized 
tomography [CT] and high-
resolution CT [HRCT] in 
addition with chest X-ray. 
Updated to align with 
Section 9.4.3. 
Section 2,
Table 2-4: Post-hospital 
Follow-up for Participants 
discharged home or to 
assisted care facility 
(Remote Contact)
Table note shown below has 
been added:
“Data collection at Day 28 is 
required if the participant is 
discharged from the hospital 
prior to Day 28.”
Table note is added for 
clarification.
Section 6.1 Inclusion 
Criterion 2) Type of 
Participant and Target 
Disease Characteristics
Criterion 2d) has been modified 
with the bold text as shown 
below:
d) Abnormal chest image (ie, 
chest x-ray, computerized 
tomography [CT] or high-
resolution CT [HRCT]) 
consistent with COVID-19 and 
no evidence of any other serious 
medical condition that would 
serve as an exclusionary 
criterion.
Clarifying that any of these 3 
forms of chest imaging are 
sufficient to meet this 
criterion as previously stated 
in Section 9.4.3
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 02
Section Number & Title
Description of Change
Brief Rationale
Section 6.2 Exclusion 
Criteria 1) Medical 
Conditions
Criterion 1b) has been updated 
as shown below: 
b) Participants with confirmed,
clinically serious acute 
infection in the previous 30 
days:
i)
Confirmed is defined as 
culture positive or 
established by any other 
lab-based diagnostic 
testing or imaging.
ii) Clinically serious is 
defined as infection 
involving deep tissues or 
organs (eg, cellulitis, 
upper urinary tract, lower 
respiratory tract).
iii) Exclusion of a highly 
suspected serious 
infection (i.e. not yet 
confirmed) is at the 
discretion of the 
investigator.
Needed to clarify the intent 
of this exclusion. The 
exclusion is for participants
with active and serious 
infections. The use of 
antibiotic therapy as a guide 
to identify these individuals 
has proven problematic 
because it was interpreted 
literally. This clarification 
anchors the exclusion to 
confirmation of the presence 
of infection and its 
seriousness. It limits the 
concern to the previous 30 
days, and overtly states that 
investigators can always 
exclude participants based on 
clinical acumen. 
Section 6.2 Exclusion 
Criteria 1) Medical 
Conditions
Criteria 1i) has been updated 
and wording that participants 
should not be administered a 
live virus vaccine for minimum 
of 3 months following last dose 
of study medication has now 
been removed.
Clarifies live vaccine use 
language.
Section 7.8.2.1 Prohibited 
Treatments
Third bullet has been added as 
listed below:
3) Administration of a live virus 
vaccine within 3 months of 
receipt of study medication.
Clarifies live vaccine use 
language.
Section 9.4.3 Chest 
Imaging
Text within this section has 
been modified. 
Modification is made for 
clarification purposes.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 02
Section Number & Title
Description of Change
Brief Rationale
Section 9.4.4 Vital Signs
Text within this section has 
been modified.
Modification is made to align 
with the vital sign text 
mentioned under
 
Appendix 1 Abbreviations 
and Trademark
Abbreviations list updated
Clarification
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 02: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 02 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.1.1 SARS-CoV-2 and COVID-19 ................................................................... 
 
3.1.2 Abatacept for the treatment of COVID-19 ............................................... 
 
3.1.3 In vitro evidence of abatacept impact on cytokine production by multiple 
cell types...................................................................................................... 
 
3.2 Background ....................................................................................................... 
 
3.2.1 Clinical Evidence for Abatacept Suppression of Cytokine Release 
Syndrome..................................................................................................... 
 
3.2.2 Safety ........................................................................................................ 
 
3.2.2.1 Concerns Over Abatacept Therapy on Viral Clearance and 
Secondary Infections ............................................................................. 
 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Screening Period ...................................................................................... 
 
5.1.2 Double-blind Treatment Period, Days 1 - 28 .......................................... 
 
5.1.3 Post-treatment Follow-up Period, Days 29 - 60 ...................................... 
 
5.1.4 Post-hospitalization ................................................................................. 
 
5.1.5 Safety Oversight Committee ..................................................................... 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.5 Justification for Dose ........................................................................................ 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening ..................................................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.4 Dosage Modification ......................................................................................... 
 
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7.5 Management of Possible Acute Hypersensitivity Reactions to Abatacept ....... 
 
7.6 Preparation/Handling/Storage/Accountability .................................................. 
 
7.6.1 Retained Samples for Bioavailability / Bioequivalence / Biocomparability
..................................................................................................................... 
 
7.7 Treatment Compliance ...................................................................................... 
 
7.8 Concomitant Therapy........................................................................................ 
 
7.8.1 Standard of Care ...................................................................................... 
 
7.8.1.1 Antiviral agents ............................................................................... 
 
7.8.1.2 Immune-based Therapies ................................................................ 
 
7.8.1.3 Antithrombotic Therapies ............................................................... 
 
7.8.1.4 Oxygen Supplementation ................................................................ 
 
7.8.1.5 Rescue Therapy ............................................................................... 
 
7.8.1.6 Other Therapies .............................................................................. 
 
7.8.2 Prohibited and/or Restricted Treatments................................................. 
 
7.8.2.1 Prohibited Treatments .................................................................... 
 
7.8.2.2 Restricted Treatments ..................................................................... 
 
7.9 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Post Study Treatment Study Follow up .................................................... 
 
8.2 Discontinuation from the Study ........................................................................ 
 
8.3 Lost to Follow-Up ............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Primary and Secondary Objectives ......................................................... 
 
9.1.1.1 Prevention of Disease Progression ................................................. 
 
9.1.1.2 Improvement in Clinical Status ....................................................... 
 
9.1.1.3 Improvement in Mortality ............................................................... 
 
9.1.1.4 Absence of Critical Disease ............................................................ 
 
9.1.1.5 Recovery of Pulmonary Function ................................................... 
 
9.1.1.6 Shortened Hospitalization ............................................................... 
 
9.2 Adverse Events ................................................................................................. 
 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
 
9.2.5 Pregnancy ................................................................................................ 
 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
 
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9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
 
9.2.8 Other Safety Considerations .................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 New infections .......................................................................................... 
 
9.4.2 Physical Examinations ............................................................................. 
 
9.4.3 Chest Imaging .......................................................................................... 
 
9.4.4 Vital Signs ................................................................................................ 
 
9.4.5 Tuberculosis Screening ............................................................................ 
 
9.4.6 Clinical Safety Laboratory Assessments .................................................. 
 
9.5 Pharmacokinetics and Immunogenicity Assessments ...................................... 
 
9.5.1 Pharmacokinetic Assessments ................................................................. 
 
9.5.2 Immunogenicity Assessments ................................................................... 
 
9.5.2.1 Immunogenicity: Blood Collection ................................................. 
 
9.5.2.2 Immunogenicity: Sample Analysis .................................................. 
 
9.6 Pharmacodynamics ........................................................................................... 
 
9.7 Pharmacogenomics ........................................................................................... 
 
 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
 
9.10 Study Materials ............................................................................................... 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.2 Safety Analyses....................................................................................... 
 
10.3.4 Interim Analyses ..................................................................................... 
 
11 REFERENCES ........................................................................................................ 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
 
 
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SYNOPSIS
Protocol Title: Phase 2, Randomized, Double-blind, Placebo Controlled Study of Intravenous 
Abatacept in the Treatment of Hospitalized COVID-19 Participants with Respiratory Compromise
Short Title: Abatacept in the Treatment of COVID-19
Study Phase: 2
Rationale:
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel enveloped RNA 
beta-coronavirus that is the etiological agent of coronavirus disease 2019 (COVID-19). While most 
infected individual have mild to no symptoms, around 15% develop a severe pneumonitis 
characterized by fever, cough, shortness of breath, myalgias, and sputum production. Dyspnea 
develops in over half of patients at a median of 8.0 days from illness onset. Older patients and 
those with leukopenia and elevated laboratory markers of systemic inflammation (measured by 
IL-1β, IL-6, and TNF-α levels) are more likely to require ICU care, mechanical ventilation and 
progression to acute respiratory distress syndrome (ARDS). Progression to ICU care with ARDS 
is associated with significant mortality. Abnormal radiographic findings (eg ground glass opacities 
on HRCT) is a common feature of COVID-19 pneumonia patients. Viral clearance coincides with
seroconversion but the role of viral load and the kinetics of viral clearance in the disease process 
is unclear. It is hypothesized that a dysregulated immune response to the infection with excessive 
release of cytokines (cytokine storm) leads to the more severe pulmonary and non-pulmonary 
manifestations of COVID-19. No specific therapy has been established. Use of available anti-viral, 
anti-malarial and immunomodulatory therapies like corticosteroids and tocilizumab are being 
studied.
The FDA has recently proposed an example for scheme for classifying the severity of COVID-19 
disease. This classification is based on positive RT-PCR, symptoms, vital signs and respiratory or 
other organ compromise and ranges from infection with no symptoms to critical disease. 
In this example, severe disease is primarily defined by the inability to maintain an SpO2 > 93% 
on room air at sea level and critical disease by reliance on oxygen supplementation devices with 
greater oxygen delivery capacity than low flow nasal cannula.
Abatacept for the treatment of COVID-19
It is hypothesized that abatacept therapy can modulate the ongoing/emerging dysregulated immune 
response considered to be driving the progression of disease severity in COVID-19. Abatacept is 
not a therapy for neutralizing cytokines but for preventing further cellular activation (eg CD4+ T 
cells, B cells, macrophages) and production of cytokines and interrupting the feedforward 
pathological process.
Study Population:
Adults (≥18 years old) who have a confirmed virological diagnosis of SARS-CoV-2 infection (by 
real-time PCR) and who are hospitalized (or in the ED awaiting hospitalization) with respiratory 
compromise as defined by requirement of oxygen supplementation to maintain oxygen saturation
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≥93% but not requiring mechanical ventilation. Participants should also have abnormal chest 
X-ray consistent with COVID-19 and not indicated other serious medical condition that would 
serve as an exclusionary criteria.
Exclusion criteria includes current recent (within 1 month) treatment with other targeted therapies 
(eg tocilizumab), known secondary infections, or current symptoms of severe, progressive, or 
uncontrolled organ disease not considered related to COVID-19 infection, systemic corticosteroid 
within 2 weeks of randomization at doses above prednisone 10 mg, or other equivalent.
Table 1-1:
Objectives and Endpoints
Objective
Endpoint
Primary
• Prevention of Disease Progression
• Proportion of participants with composite end point 
of mechanical ventilation or death prior to or on Day 
28
Secondary
• Improvement in clinical status
• Change from baseline in the Ordinal 8-point Outcome 
Scale on Day 28
• Improvement in mortality
• All-cause mortality on Day 28
• Absence of critical disease
• Proportion of participants alive and free of respiratory 
failure on Day 28
• Recovery of pulmonary function
• Proportion of participants returned to room air by Day 
28
• Shortened hospitalization
• Proportion of participants alive and discharged home
by Day 28
• Safety
• Proportion of participants with SAEs and serious 
infections
Abbreviations:
 
SAE = serious adverse event; 
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Overall Design:
This will be a randomized, double-blinded, placebo controlled study of IV abatacept for the 
purpose of efficacy and safety signal detection. Participants (≥ 18 years of age) will be those with 
confirmed COVID-19 disease who are hospitalized (or in the Emergency Department awaiting 
hospitalization) with respiratory compromise requiring supplemental oxygen but not requiring 
ventilatory support. Participants will be assessed for clinical responses to abatacept for 28 days 
and monitored for safety and some efficacy outcomes for a total of 60 days.
Figure 1-1:
Study Design Schematic
Screening Period:
Eligibility will be based on specified inclusion and exclusion criteria, medical history, disease 
activity, and safety assessments. Screening and randomization must be completed within 48 hours 
of signing the informed consent form. Screening will include testing for viral hepatitis but the 
decision to randomize will not be based on review of these screening labs. Participants that 
experience a secondary infection, serious medical complication or require mechanical ventilation 
prior to study drug infusion should not receive any study drug infusion but remain in the trial and 
complete all other study procedures.
Double-blind Treatment Period, Days 1 - 28:
On Day 1, eligible participants will be randomized to receive an intravenous (IV) infusion of 
abatacept or placebo. Randomization will be on a 2:1 ratio, abatacept vs placebo, both on standard 
of care.
Participants will receive medical care following local standards. Daily progress will be recorded 
in the study record as required. Participants who, in the opinion of the treating physician, require 
immunotherapy rescue (eg tocilizumab) should continue to complete the treatment period and 
post-treatment follow-up observation.
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Post-treatment Follow-up Period, Days 29-60:
Participants who complete the 28 day Double-blind Treatment Period will be monitored for study 
endpoints and will have follow-up information captured for Days 35, 42, 49 and 60, to perform 
safety and clinical status assessments. If routine safety labs are performed in this period, they 
should also be captured in the study record. Medical care in this period will also follow local 
standards and there will be no restrictions on treatment choices.
Post-hospitalization
Participants who are discharged from hospital care at any point before the end of this 60-day period 
will have remote follow-up visits. Post-hospital care is not considered part of this trial but 
outcomes up to 60 days are of interest. Participants who are discharged, whether home or to any 
form of assisted care facility, will be contacted remotely by the study team (eg phone, e-mail) to 
ascertain clinical status, weekly until Day 60. As a rule, remote contact should be performed 
approximately every 7 days. If the participants is discharged prior to Day 28, one of the remote
contacts should be on Day 28 (± 2 days) to coincide with the study primary endpoint. If discharge 
occurs after Day 28, remote contacts should occur as close as possible to study Days 35, 42, 49, 
and 60, at approximately7 day intervals. Level of activity (ie ambulatory status), oxygen 
requirement (eg home oxygen therapy), current location (eg home) and any intercurrent adverse 
event (eg infection) will be assessed and added to the study record. 
Number of Participants: 129 randomized participants in a 2:1 ratio (abatacept: placebo), both on 
standard of care.
Treatment Arms and Duration:
There will be 2 treatment arms, abatacept plus standard of care versus placebo plus standard of 
care. Both arms will last for 60 days with a primary endpoint at Day 28.
Study treatment:
Abatacept 10 mg/kg IV, reconstitutes in 100 mL of an appropriate diluent and administered over 
30 minutes. The minimum total dose will be 500 mg and the maximum total dose will be 1000 mg. 
Table 1-2:
Study Treatment for Study IM101873
Medication 
Potency
IP/Non-IP
Abatacept 
250 mg/vial
IP
Abbreviations: IP = investigational product; mg = milligram; IV= intravenous.
Note: BMS will provide Abatacept to all investigating sites. 
Safety Oversight Committee: 
Due to the novel design of this study and limitations imposed by the risk of contagion, the study 
will be monitored by a Safety Oversight Committee (SOC). The SOC will assist in the oversight 
of the study execution and ongoing assessment of safety and efficacy. Members will be chosen 
based on clinical expertise in the areas of infectious disease, pulmonary/critical care and 
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immunotherapy (eg rheumatology) or study outcome interpretation. The SOC will be composed 
of BMS personnel, site investigators and external experts. External members will constitute the 
majority of all voting members. The SOC will be provided with periodic data outputs and meet on 
a regular schedule (ie bi-weekly) or ad hoc basis as needed. The first meeting of the SOC will 
review the SOC charter and decide on the frequency of SOC data review meetings before finalizing 
the SOC. In the case that review of subjects grouped by treatment is required to assess changes to 
study conduct, this will be performed by a group of external members in a closed session. Details 
of the membership, meeting schedule, purpose and data access is found in the SOC charter. 
Statistical considerations
A 25% estimated rate of progression under placebo plus standard of care to one of the elements of 
the primary endpoint is derived from available literature. A two group continuity corrected χ2 test 
with a 0.150 one-sided significance level will have 80% power to detect the difference between a 
proportion of 10% abatacept treated participants and a proportion of 25% participants in the 
placebo group with a primary endpoint event (odds ratio of 0.33, ie odds of progression under 
abatacept versus placebo) when the sample sizes are 86 and 43, respectively (a total sample size 
of 129). This computation was made using nQuery Advisor version 7. The target sample size for 
this study is approximately 129 randomized participants.
The comparison between treatment groups of the proportion of participants with primary endpoint 
event (mechanical ventilation or death) prior to or on Day 28 will be performed using the Cochran-
Mantel-Haenszel (CMH) Chi-Square test, stratified by the randomization stratification factors age 
group (<60, ≥60) and remdesivir use as well as baseline severity. Baseline severity will be defined 
by the Clinical Status scale at randomization. A one-sided significance level of 0.15 will be used 
to assess statistical superiority of abatacept over placebo. The population of all randomized 
participants will be used. Randomized participants with no primary endpoint assessment due to 
withdrawal of consent or for other reasons will be imputed as treatment failures (ie. progressors). 
The OR along with its 2-sided 70% CI and 95% CI, as well as the absolute treatment difference in 
proportions with its 95% CI will be presented. The construction of CIs for absolute differences in 
proportions between treatment groups will be based on minimum risk weights to account for 
randomization stratification factors and baseline severity.
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SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (IM101873)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Enroll Participant
X
Contact IRT for subject number. If participant does not meet eligibility criteria, 
contact IRT to screen fail participant.
Inclusion/Exclusion Criteria
X
Confirm hospitalization, positive RT-PCR for SARS-Cov-2
Medical History
X
Safety Assessments
Physical Examination
X
Includes height and weight.
Vital Signs
X
Includes body temperature, respiratory rate, blood pressure and heart rate.
Prior and Concomitant Medication Use
X
Serious Adverse Events Assessment
X
All SAEs must be collected from the date of participant’s informed consent until 
60 days post discontinuation of dosing or subject’s participation in the study if 
the last scheduled visit occurs at a later time.
Smoking History and Current Status
X
Chest imaging
X
Chest X-ray (CXR), computerized tomography (CT) or high resolution 
computerized tomography (HRCT)
Laboratory Testsa
SARS-CoV-2-RT-PCR
X
If not previously performed
Hematology (CBC)
X
Chemistry Panel
X
Pregnancy Test
X
WOCBP only; see Section 9.4.6 Performed locally.
Viral Hepatitis Serology
X
Includes HCV antibody, HBsAg, HBcAb see Section 9.4.6
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Table 2-1:
Screening Procedural Outline (IM101873)
Procedure
Screening
Visit
Notes
Disease Assessments
Pulse oximetry on room air
X
Abbreviations: CBC = complete blood count; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis 
C virus; IRT = Interactive Response Technology; RT-PCR = Reverse-transcription polymerase chain reaction; WOCBP = women of childbearing potential.
a Only the laboratory tests that are readily available at the study site laboratory, will be performed.
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Table 2-2:
On Treatment Schedule of Events
Procedure
Day 1
Days 2 - 28 (daily
unless otherwise 
noted)
Hospital 
Discharge or 
Early 
Terminationa
Notes
Eligibility Assessments
Inclusion/Exclusion Criteria
X
Review of inclusion/exclusion criteria that are relative to 
the Randomization day.
Randomization
X
Weight required
Safety Assessments
Physical Examination
Xb
Targeted Physical Examination
X
X
Vital Signs
X
X
X
Body temperature, blood pressure, respiratory rate, and 
heart rate.
Monitor for Non-Serious Adverse & 
Serious Adverse Events 
Xb
X
X
All SAEs must be collected from the date of 
participant’s informed consent until 60 days post 
discontinuation of dosing or subject’s participation in the 
study if the last scheduled visit occurs at a later time.
Concomitant Medication Use
Xb
X
X
Laboratory Testsc
Chemistry Panel 
Xb
X
X
As ordered based on clinical need; See Section 9.4.6
Hematology (CBC)
Xb
X
X
As ordered based on clinical need;
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Table 2-2:
On Treatment Schedule of Events
Procedure
Day 1
Days 2 - 28 (daily
unless otherwise 
noted)
Hospital 
Discharge or 
Early 
Terminationa
Notes
Efficacy Assessments
Pulse Oximetry
X
X
X
Arterial Blood Gas
X
X
X
Only if required for clinical care
Ordinal 8-point Outcome Scale
X
X
X
See Section 9.1.1.2
Study Treatment
Drug preparation by pharmacist
X
Abatacept/placebo dosing
X
Study Materials
Provide diary card and outpatient 
monitoring equipment to participants (if 
applicable)
X
See section 9.10
Abbreviations: CBC = complete blood count; CXR - chest x-ray; 
a Early Termination only applies for participants who withdraw consent for all study procedures or those who lose ability to consent freely
b Findings at screening can be used if randomization occurs on the same day as screening.
c Only the laboratory tests that are readily available at the study site laboratory, will be performed, see Section 9.4.6.
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Table 2-3:
Post-treatment Follow-up Period for Participants in Hospital
Procedure
Day 35
Day 42
Day 49
Day 60 / Day 
of Hospital 
Discharge /
Early 
Termination
Notes
Safety Assessments
Targeted Physical examination
X
X
X
X
Vital Signs
X
X
X
X
Body temperature, seated blood pressure, 
respiratory rate, and heart rate.
Ordinal 8-point Outcome Scale
X
X
X
X
See Section 9.1.1.2
Concomitant Medication Use
X
X
X
X
Adverse Events Assessment
X
X
X
X
Laboratory Testsa
Hematology (CBC)
X
X
X
X
Only if hospitalized
Chemistry Panel
X
X
X
X
Only if hospitalized; See Section 9.4.6
Efficacy Assessments
Pulse Oximetry
X
X
X
X
Arterial Blood Gas
X
X
X
X
Only while hospitalized and if required for 
clinical care
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Table 2-3:
Post-treatment Follow-up Period for Participants in Hospital
Procedure
Day 35
Day 42
Day 49
Day 60 / Day 
of Hospital 
Discharge /
Early 
Termination
Notes
Study Materials
Provide diary card and outpatient monitoring 
equipment to participants (if applicable)
Xb
See section 9.10
a Only the laboratory tests that are readily available at the study site laboratory, will be performed
b  Only for participants discharged before Day 60
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Table 2-4:
Post-hospital Follow-up for Participants discharged home or to assisted care facility (Remote Contact)
Procedure
Weekly starting 7 days 
after hospital discharge 
until Day 60
Notes
Remote Contact
X
Defined as any form of communication such as phone or e-mail
Vital Signs
X
Body temperature, seated blood pressure, respiratory rate, and heart rate. Only 
collected if the subject has the proper equipment for home use, so respiratory rate 
may not be able to be collected.
Ordinal 8-point Outcome Scale
X
See section 9.1.1.2
Post-discharge condition
X
Level of activity (ie, ambulatory status), oxygen requirements (yes/no, method), 
current location (eg, home, assisted living)
Concomitant Medication Use
X
Adverse Events Assessment
X
Data collection at Day 28 is required if the participant is discharged from the hospital prior to Day 28.
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3
INTRODUCTION
Abatacept is being proposed as a therapy that can modulate an ongoing/emerging dysregulated 
immune response. Abatacept is not a therapy for neutralizing cytokines but for preventing further 
activation and interrupting the feedforward pathological process. One significant unknown is the 
appropriate timing of abatacept treatment. Current evidence suggests that once COVID-19 patients 
develop symptoms of respiratory compromise, their anti-viral responses, including adaptive 
immune responses, are well underway but the pathological process leading to CRS-like scenario 
has not yet initiated. It is proposed that abatacept may interrupt this process without greatly 
interfering with the viral clearance and that any study to be attempted should be aware of these 
goals and concerns.
3.1
Study Rationale
3.1.1
SARS-CoV-2 and COVID-19
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel enveloped RNA 
beta-coronavirus that is the etiological agent of coronavirus disease 2019 (COVID-19). While most 
infected individuals have mild to no symptoms, around 15% develop a severe pneumonitis 
characterized by fever, cough, shortness of breath, myalgias, and sputum production.1 Dyspnea 
develops in over half of patients at a median of 8.0 days from illness onset.2 Older patients and 
those with leukopenia and elevated laboratory markers of systemic inflammation (measured by 
IL-1β, IL-6, and TNF-α levels) are more likely to require ICU care, mechanical ventilation and 
progression to acute respiratory distress syndrome (ARDS). Progression to ICU care with ARDS 
is associated with significant mortality. Abnormal radiographic findings (eg, ground glass 
opacities on HRCT) is a common feature of COVID-19 pneumonia patients. Viral clearance 
coincides with seroconversion but the role of viral load and the kinetics of viral clearance in the 
disease process is unclear. It is hypothesized that a dysregulated immune response to the infection 
with excessive release of cytokines (cytokine storm) leads to the more severe pulmonary and non-
pulmonary manifestations of COVID-19. No specific therapy has been established. Use of 
available anti-viral, anti-malarial and immunomodulatory therapies like corticosteroids and 
tocilizumab are being studied.
The FDA has recently proposed an example for scheme for classifying the severity of COVID-19 
disease.3 This classification is based on positive RT-PCR, symptoms, vital signs and respiratory 
or other organ compromise and ranges from infection with no symptoms to critical disease. 
In this example, severe disease is primarily defined by the inability to maintain an SpO2 > 93% on 
room air at sea level and critical disease by reliance on oxygen supplementation devices with 
greater oxygen delivery capacity than low flow nasal cannula.
3.1.2
Abatacept for the treatment of COVID-19
It is hypothesized that abatacept therapy can modulate the ongoing/emerging dysregulated immune 
response considered to be driving the progression of disease severity in COVID-19. Abatacept is 
not a therapy for neutralizing cytokines but for preventing further cellular activation (eg, CD4+ T 
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cells, B cells, macrophages) and production of cytokines and interrupting the feedforward 
pathological process.
Figure 3.1.2-1:
Cellular interactions affected by abatacept
3.1.3
In vitro evidence of abatacept impact on cytokine production by 
multiple cell types
Abatacept was first studied in the setting of a pathological response to a viral infection in a murine 
model of influenza.4 In this study, abatacept could prevent development of severe lung injury while 
not inhibiting an effective memory antiviral response in the setting of secondary infection. This 
study, along with others, have continued to evolve the understanding of the mechanism of action 
(MOA) of abatacept which has proven to be much more complex than initially envisioned. 
Although CTLA-4 is central to the regulation of T cell activation, CTLA-4Ig clearly has effect on 
other cell types. Since CTLA-4 regulates interactions with T cells and professional antigen 
presenting cells (APC), it is not surprising that effects on APC populations (ie, dendritic cells, 
macrophages, B cells) can also be seen, in vitro and clinically.5 Indeed, in vitro work has 
demonstrated reverse signaling via CD80 or CD86 in APCs although the full impact of this is not 
fully understood.6,7
Treatment with abatacept has also been shown to have broad effects on cytokines in RA patients. 
Abatacept shows an impact within 24 hours in human in vitro mixed-lymphocyte reactions (MLR) 
on IL-2, TNF-a, and IFN-g.6 In vivo, abatacept reduces the levels of multiple cytokines in RA 
patients including TNF-a, sIL-2R and IL-6.8 In addition, abatacept suppresses multiple biomarkers 
(cytokines and chemokines) in the synovium from RA patients.9 What these studies don’t show, 
is which cell type(s) was (were) most impacted.
The best evidence for abatacept’s direct effects on APCs comes from reports on both in vitro and 
in vivo effects on macrophages and B cells. Abatacept inhibits pro-inflammatory cytokine (TNF-
a, IL-12, INF-g) secretion by in vitro activated human macrophages.10 Abatacept can also 
downregulate production of IL-6, TNFα, IL1-β and TGFβ from activated synovial macrophages 
from RA patients.11 B cell populations are notably decreased in RA synovium of abatacept-treated 
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patients.9 Direct effects of abatacept on plasmablasts has also been proposed.12 Together, all of 
this data suggests that abatacept’s impact on the immune system is not limited to T cells. 
Activations of macrophages and B cells are also likely impacted by abatacept therapy.
3.2
Background
Abatacept is a recombinant fusion protein (MW 92 kDa) consisting of the extracellular domain of 
human CTLA4 and a fragment (hinge - CH2 - CH3 domains) of the Fc domain of human 
immunoglobulin (Ig) GI that has been modified to prevent complement fixation and 
antibody-dependent cellular cytotoxicity. Abatacept is a selective costimulation modulator that 
inhibits T-cell activation by binding to CD80 and CD86 on antigen presenting cells, thereby 
blocking the interaction with CD28 on T-cells that provides a costimulatory signal necessary for 
full activation of T-cells. By inhibiting CD28 mediated T-cell activation upstream of inflammatory 
cytokines, such as TNF, abatacept utilizes a unique mechanism of action that offers significant 
therapeutic benefit to patients with a variety autoimmune-mediated diseases.13 Abatacept, 250 mg 
for intravenous (IV) infusion, is indicated to treat subjects with rheumatoid arthritis (RA) age 18 
and older and subjects with polyarticular juvenile idiopathic arthritis (pJIA) age 6 to 17.14
IV-administered abatacept was first approved in the US for the treatment of moderate-to-severe 
RA in adults in December 2005. Since then, IV abatacept has received marketing approval for the 
treatment of adult RA in many other countries, including the EU, Canada, Australia, and Japan. 
IV abatacept was also approved in the US for the treatment of moderately-to-severely active 
juvenile idiopathic arthritis (JIA) in pediatric patients 6 years of age or older in April 2008. In 
addition, IV abatacept has received marketing approval for the treatment of JIA in several other 
countries, including the EU, Canada, and Australia. In 2017, abatacept was approved for adult use 
in psoriatic arthritis (PsA) in the US and has also received marketing approval for the treatment of 
PsA in several other countries, including the EU, Canada, and Australia. A subcutaneous (SC) 
formulation of abatacept in a prefilled syringe and autoinjector has been approved for adult RA 
and PsA patients in the US, EU, and several other countries; it is also approved in the US and EU 
for use in JIA.
A detailed description of the chemistry, pharmacology, efficacy, and safety of abatacept is 
provided in the Investigator’s Brochure (IB).15,16
3.2.1
Clinical Evidence for Abatacept Suppression of Cytokine Release 
Syndrome
There is some clinical data to inform the impact on cytokine release syndrome (CRS). Patients 
with active systemic JIA, some with current macrophage activation syndrome (MAS), who were 
heavily treated with multiple agents, including high dose corticosteroids and anakinra, responded 
to the addition of abatacept. The time course for the benefit of abatacept is not well described but 
the ability to decrease doses or suspend some concomitant therapy is reported. 
A subject with active immune checkpoint inhibitor-associated myocarditis did demonstrate clinical 
and biochemical improvement within a day of initiating abatacept therapy.17 This clinical course 
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has been seen in other similar patients treated with abatacept (personal communication of 
unpublished data).
The strongest evidence for rapid onset of abatacept and its effect on CRS is from prevention, not 
treatment. Use of peripheral blood stem cells (PBSC) for post-transplantation cyclophosphamide 
(PTCy)-based haploidentical hematopoietic cell transplantation (HCT) is associated with early 
CRS in over 92% of patients (14% severe CRS).18 Treatment with abatacept 1 day before the 
infusion of the PBSC graft (followed by dosing on day +5, +20, +35 and every four weeks 
thereafter decreased the rate of CRS to 6% (none severe). The continued use of abatacept is 
because of ongoing donor lymphocyte infusions, which are therapeutic in this context and also 
believed to be the source of the CRS process. 
In a related clinical setting, abatacept has been studied for acute graft-versus-host disease 
(aGVHD) prevention during unrelated-donor hematopoietic cell transplantation (HCT), in both 
HLA matched (8/8) and 7/8 mismatched patients.19,20 Patients who receive mismatched, unrelated
donor HCT are at elevated risk of severe aGVHD and death. Abatacept treatment at days -1, +5, 
+14, and +28 almost completely suppresses severe (Grade III-IV) aGVHD without negative 
impact on relapse and without significant impact on patient safety. CMV reactivation, but not 
EBV, was seen more frequently (47% vs 33%, p=0.16) but uncontrolled infections were not a 
major problem.
The relevance of these reports are that they illustrate the rapid effects of abatacept on feedforward 
mechanisms that produce CRS. They also suggest that the onset of abatacept’s therapeutic effects 
can be sufficiently rapid as to be clinically relevant in the setting of COVID-19.
3.2.2
Safety
The safety profile of abatacept is well established based on the safety data collected from a number 
of clinical studies and 14-year post-marketing experience during the treatment of 
autoimmune/inflammatory diseases; abatacept has been well-tolerated and shown a favorable 
benefit-risk profile in the approved disease population (ie, RA, PsA, pJIA).
Infections and infusion related reactions (for IV formulation) are identified risks for abatacept, 
majority of these events are non-serious and do not impact benefit/risk profile of the product. For 
infections, during the double-blind, placebo-controlled period of RA studies (9 IV studies and 2 
SC studies in the integrated safety database), the incidence rate of overall infections was 
comparable between abatacept group (total of 2,653 subjects with mean exposure duration of 10.8 
months ) and placebo group (total of 1,485 subjects with mean exposure duration of 10.3 months): 
93.21 versus 93.02 per 100 patient-years; a small increase for IR of overall serious infections in 
abatacept group compared to placebo group (3.0 vs 2.25 per 100 patient-years). Majority of the 
infections were caused by common pathogens; the most commonly reported PTs of infections were 
upper respiratory tract infection (IR 14.3 per 100 patient-years) and nasopharyngitis (IR 14.3 per 
100 patient-years); the most frequently reported serious infection was pneumonia (IR 0.68 per 100 
patient-years) in abatacept group, which was comparable to that in placebo group (IR 0.72 per 100 
patient-years). The IR of opportunistic infections appeared to be numerically lower in abatacept 
group compared to placebo (0.17 vs 0.56 per 100 patient years). For the infusion related reactions 
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occurred in IV abatacept studies, most of the peri-infusional events that occurred within 24 hours 
following the start of infusion were non-serious dizziness and nausea; serious events of 
hypersensitivity/anaphylactic reactions were rare. Safety experience from clinical studies in PsA 
and pJIA patients was similar to that in RA studies. Ten-year post-marketing epidemiology studies 
in RA population did not reveal any new safety finding relevant to these two identified risks.  
Malignancies and autoimmune disorders have been reported with abatacept use; however, the 
clinical and post-marketing data do not show an increased risk of these events associated with 
abatacept use, therefore, the potential role of abatacept in the development of these diseases cannot 
be concluded based on the available evidence.    
3.2.2.1
Concerns Over Abatacept Therapy on Viral Clearance and Secondary 
Infections
The potential deleterious impact of abatacept on viral clearance is certainly a concern that we 
recognize. The previously discussed 
murine 
model of 
influenza 
infection-induced 
immunopathology clearly demonstrates the risk of blunting anti-viral responses in abatacept-
treated mice prior to viral exposure.4 These concerns are not new. Throughout the abatacept 
clinical development program, concerns over the impact of therapy on infectious agents has been 
paramount. 
During pre-clinical abatacept development, host resistance models of infection were explored.13,21
Of note, negative impacts on immune responses were only noted for herpes simplex infections. 
The observation that abatacept partially inhibits the generation of CD8 cytotoxic T cell (CTL) 
responses but does not inhibit CD8 T cell cytotoxic activity has been reported, which could also 
predict deleterious impact on viral responses.22,23
In spite of these pre-clinical observations, clinical observations, both from controlled trials and 
post marketing surveillance, have been of less concern. A review of safety data of viral infections 
from an integrated safety database of RA clinical studies (includes 7044 participants receiving IV 
or SC abatacept for a total exposure of 21994.84 patient years during the cumulative period 
(controlled plus long-term open-label)), reveals the following: 
1. During the randomized placebo-controlled double-blind short-term period of the studies, 
the most frequently (>1.0%) reported PTs of viral infections and infections that could be 
caused by virus in the ABA group vs. placebo group, respectively, were upper respiratory 
tract infection (11.9% vs 12.1%), nasopharyngitis (11.8% vs 10%), bronchitis (6.5% vs 
5.8%), influenza (5.8% vs 5.9%), pharyngitis (3.5% vs 3.3%), rhinitis (2.4% vs 1.3%), 
conjunctivitis (2.1% vs 1.5%), gastroenteritis (2.0% vs 3.0%), oral herpes (1.8% vs 1.3%), 
herpes zoster (1.5% vs 1.4%), pneumonia (1.8% vs 1.1%). The majority of these events 
were mild or moderate in severity and abatacept use did not cause increased severity of 
infections compared to placebo.
2. During the DB ST period of the studies, the most frequently reported PTs (≥ 2 cases) of 
serious viral infections and infections that could be caused by virus in the ABA group and 
placebo group were pneumonia (0.6% vs 0.6%), bronchitis (0.2% vs 0), gastroenteritis 
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(0.1% vs 0.1%) and herpes zoster (0.1% vs 0). Among these events, death outcomes were 
reported for pneumonia and the IRs for fatal pneumonia were 0.08 vs 0.16 per 100 patient-
years for abatacept and placebo, respectively.
3. There were no increases for the incident rates of serious infections reported during 
cumulative period compared to those reported in short-term period.
Of note is the absence of an imbalance in viral pneumonias, specifically influenza. Also, the 
median event duration for influenza was similar between abatacept treated patients and placebo 
group. Antibody responses to the conventional seasonal influenza vaccine in abatacept treated RA 
patients were also studied.24 The study demonstrated that most participants on abatacept were able 
to mount an appropriate immune response. While this study did not demonstrate impact on actual 
influenza rates, it does support the extensive clinical observation that abatacept therapy may not 
influence anti-influenza responses in a clinically meaningful way.
Review of the post-marketing safety experience (estimated exposure at 763,109 p-y as of 
30-Sep-2019 in over more than 13 years) identified 21 cases of coronavirus infection by 13-Apr-
2020; events of confirmed COVID-19 or suspected COVID-19 were reported in 13 of these cases. 
The majority of these cases contained minimal information and robust assessment of the impact of 
abatacept on COVID-19 is not possible. One literature report from Japan reported possible 
COVID-19 in a 
 received abatacept and tacrolimus to treat RA and interstitial 
lung disease (ILD). The patient developed respiratory compromise and ultimately required 
ventilatory support. Testing of sputum but not other sources was positive for SAR-CoV-2. A recent 
published letter describes 8 patients being treated with targeted therapies for chronic arthritis in 
Italy. Among them were 2 patients receiving therapy with abatacept, 1 with confirmed and one 
with suspected SARS-CoV-2 infection. Only 1 of the patients required hospitalization, and then 
only briefly for oxygen therapy and all recovered without incident.25 Belatacept is a related drug 
to abatacept with a similar mechanism of action. In a recent report,26 a 
 kidney 
transplant patient on belatacept and MMF became infected with SARS-CoV-2 and had a mild 
clinical course with rapid recovery. The authors hypothesized that ongoing immunotherapy with 
belatacept 
may 
protect 
from 
severe 
clinical 
course 
of 
COVID-19 
by 
limiting 
cytokines/chemokines production.
The abatacept label has a warning for risk of serious infections, including fatal sepsis and 
pneumonia. The clear risk for abatacept use is in bacterial infections, mostly of the respiratory and 
urinary tract. This includes a higher rate of complications in patients with COPD. The abatacept 
label also warns about treatment initiation in patients with an active infection until the infection is 
controlled. Of note, extensive experience in the use of abatacept to treat RA in elderly patients 
with co-morbidities has been reported.27 This suggests that among biologic DMARD therapies, 
abatacept may have less risk of infections.28,29,30
Based on the review of safety data relevant to viral infections from clinical studies and post 
marketing experience, there is no evidence suggesting increased risk of severe respiratory illnesses 
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associated with abatacept use. Current evidence suggests that once COVID-19 patients develop 
symptoms of respiratory compromise, their anti-viral responses, including adaptive immune 
responses, are well underway but the pathological process leading to CRS-like scenario has only 
just begun. It is proposed that abatacept may interrupt this process without greatly interfering with 
the viral clearance and that any study to be attempted should be aware of these goals and concerns.
The viral clearance and COVID-19 progression during abatacept use will be closely monitored
during the study.
3.3
Benefit/Risk Assessment
Current evidence indicates that once COVID-19 patients develop symptoms of respiratory 
compromise, their anti-viral responses, including adaptive immune responses, are well underway 
but the pathological process leading to CRS-like scenario has only just begun. The Sponsor
proposes that abatacept may interrupt this process without greatly interfering with the viral 
clearance. 
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Preclinical work indicates that abatacept can suppress or control cytokine production, including 
clinical scenarios consistent with cytokine release syndrome. Clinical work in multiple complex 
disease states also suggest abatacept therapy can suppress or help manage excessive cytokine 
production.
Abatacept has been studied in human clinical trials for over 15 years. Most patients studied have 
chronic, immune mediated diseases with use of concomitant immunosuppressant therapies and co-
morbid conditions. The most notable risk for abatacept use is increased risk of bacterial infections, 
particularly of the respiratory and urinary tract. Based on the review of safety data relevant to viral 
infections from clinical studies and post marketing experience, there is no evidence suggesting 
increased risk of viral respiratory illnesses, severe or otherwise, associated with abatacept use.
The study of the therapeutic potential of abatacept in symptomatic patients with COVID-19 at high 
risk for progression to respiratory failure is warranted. Concerns over the negative impact on viral 
clearance or secondary bacterial infections are appropriate. These concerns are mitigated by the 
relatively short course of treatment in the setting of hospitalized monitoring and care, monitoring 
of viral clearance during the study and an oversight by a Safety Oversight Committee (SOC).
More detailed information about the known and expected benefits and risks and reasonably 
anticipated adverse events (AEs) of abatacept may be found in the [Investigator’s Brochure.15,16
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objective
Endpoint
Primary
• Prevention of Disease Progression
• Proportion of participants with composite end point 
of mechanical ventilation or death prior to or on Day 
28
Secondary
• Improvement in clinical status
• Change from baseline in the Ordinal 8-point Outcome 
Scale on Day 28
• Improvement in mortality
• All-cause mortality on Day 28
• Absence of critical disease
• Proportion of participants alive and free of respiratory 
failure on Day 28
• Recovery of pulmonary function
• Proportion of participants returned to room air by Day 
28
• Shortened hospitalization
• Proportion of participants alive and discharged home 
by Day 28
• Safety
• Proportion of participants with SAEs and serious 
infections
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Table 4-1:
Objectives and Endpoints
Abbreviations:
 
SAE = serious adverse event; 
5
STUDY DESIGN
5.1
Overall Design
This is a randomized, double-blinded, placebo controlled study of IV abatacept for the purpose of 
efficacy and safety signal detection. Participants (≥18 years of age) will be those with confirmed 
COVID-19 disease who are hospitalized (or in the ED awaiting hospitalization) with respiratory 
compromise requiring supplemental oxygen but not requiring ventilatory support. This protocol 
will provide guidance for standard medical care but not make specific recommendations for 
treatment, given the dynamic nature of evolving clinical care of COVID-19. Participants will be 
assessed for clinical responses to abatacept for 28 days and monitored for safety and some efficacy 
outcomes for a total of 60 days. If the decision is made to treat the participant with a restricted 
immunomodulatory therapy (eg, anti-IL-6) after treatment with study drug, the subject should not 
be discontinued from the study. Rather, they should be followed for the full 60-day observation 
period.
Participants may be discharged from hospital care at any point before the end of this 60-day period. 
Post-hospital care is not considered part of this trial but outcomes up to 60 days are of interest.
Participants who are discharged, whether home or to another location like an assisted care facility, 
will be contacted remotely by the study team to ascertain clinical status periodically. Level of 
activity (ie, ambulatory status), oxygen requirements (eg, oxygen therapy), current location (eg,
home) and any intercurrent adverse event (eg, infection) will be assessed and captured in the study 
record.
Due to constraints imposed as part of infectious control measures for hospitalized patients and 
personnel during the COVID-19 pandemic, access to the participant and samples obtained from 
the participant will be more limited. Required study procedures and laboratory assessments have 
been limited to those considered necessary. Routine clinical care decisions, eg, changes to oxygen 
supplementation, and safety laboratory monitoring will be at the discretion of the clinical team but 
will be captured in the study record. The core principal of this study protocol is to identify suitable 
study participants, and to describe the therapeutic intervention and the key measures (eg,
oxygenation, safety labs) that are part of routine care to be captured in the study record for analysis.
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The study will include 129 randomized participants in a 2:1 ratio, abatacept: placebo, both on 
standard of care.
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
5.1.1
Screening Period
Eligibility will be based on specified inclusion and exclusion criteria, medical history, disease 
activity, and safety assessments. Screening and randomization must be completed within 48 hours 
of signing the informed consent form. Screening will include testing for viral hepatitis but the 
decision to randomize will not be based on review of these screening labs (See Section 9.4.4). 
Participants that experience a secondary infection, serious medical complication or require 
mechanical ventilation prior to study drug infusion should not receive any study drug infusion but 
remain in the trial and complete all other study procedures.
5.1.2
Double-blind Treatment Period, Days 1 - 28
On Day 1, eligible participants will be randomized to receive an intravenous (IV) infusion of 
abatacept or placebo. Randomization will be on a 2:1 ratio, abatacept vs placebo, both with 
standard of care.
Participants will receive medical care following local standards (see Section 7.8.1). Daily progress 
will be recorded in the study record as required. Participants who, in the opinion of the treating 
physician, require immunotherapy rescue (eg, tocilizumab) should continue to complete treatment 
period and post-treatment follow-up observation.
5.1.3
Post-treatment Follow-up Period, Days 29 - 60
Participants who complete the 28 day Double-blind Treatment Period will be monitored for study 
endpoints and will have follow-up information captured for Days 35, 42, 49 and 60, to perform 
safety and clinical status assessments. If routine safety labs are performed in this period, they 
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should also be captured in the study record. Medical care in this period will also follow local 
standards and there will be no restrictions on treatment choices. (See Table 2-3).
5.1.4
Post-hospitalization
Participants who are discharged from hospital care at any point before the end of this 60-day period 
will have remote follow-up visits. Post-hospital care is not considered part of this trial but 
outcomes up to 60 days are of interest. Participants who are discharged, whether home or to any 
form of assisted care facility, will be contacted remotely by the study team (eg, phone, e-mail) to 
ascertain clinical status, weekly until Day 60. As a rule, remote contact should be performed 
approximately every 7 days. If the subject is discharged prior to Day 28, one of the remote contacts 
should be on Day 28 (± 2 days) to coincide with the study primary endpoint. If discharge occurs 
after Day 28, remote contacts should occur as close as possible to study Days 35, 42, 49 and 60, 
at approximately 7 day interval. Level of activity (ie, ambulatory status), oxygen requirement (eg,
home oxygen therapy), current location (eg, home) and any intercurrent adverse event (eg,
infection) will be assessed and added to the study record. (See Table 2-4)
5.1.5
Safety Oversight Committee
Due to the novel design of this study and limitations imposed by the risk of contagion, the study 
will be monitored by a Safety Oversight Committee (SOC). The SOC will assist in the oversight 
of the study execution and ongoing assessment of safety and efficacy. Members will be chosen 
based on clinical expertise in the areas of infectious disease, pulmonary/critical care and 
immunotherapy (eg, rheumatology) or study outcome interpretation. The SOC will be composed 
of BMS personnel, site investigators and external experts. External members will constitute the 
majority of all voting members. The SOC will be provided with periodic data outputs and meet on 
a regular schedule (ie, bi-weekly) or ad hoc basis as needed. The first meeting of the SOC will 
review the SOC charter and decide on the frequency of SOC data review meetings before finalizing 
the SOC. In the case that review of subjects grouped by treatment is required to assess changes to 
study conduct, this will be performed by a group of external members in a closed session. Details 
of the membership, meeting schedule, purpose and data access is found in the SOC charter.
5.2
Number of Participants
One hundred and twenty nine (129) participants will be randomized.
5.3
End of Study Definition
The start of the study is defined as the first visit for the first participant screened. End of study is 
defined as last visit or scheduled procedure shown in Section 2 (Schedule of Activities) for the last 
participant. Study completion is defined as the final date on which data for the primary endpoint 
was or is expected to be collected, if this is not the same.
5.4
Scientific Rationale for Study Design
The goal of this Phase 2 study is to establish evidence for the efficacy and safety of the use of 
abatacept IV to prevent participants hospitalized with COVID-19, with respiratory compromise 
and evidence of immune activation, from progressing in severity. To do so, we have chosen to 
execute a blinded, placebo controlled, randomized study design. The main safety concern is the 
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possibility of a negative impact on viral clearance with clinical impact or an increase in the risk of 
secondary bacterial infection. Because of the unprecedented level of infectious risk in the general 
population, including hospital staff, usual study procedures and monitoring are not feasible.35 The 
study has to be streamlined for ease and speed of execution. While a lot has been reported to infer 
the clinical course for COVID-19 patients, there are still many unknowns including the efficacy 
of all currently used disease specific effective therapies. Interpretation of open-label treatment 
experience in the setting of an ongoing potentially lethal pandemic is fraught with challenges.36
The potential differential patient care and use of concomitant medication in an open-label setting
will be confounded with the treatment effect. Only a blinded, randomized study can reliably 
provide information for interpretation but this presents other complex bioethical concerns and 
challenges. In a blinded study the impact on clinical decision for off-label use of other available 
immunotherapies would be the same in both treatment arms. This study design will partly mitigate 
the above concerns by adopting a randomization ratio favoring active treatment (ie, 2:1), allowing
background therapy, utilizing a safety oversight committee to assess safety, and a sample size with 
robust power but with a higher level of significance in order to increase the speed to a larger, 
definite study if a positive signal is detected.
5.5
Justification for Dose
Abatacept is available in 2 formulations, lyophilized for intravenous infusion and pre-filled syringe 
for subcutaneous injection. Pharmacokinetic evaluation over 2 decades of clinical development 
has shown that the most relevant PK parameter are trough (Cmin) levels which are best at 
predicting maximal efficacy and are driven by weight based dosing. Superior efficacy is observed 
with 10 mg/kg dosing in RA patients. Dosing frequency of Day 1, 15, 28 and every 28 days 
afterwards was established as an efficacious dosing regimen for reaching target Cmin levels.
Evidence based on pharmacokinetic, pharmacodynamic and clinical efficacy data suggest that 
higher doses of abatacept would not be more effective in RA patients. Higher doses of abatacept 
at 30 mg/kg have been tested in BMS sponsored trials. In patients with PsA, higher doses did not 
produce better efficacy but did not result in any increase in safety signal. In inflammatory bowel 
disease, no clinical efficacy was seen. In lupus nephritis, higher doses were thought needed due to 
urinary losses of abatacept due to the severe proteinuria unique to this disease. None of these 
studies suggested higher abatacept doses were associated with increased safety concerns. 
More frequent dosing and higher doses of abatacept have been used empirically in many settings. 
While BMS is aware that this happens on occasion in the clinical practice for the care of RA 
patients, it happens most notably in the off-label treatment of other disease states. Children with 
active, refractory systemic onset JIA have been treated with empirical doses of up to 18 mg/kg 
every 3 weeks.37 Common variable immunodeficiency (CVID) is a group of genetically defined 
conditions characterized by immune dysregulation and immunodeficiency, many of which are 
characterized by CTLA-4 deficiency or impaired expression.38 Successful treatment with 
abatacept has been reported extensively with infusion as high as 20 mg/kg every 2 weeks.39,40
Immune checkpoint inhibitor associated myocarditis is a rapidly progressive adverse event with 
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high morbidity and mortality. Abatacept has been used successfully to reverse this process in 
refractory cases using weekly IV doses of 500 mg or higher.17
The largest experience with alternative abatacept dosing regimens comes from the study of acute 
graft-versus-host disease (aGVHD) prevention investigator initiated program.19,20 In this setting, 
abatacept was given at 10 mg/kg on days -1, +5, +14, and +28. Preliminary PK analysis shows 
Cmins above 40 mg/mL, which is well above the Cmin known to show optimal efficacy for RA 
patients.41
There is not enough information available to suggest that an alternative to the approved IV dose is 
required in the setting of COVID-19 but there is empirical evidence that higher doses (either on a 
per weight basis or frequency) may be beneficial and not carry untoward risk. Given the nature of 
the clinical course, it is likely that a single abatacept dose of 10 mg/kg will be sufficient for clinical 
effect since supratherapeutic drug levels will be achieved for all study participants for at least 3 
weeks.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participant is willing to participate in the study and has signed the Informed Consent Form 
(ICF).
2) Type of Participant and Target Disease Characteristics
a) Adults with a confirmed virological diagnosis of SARS-CoV-2 infection (by RT-PCR). 
Any positive test, at either the time of or prior to hospitalization, is suitable. Results must 
be documented.
b) Hospitalized (or in the Emergency Department awaiting a bed after hospitalization)
c) Respiratory compromise as defined by requirement of oxygen supplementation to maintain 
oxygen saturation ≥93% but not requiring mechanical ventilation.
d) Abnormal chest image (ie, chest X-ray, computerized tomography [CT] or high-resolution 
CT [HRCT]) consistent with COVID-19 and no evidence of any other serious medical 
condition that would serve as an exclusionary criterion.
3) Age and Reproductive Status
Investigators shall counsel women of childbearing potential (WOCBP) participants, and male 
participants who are sexually active with WOCBP, on the importance of pregnancy prevention 
and the implications of an unexpected pregnancy.
•
The investigator shall evaluate the effectiveness of the contraceptive method in relationship to 
the first dose of study intervention.
•
Local laws and regulations may require the use of alternative and/or additional contraception 
methods.
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a) Female Participants 
i)
Females, ages ≥ 18 years or local age of majority 
ii) Women who are not of childbearing potential are exempt from contraceptive 
requirements
iii) Women participants must have documented proof that they are not of childbearing 
potential.
iv) WOCBP must have a negative highly sensitive urine/serum pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) performed during screening prior to 
the start of study treatment.
(1) If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive
v) The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy
vi) WOCBP must agree to follow instructions for method(s) of contraception defined in 
Appendix 4 and as described below and included in the ICF.
vii)WOCBP are permitted to use hormonal contraception methods (as described in 
Appendix 4)
viii)
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:
(1) Is not a WOCBP 
OR
(2) Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as described in 
Appendix 4 during the intervention period and for at least 70 days and agrees not 
to donate eggs (ova, oocytes) for the purpose of reproduction for the same time 
period
b) Male Participants 
i)
Males, ages ≥ 18 years or local age of majority
ii) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception defined in Appendix 4 and as described below.
iii) Azoospermic males are exempt from contraceptive requirements.
iv) No additional contraceptive measures are required to be used
6.2
Exclusion Criteria
1) Medical Conditions
a) Woman who are breastfeeding
b) Participants with confirmed, clinically serious acute infection in the previous 30 days:
i)
Confirmed is defined as culture positive or established by any other lab-based 
diagnostic testing or imaging.
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ii) Clinically serious is defined as infection involving deep tissues or organs (eg, cellulitis, 
upper urinary tract, lower respiratory tract).
iii) Exclusion of a highly suspected serious infection (ie, not yet confirmed) is at the 
discretion of the investigator.
c) Participants with history of chronic or recurrent bacterial infection (eg, chronic 
pyelonephritis, osteomyelitis, bronchiectasis).
d) Medical history of known or suspected active or latent tuberculosis (TB), active hepatitis 
B, hepatitis C or HIV infection.
e) TB risk will be further ascertained by review of history and most recent CXR.
f)
Hepatitis B virus (HBV) testing will be ordered (surface antigen and core antibody). If 
either is positive, reflex testing for HBV DNA by PCR will be obtained. 
g) Hepatitis C virus (HCV) testing will be ordered (HCV antibody). If positive, reflex testing 
for HCV RNA by PCR will be obtained. 
h) Current clinical findings of severe, progressive, or uncontrolled renal, hepatic, 
hematological, gastrointestinal, pulmonary, psychiatric, cardiac, endocrine, neurological, 
or cerebral disease, including severe and uncontrolled infections, such as sepsis and 
opportunistic infections (except COVID-19). Caution should be used when randomizing 
participants with severe COPD or frequent COPD exacerbations. Concomitant medical 
conditions that, in the opinion of the Investigator, might place the participant at 
unacceptable risk for participation in this study.
i)
Participants who have received any live vaccines within 3 months of the study drug 
administration or are scheduled to receive live vaccines during the study. Participants who 
are in close contact with others who have received a live vaccine may be enrolled at the 
Investigator’s discretion.
j)
Participants with a history of (within 12 months of signing the ICF), or known current 
problems with drug or alcohol abuse history or known cirrhosis, including alcoholic 
cirrhosis.
k) Participants who are impaired, incapacitated, or incapable of completing study related 
assessments.
2) Prior/Concomitant Therapy
a) Participants who have been exposed within 1 month or five half-lives, whichever is longer, 
to any treatment with an approved or investigational targeted immunotherapy including, 
but not limited to, infliximab, etanercept, anakinra, rituximab, tocilizumab, golimumab, 
certolizumab, sirolumab, tofacitinib, baricitinib, upadacitinib, or filgotinib.
b) Systemic corticosteroid within 2 weeks of randomization at doses above prednisone 10 mg, 
or other equivalent. 
c) Prior exposure to BMS-188667 (abatacept).
3) Physical and Laboratory Test Findings
a) Hemoglobin (Hgb) < 8.5 g/dL.
b) White Blood Count (WBC) < 3,000/mm3 (3× 109/L).
c) Platelets < 75,000/mm3 (100× 109/L).
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d) Serum creatinine > 2× ULN.
e) Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5× ULN.
f)
Any test results that, in the opinion of the Investigator, might place the participants at 
unacceptable risk for participation in this study.
4) Allergies and Adverse Drug Reaction
a) Hypersensitivity to the IP and/or its excipients
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances and only in countries where local regulations permit, a person who has been 
imprisoned may be included or permitted to continue as a participant. Strict conditions 
apply and Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, as applicable, and to respond to queries from regulatory authorities. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and 
any serious AEs.
6.4.1
Retesting During Screening
Retesting of laboratory parameters and/or other assessments within the Screening period will be 
permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Rescreening is not allowed.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation.
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Study 
treatment
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) as shown in Table 7-1. 
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
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Table 7-1:
Study treatments for IM101873
Product Description / 
Class and Dosage 
Form
Potency
IP/Non-IMP
Open Label
Packaging / 
Appearance
Storage Conditions
(per label)
Abatacept for injection
250 mg/ vial
IP
Open Label
Vial / White to off-
white, whole or 
fragmented cake in a 
vial.
Refer to the label on the 
container
Abbreviations: IP = investigational product
Note: BMS will provide Abatacept to all investigating sites. 
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7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
Abatacept
10 mg/kg
Day 1
IV
Placebo
Normal saline or
5% Dextrose in watera
Day 1
IV
Abbreviations: IV = intravenous; kg = kilogram; mg = milligram
a Normal Saline or 5% Dextrose in water will be provided by the investigational site
Each investigator will be responsible for supplying any intravenous administrative solutions 
[Sterile Water for Injection (SWFI), 5% Dextrose in Water Injection (D5W), 0.9% Sodium 
Chloride Injection (NS)] needed for the reconstitution and dilution of investigational product 
identified in the protocol. D5W and NS will act as the intravenous placebo for this study. Handling 
and dispensing instructions will be provided separately to the unblinded pharmacist.
The dose of abatacept will be 10 mg/kg with a maximum dose of 1000 mg. Study medication will 
be administered in a fixed volume of 100 mL at a constant infusion rate over approximately 
30 minutes. The IV line must be flushed with 25 mL of D5W or NS solution at the end of the 
infusion. 
The administration window will be within 24 hours of randomization.
7.2
Method of Treatment Assignment
All participants will be randomized using an Interactive Response Technology (IRT). Before the 
study is initiated, each user will receive log in information and directions on how to access the 
IRT.
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
Participants will be randomized to receive either abatacept or placebo according to a computer-
generated randomization scheme prepared by a Randomization Coordinator within the Drug 
Supply Management Department of BMS Research and Development. 
Enrolled participants, including those not dosed, will be assigned sequential participant numbers 
starting with 00001, (eg, 00001, 00002, 00003.... 00010). 
During the screening visit, the investigative site will call into the enrollment option of the 
Interactive Response Technology (IRT) designated by BMS for assignment of a 5-digit participant
number that will be unique across the study. Enrolled participants, including those not dosed, will 
be assigned sequential participant numbers starting with 00001, (eg, 00001, 00002, 00003.... 
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00010). The patient identification number (PID) will ultimately be comprised of the site number 
and participant number. For example, the first participant screened (ie, enrolled) at site number 1, 
will have a PID of 0001 00001. Once it is determined that the participant meets the eligibility 
criteria following the screening visit, the investigative site will call the IRT to randomize the 
participant into the double-blind panel. Participants meeting all eligibility criteria will be 
randomized in a 2:1 ratio to treatment arms. The randomization schedule will be generated using 
permuted blocks of fixed size within each stratum, defined by age group and remdesivir use. Once 
enrolled in IRT, enrolled participants will be randomized through the IRT prior to the start of study 
treatment. At randomization the participants will be stratified according to age group at 
randomization (< 60 vs ≥60) and by remdesivir Use (Yes [RemYes] vs No [RemNo]). Remdesivir 
Use = Yes, will be defined as a subject having been dosed with remdesivir or for whom the decision 
to dose with remdesivir based on availability is Yes. Remdesivir Use = No will be defined as 
subjects that will not utilize or have not utilized remdesivir. The exact procedures for using the 
IRT will be detailed in the IRT manual.
7.3
Blinding
This is a randomized, double-blinded study. Access to treatment codes will be restricted from all 
participants, and site and BMS personnel prior to primary database lock, with exceptions as 
specified below.
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual participant in which knowledge of the 
investigational product is critical to the participant's management, the blind for that participant 
may be broken by the investigator. The participant’s safety takes priority over any other 
considerations in determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary, ie, that it will alter the participant's 
immediate management. In many cases, particularly when the emergency is clearly not related to 
the investigational product, the problem may be properly managed by assuming that the participant 
is receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The actual TASK of unblinding can be delegated by the investigator to a 
designee assigned the task on the Delegation of Authority. The Principal Investigator or appointed 
designee should only call in for emergency unblinding AFTER the decision to unblind the 
participant has been documented.
For this study, the method of unblinding for emergency purposes is through IRT. For information 
on how to unblind in an emergency, consult the IRT manual.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a participant for non-emergency purposes should be discussed with the 
Medical Monitor.
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7.4
Dosage Modification
Dose Modifications in the Absence of Adverse Events
In the absence of adverse events, participants will complete their scheduled infusions as prescribed 
by protocol.
Dose Modifications for Adverse Events
If there is evidence of toxicity (eg, infusion reaction) that, in the judgment of the Investigator, 
could place the subject at increased risk, study drug administration should be interrupted.
7.5
Management of Possible Acute Hypersensitivity Reactions to Abatacept
Hypersensitivity or acute allergic reactions may occur as a result of the protein nature of abatacept. 
Should any of these reactions occur during the course of the study, they need to be reported as 
specified in Section 9.2 (Adverse Events). In this study, participants’ vital signs will be monitored 
before and following study drug administration. Appropriate emergency equipment and qualified 
personnel should be available where the participants are treated in the event of a serious 
anaphylactic reaction.
The following information is provided to assist in the recognition of hypersensitivity reactions and 
in the management of those reactions should they occur during or after the administration of
abatacept. Care should be taken to treat any acute toxicities expeditiously, should they occur. When
IV dosing of abatacept is conducted, equipment such as a portable tank or wall-source of oxygen, 
endotracheal intubation set, oral airway, mask, ambu-bag, syringes, injectable epinephrine, 
injectable antihistamine, and injectable corticosteroids should be kept in the vicinity where the 
subject is treated. 
Signs and management of potential acute hypersensitivity reactions include:
a) Symptomatic Hypotension should be managed by discontinuing the infusion of study
medication, placing the subject in the Trendelenburg position and administering intravenous 
fluid. Additional medical intervention may also include the use of epinephrine, corticosteroids, 
anti-histamines and pressor agents.
b) Dyspnea should be managed by discontinuing the infusion of study medication and observing 
the subject for worsening of the event and for the appearance of additional signs and symptoms 
of anaphylaxis. Antihistamines, epinephrine and corticosteroids may be administered as 
indicated.
c) Acute pain in the chest, back or extremities may also be a sign of anaphylaxis and may be
treated as described above for dyspnea.
d) Chills, fever, urticaria or generalized erythema may all be signs of an allergic reaction to
protein products. Such signs and symptoms may be treated with acetaminophen and
antihistamines.
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The decision of whether to complete the infusion of study medication if symptoms improve or 
have resolved will be left to the medical judgment of the Investigator.
7.6
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
•
Further guidance and information for final disposition of unused study treatment are provided 
in Appendix 2.
7.6.1
Retained Samples for Bioavailability / Bioequivalence / 
Biocomparability
Not applicable.
7.7
Treatment Compliance
Study drug will be administered intravenously in the clinical facility.
7.8
Concomitant Therapy
7.8.1
Standard of Care
The management of COVID-19 is ever evolving.42,43,44,45 Beyond routine management and 
supportive care for hospitalized patients, specific COVID-19 therapies are not defined but new 
relevant insight have emerged.35 Current specific therapeutics fall into 3 categories, antiviral, 
immune-based and, most recently, antithrombotic therapies. The following outlines current 
guidelines to help inform care for participants enrolled in the study. 
7.8.1.1
Antiviral agents
Early repurposing of available antiviral agents was utilized based on empirical or in vitro evidence. 
All were initially developed as therapies for other viral infection like HIV (eg, lopinavir–ritonavir)
and Ebola (remdesivir). The results for many of these initial efforts have been reported. Currently, 
only limited use of remdesivir is supported by available clinical data. Other compounds (eg,
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lopinavir–ritonavir, chloroquine or hydroxychloroquine) are not recommended outside of the 
context of a clinical trial. This study will not be studying any of these possible agents.
Use of remdesivir is not required but is encouraged as part of standard of care in this study. Because 
abatacept is a large protein, drug-drug interactions are not anticipated. Infusion of abatacept and 
remdesivir should not be given concurrently in order not to confound attribution of possible 
infusion reactions or hypersensitivity events. Data from ACTT1 suggest clinically meaningful 
improvements associated with use in severe to critical patients. Remdesivir is not approved by the 
FDA but is available through an FDA emergency use authorization. This authorization is limited 
to severe to critical patients and is therefore suitable for subject enrolled in this study. Availability 
of remdesivir is currently unknown and neither is the supply reliability once available. Because of 
this, some but not all subject enrolled in this study may be treated with remdesivir. In order to 
control for the impact of remdesivir use, subject will be stratified at randomization by remdesivir 
use. Remdesivir use will be defined as yes if the participant has already been dosed or the decision 
to dose has been made because remdesivir is available.
7.8.1.2
Immune-based Therapies
Multiple therapies with immunomodulatory properties have been proposed for management of 
COVID-19 and have been used off label. The most common are anti-malarial agents (ie,
chloroquine & hydroxychloroquine, with or without + Azithromycin) and corticosteroids. Other 
immunotherapies have been propose and many are currently being studied. Use of these targeted 
therapies are restricted (see Section 7.8.2). The following are guidance for other immune-based 
therapies. 
Use of anti-malarial therapies is not recommended. Available data does not suggest robust efficacy 
but suggests possible toxicities. A recent report suggests use of hydroxychloroquine in COVID-
19 patients can lead to corrected QT interval prolongation.46 If hydroxychloroquine is used in 
study participants, the clinical team should strongly consider ECG monitoring. 
Routine use of systemic corticosteroids (CS) is not recommended unless indicated for other 
reasons (eg, hypersensitivity reaction).47 Use of CS will be allowed but should be minimized as 
much as possible. Prior use of CS at doses above prednisone 10 mg per day, or equivalent, in the 
2 weeks prior to randomization is an exclusion criteria. Use of topical or inhaled CS is not 
restricted.
7.8.1.3
Antithrombotic Therapies
COVID-19 has been recognized as being associated with higher risk of thrombotic events above 
the rate observed in hospitalized, ill patients. The optimal assessment, screening, prophylaxis and 
treatment of these is unknown.
 
 Any prophylaxis, anticoagulant or antiplatelet, for venous 
or arterial thrombosis should follow standard of care for other hospitalized adults. If during the 
course of this study, evidence emerges to support COVID-19-specific prophylaxis as reflected in 
guidelines (eg, NIH COVID-19 Treatment Guidelines), consideration should be given to follow 
these.
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7.8.1.4
Oxygen Supplementation
Oxygen supplementation is a key element of standard of care for the management of COVID-19. 
The protocol does not mandate nor advice use of any specific device and amount of oxygen. All 
decision on oxygen supplementation will follow local practice and will be captured in the study 
record. 
7.8.1.5
Rescue Therapy
This protocol does not define nor require rescue therapy but it recognizes that off-label use of 
targeted immunotherapies (eg, tocilizumab) for some participants has been defined by institutional 
treatment protocol or used on an ad hoc basis. The use of these agents is left at the discretion of 
the clinical team. The use of these agents in close temporal relationship to abatacept has not been 
studied. Participant who are treated with one of these agents after randomization should remain in 
the study and followed for outcome assessment.
7.8.1.6
Other Therapies
Use of Angiotensin-Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers 
(ARBs) or HMG-CoA Reductase Inhibitors (Statins) previously prescribed for cardiovascular 
disease (or other indications) should be continued when feasible.
7.8.2
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to randomization in the study are described 
below. Medications taken within 4 weeks prior to randomization must be recorded on the CRF.
7.8.2.1
Prohibited Treatments
1) Prior exposure to BMS-188667 (abatacept).
2) Exposure to any investigational drug or placebo within 1 month of study drug administration.
3) Administration of a live virus vaccine within 3 months of receipt of study medication.
7.8.2.2
Restricted Treatments
1) Use of an approved targeted immunotherapy is restricted including, but not limited to, 
infliximab, etanercept, anakinra, rituximab, tocilizumab, golimumab, certolizumab, sirolumab, 
tofacitinib, baricitinib, upadacitinib, or filgotinib. If use of one of these agents after
randomization is considered, please notify the medical monitor. Participants should remain in 
the study to capture study outcomes.
2) Use of convalescent plasma and hyperimmune globulin is restricted. Administration should be 
avoided on the same day as study drug.
7.9
Treatment After the End of the Study
Since this is a single dose study, at the end of the study, BMS will not continue to provide BMS 
supplied study treatment to participants/investigators unless BMS chooses to extend the study. The 
investigator should ensure that the participant receives appropriate standard of care to treat the 
condition under study.
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8
DISCONTINUATION CRITERIA
Participants should remain in the protocol for the duration even if the decision is made to provide 
other immunomodulatory therapy. Capture of all outcomes, including choices to seek alternative 
therapy are necessary for proper assessment of both safety and efficacy outcomes.
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.)
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. 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 (ie, is imprisoned or involuntarily incarcerated 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.
8.1.1
Post Study Treatment Study Follow up
In this study, overall survival, activity level, and oxygen supplementation are key endpoints of the 
study. Post Treatment Follow-up is of critical importance and is essential to preserving participant 
safety and the integrity of the study. All participants are required to complete the 60-day 
observation period visits regardless of hospitalization status for collection of outcome and/or 
survival follow-up data as required.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
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participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
•
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
•
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities. 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
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•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
9.1
Efficacy Assessments
9.1.1
Primary and Secondary Objectives
9.1.1.1
Prevention of Disease Progression
The primary objective will be to determine the impact of therapy on prevention of disease 
progression as defined below using a composite endpoint. This endpoint will be reached if the 
participant ever requires use of invasive mechanical ventilation or experience death.
Invasive mechanical ventilation is defined as the delivery of positive pressure to the lungs via an 
endotracheal tube (or tracheostomy).
9.1.1.2
Improvement in Clinical Status
The WHO has recommended clinical study for COVID-19 use a composite clinical endpoint and 
recommend use of an ordinal scale that measures participant’s clinical status.48 Ordinal data is a 
kind of categorical data with a set order or scale to it. Ordinal scales have been adopted in some 
current prospective clinical studies.49 The following 8-point scale was proposed for the National 
Institute of Allergy and Infectious Diseases (NIAID) Adaptive COVID-19 Treatment Trial 
(ACTT) (ClinicalTrials.gov Identifier: NCT04280705). It will be used in this study.
1) Death
2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation 
(ECMO)
3) Hospitalized, on non-invasive mechanical ventilation or high-flow oxygen devices 
4) Hospitalized, requiring supplemental oxygen 
5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-
19 related or otherwise)
6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care
7) Not hospitalized, limitation on activities and/or requiring home oxygen
8) Not hospitalized, no limitation on activities
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Patients may change between states in this scale multiple times during any 24-hour period. The 
study team will record in the study record only the worst (ie, lowest) state for each day (midnight 
to midnight). The determination of the worst state to be recorded should be made as soon as 
possible after the completion of the day to be assessed. 
ICU admission is defined as transfer of care within the hospital to a specialized medical care unit 
distinct from routine or intermediate (ie, stepdown) care. Given the increased demand for ICU 
beds as a consequence of the COVID-19 pandemic, all forms of ICUs (eg, surgical) and non-ICU 
beds have been converted into ICU care beds. Progression into any of these will be considered to 
meet these criteria.
Other elements of each point have been defined with the exception of ECMO (extra-corporeal 
membrane oxygenation). This scale captures similar information to the primary endpoint but has 
the advantage of capturing improvement. The “limitations of activities” in state #6 includes need 
for home oxygen therapy. Based on inclusion criteria, all study subjects will be in category 3 or 4, 
and can be extracted from the clinical record.
9.1.1.3
Improvement in Mortality
Mortality for this endpoint will be based on all-cause mortality at Day 28 which represent 
participants who are in state1 of the Ordinal 8-point Outcome Scale.
For participants deaths, data will be collected on whether the death occurred after withdrawal of 
care and, if so, the reason for withdrawal of care will be recorded (eg, brain death, patient/family 
request, resource constraint).
9.1.1.4
Absence of Critical Disease
This endpoint is related to the primary endpoint. It is defined as the proportion of participants alive 
and free of respiratory failure on Day 28. Respiratory failure is defined by the type of resources 
required as defined by the use of any of these: mechanical ventilation, ECMO or oxygen delivery 
by noninvasive positive pressure or high-flow nasal cannula. Participants in state 4-8 of the Ordinal 
8-point Outcome Scale meet this definition.
9.1.1.5
Recovery of Pulmonary Function
All participants randomized will be oxygen dependent and dependence on oxygen has been noted 
to be prolonged even after hospital discharge. We will assess recovery of pulmonary function by 
determining the proportion of patients returning to room air by Day 28. Participants in state 5, 6 
and 8 of the Ordinal 8-point Outcome Scale meet this definition. Some participants in state 7 will. 
9.1.1.6
Shortened Hospitalization
This endpoint will be defined as the proportion of participants alive and discharged home by Day 
28. Home as a location will include any new facility that provides ongoing support short of full 
medical care such as a rehabilitation facility or assisted living facility. Participants in state 7-8 of 
the Ordinal 8-point Outcome Scale meet this definition.
Length of hospitalization will be defined as the number of days from the day of randomization to 
the date of discharge or Day 28, whichever is sooner, measured in days.
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9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
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Contacts for SAE reporting specified in Appendix 3
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
Sections 5.5.1 in the Investigator’s Brochure (IB) represent the Reference Safety Information to 
determine expectedness of serious adverse events for expedited reporting.
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period through 
60 days s after discontinuation of dosing.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, participants should not 
be questioned regarding the specific occurrence of one or more AEs.)
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section Appendix 3).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
 All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
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9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 70 days 
after study product administration, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3.
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. 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. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
If any sexual activity (eg, vaginal, anal, oral) has occurred between a male participant and a 
pregnant partner(s) without the use of a condom during and at least for, 70 days after study product 
administration, the information should be reported to the Sponsor or designee, even if the male 
participant has undergone a successful vasectomy.
In order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner(s) must sign an informed consent form for disclosure of this 
information. Information on the pregnancy will be collected on the Pregnancy Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant 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).
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9.2.7
Potential Drug Induced Liver Injury (DILI)
Specific criteria for identifying potential DILI have not been identified for this protocol. Standard 
medical practice in identifying and monitoring hepatic issues should be followed.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined at 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 (see Section 9.2.4 for reporting details).
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities Section 2.
9.4.1
New infections
Any new infections that develop during the 60 day study period will be captured as an AE. Type, 
site and source of culture will be documented in the study record.
9.4.2
Physical Examinations
Refer to Schedule of Activities Section 2.
9.4.3
Chest Imaging
Radiological assessment of symptomatic patients with COVID-19 has been reported to reveal 
parenchymal abnormalities, regardless of the method used, whether chest x-ray (CXR), 
computerized tomography (CT) or high resolution computerized tomography (HRCT).54 These 
include bilateral involvement and multilobar ground-glass opacification.31 Clinical improvement 
is also associated with improvement by radiographic assessments. 
Because of the restrictions active during the pandemic, the protocol cannot require specific 
imaging be performed after hospitalization. At screening, it is understood that similar restrictions 
may be present at study sites, but screening with radiographic chest imaging is considered 
appropriate due to its utility in identifying other relevant chest disease. Some form of chest imaging 
(CXR, CT, or HRCT) will be required at screening as part of the inclusion criteria and will also be 
considered part of TB screening. The reports for this imaging and any additional chest imaging of 
the lungs performed during the 60 day study period, will be included in the study record.
9.4.4
Vital Signs
Vital signs (VS) will be useful for assessing the clinical progress of study participants. Since VS 
are captured at varying frequency during hospitalization and not all values will be of reporting 
utility, the study record will only capture daily values of most interest. For each day (ie, 24 hour 
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period, midnight to midnight) the participant is hospitalized, vital signs will be extracted from the 
hospital record and captured in the study record.
Refer to Schedule of Activities Section 2.
9.4.5
Tuberculosis Screening
Screening for active or latent tuberculosis is routinely performed in abatacept trials. Screening is 
based on medical history, symptoms, physical exam, CXR and specific testing, either a tuberculin 
skin test or interferon gamma release assay [(IGRA) eg., T-spot®, QuantiFERON®] approved for 
local use. Abatacept has not been studied in patients with a positive tuberculosis screen, and the 
safety of ORENCIA in individuals with latent tuberculosis infection is unknown. Due to the 
severity of COVID-19, the usual delay to complete TB screening is not feasible and the risk, 
especially in low risk populations, is low. A tuberculin skin test or IGRA should be performed at 
screening but randomization does not need to await results if all other aspects of the TB screening, 
including CXR, are not suggestive of infection. If testing reveals a positive result, medical advice 
should be obtained to determine whether therapy is warranted.
If a tuberculin skin test is performed, it should be interpreted according to the applicable local 
Health Authority and/or Medical Society guidelines. Documentation of the test results should be 
recorded in the study record. 
9.4.6
Clinical Safety Laboratory Assessments
•
Investigators must document their review of each laboratory safety report.
A local laboratory will perform the analyses and will provide reference ranges for these tests. All 
lab results will be available in an unblinded fashion to hospital clinical staff caring for the 
participant. 
The study will rely on routine safety labs performed as part of routine hospital care. When 
available, the hematology and chemistry labs listed below will be included in the study record. 
Screening for active viral hepatitis B or C is routine in abatacept studies and will be performed in 
this study, although in a different fashion. Hepatitis B reactivation has been seen in patients treated 
with abatacept but only in the setting of continuous use, and is a labeled warning. Reactivation of 
hepatitis C is not a labeled warning. Speed of screening and treatment precludes the feasibility of 
completing assessment during the screening period and are not warranted. Screening antibodies 
test will be performed but results will not be needed prior to randomization. If positive results are 
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noted, confirmatory nucleic acid reflex testing should be ordered and if positive monitor as 
appropriate. 
Table 9.4.6-1:
Clinical Safety Laboratory Assessments
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Creatinine
Blood urea nitrogen (BUN)
Uric acid 
Glucose
Total protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Creatinine kinase
Serology
Hepatitis B surface antigen, hepatitis B core antibody. If either are positive, reflex to hepatitis 
B DNA testing 
Hepatitis C antibody. If positive reflex to HCV RNA testing
Other Analyses
Pregnancy test (WOCBP only: screening)
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9.5
Pharmacokinetics and Immunogenicity Assessments
9.5.1
Pharmacokinetic Assessments
Pharmacokinetic (PK) parameters are not evaluated in this study. 
 
 
9.5.2
Immunogenicity Assessments
9.5.2.1
Immunogenicity: Blood Collection
Blood samples for determination of antibodies to abatacept and time-matched PK samples will be 
from residual volume 
on Days 1, 28/ET
and 60. For logistical reasons, blood samples will only be obtained for participants who are 
hospitalized. Sample collection for subjects after hospital discharge will not occur. Samples will 
be assayed for the presence of abatacept specific antibodies.
9.5.2.2
Immunogenicity: Sample Analysis
Anti-abatacept (BMS-188667) Antibody A validated, sensitive, electrochemiluminescence assay 
(ECL) method will be used to analyze anti-abatacept antibodies in serum. Samples that are 
confirmed positive for antibodies specific to the CTLA-4 region of abatacept and have abatacept 
serum concentrations of ≤1 μg/mL will be further analyzed with a validated, in vitro, cell-based 
bioassay to determine whether the sera contained abatacept neutralizing activity. 
9.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study. 
9.7
Pharmacogenomics
Not applicable.
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9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Not applicable.
9.10
Study Materials
For participants who are discharged from the hospital prior to Day 60, will be provided with the 
following supplies and document: 
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•
Diary Cards to record body temperature, blood pressure, heart rate, oxygenation, activity level, 
oxygen use, and symptoms
•
Digital thermometer
•
Oximeter
•
Digital blood pressure monitor
•
Subject Alert Card
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
A 25% estimated rate of progression under placebo plus standard of care to one of the elements of 
the primary endpoint (mechanical ventilation or death) of hospitalized COVID-19 untreated 
patients (in particular patients without targeted therapy) was derived from available 
literature1,2,55,56,57,58 and anecdotal feedback. Rates of progression in these reports ranged from 
8% to 32%. All reports are from China and include hospitalized patients that had respiratory 
symptoms. There are different definitions of progression in these reports but most are based on 
ICU and/or death. 
A two group continuity corrected χ2 test with a 0.150 one-sided significance level will have 80% 
power to detect the difference between a proportion of 10% abatacept treated participants and a 
proportion of 25% participants in the placebo group with a primary endpoint event (odds ratio of 
.33, ie, odds of progression under abatacept versus placebo) when the sample sizes are 86 and 43, 
respectively (a total sample size of 129). This computation was made using nQuery Advisor 
version 7. The target sample size for this study is approximately 129 randomized participants.
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent
Intent-to-treat (ITT) 
Population  
All randomized participants, also those randomized and never 
treated. This population will be used for all efficacy analysis. 
Analyses using the ITT analysis population will group the 
participants according to the treatment group to which they are 
randomized. 
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Population
Description
Per-protocol (PP) Analysis 
Population
The PP Population includes all randomized participants excluding 
the participants with relevant protocol deviations. Relevant 
protocol deviations are those that may potentially impact the 
primary endpoint. The relevant protocol deviation criteria will be 
defined in the statistical analysis plan. If more than 10% of 
subjects in either treatment group have relevant protocol 
deviations, the PP Analysis Population will be used for a 
sensitivity analysis of the primary endpoint.
As-treated Analysis 
Population
This population includes all randomized participants except those 
randomized who are not treated. Analyses using the as-treated 
analysis population will group the participants according to the 
treatment they received: abatacept or placebo. All safety analyses 
will use the As-treated Analysis Population. 
10.3
Statistical Analyses
To avoid missing data, the data obtained after hospital discharge will be considered for inclusion 
in all analyses. A description of the participant population will be included in the clinical study 
report, including subgroups of age, gender and race. Demography and baseline disease 
characteristics will be presented by randomized treatment group and overall for the ITT 
population. Continuous variables such as age and weight will be summarized using means, 
standard deviations, median and ranges. Categorical variables such as gender and race, and ordinal 
scale score will be summarized using frequencies and proportions.
10.3.1
Efficacy Analyses
Statistical analysis methods for efficacy analyses are provided in Table 10.3.1-1. The primary 
efficacy endpoint will be formally tested for difference between the treatment groups. Nominal p-
values for treatment comparison will be provided for selected secondary endpoints.  
Table 10.3.1-1:
Efficacy Statistical Analyses
Endpoint
Statistical Analysis Methods
Primary Efficacy 
Endpoint
The comparison between treatment groups of the proportion of 
participants with primary endpoint event (mechanical ventilation or 
death) prior to or on Day 28 will be performed using the Cochran-
Mantel-Haenszel 
(CMH) 
Chi-Square 
test, 
stratified 
by 
the 
randomization stratification factors age group (< 60, ≥60) and 
remdesivir use as well as baseline severity. Baseline severity will be 
defined by the Clinical Status scale at randomization. A one-sided 
significance level of 0.15 will be used to assess statistical superiority of 
abatacept over placebo. The ITT population will be used. Randomized
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Table 10.3.1-1:
Efficacy Statistical Analyses
Endpoint
Statistical Analysis Methods
participants with no primary endpoint assessment due to withdrawal of 
consent or for other reasons will be imputed as treatment failures (ie. 
progressors). The OR along with its 2-sided 70% CI and 95% CI, as 
well as the absolute treatment difference in proportions with its 95% 
will be presented. The construction of CIs for absolute differences in 
proportions between treatment groups will be based on minimum risk 
weights59 to account for randomization stratification factors and 
baseline severity. 
A supplemental analysis of the primary endpoint comparison between 
the treatment groups will be based on logistic regression with age as a 
continuous covariate and factors for baseline severity and remdesivir 
stratification in the model. The nominal p-value for the Chi-square test 
based on this model will be presented.
The primary endpoint is a composite endpoint. The number and 
percentage of participants progressing to each of the components will 
be presented by treatment group. 
The proportion and 95% CI of participants with mechanical ventilation 
or who died prior to or on Day 28 within treatment group as well as the 
difference in proportions between the treatment groups and its 95% CI 
will also be presented by site, age-subgroup (< 60, ≥60), remdesivir use 
(stratification factor), gender, and baseline severity. 
Kaplan-Meier estimates for the time from randomization to progression 
to the primary endpoint will be presented. The p-value for the treatment 
comparison based on the stratified log-rank test, stratified by age-group 
and remdesivir use, will be presented as a sensitivity analysis of the 
primary endpoint.
Secondary Binary 
Endpoints: 
Proportions and 95% CIs for the binary efficacy endpoints will be 
presented by treatment group. CIs for proportions within treatment 
groups will be based on normal approximation. Difference in 
proportions and 95% CI will be presented, as well as the nominal p-
value derived from the CMH Chi-square test stratified by baseline 
severity and the randomization stratification factors. The construction 
of CIs for differences in proportions between treatment groups will be 
based on minimum risk weights to account for randomization 
stratification factors and baseline severity. A missing response value 
due to withdrawal of consent or for other reasons will be imputed as a 
non-responder or progressing. 
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Table 10.3.1-1:
Efficacy Statistical Analyses
Endpoint
Statistical Analysis Methods
Secondary Endpoint: 
Change from baseline 
in Ordinal 8-point 
Outcome Scale
The nominal p-value will be presented for the comparison between 
treatment groups of the proportion of participants with change from 
baseline to Day 28 by 1, 2, 3, or 4 categories of worsening, no 
worsening, or 1, 2, 3, or 4 categories of improvement based on the CMH 
Row Mean Scores statistic stratified by the randomization stratification 
factors age-group and remdesivir and baseline severity. Further 
analyses based on changes in the ordinal 8-point outcome scale will be 
detailed in the SAP. 
10.3.2
Safety Analyses
The proportion (%) of participants with SAEs, AEs of special interest, and participants with 
laboratory marked abnormalities will be provided by treatment group. Summaries will include all 
events from randomization up to 60 days using the as-treated analysis population. AEs of special 
interest are infections and infusion reactions. 
10.3.4
Interim Analyses
A SOC will assist in the oversight of the study execution and ongoing assessment of safety and 
efficacy. The Charter for the SOC will include details on boundaries to be used for establishing 
early evidence of efficacy at interim analysis.
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biologic therapy for the treatment of rheumatoid arthritis: real-life data from the Italian 
LORHEN Registry. Clinical Rheumatology 36; 753–761; 2017. 
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28 Chen SK, Liao KP, Liu J, et al. Risk of hospitalized infection and initiation of abatacept versus 
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dysregulation: from bench to bedside. Front. Pediatr, 2019; 7:353.
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dysregulation activity (IDDA) score. Journal of Allergy Clin Immunology, 2019; 
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dysregulation responsive to abatacept therapy. Science 2015, 349:436-440.
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42 COVID-19: An American College of Physicians Physician's Guide + Resources; 
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48 WHO COVID-19 Therapeutic Trial Synopsis Feb 18 2020.
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54 Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus Disease 2019 (COVID-
19): A Systematic Review of Imaging Findings in 919 Patients [published online ahead of 
print, 2020 Mar 14]. AJR Am J Roentgenol. 2020;1–7. doi:10.2214/AJR.20.23034
55 Chen N, Zhou M, Dong X. et al. Epidemiological and clinical characteristics of 99 cases of 
2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395 
(10223):507-513.
56 Diao B, Wang C, Tan Y, et. al. Reduction and Functional Exhaustion of T Cells in Patients 
with 
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doi: 
https://doi.org/10.1101/2020.02.18.20024364
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57 Yang X, Yu Y, Xu J, et. al. Clinical course and outcomes of critically ill patients with SARS-
CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. 
Lancet Respir Med. 2020; S2213-2600(20)30079-5. 
58 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; 
395(10229):1054-1062.
59 Mehrota D, Railkar R. Minimum risk weights for comparing treatments in stratified binomial 
trials. Statistics in Medicine, 2000; 19:11-825
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
μg
microgram
ABA
abatacept
AE
adverse event
aGVHD
acute graft-versus-host disease
ALT
alanine aminotransferase
APC
antigen presenting cells
ARDS
acute respiratory distress syndrome
AST
aspartate aminotransferase
BMS
Bristol Myers Squibb
BUN
blood urea nitrogen
CBC
complete blood count
CD
cluster of differentiation
CDC
Center for Disease Control
CFR
Code of Federal Regulations 
CMH
Cochran-Mantel-Haenszel
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CRF
Case Report Form, paper or electronic
CRO
contract research organization
CRS
cytokine release syndrome
CS
corticosteroids
CTAg
Clinical Trial Agreement
CTLA4
cytotoxic T-lymphocyte-associated protein 4
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Term
Definition
CXR
chest X-ray
D
day
DMARD
disease modifying anti-rheumatic drug
ECMO
extracorporeal membrane oxygenation
ED
emergency department
eg
exempli gratia (for example)
ET
early termination
EUDAMED
European Database on Medical Devices
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
human chorionic gonadotropin
HCT
hematopoietic cell transplantation
Hgb
hemoglobin
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
hr
hour
ICF
informed consent form
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IFN
interferon
Ig
immunoglobulin
IL
interleukin
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Term
Definition
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IP
investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-treat
IU
International Unit
IV
intravenous(ly)
JIA
juvenile idiopathic arthritis
kg
kilogram
L
liter
MD
Doctor of Medicine
mg
milligram
min
minute
mL
milliliter
mm
millimeter
N
number of subjects or observations
NCT
national clinical trial number
NSAID
nonsteroidal anti-inflammatory drug
OR
odds ratio
PK
pharmacokinetics
PP
per-protocol
R
randomize
R&D
research and development
RA
rheumatoid arthritis
Rand.
randomization
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
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Term
Definition
SC
subcutaneous
SOC
Safety Oversight Committee
SOP
Standard Operating Procedures
SUSAR
suspected, unexpected serious adverse reaction
TNF
tumor necrosis factor
ULN
upper limit of normal
US
United States
V
visit
VS
vital sign
WBC
white blood cell
WHO
World Health Organization
Wk
week
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the CRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines Good Clinical Practice (GCP), 
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following:  (1) the physical, safety or mental 
integrity of one or more subjects/participants; (2) the scientific value of the trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or 
Trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant
recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects/participants. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or 
product labeling information to be provided to subjects/participants and any updates. 
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The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects/participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as soon 
as possible to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects/participants currently enrolled in the study if they are affected by the amendment; and (3) 
the new form must be used to obtain consent from new subjects/participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects/participants are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they volunteer 
to participate. 
In situations where consent cannot be given by subjects/participants, their legally acceptable 
representatives (as per country guidelines) are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which the participant
volunteers to participate. 
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Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects/participants, prior to the beginning of 
the study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects’/participants’ signed ICF and, in the US, the subjects’/participants’ signed HIPAA 
Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
The rights, safety, and well-being of the study subjects/participants are the most important 
considerations and should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
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devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each 
participant, including unique participant
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence/biocomparability, 
if applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the Delegation 
of Authority Form.
Sourced by site, and not supplied by 
BMS or its vendors (examples include IP 
sourced 
from 
the 
sites 
stock or 
The investigator or designee accepts responsibility 
for documenting traceability and study treatment
integrity in accordance with requirements applicable 
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If
Then
commercial supply, or a specialty 
pharmacy)
under law and the SOPs/standards of the sourcing 
pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
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MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety, 
or to meet local regulations (eg, cytotoxics or 
biologics).
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If..
Then
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, 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. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:
•
Participant recruitment (eg, among the top quartile of enrollers)
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SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors.  No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.  
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.  
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
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 treatment 
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 study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as 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)
NOTE: 
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 (e.g., 
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 (e.g., 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)
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 participant or may require intervention [e.g., 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.)
Pregnancy must follow the same transmission timing and processes to BMS as used for SAEs (see 
section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Intensity
The intensity of AEs is determined by a physician and will use the following levels:
•
Mild: An event that is easily tolerated by the subject, causing minimal discomfort, and not 
interfering with everyday activities.
•
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
•
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severe is a category utilized for rating the intensity of 
an event; and both AEs and SAEs can be assessed as severe.
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
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Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via email or 
confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
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 
> 40 mIU/mL to confirm menopause.
Note: Females 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 period 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.
End of Relevant Systemic Exposure
•
End of relevant systemic exposure is the time point where the IMP or any active major 
metabolites has decreased to a concentration that is no longer considered to be relevant for 
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human teratogenicity or fetotoxicity. This should be evaluated in context of safety margins 
from the no-observed adverse effect level (NOAEL) or the time required for 5 half-lives of the 
IMP to pass.
METHODS OF CONTRACEPTION
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 ovulation and/or implantation (This method of contraception can only be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol)b 
−
oral (birth control pills)
−
intravaginal (vaginal birth control suppositories, rings, creams, gels)
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulation (This
method of contraception can only be used by WOCBP participants in studies where 
hormonal contraception is permitted by the study protocol)b 
−
oral 
−
injectable 
Highly Effective Methods That Are User Independent 
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (This method of contraception can only be used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol)b
•
Intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS) (This method of contraception can only be 
used by WOCBP participants in studies where hormonal contraception is permitted by the 
study protocol) b,c
•
Bilateral tubal occlusion
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•
Vasectomized partner
Having 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.
Male participants will be required to always use a latex or other synthetic condom during any sexual 
activity (eg, vaginal, anal, oral) with WOCBP; even if the participants have undergone a successful 
vasectomy or if their partner is already pregnant or breastfeeding.
•
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 treatment. 
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.
•
Continuous abstinence must begin at least 30 days prior to initiation of study therapy
•
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, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
•
Periodic abstinence (including but not limited to calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception for this study.
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 treatment, 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 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
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•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)
Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal(coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 5
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Revised Protocol 01, 16-Jun-2020
The purpose of this revision is to incorporate the changes 
 
. The changes include revising the study design from a randomized, 
open-label controlled study to a randomized, double-blinded, placebo controlled study and other 
updates to protocol sections listed below. 
The Synopsis has been updated to align with the protocol section changes listed below. Minor 
grammatical and typographical revisions are also addressed in this revision. 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & Title
Description of Change
Brief Rationale
Title Page
Changed title to: Phase 2, 
Randomized, Double-Blind 
Placebo Controlled Study of 
Intravenous Abatacept in the 
Treatment of Hospitalized 
COVID-19 Participants with 
Respiratory Compromise
To align with the change to 
the study design from a 
randomized, open-label 
controlled study to a 
randomized, double-blinded, 
placebo controlled study 
 
Section 2 Schedule Of 
Activities, Table 2-2; 
Section 7 Treatment; Table 
7.1-1 Selection and Timing 
of Dose
Placebo added as a Study 
Treatment. 
Added the requirements for 
blinding and process for 
unblinding.
To align with the change to 
the study design from a 
randomized, open-label 
controlled study to a 
randomized, double-blinded, 
placebo controlled study 
 
.
Section 5 Study Design; 
Section 10 Statistical 
Considerations
All sections updated to reflect 
study design change from 
‘randomized open-label 
controlled’ to ‘randomized 
double-blinded placebo 
controlled’ study.  Schematic 
updated to include placebo.
To align with the change to 
the study design from a 
randomized, open-label 
controlled study to a 
randomized, double-blinded, 
placebo controlled study 
 
Section 5.1.5 Safety 
Oversight Committee
Clarified the Safety Oversight 
Committee (SOC) process for 
meetings and frequency and 
that external members of the 
SOC will constitute the 
majority of all voting members.
Changes made 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & Title
Description of Change
Brief Rationale
Section 6.2 Exclusion 
Criteria 2a) 
Prior/Concomitant 
Therapy
Criteria 2a) has been updated 
with the bold text shown below: 
“Participants who have been 
exposed within 1 month or five 
half-lives, whichever is longer,
to any treatment with an 
approved or investigational 
targeted immunotherapy 
including, but not limited to, 
infliximab, etanercept, anakinra, 
rituximab, tocilizumab, 
golimumab, certolizumab, 
sirolumab, tofacitinib, 
baricitinib, upadacitinib, or 
filgotinib.”
Added information 
Section 9.4.6 Clinical 
Safety Laboratory 
Assessments
Deleted HIV-1 and HIV-2 
testing.
Corrected information in the 
protocol.
Section 9.5 
Pharmacokinetics and 
Immunogenicity 
Assessments
Section 9.5 has been updated 
and immunogenicity assessment 
details have been added. 
To assess the 
immunogenicity of abatacept 
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